Salt of atr kinase inhibitor, solid form thereof, and preparation method therefor and use thereof

Abstract

Provided are a hydrochloride salt of compound A and a crystal form thereof, a preparation method therefor, a composition containing the hydrochloride salt or crystal form, and the use thereof in the treatment of diseases modulated by an ART kinase inhibitor.

Description

Salts of atr kinase inhibitors, solid forms thereof, and methods of making and using the same Field of the invention

[0001] The present invention relates to salts of (R)-4-(7-(3,5-dimethyl-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-(1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-methylmorpholine (hereinafter referred to as "Compound A") and solid forms thereof, methods of making said solid forms, pharmaceutical compositions comprising said solid forms, and uses of said solid forms as ATR kinase inhibitor modulated diseases.

[0002] BACKGROUND

[0003] ATR (Ataxia telangiectasia and Rad3-related protein) is a class of protein kinases involved in genomic stability and DNA damage repair, which belongs to the PIKK family members. The activation of ATR can be activated by stalled replication forks or DNA single-strand damage (SSB). The activated ATR will recruit repair proteins or repair factors to repair the damaged site, delay the mitotic process (especially in the G2 / M phase of mitosis), both stabilize the replication fork and ensure the stability of the genome. In addition, the DNA damage repair system in most tumor cells is abnormal, usually missing certain repair pathways (such as mutations in p53 or ATM), making them more dependent on ATR to survive. In normal cells, due to the intact repair pathway, the inhibition of ATR kinase alone will not have a significant impact. Therefore, the inhibition of ATR may have a more significant effect on the treatment of cancer, and will not have a significant side effect on normal cells.

[0004] Moreover, the inhibition of ATR can be used in combination with radiotherapy or chemotherapy drugs to synergistically enhance the effect. Widely used chemotherapy drugs include antimetabolites (such as gemcitabine), DNA cross-linking agents (such as cisplatin, carboplatin), alkylating agents (such as temozolomide), topoisomerase inhibitors (such as topotecan, irinotecan), etc. When tumor cells are affected by chemotherapy or radiotherapy, the ATR signaling pathway will be activated to a large extent to repair damaged DNA. Therefore, when treating cancer with radiotherapy or chemotherapy drugs, the inhibition of ATR at the same time can greatly enhance the effect of cancer treatment.

[0005] The present applicant has found that (R)-4-(7-(3,5-dimethyl-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-(1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-methylmorpholine can be used as an effective ATR kinase inhibitor (see PCT / CN2021 / 105867, which is incorporated herein by reference in its entirety), but there has been no report on solid forms of this compound.

[0006] SUMMARY

[0007] In one aspect, the present application provides a salt of Compound A (R)-4-(7-(3,5-dimethyl-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-(1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-methylmorpholine as shown below:

[0008] In another aspect, the present application provides a crystalline form of a salt of Compound A and solvates thereof.

[0009] The crystalline forms, including the preferred crystalline forms, of the present application not only have excellent effects in preventing and / or treating ATR kinase-mediated diseases, but also have other advantages. For example, the crystalline forms, including the preferred crystalline forms, of the present application have excellent physical properties (including solubility, dissolution rate, light resistance, low hygroscopicity, high-temperature resistance, high-humidity resistance, flowability, etc.), and in properties such as bioavailability, physical and / or chemical stability, and ease of preparation, the crystalline forms, including the preferred crystalline forms, of the present application can have more excellent properties. The crystalline forms, including the preferred crystalline forms, of the present application have good powder properties, are more suitable and convenient for mass production and for forming preparations, can reduce irritation and improve absorption, solve problems in metabolic speed, significantly reduce toxicity caused by drug accumulation, improve safety, and effectively ensure the quality and efficacy of drug products.

[0010] In another aspect, the present application provides a method of preparing the crystalline forms of the present application.

[0011] In another aspect, the present application provides a pharmaceutical composition comprising any one or more of the crystalline forms of the present application, and one or more pharmaceutically acceptable carriers.

[0012] In another aspect, the present application provides use of the crystalline forms of the present application in the preparation of a medicament for use as an ATR kinase inhibitor.

[0013] BRIEF DESCRIPTION OF DRAWINGS

[0014] FIG. 1 is an X-ray powder diffraction (XRPD) pattern of crystalline Form I of the monohydrochloride monohydrate of Compound A.

[0015] Figure 2 is a differential scanning calorimetry (DSC)-thermogravimetric analysis (TGA) pattern of crystalline Form I of the monohydrochloride monohydrate of Compound A.

[0016] Figure 3 is a scanning electron micrograph of crystalline Form I of the monohydrochloride monohydrate of Compound A.

[0017] Figure 4 is an X-ray powder diffraction (XRPD) pattern of crystalline Form II of the monohydrochloride anhydrate of Compound A.

[0018] Figure 5 is a differential scanning calorimetry (DSC)-thermogravimetric analysis (TGA) pattern of crystalline Form II of the monohydrochloride anhydrate of Compound A.

[0019] Figure 6 is a scanning electron micrograph of crystalline Form II of the monohydrochloride anhydrate of Compound A.

[0020] Figure 7 is an X-ray powder diffraction (XRPD) pattern of crystalline Form III of the dihydrochloride hydrate of Compound A.

[0021] Figure 8 is a differential scanning calorimetry (DSC)-thermogravimetric analysis (TGA) pattern of crystalline Form III of the dihydrochloride hydrate of Compound A.

[0022] Figure 9 is a scanning electron micrograph of crystalline Form III of the dihydrochloride hydrate of Compound A.

[0023] Figure 10 is an X-ray powder diffraction (XRPD) pattern of crystalline Form IV of the hydrobromide anhydrate of Compound A.

[0024] Figure 11 is a differential scanning calorimetry (DSC)-thermogravimetric analysis (TGA) pattern of crystalline Form IV of the hydrobromide anhydrate of Compound A.

[0025] Figure 12 is a scanning electron micrograph of crystalline Form IV of the hydrobromide anhydrate of Compound A.

[0026] Figure 13 is an X-ray powder diffraction (XRPD) pattern of crystalline Form V of the L-tartrate ethanol solvate of Compound A.

[0027] Figure 14 is a differential scanning calorimetry (DSC)-thermogravimetric analysis (TGA) pattern of crystalline Form V of the L-tartrate ethanol solvate of Compound A.

[0028] Figure 15 is a scanning electron micrograph of crystalline Form V of the L-tartrate ethanol solvate of Compound A.

[0029] Figure 16 is a high performance liquid chromatography (HPLC) pattern of samples obtained in the solid stability test of Example 7.

[0030] Figure 17 is an X-ray powder diffraction (XRPD) pattern of a sample obtained in the solid stability test of Example 7.

[0031] Figure 18 is an X-ray powder diffraction (XRPD) overlay of samples from the water activity experiment of Example 9 after 1 day.

[0032] Figure 19 is an X-ray powder diffraction (XRPD) overlay of samples from the water activity experiment of Example 9 after 4 days.

[0033] Figure 20 is an X-ray powder diffraction (XRPD) pattern of a sample from the crystalline form conversion experiment of Example 10 at room temperature.

[0034] Figure 21 is an X-ray powder diffraction (XRPD) pattern of a sample from the crystalline form conversion experiment of Example 10 at 50°C.

[0035] Figure 22 is an X-ray powder diffraction (XRPD) pattern of a sample obtained in the milling experiment of Example 11.

[0036] DETAILED DESCRIPTION

[0037] Unless otherwise defined, 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 application belongs. Reference herein to technical terms used herein is intended to refer to the technical as commonly understood by those in the art, including variations or substitutions of techniques or equivalents of techniques that would be apparent to those of ordinary skill in the art. Although the following terms are believed to be well understood by one of ordinary skill in the art, the following definitions are set forth to better explain the application.

[0038] The terms "comprising," "including," "having," "containing," or "involving," and other similar forms, as used herein, are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0039] The word "about" as used herein when used in connection with a quantity is meant to encompass both the stated value and variations that would be apparent to one of ordinary skill in the art, such as ±0.05, ±0.1, ±0.2, ±0.3, ±1, ±2, or ±3, etc.

[0040] The term "solid form" as used herein includes all solid state forms of Compound A or any solvate thereof, such as crystalline forms or amorphous forms.

[0041] The term "amorphous" as used herein refers to any solid material that is not ordered in three dimensions. In some cases, amorphous solids can be characterized by known techniques including XRPD crystallography, DSC, or some combination of these techniques. As explained below, amorphous solids produce diffuse XRPD patterns that typically include one or two broad peaks (i.e., peaks with a base width of about 5° 2Θ or greater).

[0042] The term "crystalline form" or "crystal" as used herein refers to any solid material that exhibits three-dimensional ordering, as opposed to amorphous solid material, which produces characteristic XRPD patterns with well-defined peaks.

[0043] The term "X-ray powder diffraction pattern (XRPD pattern)" as used herein refers to the experimentally observed diffraction pattern or parameters derived therefrom. An XRPD pattern is typically characterized by peak positions (abscissa) and / or peak intensities (ordinate).

[0044] The term "2Θ" as used herein refers to the peak position expressed in degrees based on the experimental setup of the X-ray diffraction experiment and is typically the unit of abscissa in a diffraction pattern. If a reflection is diffracted when the incident beam forms an angle of Θ with a certain lattice plane, the experimental setup requires that the reflected beam be recorded at a 2Θ angle. It should be understood that a particular 2Θ value mentioned herein for a particular crystal form is intended to represent the 2Θ value (expressed in degrees) measured using the X-ray diffraction experimental conditions described herein. For example, as described herein, Cu-Ka (Ka1 1.540598and Ka2 1.544426) are used as the source of radiation.

[0045] As used herein, "I%" means percent peak intensity.

[0046] The term "differential scanning calorimetry (DSC) pattern" as used herein refers to the curve recorded by a differential scanning calorimeter.

[0047] The term "thermogravimetric analysis (TGA) pattern" as used herein refers to the curve recorded by a thermogravimetric analyzer.

[0048] As used herein, the term "substantially the same" with respect to X-ray diffraction peak positions means that representative peak positions and intensity variations are taken into account. For example, one skilled in the art will appreciate that peak positions (2 theta) will show some variation, typically up to 0.1-0.2 degrees, and that the instrument used to measure the diffraction will also show some variation. In addition, one skilled in the art will appreciate that relative peak intensities will show inter-instrument variation as well as variation due to degree of crystallinity, preferred orientation, surface of the sample prepared, and other factors known to one skilled in the art. Similarly, as used herein, "substantially the same" with respect to DSC profiles is also intended to encompass variations known to one skilled in the art relating to these analytical techniques. For example, for well-resolved peaks, there will typically be up to ±0.2°C variation in the differential scanning calorimetry profile, and even greater (e.g., up to ±1°C) for broad peaks.

[0049] Polarizing Microscope ECLIPSE LV100POL (Nikon, JPN) is preferably used for collecting the polarizing microscopic data in the present application.

[0050] As used herein, numerical ranges (e.g., "1-10," "1-6," "2-10," "2-6," "3-10," "5-10," "3-6," etc.) encompass any number within the given range (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10).

[0051] The prepared salt or its crystalline form can be recovered by a method including decantation, centrifugation, evaporation, gravity filtration, suction filtration, or any other technique for solid recovery under pressure or under reduced pressure. The recovered solid can be optionally dried. "Drying" in the present invention is performed under reduced pressure, preferably vacuum, until the content of residual solvent is reduced to the range of the limits given by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use ("ICH") guidelines. The content of residual solvent depends on the type of solvent, but is not more than about 5000 ppm, or preferably about 4000 ppm, or more preferably about 3000 ppm. The drying can be performed in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluid bed dryer, spin flash dryer, flash dryer, or the like. The drying can be performed at a temperature of less than about 100 °C, less than about 80 °C, less than about 60 °C, less than about 50 °C, less than about 30 °C, or any other suitable temperature, under atmospheric pressure or reduced pressure, preferably vacuum, for any desired time (such as about 1, 2, 3, 5, 10, 15, 20, 24 hours, or overnight) that enables the desired result, as long as the quality of the salt is not deteriorated. The drying can be performed any desired number of times until the desired product quality is achieved. The dried product can be optionally subjected to a size reduction operation to produce a desired particle size. Milling or micronization can be performed before or after the drying of the product. Techniques that can be used to reduce the particle size include, but are not limited to, ball milling, roller milling, and hammer milling, as well as jet milling.

[0052] The term "anhydrate" as used herein preferably means a crystalline form in which no water molecules are contained as structural elements.

[0053] "Chloroalkane" refers to an alkane having 1-6 carbon atoms substituted by one or more chlorines, selected from the group consisting of dichloromethane, chloroform, and carbon tetrachloride, preferably dichloromethane.

[0054] "Anti-solvent" refers to a solvent that is miscible with a solvent, but slightly or slightly to moderately or very slightly or almost or not soluble with respect to a solute in a given solution system.

[0055] "Alcohol" refers to a compound of the formula R-OH, wherein R represents a C 1-8 alkyl group, preferably a C 1-6 alkyl group. The alcohol is selected from the group consisting of methanol, ethanol, isopropanol, isobutanol, and benzyl alcohol, preferably methanol.

[0056] "Alkyl" means a straight-chain or branched saturated hydrocarbon group having from one to eight carbon atoms. In one embodiment, the alkyl group has one to six carbon atoms. 1-6 "Alkyl" means a straight-chain or branched saturated hydrocarbon group having from one to eight carbon atoms. In one embodiment, the alkyl group has one to six carbon atoms.

[0057] "Aryl" means a carbocyclic aromatic group having 6 to 10 carbon atoms. In one embodiment, the aryl group has 6 carbon atoms. 1-6 "Alkyl" means a straight-chain or branched saturated hydrocarbon group having from one to eight carbon atoms. In one embodiment, the alkyl group has one to six carbon atoms.

[0058] "Ester" means an ester of formula R-C(=0)0-R', having 4 to 10 carbon atoms, wherein R and R' each represent a C 1-6 "Alkyl" means a straight-chain or branched saturated hydrocarbon group having from one to eight carbon atoms. In one embodiment, the alkyl group has one to six carbon atoms.

[0059] "Ether" means a chain or cyclic compound of formula R-0-R', having 2 to 10 carbon atoms, wherein R and R' each represent a C 1-6 "Alkyl" means a straight-chain or branched saturated hydrocarbon group having from one to eight carbon atoms. In one embodiment, the alkyl group has one to six carbon atoms. 1-6 "Alkyl" means a straight-chain or branched saturated hydrocarbon group having from one to eight carbon atoms. In one embodiment, the alkyl group has one to six carbon atoms.

[0060] "C 1-8 "Alkyl" means a straight-chain or branched saturated hydrocarbon group having from one to eight carbon atoms. In one embodiment, the alkyl group has one to six carbon atoms. 1-6 "Alkyl" means a straight-chain or branched saturated hydrocarbon group having from one to eight carbon atoms. In one embodiment, the alkyl group has one to six carbon atoms.

[0061] Salts of Compound A, crystalline forms thereof, and processes for their preparation

[0062] In some embodiments, the present application provides a salt of Compound A,

[0063] which is a salt of an inorganic acid or a salt of an organic acid.

[0064] In a preferred embodiment, the present application provides a salt of Compound A, which is a hydrochloride salt of Compound A.

[0065] Preferably, the hydrochloride salt of Compound A is a monohydrochloride salt of Compound A.

[0066] In some embodiments, the hydrochloride salt of Compound A is crystalline Form I of monohydrochloride monohydrate of Compound A.

[0067] The XRPD pattern of the crystalline Form I includes characteristic peaks at diffraction angles (2 theta) of about 8.7 ± 0.2°, 14.5 ± 0.2°, and 20.1 ± 0.2°.

[0068] Preferably, the XRPD pattern of the crystalline Form I includes characteristic peaks at diffraction angles (2 theta) of about 8.5 ± 0.2°, 8.7 ± 0.2°, 14.5 ± 0.2°, 16.1 ± 0.2°, 20.1 ± 0.2°, 23.5 ± 0.2°, and 27.5 ± 0.2°.

[0069] Preferably, the XRPD pattern of the crystalline Form I includes characteristic peaks at diffraction angles (2 theta) of about 8.5 ± 0.2°, 8.7 ± 0.2°, 12.7 ± 0.2°, 13.9 ± 0.2°, 14.5 ± 0.2°, 16.1 ± 0.2°, 19.0 ± 0.2°, 20.1 ± 0.2°, 21.6 ± 0.2°, 23.5 ± 0.2°, 27.5 ± 0.2°, 28.1 ± 0.2°, and 28.4 ± 0.2°.

[0070] In more preferred embodiments, the XRPD pattern of the crystalline Form I includes peaks at the following diffraction angles (2 theta):

[0071] In more preferred embodiments, the XRPD pattern of the crystalline Form I includes peaks at substantially the same diffraction angles (2 theta) as shown in Figure 1. In more preferred embodiments, the XRPD pattern of the crystalline Form I is substantially the same as shown in Figure 1.

[0072] In more preferred embodiments, the DSC pattern of the crystalline Form I includes a broad endothermic peak at about 85 °C and about 215 °C.

[0073] In more preferred embodiments, in thermogravimetric analysis, the crystalline Form I has a weight loss of about 2.9% upon heating to about 130 °C and a weight loss of about 3.8% between about 130-200 °C.

[0074] In more preferred embodiments, the DSC-TGA pattern of the crystalline Form I is substantially the same as shown in Figure 2.

[0075] In more preferred embodiments, the scanning electron micrograph of the crystalline Form I is substantially the same as shown in Figure 3.

[0076] In some embodiments, the present application provides a method of preparing crystalline Form I, comprising adding an ester, ketone or nitrile solvent to Compound A, adding hydrochloric acid under stirring, stirring at a certain temperature, filtering and optionally drying to obtain crystals.

[0077] In preferred embodiments, the weight to volume ratio (g / mL) of Compound A and the solvent is about 1 : (1-10), preferably about 1 : 6.7.

[0078] In preferred embodiments, the solvent is preferably ethyl acetate, acetone or acetonitrile.

[0079] In preferred embodiments, the concentration of hydrochloric acid is preferably 2-12 mol / L, and the molar ratio of Compound A to HCl is 1 : (1-1.2).

[0080] In preferred embodiments, the temperature is about 15-50 °C, and the stirring time is about 1-6 hours.

[0081] In one embodiment, the hydrochloride salt of Compound A is crystalline Form II of monohydrochloride anhydrate of Compound A.

[0082] The XRPD pattern of the crystalline Form II includes characteristic peaks at diffraction angles (2 theta) of about 10.6 ± 0.2°, 20.9 ± 0.2° and 21.3 ± 0.2°.

[0083] Preferably, the XRPD pattern of the crystalline Form II includes characteristic peaks at diffraction angles (2 theta) of about 10.6 ± 0.2°, 10.9 ± 0.2°, 11.4 ± 0.2°, 13.6 ± 0.2°, 16.2 ± 0.2°, 16.6 ± 0.2°, 20.9 ± 0.2° and 21.3 ± 0.2°;

[0084] Preferably, the XRPD pattern of the crystalline Form II includes characteristic peaks at diffraction angles (2 theta) of about 10.6 ± 0.2°, 10.9 ± 0.2°, 11.4 ± 0.2°, 13.6 ± 0.2°, 14.5 ± 0.2°, 16.2 ± 0.2°, 16.6 ± 0.2°, 17.2 ± 0.2°, 20.9 ± 0.2°, 21.3 ± 0.2°, 22.0 ± 0.2°, 23.0 ± 0.2°, 23.3 ± 0.2°, 24.5 ± 0.2°, 25.5 ± 0.2°, 26.4 ± 0.2° and 30.3 ± 0.2°.

[0085] In more preferred embodiments, the XRPD pattern of the crystalline Form II includes peaks at the following diffraction angles (2 theta):

[0086] In more preferred embodiments, the XRPD pattern of said Form II comprises substantially the same peaks at diffraction angles (2 theta) as shown in Figure 4. In more preferred embodiments, the XRPD pattern of said Form II is substantially the same as shown in Figure 4.

[0087] In more preferred embodiments, the DSC pattern of said Form II comprises an endothermic peak at about 231 °C.

[0088] In more preferred embodiments, in thermal gravimetric analysis, said Form II does not show significant weight loss when heated to 120 °C; and about 5.97% weight loss when heated to 120-225 °C.

[0089] In more preferred embodiments, the DSC-TGA pattern of said Form II is substantially the same as shown in Figure 5.

[0090] In more preferred embodiments, the scanning electron micrograph of said Form II is substantially the same as shown in Figure 6.

[0091] In some embodiments, the present application provides a method for preparing Form II, which comprises adding a mixed solvent of chloroalkane and alcohol to Compound A, and adding hydrochloric acid under stirring. After the addition, an anti-solvent is added to the solution, which is stirred at a certain temperature, filtered and optionally dried to obtain crystals.

[0092] In preferred embodiments, the weight to volume ratio (g / mL) of Compound A and said mixed solvent is about 1 : (1.5-12), preferably about 1 : 10.

[0093] In preferred embodiments, said mixed solvent is preferably a mixed solvent of dichloromethane and methanol.

[0094] In preferred embodiments, the volume ratio of said mixed solvent is preferably 0: 1-2: 1.

[0095] In preferred embodiments, the concentration of hydrochloric acid is preferably 2-12 mol / L, and the molar ratio of Compound A and HCl is 1 : (1-1.2).

[0096] In preferred embodiments, said anti-solvent is an ester, a ketone or an ether, and said anti-solvent is preferably ethyl acetate, acetone and methyl tert-butyl ether, and the weight to volume ratio (g / mL) of Compound A and said solvent is about 1 : (20-80).

[0097] In preferred embodiments, said temperature is about 15-60 °C, and the stirring time is about 0.5-4 hours.

[0098] In one embodiment, said hydrochloride salt of Compound A is a crystalline Form III of dihydrochloride hydrate of Compound A;

[0099] The XRPD pattern of said crystalline Form III comprises characteristic peaks at diffraction angles (2 theta) of about 6.7 ± 0.2°, 13.0 ± 0.2° and 19.7 ± 0.2°;

[0100] Preferably, the XRPD pattern of said crystalline Form III comprises characteristic peaks at diffraction angles (2 theta) of about 6.7 ± 0.2°, 10.5 ± 0.2°, 10.9 ± 0.2°, 13.0 ± 0.2° and 19.7 ± 0.2°;

[0101] Preferably, the XRPD pattern of said crystalline Form III comprises characteristic peaks at diffraction angles (2 theta) of about 6.7 ± 0.2°, 10.5 ± 0.2°, 10.9 ± 0.2°, 13.0 ± 0.2°, 19.7 ± 0.2°, 23.9 ± 0.2° and 27.1 ± 0.2°.

[0102] In more preferred embodiments, the XRPD pattern of said crystalline Form III comprises peaks at the following diffraction angles (2 theta):

[0103] In more preferred embodiments, the XRPD pattern of said crystalline Form III comprises peaks at substantially the same diffraction angles (2 theta) as shown in Figure 7. In more preferred embodiments, the XRPD pattern of said crystalline Form II is substantially the same as shown in Figure 7.

[0104] In more preferred embodiments, the DSC pattern of said crystalline Form III comprises an endothermic peak at about 66 °C and an endothermic peak at about 188 °C.

[0105] In more preferred embodiments, in thermogravimetric analysis, said crystalline Form III has a weight loss of about 10.4% between room temperature and 200 °C.

[0106] In more preferred embodiments, the DSC-TGA pattern of said crystalline Form III is substantially the same as shown in Figure 8.

[0107] In more preferred embodiments, the scanning electron micrograph of said crystalline Form III is substantially the same as shown in Figure 9.

[0108] In some embodiments, the present application provides a method of preparing crystalline Form III, comprising adding a ketone solvent to Compound A, adding hydrochloric acid under stirring, stirring at a certain temperature after the addition, filtering and optionally drying to obtain crystals.

[0109] In preferred embodiments, the weight to volume ratio (g / mL) of Compound A and said solvent is about 1 : (1-10), preferably about 1 : 6.7.

[0110] In a preferred embodiment, the concentration of hydrochloric acid is preferably 2-12 mol / L, and the molar ratio of Compound A and HCl is 1 : (1.5-2.5).

[0111] In a preferred embodiment, the solvent is preferably acetone.

[0112] In a preferred embodiment, the temperature is about 15-60 °C, and the stirring time is about 2-8 hours.

[0113] In one embodiment, the hydrobromide salt of Compound A is a crystalline form IV of Compound A hydrobromide anhydrate;

[0114] The XRPD pattern of the crystalline form IV includes characteristic peaks at diffraction angles (2 theta) of about 17.7 ± 0.2°, 21.0 ± 0.2°, 22.6 ± 0.2°, and 25.3 ± 0.2°;

[0115] Preferably, the XRPD pattern of the crystalline form IV includes characteristic peaks at diffraction angles (2 theta) of about 15.8 ± 0.2°, 17.7 ± 0.2°, 21.0 ± 0.2°, 21.5 ± 0.2°, 22.6 ± 0.2°, 25.3 ± 0.2°, and 26.9 ± 0.2°;

[0116] Preferably, the XRPD pattern of the crystalline form IV includes characteristic peaks at diffraction angles (2 theta) of about 8.3 ± 0.2°, 13.2 ± 0.2°, 15.8 ± 0.2°, 17.7 ± 0.2°, 21.0 ± 0.2°, 21.5 ± 0.2°, 22.6 ± 0.2°, 23.1 ± 0.2°, 23.6 ± 0.2°, 25.3 ± 0.2°, 26.5 ± 0.2°, 26.9 ± 0.2°, 27.8 ± 0.2°, 29.3 ± 0.2°, and 29.8 ± 0.2°.

[0117] In a more preferred embodiment, the XRPD pattern of the crystalline form IV includes peaks at the following diffraction angles (2 theta):

[0118] In a more preferred embodiment, the XRPD pattern of the crystalline form IV includes peaks at substantially the same diffraction angles (2 theta) as shown in Figure 10. In the most preferred embodiment, the XRPD pattern of the crystalline form IV is substantially the same as shown in Figure 10.

[0119] In a more preferred embodiment, the DSC pattern of the crystalline form IV includes an endothermic peak at about 270 °C.

[0120] In a more preferred embodiment, the crystalline form IV has no weight loss upon heating to about 150 °C in thermogravimetric analysis.

[0121] In more preferred embodiments, the DSC-TGA pattern of said crystalline Form IV is substantially the same as depicted in Figure 11.

[0122] In more preferred embodiments, the scanning electron micrograph of said crystalline Form IV is substantially the same as depicted in Figure 12.

[0123] In some embodiments, the present application provides a process for preparing crystalline Form IV, comprising adding a ketone solvent to Compound A, adding hydrobromic acid (HBr) under stirring conditions. After the addition, stirring at a certain temperature, filtering and optionally drying to obtain crystals.

[0124] In preferred embodiments, the weight to volume ratio (g / mL) of Compound A and said solvent is about 1 : (5-20), preferably about 1 : 16.7.

[0125] In preferred embodiments, said solvent is preferably acetone.

[0126] In preferred embodiments, the molar ratio of Compound A and HBr is 1 : (0.8-1.8).

[0127] In preferred embodiments, said temperature is about 10-40 °C and the duration of stirring is about 1-5 hours.

[0128] In one embodiment, said L-tartaric acid salt of Compound A is crystalline Form V of L-tartaric acid ethanol solvate of Compound A;

[0129] The XRPD pattern of said crystalline Form V comprises characteristic peaks at diffraction angles (2 theta) of about 11.3 ± 0.2°, 17.3 ± 0.2° and 25.0 ± 0.2°;

[0130] Preferably, the XRPD pattern of said crystalline Form V comprises characteristic peaks at diffraction angles (2 theta) of about 11.3 ± 0.2°, 13.8 ± 0.2°, 15.3 ± 0.2°, 17.3 ± 0.2°, 20.4 ± 0.2°, 21.6 ± 0.2°, 23.4 ± 0.2° and 25.0 ± 0.2°;

[0131] Preferably, the XRPD pattern of said crystalline Form V comprises characteristic peaks at diffraction angles (2 theta) of about 7.0 ± 0.2°, 11.3 ± 0.2°, 13.8 ± 0.2°, 14.2 ± 0.2°, 15.3 ± 0.2°, 17.3 ± 0.2°, 19.9 ± 0.2°, 20.4 ± 0.2°, 21.6 ± 0.2°, 22.1 ± 0.2°, 22.9 ± 0.2°, 23.4 ± 0.2°, 24.2 ± 0.2°, 25.0 ± 0.2° and 26.4 ± 0.2°.

[0132] In more preferred embodiments, the XRPD pattern of said Form V comprises peaks at the following diffraction angles (2Θ):

[0133] In more preferred embodiments, the XRPD pattern of said Form V comprises substantially the same peaks at the diffraction angles (2Θ) set forth in Figure 13. In more preferred embodiments, the XRPD pattern of said Form V is substantially the same as shown in Figure 13.

[0134] In more preferred embodiments, the DSC pattern of said Form V comprises an endothermic peak at about 56 °C, an endothermic peak at about 98 °C and an endothermic peak at about 156 °C.

[0135] In more preferred embodiments, said Form V has a weight loss of about 1.4% when heated to about 130 °C in thermogravimetric analysis.

[0136] In more preferred embodiments, the DSC-TGA pattern of said Form V is substantially the same as shown in Figure 14.

[0137] In more preferred embodiments, the scanning electron micrograph of said Form V is substantially the same as shown in Figure 15.

[0138] In some embodiments, the present application provides a method for preparing Form V, which comprises adding an alcoholic solvent to Compound A, adding an alcoholic solution of L-tartaric acid under stirring condition. After addition, stirring at a certain temperature, filtering and optionally drying to obtain crystals.

[0139] In preferred embodiments, the weight to volume ratio (g / mL) of Compound A and said solvent is about 1 : (2-10), preferably about 1 : 3.3.

[0140] In preferred embodiments, said solvent is preferably ethanol.

[0141] In preferred embodiments, the concentration of the solution of L-tartaric acid is preferably 2-4 mol / L, and the molar ratio of Compound A to L-tartaric acid is 1 : (0.8-1.4).

[0142] In preferred embodiments, said temperature is about 20-30 °C, and the stirring time is about 1-5 hours.

[0143] DETAILED DESCRIPTION

[0144] In particular, the present application relates to the following technical solutions.

[0145] In one embodiment, the present application relates to a hydrochloride salt of Compound A:

[0146] In more specific embodiments, the present application provides a hydrochloride salt of Compound A that is a mono- or di-hydrochloride salt of Compound A.

[0147] In more specific embodiments, the present application provides a hydrochloride salt of Compound A that is a solvate or non-solvate form of said hydrochloride salt.

[0148] In more specific embodiments, the present application provides a hydrochloride salt of Compound A that is a hydrate or anhydrate form of said hydrochloride salt.

[0149] In more specific embodiments, the present application provides a hydrochloride salt of Compound A that is a monohydrochloride salt of Compound A that is a monohydrate or anhydrate.

[0150] In more specific embodiments, the present application provides a hydrochloride salt of Compound A that is a monohydrochloride salt of Compound A that is a monohydrate or anhydrate.

[0151] In more specific embodiments, the present application provides a hydrochloride salt of Compound A wherein for said Form II, its XRPD pattern further comprises peaks at about 11.4 ± 0.2, 13.6 ± 0.2, and 16.2 ± 0.2 2Θ (°).

[0152] In more specific embodiments, the present application provides a hydrochloride salt of Compound A wherein for said Form II, its XRPD pattern further comprises peaks at about 10.9 ± 0.2, 16.6 ± 0.2, 24.5 ± 0.2, and 30.3 ± 0.2 2Θ (°).

[0153] In more specific embodiments, the present application provides a hydrochloride salt of Compound A wherein for said Form II, its XRPD pattern further comprises peaks at about 14.5 ± 0.2, 22.0 ± 0.2, 23.0 ± 0.2, and 23.3 ± 0.2 2Θ (°).

[0154] In more particular embodiments, the present application provides a hydrochloride salt of Compound A, wherein for said Form II, its XRPD pattern includes peaks at about the following 2 theta (°) positions: 8.4 ± 0.2, 10.6 ± 0.2, 10.9 ± 0.2, 11.4 ± 0.2, 13.6 ± 0.2, 14.5 ± 0.2, 16.2 ± 0.2, 16.6 ± 0.2, 17.2 ± 0.2, 18.3 ± 0.2, 18.7 ± 0.2, 18.9 ± 0.2, 19.6 ± 0.2, 20.9 ± 0.2, 21.3 ± 0.2, 22.0 ± 0.2, 23.0 ± 0.2, 23.3 ± 0.2, 24.5 ± 0.2, 25.5 ± 0.2, 26.4 ± 0.2, 27.2 ± 0.2, 27.7 ± 0.2, 28.8 ± 0.2, 30.3 ± 0.2, and 33.1 ± 0.2.

[0155] In more particular embodiments, the present application provides a hydrochloride salt of Compound A, wherein for said Form II, its XRPD pattern includes peaks at about the following positions:

[0156] In more particular embodiments, the present application provides a hydrochloride salt of Compound A, wherein for said Form II, it has substantially the same XRPD pattern as shown in Figure 4.

[0157] In more particular embodiments, the present application provides a hydrochloride salt of Compound A, wherein for said Form II, it has substantially the same XRPD pattern as shown in Figure 4.

[0158] In more particular embodiments, the present application provides a hydrochloride salt of Compound A, wherein for said Form II, it has substantially the same XRPD pattern as shown in Figure 4.

[0159] In more particular embodiments, the present application provides a hydrochloride salt of Compound A, wherein for said Form II, it has substantially the same XRPD pattern as shown in Figure 4.

[0160] In one embodiment, the present application provides a method for preparing the above Form II, comprising the following steps:

[0161] Method I:

[0162] 1) adding an alcohol solvent to Compound A;

[0163] 2) adding hydrochloric acid to the system obtained in step 1);

[0164] 3) adding an anti-solvent to the system obtained in step 2) and stirring at a certain temperature;

[0165] 4) filtering the system obtained in step 3) and optionally drying to obtain crystal form II; or

[0166] Method two:

[0167] 1) adding a mixed solvent of an alcohol solvent and a chloroalkane solvent to compound A;

[0168] 2) adding hydrochloric acid to the system obtained in step 1);

[0169] 3) adding an anti-solvent to the system obtained in step 2) and stirring at a certain temperature;

[0170] 4) filtering the system obtained in step 3) and optionally drying to obtain crystal form II.

[0171] In a more specific embodiment, the present application provides a method for preparing the above crystal form II, wherein the weight / volume ratio (g / mL) of compound A and the mixed solvent is about 1: (1.5-12), preferably about 1:10.

[0172] In a more specific embodiment, the present application provides a method for preparing the above crystal form II, wherein the chloroalkane solvent is selected from dichloromethane, chloroform and carbon tetrachloride, preferably dichloromethane.

[0173] In a more specific embodiment, the present application provides a method for preparing the above crystal form II, wherein the alcohol solvent is selected from methanol, ethanol, isopropanol, isobutanol and benzyl alcohol, preferably methanol.

[0174] In a more specific embodiment, the present application provides a method for preparing the above crystal form II, wherein the volume ratio of the chloroalkane solvent to the alcohol solvent in the mixed solvent is 1:10 to 10:1, preferably 1:2 to 2:1.

[0175] In a more specific embodiment, the present application provides a method for preparing the above crystal form II, wherein the concentration of hydrochloric acid in step 2) is 2-12 mol / L, and the molar ratio of compound A to HCl is 1:(1-1.2).

[0176] In a more specific embodiment, the present application provides a method for preparing the above crystal form II, wherein the anti-solvent is selected from an ester solvent, a ketone solvent and an ether solvent.

[0177] In a more specific embodiment, the present application provides a method for preparing the above crystal form II, wherein the ester solvent is an ester having 4-10 carbon atoms, preferably ethyl acetate.

[0178] In more specific embodiments, the present application provides a process for preparing the above Form II, wherein the ketone solvent is a chain hydrocarbon ketone of 3 to 6 carbon atoms, preferably acetone.

[0179] In more specific embodiments, the present application provides a process for preparing the above Form II, wherein the ether solvent is selected from diethyl ether, diisopropyl ether and methyl tert-butyl ether.

[0180] In more specific embodiments, the present application provides a process for preparing the above Form II, wherein the weight to volume ratio (g / mL) of Compound A to the antisolvent is about 1 : (20-80).

[0181] In more specific embodiments, the present application provides a process for preparing the above Form II, wherein the temperature in step 3) is about 15-60 °C.

[0182] In more specific embodiments, the present application provides a hydrochloride salt of Compound A which is Form I of Compound A monohydrochloride monohydrate comprising peaks at about 8.7 ± 0.2, 14.5 ± 0.2 and 20.1 ± 0.2 2Θ (°) in an X-ray powder diffraction (XRPD) pattern obtained using Cu Kα radiation.

[0183] In more specific embodiments, the present application provides a hydrochloride salt of Compound A wherein the XRPD pattern of the Form I further comprises peaks at about 8.5 ± 0.2, 16.1 ± 0.2, 23.5 ± 0.2 and 27.5 ± 0.2 2Θ (°).

[0184] In more specific embodiments, the present application provides a hydrochloride salt of Compound A wherein the XRPD pattern of the Form I further comprises peaks at about 13.9 ± 0.2, 19.0 ± 0.2, 21.6 ± 0.2 and 28.1 ± 0.2 2Θ (°).

[0185] In more specific embodiments, the present application provides a hydrochloride salt of Compound A wherein the XRPD pattern of the Form I further comprises peaks at about 12.7 ± 0.2, 17.4 ± 0.2, 25.5 ± 0.2 and 28.4 ± 0.2 2Θ (°).

[0186] In more particular embodiments, the present application provides a hydrochloride salt of Compound A, wherein for the crystalline Form I, the XRPD pattern includes peaks at about the following 2 theta (°) positions: 8.5 ± 0.2, 8.7 ± 0.2, 10.2 ± 0.2, 12.7 ± 0.2, 13.9 ± 0.2, 14.5 ± 0.2, 16.1 ± 0.2, 17.4 ± 0.2, 18.5 ± 0.2, 22.7 ± 0.2, 23.1 ± 0.2, 23.5 ± 0.2, 25.5 ± 0.2, 26.0 ± 0.2, 26.3 ± 0.2, 26.6 ± 0.2, 27.5 ± 0.2, 28.1 ± 0.2, 32.1 ± 0.2, 34.2 ± 0.2, and 38.0 ± 0.2.

[0187] In more particular embodiments, the present application provides a hydrochloride salt of Compound A, wherein for the crystalline Form I, the XRPD pattern includes peaks at about the following positions:

[0188] In more particular embodiments, the present application provides a hydrochloride salt of Compound A, wherein for the crystalline Form I, it has an XRPD pattern substantially the same as shown in Figure 1.

[0189] In more particular embodiments, the present application provides a hydrochloride salt of Compound A, wherein for the crystalline Form I, it includes a broad endothermic peak in the differential scanning calorimetry (DSC) pattern at about 85 °C and about 215 °C.

[0190] In more particular embodiments, the present application provides a hydrochloride salt of Compound A, wherein for the crystalline Form I, it has a thermogravimetric analysis (TGA) pattern showing about 2.9% weight loss upon heating to about 130 °C and about 3.8% weight loss between about 130-200 °C.

[0191] In more particular embodiments, the present application provides a hydrochloride salt of Compound A, wherein for the crystalline Form I, it has a DSC-TGA pattern substantially the same as shown in Figure 2.

[0192] In one embodiment, the present application provides a method of preparing the crystalline Form I described above, comprising the steps of:

[0193] 1) adding an ester solvent, a ketone solvent, or a nitrile solvent to Compound A;

[0194] 2) adding hydrochloric acid to the system obtained in step 1) and stirring at a certain temperature; and

[0195] 3) filtering the system obtained in step 2) and optionally drying to obtain the crystalline Form I.

[0196] In more specific embodiments, the present application provides a method for preparing the above-mentioned crystalline Form I, wherein the weight to volume ratio (g / mL) of Compound A and the solvent in step 1) is about 1 : (1-10), preferably about 1 : 6.7.

[0197] In more specific embodiments, the present application provides a method for preparing the above-mentioned crystalline Form I, wherein the ester solvent is an ester having 4-10 carbon atoms, preferably ethyl acetate.

[0198] In more specific embodiments, the present application provides a method for preparing the above-mentioned crystalline Form I, wherein the ketone solvent is a chain hydrocarbon ketone having 3-6 carbon atoms, preferably acetone.

[0199] In more specific embodiments, the present application provides a method for preparing the above-mentioned crystalline Form I, wherein the nitrile solvent is acetonitrile.

[0200] In more specific embodiments, the present application provides a method for preparing the above-mentioned crystalline Form I, wherein the concentration of hydrochloric acid in step 2) is 2-12 mol / L, and the molar ratio of Compound A to HCl is 1 : (1-1.2).

[0201] In more specific embodiments, the present application provides a method for preparing the above-mentioned crystalline Form I, wherein the temperature in step 2) is about 15-50 °C.

[0202] In more specific embodiments, the present application provides a hydrochloride salt of Compound A, which is crystalline Form III of Compound A dihydrochloride hydrate, comprising peaks at about 6.7 ± 0.2, 13.0 ± 0.2 and 19.7 ± 0.2 2θ (°) in an X-ray powder diffraction (XRPD) pattern obtained using Cu Kα radiation.

[0203] In more specific embodiments, the present application provides a hydrochloride salt of Compound A, wherein for the crystalline Form III, the XRPD pattern further comprises peaks at about 10.5 ± 0.2, 10.9 ± 0.2 and 23.9 ± 0.2 2θ (°).

[0204] In more specific embodiments, the present application provides a hydrochloride salt of Compound A, wherein for the crystalline Form III, the XRPD pattern further comprises peaks at about 17.2 ± 0.2, 24.1 ± 0.2 and 27.1 ± 0.2 2θ (°).

[0205] In more specific embodiments, the present application provides a hydrochloride salt of Compound A, wherein for the crystalline Form III, the XRPD pattern further comprises peaks at about 9.2 ± 0.2, 11.1 ± 0.2 and 23.7 2θ (°).

[0206] In more particular embodiments, the present application provides a hydrochloride salt of Compound A, wherein for said Form III, its XRPD pattern includes peaks at about the following 2 theta (°) positions: 6.7 ± 0.2, 9.2 ± 0.2, 9.7 ± 0.2, 10.5 ± 0.2, 10.9 ± 0.2, 11.1 ± 0.2, 13.0 ± 0.2, 17.2 ± 0.2, 19.7 ± 0.2, 22.9 ± 0.2, 23.7 ± 0.2, 23.9 ± 0.2, 24.1 ± 0.2, and 27.1 ± 0.2.

[0207] In more particular embodiments, the present application provides a hydrochloride salt of Compound A, wherein for said Form III, its XRPD pattern includes peaks at about the following positions:

[0208] In more particular embodiments, the present application provides a hydrochloride salt of Compound A, wherein for said Form III, it has substantially the same XRPD pattern as shown in Figure 7.

[0209] In more particular embodiments, the present application provides a hydrochloride salt of Compound A, wherein for said Form III, it includes an endothermic peak at about 66 °C and an endothermic peak at about 188 °C in a differential scanning calorimetry (DSC) pattern.

[0210] In more particular embodiments, the present application provides a hydrochloride salt of Compound A, wherein for said Form III, it has a thermogravimetric analysis (TGA) pattern showing about 10.4% weight loss of the Form III between room temperature and 200 °C.

[0211] In more particular embodiments, the present application provides a hydrochloride salt of Compound A, wherein for said Form III, it has substantially the same DSC-TGA pattern as shown in Figure 8.

[0212] In one embodiment, the present application provides a method of preparing the above Form III, comprising:

[0213] 1) adding a ketone solvent to Compound A;

[0214] 2) adding hydrochloric acid to the system obtained in step 1) and stirring at a certain temperature;

[0215] 3) filtering the system obtained in step 2) and optionally drying to obtain Form III.

[0216] In more particular embodiments, the present application provides a method of preparing the above Form III, wherein the weight to volume ratio (g / mL) of Compound A and the ketone solvent in step 1) is about 1: (1-10), preferably about 1:6.7.

[0217] In more specific embodiments, the present application provides a method for preparing the above-mentioned crystalline Form III, wherein the ketone solvent is a chain hydrocarbon ketone of 3-6 carbon atoms, preferably acetone.

[0218] In more specific embodiments, the present application provides a method for preparing the above-mentioned crystalline Form III, wherein the concentration of hydrochloric acid in step 2) is 2-12 mol / L, and the molar ratio of Compound A to HCl is 1 : (1.5-2.5).

[0219] In more specific embodiments, the present application provides a method for preparing the above-mentioned crystalline Form III, wherein the temperature in step 2) is about 15-60 °C.

[0220] In one embodiment, the present application relates to a composition comprising the hydrochloride salt of Compound A provided by the present application, preferably crystalline Form I, crystalline Form II or crystalline Form III, and a pharmaceutically acceptable carrier or excipient.

[0221] In one embodiment, the present application relates to the use of the hydrochloride salt of Compound A provided by the present application, preferably crystalline Form I, crystalline Form II or crystalline Form III, or a composition provided by the present application, for the preparation of a medicament for the prevention or treatment of a disease modulated by an ART kinase inhibitor.

[0222] In one embodiment, the present application relates to the use of the hydrochloride salt of Compound A provided by the present application, preferably crystalline Form I, crystalline Form II or crystalline Form III, or a composition provided by the present application, for the preparation of a medicament for the prevention or treatment of cancer.

[0223] In one embodiment, the use of the present application relates to the treatment of a cancer selected from the group consisting of lung cancer, prostate cancer, melanoma, ovarian cancer, breast cancer, endometrial cancer, renal cancer, gastric cancer, sarcoma, head and neck cancer, tumors of the central nervous system, metastases thereof and acute myelocytic leukemia.

[0224] Pharmaceutical compositions, methods of treatment and uses

[0225] In some embodiments, the present application provides a pharmaceutical composition comprising a salt of Compound A of the present application or a crystalline form thereof, and one or more pharmaceutically acceptable carriers.

[0226] In some embodiments, the present application provides the use of a salt of Compound A of the present application or a crystalline form thereof for the preparation of a medicament for the prevention or treatment of a disease modulated by an ART kinase inhibitor.

[0227] In some embodiments, the present application provides a salt of Compound A of the present application or a crystalline form thereof for the prevention or treatment of a disease modulated by an ART kinase inhibitor.

[0228] In some embodiments, the present application provides a method of preventing or treating a disease modulated by an ART kinase inhibitor, comprising administering to an individual, preferably a mammal, in need thereof, a prophylactically or therapeutically effective amount of any one or more of a salt of Compound A of the present application or a crystalline form thereof.

[0229] The ATR kinase inhibitor or a pharmaceutically acceptable salt thereof is also useful for the prevention and / or treatment of cancer patients, including but not limited to blood cancers, such as leukemias, multiple myeloma; lymphomas, such as Hodgkin's disease, non-Hodgkin's lymphoma (including mantle cell lymphoma) and myelodysplastic syndrome, and also solid tumors and metastases thereof, such as breast cancer, lung cancer (non-small cell lung cancer (NSCL), small cell lung cancer (SCLC), squamous cell carcinoma), endometrial cancer, central nervous system tumors (such as glioma, embryonal tumors of the central nervous system, glioblastoma multiforme, mixed glioma, medulloblastoma, retinoblastoma, neuroblastoma, germinoma and teratocarcinoma, gastrointestinal cancer (such as stomach cancer), esophageal cancer, hepatocellular (liver) cancer, cholangiocarcinoma, colon and rectum cancer, small intestine cancer, pancreatic cancer, skin cancer ifosfamide (especially metastatic melanoma), thyroid cancer, head and neck cancer and salivary gland cancer, prostate cancer, testicular cancer, ovarian cancer, cervical cancer, uterine cancer, vulvar cancer, bladder cancer, kidney cancer (including renal cell carcinoma, clear cell and renal oncocytoma), squamous cell carcinoma, sarcomas such as osteosarcoma, chondrosarcoma, leiomyosarcoma, soft tissue sarcoma, Ewing's sarcoma, gastrointestinal stromal tumor (GIST), Kaposi's sarcoma and pediatric cancers such as rhabdomyosarcoma and neuroblastoma.

[0230] It is contemplated that Compound A and the methods of treatment comprising the administration or use of an ATR kinase inhibitor or a pharmaceutically acceptable salt thereof are particularly useful for the treatment of patients suffering from lung cancer, prostate cancer, melanoma, ovarian cancer, breast cancer, endometrial cancer, renal cancer, gastric cancer, sarcoma, head and neck cancer, tumors of the central nervous system and metastases thereof, and also for the treatment of patients suffering from acute myelocytic leukemia.

[0231] For these routes of administration, the compositions of the present application can be administered in a suitable dosage form.

[0232] The term "therapeutically effective amount" as used herein refers to the amount of a compound that, upon administration, will relieve to some extent one or more of the symptoms of the disorder being treated.

[0233] The dosing regimen can be adjusted to provide the best desired response. For example, a single bolus can be administered, several divided doses can be administered over time or the dose can be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is to be noted that dosage values can vary with the type and severity of the condition to be alleviated. It is to be further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the

[0234] The term "treating" as used herein, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition, unless otherwise indicated.

[0235] "Individual" as used herein includes a human or non-human animal. Exemplary human individuals include a human individual (referred to as a patient) who has a disease, e.g., a disease described herein, or a normal individual. "Non-human animals" in the present application include all vertebrates, e.g., non-mammals (e.g., birds, amphibians, reptiles), and mammals, e.g., non-human primates, domestic animals, and / or laboratory animals, e.g., sheep, dogs, cats, cows, pigs, etc. Examples

[0236] The application will be explained in greater detail in connection with the following examples, which are only intended to illustrate the technical solutions of the present application, and are not intended to limit the scope of the present application. Those skilled in the art can make some non-essential improvements and adjustments, which still belong to the protection scope of the present application.

[0237] The raw materials and reagents used in the following examples are commercially available or can be prepared by known methods, unless otherwise specified.

[0238] The detection instruments and conditions used in the following examples are as follows:

[0239] (1) X-ray powder diffraction (XRPD)

[0240] (a) Instrument model: Bruker D8 advance

[0241] Test conditions: The anode target material is copper, the light tube is set to (40KV 40mA), the 2θ scanning angle of the sample is from 3° to 40°, and the scanning step is 0.02°.

[0242] (b) Instrument model: PANalytical Aeris

[0243] Test condition: Anode target material is copper, light tube is set at (40KV 7.5mA), 2 theta scan angle of sample is from 3° to 40°, scan step is 0.02°.

[0244] (2) Differential Scanning Calorimetry Analysis (DSC)

[0245] Instrument model:

[0246] (a) TA Discovery DSC 250 (TA Instruments, US);

[0247] (b) DSC Q200

[0248] Test condition: Heating rate is 10 °C / min, dry nitrogen is used as purge gas.

[0249] (3) Thermogravimetric Analysis (TGA)

[0250] Instrument model:

[0251] (a) Discovery TGA 55 (TA Instruments, US);

[0252] (b) TGA Q500

[0253] Test condition: Automatic weighing inside the heating furnace, heating rate is 10 °C / min, dry nitrogen is used as purge gas.

[0254] (4) Polarized Light Microscopy Analysis (PLM)

[0255] Instrument model: Polarizing Microscope ECLIPSE LV100POL (Nikon, JPN)

[0256] (5) Nuclear Magnetic Resonance (1H NMR) 1

[0257] Instrument model: Bruker Advance 300, equipped with B-ACS120 automatic sampling system

[0258] (6) Dynamic Vapor Sorption Analysis (DVS)

[0259] Instrument model: DVS Intrinsic PLUS (SMS, UK)

[0260] Test condition: Gradient mode is used, humidity range is from 0% to 90%, humidity increment of each gradient is 10%, holding time of each gradient is 1 h.

[0261] ​Example 1: (R)-4-(7-(3,5-dimethyl-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-(1H-pyrazol-5- yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-methylmorpholine (Compound A)

[0262] Compound A was prepared according to PCT / CN2021 / 105867.

[0263] First step:

[0264] Under nitrogen protection, A-1 (159 mmol, 40 g) and B-1 (240 mmol, 53 g) were dissolved in 500 mL mixed solution of 1,4-dioxane and water (v / v: 9 / 1). Then sodium carbonate (320 mmol, 33.9 g) and Pd(dppf)Cl2(16 mmol, 11.7 g) were added to the solution, after addition, the reaction was heated to reflux for 10 h. The reaction was stopped, filtered, and the solvent was removed under reduced pressure. Water was added, and ethyl acetate was extracted. The organic phase was combined and concentrated to dryness to obtain A-2 (32 g). LC-MS: [M+H] + : 313.

[0265] Second step:

[0266] Under ice bath, A-2 (102.5 mmol, 32 g) was dissolved in 150 mL dichloromethane, and N-bromosuccinimide (NBS) (103 mmol, 18 g) was added portionwise under stirring. After addition, the reaction was stirred at room temperature for 2 h. The reaction was stopped, and sodium thiosulfate aqueous solution was added to the solution, and dichloromethane was extracted. The organic phase was combined and dried over anhydrous sodium sulfate. The organic phase was concentrated to 2V, 3V n-heptane was added to make a slurry, filtered, and the solid was collected and oven dried to obtain A-3 (39 g). LC-MS: [M+H] + : 392.

[0267] Third step:

[0268] Under nitrogen protection, A-3 (99.6 mmol, 39 g) and B-2 (149.4 mmol, 41.4 g) were dissolved in 600 mL mixed solvent of 1,4-dioxane and water (v / v: 9 / 1). Then sodium carbonate (199.2 mmol, 21.1 g) and Pd(dppf)Cl2(9.9 mmol, 7.2 g) were added to the solution, after addition, the reaction was heated to 100 °C for 16 h. The reaction was stopped, filtered, and water was added. Ethyl acetate was extracted, and the organic phase was combined and dried over anhydrous sodium sulfate. The organic phase was concentrated to dryness to obtain A-4 (30 g). LC-MS: [M+H] + : 463.

[0269] Fourth step:

[0270] A-4 (64.9 mmol, 30 g), tribromopyridine (207.8 mmol, 66.5 g), N,N-dimethyl-1,2- cyclohexanediamine (104.2 mmol, 14.8 g) and potassium phosphate (389.6 mmol, 82.6 g) were dissolved in 210 mL of DMF under nitrogen protection, and cuprous iodide (52.1 mmol, 9.9 g) was added to the solution. After the addition was completed, the mixture was heated at 115 °C for 16 h. The reaction was stopped, and the mixture was cooled, filtered (with the addition of diatomite to assist filtration), and the filter cake was washed with EA (1.0 V). A 1 N NaOH (16.0 V) solution was added to the filtrate, the mixture was stirred until uniform, extracted with EA, and the EA phases were combined. The EA phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to about 2.5 V. Methanol (1.0 V) was added to the concentrated solution under stirring. A 1 N HCl / EA (3.0 eq.) solution was added dropwise to the system, and solid was precipitated from the system. The stirring was continued for 14 h. The solid was filtered, and the filter cake was washed with EA (2.0 V). The obtained solid was yellowish or pinkish. The solid was taken out, dried at 50 ± 5 °C under a vacuum of not less than -0.09 MPa for 12 h, and A-5 (27 g) was obtained. LC-MS: [M+H] + : 539.

[0271] Step 5:

[0272] A-5 (50.1 mmol, 27 g) was dissolved in 216 mL of dichloromethane at room temperature, and 108 mL of trifluoroacetic acid was added. The reaction was carried out at room temperature for 2 h. The reaction was stopped, and the solvent was removed by evaporation under reduced pressure. The pH was adjusted to 10 by adding a saturated aqueous sodium bicarbonate solution, and the mixture was extracted with dichloromethane three times. The organic phases were concentrated and dried to obtain compound A (17 g). LC-MS: [M+H] + : 455.

[0273] Example 2: Preparation of crystalline form I of monohydrochloride monohydrate of compound A

[0274] Compound A (3 g) was added to a reaction bottle at room temperature, and 6.7 V of ethyl acetate was added. The mixture was stirred, and 1.05 eq of a 4 M hydrochloric acid ethyl acetate solution was added to the suspension. After the addition was completed, the mixture was stirred at 40 °C for 1 h and then at room temperature for 15 min. A large amount of solid was precipitated from the solution, which was filtered, and the solid was collected and dried at 50 °C under a vacuum for 16 h to obtain crystals. The XRPD pattern of the crystals was detected by X-ray powder diffraction, as shown in FIG. 1. The DSC-TGA pattern of the crystals was analyzed by DSC and TGA, as shown in FIG. 2. The crystal morphology was observed under a scanning electron microscope, as shown in FIG. 3.

[0275] Example 3: Preparation of crystalline form II of monohydrochloride anhydrate of compound A

[0276] Compound A (3 g) was added to a reaction flask at room temperature, methanol (10 V) was added, stirred, 12 M hydrochloric acid aqueous solution (1.05 eq) was added to the suspension, the solution gradually became clear as the acid was added, after completion of the addition, methyl tert-butyl ether (40 V) was slowly added to the solution, the solution changed from clear to solid, after completion of the addition, temperature was controlled at 50 °C and stirred for 30 h, the temperature was lowered to room temperature, the solid was collected by filtration, and dried at 50 °C under vacuum for 16 h to obtain crystals. The XRPD pattern thereof was detected by X-ray powder diffraction, as shown in Figure 4; the DSC-TGA pattern thereof was analyzed by DSC and TGA, as shown in Figure 5; the crystal morphology was observed under a scanning electron microscope, as shown in Figure 6.

[0277] Example 4: Preparation of crystal form III of dihydrochloride hydrate of Compound A

[0278] Compound A (3 g) was added to a reaction flask at room temperature, acetone (6.7 V) was added, stirred, 12 M hydrochloric acid aqueous solution (2.05 eq) was added to the suspension, after completion of the addition, the reaction solution was stirred at room temperature for 4 h, the solid was precipitated in the reaction solution, the solid was collected by filtration, and dried at 50 °C under vacuum for 16 h to obtain crystals. The XRPD pattern thereof was detected by X-ray powder diffraction, as shown in Figure 7; the DSC-TGA pattern thereof was analyzed by DSC and TGA, as shown in Figure 8; the crystal morphology was observed under a scanning electron microscope, as shown in Figure 9.

[0279] Example 5: Preparation of crystal form IV of hydrobromide anhydrate of Compound A

[0280] Compound A (3 g) was added to a reaction flask at room temperature, acetone (16.7 V) was added, stirred, hydrobromic acid (1.1 eq) was added to the suspension, after completion of the addition, the reaction solution was stirred at room temperature for 3 h, the solid was precipitated in the reaction solution, the solid was collected by filtration, and dried at 50 °C under vacuum for 16 h to obtain crystals. The XRPD pattern thereof was detected by X-ray powder diffraction, as shown in Figure 10; the DSC-TGA pattern thereof was analyzed by DSC and TGA, as shown in Figure 11; the crystal morphology was observed under a scanning electron microscope, as shown in Figure 12.

[0281] Example 6: Preparation of crystal form V of L-tartrate ethanolate of Compound A

[0282] Compound A (3 g) was added to a reaction bottle, ethanol (3.3 V) was added, stirred, 3.3 mL of a solution of tartaric acid in ethanol (1.1 eq) was added to the suspension, after addition, it was stirred at room temperature for 4 h, solid was precipitated in the reaction solution, filtered, the solid was collected, and vacuum dried at 50 °C for 16 h to obtain crystals. The XRPD pattern of the crystals was detected by X-ray powder diffraction, as shown in Figure 13; the DSC-TGA pattern was analyzed by DSC and TGA, as shown in Figure 14; the crystal morphology was observed under a scanning electron microscope, as shown in Figure 15.

[0283] Example 7: Solid stability test

[0284] The crystal form II of the monohydrochloride anhydrate of Compound A was placed in an environment of 40 °C / 75% RH and 60 °C / 75% RH respectively for 9 days, and detected by HPLC, and the detection results are shown in Figure 16. The detection results were detected by X-ray powder diffraction, as shown in Figure 17. The results showed that the crystal form II of the monohydrochloride anhydrate of Compound A did not change.

[0285] Example 8: Solubility test

[0286] The crystal form II of the monohydrochloride anhydrate of Compound A was tested for solubility in simulated gastric fluid (SGF), fasted state simulated intestinal fluid (FeSSIF), and fed state simulated intestinal fluid (FaSSIF) solvents respectively, and the test results are as follows:

[0287] The experimental results showed that the solubility of the crystal form II sample showed pH dependence, with the highest solubility in SGF, greater than 5 mg / mL, and the lowest solubility in FaSSIF.

[0288] Example 9: Water activity experiment

[0289] A DVS Intrinsic (SMS, UK) was used to determine the dynamic water adsorption and desorption curve of the crystal form II of the monohydrochloride anhydrate of Compound A using gradient mode, with a humidity range of 0% to 90%, a humidity increment of 10% for each gradient, and a holding time of 1 h for each gradient. The crystal form change of the sample was tested by XRPD. The water activity results are shown in the table below: when the water activity is higher than 0.337, the crystal form II changes to crystal form I; and when the water activity is not higher than 0.227, the crystal form II does not change. The XRPD comparison pattern of the sample after 1 day of water activity experiment is shown in Figure 18, and the XRPD comparison pattern of the sample after 4 days of water activity experiment is shown in Figure 19.

[0290] Example 10: Crystal form conversion experiment

[0291] About 5 mg of Form I hydrochloride salt and Form II hydrochloride salt were mixed in a sample bottle, respectively in 0.4 mL of n-heptane, methyl tert-butyl ether and ethanol, and stirred at room temperature and 50°C, and the mixture was detected by X-ray powder diffraction. The results are shown in Table 2: Form II is more stable than Form I in ethanol at room temperature or 50°C, and in methyl tert-butyl ether at 50°C, thus Form II is the stable form in non-aqueous solvents. The results of the X-ray powder diffraction detection of the polymorphic transformation experiment at room temperature are shown in Figure 20, and the results of the X-ray powder diffraction detection of the polymorphic transformation experiment at 50°C are shown in Figure 21.

[0292] Example 11: Grinding experiment

[0293] About 5 mg of Form I hydrochloride salt and Form II hydrochloride salt were mixed in a sample bottle, respectively in 0.4 mL of n-heptane, methyl tert-butyl ether and ethanol, and stirred at room temperature and 50°C, and the mixture was detected by X-ray powder diffraction. The results are shown in Table 2: Form II is more stable than Form I in ethanol at room temperature or 50°C, and in methyl tert-butyl ether at 50°C, thus Form II is the stable form in non-aqueous solvents. The results of the X-ray powder diffraction detection of the polymorphic transformation experiment at room temperature are shown in Figure 20, and the results of the X-ray powder diffraction detection of the polymorphic transformation experiment at 50°C are shown in Figure 21.

[0294] Example 12: PK experiment of Compound A and Compound A hydrochloride in beagle dogs

[0295] Beagle dogs were orally administered with 10 mg / kg of Compound A in free base form, and blood samples were collected from the lower limbs of the dogs at 0 h (before administration), 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h after administration, and about 1 mL of blood was collected at each time point in an EDTA-K2 anticoagulant tube. After one week of elution, the dogs were orally administered with 10 mg / kg of Compound A in hydrochloride salt form, and blood samples were collected from the lower limbs of the dogs at 0 h (before administration), 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h after administration, and 1 mL of blood was collected at each time point in an EDTA-K2 anticoagulant tube. The collected whole blood was centrifuged at 2000 g for 10 min at 4°C, and the plasma was collected and analyzed for the concentration of Compound A by LC-MS / MS method. The results are shown in the following table: after oral administration of Compound A in free base form and in hydrochloride salt form to beagle dogs at a dose of 10 mg / kg, the Cmax was 954 ng / mL and 7129 ng / mL, respectively, and the AUC0-t was 13035 h*ng / mL and 37350 h*ng / mL, respectively, indicating that Compound A in hydrochloride salt form has a higher systemic exposure in beagle dogs than Compound A in free base form.

[0296] Numerous modifications to the present application will be apparent to those skilled in the art based upon the foregoing description. Such modifications are intended to fall within the scope of the appended claims. Each of the references cited herein, including all patents, patent applications, journal articles, books, and any other publications, are hereby incorporated by reference in their entireties.

Claims

1. The hydrochloride salt of compound A:

2. The hydrochloride salt of claim 1, wherein it is a monohydrochloride salt or a dihydrochloride salt of compound A.

3. The hydrochloride salt of claim 1 or 2, wherein it is a solvated or non-solventized form of the hydrochloride salt.

4. The hydrochloride salt of claim 1 or 2, wherein the hydrochloride salt is in hydrated or anhydrous form.

5. The hydrochloride salt of claim 4, wherein it is a monohydrate or anhydrous form of the monohydrochloride salt of compound A.

6. The hydrochloride of claim 5, which is crystal form II of the anhydrous monohydrochloride of compound A, having peaks at approximately 10.6 ± 0.2, 20.9 ± 0.2, and 21.3 ± 0.2 2θ (°) in an X-ray powder diffraction (XRPD) spectrum obtained using Cu Kα radiation.

7. The hydrochloride of claim 6, wherein for crystal form II, its XRPD spectrum further includes peaks at approximately 11.4 ± 0.2, 13.6 ± 0.2, and 16.2 ± 0.2 2θ (°).

8. The hydrochloride of claim 6 or 7, wherein for crystal form II, its XRPD spectrum further includes peaks at approximately 10.9 ± 0.2, 16.6 ± 0.2, 24.5 ± 0.2, and 30.3 ± 0.2 2θ (°).

9. The hydrochloride salt of any one of claims 6-8, wherein for crystal form II, its XRPD spectrum further includes peaks at about 14.5±0.2, 22.0±0.2, 23.0±0.2 and 23.3±0.2 2θ (°).

10. The hydrochloride salt of claim 6, wherein for said crystal form II, its XRPD spectrum includes peaks at approximately the following 2θ (°) positions: 8.4±0.2, 10.6±0.2, 10.9±0.2, 11.4±0.2, 13.6±0.2, 14.5±0.2, 16.2±0.2, 16.6±0.2, 17.2±0.2, 18.3±0.2, 18. 7±0.2, 18.9±0.2, 19.6±0.2, 20.9±0.2, 21.3±0.2, 22.0±0.2, 23.0±0.2, 23.3±0.2, 24.5±0.2, 25.5±0.2, 26.4±0.2, 27.2±0.2, 27.7±0.2, 28.8±0.2, 30.3±0.2 and 33.1±0.

2.

11. The hydrochloride salt of claim 6, wherein for crystal form II, its XRPD spectrum includes peaks at approximately the following positions:

12. The hydrochloride of claim 6, wherein for crystal form II, it has substantially the same XRPD pattern as shown in FIG4.

13. The hydrochloride salt of any one of claims 6-12, wherein for said crystal form II, it includes an endothermic peak at about 231°C in a differential scanning calorimetry (DSC) spectrum.

14. The hydrochloride salt of any one of claims 6-13, wherein for crystal form II, it has a thermogravimetric analysis (TGA) spectrum showing that no weight loss was observed when the crystal form was heated to 120°C; and approximately 5.97% weight loss was observed when heated to 120-225°C.

15. The hydrochloride salt of any one of claims 6-14, wherein for crystal form II, it has a DSC-TGA pattern substantially the same as that shown in FIG5.

16. A method for preparing crystal form II according to any one of claims 6-15, comprising the following steps: Method 1: 1) Add an alcohol solvent to compound A; 2) Add hydrochloric acid to the system obtained in step 1); 3) Add the antisolvent to the system obtained in step 2) and stir at a certain temperature; 4) Filter the system obtained in step 3) and optionally dry it to obtain crystal form II; or Method 2: 1) Add a mixed solvent of alcohol and chloroalkane to compound A; 2) Add hydrochloric acid to the system obtained in step 1); 3) Add the antisolvent to the system obtained in step 2) and stir at a certain temperature; 4) Filter the system obtained in step 3) and optionally dry it to obtain crystal form II.

17. The method of claim 16, wherein the weight-to-volume ratio (g / mL) of compound A and the mixed solvent is about 1:(1.5-12), preferably about 1:

10.

18. The method of claim 16 or 17, wherein the chloroalkane solvent is selected from dichloromethane, chloroform and carbon tetrachloride, preferably dichloromethane.

19. The method of claim 16 or 17, wherein the alcohol solvent is selected from methanol, ethanol, isopropanol, isobutanol and benzyl alcohol, preferably methanol.

20. The method of any one of claims 16-19, wherein the volume ratio of the chloroalkane solvent to the alcohol solvent in the mixed solvent is 1:10 to 10:1, preferably 1:2 to 2:

1.

21. The method of any one of claims 16-20, wherein the concentration of hydrochloric acid in step 2) is 2-12 mol / L, and the molar ratio of compound A to HCl is 1:(1-1.2).

22. The method of any one of claims 16-21, wherein the antisolvent is selected from ester solvents, ketone solvents and ether solvents.

23. The method of claim 22, wherein the ester solvent is an ester having 4-10 carbon atoms, preferably ethyl acetate.

24. The method of claim 22, wherein the ketone solvent is a chain hydrocarbon ketone with 3-6 carbon atoms, preferably acetone.

25. The method of claim 22, wherein the ether solvent is selected from diethyl ether, diisopropyl ether, and methyl tert-butyl ether.

26. The method according to any one of claims 22-25, wherein the weight-to-volume ratio (g / mL) of compound A and the antisolvent is about 1:(20-80).

27. The method according to any one of claims 16-26, wherein the temperature in step 3) is about 15-60°C.

28. The hydrochloride salt of claim 5, which is crystal form I of the monohydrochloride monohydrate of compound A, having peaks at approximately 8.7 ± 0.2, 14.5 ± 0.2, and 20.1 ± 0.2 2θ (°) in an X-ray powder diffraction (XRPD) spectrum obtained using Cu Kα radiation.

29. The hydrochloride of claim 28, wherein for crystal form I, its XRPD spectrum further includes peaks at approximately 8.5 ± 0.2, 16.1 ± 0.2, 23.5 ± 0.2, and 27.5 ± 0.2 2θ (°).

30. The hydrochloride salt of claim 28 or 29, wherein for crystal form I, its XRPD spectrum further includes peaks at approximately 13.9 ± 0.2, 19.0 ± 0.2, 21.6 ± 0.2, and 28.1 ± 0.2 2θ (°).

31. The hydrochloride salt of any one of claims 28-30, wherein for the crystal form I, its XRPD spectrum further includes peaks at about 12.7±0.2, 17.4±0.2, 25.5±0.2 and 28.4±0.2 2θ (°).

32. The hydrochloride of claim 28, wherein for said crystal form I, its XRPD spectrum includes peaks at approximately the following 2θ (°) positions: 8.5±0.2, 8.7±0.2, 10.2±0.2, 12.7±0.2, 13.9±0.2, 14.5±0.2, 16.1±0.2, 17.4±0.2, 18.5±0.2, 22.7±0.2, 23.1±0.2, 23.5±0.2, 25.5±0.2, 26.0±0.2, 26.3±0.2, 26.6±0.2, 27.5±0.2, 28.1±0.2, 32.1±0.2, 34.2±0.2, and 38.0±0.

2.

33. The hydrochloride salt of claim 28, wherein for said crystal form I, its XRPD spectrum includes peaks at approximately the following positions:

34. The hydrochloride of claim 28, wherein for crystal form I, it has substantially the same XRPD pattern as shown in FIG1.

35. The hydrochloride salt of any one of claims 28-34, wherein for said crystal form I, it includes broad endothermic peaks at about 85°C and about 215°C in a differential scanning calorimetry (DSC) spectrum.

36. The hydrochloride salt of any one of claims 28-35, wherein for said crystal form I, it has a thermogravimetric analysis (TGA) spectrum showing that said crystal form has a weight loss of about 2.9% when heated to about 130°C and a weight loss of about 3.8% between about 130 and 200°C.

37. The hydrochloride salt of any one of claims 28-36, wherein for said crystal form I, it has a DSC-TGA pattern substantially the same as that shown in FIG2.

38. A method for preparing crystal form I according to any one of claims 28-37, comprising the following steps: 1) Add an ester solvent, ketone solvent, or nitrile solvent to compound A; 2) Add hydrochloric acid to the system obtained in step 1) and stir at a certain temperature; and 3) Filter the system obtained in step 2) and optionally dry it to obtain crystal form I.

39. The method of claim 38, wherein the weight-to-volume ratio (g / mL) of compound A and the solvent in step 1) is about 1:(1-10), preferably about 1:6.

7.

40. The method of claim 38 or 39, wherein the ester solvent is an ester having 4-10 carbon atoms, preferably ethyl acetate.

41. The method of claim 38 or 39, wherein the ketone solvent is a chain hydrocarbon ketone with 3-6 carbon atoms, preferably acetone.

42. The method of claim 38 or 39, wherein the nitrile solvent is acetonitrile.

43. The method of any one of claims 38-42, wherein the concentration of hydrochloric acid in step 2) is 2-12 mol / L, and the molar ratio of compound A to HCl is 1:(1-1.2).

44. The method of any one of claims 38-43, wherein the temperature in step 2) is about 15-50°C.

45. The hydrochloride salt of claim 4, which is crystal form III of the compound A dihydrochloride hydrate, having peaks at approximately 6.7 ± 0.2, 13.0 ± 0.2, and 19.7 ± 0.2 2θ (°) in an X-ray powder diffraction (XRPD) spectrum obtained using Cu Kα radiation.

46. ​​The hydrochloride of claim 45, wherein for crystal form III, its XRPD spectrum further includes peaks at approximately 10.5 ± 0.2, 10.9 ± 0.2, and 23.9 ± 0.2 2θ (°).

47. The hydrochloride of claim 45 or 46, wherein for the crystal form III, its XRPD spectrum further includes peaks at about 17.2 ± 0.2, 24.1 ± 0.2, and 27.1 ± 0.2 2θ (°).

48. The hydrochloride salt of any one of claims 45-47, wherein for the crystal form III, its XRPD spectrum further includes peaks at about 9.2 ± 0.2, 11.1 ± 0.2, and 23.7 2θ (°).

49. The hydrochloride of claim 45, wherein for the crystal form III, its XRPD spectrum includes peaks at approximately the following 2θ (°) positions: 6.7±0.2, 9.2±0.2, 9.7±0.2, 10.5±0.2, 10.9±0.2, 11.1±0.2, 13.0±0.2, 17.2±0.2, 19.7±0.2, 22.9±0.2, 23.7±0.2, 23.9±0.2, 24.1±0.2, and 27.1±0.

2.

50. The hydrochloride of claim 49, wherein for crystal form III, its XRPD spectrum includes peaks at approximately the following positions:

51. The hydrochloride of claim 49, wherein for crystal form III, it has substantially the same XRPD pattern as shown in FIG7.

52. The hydrochloride salt of any one of claims 45-51, wherein for crystal form III, it includes an endothermic peak at about 66°C and an endothermic peak at about 188°C in a differential scanning calorimetry (DSC) spectrum.

53. The hydrochloride salt of any one of claims 45-52, wherein for crystal form III, it has a thermogravimetric analysis (TGA) spectrum showing that the crystal form has a weight loss of about 10.4% between room temperature and 200°C.

54. The hydrochloride salt of any one of claims 45-53, wherein for said crystal form III, it has a DSC-TGA pattern substantially the same as that shown in FIG8.

55. A method for preparing crystal form III according to any one of claims 45-54, comprising: 1) Add a ketone solvent to compound A; 2) Add hydrochloric acid to the system obtained in step 1) and stir at a certain temperature; 3) Filter the system obtained in step 2) and optionally dry it to obtain crystal form III.

56. The method of claim 55, wherein the weight-to-volume ratio (g / mL) of compound A and the ketone solvent in step 1) is about 1:(1-10), preferably about 1:6.

7.

57. The method of claim 55 or 56, wherein the ketone solvent is a chain hydrocarbon ketone with 3-6 carbon atoms, preferably acetone.

58. The method of any one of claims 55-57, wherein the concentration of hydrochloric acid in step 2) is 2-12 mol / L, and the molar ratio of compound A to HCl is 1:(1.5-2.5).

59. The method according to any one of claims 55-58, wherein the temperature in step 2) is about 15-60°C.

60. A composition comprising the hydrochloride salt of any one of claims 1-15, 28-37 and 45-54 and a pharmaceutically acceptable carrier or excipient.

61. Use of the hydrochloride salt of any one of claims 1-15, 28-37 and 45-54 or the composition of claim 60 in the preparation of a medicament for the prevention or treatment of diseases regulated by ART kinase inhibitors.

62. Use of the hydrochloride salt of any one of claims 1-15, 28-37 and 45-54 or the composition of claim 60 in the preparation of a medicament for the prevention or treatment of cancer.

63. The use of claim 62, wherein the cancer is selected from lung cancer, prostate cancer, melanoma, ovarian cancer, breast cancer, endometrial cancer, kidney cancer, gastric cancer, sarcoma, head and neck cancer, tumors of the central nervous system and their metastases, and acute myeloid leukemia.

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