Salts of aminopyrimidine compounds and their uses

Abstract

The present invention relates to a salt of an aminopyrimidine compound and its use. Specifically, the present invention relates to a salt of (S)-2-(1-((6-amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl)amino)ethyl)-5-(3-hydroxyprop-1-yn-1-yl)-3-phenylquinazolin-4(3H)-one and a pharmaceutical composition containing said salt, and further to the use thereof in the manufacture of a medicament for treating and preventing a disease associated with abnormality in PI3K kinase.

Description

[Technical field]

[0001] The present invention belongs to the technical field of medicine and relates to a salt of an aminopyrimidine compound and its use, in particular to a salt of (S)-2-(1-((6-amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl)amino)ethyl)-5-(3-hydroxyprop-1-yn-1-yl)-3-phenylquinazolin-4(3H)-one and a pharmaceutical composition containing said salt, and further to the use thereof in the manufacture of medicines. [Background technology]

[0002] Inositol phosphate 3-kinases (PI3K kinases or PI3Ks), as a family of lipid kinases, exert important regulatory effects in many cellular processes, such as cell survival, proliferation and differentiation. As the main influencers in downstream transduction of receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs), PI3Ks transmit signals from various growth factors and factors into cells by generating phospholipids to activate the serine-threonine protein kinase AKT (also called protein kinase B (PKB)) and other downstream pathways. The tumor suppressor gene or PTEN (phosphatase and tensin homolog) is the most important counter-regulator in the PI3K signaling pathway ("Small-molecule inhibitors of the PI3K signaling network." Future Med Chem. 2011, 3(5), 549-565).

[0003] So far, eight mammalian PI3Ks have been identified and are divided into three types (I, II, and III) according to differences in gene sequence, structure, adaptor molecule, expression, activation mechanism, and substrate. Among them, type I PI3Ks are divided into two types, IA and IB, according to signal transduction pathways and regulatory proteins. Type IA PI3Ks (PI3Kα, PI3Kβ, and PI3Kδ) are heterodimeric complexes consisting of catalytic subunit p110 (p110α, p110β, and p110δ, respectively) and regulatory subunit p85 (e.g., p85α, p85β, p55δ, p55α, and p50α). ATP-phosphorylated phosphatidylinositol (PI, PtdIns), PI4P, and PI(4,5)P2 are used for the catalytically active subunit p110. These signal responses are generally transmitted by receptor tyrosine kinases (RTKs). Type IB PI3Kγ signals are transmitted by G protein-coupled receptors (GPCRs) and consist of the catalytic subunit p110γ, the regulatory subunits associated with p110γ being distinct from type IA subtypes.

[0004] PI3Kδ signaling has been linked to B cell survival, migration and activation (Puri, Frontiers inImmunology, 2012, 3(256), 1-16, pp. 1-5, and Clayton, J Exp Med, 2002, 196(6):753-63). For example, PI3Kδ is required for B cell receptor-driven antigen-dependent B cell activation. PI3Kδ inhibition blocks B cell adhesion, survival, activation and proliferation, inhibiting their activation and reducing the secretion of autoantibodies and proinflammatory cytokines by blocking their activation and inhibiting the ability of B cells to activate T cells. Thus, due to their ability to inhibit B cell activation, PI3Kδ inhibitors are expected to treat B cell mediated diseases that can be treated in a similar manner (e.g., depleting B cells with rituximab). Indeed, PI3Kδ inhibitors have been shown to be applicable to mouse models with multiple autoimmune diseases (e.g., arthritis) that can be treated with rituximab (Puri(2012)). Also, innate B cells associated with autoimmunity are sensitive to PI3Kδ activity, as MZ and B-1 cells are largely absent in mice lacking the p110δ gene (Puri (2012)). PI3Kδ inhibitors can reduce trafficking and activation of MZ and B-1 cells involved in autoimmune disease.

[0005] In addition to their potential role in inflammatory diseases, all four type I PI3K subtypes can also play a role in cancer. The gene encoding p110α is frequently mutated in common cancers, including breast, prostate, colon and endometrial cancers (Samuels et al., Science, 2004, 304(5670):554; Samuels et al., Curr Opin Oncol. 2006, 18(1):77-82). 80% of these mutations are represented by one of three amino acid substitutions in the helical or kinase domain of the enzyme, leading to a marked upregulation of kinase activity, thus resulting in oncogenic transformation in cell cultures and animal models (Kang et al., Proc Natl Acad Sci US A. 2005, 102(3):802-7; Bader et al., Proc Natl Acad Sci US A. 2006, 103(5):1475-9). Although such mutations have not been identified in other PI3K subtypes, there is evidence that they can promote the development and development of malignant tumors. Consistent overexpression of PI3Kδ has been observed in acute myeloblastic leukemia (Sujobert et al., Blood, 2005, 106(3):1063-6), and PI3Kδ inhibitors can block the growth of leukemia cells (Billottet et al., Oncogene. 2006, 25(50):6648-59). Increased expression of PI3Kγ has been observed in chronic myelogenous leukemia (Hickey et al., J Biol. Chem. 2006, 281(5):2441-50). Additionally, changes in the expression of PI3Kβ, PI3Kγ and PI3Kδ are observed in brain tumors, colon cancer and bladder cancer (Benistant et al., Oncogene, 2000, 19(44):5083-90; Mizoguchi et al., Brain Pathol. 2004, 14(4):372-7; Knobbe et al., Neuropathol Appl Neurobiol. 2005, 31(5):486-90).

[0006] International Patent Application WO2019143874A1 discloses the compound (S)-2-(1-((6-amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl)amino)ethyl)-5-(3-hydroxyprop-1-yn-1-yl)-3-phenylquinazolin-4(3H)-one (compound represented by formula (I)), which can treat or alleviate diseases associated with abnormal expression of PI3K kinase, such as hematological malignancies. The compound has problems such as low solubility, poor absorption in the animal body, and low stability, and these defects cause many inconveniences in the subsequent formulation development. [ka]

[0007] Different salts or solid forms of a pharmaceutical active ingredient may have different properties. The properties of different salts or solid forms can be changed to provide improved formulation methods, for example, to facilitate synthesis or processing, improve dissolution rate, or improve stability and shelf life. The change in properties of different salts or solid forms can also improve the pharmacological properties of the final formulation product, for example, to improve exposure, bioavailability, or extend half-life. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] International Patent Application No. 2019143874 [Non-patent literature]

[0009] [Non-Patent Document 1] "Small-molecule inhibitors of the PI3K signaling network."Future Med Chem.2011, 3(5), 549-565) [Non-Patent Document 2] Puri, Frontiers inImmunology, 2012, 3(256), 1-16, pp. 1-5 [Non-Patent Document 3] Clayton, J Exp Med, 2002, 196(6):753-63 [Non-Patent Document 4] Samuels et al., Science, 2004, 304(5670):554; [Non-Patent Document 5] Samuels et al., Curr Opin Oncol.2006, 18(1):77-82 [Non-Patent Document 6] Kang et al., Proc Natl Acad Sci US A.2005,102(3):802-7 [Non-Patent Document 7] Bader et al., Proc Natl Acad Sci U S A. 2006, 103(5):1475-9 [Non-Patent Document 8] Sujobert et al., Blood, 2005, 106(3):1063-6 [Non-Patent Document 9] Billottet et al., Oncogene.2006, 25(50):6648-59 [Non-Patent Document 10] Hickey et al., J Biol. Chem. 2006, 281(5):2441-50 [Non-Patent Document 11] Benistant et al., Oncogene, 2000, 19(44):5083-90 [Non-Patent Document 12] Mizoguchi et al., Brain Pathol.2004, 14(4):372-7 [Non-Patent Document 13] Knobbe et al., Neuropathol Appl Neurobiol.2005, 31(5):486-90 Summary of the Invention [Problem to be solved by the invention]

[0010] The present invention provides salts of the compound represented by formula (I). Specifically, the present invention provides sulfate, hydrogen sulfate, phosphate and p-toluenesulfonate of the compound represented by formula (I), and the salts described in the present invention have high stability and excellent pharmacokinetic properties, and therefore have better pharmaceutical potential.

[0011] In particular, the present invention relates to salts of compounds of formula (I) and pharmaceutical compositions comprising said salts, and further to their use in the manufacture of medicaments for the treatment or prevention of diseases associated with the abnormal expression of PI3K kinase. The salts according to the present invention may be in the form of solvates, such as hydrates. [Means for solving the problem]

[0012] In one aspect, the present invention provides a salt of a compound of formula (I). [ka]

[0013] In some embodiments, salts of the compound of formula (I) according to the present invention include, but are not limited to, hydrochloride, hydrobromide, phosphate, sulfate, hydrogen sulfate, p-toluenesulfonate, benzenesulfonate, benzoate, acetate, oxalate, maleate, tartrate, or citrate salts.

[0014] In some embodiments, the salt of the compound represented by formula (I) according to the present invention is a sulfate salt of the compound represented by formula (I).

[0015] In some embodiments, the sulfate salt of the compound of Formula (I) according to the present invention is crystalline form A of the sulfate salt of the compound of Formula (I).

[0016] In some embodiments, the X-ray powder diffraction pattern of crystalline form A of the sulfate salt of compound of formula (I) according to the present invention comprises diffraction peaks at 2θ angles of 5.37°±0.2°, 6.90°±0.2°, 11.82°±0.2°, 16.51°±0.2°, 20.50°±0.2° and 25.95°±0.2°.

[0017] In some further embodiments, the X-ray powder diffraction pattern of crystalline form A of the sulfate salt of compound of formula (I) according to the present invention comprises diffraction peaks at 2θ angles of 5.37°±0.2°, 6.20°±0.2°, 6.90°±0.2°, 11.82°±0.2°, 16.51°±0.2°, 16.60°±0.2°, 19.18°±0.2°, 20.10°±0.2°, 20.50°±0.2°, 21.64°±0.2°, 25.95°±0.2° and 29.63°±0.2°.

[0018] In some further embodiments, the X-ray powder diffraction pattern of crystalline form A of the sulfate salt of compound of formula (I) according to the present invention is 5.37°±0.2°, 6.20°±0.2°, 6.90°±0.2°, 8.74°±0.2°, 10.77°±0.2°, 10.99°±0.2°, 11.82°±0.2°, 12.45°±0.2°, 15.61°±0.2°, 16.51°±0.2°, 16.60°±0.2°, 17.08°±0.2°, 17.57°±0.2°, 17.91°±0.2°, 18.62°±0.2°, 19.18°±0.2°, 20.10°±0.2°, 20.50°±0.2° , 20.91°±0.2°, 21.64°±0.2°, 22.24°±0.2°, 23.31°±0.2°, 23.70°±0.2°, 23.83°±0.2°, 24.41°±0.2°, 24.87°±0.2°, 25.18°±0.2°, 25.59°±0.2°, 25.95°±0.2°, 2 The diffraction peaks are at 2θ angles of 7.15°±0.2°, 27.55°±0.2°, 27.98°±0.2°, 28.19°±0.2°, 28.51°±0.2°, 29.63°±0.2°, 30.19°±0.2°, 31.83°±0.2°, 36.11°±0.2° and 41.55°±0.2°.

[0019] In some embodiments, the hydrogen sulfate salt of the compound of Formula (I) according to the present invention is crystalline form A of the hydrogen sulfate salt of the compound of Formula (I).

[0020] In some embodiments, the X-ray powder diffraction pattern of crystalline form A of the hydrogen sulfate salt of compound of formula (I) according to the present invention comprises diffraction peaks at 2θ angles of 6.49°±0.2°, 6.81°±0.2°, 11.54°±0.2°, 13.79°±0.2°, 21.99°±0.2°, 25.99°±0.2° and 26.32°±0.2°.

[0021] In some further embodiments, the X-ray powder diffraction pattern of crystalline form A of the hydrogen sulfate salt of compound of formula (I) according to the present invention comprises diffraction peaks at 2θ angles of 6.49°±0.2°, 6.81°±0.2°, 8.75°±0.2°, 11.54°±0.2°, 13.06°±0.2°, 13.64°±0.2°, 13.79°±0.2°, 16.24°±0.2°, 17.11°±0.2°, 21.99°±0.2°, 25.99°±0.2°, 26.32°±0.2°, 26.90°±0.2° and 27.91°±0.2°.

[0022] In some further embodiments, the X-ray powder diffraction pattern of crystalline form A of the hydrogen sulfate salt of compound of formula (I) according to the present invention is 6.49°±0.2°, 6.81°±0.2°, 8.75°±0.2°, 11.54°±0.2°, 13.06°±0.2°, 13.64°±0.2°, 13.79°±0.2°, 14.19°±0.2°, 14.70°±0.2°, 16.24°±0.2°, 17.11°±0.2°, 18.10°±0.2°, 18.59°±0.2°, 19.48°±0.2°, 19.68°±0.2°, 21.20°±0.2°, 21.52°±0.2°, 21. 99°±0.2°, 23.25°±0.2°, 24.05°±0.2°, 24.57°±0.2°, 25.57°±0.2°, 25.99°±0.2°, 26.32°±0.2°, 26.90°±0.2°, 27.08°±0.2°, 27.91°±0.2°, 28.61°±0.2°, 29. Includes diffraction peaks at 2θ angles of 48°±0.2°, 31.02°±0.2°, 32.88°±0.2°, 33.53°±0.2°, 35.20°±0.2°, 38.45°±0.2°, 39.52°±0.2°, 40.58°±0.2°, 41.72°±0.2° and 43.81°±0.2°.

[0023] In some embodiments, the salt of the compound represented by formula (I) according to the present invention is a phosphate salt of the compound represented by formula (I).

[0024] In some embodiments, the phosphate salt of the compound of formula (I) according to the present invention is crystalline form A of the phosphate salt of the compound of formula (I).

[0025] In some embodiments, the X-ray powder diffraction pattern of crystalline form A of the phosphate salt of compound of formula (I) according to the present invention comprises diffraction peaks at 2θ angles of 7.41°±0.2°, 11.06°±0.2°, 11.27°±0.2°, 16.62°±0.2°, 19.32°±0.2°, 22.27°±0.2° and 24.38°±0.2°.

[0026] In some further embodiments, the X-ray powder diffraction pattern of crystalline form A of the phosphate salt of compound of formula (I) according to the present invention comprises diffraction peaks at 2θ angles of 7.41°±0.2°, 9.27°±0.2°, 11.06°±0.2°, 11.27°±0.2°, 12.02°±0.2°, 13.30°±0.2°, 16.62°±0.2°, 19.32°±0.2°, 20.69°±0.2°, 22.27°±0.2°, 24.38°±0.2°, 26.58°±0.2°, 27.87°±0.2° and 28.32°±0.2°.

[0027] In some further embodiments, the X-ray powder diffraction pattern of crystalline form A of the phosphate salt of the compound of formula (I) according to the present invention is 5.02°±0.2°, 5.95°±0.2°, 7.41°±0.2°, 8.15°±0.2°, 9.27°±0.2°, 9.93°±0.2°, 11.06°±0.2°, 11.27°±0.2°, 12.02°±0.2°, 12.82°±0.2°, 13.30°±0.2°, 14.87°±0.2°, 16.62°±0.2°, 17.09°±0.2° , diffraction peaks at 2θ angles of 18.11°±0.2°, 19.32°±0.2°, 19.79°±0.2°, 20.69°±0.2°, 21.22°±0.2°, 22.27°±0.2°, 23.41°±0.2°, 24.38°±0.2°, 25.47°±0.2°, 26.58°±0.2°, 27.43°±0.2°, 27.87°±0.2°, 28.32°±0.2°, 29.45°±0.2°, 30.34°±0.2°, 31.62°±0.2° and 33.79°±0.2°.

[0028] In some embodiments, the salt of the compound represented by formula (I) according to the present invention is a p-toluenesulfonic acid salt of the compound represented by formula (I).

[0029] In some embodiments, the p-toluenesulfonic acid salt of compound represented by Formula (I) according to the present invention is crystalline form A of the p-toluenesulfonic acid salt of compound represented by Formula (I).

[0030] In some embodiments, the X-ray powder diffraction pattern of crystalline form A of p-toluenesulfonate salt of compound of formula (I) according to the present invention comprises diffraction peaks at 2θ angles of 6.49°±0.2°, 10.04°±0.2°, 11.71°±0.2°, 14.10°±0.2°, 17.86°±0.2°, 20.84°±0.2° and 21.87°±0.2°.

[0031] In some further embodiments, the X-ray powder diffraction pattern of crystalline form A of p-toluenesulfonate salt of compound of formula (I) according to the present invention comprises diffraction peaks at 2θ angles of 6.49°±0.2°, 9.51°±0.2°, 10.04°±0.2°, 10.51°±0.2°, 10.72°±0.2°, 11.71°±0.2°, 14.10°±0.2°, 14.94°±0.2°, 16.82°±0.2°, 17.86°±0.2°, 20.84°±0.2°, 21.87°±0.2°, 26.20°±0.2° and 28.26°±0.2°.

[0032] In some further embodiments, the X-ray powder diffraction pattern of the crystalline form A of p-toluenesulfonate salt of the compound represented by formula (I) according to the present invention is 6.49°±0.2°, 9.51°±0.2°, 10.04°±0.2°, 10.51°±0.2°, 10.72°±0.2°, 11.71°±0.2°, 12.65°±0.2°, 13.20°±0.2°, 14.10°±0.2°, 14.35°±0.2°, 14.94°±0.2°, 15.88°±0.2°, 16.44°±0.2°, 16.82°±0.2°, 17.21°±0.2°, 17.86°±0.2°, 18.34°±0.2°, 19.08°±0.2°, 19.57°±0.2°, 20.17°±0.2°, 20.65°±0.2°, 20.84°±0.2°, 21.26°±0.2°, 21.87°±0.2°, 22.27°±0.2°, 22.44°±0.2°, 23.02°±0.2°, 24.01°±0.2°, 25.01°±0.2°, 26.01°±0.2°, 27.01°±0.2°, 28.01°±0.2°, 29.01°±0.2°, 30.01°±0.2°, 31.01°±0.2°, 32.01°±0.2°, 33.01°±0.2°, 34.01°±0.2°, 35.01°±0.2°, 36.01°±0.2°, 37.01°±0.2°, 38.01°±0.2°, 39.01°±0.2°, 40.01°±0.2°, 41.01°±0.2°, 42.01°±0.2°, 43.01°±0.2°, 44.01°±0.2°, 45.01°±0.2°, 46. °±0.2°, 22.84°±0.2°, 23.19°±0.2°, 23.55°±0.2°, 24.25°±0.2°, 24.81°±0.2°, 25.59°±0.2°, 26.21°±0.2°, 26.91°±0.2°, 27.38°±0.2°, 27.93°±0.2°, 28.26°±0.2°, 28.82°±0.2°, 29.16°±0.2°, 29.61°±0.2°, 30.19°±0.2 The diffraction peaks include those at 2θ angles of 31.30°±0.2°, 31.90°±0.2°, 32.44°±0.2°, 33.21°±0.2°, 33.94°±0.2°, 35.32°±0.2°, 36.44°±0.2°, 37.30°±0.2°, 37.61°±0.2°, 38.59°±0.2°, 39.54°±0.2°, 42.25°±0.2°, 44.61°±0.2° and 47.32°±0.2°.

[0033] In some embodiments, the sulfate salt of the compound of formula (I) according to the present invention is in crystalline form A of the sulfate salt, and the differential scanning calorimetry pattern of crystalline form A of the sulfate salt comprises endothermic peaks at 105.07°C±3°C and 185.08°C±3°C, and an exothermic peak at 233.00°C±3°C.

[0034] In some embodiments, the hydrogen sulfate salt of the compound of formula (I) according to the present invention is in crystalline form A of the hydrogen sulfate salt, and the differential scanning calorimetry pattern of the crystalline form A of the hydrogen sulfate salt comprises an endothermic peak at 196.02°C±3°C and exothermic peaks at 201.85°C±3°C and 246.30°C±3°C.

[0035] In some embodiments, the phosphate salt of the compound of formula (I) according to the present invention is in crystalline form A of the phosphate salt, and the differential scanning calorimetry pattern of the crystalline form A of the phosphate salt comprises an exothermic peak at 205.70°C ± 3°C.

[0036] In some embodiments, the p-toluenesulfonate salt of the compound represented by formula (I) according to the present invention is crystalline form A of the p-toluenesulfonate salt, and the differential scanning calorimetry pattern of the crystalline form A of the p-toluenesulfonate salt comprises an endothermic peak at 73.89°C±3°C and an exothermic peak at 231.68°C±3°C.

[0037] In some embodiments, the sulfate salt of the compound of Formula (I) according to the present invention is in crystalline form A of the sulfate salt, wherein said crystalline form A of the sulfate salt loses weight by 6.408% when heated to 100.06° C. and loses weight by 3.058% when continuously heated from 100.06° C. to 205.23° C., with a tolerance of ±0.1%.

[0038] In some embodiments, the hydrogen sulfate salt of the compound of formula (I) according to the present invention is crystalline form A of the hydrogen sulfate salt, wherein the crystalline form A of the hydrogen sulfate salt loses weight by 6.869% when heated to 137.49°C and loses weight by 2.873% when continuously heated from 137.49°C to 215.40°C, and the weight loss percentage has a margin of error of ±0.1%.

[0039] In some embodiments, the phosphate salt of the compound of formula (I) according to the present invention is in crystalline form A of the phosphate salt, and when heated to 119.39° C., said crystalline form A of the phosphate salt loses weight by 3.294%, and the weight loss percentage has a margin of error of ±0.1%.

[0040] In some embodiments, the p-toluenesulfonate salt of compound represented by formula (I) according to the present invention is crystalline form A of p-toluenesulfonate salt, and when heated to 150.10° C., the crystalline form A of p-toluenesulfonate loses weight by 1.709%, and the weight loss percentage has a margin of error of ±0.1%.

[0041] In some embodiments, the sulfate salt of the compound of Formula (I) according to the present invention is crystalline form A of the sulfate salt, and the crystalline form A of the sulfate salt has an X-ray powder diffraction pattern substantially as shown in FIG.

[0042] In some embodiments, the sulfate salt of the compound of Formula (I) according to the present invention is in crystalline form A of the sulfate salt, and the crystalline form A of the sulfate salt has a differential scanning calorimetry pattern substantially as shown in FIG.

[0043] In some embodiments, the sulfate salt of the compound of Formula (I) according to the present invention is crystalline form A of the sulfate salt, and the crystalline form A of the sulfate salt has a thermogravimetric analysis pattern substantially as shown in FIG.

[0044] In some embodiments, the hydrogen sulfate salt of the compound of formula (I) according to the present invention is crystalline form A of the hydrogen sulfate salt, and the crystalline form A of the hydrogen sulfate salt has an X-ray powder diffraction pattern substantially as shown in FIG.

[0045] In some embodiments, the hydrogen sulfate salt of the compound of formula (I) according to the present invention is crystalline form A of the hydrogen sulfate salt, and the crystalline form A of the hydrogen sulfate salt has a differential scanning calorimetry pattern substantially as shown in FIG.

[0046] In some embodiments, the hydrogen sulfate salt of the compound of Formula (I) according to the present invention is crystalline form A of the hydrogen sulfate salt, and the crystalline form A of the hydrogen sulfate salt has a thermogravimetric analysis pattern substantially as shown in FIG.

[0047] In some embodiments, the phosphate salt of the compound of formula (I) according to the present invention is in crystalline form A of the phosphate salt, and the crystalline form A of the phosphate salt has an X-ray powder diffraction pattern substantially as shown in FIG.

[0048] In some embodiments, the phosphate salt of the compound of formula (I) according to the present invention is in crystalline form A of the phosphate salt, and the crystalline form A of the phosphate salt has a differential scanning calorimetry pattern substantially as shown in FIG.

[0049] In some embodiments, the phosphate salt of the compound of formula (I) according to the present invention is crystalline form A of the phosphate salt, and the crystalline form A of the phosphate salt has a thermogravimetric analysis pattern substantially as shown in FIG.

[0050] In some embodiments, the p-toluenesulfonate salt of the compound of formula (I) according to the present invention is crystalline form A of the p-toluenesulfonate salt, and the crystalline form A of the p-toluenesulfonate salt has an X-ray powder diffraction pattern substantially as shown in FIG. 10.

[0051] In some embodiments, the p-toluenesulfonate salt of the compound of formula (I) according to the present invention is crystalline form A of the p-toluenesulfonate salt, and the crystalline form A of the p-toluenesulfonate salt has a differential scanning calorimetry pattern substantially as shown in FIG.

[0052] In some embodiments, the p-toluenesulfonate salt of the compound represented by formula (I) according to the present invention is crystalline form A of the p-toluenesulfonate salt, and the crystalline form A of the p-toluenesulfonate salt has a thermogravimetric analysis pattern substantially as shown in FIG. 12.

[0053] In another aspect, the invention relates to a pharmaceutical composition comprising a salt according to the invention and a pharma- ceutically acceptable carrier, excipient, diluent, adjuvant, or combination thereof.

[0054] In one aspect, the invention relates to the use of said salt or said pharmaceutical composition in the manufacture of a medicament for preventing, treating or ameliorating a disease associated with aberrant expression of PI3K kinase in a patient.

[0055] In some embodiments, the disease according to the invention is a respiratory disease, a viral infection, a non-viral airway infection, an allergic disease, an autoimmune disease, an inflammatory disease, a cardiovascular disease, a hematological malignancy, a neurodegenerative disease, pancreatitis, multiple organ failure, renal disease, platelet aggregation, cancer, transplant rejection, lung injury or pain.

[0056] In another aspect, the invention relates to the use of said salt or said pharmaceutical composition in the manufacture of a medicament for preventing, treating or ameliorating at least part of a disease associated with aberrant expression of PI3K kinase in a patient.

[0057] In some embodiments, the disease according to the invention is asthma, chronic obstructive pulmonary disease (COPD), viral airway infection, viral respiratory disease exacerbation, aspergillosis, leishmaniasis, allergic rhinitis, allergic dermatitis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, thrombosis, atherosclerosis, hematological malignancies, neurodegenerative diseases, pancreatitis, multiple organ failure, renal disease, platelet aggregation, cancer, transplant rejection, lung injury, systemic inflammatory pain, diabetic neuropathy, chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), hairy cell leukemia, mantle cell lymphoma, Burkholderia purpura, pulmonary edema ... lymphoma, small lymphocytic lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, prolymphocytic leukemia, acute lymphoblastic leukemia, myelofibrosis, mucosa-associated lymphoid tissue (MALT) lymphoma, B-cell lymphoma, thymic-mediastinal large B-cell lymphoma, lymphomatoid granulomatosis, splenic marginal zone lymphoma, primary effusion lymphoma, intravascular large B-cell lymphoma, plasma cell leukemia, extramedullary plasmacytoma, smoldering myeloma, monoclonal gammopathy (MGUS) or B-cell lymphoma.

[0058] According to one aspect of the present invention, there is provided a method for preventing, treating or ameliorating a disease associated with aberrant expression of PI3K kinase in a patient, comprising administering to the patient a pharma- ceutical effective amount of a salt or said pharmaceutical composition according to the present invention.

[0059] In another aspect, the present invention further relates to a process for preparing a salt of a compound of formula (I).

[0060] The solvent used in the method for preparing the salt according to the present invention is not particularly limited, and any solvent that dissolves the starting material to a certain extent and does not affect its properties is included in the present invention. However, many similar modifications, equivalent substitutions, or solvents equivalent to those described in the present invention, combinations of solvents, and various ratios of combining solvents in the field are considered to be included in the scope of the present invention. The present invention provides preferred solvents for use in each reaction step.

[0061] The preparation experiments of the salt or its crystalline form according to the present invention are described in detail in the Examples section. The present invention also provides pharmacological measurement experiments (e.g., pharmacokinetic experiments) and stability experiments of the salt or its crystalline form. The experiments prove that the salt or its crystalline form according to the present invention has high stability and pharmacokinetic properties. Definitions and General Terms

[0062] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. All patents and published publications related to this invention are incorporated herein by reference in their entirety. Although any methods and materials similar or equivalent to those described in this invention can be used in the practice or testing of this invention, the methods, devices and materials described in this invention are preferred.

[0063] "Crystal form" or "crystalline morphology" refers to a solid having a highly ordered chemical structure, including, but not limited to, single or multi-component crystals, and / or crystalline polymorphs of a compound, solvates, hydrates, clathrates, eutectics, salts, solvates of salts, and hydrates of salts. Crystalline forms of a substance can be obtained by many methods known in the art. Such methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in confined spaces such as nanopores or capillaries, crystallization on surfaces or templates such as polymers, crystallization in the presence of additives such as co-crystalline antimolecules, solvent removal, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, antisolvent addition, grinding, and solvent drop grinding.

[0064] "Solvent" refers to a substance (typically a liquid) that can completely or partially dissolve other substances (typically solids). Solvents that may be used in the practice of the present invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethylsulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, t-butyl alcohol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, and the like.

[0065] "Anti-solvent" refers to a fluid that promotes precipitation of a product (or product precursor) from a solvent. An anti-solvent may include a cryogenic gas, or a fluid that promotes precipitation by chemical reaction, or a fluid that reduces the solubility of the product in the solvent. It may be the same liquid as the solvent but at a different temperature, or it may be a different liquid than the solvent.

[0066] "Solvate" refers to a compound having a solvent on the surface, in the lattice, or on the surface and in the lattice, and the solvent may be water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethylsulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, t-butyl alcohol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, methylpyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, and mixtures thereof. One specific example of a solvate is a hydrate, in which the solvent on the surface, in the lattice, or on the surface and in the lattice is water. The hydrate may or may not have other solvents other than water on the surface, in the lattice, or on the surface and in the lattice of the material.

[0067] Crystalline forms can be identified by a variety of techniques, such as X-ray powder diffraction (XRPD), infrared spectroscopy (IR), melting point, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance, Raman spectroscopy, X-ray single crystal diffraction, solution calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate.

[0068] X-ray powder diffraction (XRPD) can measure information such as changes in crystal form, crystallinity, and crystal structure state, and is a common means for identifying crystal forms. The peak positions of the XRPD pattern are determined primarily by the structure of the crystal form and are relatively insensitive to experimental details, and the relative peak heights are determined by many factors related to the preparation of the sample and the geometry of the instrument. Thus, in some embodiments, the crystal forms of the present invention are characterized by an XRPD pattern having several peak positions, which are substantially as shown in the XRPD patterns provided in the drawings of the present invention. In addition, there may be experimental errors in the measurement of 2θ in the XRPD pattern, and the measurement of 2θ in the XRPD pattern by different instruments and different samples may be slightly different, so the above values ​​of 2θ cannot be considered absolute. According to the conditions of the instrument used in this test, the allowable error of the diffraction peaks is ±0.2. o It is.

[0069] Differential scanning calorimetry (DSC) is a technique that measures the change with temperature of the energy difference between a sample and an inert reference (commonly α-Al2O3) by constantly heating or cooling under procedural control. The endothermic peak height of the DSC curve is determined by many factors related to the preparation of the sample and the geometry of the instrument, while the peak position is relatively insensitive to experimental details. Thus, in some embodiments, the crystalline forms described in the present invention are characterized by a DSC pattern having a characteristic peak position, which is substantially as shown in the DSC pattern provided in the drawings of the present invention. In addition, the peak position or peak value of the DSC endothermic peak cannot be considered absolute, since there may be experimental errors in the DSC pattern, and the peak positions and peak values ​​of the DSC patterns from different instruments and different samples may be slightly different. According to the conditions of the instrument used in this test, the tolerance of the endothermic peak is ±3°.

[0070] Thermogravimetric analysis (TGA) is a technique to measure the mass change of a substance with temperature under procedural control, which is suitable for examining the process of solvent loss in crystals or sublimation and decomposition of samples, and can infer the presence of crystal water or crystal solvent in crystals. The mass change shown by the TGA curve is determined by many factors such as sample preparation and equipment, and the mass changes detected by TGA with different equipment and different samples are slightly different. According to the conditions of the equipment used in this test, the allowable error of the mass change is ±0.1%.

[0071] In the context of the present invention, all 2θ values ​​in an X-ray powder diffraction pattern are in degrees (°).

[0072] The term "substantially as shown in the figure" means that at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% of the peaks in the X-ray powder diffraction pattern, DSC pattern, Raman spectral pattern, or infrared spectral pattern are represented in the figure.

[0073] When referring to data shown in a spectrum and / or graph, a "peak" refers to a feature that one of skill in the art would recognize as not being due to background noise.

[0074] The present invention relates to the above salt of (S)-2-(1-((6-amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl)amino)ethyl)-5-(3-hydroxyprop-1-yn-1-yl)-3-phenylquinazolin-4(3H)-one and its crystalline form, for example crystalline form A of the p-toluenesulfonic acid salt, which exist in a substantially pure crystalline form.

[0075] "Substantially pure" refers to one crystalline form being substantially free of one or more other crystalline forms, i.e., the purity of the crystalline form is at least 80%, at least 85%, at least 90%, at least 93%, at least 95%, at least 98%, at least 99%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, or at least 99.9%, or the crystalline form contains other crystalline forms, but the percentage of the other crystalline forms relative to the total volume or weight of the crystalline form is less than 20%, less than 10%, less than 5%, less than 3%, less than 1%, less than 0.5%, less than 0.1%, or less than 0.01%.

[0076] "Substantially free" refers to the percentage of one or more other crystalline forms relative to the total volume or weight of the crystalline forms being less than 20%, less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, or less than 0.01%.

[0077] "Relative intensity" (or "relative peak height") in an XRPD pattern refers to the ratio of the intensity of the most intense peak to the intensity of other peaks, when the intensity of the most intense peak among all diffraction peaks in an X-ray powder diffraction (XRPD) pattern is taken as 100%.

[0078] In the context of the present invention, whether or not the phrases "about", "approximately" and the like are used, it means within 10%, preferably within 5%, particularly within 1% of a given value or range. Alternatively, for those skilled in the art, the term "about" or "approximately" means within an acceptable standard error of the mean. When a number having a value N is disclosed, any number having a value within N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8% or N+ / -10% is expressly disclosed, where "+ / -" refers to plus or minus.

[0079] In the present invention, "room temperature" refers to about 10 o C~about 40 oIn some embodiments, "room temperature" refers to a temperature of about 20 o C ~ about 30 o In some other examples, "room temperature" refers to a temperature of 20 o C, 22.5 o C, 25 o C, 27.5 o C, etc. Pharmaceutical compositions, formulations, administration and uses of salts of the compounds according to the invention

[0080] The pharmaceutical composition of the present invention is characterized by comprising a salt of a compound represented by formula (I) and a pharma- ceutical acceptable carrier, adjuvant, or excipient. The amount of the salt of the compound in the pharmaceutical composition of the present invention is capable of effectively and detectably treating or alleviating a disease associated with an abnormality in PI3K kinase.

[0081] As described in the present invention, the pharma- ceutically acceptable composition of the present invention further comprises a pharma- ceutically acceptable carrier, adjuvant, or excipient, which may be used in the present invention includes any solvent, diluent, or other liquid excipient, dispersing or suspending agent, surfactant, isotonicity agent, thickener, emulsifier, preservative, solid binder, or lubricant, etc., suitable for a particular target dosage form. As described in the literature of Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed.DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York, the contents of which taken together show that different carriers can be applied to the formulation of pharma- ceutical acceptable compositions and their known manufacturing methods. Except insofar as any conventional carrier medium is incompatible with the salt of the compound of the present invention or its crystalline form A, e.g., gives rise to any undesirable biological effect or interacts in a deleterious manner with any other component of the pharma- ceutically acceptable composition, their use is within the scope of the present invention.

[0082] Pharmaceutically acceptable carrier substances include ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins (e.g. human serum proteins), buffer substances (e.g. phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g. protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylic esters, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars (e.g. lactose, glucose and sucrose), starches (e.g. corn starch and potato starch), cellulose and its derivatives (e.g. carboxymethylcellulose sodium). Examples of suitable carriers include, but are not limited to, cellulose acetate, ethylcellulose, ethylcellulose and cellulose acetate), gum powder, malt, gelatin, talc powder, excipients (e.g., cocoa butter and suppository wax), oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil), diol compounds (e.g., propylene glycol and polyethylene glycol), esters (e.g., ethyl oleate and ethyl laurate), agar, buffers (e.g., magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline solution, Ringer's solution, ethanol, phosphate buffer solution, other non-toxic and suitable lubricants (e.g., sodium lauryl sulfate and magnesium stearate), colorants, release agents, coating agents, sweeteners, flavorings, fragrances, preservatives and antioxidants.

[0083] The pharmaceutical compositions of the present invention may be in the form of capsules, tablets, pills, powders, granules, and aqueous suspensions or solutions and may be administered orally, by injection, aerosol inhalation, topically, rectally, nasally, sublingually, intravaginally, or by an implantable drug injection device.

[0084] Oral administration can be in the form of tablets, pills, capsules, dispersible powders, granules or suspensions, syrups, elixirs, etc., and topical administration can be in the form of ointments, gels, drug-containing tapes, etc.

[0085] The salt or crystalline form of the present invention is preferably prepared in a dosage unit form depending on the formulation method for reducing the dosage amount and uniformity of the dose. The term "dosage unit form" herein refers to a physically separate unit of a pharmaceutical agent required for the proper treatment of a patient. However, it should be understood that the total daily dosage of the salt of the compound of formula (I) of the present invention or a crystalline form thereof, or the pharmaceutical composition of the present invention, is determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level is determined for any particular patient or organism by many factors, including the disease and severity of the disease being treated, the activity of the specific salt or crystalline form of the compound, the specific composition used, the age, weight, health, sex, and dietary habits of the patient, the time of administration, the route of administration, the excretion rate of the specific salt or crystalline form of the compound used, the duration of treatment, the co-administration of pharmaceutical agents or combinations with salts or crystalline forms of compounds having special effects, and several other factors known in the pharmaceutical art.

[0086] The effective dosage of the active ingredient used may vary depending on the salt of the compound or its crystalline form used, the mode of administration and the severity of the disease being treated. In general, however, the salt of the compound of the present invention or its crystalline form can achieve the desired effect when administered at a dosage of approximately 0.25-1000 mg / kg of animal body weight daily, preferably administered in 2-4 divided doses daily or administered in a sustained release manner. For most large mammals, the total daily dosage is approximately 1-100 mg / kg, preferably approximately 2-80 mg / kg of the salt of the active compound or its crystalline form. A suitable dosage form for internal administration contains approximately 0.25-500 mg of the salt of the active compound or its crystalline form intimately mixed with a solid or liquid pharma- ceutically acceptable carrier. This dosage regimen can be adjusted to provide the optimal therapeutic response. Also, multiple divided doses can be administered daily or the dosage can be proportionally reduced depending on the treatment situation.

[0087] The salt of the compound according to the present invention or a crystalline form thereof, and the pharmaceutical composition of the present invention can regulate the stability and / or activity of PI3K kinase by inhibiting the activity of PI3K kinase, and can activate PI3K to regulate gene expression. The salt of the compound according to the present invention or a crystalline form thereof, or the pharmaceutical composition can be used in a method for treating, preemptively treating, or delaying the onset or development of PI3K kinase-related diseases, including but not limited to hematological malignancies.

[0088] Specifically, the salt of the compound according to the present invention or a crystalline form thereof can be used to inhibit the activity of PI3K kinase. By administering the salt of the compound according to the present invention or a crystalline form thereof, diseases associated with abnormal expression of PI3K kinase can be prevented, preliminarily treated or treated, such as asthma, chronic obstructive pulmonary disease (COPD), viral airway infection, viral respiratory disease exacerbation, aspergillosis, leishmaniasis, allergic rhinitis, allergic dermatitis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, thrombosis, atherosclerosis, hematological malignancies, neurodegenerative diseases, pancreatitis, multiple organ failure, renal diseases, platelet aggregation, cancer, sperm motility, transplant rejection, lung injury, systemic inflammatory pain, diabetic neuropathy, chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), hairy lymphoma, and the like. These include: myeloma, idiopathic myeloma, pulmonary myeloma, pulmonary leukemia, myelofibrosis, myelofibrosis, myelofibrosis, myelofibrosis, myelofibrosis, myelofibrosis, myelofibrosis, myelofibrosis, myelomatous myeloma, myelomatous myeloma, myelomatous myeloma, myelomatous myeloma, myelomatous myeloma, myelomatous myelomatosis ... [Brief description of the drawings]

[0089] [Figure 1] 1 is an X-ray powder diffraction (XRPD) pattern of crystalline form A of the sulfate salt of compound of formula (I). [Diagram 2] 1 is a differential scanning calorimetry (DSC) pattern of crystalline form A of the sulfate salt of compound of formula (I). [Diagram 3] 1 is a thermogravimetric analysis (TGA) pattern of crystalline form A of the sulfate salt of compound of formula (I). [Figure 4] 1 is an X-ray powder diffraction (XRPD) pattern of crystalline form A of the hydrogen sulfate salt of compound of formula (I). [Diagram 5] 1 is a differential scanning calorimetry (DSC) pattern of crystalline form A of the hydrogen sulfate salt of compound of formula (I). [Figure 6] 1 is a thermogravimetric analysis (TGA) pattern of crystalline form A of the hydrogen sulfate salt of compound of formula (I). [Figure 7] 1 is an X-ray powder diffraction (XRPD) pattern of crystalline form A of the phosphate salt of compound of formula (I). [Figure 8] 1 is a differential scanning calorimetry (DSC) pattern of crystalline form A of the phosphate salt of compound of formula (I). [Figure 9] 1 is a thermogravimetric analysis (TGA) pattern of crystalline form A of the phosphate salt of compound of formula (I). [Figure 10] 1 is an X-ray powder diffraction (XRPD) pattern of crystalline form A of the p-toluenesulfonate salt of compound of formula (I). [Figure 11] 1 is a differential scanning calorimetry (DSC) pattern of crystalline form A of the p-toluenesulfonate salt of compound of formula (I). [Figure 12] 1 is a thermogravimetric analysis (TGA) pattern of crystalline form A of p-toluenesulfonate salt of compound of formula (I). [Figure 13] 1 is an X-ray powder diffraction (XRPD) pattern of crystalline Form 2 of the free base of compound of formula (I). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0090] The present invention will be further described below by way of examples, but the present invention is not limited to the scope of the above examples.

[0091] The X-ray powder diffraction analysis method used in the present invention is as follows: Obtain X-ray powder diffraction patterns using Cu-Kα radiation (45 KV, 40 mA) on an Empyrean diffractometer. Thin layer the powdered sample on a single crystal silicon sample holder, place it on a rotating sample stage, and analyze it in the range of 3°-40° with a step size of 0.0168°. Collect the data with Data Collector software, process the data with HighScore Plus software, and read the data with Data Viewer software.

[0092] The differential scanning calorimetry (DSC) analysis method used in the present invention is as follows: Differential scanning calorimetry is performed using a TA Q2000 module with a thermal analysis controller. Data is collected and analyzed using TA Instruments Thermal Solutions software. Approximately 1-5 mg of sample is accurately weighed into a specially made aluminum crucible with a cover and heated at 10°C / min using a linear heating device from room temperature to approximately 300°C for analysis. The DSC cell is purged with dry nitrogen gas during use.

[0093] The thermogravimetry analysis (TGA) method used in the present invention is as follows: Thermogravimetry is performed using a TAQ500 module with a thermal analysis controller. Data is collected and analyzed using TA Instruments Thermal Solutions software. Approximately 10 mg of sample is accurately weighed into a platinum sample disk and heated at 10°C / min using a linear heating device to analyze the sample from room temperature to approximately 300°C. The TGA furnace chamber is purged with dry nitrogen gas during use.

[0094] The compound (S)-2-(1-((6-amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl)amino)ethyl)-5-(3-hydroxyprop-1-yn-1-yl)-3-phenylquinazolin-4(3H)-one represented by formula (I) can be obtained by referring to the synthesis method of Example 34 in International Application WO2019143874A1. Working Example Example 1 Crystalline Form A of the Sulfate of the Compound of Formula (I) 1. Preparation of sulfate crystalline form A

[0095] A solution of sulfuric acid (0.11 g, 1.14 mmol) in water (0.3 mL) was added to a solution of (S)-2-(1-((6-amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl)amino)ethyl)-5-(3-hydroxyprop-1-yn-1-yl)-3-phenylquinazolin-4(3H)-one (0.50 g, 1.01 mmol, prepared with reference to Example 5) in methanol (4.0 mL), and the sulfuric acid weighing bottle was rinsed with water (0.2 mL) and then added to the system. The system was heated to reflux and stirred for 20 min, methanol (6.0 mL) was added, and the mixture was stirred under reflux for 4 h, but the system could not be cleared during dissolution. It was cooled to room temperature, filtered, and the filter cake was blow-dried at 60° C. for 12 h to obtain crystalline form A of the sulfate salt as a white solid (0.46 g, 77% yield). 2. Identification of crystalline form A of sulfate

[0096] (1) X-ray powder diffraction (XRPD) analysis by Empyrean for identification using Cu-Kα radiation at 5.37°, 6.20°, 6.90°, 8.74°, 10.77°, 10.99°, 11.82°, 12.45°, 15.61°, 16.51°, 16.60°, 17.08°, 17.57°, 17.91°, 18.62°, 19.18°, 20.10°, 20.50°, 20.91°, It had characteristic peaks represented at angles 2θ of 21.64°, 22.24°, 23.31°, 23.70°, 23.83°, 24.41°, 24.87°, 25.18°, 25.59°, 25.95°, 27.15°, 27.55°, 27.98°, 28.19°, 28.51°, 29.63°, 30.19°, 31.83°, 36.11° and 41.55° with a tolerance of ±0.2°.

[0097] (2) For differential scanning calorimetry (DSC) analysis identification by TA Q2000, the scanning rate was 10°C / min, and the obtained DSC curve included endothermic peaks at 105.07°C and 185.08°C and an exothermic peak at 233.00°C, substantially as shown in Figure 2, with a tolerance of ±3°C.

[0098] (3) Thermogravimetric analysis (TGA) identification by TA Q500, the heating rate was 10°C / min, and the obtained TGA curve was substantially as shown in Figure 3, which included a weight loss of 6.408% when heated to 100.06°C, and a weight loss of 3.058% when continuously heated from 100.06°C to 205.23°C, with a tolerance of ±0.1%. Example 2 Crystalline Form A of the hydrogen sulfate salt of the compound of formula (I) 1. Preparation of hydrogen sulfate crystal form A

[0099] A solution of sulfuric acid (0.11 g, 1.12 mmol) in water (0.3 mL) was added to a solution of (S)-2-(1-((6-amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl)amino)ethyl)-5-(3-hydroxyprop-1-yn-1-yl)-3-phenylquinazolin-4(3H)-one (0.50 g, 1.01 mmol, prepared with reference to Example 5) in acetonitrile (4.0 mL), and the sulfuric acid weighing bottle was rinsed with water (0.2 mL) and then added to the system. The system was heated to reflux and stirred for 20 min, acetonitrile (6.0 mL) was added, and the mixture was stirred under reflux for 4 h, and the system became clear during dissolution. It was cooled to room temperature, filtered, rinsed with acetonitrile (2.0 mL), and the filter cake was blow-dried at 60° C. for 12 h to give crystalline form A of the hydrogen sulfate salt as a pale yellow solid (0.60 g, 100% yield). 2. Identification of crystal form A of hydrogen sulfate

[0100] (1) X-ray powder diffraction (XRPD) analysis identification by Empyrean using Cu-Kα radiation at 6.49°, 6.81°, 8.75°, 11.54°, 13.06°, 13.64°, 13.79°, 14.19°, 14.70°, 16.24°, 17.11°, 18.10°, 18.59°, 19.48°, 19.68°, 21.20°, 21.52°, 21.99°, 23.02°, 23.29°, 24.07°, 25.09°, 26.26°, 27.04°, 28.01°, 29.06°, 30.09°, 31.06°, 32.02°, 33.09°, 34.02°, 35.02°, 36.02°, 37.02°, 38.02°, 39.02°, 40.02°, 41.02°, 42.02°, 43.02°, 44.02°, 45.02°, 46.02°, 47.02°, 48.02°, 49.02°, 50.02°, 51.02°, 52.02°, 53.02°, 54.02°, 55.02°, 56.02°, 57.02°, 58.02°, 59.02°, 60.02°, 61.02°, 62.02°, 63.02°, 64.02° It had characteristic peaks represented by angles 2θ of 0.25°, 24.05°, 24.57°, 25.57°, 25.99°, 26.32°, 26.90° 27.08°, 27.91°, 28.61°, 29.48°, 31.02°, 32.88°, 33.53°, 35.20°, 38.45°, 39.52°, 40.58°, 41.72° and 43.81° with a tolerance of ±0.2°.

[0101] (2) For differential scanning calorimetry (DSC) analysis identification by TA Q2000, the scanning rate was 10°C / min, and the obtained DSC curve included an endothermic peak at 196.02°C and exothermic peaks at 201.85°C and 246.30°C, substantially as shown in Figure 5, with a tolerance of ±3°C.

[0102] (3) Thermogravimetric analysis (TGA) identification by TA Q500, the heating rate was 10°C / min, and the obtained TGA curve was substantially as shown in Figure 6, which included a weight loss of 6.869% when heated to 137.49°C, and a weight loss of 2.873% when continuously heated from 137.49°C to 215.40°C, with a tolerance of ±0.1%. Example 3 Crystalline Form A of the Phosphate of the Compound of Formula (I) 1. Preparation of phosphate crystal form A

[0103] A solution of (S)-2-(1-((6-amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl)amino)ethyl)-5-(3-hydroxyprop-1-yn-1-yl)-3-phenylquinazolin-4(3H)-one (0.50 g, 1.02 mmol, prepared with reference to Example 5) in acetonitrile (4.0 mL) was added with a solution of sulfuric acid (0.11 g, 1.16 mmol) in water (0.3 mL), and the phosphoric acid weighing bottle was rinsed with water (0.2 mL) and then added to the system. The system was heated to reflux and stirred for 20 min, acetonitrile (6.0 mL) was added, and the mixture was stirred under reflux for 4 h, but the system could not be cleared during dissolution. It was cooled to room temperature, filtered, rinsed with acetonitrile (2.0 mL), and the filter cake was blown dry at 60° C. for 12 hours to give crystalline form A of the phosphate salt as a white solid (0.57 g, 95% yield). 2. Identification of phosphate crystal form A

[0104] (1) X-ray powder diffraction (XRPD) analysis identification by Empyrean using Cu-Kα radiation at 5.02°, 5.95°, 7.41°, 8.15°, 9.27°, 9.93°, 11.06°, 11.27°, 12.02°, 12.82°, 13.30°, 14.87°, 16.62°, 17.09°, 18.11°, 1 It had characteristic peaks represented at angles 2θ of 9.32°, 19.79°, 20.69°, 21.22°, 22.27°, 23.41°, 24.38°, 25.47°, 26.58°, 27.43°, 27.87°, 28.32°, 29.45°, 30.34°, 31.62° and 33.79° with a tolerance of ±0.2°.

[0105] (2) For differential scanning calorimetry (DSC) analysis identification by TA Q2000, the scan rate was 10°C / min, and the obtained DSC curve contained an exothermic peak at 205.70°C, substantially as shown in Figure 8, with a tolerance of ±3°C.

[0106] (3) For thermogravimetric analysis (TGA) identification by TA Q500, the heating rate was 10°C / min, and the obtained TGA curve contained a weight loss of 3.294% when heated to 119.39°C, with a tolerance of ±0.1%, substantially as shown in Figure 9. Example 4 Crystalline Form A of p-toluenesulfonate of compound of formula (I) 1. Preparation of crystalline form A of p-toluenesulfonate

[0107] A solution of p-toluenesulfonic acid monohydrate (16.13 g, 84.80 mmol) in water (60 mL) was added to a suspension of (S)-2-(1-((6-amino-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl)amino)ethyl)-5-(3-hydroxyprop-1-yn-1-yl)-3-phenylquinazolin-4(3H)-one (38.00 g, 76.85 mmol, prepared with reference to Example 5), ethanol (230 mL) and water (150 mL), and the bottle containing the acid solution was washed with water (20 mL) and then added to the system. The system was heated to reflux and stirred for 2 h, then cooled to room temperature and stirred for 30 min, water (690 mL) was added, stirring was continued for 1 h, filtered, the reaction flask was washed with ethanol / water (v / v=1 / 4, 50 mL), and the washings were filtered together. The filter cake was blown dry at 60° C. overnight to give a pale yellow solid (45.8 g, 89.4% yield). 2. Identification of crystal form A of p-toluenesulfonate

[0108] (1) X-ray powder diffraction (XRPD) analysis by Empyrean: Identification using Cu-Kα radiation at 6.49°, 9.51°, 10.04°, 10.51°, 10.72°, 11.71°, 12.65°, 13.20°, 14.10°, 14.35°, 14.94°, 15.88°, 16.44°, 16.82°, 17.21°, 17.86°, 18.34°, 19.08°, 19.57°, 20.17°, 20.65°, 20.84°, 21.26°, 21.87°, 22.27°, 22.44°, 22.84° , 23.19°, 23.55°, 24.25°, 24.81°, 25.59°, 26.21°, 26.91°, 27.38°, 27.93°, 28.26°, 28.82°, 29.16°, 29.61°, 30.19°, 31.30°, 31.90°, 32.44°, 33.21°, 33.94°, 35.32°, 36.44°, 37.30°, 37.61°, 38.59°, 39.54°, 42.25°, 44.61° and 47.32° in angle 2θ with a tolerance of ±0.2°.

[0109] (2) For differential scanning calorimetry (DSC) analysis identification by TA Q2000, the scanning rate was 10°C / min, and the obtained DSC curve included an endothermic peak at 73.89°C and an exothermic peak at 231.68°C, substantially as shown in Figure 11, with a tolerance of ±3°C.

[0110] (3) For thermogravimetric analysis (TGA) identification by TA Q500, the heating rate was 10°C / min, and the obtained TGA curve was substantially as shown in Figure 12, containing a weight loss of 1.709% when heated to 150.10°C, with a tolerance of ±0.1%. Example 5 Crystalline Form 2 of the Free Base of the Compound of Formula (I) 1. Preparation of crystalline form 2 of the free base of the compound represented by formula (I)

[0111] This was obtained by reference to the synthesis method of Example 34 in International Application WO2019143874A1. 2. Identification of Crystalline Form 2 of the Free Base of the Compound of Formula (I)

[0112] X-ray powder diffraction (XRPD) analysis identification by Empyrean using Cu-Kα radiation. The X-ray powder diffraction pattern of the crystalline form 2 of the free base prepared by the process of this example is substantially as shown in FIG. Example 6 Pharmacokinetic studies of the salts according to the invention Experimental method for measuring the pharmacokinetics of the salt and free base of the present invention in Beagle dogs

[0113] The salt of the compound represented by formula (I) according to the present invention and crystalline form 2 of the free base of the compound represented by formula (I) were each filled into capsules and used for oral administration.

[0114] Male Beagle dogs weighing 8-12 kg were divided into two groups, with three dogs in each group. Capsules containing the test sample were orally administered at a dose of 10 mg / kg, and blood was collected at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24 h. Based on the sample concentrations, a standard curve with an appropriate range was established, and the concentrations of the test samples in the plasma samples were measured using an AB SCIEX API4000 LC-MS / MS in MRM mode, and quantitative analysis was performed. Based on the drug concentration-time curves, the pharmacokinetic parameters were calculated using a non-compartmental model with WinNonLin 6.3 software. The experimental results are shown in Table 1. Table 1. Pharmacokinetic data of the salt and free base of the present invention in Beagle dogs. [Table 1]

[0115] In conclusion, the salts described in the present invention have excellent pharmacokinetic properties in the body of Beagle dogs, and in particular, the exposure amount of the crystalline form A of the p-toluenesulfonate salt in the body of Beagle dogs is high, the drug blood concentration is also high, and the salts have excellent pharmacokinetic properties. Experimental method for measuring the pharmacokinetics of the salt and free base of the present invention in SD rats

[0116] The salt of the compound represented by formula (I) and the crystalline form 2 of the free base of the compound represented by formula (I) according to the present invention were respectively formulated into a suspension using PEG400, and the test samples were administered orally at 200 mg / kg to SD rats, with three animals in each group. Blood was collected at 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24 h after administration. A standard curve with an appropriate range was established based on the sample concentration, and the concentration of the test sample in the plasma sample was measured using AB SCIEX API4000 LC-MS / MS in MRM mode, and quantitative analysis was performed. Based on the drug concentration-time curve, the pharmacokinetic parameters were calculated using a non-compartmental model with WinNonLin 6.3 software. The experimental results are shown in Table 2. Table 2. Pharmacokinetics data of the salt and free base crystalline form 2 according to the present invention in male SD rats. [Table 2]

[0117] Regarding the experimental conclusions, As can be seen from Table 2, the salts described in the present invention have high exposure in the bodies of SD rats and excellent pharmacokinetic properties. Example 7 Stability study of the salts described in the present invention Experimental Method

[0118] For the high temperature experiment, an appropriate amount of the salt of the compound represented by formula (I) according to the present invention was placed in a flat weighing bottle, spread into a thin layer with a thickness of 3 mm or less, and left at two temperatures of 60°C and 40°C for 30 days, and samples were taken on the 5th, 10th and 30th days to observe the color change of the samples, and the purity of the samples was measured by HPLC.

[0119] For the high humidity experiment, an appropriate amount of the salt of the compound represented by formula (I) described in the present invention was placed in a flat weighing bottle, spread into a thin layer with a thickness of 3 mm or less, and left for 30 days under two conditions of 25°C, RH 90%±5% and 25°C, RH 75%±5%, respectively, and samples were taken on the 5th, 10th and 30th days, and the color change of the samples was observed, and the purity of the samples was measured by HPLC.

[0120] For the light irradiation experiment, a suitable amount of the salt of the compound represented by formula (I) described in the present invention was placed in a flat weighing bottle, spread into a thin layer with a thickness of 3 mm or less, and placed in a light irradiation test box (with ultraviolet light) with an open end, and exposed to an illuminance of 4500±500lx and ultraviolet light ≧0.7w / m 2 The samples were left for 30 days under the above conditions, and samples were taken on the 5th, 10th, and 30th days. The color change of the samples was observed, and the purity of the samples was measured by HPLC.

[0121] For the long-term stability test, the test sample was placed in a single-layer PE bag, wrapped in an aluminum foil bag, and then a KD-20 oxygen absorber was installed. The sample was then evacuated and filled with nitrogen gas, after which it was heat sealed and packaged. The test was then carried out over a long period at a low temperature of 5℃±3℃, and the color change of the sample was observed, and the purity of the sample was measured by HPLC.

[0122] The experimental results are shown in Table 3. Table 3. Experimental results of stability of the crystal form A of the p-toluenesulfonate salt according to the present invention - high temperature, high humidity, long-term stability [Table 3]

[0123] As can be seen from the experimental results, the salt according to the present invention is stable under high temperature and high humidity conditions, and in particular, the appearance and purity of the crystalline form A of the p-toluenesulfonic acid salt according to the present invention both do not change obviously.

[0124] Under the conditions of long-term stability testing, neither the appearance nor the purity of the crystalline form A of the p-toluenesulfonate salt described in the present invention changes obviously.

[0125] From the above, the crystalline form A of the p-toluenesulfonate salt according to the present invention is highly stable and suitable for pharmaceutical use. The above is a basic description of the concept of the present invention, and any equivalent transformation made based on the technical means of the present invention should fall within the protection scope of the present invention.

[0126] In the description of this specification, a description referring to terms such as "one embodiment", "several embodiments", "examples", "specific examples" or "several examples" means that the specific features, structures, materials or characteristics described in combination with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the exemplary expressions of the above terms are not necessarily limited to the same embodiment or example. In addition, the specific features, structures, materials or characteristics described can be appropriately combined in any one or more embodiments or examples. In addition, if not mutually inconsistent, a person skilled in the art can combine or combine different embodiments or examples described in this specification and features of different embodiments or examples.

[0127] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are illustrative and should not be construed as limiting the present invention, and that those skilled in the art may make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. A salt of the compound of formula (I) which is a sulfate, hydrogen sulfate, phosphate or p-toluenesulfonate. 【Chemistry 1】

2. the Sulfate Salt is crystalline form A of the Sulfate Salt, and the X-ray powder diffraction pattern of crystalline form A of the Sulfate Salt is characterized by comprising diffraction peaks at 2θ angles of 5.37°±0.2°, 6.90°±0.2°, 11.82°±0.2°, 16.51°±0.2°, 20.50°±0.2°, and 25.95°±0.2°; the hydrogen sulfate salt is crystalline form A of the hydrogen sulfate salt, and the X-ray powder diffraction pattern of the crystalline form A of the hydrogen sulfate salt is characterized by including diffraction peaks at 2θ angles of 6.49°±0.2°, 6.81°±0.2°, 11.54°±0.2°, 13.79°±0.2°, 21.99°±0.2°, 25.99°±0.2°, and 26.32°±0.2°; the phosphate is crystalline form A of the phosphate salt, and the X-ray powder diffraction pattern of the crystalline form A of the phosphate salt is characterized by comprising diffraction peaks at 2θ angles of 7.41°±0.2°, 11.06°±0.2°, 11.27°±0.2°, 16.62°±0.2°, 19.32°±0.2°, 22.27°±0.2° and 24.38°±0.2°; or The salt according to claim 1, wherein the p-toluenesulfonate is crystalline form A of the p-toluenesulfonate, and the X-ray powder diffraction pattern of the crystalline form A of the p-toluenesulfonate includes diffraction peaks at 2θ angles of 6.49°±0.2°, 10.04°±0.2°, 11.71°±0.2°, 14.10°±0.2°, 17.86°±0.2°, 20.84°±0.2° and 21.87°±0.2°.

3. the Sulfate Salt is crystalline form A of the Sulfate Salt, and the X-ray powder diffraction pattern of crystalline form A of the Sulfate Salt is characterized by comprising diffraction peaks at 2θ angles of 5.37°±0.2°, 6.20°±0.2°, 6.90°±0.2°, 11.82°±0.2°, 16.51°±0.2°, 16.60°±0.2°, 19.18°±0.2°, 20.10°±0.2°, 20.50°±0.2°, 21.64°±0.2°, 25.95°±0.2°, and 29.63°±0.2°; the hydrogen sulfate salt is crystalline form A of the hydrogen sulfate salt, and the X-ray powder diffraction pattern of the crystalline form A of the hydrogen sulfate salt is characterized by comprising diffraction peaks at 2θ angles of 6.49°±0.2°, 6.81°±0.2°, 8.75°±0.2°, 11.54°±0.2°, 13.06°±0.2°, 13.64°±0.2°, 13.79°±0.2°, 16.24°±0.2°, 17.11°±0.2°, 21.99°±0.2°, 25.99°±0.2°, 26.32°±0.2°, 26.90°±0.2° and 27.91°±0.2°; the phosphate is crystalline form A of the phosphate salt, and the X-ray powder diffraction pattern of crystalline form A of the phosphate salt is characterized by comprising diffraction peaks at 2θ angles of 7.41°±0.2°, 9.27°±0.2°, 11.06°±0.2°, 11.27°±0.2°, 12.02°±0.2°, 13.30°±0.2°, 16.62°±0.2°, 19.32°±0.2°, 20.69°±0.2°, 22.27°±0.2°, 24.38°±0.2°, 26.58°±0.2°, 27.87°±0.2° and 28.32°±0.2°; or 3. The salt according to claim 1 or 2, wherein the p-toluenesulfonate is crystalline form A of p-toluenesulfonate, and the X-ray powder diffraction pattern of the crystalline form A of p-toluenesulfonate comprises diffraction peaks at 2θ angles of 6.49°±0.2°, 9.51°±0.2°, 10.04°±0.2°, 10.51°±0.2°, 10.72°±0.2°, 11.71°±0.2°, 14.10°±0.2°, 14.94°±0.2°, 16.82°±0.2°, 17.86°±0.2°, 20.84°±0.2°, 21.87°±0.2°, 26.20°±0.2° and 28.26°±0.2°.

4. The Sulfate Salt is crystalline form A of the Sulfate Salt, and the X-ray powder diffraction pattern of crystalline form A of the Sulfate Salt is 5.37°±0.2°, 6.20°±0.2°, 6.90°±0.2°, 8.74°±0.2°, 10.77°±0.2°, 10.99°±0.2°, 11.82°±0.2°, 12.45°±0.2°. °, 15.61°±0.2°, 16.51°±0.2°, 16.60°±0.2°, 17.08°±0.2°, 17.57°±0.2°, 17.91°±0.2°, 18.62°±0.2°, 19.18°±0.2°, 20.10°±0.2°, 20.50°±0.2°, 20.91°±0.2 °, 21.64°±0.2°, 22.24°±0.2°, 23.31°±0.2°, 23.70°±0.2°, 23.83°±0.2°, 24.41°±0.2°, 24.87°±0.2°, 25.18°±0.2°, 25.59°±0.2°, 25.95°±0.2°, 27.15°±0.2 and comprising diffraction peaks at 2θ angles of 27.55°±0.2°, 27.98°±0.2°, 28.19°±0.2°, 28.51°±0.2°, 29.63°±0.2°, 30.19°±0.2°, 31.83°±0.2°, 36.11°±0.2° and 41.55°±0.2°; The hydrogen sulfate salt is crystalline form A of the hydrogen sulfate salt, and the X-ray powder diffraction pattern of the crystalline form A of the hydrogen sulfate salt is 6.49°±0.2°, 6.81°±0.2°, 8.75°±0.2°, 11.54°±0.2°, 13.06°±0.2°, 13.64°±0.2°, 13.79°±0.2°, 14.19°±0.2°, 14.70°±0.2°, 16.24°±0.2°, 17.11°±0.2°, 18.10°±0.2°, 18.59°±0.2°, 19.48°±0.2°, 19.68°±0.2°, 21.20°±0.2°, 21.52°±0.2°, 21.99°±0.2°, 23.25°±0.2°, 24.05°±0.2°, 24.57°±0.2°, 25.57°±0.2°, 25.99°±0.2°, 26.32°±0.2°, 26.90°±0.2°, 27.08°±0.2°, 27.91°±0.2°, 28.61°±0.2°, 29.48°±0.2° , 31.02°±0.2°, 32.88°±0.2°, 33.53°±0.2°, 35.20°±0.2°, 38.45°±0.2°, 39.52°±0.2°, 40.58°±0.2°, 41.72°±0.2° and 43.81°±0.2°; The phosphate is crystalline form A of the phosphate, and the X-ray powder diffraction pattern of the crystalline form A of the phosphate is 5.02°±0.2°, 5.95°±0.2°, 7.41°±0.2°, 8.15°±0.2°, 9.27°±0.2°, 9.93°±0.2°, 11.06°±0.2°, 11.27°±0.2°, 12.02°±0.2°, 12.82°±0.2°, 13.30°±0.2°, 14.87°±0.2°, 16.62°±0.2°, 17.09°±0.2°, 18.11°±0.2° , 19.32°±0.2°, 19.79°±0.2°, 20.69°±0.2°, 21.22°±0.2°, 22.27°±0.2°, 23.41°±0.2°, 24.38°±0.2°, 25.47°±0.2°, 26.58°±0.2°, 27.43°±0.2°, 27.87°±0.2°, 28.32°±0.2°, 29.45°±0.2°, 30.34°±0.2°, 31.62°±0.2° and 33.79°±0.2°, or The p-toluenesulfonate salt is crystalline form A of p-toluenesulfonate, and the X-ray powder diffraction pattern of the crystalline form A of p-toluenesulfonate is 6.49°±0.2°, 9.51°±0.2°, 10.04°±0.2°, 10.51°±0.2°, 10.72°±0.2°, 11.71°±0.2°, 12.65°±0.2°, 13.20°±0.2°, 14.10°±0.2°, 14.35°±0.2°, 14.94°±0.2°, 15.08°±0.2°, 16.06°±0.2°, 17.05°±0.2°, 18.04°±0.2°, 19.03°±0.2°, 20.08°±0.2°, 21.09°±0.2°, 22.06°±0.2°, 23.04°±0.2°, 24.08°±0.2°, 25.09°±0.2°, 26.08°±0.2°, 27.06°±0.2°, 28.08°±0.2°, 29.08°±0.2°, 30.08°±0.2°, 31.08°±0.2°, 32.08°±0.2°, 33.08°±0.2°, 34.08°±0.2°, 35.08°±0.2°, 36.08°±0.2°, 37.08°±0.2°, 38.08°±0.2°, 39.08°±0.2° ±0.2°, 15.88°±0.2°, 16.44°±0.2°, 16.82°±0.2°, 17.21°±0.2°, 17.86°±0.2°, 18.34°±0.2°, 19.08°±0.2°, 19.57°±0.2°, 20.17°±0.2°, 20.65°±0.2°, 20.84°±0.2°, 21.26°±0.2°, 21.87°±0.2°, 22.27°±0.2°, 22.44°±0.2°, 22.84°±0.2°, 23.08°±0.2°, 24.08°±0.2°, 25.08°±0.2°, 26.08°±0.2°, 27.08°±0.2°, 28.08°±0.2°, 29.08°±0.2°, 30.08°±0.2°, 31.08°±0.2°, 32.08°±0.2°, 33.08°±0.2°, 34.08°±0.2°, 35.08°±0.2°, 36.08°±0.2°, 37.08°±0.2°, 38.08°±0.2°, 39.08°±0.2°, 40.08°±0.2°, 41.08°±0.2°, 42.08°±0.2°, 43.08°±0.2°, 44.08°±0.2°, 45.08°±0.2 23.19°±0.2°, 23.55°±0.2°, 24.25°±0.2°, 24.81°±0.2°, 25.59°±0.2°, 26.21°±0.2°, 26.91°±0.2°, 27.38°±0.2°, 27.93°±0.2°, 28.26°±0.2°, 28.82°±0.2°, 29.16°±0.2°, 29.61°±0.2°, 30.19°±0.2°, 31.30°±0.2°, 31.90°±0.2°, 32.19°±0.2°, 33.21°±0.2°, 34.25°±0.2°, 34.81°±0.2°, 35.59°±0.2°, 36.21°±0.2°, 36.91°±0.2°, 37.38°±0.2°, 37.93°±0.2°, 38.26°±0.2°, 38.82°±0.2°, 39.16°±0.2°, 39.61°±0.2°, 40.19°±0.2°, 41.30°±0.2°, 42.19°±0.2°, 43.21°±0.2°, 44.21°±0.2°, 45.21°±0.2°, 46.21°±0.2°, 47.21°±0.2°, 47.21°±0.2°, 48.21°±0.2°, 49.

4. The salt according to claim 1 , characterized in that it comprises diffraction peaks at 2θ angles of 32.44°±0.2°, 32.44°±0.2°, 33.21°±0.2°, 33.94°±0.2°, 35.32°±0.2°, 36.44°±0.2°, 37.30°±0.2°, 37.61°±0.2°, 38.59°±0.2°, 39.54°±0.2°, 42.25°±0.2°, 44.61°±0.2° and 47.32°±0.2°.

5. the Sulfate Salt is crystalline form A of the Sulfate Salt, and crystalline form A of the Sulfate Salt is characterized by having an X-ray powder diffraction pattern substantially as shown in FIG. the hydrogen sulfate salt is crystalline form A of the hydrogen sulfate salt, the crystalline form A of the hydrogen sulfate salt being characterized by having an X-ray powder diffraction pattern substantially as shown in FIG. the Phosphate Salt is in crystalline form A of the Phosphate Salt, said crystalline form A of the Phosphate Salt being characterised by an X-ray powder diffraction pattern substantially as shown in Figure 7; or The salt according to any one of claims 1 to 4, wherein the p-toluenesulfonate is crystalline form A of the p-toluenesulfonate, and the crystalline form A of the p-toluenesulfonate is characterized in that it has an X-ray powder diffraction pattern substantially as shown in Figure 10.

6. the Sulfate Salt is in crystalline form A of the Sulfate Salt, and the differential scanning calorimetry pattern of the crystalline form A of the Sulfate Salt is characterized by including endothermic peaks at 105.07°C±3°C and 185.08°C±3°C and an exothermic peak at 233.00°C±3°C; The hydrogen sulfate salt is a crystalline form A of the hydrogen sulfate salt, and the differential scanning calorimetry pattern of the crystalline form A of the hydrogen sulfate salt is characterized by including an endothermic peak at 196.02°C±3°C and exothermic peaks at 201.85°C±3°C and 246.30°C±3°C; The phosphate is in crystalline form A of the phosphate, and the differential scanning calorimetry pattern of the crystalline form A of the phosphate is characterized by including an exothermic peak at 205.70°C ± 3°C; or The salt according to any one of claims 1 to 5, wherein the p-toluenesulfonate is in crystalline form A of the p-toluenesulfonate, and the differential scanning calorimetry pattern of the crystalline form A of the p-toluenesulfonate includes an endothermic peak at 73.89°C ± 3°C and an exothermic peak at 231.68°C ± 3°C.

7. the Sulfate Salt is crystalline form A of the Sulfate Salt, and the crystalline form A of the Sulfate Salt is characterized by having a differential scanning calorimetry pattern substantially as shown in FIG. the hydrogen sulfate salt is crystalline form A of the hydrogen sulfate salt, said crystalline form A of the hydrogen sulfate salt being characterized by having a differential scanning calorimetry pattern substantially as shown in FIG. the Phosphate Salt is in crystalline form A of the Phosphate Salt, the crystalline form A of the Phosphate Salt being characterised by having a differential scanning calorimetry pattern substantially as shown in Figure 8; or The salt according to any one of claims 1 to 6, wherein the p-toluenesulfonate salt is crystalline form A of the p-toluenesulfonate salt, and the crystalline form A of the p-toluenesulfonate salt is characterized in that it has a differential scanning calorimetry pattern substantially as shown in Figure 11.

8. the Sulfate Salt is a crystalline form A of the Sulfate Salt, and the crystalline form A of the Sulfate Salt is characterized by having a thermogravimetric analysis pattern substantially as shown in FIG. the hydrogen sulfate salt is a crystalline form A of the hydrogen sulfate salt, the crystalline form A of the hydrogen sulfate salt being characterized by having a thermogravimetric analysis pattern substantially as shown in FIG. the phosphate is crystalline form A of the phosphate, the crystalline form A of the phosphate being characterized by having a thermogravimetric analysis pattern substantially as shown in FIG. 9; or The salt according to any one of claims 1 to 7, wherein the p-toluenesulfonate is crystalline form A of the p-toluenesulfonate, and the crystalline form A of the p-toluenesulfonate has a thermogravimetric analysis pattern substantially as shown in Figure 12.

9. A pharmaceutical composition comprising the salt of any one of claims 1 to 8 and a pharma- ceutically acceptable carrier, excipient, diluent, adjuvant, or combination thereof.

10. Use of the salt according to any one of claims 1 to 8 or the pharmaceutical composition according to claim 9 in the manufacture of a medicament for preventing, treating, curing or alleviating a disease associated with an abnormality in PI3K kinase.

11. The use according to claim 10, wherein the disease associated with abnormal PI3K kinase is a respiratory disease, a viral infection, a non-viral airway infection, an allergic disease, an autoimmune disease, an inflammatory disease, a cardiovascular disease, a hematological malignancy, a neurodegenerative disease, pancreatitis, multiple organ failure, a kidney disease, platelet aggregation, cancer, transplant rejection, lung injury or pain.

12. The diseases associated with the abnormality of PI3K kinase include asthma, chronic obstructive pulmonary disease, viral airway infection, aggravation of viral respiratory disease, aspergillosis, leishmaniasis, allergic rhinitis, allergic dermatitis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, thrombosis, atherosclerosis, hematological malignancies, neurodegenerative diseases, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, cancer, transplant rejection, lung injury, systemic inflammatory pain, diabetic neuropathy, chronic lymphocytic leukemia, non-Hodgkin's lymphoma, hairy cell leukemia, mantle cell lymphoma, Burkitt's lymphoma, small lymphocyte lymphoma, and leukemia.

11. The use according to claim 10, wherein the tumor is selected from the group consisting of myeloma, follicular lymphoma, lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, prolymphocytic leukemia, acute lymphoblastic leukemia, myelofibrosis, mucosa-associated lymphoid tissue lymphoma, B-cell lymphoma, thymic-mediastinal large B-cell lymphoma, lymphomatoid granulomatosis, splenic marginal zone lymphoma, primary effusion lymphoma, intravascular large B-cell lymphoma, plasma cell leukemia, extramedullary plasmacytoma, smoldering myeloma, monoclonal gammopathy, and B-cell type lymphoma.

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