Salts of aminopyrimidines and uses thereof

Abstract

The present invention relates to salts of aminopyrimidine compounds and uses thereof. In particular, the present invention relates to salts 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 pharmaceutical compositions comprising said salts, further to their use in the manufacture of a medicament for the treatment and prevention of diseases associated with PI3K kinase abnormalities.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to salts of aminopyrimidine compounds and their uses, specifically to salts 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-phenylquinazoline-4(3H)-one and pharmaceutical compositions comprising said salts, and further to their use in the preparation of pharmaceuticals. Background Technology

[0002] Phosphoinositol 3-kinases (PI3K kinases or PI3Ks), as a family of lipid kinases, play an important regulatory role in many cellular processes, such as cell survival, proliferation, and differentiation. As major influencing factors in the downstream transduction of receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs), PI3Ks transduce signals from various growth factors and factors into the cell through the production of phospholipids, activating serine-threonine protein kinase AKT (also known as protein kinase B (PKB)) and other downstream pathways. Tumor suppressor genes or PTEN (homophore phosphatase-tensin) are the most important inverse regulators in the PI3K signaling pathway ("Small-molecule inhibitors of the PI3K signaling network." FutureMed Chem. 2011, 3(5), 549-565).

[0003] To date, eight mammalian PI3Ks have been identified, and based on differences in gene sequence, structure, adaptor molecules, expression, activation mechanisms, and substrates, they can be classified into three classes (I, II, and III). Class I PI3Ks can be further divided into IA and IB classes based on signaling pathways and regulatory proteins. Class IA PI3Ks (PI3Kα, PI3Kβ, and PI3Kδ) are heterodimeric complexes composed of the catalytic subunit p110 (p110α, p110β, and p110δ, respectively) and the regulatory subunit p85 (e.g., p85α, p85β, p55δ, p55α, and p50α). The catalytically active p110 subunit uses ATP to phosphorylate phosphatidylinositol (PI,PtdIns), PI4P, and PI(4,5)P2. These signaling responses are typically delivered via receptor tyrosine kinases (RTKs). In class IB, the PI3Kγ signal is transmitted via G protein-coupled receptors (GPCRs) composed of the catalytic subunit p110γ. The regulatory subunit associated with p110γ is different from that in class IA.

[0004] PI3Kδ signaling has been associated with B cell survival, migration, and activation (Puri, Frontiers in Immunology, 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. By blocking B cell adhesion, survival, activation, and proliferation, PI3Kδ inhibition can impair the ability of B cells to activate T cells, thereby preventing their activation and reducing the secretion of autoantibodies and pro-inflammatory cytokines. Therefore, by virtue of its ability to inhibit B cell activation, PI3Kδ inhibitors are expected to treat B cell-mediated diseases that can be treated by similar methods (such as rituximab-induced B cell depletion). Indeed, PI3Kδ inhibitors have been shown to be effective in mouse models of a variety of autoimmune diseases (such as arthritis) that can also be treated with rituximab (Puri (2012)). Furthermore, innate-like B cells associated with autoimmunity are sensitive to PI3Kδ activity because MZ and B-1 cells are almost nonexistent in mice lacking the p110δ gene (Puri (2012)). PI3Kδ inhibitors reduce the transport and activation of MZ and B-1 cells involved in autoimmune diseases.

[0005] In addition to their potential role in inflammatory diseases, all four class I PI3K subtypes 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). Eighty percent of these mutations are represented by the substitution of one of three amino acids in the helix or kinase domain of the enzyme and result in a significant upregulation of kinase activity, leading to 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). These mutations have not been identified in other PI3K subtypes, but there is evidence that they can promote the occurrence and development of malignant tumors. Consistent overexpression of PI3Kδ has been observed in acute myeloid leukemia (Sujobert et al., Blood, 2005, 106(3):1063-6), and inhibitors of PI3Kδ can prevent the growth of leukemia cells (Billottet et al., Oncogene. 2006, 25(50):6648-59). Increased expression of PI3Kγ has been observed in chronic myeloid leukemia (Hickey et al., J Biol. Chem. 2006, 281(5):2441-50). Alterations in the expression of PI3Kβ, PI3Kγ and PI3Kδ have also been observed in brain cancer, 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 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-phenylquinazoline-4(3H)-one (the compound shown in formula (I)), which can treat or alleviate diseases related to abnormal expression of PI3K kinase, such as hematologic malignancies. This compound suffers from poor solubility, inadequate absorption in animals, and poor stability, which pose significant challenges to subsequent formulation development.

[0007]

[0008] Different salts or solid forms of a drug's active ingredient may possess different properties. Changes in properties due to different salt or solid forms can provide improved formulations, such as ease of synthesis or processing, increased dissolution, or improved stability and shelf life. These property changes can also improve the pharmacological properties of the final formulation, for example, increasing exposure, bioavailability, or prolonging half-life. Summary of the Invention

[0009] This invention provides salts of the compound shown in formula (I). Specifically, this invention provides sulfates, hydrogen sulfates, phosphates, and p-toluenesulfonates of the compound shown in formula (I). The salts of this invention have good stability and good pharmacokinetic properties, thus exhibiting superior drug-like properties.

[0010] Specifically, the present invention relates to salts of compounds of formula (I), pharmaceutical compositions comprising said salts, and their use in the preparation of medicaments for treating or preventing diseases related to abnormal expression of PI3K kinase. The salts of the present invention may also be in solvate form, such as hydrate form.

[0011] On the one hand, the present invention provides a salt of the compound shown in formula (I);

[0012]

[0013] In some embodiments, the salts of the compounds represented by formula (I) of 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, etc.

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

[0015] In some embodiments, the sulfate of the compound represented by formula (I) of the present invention is crystal form A of the sulfate of the compound represented by formula (I).

[0016] In some embodiments, the X-ray powder diffraction pattern of the sulfate form A of the compound of formula (I) of the present invention contains diffraction peaks at the following 2θ angles: 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 other embodiments, the X-ray powder diffraction pattern of the sulfate form A of the compound of formula (I) of the present invention contains the following diffraction peaks at the 2θ angle: 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 other embodiments, the X-ray powder diffraction pattern of the sulfate form A of the compound of formula (I) of the present invention contains the following diffraction peaks at the 2θ angle: 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°, 20.5°±0.2°. 0°±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 0.95°±0.2°, 27.15°±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 of the compound of formula (I) of the present invention is crystal form A of the hydrogen sulfate of the compound of formula (I).

[0020] In some embodiments, the X-ray powder diffraction pattern of crystal form A of the hydrogen sulfate of the compound shown in formula (I) of the present invention contains diffraction peaks at the following 2θ angles: 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 other embodiments, the X-ray powder diffraction pattern of crystal form A of the hydrogen sulfate of the compound shown in formula (I) of the present invention contains the following diffraction peaks at the 2θ angle: 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 other embodiments, the X-ray powder diffraction pattern of crystal form A of the hydrogen sulfate of the compound shown in formula (I) of the present invention contains the following diffraction peaks at the 2θ angle: 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°. 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°, 28.6 1°±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°.

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

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

[0025] In some embodiments, the X-ray powder diffraction pattern of crystal form A of the phosphate of the compound of formula (I) of the present invention contains the following diffraction peaks at the 2θ angle: 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 other embodiments, the X-ray powder diffraction pattern of crystal form A of the phosphate of the compound of formula (I) of the present invention contains the following diffraction peaks at the 2θ angle: 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 other embodiments, the X-ray powder diffraction pattern of crystal form A of the phosphate of the compound of formula (I) of the present invention contains the following diffraction peaks at the 2θ angle: 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°. °±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°.

[0028] In some embodiments, the salt of the compound represented by formula (I) of the present invention is the p-toluenesulfonate of the compound represented by formula (I).

[0029] In some embodiments, the p-toluenesulfonate of the compound of formula (I) of the present invention is crystal form A of the p-toluenesulfonate of the compound of formula (I).

[0030] In some embodiments, the X-ray powder diffraction pattern of crystal form A of the p-toluenesulfonate of the compound of formula (I) of the present invention contains diffraction peaks at the following 2θ angles: 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 other embodiments, the X-ray powder diffraction pattern of crystal form A of the p-toluenesulfonate of the compound of formula (I) of the present invention contains the following diffraction peaks at the 2θ angle: 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 other embodiments, the X-ray powder diffraction pattern of crystal form A of the p-toluenesulfonate of the compound shown in formula (I) of the present invention contains the following diffraction peaks at the 2θ angle: 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 0.44°±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°, 3 0.19°±0.2°, 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 of the compound represented by formula (I) of the present invention is sulfate crystal form A, wherein the differential scanning calorimetry (DSC) of sulfate crystal form A includes endothermic peaks at 105.07℃±3℃ and 185.08℃±3℃ and an exothermic peak at 233.00℃±3℃.

[0034] In some embodiments, the bisulfate of the compound represented by formula (I) of the present invention is a crystalline form A of the bisulfate, wherein the differential scanning calorimetry (DSC) of the crystalline form A of the bisulfate includes 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 of the compound represented by formula (I) of the present invention is phosphate crystal form A, wherein the differential scanning calorimetry (DSC) of phosphate crystal form A contains an exothermic peak at 205.70 °C ± 3 °C.

[0036] In some embodiments, the p-toluenesulfonate of the compound represented by formula (I) of the present invention is crystal form A of p-toluenesulfonate, wherein the differential scanning calorimetry (DSC) of crystal form A of p-toluenesulfonate includes 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 of the compound represented by formula (I) of the present invention is sulfate crystal form A, wherein the sulfate crystal form A loses 6.408% of its weight when heated to 100.06°C; and loses 3.058% of its weight when heated further from 100.06°C to 205.23°C, with an error tolerance of ±0.1% for the weight loss ratio.

[0038] In some embodiments, the bisulfate of the compound represented by formula (I) of the present invention is crystalline form A of the bisulfate, wherein crystalline form A of the bisulfate loses 6.869% of its weight when heated to 137.49°C; and loses 2.873% of its weight when heated further from 137.49°C to 215.40°C, with an error tolerance of ±0.1% for the weight loss ratio.

[0039] In some embodiments, the phosphate of the compound represented by formula (I) of the present invention is phosphate crystal form A, wherein phosphate crystal form A loses 3.294% of its weight when heated to 119.39°C, and the weight loss ratio has an error tolerance of ±0.1%.

[0040] In some embodiments, the p-toluenesulfonate of the compound represented by formula (I) of the present invention is crystal form A of p-toluenesulfonate, wherein crystal form A of p-toluenesulfonate loses 1.709% of its weight when heated to 150.10°C, and the weight loss ratio has an error tolerance of ±0.1%.

[0041] In some embodiments, the sulfate of the compound represented by formula (I) of the present invention is a sulfate crystal form A, wherein the sulfate crystal form A has substantially the following characteristics: Figure 1 The X-ray powder diffraction pattern shown.

[0042] In some embodiments, the sulfate of the compound represented by formula (I) of the present invention is a sulfate crystal form A, wherein the sulfate crystal form A has substantially the following characteristics: Figure 2 The differential scanning calorimetry (DSC) heatmap shown is shown.

[0043] In some embodiments, the sulfate of the compound represented by formula (I) of the present invention is a sulfate crystal form A, wherein the sulfate crystal form A has substantially the following characteristics: Figure 3 The thermogravimetric analysis diagram is shown.

[0044] In some embodiments, the hydrogen sulfate of the compound represented by formula (I) of the present invention is a hydrogen sulfate crystal form A, wherein the hydrogen sulfate crystal form A has substantially the following characteristics: Figure 4 The X-ray powder diffraction pattern shown.

[0045] In some embodiments, the hydrogen sulfate of the compound represented by formula (I) of the present invention is a hydrogen sulfate crystal form A, wherein the hydrogen sulfate crystal form A has substantially the following characteristics: Figure 5 The differential scanning calorimetry (DSC) heatmap shown is shown.

[0046] In some embodiments, the hydrogen sulfate of the compound represented by formula (I) of the present invention is a hydrogen sulfate crystal form A, wherein the hydrogen sulfate crystal form A has substantially the following characteristics: Figure 6 The thermogravimetric analysis diagram is shown.

[0047] In some embodiments, the phosphate of the compound represented by formula (I) of the present invention is phosphate crystal form A, wherein the phosphate crystal form A has substantially as follows: Figure 7 The X-ray powder diffraction pattern shown.

[0048] In some embodiments, the phosphate of the compound represented by formula (I) of the present invention is phosphate crystal form A, wherein the phosphate crystal form A has substantially as follows: Figure 8 The differential scanning calorimetry (DSC) heatmap shown is shown.

[0049] In some embodiments, the phosphate of the compound represented by formula (I) of the present invention is phosphate crystal form A, wherein the phosphate crystal form A has substantially as follows: Figure 9 The thermogravimetric analysis diagram is shown.

[0050] In some embodiments, the p-toluenesulfonate of the compound represented by formula (I) of the present invention is crystal form A of p-toluenesulfonate, wherein crystal form A of said p-toluenesulfonate has substantially the following characteristics: Figure 10 The X-ray powder diffraction pattern shown.

[0051] In some embodiments, the p-toluenesulfonate of the compound represented by formula (I) of the present invention is crystal form A of p-toluenesulfonate, wherein crystal form A of said p-toluenesulfonate has substantially the following characteristics: Figure 11 The differential scanning calorimetry (DSC) heatmap shown is shown.

[0052] In some embodiments, the p-toluenesulfonate of the compound represented by formula (I) of the present invention is crystal form A of p-toluenesulfonate, wherein crystal form A of said p-toluenesulfonate has substantially the following characteristics: Figure 12 The thermogravimetric analysis diagram is shown.

[0053] On the other hand, the present invention relates to a pharmaceutical composition comprising the salt described herein, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or combination thereof.

[0054] On one hand, the present invention relates to the use of the salt or the pharmaceutical composition thereof in the preparation of a medicament for the prevention, treatment or relief of diseases associated with abnormal expression of PI3K kinase in patients.

[0055] In some embodiments, the diseases described in this invention are respiratory diseases, viral infections, non-viral respiratory infections, allergic diseases, autoimmune diseases, inflammatory diseases, cardiovascular diseases, malignant hematological diseases, neurodegenerative diseases, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, cancer, transplant rejection, lung injury, or pain.

[0056] On the other hand, the present invention relates to the use of the salt or the pharmaceutical composition thereof in the preparation of a medicament for the prevention, treatment or relief of a disease in a patient that is at least partially associated with abnormal expression of PI3K kinase.

[0057] In some embodiments, the diseases described in this invention are asthma, chronic obstructive pulmonary disease (COPD), viral respiratory infections, exacerbations of viral respiratory diseases, aspergillosis, leishmaniasis, allergic rhinitis, allergic dermatitis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, thrombosis, atherosclerosis, hematologic malignancies, neurodegenerative diseases, pancreatitis, multiple organ failure, nephropathy, platelet aggregation, cancer, transplant rejection, lung injury, generalized inflammatory pain, diabetic neuropathy, chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), hairy cell leukemia, and mantle cell lymphoma. Burkitt lymphoma, small lymphocytic lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, Hodgkin's lymphoma, Waldenström 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 exudative lymphoma, intravascular large B-cell lymphoma, plasma cell leukemia, extramedullary plasmacytoma, stagnant myeloma, monoclonal gammaglobulinemia (MGUS), or B-cell lymphoma.

[0058] One aspect of this invention relates to a method for preventing, treating, or alleviating diseases associated with abnormal expression of PI3K kinase in patients, comprising administering medication to patients in a pharmaceutically acceptable and effective dose using the salt or pharmaceutical composition described herein.

[0059] On the other hand, the present invention also relates to a method for preparing salts of the compounds shown in formula (I).

[0060] The solvents used in the salt preparation method described in this invention are not particularly limited; any solvent capable of dissolving the starting material to a certain extent without affecting its properties is included in this invention. Furthermore, many similar modifications, equivalent substitutions, or solvents, solvent combinations, and different proportions of solvent combinations described in this invention are considered to be within the scope of this invention. This invention provides preferred solvents for each reaction step.

[0061] The preparation experiments of the salt or its crystal form described in this invention are described in detail in the Examples section. Furthermore, this invention provides pharmacological testing experiments (such as pharmacokinetic experiments) and stability experiments for the salt or its crystal form. Experiments have demonstrated that the salt or its crystal form described in this invention possesses good stability and pharmacokinetic properties.

[0062] Definitions and general terms

[0063] Unless otherwise stated, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. All patents and publications related to this invention are incorporated herein by reference in their entirety. Although any methods and substances similar to or identical to those described herein may be used in the practice or testing of this invention, preferred methods, apparatus, and substances are described herein.

[0064] "Crystal form" or "crystalline shape" refers to a solid having a highly regular chemical structure, including, but not limited to, single-component or multi-component crystals, and / or polymorphs of compounds, solvates, hydrates, inclusion compounds, eutectics, salts, solvates of salts, and hydrates of salts. The crystalline form of a substance can be obtained by many methods known in the art. These methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in a confined space, such as in nanopores or capillaries, crystallization on a surface or template, such as on a polymer, crystallization in the presence of additives such as co-crystallized antimolecules, desolventization, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, antisolvent addition, grinding, and solvent drop grinding, etc.

[0065] "Solvent" refers to a substance (typically a liquid) that can completely or partially dissolve another substance (typically a solid). Solvents used in the implementation of this invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, 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, etc.

[0066] An antisolvent is a fluid that promotes the precipitation of a product (or product precursor) from a solvent. Antisolvents can include cold gases, fluids that promote precipitation through chemical reactions, or fluids that reduce the solubility of a product in a solvent; they can be the same liquid as the solvent but at a different temperature, or they can be a different liquid from the solvent.

[0067] A "solvent" is a compound that has a solvent on its surface, in its crystal lattice, or both on its surface and in its crystal lattice. The solvent can be water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, methyl pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, and mixtures thereof. A specific example of a solvate is a hydrate, in which water is the solvent on its surface, in its crystal lattice, or both on its surface and in its crystal lattice. A hydrate may or may not have other solvents besides water on its surface, in its crystal lattice, or both on its surface and in its crystal lattice.

[0068] Crystal forms can be identified using a variety of techniques, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point method, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance, Raman spectroscopy, X-ray single crystal diffraction, calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate, etc.

[0069] X-ray powder diffraction (XRPD) can detect changes in crystal form, crystallinity, and crystal structure, and is a commonly used method for identifying crystal forms. The peak positions of XRPD spectra depend primarily on the crystal structure and are relatively insensitive to experimental details, while their relative peak heights depend on many factors related to sample preparation and instrument geometry. Therefore, in some embodiments, the crystal form of the present invention is characterized by an XRPD pattern with certain peak positions, which is essentially as shown in the XRPD patterns provided in the accompanying drawings. Furthermore, the measurement of 2θ in the XRPD spectra can be subject to experimental error; the measurement of 2θ in XRPD spectra may vary slightly between different instruments and different samples, therefore the value of 2θ cannot be considered absolute. Based on the instrument used in this experiment, there is an error tolerance of ±0.2° for the diffraction peaks.

[0070] Differential scanning calorimetry (DSC) is a technique that measures the energy difference between a sample and an inert reference (commonly α-Al₂O₃) as a function of temperature under programmed control by continuously heating or cooling. The height of the endothermic peak in a DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the crystal form described in this invention is characterized by a DSC plot with characteristic peak positions, which is essentially as shown in the DSC plots provided in the accompanying drawings. However, DSC spectra can be subject to experimental error; the peak positions and peak values ​​may vary slightly between different instruments and different samples. Therefore, the peak positions or peak values ​​of the endothermic peaks in the DSC should not be considered absolute. Depending on the instrument used in this experiment, there is an error tolerance of ±3° for the endothermic peaks.

[0071] Thermogravimetric analysis (TGA) is a technique used under programmed control to determine the change in mass of a substance with temperature. It is suitable for examining the loss of solvent in crystals or the sublimation and decomposition of samples, and can infer the presence of water of crystallization or crystallization solvent in the crystal. The mass change shown by the TGA curve depends on many factors, including sample preparation and instrumentation; the mass change detected by TGA varies slightly between different instruments and different samples. Based on the instrument used in this experiment, there is an error tolerance of ±0.1% for the mass change.

[0072] In the context of this invention, the 2θ values ​​in X-ray powder diffraction patterns are all in degrees (°).

[0073] The term “basically as shown” means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks in an X-ray powder diffraction pattern, DSC pattern, Raman spectrum, or infrared spectrum are shown in the pattern.

[0074] When referring to a spectrum or / and the data appearing in the graph, a "peak" refers to a feature that a person skilled in the art can identify and that is not attributable to background noise.

[0075] The present invention relates to salts 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-phenylquinazoline-4(3H)-one and their crystal forms, for example, crystal form A of p-toluenesulfonate, which exist in substantially pure crystalline form.

[0076] "Substantially pure" means that a crystal form substantially contains no other crystal forms, i.e., the purity of the crystal form is at least 80%, or at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9%, or the crystal form contains other crystal forms whose percentage in the total volume or total weight of the crystal form is less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.

[0077] "Substantially free of" means that one or more other crystal forms account for less than 20%, or less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01% of the total volume or weight of the crystal form.

[0078] The "relative intensity" (or "relative peak height") in an XRPD pattern refers to the ratio of the intensity of the other peaks to the intensity of the first strongest peak when the intensity of the first strongest peak in the X-ray powder diffraction pattern (XRPD) is 100%.

[0079] In the context of this invention, when the terms "about" or "approximately" are used, whether or not they are used, it means within 10% of a given value or range, appropriately within 5%, and particularly within 1%. Alternatively, for those skilled in the art, the term "about" or "approximately" means within an acceptable standard error of the average. Whenever a number with a value of 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 explicitly disclosed, where "+ / -" refers to addition or subtraction.

[0080] In this invention, "room temperature" refers to a temperature from about 10°C to about 40°C. In some embodiments, "room temperature" refers to a temperature from about 20°C to about 30°C; in other embodiments, "room temperature" refers to 20°C, 22.5°C, 25°C, 27.5°C, etc.

[0081] Pharmaceutical compositions, formulations, administration and uses of the salts of the compounds described in this invention.

[0082] The pharmaceutical compositions of the present invention are characterized by a salt of a compound of formula (I) and a pharmaceutically acceptable carrier, excipient, or excipient. The amount of the salt of the compound in the pharmaceutical compositions of the present invention can effectively and detectably treat or alleviate diseases associated with PI3K kinase abnormalities.

[0083] As described in this invention, pharmaceutically acceptable compositions of this invention further comprise pharmaceutically acceptable carriers, excipients, or excipients, such as those used in this invention, including any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder, or lubricant, etc., suitable for a particular target dosage form. As described in the following literature: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York, the contents of this literature demonstrate that different carriers can be used in the formulation of pharmaceutically acceptable compositions and their known methods of preparation. Except for any conventional carrier media that are incompatible with the salts or crystal forms of the compounds of the present invention, such as those that produce any adverse biological effects or interactions with any other component of a pharmaceutically acceptable composition in a harmful manner, their use is also within the scope of this invention.

[0084] Substances that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffering substances such as phosphates; glycine; sorbic acid; potassium sorbate; mixtures of partial glycerides of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; polyacrylates; waxes; polyethylene-polyoxypropylene-blocking polymers; lanolin; sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as carboxymethyl cellulose. Sodium cellulose, ethyl cellulose, and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol; phosphate buffer solutions; and other non-toxic and suitable lubricants such as sodium lauryl sulfate and magnesium stearate; colorants; release agents; coatings; sweeteners; flavorings; fragrances; preservatives and antioxidants.

[0085] The pharmaceutical compositions of the present invention may be capsules, tablets, pills, powders, granules, and aqueous suspensions or solutions; and may be administered via the following routes: oral administration, injection administration, inhalation spray, topical administration, rectal administration, nasal administration, sublingual administration, vaginal administration, or via implantable cassette.

[0086] Oral administration can be in the following forms: tablets, pills, capsules, dispersible powders, granules or suspensions, syrups, and elixirs, etc.; topical administration can be in the following forms: ointments, gels, medicated plasters, etc.

[0087] The salts or crystal forms thereof of the present invention are preferably formulated in a dosage unit form to reduce the uniformity of dosage and administration. The term "dosage unit form" here refers to the physical dispersion unit of the drug required for the patient to receive adequate treatment. However, it should be understood that the total daily dosage of the salts or crystal forms thereof of the compounds of formula (I) of the present invention, or the pharmaceutical compositions of the present invention, will be determined by the attending physician based on reliable medical judgment. The specific effective dosage level for any particular patient or organism will depend on many factors including the condition being treated and its severity, the activity of the salts or crystal forms thereof of the specific compound, the specific composition used, the patient's age, weight, health status, sex and dietary habits, the time of administration, the route of administration and the excretion rate of the salts or crystal forms thereof of the specific compound used, the duration of treatment, whether the drug is used in combination therapy or in combination with salts or crystal forms thereof of a specific compound, and other factors known in the pharmaceutical field.

[0088] The effective dose of the active ingredient used can vary depending on the salt or crystal form of the compound used, the administration method, and the severity of the disease being treated. However, generally, satisfactory effects are obtained when the salt or crystal form of the compound of the present invention is administered daily at a dose of about 0.25-1000 mg / kg of animal body weight, preferably in 2-4 separate doses daily, or in a sustained-release form. For most large mammals, the total daily dose is about 1-100 mg / kg, preferably about 2-80 mg / kg of the salt or crystal form of the active compound. Suitable oral dosage forms comprise about 0.25-500 mg of the salt or crystal form of the active compound, closely mixed with a pharmaceutically acceptable solid or liquid carrier. This dosage regimen can be adjusted to provide the optimal therapeutic response. Additionally, depending on the treatment condition, several separate doses may be administered daily, or the dose may be reduced proportionally.

[0089] The salts of the compounds or their crystal forms, and the pharmaceutical compositions of the present invention, may be used to inhibit the activity of PI3K kinase, thereby regulating the stability and / or activity of PI3K kinase and activating the expression of PI3K-regulated genes. The salts of the compounds or their crystal forms, or the pharmaceutical compositions thereof, may be used in methods for treating, pre-treating, or delaying the onset or development of PI3K kinase-related conditions, including but not limited to hematologic malignancies.

[0090] Specifically, the salts or crystal forms of the compounds involved in this invention can be used to inhibit the activity of PI3K kinase. The salts or crystal forms of said compounds can be applied to prevent, pre-treat, or treat conditions associated with abnormal PI3K kinase expression, including, for example, asthma, chronic obstructive pulmonary disease (COPD), viral respiratory infections, exacerbations of viral respiratory diseases, aspergillosis, leishmaniasis, allergic rhinitis, allergic dermatitis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, thrombosis, atherosclerosis, hematologic malignancies, neurodegenerative diseases, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, cancer, sperm motility, transplant rejection, lung injury, generalized inflammatory pain, diabetic neuropathy, chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), and hairy cell leukemia. Mantle cell lymphoma, Burkitt lymphoma, small lymphocytic lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, Hodgkin's lymphoma, Waldenström macroglobulinemia, prolymphocytic leukemia, acute lymphoblastic leukemia, myelofibrosis, mucosa-associated lymphoid tissue (MALT) lymphoma, B-cell lymphoma, mediastinal (thymic) large B-cell lymphoma, lymphomatoid granulomatosis, splenic marginal zone lymphoma, primary exudative lymphoma, intravascular large B-cell lymphoma, plasma cell leukemia, extramedullary plasmacytoma, stagnant myeloma (also known as asymptomatic myeloma), monoclonal gammopathy of undetermined significance (MGUS), and B-cell lymphoma. Attached Figure Description

[0091] Figure 1 X-ray powder diffraction (XRPD) pattern of crystal form A of the sulfate of the compound shown in formula (I).

[0092] Figure 2 The differential scanning calorimetry (DSC) curve is shown for crystal form A of the sulfate of the compound shown in formula (I).

[0093] Figure 3 The thermogravimetric analysis (TGA) diagram shows the crystal form A of the sulfate of the compound shown in formula (I).

[0094] Figure 4 The image shows the X-ray powder diffraction (XRPD) pattern of the crystal form A of the hydrogen sulfate salt of the compound shown in formula (I).

[0095] Figure 5 The differential scanning calorimetry (DSC) curve is shown for crystal form A of the hydrogen sulfate salt of the compound shown in formula (I).

[0096] Figure 6 The thermogravimetric analysis (TGA) diagram shows the crystal form A of the hydrogen sulfate salt of the compound shown in formula (I).

[0097] Figure 7The image shows the X-ray powder diffraction (XRPD) pattern of crystal form A of the phosphate of the compound shown in formula (I).

[0098] Figure 8 The differential scanning calorimetry (DSC) curve is shown for crystal form A of the phosphate of the compound shown in formula (I).

[0099] Figure 9 The thermogravimetric analysis (TGA) diagram shows the crystal form A of the phosphate of the compound shown in formula (I).

[0100] Figure 10 The image shows the X-ray powder diffraction (XRPD) pattern of crystal form A of the p-toluenesulfonate of the compound shown in formula (I).

[0101] Figure 11 The differential scanning calorimetry (DSC) curve is shown for crystal form A of the p-toluenesulfonate of the compound shown in formula (I).

[0102] Figure 12 The thermogravimetric analysis (TGA) diagram shows the crystal form A of the p-toluenesulfonate of the compound shown in formula (I).

[0103] Figure 13 The image shows the X-ray powder diffraction (XRPD) pattern of the free alkali crystal form 2 of the compound shown in formula (I). Detailed Implementation

[0104] The present invention will be further illustrated by means of embodiments below, but the invention is not limited to the scope of the embodiments described herein.

[0105] The X-ray powder diffraction analysis method used in this invention is as follows: An Empyrean diffractometer is used, employing Cu-Kα radiation (45 kV, 40 mA) to obtain the X-ray powder diffraction pattern. The powdered sample is prepared into a thin layer on a single-crystal silicon sample holder, placed on a rotating sample stage, and analyzed in 0.0168° steps within a range of 3°–40°. Data is collected using Data Collector software, processed using HighScore Plus software, and read using Data Viewer software.

[0106] The differential scanning calorimetry (DSC) analysis method used in this 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 designed aluminum crucible with a lid, and sample analysis is performed using a linear heating device at 10°C / min, from room temperature to approximately 300°C. During use, the DSC chamber is purged with dry nitrogen.

[0107] The thermogravimetric analysis (TGA) method used in this invention is as follows: TGA is performed using a TA Q500 module equipped 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 pan, and sample analysis is performed using a linear heating device at 10 °C / min, from room temperature to approximately 300 °C. During use, the TGA furnace chamber is purged with dry nitrogen.

[0108] 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-phenylquinazoline-4(3H)-one shown in Formula (I) was synthesized according to the method of Example 34 in International Application WO2019143874A1.

[0109] Example

[0110] Example 1: Crystal form A of the sulfate of compound (I)

[0111] 1. Preparation of Sulfate Crystal Form A

[0112] A methanol (4.0 mL) 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-phenylquinazoline-4(3H)-one (0.50 g, 1.01 mmol, prepared according to Example 5) was added to a water (0.3 mL) solution containing sulfuric acid (0.11 g, 1.14 mmol). The sulfuric acid weighing flask 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 refluxed and stirred for another 4 h. The system did not dissolve completely. After cooling to room temperature, the mixture was filtered. The filter cake was dried at 60 °C for 12 h to obtain sulfate crystal form A as a white solid (0.46 g, yield 77%).

[0113] 2. Identification of Sulfate Crystal Form A

[0114] (1) Identification by Empyrean X-ray powder diffraction (XRPD): Using Cu-Kα radiation, the following characteristic peaks, expressed in terms of angle 2θ, are observed: 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°, 20.5°. For the angles 0°, 20.91°, 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°, there is an error tolerance of ±0.2°.

[0115] (2) Identification by TA Q2000 differential scanning calorimetry (DSC): The scanning speed was 10℃ / min, and the obtained DSC curves were basically as follows: Figure 2 As shown, it includes endothermic peaks at 105.07℃ and 185.08℃ and an exothermic peak at 233.00℃, with an error tolerance of ±3℃.

[0116] (3) Thermogravimetric analysis (TGA) was performed using a TA Q500: the heating rate was 10℃ / min, and the obtained TGA curve was basically as follows. Figure 3 As shown, when heated to 100.06°C, it contains a weight loss of 6.408%; when heated further from 100.06°C to 205.23°C, it contains a weight loss of 3.058%, with an error tolerance of ±0.1%.

[0117] Example 2: Crystal form A of the hydrogen sulfate salt of compound (I)

[0118] 1. Preparation of crystal form A of hydrogen sulfate

[0119] Add 0.3 mL of a solution of sulfuric acid (0.11 g, 1.12 mmol) in acetonitrile (4.0 mL) 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-phenylquinazoline-4(3H)-one (0.50 g, 1.01 mmol, prepared according to Example 5). Rinse the sulfuric acid weighing bottle with water (0.2 mL) and add it to the system. Heat the system to reflux and stir for 20 min, add 6.0 mL of acetonitrile, and continue to reflux and stir for 4 h until the system is completely dissolved. Cool to room temperature, filter, wash with acetonitrile (2.0 mL), and dry the filter cake at 60 °C for 12 h to obtain hydrogen sulfate crystal form A as a pale yellow solid (0.60 g, yield 100%).

[0120] 2. Identification of crystal form A of hydrogen sulfate

[0121] (1) Identification by Empyrean X-ray powder diffraction (XRPD): Using Cu-Kα radiation, the following characteristic peaks, expressed in terms of angle 2θ, were observed: 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°. The following angles are given: 21.99°, 23.25°, 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 an error tolerance of ±0.2°.

[0122] (2) Identification by TA Q2000 differential scanning calorimetry (DSC): The scanning speed was 10℃ / min, and the obtained DSC curves were basically as follows: Figure 5 As shown, it includes an endothermic peak at 196.02℃ and exothermic peaks at 201.85℃ and 246.30℃, with an error tolerance of ±3℃.

[0123] (3) Thermogravimetric analysis (TGA) was performed using a TA Q500: the heating rate was 10℃ / min, and the obtained TGA curve was basically as follows. Figure 6 As shown, when heated to 137.49°C, it contains a weight loss of 6.869%; when heated further from 137.49°C to 215.40°C, it contains a weight loss of 2.873%, with an error tolerance of ±0.1%.

[0124] Example 3 Crystal form A of the phosphate of compound (I)

[0125] 1. Preparation of phosphate crystal form A

[0126] A solution of phosphoric acid (0.11 g, 1.16 mmol) in water (0.3 mL) was added to an acetonitrile (4.0 mL) 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-phenylquinazoline-4(3H)-one (0.50 g, 1.02 mmol, prepared according to Example 5). The phosphoric acid weighing flask 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 reflux and stirring continued for 4 h until the system did not dissolve completely. The solution was cooled to room temperature, filtered, and rinsed with acetonitrile (2.0 mL). The filter cake was dried at 60 °C for 12 h to obtain phosphate crystal form A as a white solid (0.57 g, yield 95%).

[0127] 2. Identification of phosphate crystal form A

[0128] (1) Identification by Empyrean X-ray powder diffraction (XRPD): Using Cu-Kα radiation, the following characteristic peaks, expressed in terms of angle 2θ, are observed: 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°. For the following angles: °, 18.11°, 19.32°, 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°, there is an error tolerance of ±0.2°.

[0129] (2) Identification by TA Q2000 differential scanning calorimetry (DSC): The scanning speed was 10℃ / min, and the obtained DSC curves were basically as follows: Figure 8 As shown, it contains an exothermic peak at 205.70℃, with an error tolerance of ±3℃.

[0130] (3) Thermogravimetric analysis (TGA) was performed using a TA Q500: the heating rate was 10℃ / min, and the obtained TGA curve was basically as follows. Figure 9 As shown, when heated to 119.39°C, it contains a weight loss of 3.294%, with an error tolerance of ±0.1%.

[0131] Example 4: Crystal form A of p-toluenesulfonate of compound (I)

[0132] 1. Preparation of crystal form A of p-toluenesulfonate

[0133] 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-phenylquinazoline-4(3H)-one (38.00 g, 76.85 mmol, prepared according to Example 5), ethanol (230 mL), and water (150 mL), a solution of p-toluenesulfonic acid monohydrate (16.13 g, 84.80 mmol) in water (60 mL) was added. The bottle containing the acid solution was washed with water (20 mL), which was also 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, and stirring continued for 1 h. The mixture was filtered, and the reaction flask was washed with ethanol / water (v / v = 1 / 4, 50 mL), with the washings also filtered. The filter cake was dried overnight at 60°C by forced air drying to obtain a pale yellow solid (45.8 g, yield 89.4%).

[0134] 2. Identification of crystal form A of p-toluenesulfonate

[0135] (1) Identification by Empyrean X-ray powder diffraction (XRPD): Using Cu-Kα radiation, the following characteristic peaks, expressed in terms of angle 2θ, are observed: 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. For the angles 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°, there is an error tolerance of ±0.2°.

[0136] (2) Identification by TA Q2000 differential scanning calorimetry (DSC): The scanning speed was 10℃ / min, and the obtained DSC curves were basically as follows: Figure 11 As shown, it includes an endothermic peak at 73.89℃ and an exothermic peak at 231.68℃, with an error tolerance of ±3℃.

[0137] (3) Thermogravimetric analysis (TGA) was performed using a TA Q500: the heating rate was 10℃ / min, and the obtained TGA curve was basically as follows. Figure 12 As shown, when heated to 150.10°C, it contains a weight loss of 1.709%, with an error tolerance of ±0.1%.

[0138] Example 5: Free base crystal form 2 of the compound shown in formula (I)

[0139] 1. Preparation of the free base crystal form 2 of the compound shown in formula (I)

[0140] It was obtained by referring to the synthesis method of Example 34 in International Application WO2019143874A1.

[0141] 2. Identification of the free basal crystal form 2 of the compound shown in formula (I)

[0142] Identification was performed using Empyrean X-ray powder diffraction (XRPD) analysis: Cu-Kα radiation was used. The X-ray powder diffraction pattern of the free alkali crystal form 2 prepared by the method in this embodiment is basically as follows. Figure 13 As shown.

[0143] Example 6: Pharmacokinetic Experiment of the Salt of the Present Invention

[0144] The pharmacokinetic assay method for the salt and free base crystal form 2 described in this invention in Beagle dogs.

[0145] The salt of the compound shown in formula (I) of the present invention and the free base crystal form 2 of the compound shown in formula (I) are respectively filled into capsules for oral administration.

[0146] Male Beagle dogs weighing 8-12 kg were divided into two groups of three each. Each group was orally administered capsules containing the test sample at a dose of 10 mg / kg. Blood samples were collected at time points of 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24 hours. A standard curve was established based on the sample concentration. The concentration of the test sample in plasma samples was determined using an AB SCIEX API4000 LC-MS / MS in MRM mode, and quantitative analysis was performed. Pharmacokinetic parameters were calculated using the non-compartmental model method in WinNonLin 6.3 software based on the drug concentration-time curve. The experimental results are shown in Table 1.

[0147] Table 1. Pharmacokinetic experimental results of the salt and free alkali crystal form 2 described in this invention in Beagle dogs.

[0148]

[0149] Conclusion: The salts described in this invention have good pharmacokinetic properties in Beagle dogs, especially the p-toluenesulfonate crystal form A, which has a high exposure and high blood concentration in Beagle dogs, indicating good pharmacokinetic properties.

[0150] The pharmacokinetic assay method for salt and free base crystal form 2 in SD rats as described in this invention

[0151] The salt of the compound shown in formula (I) and the free base crystal form 2 of the compound shown in formula (I) of this invention were prepared into suspensions using PEG400. Male SD rats were administered the test sample at 200 mg / kg via gavage or orally, with three animals per group. Blood samples were collected at time points of 0.25, 0.5, 1.0, 2.0, 5.0, 7.0, and 24 h after administration. A standard curve was established based on the sample concentration. The concentration of the test sample in plasma was determined using an AB SCIEX API4000 LC-MS / MS in MRM mode, and quantitative analysis was performed. Pharmacokinetic parameters were calculated using a non-compartmental model in WinNonLin 6.3 software based on the drug concentration-time curve. The experimental results are shown in Table 2.

[0152] Table 2. Pharmacokinetic results of the salt and free alkali crystal form 2 described in this invention in male SD rats.

[0153] Crystal form A of p-toluenesulfonate 200 1.33±0.58 6810±1700 55200±8700 Sulfate crystal form A 200 1.17±0.764 3310±993 35300±8920 Crystal form A of hydrogen sulfate 200 1.50±0.866 4080±375 40600±183 Phosphate crystal form A 200 1.50±0.866 3950±1500 37800±6550 Free alkali crystal form 2 200 1.67±0.58 5800±850 39800±7600

[0154] Experimental conclusion:

[0155] As shown in Table 2, the salt described in this invention has a high exposure level in SD rats and exhibits good pharmacokinetic properties.

[0156] Example 7: Stability experiment of the salt described in this invention

[0157] Experimental methods:

[0158] (1) High temperature experiment Take an appropriate amount of the salt of the compound shown in formula (I) of the present invention and put it into a flat weighing bottle. Spread it into a thin layer of ≤3mm thickness and place it at two temperatures of 60℃ and 40℃ for 30 days respectively. Take samples on the 5th, 10th and 30th days, observe the color change of the sample, and detect the purity of the sample by HPLC.

[0159] (2) High humidity testTake an appropriate amount of the salt of the compound shown in formula (I) of the present invention and put it into a flat weighing bottle. Spread it into a thin layer of ≤3mm thickness. Place it under two conditions of 25℃, RH 90%±5% and 25℃, RH 75%±5% for 30 days respectively. Take samples on the 5th, 10th and 30th days, observe the color change of the sample, and detect the purity of the sample by HPLC.

[0160] (3) Light Experiment Take an appropriate amount of the salt of the compound shown in formula (I) of this invention and place it in a flat weighing bottle, spreading it into a thin layer ≤3mm thick. Place the bottle open in a light box (with ultraviolet light) and expose it to an illuminance of 4500±500lx and ultraviolet light ≥0.7w / m². 2 The samples were placed under the specified conditions for 30 days, and samples were taken on the 5th, 10th and 30th days to observe the color change of the samples. The purity of the samples was detected by HPLC.

[0161] (4) Long-term stability test The experiment investigated the color changes of samples under long-term low-temperature (5℃±3℃) conditions, with the samples packaged in single-layer PE inner packaging, aluminum foil outer packaging, KD-20 deoxidizer inside, vacuum-sealed with nitrogen, and then subjected to a long-term test. The purity of the samples was determined by HPLC.

[0162] The experimental results are shown in Table 3.

[0163] Table 3. Stability test results of crystal form A of p-toluenesulfonate described in this invention - high temperature, high humidity, and long-term stability.

[0164]

[0165]

[0166] The experimental results show that the salt described in this invention is stable under high temperature and high humidity conditions. In particular, the appearance and purity of the p-toluenesulfonate crystal form A described in this invention do not change significantly.

[0167] Under long-term stability test conditions, the appearance and purity of p-toluenesulfonate crystal form A of the present invention showed no significant changes.

[0168] In summary, the p-toluenesulfonate crystal form A described in this invention has good stability and is suitable for pharmaceutical applications.

[0169] The above description is merely a basic explanation of the concept of this invention, and any equivalent modifications made based on the technical solution of this invention shall fall within the protection scope of this invention.

[0170] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0171] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. A salt of a compound as shown in formula (I), wherein the salt is a p-toluenesulfonate. (I)， The X-ray powder diffraction pattern of p-toluenesulfonate crystal form A contains the following diffraction peaks at the 2θ angle: 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°.

2. The salt according to claim 1, wherein The p-toluenesulfonate is p-toluenesulfonate crystal form A, characterized in that, The X-ray powder diffraction pattern of the p-toluenesulfonate crystal form A contains the following diffraction peaks at the 2θ angle: 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°.

3. The salt according to claim 1, wherein The p-toluenesulfonate is p-toluenesulfonate crystal form A, characterized in that, The X-ray powder diffraction pattern of p-toluenesulfonate crystal form A contains the following diffraction peaks at the 2θ angle: 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°, 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°, 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°.

4. The salt according to claim 1, wherein The p-toluenesulfonate is p-toluenesulfonate crystal form A, characterized in that, The crystal form A of the p-toluenesulfonate has an X-ray powder diffraction pattern that is substantially as shown in Figure 10.

5. The salt according to claim 1, wherein, The p-toluenesulfonate is crystal form A of p-toluenesulfonate, characterized in that the differential scanning calorimetry (DSC) of crystal form A of p-toluenesulfonate includes an endothermic peak at 73.89°C ± 3°C and an exothermic peak at 231.68°C ± 3°C.

6. The salt according to claim 1, wherein The p-toluenesulfonate is p-toluenesulfonate crystal form A, characterized in that, The crystal form A of the p-toluenesulfonate has a differential scanning calorimeter that is substantially as shown in Figure 11.

7. The salt according to claim 1, wherein The p-toluenesulfonate is p-toluenesulfonate crystal form A, characterized in that, The crystal form A of the p-toluenesulfonate has a thermogravimetric analysis diagram that is essentially as shown in Figure 12.

8. A pharmaceutical composition comprising the salt according to any one of claims 1-7, and a pharmaceutically acceptable excipient.

9. Use of the salt of any one of claims 1-7 or the pharmaceutical composition of claim 8 in the preparation of a medicament, wherein the medicament is used to protect against, treat, cure, or alleviate diseases associated with PI3K kinase abnormalities.

10. The use according to claim 9, wherein the PI3K kinase abnormality-related disease is a respiratory disease, viral infection, allergic disease, autoimmune disease, inflammatory disease, cardiovascular disease, hematologic malignancy, neurodegenerative disease, pancreatitis, multiple organ failure, kidney disease, cancer, transplant rejection, lung injury, or pain.

11. The use according to claim 9, wherein the PI3K kinase abnormality-related diseases are asthma, chronic obstructive pulmonary disease, viral respiratory infections, aspergillosis, leishmaniasis, allergic rhinitis, allergic dermatitis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, thrombosis, atherosclerosis, neurodegenerative diseases, pancreatitis, multiple organ failure, nephropathy, transplant rejection, lung injury, generalized inflammatory pain, diabetic neuropathy, chronic lymphocytic leukemia, hairy cell leukemia, mantle cell lymphoma, Burkitt lymphoma. Lymphoma, small lymphocytic lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, Hodgkin's lymphoma, Waldenström macroglobulinemia, prolymphocytic leukemia, acute lymphoblastic leukemia, myelofibrosis, mucosa-associated lymphoid tissue lymphoma, thymic mediastinal large B-cell lymphoma, lymphomatoid granulomatosis, splenic marginal zone lymphoma, primary exudative lymphoma, intravascular large B-cell lymphoma, plasma cell leukemia, extramedullary plasmacytoma, stagnant myeloma, or monoclonal gammaglobulinemia.

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