Salts of pyrazolo[1,5-a]pyridine derivatives and their uses

Abstract

The present invention provides salts of pyrazolo[1,5-a]pyridine derivatives and uses thereof. The present invention further relates to pharmaceutically acceptable compositions containing such salts, and methods of using the salts and pharmaceutically acceptable compositions to prevent or treat proliferative diseases or pulmonary fibrosis in a patient.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 62 / 608,330, filed December 20, 2017, which is incorporated herein by reference in its entirety.

[0002] The present invention relates to salts of pyrazolo[1,5-a]pyridine derivatives and uses thereof, in particular to salts of N-(5-(3-cyanopyrazolo[1,5-a]pyridin-5-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (compound of formula (I)) and uses thereof, and further to compositions containing said salts. The salts or compositions inhibit / modulate protein kinases and can be used in the prevention, management or treatment of proliferative diseases or pulmonary fibrosis in patients. [Background technology]

[0003] Phosphoinositide 3-kinases (PI3 kinases or PI3Ks), a family of lipid kinases, have been found to play important regulatory roles in many cellular processes, including cell survival, proliferation, and differentiation. PI3K enzymes consist of three classes with variable primary structure, function, and substrate specificity. Class I PI3Ks consist of heterodimers of a regulatory subunit and a catalytic subunit and are subdivided into 1A and 1B subunits based on their activation mechanism. Class 1A PI3Ks are activated by various cell surface tyrosine kinases and consist of a catalytic p110 subunit and a regulatory p85 subunit. The three known isoforms of class 1A p110 are p110α, p110β, and p110δ, all of which contain an amino-terminal regulatory interaction region (which interacts with p85), a Ras-binding domain, and a carboxy-terminal catalytic domain. Class 1B PI3Ks consist of a catalytic (p110γ) subunit and a regulatory (p101) subunit and are activated by G protein-coupled receptors ("Small-molecule inhibitors of the PI3K signaling network", Future Med. Chem., 2011, 3, 5, pp. 549-565).

[0004] As a major downstream effector of receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs), PI3K converts signals from various growth factors and cytokines into intracellular messages by generating phospholipids, which activate the serine-threonine protein kinase AKT (also known as protein kinase B (PKB)) and other downstream effector pathways. The tumor suppressor PTEN (phosphatase and tensin homolog) is the most important negative regulator of the PI3K signaling pathway ("Status of PI3K / Akt / mTOR Pathway Inhibitors in Lymphoma." Clin Lymphoma, Myeloma Leuk, 2014, 14(5), pp. 335-342).

[0005] The signaling network defined by phosphoinositide 3-kinase (PI3K), AKT, and mammalian target of rapamycin (mTOR) regulates most hallmarks of cancer, including cell cycle, survival, metabolism, motility, and genomic instability. The pathway also contributes to cancer-promoting aspects of the tumor environment, such as angiogenesis and inflammatory cell recruitment. The lipid second messenger phosphatidylinositol-3,4,5-triphosphate (PtdIns(3,4,5)P3; also known as PIP3), generated by the PI3K enzyme, is constitutively elevated in most cancer cells and recruits cytoplasmic proteins to membrane-localized "onco" signalosomes.

[0006] Cancer genetic studies suggest that the PI3K pathway is the most frequently altered pathway in human tumors: the PIK3CA gene (encoding the PI3K catalytic isoform p110α) is the second most frequently mutated oncogene, and PTEN (encoding phosphatase and tensin homolog, a major PtdIns(3,4,5)P3 phosphatase) is one of the most frequently mutated tumor suppressor genes. In line with this, recent genomic studies of head and neck cancer have found that the PI3K pathway is the most frequently mutated. Indeed, even in cancer cells expressing normal PI3K and PTEN genes, other lesions that activate the PI3K signaling network (i.e., activated tyrosine kinases, RAS and AKT, etc.) are present. As a final result of these abnormalities, the PI3K pathway is involved in the development of ovarian cancer (Campbell et al., Cancer Res., 2004, 64, pp. 7678-7681; Levine et al., Clin. Cancer Res., 2005, 11, pp. 2875-2878; Wang et al., Hum. Mutat., 2005, 25, pp. 322; Lee et al., Gynecol. Oncol., 2005, 97, pp. 26-34), cervical cancer, and breast cancer (Bachman et al., Cancer Biol. Ther., 2004, 3, pp. 772-775; Levine et al., supra; Li et al., Breast Cancer Res. Treat., 2006, 96, pp. 91-95; Saal et al., Cancer Res., 2005, 65, pp. 2554-2559; Samuels and Velculescu, Cell Cycle, 2004, 3, pp. 1221-1224), colorectal cancer (Samuels et al., Science, 2004, 304, pp. 554; Velho et al., Eur. J. Cancer, 2005, 41, pp. 1649-1654), endometrial cancer (Oda et al., Cancer Res., 2005, 65, pp. 10669-10673), gastric cancer (Byun et al., MJCancer, 2003, 104, pp. 318-327; Li et al., supra; Velho et al., supra; Lee et al., Oncogene, 2005, 24, pp. 1477-1480), hepatocellular carcinoma (Lee et al., supra), small cell and non-small cell lung cancer (Tang et al., Lung Cancer 2006, 11, pp. 181-191; Massion et al., Am. J. Respir. Crit. Care Med., 2004, 170, pp. 1088-1094), thyroid cancer (Wu et al., J. Clin. Endocrinol. Metab., 2005, 90, pp. 4688-4693), acute myeloid leukemia (AML) (Sujobert et al., Blood, 1997, 106, pp. 1063-1066), chronic myeloid leukemia (CML) (Hickey et al., J. Biol. Chem., 2006, 281, pp. 2441-2450), glioblastoma (Hartmann et al., Acta Neuropathol (Berl), 2005, 109, pp. 639-642; Samuels et al., supra), and Hodgkin's and non-Hodgkin's lymphoma ("PI3K and cancer: lessons, challenges, and opportunities", Nature Reviews Drug Discovery., 2014, 13, pp. 140).

[0007] The PI3K pathway is overactivated in most cancers, yet the ability of PI3K inhibitors to induce tumor cell death is limited. The effectiveness of PI3K inhibition can also be derived from interfering with the ability of cancer cells to respond to stromal signals, as demonstrated by the PI3Kδ inhibitor idelalisib, approved for use in B-cell malignancies. Inhibition of leukocyte-enriched PI3Kδ or PI3Kγ can trigger antitumor T cell responses by inhibiting regulatory T cells and immunosuppressive myeloid cells. Furthermore, tumor angiogenesis can be targeted by PI3K inhibitors to enhance cancer therapy ("Targeting PI3K in Cancer: Impact on Tumor Cells, Their Protective Stroma, Angiogenesis, and Immunotherapy," Cancer Discov., 2016, 6(10), pp. 1090-1105).

[0008] mTOR is a highly conserved serine-threonine kinase with lipid kinase activity and participates as an effector in the PI3K / AKT pathway. mTOR exists in two distinct complexes, mTORC1 and mTORC2, and plays an important role in cell proliferation by monitoring nutrient availability and cellular energy levels. Downstream targets of mTORC1 are ribosomal protein S6 kinase 1 and eukaryotic translation initiation factor 4E-binding protein 1, both of which are essential for regulating protein synthesis ("Present and future of PI3K pathway inhibition in cancer: perspectives and limitations," Current Med. Chem., 2011, 18, pp. 2647-2685).

[0009] Knowledge of the consequences of dysregulated mTOR signaling on tumorigenesis comes primarily from studies of pharmacological disruption of mTOR with rapamycin and its analogs, such as temsirolimus (CCI-779) and everolimus (RAD001). Rapamycin was found to inhibit mTOR, thereby inducing G1 arrest and apoptosis. The mechanism of growth inhibition by rapamycin was found to be related to the formation of complexes between rapamycin and FKBP-12 (FKBP-12). These complexes then bind to mTOR with high affinity and suppress its activation, resulting in the inhibition of protein translation and cell growth. The cellular effects of mTOR inhibition are even more pronounced in cells with concomitant inactivation of PTEN. The antitumor activity of rapamycin was subsequently identified, and many rapamycin analogs, such as temsirolimus and everolimus, have been approved by the U.S. Food and Drug Administration for the treatment of certain types of cancer.

[0010] Fibrosis is the formation of excess fibrous connective tissue in organs or tissues during repair or reaction processes. Examples of fibrosis include, but are not limited to, pulmonary fibrosis, liver fibrosis, skin fibrosis, and renal fibrosis. Pulmonary fibrosis, also known as idiopathic pulmonary fibrosis (IPF), interstitial diffuse pulmonary fibrosis, inflammatory pulmonary fibrosis, or fibrosing alveolitis, is a heterogeneous group of lung diseases characterized by the abnormal formation of fibrous tissue between alveoli caused by alveolitis, including cellular infiltration into the alveolar septa, resulting in fibrosis. The effects of IPF are chronic and progressive, and often fatal.

[0011] The clinical course of IPF is variable and largely unpredictable. IPF is ultimately fatal, and historical data suggest a median survival of 2 to 3 years from diagnosis. A decline in forced vital capacity (FVC) indicates disease progression in patients with IPF, and change in FVC is the most commonly used endpoint in clinical trials. A decline in FVC of 5% or 10% of predicted value over 6 to 12 months is associated with increased mortality in patients with IPF.

[0012] Our understanding of the pathogenesis of IPF has evolved from one primarily due to inflammatory disease to one driven by a complex interplay between repeated epithelial cell injury and abnormal wound healing, involving fibroblast recruitment, proliferation, and differentiation, ultimately leading to excessive deposition of extracellular matrix. This shift in knowledge has led to a change in the types of compounds being investigated as potential therapies, with a focus on targeting specific pathways in the development and progression of fibrosis.

[0013] In patients with IPF, the mechanism of action of PI3K / mTOR inhibitors may involve the inhibition of kinases such as PI3K and mTOR. This leads to the inactivation of cellular receptors for mediators involved in the development of pulmonary fibrosis. As a result, fibroblast proliferation is inhibited and extracellular matrix deposition is reduced ("Update on diagnosis and treatment of idiopathic pulmonary fibrosis," J Bras Pneumol. 2015, 41(5), pp. 454-466).

[0014] Thus, small molecule compounds that specifically inhibit, regulate and / or modulate signal transduction of kinases, including PI3K and mTOR, as described above, are desirable as a means of preventing, managing, or treating proliferative diseases and fibrotic diseases, particularly idiopathic pulmonary fibrosis, in patients. One such small molecule is N-(5-(3-cyanopyrazolo[1,5-a]pyridin-5-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide, which has the chemical structure shown below:

[0015] [ka]

[0016] WO2014130375A1 describes the synthesis of N-(5-(3-cyanopyrazolo[1,5-a]pyridin-5-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (Example 3) and also disclosed the therapeutic activity of this molecule in the inhibition, regulation and modulation of protein kinase signal transduction.

[0017] Different salts and solid forms of an active pharmaceutical ingredient may have different properties. These differences in the properties of different salts and solid forms may provide a basis for improving formulations, for example, by promoting better processing or handling characteristics, improving dissolution profiles, stability (polymorphic and chemical stability), and shelf life. These differences in the properties of different salts and solid forms may also result in improvements to the final dosage form, for example, if they function to improve bioavailability. Different salts and solid forms of an active pharmaceutical ingredient may also give rise to various polymorphs or crystalline forms, which may then provide further opportunities to evaluate differences in the properties and characteristics of the solid active pharmaceutical ingredient.

[0018] Various salts and solid forms of N-(5-(3-cyanopyrazolo[1,5-a]pyridin-5-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide are described herein. [Prior art documents] [Patent documents]

[0019] [Patent Document 1] WO2014130375A1 [Non-patent literature]

[0020] [Non-Patent Document 1] "Small-molecule inhibitors of the PI3K signaling network", Future Med. Chem., 2011, 3, 5, pp. 549-565 [Non-patent document 2] "Status of PI3K / Akt / mTOR Pathway Inhibitors in Lymphoma.", Clin Lymphoma, Myeloma Leuk, 2014, 14(5), pages 335~342 [Non-licensed Document 3] Campbellら, Cancer Res., 2004, 64, pages 7678~7681 [Non-licensed Document 4] Levine, Clin. Cancer Res., 2005, 11, pages 2875~2878 [Non-licensed Document 5] Wangら, Hum. Mutat., 2005, 25, 322 pages [Non-licensed Document 6] Lee, Gynecol. Oncol., 2005, 97, pp. 26-34 [Non-licensed Document 7] Bachmanら, Cancer Biol., Ther., 2004, 3, pages 772~775 [Non-licensed Document 8] Liら, Breast Cancer Res. Treat., 2006, pages 96, 91~95 [Non-licensed Document 9] Saalら, Cancer Res., 2005, 65, pages 2554~2559 [Non-licensed Document 10] Samuels and Velculescu, Cell Cycle, 2004, 3, pp. 1221-1224 [Non-licensed Document 11] Samuelsら, Science, 2004, 304, 554 pages [Non-licensed Document 12] Velho, Eur. J. Cancer, 2005, 41, pages 1649~1654 [Non-licensed Document 13] Odaら, Cancer Res., 2005, 65, pages 10669~10673 [Non-licensed Document 14] Byunら, MJ Cancer, 2003, 104, pages 318~327 [Non-licensed Document 15] Lee, Oncogene, 2005, 24, pages 1477~1480 [Non-licensed Document 16] Tangら, Lung Cancer 2006, 1l, pages 181~191 [Non-licensed Document 17] Massion, Am. J. Respir. Crit. Care Med., 2004, pp. 170, 1088-1094 [Non-licensed Document 18] Wu ら, J. Clin. Endocrinol. Metab., 2005, 90, pages 4688~4693 [Non-licensed Document 19] Sujobertら, Blood, 1997, 106, pages 1063~1066 [Non-licensed Document 20] Hickey, J. Biol. Chem., 2006, 281, pages 2441~2450 [Non-licensed Document 21] Hartmannら, Acta Neuropathol (Berl), 2005, 109, pages 639~642 [Non-licensed Document 22] "PI3K and cancer: lessons, challenges and opportunities", Nature Reviews Drug Discovery., 2014, 13, 140 pages [Non-licensed Document 23] "Targeting PI3K in Cancer: Impact on Tumor Cells, Their Protective Stroma, Angiogenesis, and Immunotherapy", Cancer Discov., 2016, 6(10), pp. 1090~1105 [Non-licensed Document 24] "Present and future of PI3K pathway inhibition in cancer: perspectives and limitations", Current Med. Chem., 2011, 18, pp. 2647-2685 [Non-Patent Document 25] "Update on diagnosis and treatment of idiopathic pulmonary fibrosis", J Bras Pneumol.2015, 41(5), pp. 454-466 [Non-Patent Document 26] Solid-State Chemistry of Drugs, S.R. Byrn, R.R. Pfeiffer, and J.G. Stowell, 2nd ed., SSCI, West Lafayette, Indiana (1999) [Non-Patent Document 27] "Programmed Cooling Batch Crystallizers," J. W. Mullin and J. Nyvlt, Chemical Engineering Science, 1971, 26, pp. 369-377 Summary of the Invention [Means for solving the problem]

[0021] The present invention provides a base addition salt of a compound of formula (I) that inhibits, regulates, and / or modulates PI3K and / or mTOR and is useful for treating hyperproliferative diseases, such as cancer, in humans. The present invention also provides a method for preparing the salt. The base addition salt of the present invention can be in a crystalline form, a partially crystalline form, a polymorph, or an amorphous form. The base addition salt of the present invention can also be a solvate, such as a hydrate.

[0022] In one aspect, provided herein is a compound of formula (I):

[0023] [ka]

[0024] wherein the base addition salt is a sodium salt, a lithium salt, a potassium salt, a choline salt, a calcium salt, a magnesium salt, an amine salt, a lysinate salt, an arginine salt, an ethanolamine salt, a tromethamine salt, an N-methylglucosamine salt, a morpholine salt, a piperazine salt, a tert-butylamine salt, a dicyclohexylamine salt, or a combination thereof.

[0025] In another embodiment, the sodium salt is a monosodium salt of the compound of formula (I).

[0026] In some embodiments, the monosodium salt is crystalline Form A of the monosodium salt of the compound of Formula (I) having an X-ray powder diffraction pattern comprising 2θ values ​​at 14.73°±0.2°, 14.93°±0.2°, 21.77°±0.2°, 22.59°±0.2°, 23.29°±0.2°, and 24.87°±0.2°.

[0027] In another embodiment, the monosodium salt is crystalline Form A of the monosodium salt of compound of formula (I) having an X-ray powder diffraction pattern comprising 2θ values ​​at 10.71°±0.2°, 14.73°±0.2°, 14.93°±0.2°, 19.01°±0.2°, 19.41°±0.2°, 21.57°±0.2°, 21.77°±0.2°, 22.59°±0.2°, 23.29°±0.2°, 24.87°±0.2°, 28.36°±0.2°, and 30.18°±0.2°.

[0028] In some embodiments, the monosodium salt has the following refractive indices: 5.59°±0.2°, 9.33°±0.2°, 10.71°±0.2°, 11.21°±0.2°, 14.73°±0.2°, 14.93°±0.2°, 15.39°±0.2°, 16.55°±0.2°, 17.36°±0.2°, 17.64°±0.2°, 18.42°±0.2°, 19.01°±0.2°, 19.41°±0.2°, 20.41°±0.2°, 21.41°±0.2°, 22.41°±0.2°, 23.41°±0.2°, 24.41°±0.2°, 25.41°±0.2°, 26.41°±0.2°, 27.41°±0.2°, 28.41°±0.2°, 29.41°±0.2°, 30.41°±0.2°, 31.41°±0.2°, 32.41°±0.2°, 33.41°±0.2°, 34.41°±0.2°, 35.41°±0.2°, 36.41°±0.2°, 37.41°±0.2°, 38.41°±0.2°, 39.41°±0.2°, 40.41°±0.2°, 41.41°±0.2°, 42.41°±0.2°, 43.41°±0.2°, 44.41°±0.2°, 4 °±0.2°, 19.66°±0.2°, 19.84°±0.2°, 20.26°±0.2°, 21.57°±0.2°, 21.77°±0.2°, 22.34°±0.2°, 22.59°±0.2°, 23.29°±0.2°, 24.15°±0.2°, 24.87°±0.2°, 25.59°±0.2°, 26.26°±0.2°, 26.75°±0.2°, 27.32°± 0.2°, 27.87°±0.2°, 28.36°±0.2°, 28.71°±0.2°, 29.08°±0.2°, 29.59°±0.2°, 30.18°±0.2°, 30.56°±0.2°, 31.01°±0.2°, 31.61°±0.2°, 31.81°±0.2°, 32.14°±0.2°, 32.72°±0.2°, 33.26°±0.2°, 34.14°±0.2°. 2°, 35.97°±0.2°, 36.46°±0.2°, 38.40°±0.2°, 38.83°±0.2°, 39.49°±0.2°, 40.04°±0.2°, 41.32°±0.2°, 42.80°±0.2°, 43.89°±0.2° and 45.77°±0.2°.

[0029] In some embodiments, the monosodium salt is crystalline Form A of the monosodium salt of the compound of Formula (I), having an X-ray powder diffraction (XRPD) pattern substantially in accordance with the pattern shown in FIG.

[0030] In some embodiments, the monosodium salt is crystalline Form B of the monosodium salt of the compound of Formula (I) having an X-ray powder diffraction pattern comprising 2θ values ​​at 8.75°±0.2°, 12.27°±0.2°, 14.42°±0.2°, 20.46°±0.2°, 23.64°±0.2°, 25.14°±0.2°, and 25.89°±0.2°.

[0031] In another embodiment, the monosodium salt is crystalline Form B of the monosodium salt of the compound of formula (I) having an X-ray powder diffraction pattern comprising 2θ values ​​at 8.75°±0.2°, 12.27°±0.2°, 14.42°±0.2°, 15.62°±0.2°, 20.46°±0.2°, 23.32°±0.2°, 23.64°±0.2°, 25.14°±0.2°, 25.89°±0.2°, 26.87°±0.2°, 27.43°±0.2°, 28.09°±0.2°, 32.95°±0.2°, and 36.47°±0.2°.

[0032] In some embodiments, the monosodium salt has the following refractive indices: 7.23°±0.2°, 8.75°±0.2°, 12.27°±0.2°, 12.88°±0.2°, 13.94°±0.2°, 14.42°±0.2°, 14.87°±0.2°, 15.62°±0.2°, 17.85°±0.2°, 18.51°±0.2° , 18.94°±0.2°, 19.33°±0.2°, 19.79°±0.2°, 20.46°±0.2°, 21.50°±0.2°, 22.23°±0.2°, 22.79°±0.2°, 23.32°±0.2°, 23.64°±0.2°, 24.67°±0.2°, 25.14°±0.2°, 25.89°± 0.2°, 26.87°±0.2°, 27.43°±0.2°, 28.09°±0.2°, 28.54°±0.2°, 29.02°±0.2°, 29.48°±0.2°, 29.96°±0.2°, 30.74°±0.2°, 31.56°±0.2°, 32.95°±0.2°, 33.50°±0.2°, 35. Crystalline Form B of the monosodium salt of compound of formula (I) having an X-ray powder diffraction pattern with 2θ values ​​at 86°±0.2°, 36.47°±0.2°, 37.32°±0.2°, 39.11°±0.2°, 39.84°±0.2°, 42.23°±0.2°, 42.93°±0.2° and 44.44°±0.2°.

[0033] In another embodiment, the monosodium salt is crystalline Form B of the monosodium salt of the compound of Formula (I), having an X-ray powder diffraction (XRPD) pattern substantially in accordance with the pattern shown in FIG.

[0034] In some embodiments, the monosodium salt is crystalline Form C of the monosodium salt of the compound of Formula (I) having an X-ray powder diffraction pattern comprising 2θ values ​​at 10.52°±0.2°, 13.64°±0.2°, 14.40°±0.2°, 15.86°±0.2°, 18.72°±0.2°, 19.14°±0.2°, and 24.68°±0.2°.

[0035] In another embodiment, the monosodium salt is Form C of the monosodium salt of the compound of formula (I) having an X-ray powder diffraction pattern comprising 2θ values ​​at 10.52°±0.2°, 13.64°±0.2°, 14.40°±0.2°, 15.86°±0.2°, 18.72°±0.2°, 19.14°±0.2°, 19.47°±0.2°, 20.31°±0.2°, 21.16°±0.2°, 23.94°±0.2°, 24.68°±0.2°, 26.21°±0.2°, and 29.03°±0.2°.

[0036] In other embodiments, the monosodium salt has the following refractive indices: 5.24°±0.2°, 5.61°±0.2°, 8.88°±0.2°, 9.54°±0.2°, 10.52°±0.2°, 13.64°±0.2°, 14.40°±0.2°, 14.78°±0.2°, 15.86°±0.2°, 16.46°±0.2°, 16.95°±0.2°, 17.62°±0.2°, 18.62°±0.2°, 19.62°±0.2°, 20.62°±0.2°, 21.62°±0.2°, 22.62°±0.2°, 23.62°±0.2°, 24.62°±0.2°, 25.62°±0.2°, 26.62°±0.2°, 27.62°±0.2°, 28.62°±0.2°, 29.62°±0.2°, 30.62°±0.2°, 31.62°±0.2°, 32.62°±0.2°, 33.62°±0.2°, 34.62°±0.2°, 35.62°±0.2°, 36.62°±0.2°, 37.62°±0.2°, 38.62°±0.2°, 39.62°±0.2°, 40.62°±0.2°, 41.62°±0.2°, 42.62°±0.2°, 43.62°±0.2°, 44. °±0.2°, 17.86°±0.2°, 18.72°±0.2°, 19.14°±0.2°, 19.47°±0.2°, 20.31°±0.2°, 20.74°±0.2°, 21.16°±0.2°, 22.09°±0.2°, 22.61°±0.2°, 23.94°±0.2°, 24.29°±0.2°, 24. 68°±0.2°, 26.21°±0.2°, 27.03°±0.2°, 27.60°±0.2°, 28.32°±0.2°, 29.03°±0.2°, 30.10°±0.2°, 31.73°±0.2°, 31.94°±0.2°, 33.86°±0.2°, 34.33°±0.2°, 35.60°±0.2°, 3 Crystalline Form C of the monosodium salt of compound of formula (I) having an X-ray powder diffraction pattern with 2θ values ​​at 6.01°±0.2°, 36.95°±0.2°, 38.02°±0.2°, 38.86°±0.2°, 40.32°±0.2°, 41.00°±0.2°, 42.08°±0.2° and 44.21°±0.2°.

[0037] In another embodiment, the monosodium salt is crystalline Form C of the monosodium salt of the compound of Formula (I) having an X-ray powder diffraction (XRPD) pattern substantially in accordance with the pattern shown in FIG.

[0038] In some embodiments, the monosodium salt is an amorphous form of the monosodium salt of the compound of Formula (I) having an X-ray powder diffraction (XRPD) pattern substantially in accordance with the pattern shown in FIG.

[0039] In some embodiments, the lithium salt is crystalline Form A of the monolithium salt of the compound of Formula (I) having an X-ray powder diffraction pattern comprising 2θ values ​​at 9.98°±0.2°, 13.82°±0.2°, 21.74°±0.2°, 23.70°±0.2°, 25.03°±0.2°, 26.82°±0.2°, and 32.96°±0.2°.

[0040] In another embodiment, the lithium salt is crystalline Form A of the monolithium salt of the compound of formula (I) having an X-ray powder diffraction pattern comprising 2θ values ​​at 9.98°±0.2°, 13.82°±0.2°, 15.83°±0.2°, 16.25°±0.2°, 19.64°±0.2°, 20.02°±0.2°, 21.74°±0.2°, 22.16°±0.2°, 23.70°±0.2°, 25.03°±0.2°, 26.38°±0.2°, 26.82°±0.2°, 30.27°±0.2°, and 32.96°±0.2°.

[0041] In other embodiments, the lithium salts are at 3.60°±0.2°, 8.33°±0.2°, 8.97°±0.2°, 9.58°±0.2°, 9.98°±0.2°, 11.25°±0.2°, 12.24°±0.2°, 13.26°±0.2°, 13.82°±0.2°, 15.34°±0.2°, 15.83°±0.2°, 16.25°±0.2°, 17.25°±0.2°, 18.25°±0.2°, 19.25°±0.2°, 20.25°±0.2°, 21.25°±0.2°, 22.25°±0.2°, 23.25°±0.2°, 24.25°±0.2°, 25.25°±0.2°, 26.25°±0.2°, 27.25°±0.2°, 28.25°±0.2°, 29.25°±0.2°, 30.25°±0.2°, 31.25°±0.2°, 32.25°±0.2°, 33.25°±0.2°, 34.25°±0.2°, 35.25°±0.2°, 36.25°±0.2°, 37.25°±0.2°, 38.25°±0.2°, 39.25°±0.2°, 40.25°±0.2°, 41.25°±0.2°, 42.25°±0.2°, 43.25°±0.2° °, 16.61°±0.2°, 17.31°±0.2°, 18.06°±0.2°, 18.90°±0.2°, 19.64°±0.2°, 20.02°±0.2°, 21.02°±0.2°, 21.28°±0.2°, 21.74°±0.2°, 22.16°±0.2°, 23.70°±0.2°, 24.37°±0.2°, 25.03°±0.2 °, 25.52°±0.2°, 26.38°±0.2°, 26.82°±0.2°, 27.59°±0.2°, 28.15°±0.2°, 28.74°±0.2°, 29.30°±0.2°, 29.69°±0.2°, 30.27°±0.2°, 30.82°±0.2°, 31.45°±0.2°, 32.60°±0.2°, 32.96°±0.2 2θ values ​​at 33.96°±0.2°, 36.26°±0.2°, 37.86°±0.2°, 38.76°±0.2°, 39.40°±0.2°, 41.02°±0.2°, 41.98°±0.2°, 42.73°±0.2° and 43.64°±0.2°.

[0042] In another embodiment, the lithium salt is crystalline Form A of the monolithium salt of the compound of Formula (I), having an X-ray powder diffraction (XRPD) pattern substantially in accordance with the pattern shown in FIG.

[0043] In some embodiments, the potassium salt is crystalline Form A of the monopotassium salt of the compound of Formula (I) having an X-ray powder diffraction pattern comprising 2θ values ​​at 11.04°±0.2°, 16.29°±0.2°, 19.75°±0.2°, 21.26°±0.2°, 22.22°±0.2°, and 23.33°±0.2°.

[0044] In another embodiment, the potassium salt is crystalline Form A of the monopotassium salt of the compound of formula (I) having an X-ray powder diffraction pattern comprising 2θ values ​​at 11.04°±0.2°, 14.28°±0.2°, 16.29°±0.2°, 19.75°±0.2°, 20.01°±0.2°, 21.26°±0.2°, 22.22°±0.2°, 23.33°±0.2°, 24.02°±0.2°, 25.87°±0.2°, 27.83°±0.2°, and 32.47°±0.2°.

[0045] In other embodiments, the potassium salt is at 5.53°±0.2°, 11.04°±0.2°, 14.28°±0.2°, 14.67°±0.2°, 16.29°±0.2°, 17.19°±0.2°, 19.18°±0.2°, 19.75°±0.2°, 20.01°±0.2°, 21.26°±0.2°, 22.01°±0.2°, 23.01°±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°, 46.01°±0.2°, 47.01°±0.2°, 48.01°±0.2°, 49.01°±0.2°, 50.01°±0 1.61°±0.2°, 22.22°±0.2°, 23.33°±0.2°, 24.02°±0.2°, 25.47°±0.2°, 25.87°±0.2°, 26.46°±0.2°, 27.07°±0.2°, 27.83°±0.2°, 28.76°±0.2°, 29.49°±0.2°, 30.37°±0.2° .2°, 31.01°±0.2°, 32.47°±0.2°, 32.96°±0.2°, 33.64°±0.2°, 33.98°±0.2°, 36.27°±0.2°, 38.87°±0.2°, 39.22°±0.2°, 40.59°±0.2°, 41.36°±0.2°, 41.77°±0.2°, 43. The compound of formula (I) is crystalline Form A of the monopotassium salt of the compound of formula (I), having an X-ray powder diffraction pattern comprising 2θ values ​​at: 44.51°±0.2°, 46.39°±0.2°, 47.48°±0.2°, 48.26°±0.2°, 50.58°±0.2°, 51.71°±0.2° and 54.23°±0.2°.

[0046] In another embodiment, the potassium salt is crystalline Form A of the monopotassium salt of the compound of Formula (I), said crystalline Form A of the monopotassium salt being characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with the pattern depicted in FIG.

[0047] In some embodiments, the choline salt is crystalline Form A of the monocholine salt of the compound of Formula (I) having an X-ray powder diffraction pattern comprising 2θ values ​​at 8.31°±0.2°, 16.94°±0.2°, 19.82°±0.2°, 22.20°±0.2°, 22.63°±0.2°, and 22.85°±0.2°.

[0048] In another embodiment, the choline salt is crystalline Form A of the monocholine salt of the compound of Formula (I) having an X-ray powder diffraction pattern comprising 2θ values ​​at 5.65°±0.2°, 8.31°±0.2°, 10.31°±0.2°, 16.53°±0.2°, 16.94°±0.2°, 17.27°±0.2°, 19.82°±0.2°, 22.20°±0.2°, 22.63°±0.2°, 22.85°±0.2°, 23.97°±0.2°, 24.81°±0.2°, and 29.07°±0.2°.

[0049] In other embodiments, the choline salt is at 5.65°±0.2°, 7.12°±0.2°, 7.52°±0.2°, 8.31°±0.2°, 9.40°±0.2°, 10.31°±0.2°, 11.29°±0.2°, 13.51°±0.2°, 14.92°±0.2°, 15.29°±0.2°, 16.53°±0.2°, 17.92°±0.2°, 18.92°±0.2°, 19.92°±0.2°, 20.92°±0.2°, 21.92°±0.2°, 22.92°±0.2°, 23.92°±0.2°, 24.92°±0.2°, 25.92°±0.2°, 26.92°±0.2°, 27.92°±0.2°, 28.92°±0.2°, 29.92°±0.2°, 30.92°±0.2°, 31.92°±0.2°, 32.92°±0.2°, 33.92°±0.2°, 34.92°±0.2°, 35.92°±0.2°, 36.92°±0.2°, 37.92°±0.2°, 38.92°±0.2°, 39.92°±0.2°, 40.92°±0.2°, 41.92°±0.2°, 42.92°±0.2°, 43.92°±0.2°, 44.92°±0.2 .2°, 16.94°±0.2°, 17.27°±0.2°, 17.50°±0.2°, 18.80°±0.2°, 19.82°±0.2°, 22.20°±0.2°, 22.63°±0.2°, 22.85°±0.2°, 23.42°±0.2°, 23.97°±0.2°, 24.39°±0.2°, 24.8 1°±0.2°, 25.11°±0.2°, 25.45°±0.2°, 26.19°±0.2°, 26.95°±0.2°, 27.70°±0.2°, 28.52°±0.2°, 29.07°±0.2°, 30.15°±0.2°, 31.21°±0.2°, 32.12°±0.2°, 32.95°±0.2°, Crystalline Form A of the monocholine salt of compound of formula (I) having an X-ray powder diffraction pattern with 2θ values ​​at 33.33°±0.2°, 34.15°±0.2°, 35.49°±0.2°, 36.11°±0.2°, 38.57°±0.2°, 40.18°±0.2°, 41.92°±0.2° and 42.99°±0.2°.

[0050] In another embodiment, the choline salt is crystalline Form A of the monocholine salt of the compound of Formula (I) having an X-ray powder diffraction (XRPD) pattern substantially in accordance with the pattern presented in FIG.

[0051] In another aspect, provided herein is a pharmaceutical composition comprising a base addition salt disclosed herein and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or combination thereof.

[0052] In some embodiments, the pharmaceutical compositions disclosed herein further comprise an additional therapeutic agent selected from a chemotherapeutic agent, an antiproliferative agent, an agent for treating atherosclerosis, an agent for treating pulmonary fibrosis, or a combination thereof.

[0053] In some embodiments, the base addition salt in the pharmaceutical compositions disclosed herein can be in any solid form, particularly any crystalline form, amorphous form, or a combination thereof.

[0054] In further embodiments, the additional therapeutic agent is chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecachine irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin, daunorubicin, mitoxantrone, bleomycin, mitomycin, ixabepilone, tamoxifen, flutamide, gonadorelin analogues, megestrol, prednisone, dexamethasone, methylprednisolone, thalidomide, interferon alpha, leucovorin, sirolimus, temsirolimus, everolimus, afatinib, alisertib, amuvatinib, apatinib , axitinib, bortezomib, bosutinib, brivanib, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, danusertib, dasatinib, erlotinib, ganetespib, gefitinib, ibrutinib, icotinib, imatinib, iniparib, lapatinib, lenvatinib, masitinib, neratinib, nilotinib, niraparib, oprozomib, olaparib, pazopanib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib tivozanib, ruxolitinib, saracatinib, salidegib, sorafenib, sunitinib, tasocitinib, telatinib, tivozanib, tofacitinib, trametinib, vandetanib, veliparib, vemurafenib, vismodegib, alemtuzumab, bevacizumab, brentuximab vedotin, catumaxomab, cetuximab, denosumab, gemtuzumab, ipilimumab, nimotuzumab, ofatumumab, panitumumab, ramucirumab, rituximab, trastuzumab, or a combination thereof.

[0055] In another aspect, provided herein is a method for the prevention, management, treatment or lessening of severity of a proliferative disorder in a patient suffering from the disorder, comprising administering to the patient a pharmaceutically effective amount of a base addition salt disclosed herein or a pharmaceutical composition disclosed herein.

[0056] In another aspect, provided herein is the use of the base addition salts disclosed herein and pharmaceutical compositions thereof in the manufacture of a medicament for the prevention, management, treatment or lessening of the severity of a proliferative disorder in a patient.

[0057] In some embodiments, the proliferative disorder is metastatic cancer, colon cancer, gastric adenocarcinoma, bladder cancer, breast cancer, kidney cancer, liver cancer, lung cancer, skin cancer, thyroid cancer, head and neck cancer, prostate cancer, pancreatic cancer, cancer of the CNS, glioblastoma, a myeloproliferative disorder, atherosclerosis, or pulmonary fibrosis.

[0058] In another aspect, provided herein is the use of the base addition salts disclosed herein and pharmaceutical compositions thereof in the manufacture of a medicament for inhibiting or modulating a protein kinase.

[0059] In some embodiments, the protein kinase is PI3K, mTOR, or a combination thereof.

[0060] In another aspect, provided herein is a base addition salt or a pharmaceutical composition thereof for use in the prevention, management, treatment or lessening of the severity of a proliferative disorder in a patient.

[0061] In some embodiments, the proliferative disorder is metastatic cancer, colon cancer, gastric adenocarcinoma, bladder cancer, breast cancer, kidney cancer, liver cancer, lung cancer, skin cancer, thyroid cancer, head and neck cancer, prostate cancer, pancreatic cancer, cancer of the CNS, glioblastoma, a myeloproliferative disorder, atherosclerosis, or pulmonary fibrosis.

[0062] In another aspect, provided herein is a base addition salt or pharmaceutical composition thereof for use in inhibiting or modulating the activity of a protein kinase.

[0063] In some embodiments, the protein kinase is PI3K, mTOR, or a combination thereof.

[0064] In some embodiments, provided herein are methods for inhibiting or modulating PI3K or mTOR, comprising contacting a kinase with a base addition salt according to the present invention or a composition according to the present invention. In some embodiments, the present invention provides methods for inhibiting or modulating PI3K or mTOR signaling, comprising contacting a receptor with a base addition salt according to the present invention or a composition according to the present invention. In some embodiments, the inhibition or modulation of PI3K or mTOR activity can be in a cell or a multicellular organism. If in a multicellular organism, the method according to this aspect of the present invention comprises administering a base addition salt according to the present invention or a composition according to the present invention to the organism. In some embodiments, the organism is a mammal. In other embodiments, the mammal is a human. In still other embodiments, the method further comprises contacting the kinase with an additional therapeutic agent.

[0065] In another aspect, provided herein are methods of inhibiting the proliferative activity of a cell, comprising contacting the cell with an effective growth-inhibiting amount of a base addition salt according to the invention or a composition thereof. In some embodiments, the method further comprises contacting the cell with an additional therapeutic agent.

[0066] In another aspect, provided herein are methods of treating a cell proliferative disorder in a patient, comprising administering to a patient in need of such treatment an effective therapeutic amount of a base addition salt according to the invention or a composition thereof. In some embodiments, the method further comprises administering an additional therapeutic agent.

[0067] In some embodiments, provided herein are methods of inhibiting tumor growth in a patient, comprising administering to a patient in need thereof an effective therapeutic amount of a base addition salt according to the present invention or a composition thereof. In some embodiments, the method further comprises administering an additional therapeutic agent.

[0068] In another aspect, provided herein is a method for preparing a base addition salt of a compound of Formula (I).

[0069] The crystalline forms of the base addition salts of the present invention can be prepared by conventional preparation methods, and some crystalline forms can be prepared by crystal transformation.

[0070] The amorphous form of the present invention can be prepared by spray drying. The yield of spray drying as described in the present invention is affected by several factors, such as the air inlet temperature, air outlet temperature, and system pressure during the spraying process. The air inlet temperature, air outlet temperature, and system pressure during the spraying process are related to the type of equipment and the solvent used.

[0071] The solvent used in the preparation of the salt in the present invention is not particularly limited, and any solvent that can dissolve the starting material and does not affect its properties is included in the present invention.In addition, similar modifications in the art, equivalent replacements, or equivalents of the solvents described in the present invention, solvent combinations, and solvent combinations with different ratios are considered to be included in the scope of the present invention.The present invention provides a better solvent to be used in each reaction step.

[0072] The preparation of the salts in the present invention is described in detail in the Examples section. Meanwhile, the present invention provides biological test experiments (such as pharmacokinetic experiments), solubility experiments, stability experiments (including high temperature, high humidity and lighting experiments), and hygroscopicity experiments for the salts. The results show that the salts have good biological activity, good solubility and high stability, and are suitable for pharmaceutical use.

[0073] Definitions and General Terms Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. The present invention is intended to cover all alternatives, modifications, and equivalents that may be included within the scope of the present invention, as defined by the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated literature, patents, and similar materials differs or contradicts with this application, including but not limited to defined terms, term usage, described techniques, etc., this application controls.

[0074] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications mentioned herein are incorporated by reference in their entirety.

[0075] The term "comprising" means open-ended, including the indicated elements but not excluding other elements.

[0076] Crystalline forms are considered to be "described" graphical representations in this invention. These include, for example, X-ray single crystal diffraction patterns, X-ray powder diffraction patterns, Raman spectroscopy, Fourier transform-infrared spectra, DSC curves, and solid-state NMR spectra. A skilled artisan will appreciate that slight errors may exist in the graphical representation of this type of data (e.g., relative peak intensities and peak positions) due to variations in instrument response, sample concentration, and purity, which are well known in the art. Nevertheless, a skilled artisan can compare the graphical data in this literature with that of an unknown crystalline form to determine whether the two sets of graphical data represent the same crystalline form.

[0077] "XRD" refers to X-ray diffraction.

[0078] The terms "amorphous" or "non-crystalline" as used herein are intended to denote that a substance, composition, or product lacks the characteristics of a crystalline form or structure. They are not crystalline as determined by XRPD, are not birefringent or cubic under a polarized light microscope, or are characterized by a diffuse X-ray powder diffraction pattern lacking sharp peaks. In some embodiments, a sample containing an amorphous form of a substance may be essentially free of other amorphous and / or crystalline forms.

[0079] As used herein, a "substantially pure" crystalline form refers to a crystalline form that is substantially free of one or more other crystalline forms, i.e., the crystalline form has a purity of at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 93%, at least about 95%, at least about 98%, at least about 99%, at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, or at least about 99.9%; or the crystalline form has 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% of one or more other crystalline forms and / or impurities, based on the total volume or weight of the crystalline form and one or more other crystalline forms and / or impurities.

[0080] As used herein, an X-ray powder diffraction (XRPD) pattern or differential scanning calorimetry (DSC) thermogram that is "substantially the same as" the figure refers to an X-ray powder diffraction (XRPD) pattern, differential scanning calorimetry (DSC) thermogram, or thermogravimetric analysis curve (TGA) that has 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 shown in the figure.

[0081] The term "2-theta value" or "2θ" refers to the peak position in degrees based on the experimental setup of an X-ray diffraction experiment, which is the common abscissa unit in a diffraction pattern. The experimental setup requires that the reflected beam is recorded at an angle 2-theta (2θ) when the incident beam forms an angle theta (θ) with a particular lattice plane and the reflected beam is diffracted. It should be understood that references herein to specific 2θ values ​​for a particular polymorph are intended to mean the 2θ value (in degrees) as measured using the X-ray diffraction experimental conditions described herein. For example, as described in this invention, a radiation source (Cu, kα, Kα1 (Å): 1.540598; Kα2 (Å): 1.544426; Kα2 / Kα1 intensity ratio: 0.50) was used.

[0082] The terms "X-ray powder diffraction pattern" or "XPRD pattern" or "XRD pattern" refer to an experimentally observed diffractogram or parameters derived therefrom. X-ray powder diffraction patterns are characterized by peak positions (abscissa) and intensities (ordinate). In the realm of X-ray powder diffraction (XRD), relative peak heights in an XRD pattern depend on many factors related to sample preparation and instrument geometry, while peak positions are relatively insensitive to experimental details. Thus, in some embodiments, crystalline compounds described herein characterized by an XRD pattern with several peak positions have essentially the same properties as the XRD patterns shown in the accompanying drawings of the present invention. Depending on the current state of the experimental equipment, the error range in the scattering angles (2θ) of the diffraction peaks is ±0.1°, ±0.2°, ±0.3°, ±0.4°, or ±0.5°. In some embodiments, the error range is ±0.2°.

[0083] In the realm of differential scanning calorimetry (DSC), the relative peak heights of a DSC trace depend on many factors related to sample preparation and instrument geometry, while peak positions are relatively insensitive to experimental details. Thus, in some embodiments, crystalline compounds disclosed herein characterized by a DSC trace having several peak positions have essentially the same properties as the DSC traces shown in the accompanying drawings of the invention. Depending on the current state of the experimental equipment, the margin of error in the melting peak is in the range of ±1°C, ±2°C, ±3°C, ±4°C, or ±5°C. In some embodiments, the margin of error is ±3°C.

[0084] The term "relative intensity" refers to the intensity of a peak relative to the intensity of the most intense peak in an X-ray powder diffraction pattern, which is taken as 100%.

[0085] As used herein, when referring to data presented in a spectrum and / or graph, the term "peak" refers to a feature that one of ordinary skill in the art would recognize as not being attributable to background noise.

[0086] As used herein, all numbers disclosed herein are approximations regardless of whether the word "about" is used in connection therewith. The value of each number may vary by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, or 20%.

[0087] General method for preparing crystalline forms Crystalline forms may be prepared by various methods, including, but not limited to, crystallization or recrystallization from an appropriate solvent mixture; sublimation; growth from the melt; solid-state transformation from another phase; crystallization from supercritical fluids; and jet atomization. Techniques for crystallizing or recrystallizing crystalline forms in a solvent mixture include, but are not limited to, evaporation of the solvent; reducing the temperature of the solvent mixture; seeding a supersaturated solvent mixture of the compound and / or its salt; freeze-drying the solvent mixture; and adding an anti-solvent (counter-solvent) to the solvent mixture. High-throughput crystallization techniques may also be used to prepare crystalline forms, including polymorphs.

[0088] Drug crystals, including polymorphs, methods of preparation, and characterization of drug crystals are reviewed in Solid-State Chemistry of Drugs, SR Byrn, RR Pfeiffer, and JG Stowell, 2nd ed., SSCI, West Lafayette, Indiana (1999).

[0089] In the crystallization technique that employs a solvent or multiple solvents, the solvent is typically selected based on one or more factors, including but not limited to, for example, the solubility of the compound; the crystallization technique used; and the vapor pressure of the solvent.A combination of solvents may also be employed.For example, a compound may be solubilized in a first solvent to obtain a solution, and then an anti-solvent may be added thereto to reduce the solubility of the compound in the solution, thereby forming precipitation crystals.Anti-solvent is a solvent in which a compound has low solubility.

[0090] Seed crystals may be added to any crystallization mixture to promote crystallization. Seeding may be employed to control the growth of a particular polymorph and / or to control the particle size distribution of the crystalline product. Therefore, calculating the amount of seed required depends on the size of the available seeds and the desired average product particle size, as described, for example, in "Programmed Cooling Batch Crystallizers," J. W. Mullin and J. Nyvlt, Chemical Engineering Science, 1971, 26, pp. 369-377. Generally, small-sized seeds are required to effectively control the growth of crystals in a batch. Small-sized seeds may be produced by sieving, grinding, or micronizing larger crystals or by microcrystallizing a solution. Care must be taken when grinding or micronizing crystals to avoid a change in crystallinity from the desired crystalline form (i.e., to amorphous or another polymorphic phase).

[0091] The cooled crystallization mixture may be filtered under vacuum, and the isolated solid product may be washed with a suitable solvent, such as a cold recrystallization solvent. After washing, the product may be dried under a nitrogen or air purge to obtain the desired crystalline form. The product may be analyzed by suitable spectroscopic or analytical techniques, including, but not limited to, differential scanning calorimetry (DSC); X-ray powder diffraction (XRD); and thermogravimetric analysis (TGA), to ensure that a crystalline form of the compound has formed. The resulting crystalline form is obtained in an isolated yield of greater than about 70 wt.%, preferably greater than about 90 wt.%, based on the mass of compound initially employed in the crystallization procedure.

[0092] X-ray powder diffraction studies (XRPD): X-ray powder diffraction (XRPD) patterns were collected on an X-ray powder diffractometer (Empyrean, PANalytical, Holland) equipped with an automatic transmission-reflection sample holder (3*15). The X-ray tube (Cu, kα, Kα1 (Å): 1.540598; Kα2 (Å): 1.544426; Kα2 / Kα1 = 0.50) was set at a voltage of 45 kV, a current of 40 mA, and an exposure length of 10.0 mm. Scanning parameters were continuous scan; range of 3° to 40° (2θ ± 0.2°); step size of 0.0168°; time per step of 10 s. Data were collected at room temperature (approximately 18 to 30°C). Samples (typically 1–2 mg) were prepared as slabs by slightly pressing them onto a glass slide to obtain a flat surface. Data were collected by Data collector software and analyzed by Data viewer and HighScore Plus software.

[0093] Differential Scanning Calorimetry (DSC) Analysis: All DSC measurements were performed on a TA Instruments™ Model Q2000 Differential Scanning Calorimeter. Samples (approximately 2-6 mg) were weighed into aluminum pans, recorded to the nearest hundredth of a milligram, and transferred to the DSC instrument. The instrument was purged with nitrogen gas at 50 mL / min. Data were collected between room temperature and 300°C at a heating rate of 10°C / min. Data were analyzed using TA Universal Analysis software.

[0094] Thermogravimetric Analyzer (TGA): All TGA scans were performed on a TGA TAQ500 thermogravimetric analyzer. Samples (approximately 10-30 mg) were placed in pre-tared platinum pans. The sample mass was accurately measured and recorded to the nearest thousandth of a milligram by the instrument. The furnace was purged with nitrogen gas at 60 mL / min. Data were collected between room temperature and 300 °C at a heating rate of 10 °C / min. Data were analyzed using TA Universal Analysis software.

[0095] 1H NMR spectra were recorded at room temperature on a Bruker 400 MHz or 600 MHz spectrometer. 13 C NMR spectra were recorded at room temperature (about 21° C. to about 25° C.) on a Bruker 100 MHz spectrometer using TMS (0 ppm) as the reference standard. 1 H NMR spectra were obtained as CDCl3, DMSO-d6, CD3OD, or d6-acetone solutions (reported in ppm) using TMS (0 ppm) or chloroform (7.25 ppm) as reference standards. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, J, when given, are reported in hertz (Hz).

[0096] Low-resolution mass spectral (MS) data were typically determined on an Agilent 6120 quadrupole HPLC-MS (Zorbax SB-C18, 2.1 × 30 mm, 3.5 microns, 6-minute run, 0.6 mL / minute flow rate, 5% to 95% (0.1% formic acid in CH3CN) in (0.1% formic acid in H2O)) using UV detection at 210 nm / 254 nm and electrospray ionization mode (ESI).

[0097] The ratio of the compound of formula (I) to the inorganic base was analyzed and determined using inductively coupled plasma mass spectrometry (ICP-MS). Test conditions: Agilent 7800 ICP-MS system, He model, Sc45 as internal standard element. [Brief explanation of the drawings]

[0098] [Figure 1] 1 is a graph depicting the X-ray powder diffraction pattern of crystalline form A of the monosodium salt of the compound of formula (I). [Figure 2] 1 is a graph illustrating the X-ray powder diffraction pattern of crystalline form B of the monosodium salt of the compound of formula (I). [Figure 3] 1 is a graph depicting the X-ray powder diffraction pattern of crystalline form C of the monosodium salt of the compound of formula (I). [Figure 4] 1 is a graph depicting the X-ray powder diffraction pattern of the amorphous form of the monosodium salt of the compound of formula (I). [Figure 5] 1 is a graph illustrating the X-ray powder diffraction pattern of crystalline form A of the monolithium salt of compound of formula (I). [Figure 6] 1 is a graph illustrating the X-ray powder diffraction pattern of crystalline form A of the monopotassium salt of the compound of formula (I). [Figure 7] 1 is a graph illustrating the X-ray powder diffraction pattern of crystalline form A of the monocholine salt of the compound of formula (I). [Figure 8] 1 is a graph illustrating the differential scanning calorimetry thermogram of crystalline Form A of the monosodium salt of the compound of formula (I). [Figure 9] 1 is a graph illustrating the differential scanning calorimetry thermogram of crystalline form B of the monosodium salt of the compound of formula (I). [Figure 10] 1 is a graph illustrating the differential scanning calorimetry thermogram of crystalline Form C of the monosodium salt of the compound of formula (I). [Figure 11] 1 is a graph illustrating the differential scanning calorimetry thermogram of the amorphous form of the monosodium salt of the compound of formula (I). [Figure 12] 1 is a graph illustrating the differential scanning calorimetry thermogram of crystalline Form A of the monolithium salt of the compound of formula (I). [Figure 13] 1 is a graph illustrating the differential scanning calorimetry thermogram of crystalline Form A of the monopotassium salt of the compound of formula (I). [Figure 14] 1 is a graph illustrating the differential scanning calorimetry thermogram of crystalline Form A of the monocholine salt of the compound of formula (I). DETAILED DESCRIPTION OF THE INVENTION

[0099] The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention.

[0100] N-(5-(3-cyanopyrazolo[1,5-a]pyridin-5-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide can be prepared according to the synthesis method of Example 3 disclosed in WO2014130375A1. [Example]

[0101] Example 1 Crystalline Form A of the monosodium salt of N-(5-(3-cyanopyrazolo[1,5-a]pyridin-5-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide Method I for preparing crystalline form A of the monosodium salt To a mixture of N-(5-(3-cyanopyrazolo[1,5-a]pyridin-5-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (600.00 g, 1359 mmol) in acetone (5400 mL) was added aqueous sodium hydroxide solution (59.81 g, 1495 mmol, 600 mL) at room temperature. The mixture was heated to 60±5°C and stirred for 0.5 hours, then cooled to 25±5°C and filtered. The filtrate was added to a reaction kettle. The temperature was controlled at 25±5°C, and then isopropanol (12000 mL) was added. The mixture was cooled to 0±5°C, stirred for 1 hour, and filtered to obtain a filter cake, which was dried at 60°C for 24 hours to obtain the crude sodium salt. A mixture of the crude sodium salt in absolute ethanol (5500 mL) was heated to 78±5°C and stirred for 4 hours, then cooled to 0±5°C and stirred for 1 hour, filtered, and the filter cake was dried at 60°C for 24 hours to give a pale yellow solid (475 g, 86.4%).

[0102] Method II for preparing crystalline form A of the monosodium salt To a mixture of N-(5-(3-cyanopyrazolo[1,5-a]pyridin-5-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (500 mg, 1.13 mmol) in ethanol (8 mL) was added a solution of sodium hydroxide (50 mg, 1.25 mmol) in ethanol (2 mL) at room temperature. The mixture was heated to 80±5°C and stirred for 0.5 h, then cooled to 25±5°C and filtered to obtain a filter cake, which was dried at 60°C for 24 h to obtain a yellow solid (446 mg, 84.97%).

[0103] Identification of crystalline form A of the monosodium salt (1) The salt formation ratio was 1:1 as determined by ICP-MS. (2) The X-ray powder diffraction pattern of crystalline form A of the monosodium salt is shown in Figure 1. The error range of the characteristic peaks in 2θ was ±0.2°. (3) The differential scanning calorimetry thermogram of crystalline form A of the monosodium salt is shown in Figure 8 and contains an endothermic peak at 307.72°C. The error bar was ±3°C.

[0104] Example 2 Crystalline Form B of the monosodium salt of N-(5-(3-cyanopyrazolo[1,5-a]pyridin-5-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide Preparation of crystalline form B of the monosodium salt To a mixture of N-(5-(3-cyanopyrazolo[1,5-a]pyridin-5-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (2.00 g, 4.53 mmol) in acetone (40 mL) was added aqueous sodium hydroxide solution (190 mg, 4.75 mmol, 2 mL) at room temperature. The mixture was heated to 60±5°C and stirred for 0.5 hours, then cooled to 25±5°C and filtered. The temperature of the filtrate was controlled at 25±5°C, and then isopropanol (40 mL) was added. The mixture was stirred for 1 hour and filtered to obtain a filter cake, which was dried at 60°C for 24 hours to obtain a yellow solid (1.27 g, 60.5%).

[0105] Identification of crystalline form B of the monosodium salt (1) The salt formation ratio was 1:1 as determined by ICP-MS. (2) The X-ray powder diffraction pattern of the crystalline form B of the monosodium salt is shown in Figure 2. The error range of the characteristic peaks in 2θ was ±0.2°. (3) The differential scanning calorimetry thermogram of crystalline form B of the monosodium salt is shown in Figure 9 and contains an endothermic peak at 181.60°C. The error range was ±3°C.

[0106] Example 3 Crystalline form C of the monosodium salt of N-(5-(3-cyanopyrazolo[1,5-a]pyridin-5-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide Preparation of crystalline form C of the monosodium salt A mixture of N-(5-(3-cyanopyrazolo[1,5-a]pyridin-5-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide sodium salt (1.00 g, 2.16 mmol) in water (2 mL) and absolute ethanol (8 mL) was heated to reflux until the solid was completely dissolved, then cooled to 44° C. and filtered. The filter cake was dried at 60° C. for 24 hours to give a pale yellow solid (0.35 g, 35.0%).

[0107] Identification of crystalline form C of the monosodium salt (1) The salt formation ratio was 1:1 as determined by ICP-MS. (2) The X-ray powder diffraction pattern of crystalline form C of the monosodium salt is shown in FIG. The error range in 2θ of the characteristic peak was ±0.2°. (3) The differential scanning calorimetry thermogram of crystalline form C of the monosodium salt is shown in Figure 10 and contains an endothermic peak at 215.76°C. The error bar was ±3°C.

[0108] Example 4 Amorphous form of the monosodium salt of N-(5-(3-cyanopyrazolo[1,5-a]pyridin-5-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide Preparation of the amorphous form of the monosodium salt To a mixture of N-(5-(3-cyanopyrazolo[1,5-a]pyridin-5-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (1.00 g, 2.27 mmol) in dichloromethane (75 mL) and methanol (20 mL) was added a solution of sodium hydroxide (90 mg, 2.25 mmol) in methanol (5 mL) at room temperature. The mixture was heated to 80±5° C. and stirred for 0.5 h, then cooled to 25±5° C. and filtered. The filtrate was concentrated under reduced pressure to give a solid, which was dried at 60° C. for 24 h to give a pale yellow solid (1.05 g, 100%).

[0109] Identification of the amorphous form of the monosodium salt (1) The salt formation ratio was 1:1 as determined by ICP-MS. (2) The X-ray powder diffraction pattern of the amorphous form of the monosodium salt is shown in Figure 4. The error range of the characteristic peaks in 2θ was ±0.2°. (3) The differential scanning calorimetry thermogram of the amorphous form of the monosodium salt is shown in Figure 11 and contains an exothermic peak at 214.79°C. The error bar was ±3°C.

[0110] Example 5 Crystalline Form A of the monolithium salt of N-(5-(3-cyanopyrazolo[1,5-a]pyridin-5-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide Preparation of crystalline form A of the monolithium salt To a mixture of N-(5-(3-cyanopyrazolo[1,5-a]pyridin-5-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (2.00 g, 4.53 mmol) in ethanol (30 mL) was added a solution of lithium hydroxide (141 mg, 5.89 mmol) in ethanol (10 mL) at room temperature. The mixture was heated to reflux and stirred for 1 hour, cooled to room temperature and stirred for 0.5 hours, filtered to give a filter cake, which was dried at 60° C. for 24 hours to give a pale yellow solid (1.84 g, 90.8%).

[0111] Identification of Crystal Form A of the Monolithium Salt (1) The salt formation ratio was 1:1 as determined by ICP-MS. (2) The X-ray powder diffraction pattern of crystalline form A of the monolithium salt is shown in Figure 5. The error range in 2θ of the characteristic peaks was ±0.2°. (3) The differential scanning calorimetry thermogram of crystalline form A of the monolithium salt is shown in Figure 12 and contains an endothermic peak at 209.24°C. The error range was ±3°C.

[0112] Example 6 Crystalline Form A of the monopotassium salt of N-(5-(3-cyanopyrazolo[1,5-a]pyridin-5-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide Preparation of crystalline form A of the monopotassium salt To a mixture of N-(5-(3-cyanopyrazolo[1,5-a]pyridin-5-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (2.00 g, 4.53 mmol) in ethanol (30 mL) was added a solution of potassium hydroxide (280 mg, 4.99 mmol) in ethanol (10 mL) at room temperature. The mixture was heated to reflux and stirred for 1 hour, then cooled to room temperature and stirred for 0.5 hours, filtered to give a filter cake, which was dried at 60° C. for 24 hours to give a pale yellow solid (2.11 g, 97.1%).

[0113] Identification of crystalline form A of the monopotassium salt (1) The salt formation ratio was 1:1 as determined by ICP-MS. (2) The X-ray powder diffraction pattern of crystalline form A of the monopotassium salt is shown in Figure 6. The error range of the characteristic peaks in 2θ was ±0.2°. (3) The differential scanning calorimetry thermogram of crystalline form A of the monopotassium salt is shown in Figure 13 and contains an endothermic peak at 301.12°C. The error range was ±3°C.

[0114] Example 7 Crystalline Form A of the monocholine salt of N-(5-(3-cyanopyrazolo[1,5-a]pyridin-5-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide Preparation of crystalline form A of monocholine salt To a mixture of N-(5-(3-cyanopyrazolo[1,5-a]pyridin-5-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (2.00 g, 4.53 mmol) in ethanol (40 mL) was added an aqueous solution of choline (1.56 g, 46% w / w, 5.89 mmol) at room temperature. The mixture was heated to reflux and stirred for 1 hour, then cooled to room temperature and stirred for 0.5 hours, filtered to give a filter cake, which was dried at 60° C. for 24 hours to give a yellow solid (1.91 g, 77.4%).

[0115] Identification of crystalline form A of monocholine salt. (1) The salt formation ratio is 1 The ratio was 1:1 as determined by 1 H NMR. (2) The X-ray powder diffraction pattern of crystalline form A of the monocholine salt is shown in Figure 7. The error range in 2θ of the characteristic peaks was ±0.2°. (3) The differential scanning calorimetry thermogram of crystalline form A of the monocholine salt is shown in Figure 14, which contains an endothermic peak at 215.43°C. The error range was ±3°C.

[0116] Example 8 Pharmacokinetic studies The pharmacokinetic properties of amorphous and crystalline forms of the base addition salt of Compound (I) disclosed herein were evaluated in beagle dogs. The LC / MS / MS system used for the analysis consisted of an Agilent 1200 Series vacuum degasser, a binary pump, a well-plate autosampler, a thermostatted column compartment, and an Agilent G6430 triple quadrupole mass spectrometer equipped with an electrospray ionization (ESI) source. Quantitative analysis was performed using MRM mode. The parameters for MRM conversion are listed in Table A.

[0117] [Table 1]

[0118] An Agilent XDB-C18, 2.1 x 30 mm, 3.5 μM column was used for the analysis. 5 μL of sample was injected. Analysis conditions: The mobile phases were 0.1% formic acid in water (A) and 0.1% formic acid in methanol (B). The flow rate was 0.4 mL / min. The mobile phase gradient is shown in Table B.

[0119] [Table 2]

[0120] Alternatively, an Agilent 6330 Series LC / MS / MS spectrometer equipped with a G1312A binary pump, a G1367A autosampler, and a G1314C UV detector was used for the analysis. An ESI source was used on the LC / MS / MS spectrometer. Analysis was performed in positive ion mode as needed, and the MRM conversion for each analyte was optimized using a standard solution. A Capcell MP-C18 100 x 4.6 mm I.D., 5 μM column (Phenomenex, Torrance, California, USA) was used during the analysis. The mobile phase was 5 mM ammonium acetate, 0.1% MeOH in water (A): 5 mM ammonium acetate, 0.1% MeOH in acetonitrile (B) (70 / 30, v / v). The flow rate was 0.6 mL / min. The column was maintained at room temperature. 20 μL of sample was injected.

[0121] Capsules of amorphous or crystalline base addition salt of Compound (I) mixed with excipients were administered to beagle dogs by gavage at doses of 2.5 mg / kg, 5.0 mg / kg, 7 mg / kg, or 10 mg / kg, respectively. Blood samples (0.3 mL) were collected at 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12, and 24 hours or at 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24 hours and centrifuged at 3,000 or 4,000 rpm for 2 to 10 minutes. Plasma solutions were collected and analyzed by LC / MS / MS as described above. Pharmacokinetic parameters were calculated according to a noncompartmental model using the WinNonlin procedure. Pharmacokinetic parameters are shown in Table 1.

[0122] [Table 3]

[0123] The results listed in Table 1 above are for crystalline form A of the monosodium salt, crystalline form B of the monosodium salt, crystalline form C of the monosodium salt, amorphous form A of the monolithium salt, crystalline form A of the monopotassium salt, and crystalline form A of the monocholine salt. max and AUC最終 are much greater than that of the compound of formula (I), indicating that crystalline form A of the monosodium salt, crystalline form B of the monosodium salt, crystalline form C of the monosodium salt, amorphous form A of the monolithium salt, crystalline form A of the monopotassium salt and crystalline form A of the monocholine salt have good exposure and bioavailability in vivo in beagle dogs.

[0124] Example 9 Stability testing An appropriate amount of sample (100-200 mg) was placed on a glass observation glass in the form of a thin layer (less than 5 mm thick). The sample was exposed to the following conditions: high temperature (60 ± 2 °C) for 10 days; high humidity (25 ± 2 °C, 90% ± 5% relative humidity) for 10 days; and lighting conditions (0.7 W h / m 2 The samples were exposed to UV-containing visible light at 4500 lx ± 500 lx, 25 ± 2°C, and 60% ± 5% relative humidity for 10 days; and at room temperature (30 ± 2°C, 65% ± 5% relative humidity) for 10 days. The impurity content of the samples was determined by high-performance liquid chromatography (HPLC) at different time points (days 0, 5, and 10), with the absorption peaks normalized to the highest peak (corresponding to Compound I), which was set to 100%. The HPLC equipment and conditions are shown in Table 2.

[0125] [Table 4]

[0126] The results showed that the crystalline and amorphous forms of the base addition salt of the compound of formula (I) showed no obvious changes in appearance and purity under conditions of high temperature (60°C) and high humidity (25°C, RH 90%±5%), and were stable and suitable for medical use.

[0127] Example 10 Moisture absorption test A stoppered glass weighing bottle was tared and the mass was recorded as m1. Different crystalline or amorphous forms of base addition salts of Compound (I) (approximately 1.0 g) were placed in the tared weighing bottle and capped with a stopper. The total mass was then recorded as m2. The weighing bottle (excluding stopper) was placed in a desiccator containing a saturated solution of ammonium chloride (80% ± 2% RH (relative humidity)) at 25 ± 1 °C. The stoppered weighing bottle was weighed on the 5th and 10th days and the mass was recorded as m3. The moisture absorption capacity was calculated according to the following formula:

[0128]

number

[0129] Experimental results show that the base addition salts of Compound (I) in different crystalline and amorphous forms in the present invention are not hygroscopic.

[0130] Example 11 Solubility Test 0.5 mg of the crystalline form of the base addition salt of Compound (I) was weighed and placed in a 30 mL penicillin bottle, followed by the addition of 15 mL of purified water. The bottle was shaken in a 37°C water bath and the sample was monitored for dissolution. When the sample in the bottle was completely dissolved, small amounts of additional sample were added to the solution several times until the solution was saturated and no further sample could be dissolved. After shaking the bottle for another 24 / 48 hours, an appropriate amount of the 37°C saturated solution was removed from the penicillin bottle and filtered through a membrane filter (polyethersulfone, 0.45 m, 13 mm, JINTENG Co.). 2 mL of the primary filtrate was discarded, and 600 μL of the filtrate and 600 μL of acetonitrile were accurately and quickly measured and then mixed uniformly to obtain an equilibrium test solution. The solubility of the sample was determined by the external standard method.

[0131] The chromatography column used for the analysis was Agilent's ZORBAX SB-C18, 4.6 × 50 mm, 5 μM (or other suitable chromatography column), the detector was an ultraviolet detector with a detection wavelength of 264 nm, the flow rate was 1.0 mL / min, the column temperature was 35°C, the injection volume was 10 μL, the mobile phase was 10 mM sodium dihydrogen phosphate buffer (pH 3.0) and acetonitrile (V:V = 50:50), and the run time was 7 min.

[0132] Conclusion: The experimental results showed that all the crystalline forms of base addition salts of Compound (I) have good solubility.

[0133] The foregoing disclosure has been described in some detail by way of illustration and example, for purposes of clarity and understanding. The invention has been described with reference to various specific preferred embodiments and techniques. It should be understood, however, that many changes and modifications can be made while remaining within the spirit and scope of the invention. As will be apparent to those skilled in the art, changes and modifications can be practiced within the scope of the appended claims. It is therefore to be understood that the above description is intended to be illustrative and not limiting. The scope of the invention should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled.

Claims

1. Formula (I): 【Chemistry 1】 A crystalline or amorphous form of the monosodium, monopotassium or monocholine salt of the compound of formula (I), the crystals are crystalline form A of the monosodium salt of the compound of formula (I) having an X-ray powder diffraction pattern comprising 2θ values ​​at 14.73°±0.2°, 14.93°±0.2°, 21.77°±0.2°, 22.59°±0.2°, 23.29°±0.2° and 24.87°±0.2°; or the crystals are crystalline form B of the monosodium salt of the compound of formula (I) having an X-ray powder diffraction pattern comprising 2θ values ​​at 8.75°±0.2°, 12.27°±0.2°, 14.42°±0.2°, 20.46°±0.2°, 23.64°±0.2°, 25.14°±0.2°, and 25.89°±0.2°; or the crystals are crystalline form C of the monosodium salt of the compound of formula (I) having an X-ray powder diffraction pattern comprising 2θ values ​​at 10.52°±0.2°, 13.64°±0.2°, 14.40°±0.2°, 15.86°±0.2°, 18.72°±0.2°, 19.14°±0.2°, and 24.68°±0.2°; or the amorphous form being an amorphous form of the monosodium salt of the compound of formula (I) having an X-ray powder diffraction (XRPD) pattern substantially in accordance with the pattern set forth in Table 1 below; or Table 1 the crystals are crystalline form A of the monopotassium salt of the compound of formula (I) having an X-ray powder diffraction pattern comprising 2θ values ​​at 11.04°±0.2°, 16.29°±0.2°, 19.75°±0.2°, 21.26°±0.2°, 22.22°±0.2° and 23.33°±0.2°; or the crystals are crystalline form A of the monocholine salt of the compound of formula (I) having an X-ray powder diffraction pattern comprising 2θ values ​​at 8.31°±0.2°, 16.94°±0.2°, 19.82°±0.2°, 22.20°±0.2°, 22.63°±0.2° and 22.85°±0.2°; Crystalline or amorphous.

2. a crystalline form A of the monosodium salt of the compound of formula (I) having an X-ray powder diffraction pattern comprising 2θ values ​​at 10.71°±0.2°, 14.73°±0.2°, 14.93°±0.2°, 19.01°±0.2°, 19.41°±0.2°, 21.57°±0.2°, 21.77°±0.2°, 22.59°±0.2°, 23.29°±0.2°, 24.87°±0.2°, 28.36°±0.2°, and 30.18°±0.2°; or a crystalline form B of the monosodium salt of the compound of formula (I) having an X-ray powder diffraction pattern comprising 2θ values ​​at 8.75°±0.2°, 12.27°±0.2°, 14.42°±0.2°, 15.62°±0.2°, 20.46°±0.2°, 23.32°±0.2°, 23.64°±0.2°, 25.14°±0.2°, 25.89°±0.2°, 26.87°±0.2°, 27.43°±0.2°, 28.09°±0.2°, 32.95°±0.2° and 36.47°±0.2°; or a crystalline form C of the monosodium salt of compound of formula (I), having an X-ray powder diffraction pattern comprising 2θ values ​​at 10.52°±0.2°, 13.64°±0.2°, 14.40°±0.2°, 15.86°±0.2°, 18.72°±0.2°, 19.14°±0.2°, 19.47°±0.2°, 20.31°±0.2°, 21.16°±0.2°, 23.94°±0.2°, 24.68°±0.2°, 26.21°±0.2° and 29.03°±0.2°; The crystalline or amorphous form according to claim 1.

3. 5.59°±0.2°, 9.33°±0.2°, 10.71°±0.2°, 11.21°±0.2°, 14.73°±0.2°, 14.93°±0.2°, 15.39°±0.2°, 16.55°±0.2°, 17.36°±0.2°, 17.64°±0.2°, 18.42°±0.2°, 19.01°±0.2°, 19.41°±0.2°, 19.66°±0.2° , 19.84°±0.2°, 20.26°±0.2°, 21.57°±0.2°, 21.77°±0.2°, 22.34°±0.2°, 22.59°±0.2°, 23.29°±0.2°, 24.15°±0.2°, 24.87°±0.2°, 25.59°±0.2°, 26.26°±0.2°, 26.75°±0.2°, 27.32°±0.2°, 27.87°±0. 2°, 28.36°±0.2°, 28.71°±0.2°, 29.08°±0.2°, 29.59°±0.2°, 30.18°±0.2°, 30.56°±0.2°, 31.01°±0.2°, 31.61°±0.2°, 31.81°±0.2°, 32.14°±0.2°, 32.72°±0.2°, 33.26°±0.2°, 34.14°±0.2°, 35.97° or a crystalline form A of the monosodium salt of compound of formula (I) having an X-ray powder diffraction pattern comprising 2θ values ​​at 36.46°±0.2°, 38.40°±0.2°, 38.83°±0.2°, 39.49°±0.2°, 40.04°±0.2°, 41.32°±0.2°, 42.80°±0.2°, 43.89°±0.2° and 45.77°±0.2°; or 7.23°±0.2°, 8.75°±0.2°, 12.27°±0.2°, 12.88°±0.2°, 13.94°±0.2°, 14.42°±0.2°, 14.87°±0.2°, 15.62°±0.2°, 17.85°±0.2°, 18.51°±0.2°, 18.94°±0.2°, 19.33 °±0.2°, 19.79°±0.2°, 20.46°±0.2°, 21.50°±0.2°, 22.23°±0.2°, 22.79°±0.2°, 23.32°±0.2°, 23.64°±0.2°, 24.67°±0.2°, 25.14°±0.2°, 25.89°±0.2°, 26.87°±0. 2°, 27.43°±0.2°, 28.09°±0.2°, 28.54°±0.2°, 29.02°±0.2°, 29.48°±0.2°, 29.96°±0.2°, 30.74°±0.2°, 31.56°±0.2°, 32.95°±0.2°, 33.50°±0.2°, 35.86°±0.2°, a crystalline form B of the monosodium salt of the compound of formula (I) having an X-ray powder diffraction pattern comprising 2θ values ​​at 36.47°±0.2°, 37.32°±0.2°, 39.11°±0.2°, 39.84°±0.2°, 42.23°±0.2°, 42.93°±0.2°, and 44.44°±0.2°; or 5.24°±0.2°, 5.61°±0.2°, 8.88°±0.2°, 9.54°±0.2°, 10.52°±0.2°, 13.64°±0.2°, 14.40°±0.2°, 14.78°±0.2°, 15.86°±0.2°, 16.46°±0.2°, 16.95°±0.2°, 17.86°±0.2°. 2°, 18.72°±0.2°, 19.14°±0.2°, 19.47°±0.2°, 20.31°±0.2°, 20.74°±0.2°, 21.16°±0.2°, 22.09°±0.2°, 22.61°±0.2°, 23.94°±0.2°, 24.29°±0.2°, 24.68°±0.2°, 26. 21°±0.2°, 27.03°±0.2°, 27.60°±0.2°, 28.32°±0.2°, 29.03°±0.2°, 30.10°±0.2°, 31.73°±0.2°, 31.94°±0.2°, 33.86°±0.2°, 34.33°±0.2°, 35.60°±0.2°, 36.01°±0.2° and 44.21°±0.2°, wherein the crystalline form C of the monosodium salt of the compound of formula (I) has an X-ray powder diffraction pattern comprising 2θ values ​​at 36.95°±0.2°, 38.02°±0.2°, 38.86°±0.2°, 40.32°±0.2°, 41.00°±0.2°, 42.08°±0.2°, and 44.21°±0.2°. The crystalline or amorphous form according to claim 1 or 2.

4. A crystalline form A of the monosodium salt of the compound of formula (I) having an X-ray powder diffraction (XRPD) pattern substantially in accordance with the pattern set forth in Table 2 below; Table 2 or Crystals of crystalline form B of the monosodium salt of the compound of formula (I), having an X-ray powder diffraction (XRPD) pattern substantially in accordance with the pattern set forth in Table 3 below; Table 3 or Crystals of crystalline form C of the monosodium salt of the compound of formula (I), having an X-ray powder diffraction (XRPD) pattern substantially in accordance with the pattern set out in Table 4 below. Table 4 The crystalline or amorphous form according to claim 1.

5. a crystalline form A of the monopotassium salt of compound of formula (I) having an X-ray powder diffraction pattern comprising 2θ values ​​at 11.04°±0.2°, 14.28°±0.2°, 16.29°±0.2°, 19.75°±0.2°, 20.01°±0.2°, 21.26°±0.2°, 22.22°±0.2°, 23.33°±0.2°, 24.02°±0.2°, 25.87°±0.2°, 27.83°±0.2°, and 32.47°±0.2°; a crystalline form A of the monocholine salt of the compound of formula (I), having an X-ray powder diffraction pattern comprising 2θ values ​​at 5.65°±0.2°, 8.31°±0.2°, 10.31°±0.2°, 16.53°±0.2°, 16.94°±0.2°, 17.27°±0.2°, 19.82°±0.2°, 22.20°±0.2°, 22.63°±0.2°, 22.85°±0.2°, 23.97°±0.2°, 24.81°±0.2° and 29.07°±0.2°; The crystalline or amorphous form according to claim 1.

6. 5.53°±0.2°, 11.04°±0.2°, 14.28°±0.2°, 14.67°±0.2°, 16.29°±0.2°, 17.19°±0.2°, 19.18°±0.2°, 19.75°±0.2°, 20.01°±0.2°, 21.26°±0.2°, 21.61°±0.2°, 22.2 2°±0.2°, 23.33°±0.2°, 24.02°±0.2°, 25.47°±0.2°, 25.87°±0.2°, 26.46°±0.2°, 27.07°±0.2°, 27.83°±0.2°, 28.76°±0.2°, 29.49°±0.2°, 30.37°±0.2°, 31.01°± 0.2°, 32.47°±0.2°, 32.96°±0.2°, 33.64°±0.2°, 33.98°±0.2°, 36.27°±0.2°, 38.87°±0.2°, 39.22°±0.2°, 40.59°±0.2°, 41.36°±0.2°, 41.77°±0.2°, 43.03°±0.2 crystalline Form A of the monopotassium salt of compound of formula (I), having an X-ray powder diffraction pattern comprising 2θ values ​​at 44.51°±0.2°, 46.39°±0.2°, 47.48°±0.2°, 48.26°±0.2°, 50.58°±0.2°, 51.71°±0.2°, and 54.23°±0.2°; 5.65°±0.2°, 7.12°±0.2°, 7.52°±0.2°, 8.31°±0.2°, 9.40°±0.2°, 10.31°±0.2°, 11.29°±0.2°, 13.51°±0.2°, 14.92°±0.2°, 15.29°±0.2°, 16.53°±0.2°, 16.94°±0. 2°, 17.27°±0.2°, 17.50°±0.2°, 18.80°±0.2°, 19.82°±0.2°, 22.20°±0.2°, 22.63°±0.2°, 22.85°±0.2°, 23.42°±0.2°, 23.97°±0.2°, 24.39°±0.2°, 24.81°±0.2°, 25 .11°±0.2°, 25.45°±0.2°, 26.19°±0.2°, 26.95°±0.2°, 27.70°±0.2°, 28.52°±0.2°, 29.07°±0.2°, 30.15°±0.2°, 31.21°±0.2°, 32.12°±0.2°, 32.95°±0.2°, 33.33°± 2. The compound of claim 1, wherein the crystalline form A of the monocholine salt of the compound of formula (I) has an X-ray powder diffraction pattern comprising 2θ values ​​at 0.2°, 34.15°±0.2°, 35.49°±0.2°, 36.11°±0.2°, 38.57°±0.2°, 40.18°±0.2°, 41.92°±0.2° and 42.99°±0.2°. The crystalline or amorphous form according to claim 1 or 5.

7. Crystals of crystalline Form A of the monopotassium salt of the compound of formula (I), having an X-ray powder diffraction (XRPD) pattern substantially in accordance with the pattern set forth in Table 6 below; Table 6 A crystalline form A of the monocholine salt of the compound of formula (I) having an X-ray powder diffraction (XRPD) pattern substantially in accordance with the pattern set forth in Table 7 below. Table 7 The crystalline or amorphous form according to claim 1.

8. 8. A pharmaceutical composition comprising the crystalline or amorphous form of any one of claims 1 to 7 and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or combination thereof.

9. 10. The pharmaceutical composition of claim 8, further comprising an additional therapeutic agent selected from a chemotherapeutic agent, an antiproliferative agent, an agent for treating atherosclerosis, an agent for treating pulmonary fibrosis, or a combination thereof.

10. The additional therapeutic agent may be chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, riboflavin ... Poside, trabectedin, dactinomycin, doxorubicin, epirubicin, daunorubicin, mitoxantrone, bleomycin, mitomycin, ixabepilone, tamoxifen, flutamide, gonadorelin analogues, megestrol, prednisone, dexamethasone, methylprednisolone, thalidomide, interferon alpha, leucovorin, sirolimus, temsirolimus, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib Mibuxin, bosutinib, brivanib, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, danusertib, dasatinib, erlotinib, ganetespib, gefitinib, ibrutinib, icotinib, imatinib, iniparib, lapatinib, lenvatinib, masitinib, neratinib, nilotinib, niraparib, oprozomib, olaparib, pazopanib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saraca 10. The pharmaceutical composition of claim 9, wherein the medicament is rituximab, salidegib, sorafenib, sunitinib, tasocitinib, telatinib, tivozanib, tofacitinib, trametinib, vandetanib, veliparib, vemurafenib, vismodegib, alemtuzumab, bevacizumab, brentuximab vedotin, catumaxomab, cetuximab, denosumab, gemtuzumab, ipilimumab, nimotuzumab, ofatumumab, panitumumab, ramucirumab, rituximab, trastuzumab, or a combination thereof.

11. Use of a crystalline or amorphous form of any one of claims 1 to 7 or a pharmaceutical composition of any one of claims 8 to 10 in the manufacture of a medicament for the prevention, management, treatment or lessening of the severity of a proliferative disorder in a patient.

12. 12. The use according to claim 11, wherein the proliferative disease is metastatic cancer, colon cancer, gastric adenocarcinoma, bladder cancer, breast cancer, kidney cancer, liver cancer, lung cancer, skin cancer, thyroid cancer, head and neck cancer, prostate cancer, pancreatic cancer, cancer of the CNS, glioblastoma, myeloproliferative disorders, atherosclerosis or pulmonary fibrosis.

13. 11. A crystalline or amorphous form of any one of claims 1 to 7 or a pharmaceutical composition of any one of claims 8 to 10 for use in the prevention, management, treatment or lessening of severity of a proliferative disorder in a patient.

14. 14. The crystalline or amorphous form or pharmaceutical composition of claim 13, wherein the proliferative disorder is metastatic cancer, colon cancer, gastric adenocarcinoma, bladder cancer, breast cancer, kidney cancer, liver cancer, lung cancer, skin cancer, thyroid cancer, head and neck cancer, prostate cancer, pancreatic cancer, cancer of the CNS, glioblastoma, a myeloproliferative disorder, atherosclerosis, or pulmonary fibrosis.

15. 11. Use of a crystalline or amorphous form according to any one of claims 1 to 7 or a pharmaceutical composition according to any one of claims 8 to 10 in the manufacture of a medicament for inhibiting or modulating the activity of a protein kinase.

16. 16. The use of claim 15, wherein the protein kinase is PI3K, mTOR, or a combination thereof.

17. 11. A crystalline or amorphous form according to any one of claims 1 to 7 or a pharmaceutical composition according to any one of claims 8 to 10 for use in inhibiting or modulating the activity of a protein kinase.

18. 18. The crystalline or amorphous form or pharmaceutical composition for use according to claim 17, wherein the protein kinase is PI3K, mTOR, or a combination thereof.

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