Crystalline salts of b-raf kinase inhibitors

Abstract

The present invention relates to crystalline salts of the RAF kinase inhibitor N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide, which are useful in the treatment of cancer and other diseases.

Description

[0001] Cross-references to related applications

[0002] This application is a divisional application of Chinese invention patent application No. 201880081003.9. That Chinese invention patent application is based on international application PCT / US2018 / 057792, filed on October 26, 2018, entitled "Crystalized Salt of B-RAF Kinase Inhibitor". Technical Field

[0003] This application relates to the salt form, in particular the crystalline salt of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide (BI 882370), a RAF kinase inhibitor, which may be used to treat cancer and other diseases. Background Technology

[0004] Compound N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide (BI 882370) has formula I:

[0005]

[0006] It is a RAF kinase inhibitor and can be used to treat various diseases, including cancer. The compound of formula I, its preparation and uses are described in WO / 2012 / 104388, the entire contents of which are incorporated herein by reference.

[0007] The RAS-RAF-MAPK (mitogen-activated protein kinase) signaling pathway plays a crucial role in transmitting proliferation signals generated by cell surface receptors and cytoplasmic signaling elements to the nucleus. Constitutive activation of this pathway is involved in the malignant transformation of several oncogenes. Activating mutations in RAS occur in approximately 15% of cancers, and recent data indicate that B-RAF is mutated in approximately 7% of cancers (Wellbrock et al., "The RAF proteins take center stage", Nature Rev. Mol. Cell Biol., 2004, 5, 875-885), identifying it as another important oncogene in this pathway. In mammals, the RAF family of serine / threonine kinases comprises three members: A-RAF, B-RAF, and C-RAF. However, to date, activating mutations have only been identified in B-RAF, highlighting the importance of this isoform. B-RAF is believed to be the major isoform for RAS-MEK coupling, while C-RAF and A-RAF signal to ERK only to fine-tune cellular responses (Wellbrock et al., Nature Rev. Mol. Cell Biol., 2004, 5, 875-885). The most common cancer mutation in B-RAF leads to a valine exchange of glutamate at position 600 of the protein (V600E), which significantly enhances B-RAF activity, possibly because its negative charge mimics phosphorylation of the activation loop (Wan et al., "Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF", Cell, 2004, 116, 855-867). B-RAF V600 mutations have the highest incidence, occurring in malignant melanoma (39%), thyroid cancer (46%), colorectal cancer (10%), biliary tract cancer (10%), prostate cancer (4%), ovarian cancer (3%), and non-small cell lung cancer (2%). However, they also occur at low frequencies in many other cancers (the frequency of mutations is based on a report in COSMIC (Catalogue of Somatic Mutations in Cancer; Wellcome Trust Sanger Institute), Volume 53, May 15, 2011). http: / / www.sanger.ac.uk / genetics / CGP / cosmic / The literature supports the hypothesis that B-RAF... V600E Mutated tumor cells appear to depend heavily on the continuous activation of this pathway, a phenomenon known as "oncogene addiction," while normal B-RAF... wtThis signals a broader range of cellular applications. This provides the Achilles' heel, which can be addressed by treating somatic mutations of B-RAF with orally available B-RAF inhibitors. V600E The patient came for treatment.

[0008] B-RAF V600E The crucial role of ERK signaling in aberrant BRAF and its consequent carcinogenesis has been demonstrated in several independent experimental approaches, such as in vitro and in vivo oncogenic / mutant BRAF overexpression (Wan et al., Cell, 2004, 116, 855-867; Wellbrock et al., Cancer Res. 2004, 64: 2338-2342), in vitro siRNA knockout (Karasarides et al., Oncogene, "V599EB-RAF is an oncogene in melanocytes", 2004, 23, 6292-6298), or in induced short hairpin RNA xenograft models, where gain-of-function BRAF signaling has been found to be closely associated with in vivo tumorigenesis (Hoeflich et al., "Oncogenic BRAF is required for tumor growth and maintenance in melanoma models", Cancer Res., 2006, 66, 999-1006).

[0009] B-RAF V600E Treatment of mutated melanoma or colon cancer cells induces a B-RAF repressive phenotype (e.g., reduced levels of phosphorylated MEK and ERK, decreased cyclin D expression, and induced p27 expression). Consequently, these cells are locked in the G1 phase of the cell cycle and do not proliferate.

[0010] A system has been established using B-RAF inhibitors (PLX-4032, vemurafenib, from Plexxikon / Daiichi Sankyo / Roche) for the treatment of B-RAF V600EClinical evidence and proof-of-concept for cancer treatment mechanisms in patients with BRAF-mutant melanoma (Bollag et al., "Clinical efficacy of a RAF inhibitor needs broadtarget blockade in BRAF-mutant melanoma", Nature, 2010, 467(7315), 596-9; Flaherty et al., New Engl. J. Med., "Inhibition of Mutated,Activated BRAF in Metastatic Melanoma", 2010, 363, 809-819; Chapman et al., "Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation", New Engl. J. Med., 2011, 364: 2507-2516). Favorable response rates were observed in both phase I and phase III clinical trials. It has been reported that patients carrying BRAF... V600K Patients with mutated melanoma also respond to treatment (Rubinstein et al., "Incidence of the V600K mutation among melanoma patients with BRAF mutations, and potential therapeutic response to the specific BRAF inhibitor PLX4032", J. Transl. Med., 2010, 8, 67).

[0011] The most frequent B-RAF mutation is the 600th amino acid exchange from valine to glutamate, with all B-RAF mutations occurring in more than 90% of cases (Wellbrock et al., Nature Rev. Mol. Cell Biol., 2004, 5, 875-885). The second most common mutation is the valine-lysine mutation, with other mutations at this position occurring less frequently (Wellbrock et al., Nature Rev. Mol. Cell Biol., 2004, 5, 875-885; mutation frequencies are based on a report in COSMIC (Catalogue of Somatic Mutations in Cancer; Wellcome Trust Sanger Institute), Volume 53, May 15, 2011). http: / / www.sanger.ac.uk / genetics / CGP / cosmic / Further mutations were found, for example, on glycine-rich rings (Wellbrock et al., Nature Rev. Mol. Cell Biol., 2004, 5, 875-885). It does not appear that all of these rather rare mutations lead to direct activation of B-RAF (Wan et al., "Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF", Cell, 2004, 116, 855-867).

[0012] The compound of formula I is a potent and selective RAF inhibitor that binds to the DFG-out (inactive) conformation of B-RAF kinase. The compound's potency in inhibiting the proliferation of human B-RAF-mutant melanoma cells (1–10 nmol / L) is 100 times that of vemurafenib, while wild-type cells are unaffected at 1,000 nmol / L. Orally administered solutions of the compound are effective in mouse models of B-RAF-mutant melanoma and colorectal cancer, and show greater efficacy at twice-daily doses of 25 mg / kg compared to vemurafenib, dabrafenib, or trametinib. The compound is also active in A375 melanoma-bearing mice resistant to vemurafenib, particularly when administered in combination with trametinib. Mice treated with the compound showed no clinical signs of weight loss or intolerance, and no pathological changes were observed in several major organs studied, including the skin. Furthermore, in a rat study (up to 60 mg / kg daily for 2 weeks), the compound was found to be lacking in clinical chemistry, hematology, pathology, and toxicogenomics. These results are described in Waizengeger et al., Mol. Cancer Ther., 2016, 15(3); 354–65, the entire contents of which are incorporated herein by reference.

[0013] For the manufacture, purification, and formulation of pharmaceuticals, it can be advantageous to use a pharmaceutical form exhibiting, for example, excellent stability or other desired formulation properties as demonstrated by one or more salts or crystalline forms of the drug. The formation of salts of basic or acidic drugs can sometimes provide pharmaceutical forms with advantageous properties, such as solubility, non-hygroscopicity, crystallinity, and other physical properties favorable for drug formulation. On the other hand, discovering a suitable salt or other crystalline form for formulation is difficult due to the numerous variables involved in the formation of salts or crystalline forms. These include the presence of numerous possible acids and bases that can serve as counterions, various stoichiometric ratios that can be used to combine a given basic or acidic drug with an acid or base counterion, various solvents and solvent systems (including combinations of solvents) that can be used to attempt to form salts or crystalline forms, and various conditions (e.g., temperature, heating or cooling conditions) under which salts or crystalline forms can be formed. All these variables can affect the properties of the salts or crystalline forms that may be obtained. Salts or solid forms can also possess a variety of properties that make them unsuitable for drug development and formulation, such as lack of crystallinity (amorphous form), the presence or formation of multiple crystalline forms that can interconvert and / or have different properties (polymorphism), and the lack of water solubility, hygroscopicity, or viscosity of solids. Furthermore, the formation and properties of salts and crystalline forms are often very difficult to predict.

[0014] Therefore, the crystalline salt form of the Formula I compound provided in this application helps meet the ongoing need to develop RAF kinase inhibitors for the treatment of serious diseases. Summary of the Invention

[0015] This application provides crystalline N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate and specific crystalline forms of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate.

[0016] In some implementations, the crystalline salt is essentially anhydrous.

[0017] In some implementations, the crystalline salt is essentially non-solventized.

[0018] In some embodiments, the crystalline salt is N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate of form A.

[0019] In some embodiments, the crystalline salt has an X-ray powder diffraction pattern including at least one of the following peaks in terms of 2θ: 15.4°±0.5°; 20.0°±0.5°; and 21.8°±0.5°. In some embodiments, the peaks at 15.4°±0.5°; 20.0°±0.5°; and 21.8°±0.5° are the peaks with the highest relative intensity in the X-ray powder diffraction pattern.

[0020] In some embodiments, the crystalline salt has an X-ray powder diffraction pattern including at least one of the following peaks in terms of 2θ: 15.4°±0.2°; 20.0°±0.2°; and 21.8°±0.2°. In some embodiments, the peak at 15.4°±0.2°; 20.0°±0.2°; or 21.8°±0.2° is the peak with the highest relative intensity in the X-ray powder diffraction pattern.

[0021] In some embodiments, the crystalline salt has an X-ray powder diffraction pattern including at least one peak at 15.4° ± 0.5° (measured in 2θ). In some embodiments, the peak at 15.4° ± 0.5° is the peak with the highest relative intensity in the X-ray powder diffraction pattern.

[0022] In some embodiments, the crystalline salt has an X-ray powder diffraction pattern including at least one peak at 15.4° ± 0.2° (measured in 2θ). In some embodiments, the peak at 15.4° ± 0.2° is the peak with the highest relative intensity in the X-ray powder diffraction pattern.

[0023] In some embodiments, the crystalline salt has an X-ray powder diffraction pattern including the following peaks in terms of 2θ: 15.4°±0.5°; 20.0°±0.5°; and 21.8°±0.5°. In some embodiments, the peaks at 15.4°±0.5°; 20.0°±0.5°; and 21.8°±0.5° are the peaks with the highest relative intensity in the X-ray powder diffraction pattern.

[0024] In some embodiments, the crystalline salt has an X-ray powder diffraction pattern including the following peaks in terms of 2θ: 15.4°±0.2°; 20.0°±0.2°; and 21.8°±0.2°. In some embodiments, the peaks at 15.4°±0.2°; 20.0°±0.2°; or 21.8°±0.2° are the peaks with the highest relative intensity in the X-ray powder diffraction pattern.

[0025] In some implementations, the crystalline salt has essentially the following properties: Figure 10 , Figure 26 or Figure 38 The X-ray powder diffraction pattern shown is shown in the image.

[0026] In some implementations, the crystalline salt has essentially the following properties: Figure 11 , Figure 27 or Figure 39 The differential scanning calorimetry (DSC) spectrum shown is shown.

[0027] In some implementations, the crystalline salt has essentially the following properties: Figure 12 , Figure 28 or Figure 39 Thermogravimetric analysis (TGA) is shown in the figure.

[0028] In some implementations, the crystalline salt is essentially separated.

[0029] This application provides compositions (e.g., pharmaceutical compositions) comprising crystalline N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate, or any embodiment thereof. The composition may include at least one pharmaceutically acceptable carrier.

[0030] This application provides a dosage form comprising a crystalline salt N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate, or any embodiment thereof, or a composition comprising a crystalline salt, or any embodiment thereof. The dosage form may be in tablet form.

[0031] This application provides a method for preparing crystalline N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate. The method comprises reacting N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide with an equivalent amount of succinic acid. The method may include reacting the salt from C 1-4 alcohols, water-containing C 1-4 Crystallization or recrystallization from alcohol or ethyl acetate. The method may include crystallizing or recrystallizing the salt from ethanol, isopropanol, aqueous ethanol, aqueous isopropanol, or ethyl acetate.

[0032] This application provides a method for treating a patient’s disease, wherein the disease is related to the abnormal expression or activity of RAF kinase, comprising administering to the patient a therapeutically effective amount of crystalline N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate, or any embodiment thereof, or a composition comprising crystalline N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate. This application also provides crystalline N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate, or any embodiment thereof, for the treatment of diseases associated with aberrant expression or activity of RAF kinase. It also provides the use of crystalline N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate, or any embodiment thereof, in the treatment of diseases associated with aberrant expression or activity of RAF kinase. It also provides the use of crystalline N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate, or any embodiment thereof, in the preparation of a medicament for treating diseases associated with abnormal expression or activity of RAF kinase.

[0033] In some embodiments, the disease is associated with abnormal expression or activity of the B-RAF kinase. In some embodiments, the B-RAF kinase is a mutated B-RAF kinase. In some embodiments, the B-RAF kinase is a V600E mutated B-RAF kinase. In some embodiments, the disease is selected from cancer, infection, inflammation, and autoimmune diseases.

[0034] This application further provides a method of treating cancer, comprising administering to the patient a therapeutically effective amount of crystalline N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate, or any embodiment thereof, or a composition comprising crystalline N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate. This application also provides crystalline N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate, or any embodiment thereof, for the treatment of cancer. It also provides the use of crystalline N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate, or any embodiment thereof, in the treatment of cancer. It also provides the use of crystalline N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate, or any embodiment thereof, in the preparation of a medicament for treating cancer.

[0035] In some embodiments, the cancer is breast cancer, prostate cancer, colon cancer, endometrial cancer, brain cancer, bladder cancer, skin cancer, uterine cancer, ovarian cancer, lung cancer, pancreatic cancer, kidney cancer, stomach cancer, or hematologic cancer. In some embodiments, the cancer is malignant melanoma, thyroid cancer, colorectal cancer, biliary tract cancer, prostate cancer, ovarian cancer, or non-small cell lung cancer.

[0036] In some embodiments, the cancer is associated with the expression or activity of RAF kinase. In some embodiments, the cancer is associated with the expression or activity of B-RAF kinase. In some embodiments, the B-RAF kinase is a mutated B-RAF kinase. In some embodiments, the B-RAF kinase is a V600E mutated B-RAF kinase. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is thyroid cancer. In some embodiments, the cancer expresses a mutated B-RAF kinase. In some embodiments, the cancer expresses a V600E mutated B-RAF kinase. Attached Figure Description

[0037] Figure 1 It is the XRPD of the free base of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide.

[0038] Figure 2A This is an image of a master plate showing the salts of N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide prepared by crystallization in slurry experiments using various acids and solvents.

[0039] Figure 2B Yes Figure 2A An image set of XRPD scans performed on each of the main plate wells, showing the crystallinity of salts of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide prepared by slurrying with various acids and solvents.

[0040] Figure 3A This is an image of an evaporation plate showing the salts of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide prepared by crystallization in an evaporation experiment using various acids and solvents.

[0041] Figure 3B Yes Figure 3A An image set of XRPD scans performed on each of the main plate wells, showing the crystallinity of salts of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide prepared by evaporation with various acids and solvents.

[0042] Figure 4 This is a collection of XRPD scan images performed on various crystalline salt samples of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide.

[0043] Figure 5The image below shows the XRPD plot of N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride from pore E2, compared to the sample obtained by amplified synthesis (top image).

[0044] Figure 6 This is the DSC diagram of N-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride.

[0045] Figure 7 This is the TGA diagram of N-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride.

[0046] Figure 8 The adsorption-desorption curves are for N-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride, showing the increase and decrease in weight as the relative humidity varies between 0 and 100%.

[0047] Figure 9 The images show the XRPD diagrams of N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride before (bottom) and after (top) the adsorption-desorption experiment.

[0048] Figure 10 The image below shows the XRPD plot of N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate from pore F10, compared to the sample obtained by amplified synthesis (top image).

[0049] Figure 11 This is the DSC diagram of N-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate.

[0050] Figure 12 This is the TGA diagram of N-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate.

[0051] Figure 13 The adsorption-desorption curves are for N-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate, showing the increase and decrease in weight as the relative humidity varies between 0 and 100%.

[0052] Figure 14 The images show the XRPD plots of N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride before (bottom) and after (top) the adsorption-desorption experiment, indicating that no significant structural changes occurred.

[0053] Figure 15 This is the XRPD diagram of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride.

[0054] Figure 16 This is the DSC chromatogram of N-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride. The sample exhibits endothermic activity starting at approximately 313 °C. Typically, the sample begins to endothermic in the range of 312–322 °C, corresponding to the melting point. Therefore, the melting point is measured to be approximately 317 ± 5 °C. Some samples exhibit additional endothermic activity at approximately 250 °C, corresponding to solvent loss.

[0055] Figure 17 This is the TGA chromatogram of N-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride. The sample exhibited approximately 1.7–2.5% drying loss at temperatures up to approximately 250 °C, corresponding to the release of water and solvent. The water content was measured to be approximately 0.9% (Karl Fischer method).

[0056] Figure 18The isothermal adsorption-desorption plot of N-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride shows the increase and decrease in weight as the relative humidity varies between 0 and 90%.

[0057] Figure 19 The images show the XRPD plots of N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride before (bottom) and after (top) the adsorption-desorption experiment, indicating that no significant structural changes occurred.

[0058] Figure 20 This is the XRPD diagram of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride after grinding at 30 rpm for 10 min in a gyratory mill.

[0059] Figure 21 This is the XRPD diagram of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride after being compressed at 2000N for 1 second to form a tablet (diameter -5mm).

[0060] Figure 22 It is N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride 1 1H NMR spectrum (400MHz, DMSO-d6).

[0061] Figure 23 It is N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride 1 An inset of 1H NMR spectra (400 MHz, DMSO-d6) in the aliphatic region (δ -0.5–6.0).

[0062] Figure 24It is N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride 1 An inset of 1H NMR spectra (400MHz, DMSO-d6) in the aromatic region (δ6.0–11.5).

[0063] Figure 25 This is a graph showing the dissolution rate of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride in aqueous media at pH values ​​from 1.0 to 7.4 over 0–60 min.

[0064] Figure 26 This is the XRPD diagram of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate).

[0065] Figure 27 This is the DSC diagram of N-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate.

[0066] Figure 28 This is the TGA diagram of N-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate.

[0067] Figure 29 The isothermal adsorption-desorption plot of N-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate shows the increase and decrease in weight as the relative humidity varies between 0 and 90%.

[0068] Figure 30The images show the XRPD plots of N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate before (bottom) and after (top) the adsorption-desorption experiment, indicating that no significant structural changes occurred.

[0069] Figure 31 This is the XRPD diagram of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate after grinding at 30 rpm for 10 min in a gyratory mill.

[0070] Figure 32 This is the XRPD diagram of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate after being compressed at 2000N for 1 second to form a tablet (diameter -5mm).

[0071] Figure 33 It is N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate 1 1H NMR spectrum (400MHz, DMSO-d6).

[0072] Figure 34 It is N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate 1 An inset of 1H NMR spectra (400 MHz, DMSO-d6) in the aliphatic region (δ -0.5–6.0).

[0073] Figure 35 It is N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate 1 An inset of 1H NMR spectra (400MHz, DMSO-d6) in the aromatic region (δ6.0–10.0).

[0074] Figure 36This is a graph showing the dissolution rate of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride in aqueous media at pH values ​​from 1.0 to 7.4 over 0–60 min.

[0075] Figure 37A -D is a graph showing the relationship between plasma concentrations and time in rats after oral administration of the following substances: (A) at 40 mg / kg of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride; (B) at 80 mg / kg of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl) (C) Propane-1-sulfonamide monosuccinate at 40 mg / kg; (D) N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate at 80 mg / kg.

[0076] Figure 38 These are XRPD diagrams of two batches of form A of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate.

[0077] Figure 39 This is a pair of TGA and DSC analyses of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate of form A.

[0078] Figure 40 It is form A of N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate 11H NMR spectrum (DMSO-d6).

[0079] Figure 41 It is form A of N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate 1 1H NMR spectrum (deuterated methanol).

[0080] Figure 42 These are a pair of XRPD curves for N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate in form A before and after heating to 170°C and cooling to room temperature.

[0081] Figure 43 These are a pair of TGA curves of N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate in form A before and after heating to 170°C and cooling to room temperature.

[0082] Figure 44 These are a pair of DSC curves for N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate in form A before and after heating to 170°C and cooling to room temperature.

[0083] Figure 45 It is the N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate of form A before and after heating to 170°C and cooling to room temperature. 1 A pair of 1H NMR spectra (DMSO-d6).

[0084] Figure 46 These are a set of XPRD plots showing that N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate in form A remains unchanged in the equilibrium solubility test.

[0085] Figure 47 These are a set of XPRD plots showing the stability of N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate of form A after storage under various conditions.

[0086] Figure 48 This is a set of DVS isotherms showing the low hygroscopicity of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate of form A.

[0087] Figure 49 These are a pair of XPRD plots showing that form A of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate does not change form after DVS testing.

[0088] Figure 50 These are a pair of polarized light microscopy images of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate of form A. Detailed Implementation

[0089] I. Definition

[0090] Unless otherwise defined, all technical and scientific terms used in this application have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains.

[0091] The terms “for example” and “as,” and their grammatically equivalent terms, should be understood to be followed by “and not limited to”, unless otherwise expressly indicated.

[0092] As used in this application, unless the context clearly indicates otherwise, the singular forms “a,” “an,” and “the” include plural indicators.

[0093] As used in this application, the term "about" means "approximately" (e.g., ± about 10% of an indicated value).

[0094] Throughout this specification, certain features may be disclosed in groups or as a scope. Specifically, such disclosure means that each individual sub-combination of such groups and scope members is included. For example, the term "C"1-4 "alkyl" specifically means, but is not limited to, methyl, ethyl, C3 alkyl and C4 alkyl.

[0095] The terms “individual,” “subject,” or “patient,” used interchangeably, refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with human being being the most preferred.

[0096] The term “treating” or “treatment” means one or more of the following: (1) preventing disease; for example, preventing disease, condition or symptom in an individual who may be susceptible to disease, condition or symptom but has not yet experienced or exhibited the pathology or symptoms of disease; (2) suppressing disease; for example, suppressing disease, condition or symptom in an individual who experiences or exhibits the pathology or symptoms of disease, condition or symptom (i.e., preventing or slowing the further development of pathology and / or symptoms); and (3) improving disease; for example, improving disease, condition or symptom in an individual who experiences or exhibits the pathology or symptoms of disease, condition or symptom (i.e., reversing pathology and / or symptoms), for example, reducing the severity of disease.

[0097] The term "therapeutic effective amount" refers to the amount of an active salt or crystalline form or agent that elicits a biological or medical response sought by researchers, veterinarians, physicians in the medical field, or other clinicians in a tissue, system, animal, individual, or human.

[0098] For clarity, certain features of the invention described in the context of individual embodiments may also be provided in combination in a single embodiment. Conversely, for brevity, various features of the invention described in the context of individual embodiments may also be provided individually or in any suitable sub-combination.

[0099] abbreviation

[0100] The following abbreviations and symbols may be used in this application: Ac (acetyl); aq. (aqueous); Boc (tert-butoxycarbonyl); Bu (butyl); ℃ (degrees Celsius); c (concentration); conc. (concentration); d (day); DCM (dichloromethane); DEA (diethylamine); DIPEA (N-ethyl-N,N-diisopropylamine (Shunish base)); DMF (N,N-dimethylformamide); DMSO (dimethyl sulfoxide); DSC (Differential Scanning Calorimetry); DVS (Dynamic Vapor Adsorption); EDTA (Ethylenediaminetetraacetic Acid); EGTA (Ethylene Glycol Tetraacetic Acid); eq. (equivalent); ESI (Electrospray Ionization); Et (ethyl); Et₂O (diethyl ether); EtOAc (ethyl acetate); EtOH (ethanol); g (gram); h (hour); HPLC (High Performance Liquid Chromatography); HCl (hydrochloric acid); i (isopropanol); iPrOH (isopropanol) L (liter); LC (liquid chromatography); M (molar concentration); mg (milligram); Me (methyl); MeCN (acetonitrile); MeOH (methanol); min (minute); mL (milliliter); mM (millimolecular concentration); MPLC (medium-pressure liquid chromatography); MS (mass spectrometry); NP (normal phase); Ph (phenyl); Pr (propyl); Py (pyridine); rac (racemic); Rf (retention factor); RH (relative humidity); RP (reversed phase); rps (revolutions per second); rt (ambient temperature); tBu (tert-butyl); TEA (triethylamine); temp. (temperature); tert (tert-butyl); Tf (trifluoromethanesulfonate); TFA (trifluoroacetic acid); TGA (thermogravimetric analysis); THF (tetrahydrofuran); TLC (thin-layer chromatography); tRet. (retention time (HPLC)); UV (ultraviolet); XRPD (X-ray powder diffraction). Other commonly used abbreviations may also be used in this application.

[0101] II. Crystalline Salts

[0102] This application particularly relates to the salt form, especially the crystalline salt form, of (N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide (BI 882370), having formula I:

[0103]

[0104] It can be used, for example, to prepare solid dosage forms of the above-mentioned compounds to treat various diseases, including cancer.

[0105] Different salts and crystalline forms of the same substance can possess different overall properties related to, for example, hygroscopicity, solubility, and stability. Forms with high melting points can exhibit good thermodynamic stability, which is advantageous for pharmaceutical formulations containing specific salts or crystalline forms with extended shelf lives. Forms with lower melting points may be thermodynamically less stable, but their advantage lies in their increased water solubility, translating into increased drug bioavailability. Forms with poor hygroscopicity are desirable because they exhibit stability against heat and moisture and resistance to degradation during long-term storage. Anhydrous forms are desirable because they can be prepared consistently without concern about changes in weight or composition due to variations in solvent or water content. On the other hand, hydrated or solvated forms are advantageous if they are less hygroscopic and exhibit improved stability against humidity under storage conditions.

[0106] As used in this application, "crystalline form" refers to a specific crystal lattice structure of a crystalline substance (which may include the salts described in this application). Different crystalline forms of the same substance may have different crystal lattices (e.g., unit cells), which can be attributed to the distinct physical properties characteristic of each crystalline form. In some cases, different lattice structures have different water or solvent contents. Different crystal lattices can be identified using solid-state characterization methods (e.g., X-ray powder diffraction (XRPD)). Other characterization methods, such as differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor adsorption (DVS), and solid-state NMR, further aid in identifying crystalline forms and helping to determine stability and solvent / water content.

[0107] The crystalline forms of a substance can include solvated (e.g., hydrated) and non-solvated (e.g., anhydrous) forms. A hydrated form is a crystalline form in which water is contained within the crystal lattice. A hydrated form can be a stoichiometric hydrate, where water exists in the crystal lattice at a specific water / molecule ratio, such as a hemihydrate, monohydrate, dihydrate, etc. A hydrated form can also be a non-stoichiometric form, where the water content is variable and depends on external conditions such as humidity.

[0108] Crystallization forms can be characterized by X-ray powder diffraction (XRPD). The XRD pattern of reflection (peaks) is generally considered to be the fingerprint of a specific crystallization form. It is well known that the relative intensity of XRPD peaks can vary widely, depending particularly on sample preparation techniques, crystal size distribution, filters, sample setup procedures, and the specific instrument used. In some cases, new peaks may be observed, or existing peaks may disappear, depending on the instrument type or setup (e.g., whether a Ni filter is used). The term "peak" as used in this application refers to a reflection with a relative height / intensity of at least about 4% of the maximum peak height / intensity. Furthermore, instrument variations and other factors can affect the 2θ value. Therefore, peak assignments such as those reported in this application can vary between ±0.2° (2θ), and the term "substantially" as used in the XRPD context of this application is intended to include the aforementioned variations.

[0109] Similarly, temperature readings associated with differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), or other thermal experiments can vary by approximately ±4 °C, depending on the instrument, specific settings, sample preparation, etc. For example, with DSC, it is known that the observed temperature will depend on the rate of temperature change and the sample preparation technique and the specific instrument used. Therefore, as shown above, the values ​​associated with DSC temperature spectra reported in this application can differ by ±4 °C. Therefore, the crystalline forms reported in this application having DSC temperature spectra "substantially" as shown in any of the figures are understood to accommodate this variation.

[0110] The salts described in this application can be separated into various crystalline forms, including anhydrous, hydrated, non-solventized, or solvated crystalline forms. Examples of hydrates include hemihydrates, monohydrates, dihydrates, etc. In some embodiments, the crystalline form is anhydrous and non-solventized. "Anhydrous" means that the crystalline form of the compound of formula I contains essentially no bound water in its crystal lattice structure, i.e., the compound does not form crystalline hydrates.

[0111] In some embodiments, the salt and crystalline form of the present invention may be substantially separated. "Substantially separated" means that a particular salt or crystalline form of the compound is at least partially separated from the impurities. For example, in some embodiments, the salt or crystalline form of the present invention comprises less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 2.5%, less than about 1%, or less than about 0.5% of impurities. Impurities generally include any substance that is not a substantially separated salt or crystalline form, including other salts or other crystalline forms and other substances.

[0112] In some implementations, the salt or crystalline form is substantially free of other crystalline forms. The phrase "substantially free of other crystalline forms" means that the specific crystalline form constitutes a specific crystalline form in greater than about 80% by weight, greater than about 90% by weight, greater than about 95% by weight, greater than about 98% by weight, greater than about 99% by weight, or greater than about 99.5% by weight.

[0113] This application provides crystalline N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate and specific crystalline forms of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate.

[0114] The term "monosuccinate" means that the acid-to-base ratio of the succinic acid and the base moiety of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide present in the salt is about 1:1, for example, the ratio ranges from about 0.8:1 to about 1.2:1, about, about 0.9:1 to about 1.1:1, about 1:1.2 to about 1:0.8, or about 1:1.1 to about 1:0.9, for example, the ratio is about 0.8:1, about 0.9:1, about 1:1, or about 1.1:1, or about 1:0.8, about 1:0.9, about 1:1, about 1:1.1, or about 1:1.2.

[0115] As further detailed below, compared with the free base and other salt forms of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide, crystalline N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate has unexpected properties, such as improved solubility, improved intrinsic dissolution rate and improved pharmacokinetic characteristics.

[0116] In some embodiments, the crystalline salt is substantially anhydrous. "Substantially anhydrous" means that the crystalline salt contains less than a stoichiometric amount of water and does not contain water as part of the salt's crystalline structure. In some embodiments, if present, the amount of water present is about 5% by weight or less, about 4% by weight or less, about 3% by weight or less, about 2% by weight or less, about 1% by weight or less, about 0.5% by weight or less, about 0.2% by weight or less, or about 0.1% by weight or less in the crystalline salt. The use of the term "substantially anhydrous" does not exclude the presence of trace amounts of water.

[0117] In some embodiments, the crystalline salt is substantially non-solventized. "Substantially non-solventized" means that the crystalline salt contains less than a stoichiometric amount of solvent and does not contain solvent molecules that form part of the salt's crystal structure. In some embodiments, if present, the solvent is present in an amount of about 5% by weight or less, about 4% by weight or less, about 3% by weight or less, about 2% by weight or less, about 1% by weight or less, about 0.5% by weight or less, about 0.2% by weight or less, or about 0.1% by weight or less of the crystalline salt. The use of the term "substantially non-solventized" does not exclude the presence of trace amounts of solvent.

[0118] In some embodiments, the crystalline salt is substantially free of solvents other than water. "Substantially free" means that the crystalline salt contains less than a stoichiometric amount of solvents other than water and does not contain solvent molecules other than water that form part of the crystal structure of the salt. In some embodiments, if present, the amount of solvents other than water present is about 5% by weight or less, about 4% by weight or less, about 3% by weight or less, about 2% by weight or less, about 1% by weight or less, about 0.5% by weight or less, about 0.2% by weight or less, or about 0.1% by weight or less of the crystalline salt. The use of the term "substantially free of solvents other than water" does not exclude the presence of trace amounts of such solvents.

[0119] In some embodiments, the crystalline salt is N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate of form A (as further detailed below).

[0120] The crystalline form of salts is identified by unique characteristics, such as those obtained through X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and dynamic vapor adsorption (DVS).

[0121] In some embodiments, N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate of form A is characterized by being substantially as Figure 10 , Figure 26 or Figure 38 The XRPD diagram shown is shown below.

[0122] In some embodiments, N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate of form A is characterized by having an XRPD plot substantially as shown in Table 9.

[0123] In some embodiments, the crystalline salt has an X-ray powder diffraction pattern including at least one of the following peaks in terms of 2θ: 15.4°±0.5°; 20.0°±0.5°; and 21.8°±0.5°. In some embodiments, the peaks at 15.4°±0.5°; 20.0°±0.5°; and 21.8°±0.5° are the peaks with the highest relative intensity in the X-ray powder diffraction pattern.

[0124] In some embodiments, the crystalline salt has an X-ray powder diffraction pattern including at least one of the following peaks in terms of 2θ: 15.4°±0.2°; 20.0°±0.2°; and 21.8°±0.2°. In some embodiments, the peak at 15.4°±0.2°; 20.0°±0.2°; or 21.8°±0.2° is the peak with the highest relative intensity in the X-ray powder diffraction pattern.

[0125] In some embodiments, the crystalline salt has an X-ray powder diffraction pattern including at least one peak at 15.4° ± 0.5° (measured in 2θ). In some embodiments, the peak at 15.4° ± 0.5° is the peak with the highest relative intensity in the X-ray powder diffraction pattern.

[0126] In some embodiments, the crystalline salt has an X-ray powder diffraction pattern including at least one peak at 15.4° ± 0.2° (measured in 2θ). In some embodiments, the peak at 15.4° ± 0.2° is the peak with the highest relative intensity in the X-ray powder diffraction pattern.

[0127] In some embodiments, the crystalline salt has an X-ray powder diffraction pattern including the following peaks in terms of 2θ: 15.4°±0.5°; 20.0°±0.5°; and 21.8°±0.5°. In some embodiments, the peaks at 15.4°±0.5°; 20.0°±0.5°; or 21.8°±0.5° are the peaks with the highest relative intensity in the X-ray powder diffraction pattern.

[0128] In some embodiments, the crystalline salt has an X-ray powder diffraction pattern including the following peaks in terms of 2θ: 15.4°±0.2°; 20.0°±0.2°; and 21.8°±0.2°. In some embodiments, the peaks at 15.4°±0.2°; 20.0°±0.2°; or 21.8°±0.2° are the peaks with the highest relative intensity in the X-ray powder diffraction pattern.

[0129] In some embodiments, the crystalline salt has an X-ray powder diffraction pattern comprising at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or all of the following peaks in 2θ: 15.4°±0.5°; 16.1°±0.5°; 17.2°±0.5°; 19.1°±0.5°; 19.8°±0.5°; 20.0°±0.5°; 20.2°±0.5°; 20.5°±0.5°; 21.5°±0.5°; and 21.8°±0.5°. In some embodiments, the peak at 15.4°±0.5°; 20.0°±0.5°; or 21.8°±0.5° is considered the peak with the highest relative intensity in the X-ray powder diffraction pattern.

[0130] In some implementations, the X-ray powder diffraction pattern includes a peak at 15.4° ± 0.5° as the peak with the highest relative intensity in the X-ray powder diffraction pattern.

[0131] In some embodiments, the crystalline salt has an X-ray powder diffraction pattern comprising at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or all of the following peaks in 2θ: 15.4°±0.2°; 16.1°±0.2°; 17.2°±0.2°; 19.1°±0.2°; 19.8°±0.2°; 20.0°±0.2°; 20.2°±0.2°; 20.5°±0.2°; 21.5°±0.2°; and 21.8°±0.2°. In some embodiments, the peak at 15.4°±0.2°; 20.0°±0.2°; or 21.8°±0.2° is considered the peak with the highest relative intensity in the X-ray powder diffraction pattern. In some implementations, the X-ray powder diffraction pattern includes a peak at 15.4° ± 0.2° as the peak with the highest relative intensity in the X-ray powder diffraction pattern.

[0132] In some embodiments, the X-ray powder diffraction pattern includes at least two peaks at 15.4°±0.5°; 20.0°±0.5°; or 21.8°±0.5° as the peaks with the highest relative intensity in the X-ray powder diffraction pattern.

[0133] In some embodiments, the X-ray powder diffraction pattern includes at least three peaks at 15.4°±0.5°; 20.0°±0.5°; or 21.8°±0.5° as the peaks with the highest relative intensity in the X-ray powder diffraction pattern.

[0134] In some embodiments, the X-ray powder diffraction pattern includes at least two of the peaks at 15.4°±0.2°; 20.0°±0.2°; or 21.8°±0.2° as the two peaks with the highest relative intensity in the X-ray powder diffraction pattern.

[0135] In some embodiments, the X-ray powder diffraction pattern includes peaks at 15.4°±0.2°; 20.0°±0.2°; or 21.8°±0.2° as the three peaks with the highest relative intensity in the X-ray powder diffraction pattern.

[0136] In some implementations, the crystalline salt has essentially the following properties: Figure 11 , Figure 27 or Figure 39 The differential scanning calorimetry (DSC) spectrum shown is shown.

[0137] In some implementations, the crystalline salt has essentially the following properties: Figure 12 , Figure 28 or Figure 39 Thermogravimetric analysis (TGA) is shown in the figure.

[0138] In some embodiments, the crystalline salt is substantially isolated. In some embodiments, the crystalline salt is in the form of N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate A, comprising at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%.

[0139] N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate can be prepared by reacting N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide with an appropriate amount, usually about one equivalent, of succinic acid.

[0140] The reaction can be carried out in a suitable solvent. The reaction can be carried out by dissolving N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide in succinic acid, or by dissolving it in an acid. If desired, the compound can be dissolved by heating the solution of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide and / or succinic acid. Heating can be performed above the following temperatures: room temperature, for example, about 30°C, about 40°C, about 50°C, about 60°C, about 70°C, about 80°C, about 90°C, or about 100°C. The reaction can proceed for a period of time, for example, about 5 min, about 10 min, about 20 min, about 30 min, about 40 min, about 50 min, about 1 h, about 2 h, about 3 h, or about 4 h. After heating, the solution can be cooled to, for example, room temperature or a lower temperature, for example, about 25 °C, about 20 °C, about 15 °C, about 10 °C, about 5 °C, or about 0 °C. After such cooling, the reaction mixture can be maintained at a lower temperature for another period of time, for example, about 5 min, about 10 min, about 20 min, about 30 min, about 40 min, about 50 min, about 1 h, about 2 h, about 3 h, about 4 h, about 8 h, about 16 h, or about 24 h.

[0141] During the steps of forming its salt or crystalline form, the solution or suspension in which the reaction takes place can be agitated, for example by stirring.

[0142] Suitable solvents for forming N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate, including salts of form A, include C 1-4 alcohols, water-containing C 1-4 Alcohol or ethyl acetate. Solvents may include methanol, ethanol, isopropanol, aqueous methanol, aqueous ethanol, aqueous isopropanol, or ethyl acetate.

[0143] Crystalline N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate, particularly form A, can be obtained directly from the reaction of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide with succinic acid under suitable conditions. Alternatively, the crystalline salt or form A thereof can be prepared by crystallizing and / or recrystallizing the salt in a suitable solvent.

[0144] Suitable methods for crystallizing or recrystallizing salts include solutions or suspensions of salts in suitable solvents. Heating can be performed at temperatures above room temperature, such as about 30°C, about 40°C, about 50°C, about 60°C, about 70°C, about 80°C, about 90°C, or about 100°C. Heating can be carried out for a period of time, such as about 5 min, about 10 min, about 20 min, about 30 min, about 40 min, about 50 min, about 1 h, about 2 h, about 3 h, or about 4 h. After heating, the solution can be cooled to, for example, room temperature or lower, such as about 25°C, about 20°C, about 15°C, about 10°C, about 5°C, or about 0°C. After such cooling, the reaction mixture can be held at a lower temperature for an additional period of time, such as about 5 min, about 10 min, about 20 min, about 30 min, about 40 min, about 50 min, about 1 h, about 2 h, about 3 h, about 4 h, about 8 h, about 16 h, or about 24 h. In the step of crystallizing or recrystallizing a salt or its crystalline form, the solution or suspension in which the reaction takes place may be agitated, for example by stirring.

[0145] III. How to Use

[0146] The salt and crystalline forms described in this application are B-RAF kinase inhibitors and therefore can be used to treat pathological conditions (diseases) that activate the RAS-RAF-MAPK signaling pathway, particularly proliferative conditions such as cancer. The salt and crystalline forms can inhibit cell proliferation, especially by inhibiting entry into the DNA synthesis phase. Treated cells are arrested in the G1 phase of the cell cycle. Therefore, the salt and crystalline forms can be used to treat diseases characterized by excessive or abnormal cell proliferation.

[0147] Pathological conditions that can be treated with the salts and crystalline forms described in this application include diseases associated with aberrant expression or activity of RAF kinase. The disease can be treated by administering a therapeutically effective amount of the crystalline salts described in this application or any embodiment thereof to a patient requiring such treatment. In some embodiments, the disease is associated with aberrant expression or activity of B-RAF kinase. In some embodiments, the disease is associated with aberrant expression or activity of mutated B-RAF kinase. In some embodiments, the disease is associated with aberrant expression or activity of V600E-mutated B-RAF kinase. In other embodiments, the disease may be associated with the expression or activity of a mutant B-RAF kinase selected from the following mutants: R461I, I462S, G463E, G463V, G465A, G465E, G465V, G468A, G468E, N580S, E585K, D593V, F594L, G595R, L596V, T598I, V599D, V599E, V599K, V599R, V600K, and A727V.

[0148] Pathological conditions that can be treated with the salts and crystalline forms described in this application include cancer, infections, inflammation, and autoimmune diseases.

[0149] Pathological conditions that can be treated with the salts and crystalline forms described in this application include cancer. Cancer can include tumors, but can also include cancers that do not form tumors, such as hematologic cancers.

[0150] In some implementations, the cancer is breast cancer, prostate cancer, colon cancer, endometrial cancer, brain cancer, bladder cancer, skin cancer, uterine cancer, ovarian cancer, lung cancer, pancreatic cancer, kidney cancer, stomach cancer, or hematologic cancer. In some implementations, the hematologic cancer is acute myeloid leukemia, chronic myeloid leukemia, B-cell lymphoma, chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma, hairy cell leukemia, mantle cell lymphoma, Burkitt lymphoma, small lymphocytic lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, activated B-cell-like (ABC) diffuse large B-cell lymphoma, or germinal center B-cell (GCB) diffuse large B-cell lymphoma. In some implementations, non-Hodgkin lymphoma (NHL) is selected from relapsed NHL, refractory NHL, and relapsed follicular NHL.

[0151] In some implementation schemes, cancer is breast cancer, prostate cancer, colon cancer, endometrial cancer, brain cancer, bladder cancer, skin cancer, uterine cancer, ovarian cancer, lung cancer, pancreatic cancer, kidney cancer, stomach cancer, or hematologic cancer.

[0152] In some implementation schemes, the cancer is malignant melanoma, thyroid cancer, colorectal cancer, biliary tract cancer, prostate cancer, ovarian cancer, or non-small cell lung cancer.

[0153] In some implementations, cancer is associated with the expression or activity of RAF kinases.

[0154] In some implementations, cancer is associated with the expression or activity of B-RAF kinase.

[0155] In some implementations, cancer is associated with the expression or activity of mutated B-RAF kinases.

[0156] In some implementations, cancer is associated with the expression or activity of V600E-mutated B-RAF kinase.

[0157] In some implementations, cancer is associated with the expression or activity of a mutant B-RAF kinase selected from the following mutants: R461I, I462S, G463E, G463V, G465A, G465E, G465V, G468A, G468E, N580S, E585K, D593V, F594L, G595R, L596V, T598I, V599D, V599E, V599K, V599R, V600K, and A727V.

[0158] In some implementations, the cancer is melanoma.

[0159] In some implementations, the cancer is colorectal cancer.

[0160] In some implementations, the cancer is colon cancer.

[0161] In some implementation schemes, the cancer is thyroid cancer.

[0162] In some embodiments, the cancer expresses a mutated B-RAF kinase. In some embodiments, the cancer expresses a V600E mutated B-RAF kinase. In some embodiments, the cancer expresses one or more of the following B-RAF kinase mutants: R461I, I462S, G463E, G463V, G465A, G465E, G465V, G468A, G468E, N580S, E585K, D593V, F594L, G595R, L596V, T598I, V599D, V599E, V599K, V599R, V600K, and A727V.

[0163] The compounds according to the invention can be used to treat, but are not limited to, the following cancers: brain tumors such as acoustic neuroma, astrocytomas such as pilocytic astrocytoma, fibrous astrocytoma, protoplasmic astrocytoma, basophilic astrocytoma, anaplastic astrocytoma and glioblastoma, brain lymphoma, brain metastases, pituitary tumors such as prolactinoma, HGH (human growth hormone) producing tumors and ACTH (adrenocorticotropic hormone) producing tumors, craniopharyngioma, medulloblastoma, meningioma and oligodendroglioma; neuronal tumors (tumors), such as tumors of the autonomic nervous system, such as sympathetic neuroblastoma, ganglioneuroma, paraganglioma (pheochromocytoma). Tumors of the ochromocytoma, pheochromocytoma, and carotid body; tumors of the peripheral nervous system such as amputation neuroma, neurofibroma, schwannoma (neurilemmoma, schwannoma) and malignant schwannoma; tumors of the central nervous system such as brain tumors and myeloma; colorectal cancers such as rectal cancer, colon cancer, colorectal cancer, anal cancer, large intestine cancer, small intestine and duodenal tumors; eyelid tumors such as basal cell carcinoma or basal cell tumor; pancreatic cancer. Cancer (pancreatic cancer); bladder cancer; lung cancer (bronchial cancer) such as small cell bronchial carcinoma (oat cell carcinoma), and non-small cell bronchial carcinoma (NSCLC) such as lamellar carcinoma, adenocarcinoma, and large cell bronchial carcinoma; breast cancer, such as mammary carcinoma, including invasive ductal carcinoma, colloid carcinoma, lobular invasive carcinoma, tubular carcinoma, adenocystic carcinoma, and papillary carcinoma; non-Hodgkin lymphoma (NHL) such as Burkitt's lymphoma, low-grade non-Hodgkin lymphoma (NHL), and mycosis fungoides; uterine cancer or endometrial cancer or uterine corpus cancer; CUP syndrome (cancer of unknown primary origin); ovarian cancer. Carcinomas include mucinous, endometrial, or serous carcinomas; gallbladder cancer; bile duct cancers such as kratzkinoma; testicular cancers such as seminoma and non-seminomatous tumors; lymphomas (lymphosarcomas) such as malignant lymphomas, Hodgkin's disease, and non-Hodgkin's lymphomas (NHL) such as chronic lymphocytic leukemia, leukemic reticuloendothelial hyperplasia, immunocytomas, plasmacytomas (multiple myeloma), immunoblastomas, Burkitt's lymphoma, T-zone mycosis fungoides, large cell anaplastic lymphoblastoma, and lymphoblastoma.Laryngeal cancer, such as vocal cord tumors, supraglottic, glottic, and subglottic laryngeal tumors; bone cancer, such as osteochondroma, chondroblastoma, chondroblastoma, chondromycinoid fibroma, osteoma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, giant cell tumor, chondrosarcoma, osteosarcoma, Ewing sarcoma, reticulum cell sarcoma, plasmacytoma, fibrosis, juvenile bone cysts, and aneurysmal bone cysts; head and neck tumors, such as tumors of the lips, tongue, floor of mouth, oral cavity, gums, palate, salivary glands, larynx, nasal cavity, paranasal sinuses, larynx, and middle ear; liver cancer, such as hepatocellular carcinoma (HCC); leukemia, such as acute leukemia like acute lymphoblastic / lymphocytic leukemia (ALL) and acute myeloid leukemia (AML); chronic leukemia, such as chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML); stomach cancer. Cancers including: gastric carcinoma (e.g., papillary, tubular, and mucinous adenocarcinoma, signet ring cell carcinoma, adenosquamous carcinoma, small cell carcinoma, and undifferentiated carcinoma); melanoma (e.g., superficial spreading, nodular, malignant lentigines, and acral malignant melanoma); kidney cancer (e.g., renal cell carcinoma, adrenal adenoma, or Graves' tumor); esophageal cancer (e.g., esophageal cancer or carcinoma of the esophagus); penile cancer; prostate cancer; laryngeal or pharyngeal cancer (e.g., nasopharyngeal carcinoma, oropharyngeal carcinoma, and hypopharyngeal carcinoma); retinoblastoma, vaginal cancer (e.g., vaginal carcinoma); squamous cell carcinoma, adenocarcinoma, carcinoma in situ, malignant melanoma, and sarcoma); thyroid cancer (e.g., papillary, follicular, and medullary thyroid carcinoma, and anaplastic carcinoma); spinalis carcinoma, epidermoid carcinoma, and squamous cell carcinoma of the skin; thymoma, urethral cancer, and vulvar cancer.

[0164] The new salt and crystalline form can be used for the prevention, short-term or long-term treatment of the aforementioned diseases, and can optionally be combined with radiotherapy or other "state-of-the-art" compounds such as cell growth inhibitors or cytotoxic substances, cell proliferation inhibitors, anti-angiogenic substances, steroids or antibodies.

[0165] The salts and crystalline forms described in this application can also be used to treat non-cancerous proliferative conditions. Examples of proliferative conditions that can be treated include, but are not limited to, benign soft tissue tumors, bone tumors, brain and spinal tumors, eyelid and orbital tumors, granulomas, lipomas, meningiomas, multiple endocrine tumors, nasal polyps, pituitary adenomas, prolactinomas, pseudotumors of the brain, seborrheic keratosis, gastric polyps, thyroid nodules, pancreatic cystic tumors, hemangiomas, vocal cord nodules, polyps and cysts, Castrmann's disease, chronic chorioretinopathy, dermatofibromas, pilocysts, pyogenic granulomas, and juvenile polyposis syndrome.

[0166] Other treatable diseases include viral infections (e.g., Epstein-Barr virus, hepatitis B virus, hepatitis C virus, herpesvirus, human immunodeficiency virus, human papillomavirus, Kaposi's sarcoma, adenovirus, poxvirus, and other episome-based DNA viruses). Therefore, both salt and crystalline forms can be used to treat diseases and conditions such as herpes simplex infection and reactivation, cold sores, herpes zoster infection and reactivation, varicella, herpes zoster, human papillomavirus, cervical cancer, adenovirus infections, including acute respiratory illnesses, and poxvirus infections such as cowpox and smallpox, and African swine fever virus. In one particular embodiment, the salt and crystalline forms are specified for treating skin or cervical epithelium infected with human papillomavirus.

[0167] Other treatable conditions include inflammation and autoimmune diseases. Examples of treatable autoimmune and inflammatory conditions include: acute, hyperacute, or chronic rejection of transplanted organs; acute gout; acute inflammatory reactions (e.g., acute respiratory distress syndrome and ischemia / reperfusion injury); Addison's disease; agammaglobulinemia; allergic rhinitis; allergies; alopecia; Alzheimer's disease; appendicitis; atherosclerosis; asthma; osteoarthritis; juvenile arthritis; psoriatic arthritis; rheumatoid arthritis; idiopathic dermatitis; autoimmune alopecia; autoimmune hemolysis and thrombocytopenia; autoimmune hypopituitarism; autoimmune polyglandular disease; Behcet's disease; bullous dermatitis; cholecystitis; chronic idiopathic thrombocytopenic purpura; chronic obstructive pulmonary disease (COPD); cirrhosis; degenerative joint diseases; depression; dermatitis; dermatomyositis; eczema; enteritis; encephalitis; gastritis; glomerulonephritis; giant cell arteritis; Goodpass syndrome; Guillain-Barré syndrome. Symptoms, gingivitis, Graves' disease, Hashimoto's thyroiditis, hepatitis, hypophysitis, inflammatory bowel disease (Crohn's disease and ulcerative colitis), pelvic inflammatory disease, irritable bowel syndrome, Kawasaki disease, LPS-induced endotoxic shock, meningitis, multiple sclerosis, myocarditis, myasthenia gravis, mycosis fungoides, myositis, nephritis, osteomyelitis, pancreatitis, Parkinson's disease, pericarditis, pernicious anemia, pneumonia, primary biliary sclerosing cholangitis, polyarteritis nodosa, psoriasis Diseases, retinitis, scleritis, scleracierma, scleroderma, sinusitis, Sjögren's disease, sepsis, septic shock, sunburn, systemic lupus erythematosus, tissue transplant rejection, thyroiditis, type I diabetes, aortitis, urethritis, uveitis, vasculitis including giant cell arteritis, vasculitis with organ involvement such as glomerulonephritis, vitiligo, Waldenström macroglobulinemia, and Wegener's granulomatosis.

[0168] Other diseases include bacterial, fungal, and / or parasitic infections; skin diseases (e.g., psoriasis); proliferative diseases characterized by an increased number of cells (e.g., fibroblasts, hepatocytes, bone and bone marrow cells, cartilage or smooth muscle cells, or epithelial cells) (e.g., endometrial hyperplasia); bone diseases and cardiovascular diseases (e.g., restenosis and hypertrophy).

[0169] The salts and crystalline forms described in this application are also suitable for protecting proliferating cells (e.g., hair, intestines, blood, and progenitor cells) from DNA damage caused by radiation, UV treatment, and / or cell-suppressing therapy.

[0170] Combination therapy

[0171] The salts and crystalline forms described in this application can be used alone or in combination with other active substances according to the invention, and optionally also in combination with other pharmacologically active substances such as other chemotherapeutic agents.

[0172] For the treatment of cancer and other proliferative diseases, the compounds of the present invention can be used in combination with chemotherapeutic agents or other antiproliferative agents. Chemotherapeutic agents that can be administered in combination with the salts and crystalline forms described in this application for the treatment of cancer or other proliferative diseases include, but are not limited to, hormones, hormone analogs and anti-hormonal drugs (e.g., tamoxifen, toremifene, raloxifene, fulvestrant, medroxyprogesterone acetate, flutamide, nilumethoxazole, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buterlein acetate, fludrocortisone, fluorometholone, medroxyprogesterone acetate, octreotide), aromatase inhibitors (e.g., anastrozole, letrozole, riazole, voroxyzole, exemestane, atametane). LHRH agonists and antagonists (e.g., goserelin acetate, leuprorelin), growth factor inhibitors (growth factors such as platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insulin-like growth factor (IGF), human epidermal growth factor (HER, such as HER2, HER3, HER4), and hepatocyte growth factor (HGF)), and other growth factors. Pharmaceutical formulations include, for example, growth factor antibodies, growth factor receptor antibodies, and tyrosine kinase inhibitors such as cetuximab, gefitinib, imatinib, lapatinib, and trastuzumab; antimetabolites (such as antifolate drugs like methotrexate and raltitrexed, pyrimidine analogs such as 5-fluorouracil, capecitabine, and gemcitabine, purine and adenosine analogs such as mercaptopurine, thioguanine, cladribine, pentostatin, cytarabine, and fludarabine); and antitumor antibiotics (such as anthracyclines like doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin C, etc.). Bleomycin, actinomycin, procainamide, streptozotocin; platinum derivatives (e.g., cisplatin, oxaliplatin, carboplatin); alkylating agents (e.g., estradiol, meclorethamine, melphalan, chlorambucil, busulfan, dacarbazamide, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas such as carmustine and lomustine, thiotepa); antimitotic agents (e.g., vinca alkaloids such as vincristine, vinorelbine, vinblastine, and vinblastine; taxanes such as paclitaxel, docetaxel); microtubule inhibitors;PARP inhibitors, topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and vanbex, teniposide, amsacrin, topotecan, irinotecan, mitoxantrone), serine / threonine kinase inhibitors (e.g., PDK1 inhibitors, β-Raf inhibitors, mTOR inhibitors, mTORC1 inhibitors, PI3K inhibitors, mTOR / PI3K dual inhibitors, STK33 inhibitors, AKT inhibitors, PLK inhibitors), 1. Inhibitors, including CDK inhibitors, Aurora kinase inhibitors, tyrosine kinase inhibitors (e.g., PTK2 / FAK inhibitors), protein-protein interaction inhibitors (e.g., IAP, Mcl-1, MDM2 / MDMX), MEK inhibitors, ERK inhibitors, IGF-1R inhibitors, ErbB receptor inhibitors, rapamycin analogs (e.g., everolimus, tesirobolimus, desfolimex, sirolimus), and various chemotherapeutic agents such as amifostine, anagrelide, clodronate, filstastatin, interferon, alpha-interferon, leucovorin, rituximab, procarbazine, levamisole, mesna, mitotane, pamidronate, and porphyrin sodium.

[0173] Other reagents that can be used in combination with the salts and crystalline forms described in this application include 2-chlorodeoxyadenosine, 2-fluorodeoxycytidine, 2-methoxyestradiol, 2C4, 3-alanine, 131-I-TM-601, 3CPA, 7-ethyl-10-hydroxycamptothecin, 16-aza-epotassium B, A 105972, A 204197, Abaricicli, Abiraterone, Aldehyde Interleukin, Alemptuzumab, Alireta-Retinoic Acid, Allopurinol, Allolovectin-7, Hexamethylmelamine, Alvocidib, Aminoflavone, Anastrozole, Anthrapidazole, AG-2037, AP-5280, Apaziquone, Apomine, Aranose, Agrabin, Arsenic Trioxide, Azoxifen, Asparaginase, Atamitan, Atrasentan, Auristatin PE, AVLB, AZ10992, ABX-EGF, AMG-479 (Ganitumab), ARRY 162, ARRY 438162, ARRY-300, ARRY-142886 / AZD-6244 (Selmetinib), ARRY-704 / AZD-8330, AR-12, AR-42, AS-703988, AXL-1717, AZD-8055, AZD-5363, AZD-6244, ARQ-736, ARQ 680, AS-703026 (Primasertib), Avastin, AZD-2014, Azacytidine, Azaepomycin B, azonafide, BAY-43-9006, BAY 80-6946, BBR-3464, BBR-3576, Bevacizumab, Bexarotin, BEZ-235, Bilicorice Disitate, BCX-1777, BKM-120, Bleomycin, BLP-25, BMS-184476, BMS-247550, BMS-188797, BMS-275291, BMS-663513, BMS-754807, BNP-1350, BNP-7787, BIBW 2992 (Afatinib, Afatinib (Tomtovok)), BIBF 1120 (Nintedanib (Vargatef)), BI836845, BI 2536, BI 6727, BI 836845, BI 847325, BI 853520, BIIB-022, Bleomycin A, Bleomycin B, Brinnib, Limonenestatin-1, Bortezomib, Brotalifen, Busulfan, BYL-719, CA-4 Prodrug, CA-4, CapCell, Calcitriol, Carutestosterone, Cannatinib, Canfosfamide, Capecitabine, CarboplatinCarboxyphthalatoplatin, carmustine, CCI-779, CC-115, CC-223, CEP-701, CEP-751, CBT-1 cefixime, homoharringtonine, ceftriaxone, celecoxib, simomadolone, cisadoxime, cetuximab, chlorambucil, CH4987655 / RO-4987655, chlorestradiol, silengiptide, cisplatin, CDA-II, CDC-394, CKD-602, CKI-27, cladribine, clofarabine, colchicine, cobustatin A4, COT inhibitors, CHS-828, CH-5132799, CLL-Thera CMT-3 Candida 52, CTP-37, CTLA-4 Monoclonal Antibody, CP-461, CV-247, Cyanomorpholine Doxorubicin, Cyclophosphamide, Cyclosporine, Cytarabine, D24851, Dacarbazine, Actinomycin D, Dalteparin Sodium, Dasatinib, Daunorubicin, Decitabine, Dine Interleukin-Diphtheria Toxin Conjugate, Doxorubicin, Deoxyrubicin, Deoxycofromycin, Phenyleukin Peptide, Deoxyepotassium B, Dexamethasone, Dextromethorphan, Dextromethorphan, Diethylstilbestrol, Diflutamide, 3,4-Dihydroxybenzoxazole (didox), DMDC, Dolasatin 10, Docetaxel, Doladazol, Doxorubicin, Drotahistone Propionate, D S-7423, E7010, E-6201, Iculizumab, Edatraxa, Edotriptide, Eproxiro, Eflunomide, EGFR inhibitors, EKB-569, EKB-509, Enzatolin, Exarucin, Epirubicin, Epothilone B, Ipatizumab, ER-86526, Erlotinib, Estradiol, ET-18-0CH3, Ethynylcytidine, Ethynylestradiol, Etoposide Phosphate, Etoposide, Exanotecan, Exanotecan Mesylate, Exemestane, Exixisulline, Fentanyl Citrate, Fenivel Aamine, Figitumumab, Filgrastim, Fluorouracil, Fludarabine, Folic Acid, Fluorouracil, FOLFOX, FOLFOX4, FOLFIRI, Formestane Formustine, Fulvestrant, Galorubicin, Maltodextrin, Gefitinib, Gemcitabine, Giemumab, Gemtuzumab / Ozomicin, Gematicotinib, Glucophosphamide, GCS-100, GDC-0623, GDC-0941 (pictrelisib), GDC-0980, GDC-0032, GDC-0068, GDC-0349, GDC-0879, G17DT Immunogen, GMK, GPX-100, gp100-peptide vaccine, GSK-5126766, GSK-690693, GSK-1120212 (Trametinib), GSK-2118436 (Dabrafenib), GSK-2126458GSK-2132231A, GSK-2334470, GSK-2110183, GSK-2141795, GW2016, Goserelin Acetate, Granisetron, Herceptin, Hexamethylmelamine, Histamine, Histamine Relin Acetate, Homoharringtonine, Hyaluronic Acid, Hydroxyurea, Hydroxyprogesterone Hexanoate, Ibandronate, Ibrimomab, Ibrimomab Tiuxetan, Idarubicin, Idatrexate, Idemestrol, IDN-5109, Ifosfamide, IGF-1R inhibitor, IMC-1C11, IMC-A12 (Cetuximab), Imatinib Mesylate, Immunol, Indisulam, Interferon α-2a, Interferon α-2b, Pegylated Interferon α-2b, Interleukin-2, INK-1117, INK-128, INSM-18, Lonafarnib, Ipilimumab, Isopropylplatin, Irinotecan, Irovvin, Isosomal Sponge B, Isoflavones, Isotretinoin, Ixaspirone, JRX-2, JSF-154, J-107088, Pregnant Horse Estrogen, Kahalid F, Ketoconazole, KW-2170, KW-2450, Lapatinib Besylate, Leflunomide, Lenalidomide, Legasemid, Letrozole, Folic Acid, Leuporelin, Leuporelin Acetate, Leuporelin, Levamisole, Lexiparan, LGD-1550, Linezolid, Lobaplatin, Lutetium Texaphyrin, Lometroxobin, Lomustine, Loxoanthraquinone, LU 223651, Letopecan, LY-S6AKT1, LY-2780301, Maphosphatamide, Mamasitol, Mechloroethamine, Medroxyprogesterone acetate, MEK inhibitors, MEK-162, Melphalan, Mercaptopurine, Methotrexate, Methoxam, Methyltestosterone, Methylprednisolone, MEDI-573, MEN-10755, MDX-H210, MDX-447, MDX-1379, MGV, Midotaurine, Minodronate, Mitomycin C, Mitotan Mitoxanthione, Mivobulin, MK-2206, MK-0646 (dalotuzumab), MLN518, Motsafengadolin, MS-209, MS-275, MX6, Nandrolone phenylpropionate, Nerapine, Neridonidine, Lenatinib, Sorafenib (Nexavar), Neovastatin, Nilotinib, Nimesulide, Nitroglycerin, Nofetumab, Noratrexed, Norelin, N-acetylcysteine, O6-benzylguanine, Olimex, Omeprazole, Cancer Phage, OncoVEX GM-CSFOmeprazole, Ormiplatin, Ortataxel, Oxaliplatin, OX44 antibody, OSI-027, OSI-906 (linsitinib), 4-1BB antibody, Pyrroloanthraquinone, Estrogen, Paclitaxel, Pamidronate, Panitumumab, Patospirone, Filgrastim, PCK-3145, Pegaspargase, Pefilgrastim, PBI-1402, PBI-05204, PDO325901, PD-1 antibody, PEG-paclitaxel, Albumin-Stable Paclitaxel, PEP-005, PF-05197281, PF-05212384, PF-04691502, PHT-427, P-04, PKC412, P54, PI-88, Peritoltinib, Pemetrexed Pemetrexed, Pemetrexed disodium, Pentostatin, Pentrix, Perifoxine, Pertuzumab, Pertuzumab, PI3K inhibitor, PI3K / mTOR inhibitor, PG-TXL, PG2, PLX-4032 / RO-5185426 (Vemurafenib), PLX-3603 / RO-5212054, PT-100, PWT-33597, PX-866, Methidazole, Piperbromo, Pivaloyloxymethylbutyrate, Pifenamic acid, Dehydroestradiol O, PKI166, Predrexed, Pucarimycin, Perbromoic acid, Prednisone, Prednisolone, Procarbazine, Quinacrine, Quinamed, Quinupristin, R115777, RAF-265, Ramosetron, Leptospirase, Raburicase, RDEA-119 / BAY 869766, RDEA-436, doxycycline analogue, receptor tyrosine kinase (RTK) inhibitor, revimid, RG-7167, RG-7304, RG-7421, RG-7321, RG 7440, rhizomycin, rhu-MAb, linfepristone, risedronate.Rituximab, Rostrumab, Rofecoxib, RO-31-7453, RO-5126766, RO-5068760, RPR 109881A, Benzoylhydrazone dauremycin, Rubotecan, R-Flurbiprofen, RX-0201, S-9788, Sabarubicin, SAHA, Samostin, Saplatin, SB 408075, Se-015 / Ve-015, SU5416, SU6668, SDX-101, Semustine, Cioliquirol, SM-11355, SN-38, SN-4071, SR-27897, SR-31747, SR-13668, SRL-172, Sorafenib, Spiroplatin, Squalamine, Levozocin, Suberanilohydroxamic acid, Sunitinib, Sunitinib Maleate, Sutent, T 900607, T 138067, TAK-733, TAS-103, Tetracycline, Tarapofen, Tamoxifen, Tarceva, Tariquitar, Tassolan, Taxoprexin, Tazolotine, Tegafur, Temozolomide, Teniposide, Telmilifen, Testosterone, Testosterone Propionate, Telmilifen, Testrolide, Tetraplatin, Tetrodotoxin, Tezatabin, Thalidomide, Theralux, Tetrahydropyranosynovitis, Thioguanine, Thiotepa, Thymofasin, Thymectacin, Thiazofuranoline, Tepififibrin, Tilazamin, Toradexin, Raltitrexed, Topotecan, Toremifen, Toremofin, Tosimomab, Trabectedin, TransMID-107, Trans-retinoic acid, Traszutumab, Temimumab, Retinoic acid, Triacetyluridine, Tri apine, trimethoprim, trimethoprim, TLK-286TXD258, tyverb, urocidin, uracil mustard, penoxuridine, valproic acid, vincristine, vinblastine, vinorelbine, vinorelbine, verulin, WX-UK1, WX-554, victibi, virex, capredo, XELOX, XL-147, XL- 228, XL-281, XL-518 / R-7420 / GDC-0973, XL-765, YM-511, YM-598, ZD-4190, ZD-6474, ZD-4054, ZD-0473, ZD-6126, ZD-9331, ZD1839, ZSTK-474, zoledronic acid, and zosuquidar.

[0174] The compounds of the present invention can also be used in combination with medical treatments such as surgery or radiation therapy (e.g., gamma rays, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy and whole-body radioisotopes).

[0175] For the treatment of autoimmune or inflammatory conditions, the compounds of the present invention can be used in combination with corticosteroids such as triamcinolone, dexamethasone, fluocinolone acetonide, cortisone, prednisolone, or fluocinolone acetonide.

[0176] For the treatment of autoimmune or inflammatory conditions, the compounds of the present invention can be combined with immunosuppressants such as fluocinolone acetonide. Rimesoporone (AL-2178, Vexol, Alcon) or Cyclosporine Combination therapy.

[0177] For the treatment of autoimmune or inflammatory conditions, the compounds of the present invention can be administered in combination with one or more other agents selected from Dehydrex. TM (Holles Labs), Zicascetin (Opko), Sodium Hyaluronate (Vismed, Lantibio / TRB Chemedia), Cyclosporine (ST-603, Sirion Therapeutics), ARG101(T) (Testosterone, Argentis), AGR1012(P) (Argentis), Sodium Ecapate (Senju-Ista), Gefaryl Acetate (Santen), 15-(S)-Hydroxyeicosatetraenoic acid (15(S)-HETE), Cevimeline, Doxycycline (ALTY-0501, Alacrity), Minocycline, iDestrin TM(NP50301, Nascent Pharmaceuticals), Cyclosporine A (Nova22007, Novagali), Oxytetracycline (Duramycin, MOLI1901, Lantibio), CF101 (2S,3S,4R,5R)-3,4-dihydroxy-5-[6-[(3-iodophenyl)methylamino]purine-9-yl]-N-methyl-oxacyclopentane-2-carbamoyl, Can-Fite Biopharma), voclosporin (LX212 or LX214, Lux Biosciences), ARG103 (Agentis), RX-10045 (synthetic resolvin analog, Resolvyx), DYN15 (Dyanmis Therapeutics), Linaglitazone (DE011, Daiichi Sanko), TB4 (RegeneRx), OPH-01 (Ophtalmis Monaco), PCS101 (Pericor) Science), REV1-31 (Evolutec), Lacritin (Senju), Rebamipide (Otsuka-Novartis), OT-551 (Othera), PAI-2 (University of Pennsylvania and Temple University), Pilucarpine, Tacrolimus, Pimecrolimus (AMS981, Novartis), Clotiprazole, Rituximab, Dequafosol Tetrasodium (INS365, Inspire), KLS-0611 (Kissei Pharmaceuticals), Dehydroepiandrosterone, Anazolinone, Efalizumab, Sodium Mycophenolate Mofetil, Etanercept Hydroxychloroquine, NGX267 (TorreyPines Therapeutics), or phthalimide piperidone.

[0178] In some embodiments, the compounds of the present invention can be administered in combination with one or more agents selected from the group consisting of antibiotics, antiviral agents, antifungal agents, anesthetics, anti-inflammatory drugs (including steroidal and nonsteroidal anti-inflammatory drugs), and anti-allergic agents. Examples of suitable drugs include aminoglycosides such as amikacin, gentamicin, tobramycin, streptomycin, netilmicin, and kanamycin; fluoroquinolones such as ciprofloxacin, norfloxacin, ofloxacin, trovafloxacin, lomefloxacin, levofloxacin, and enoxacin; naproxen; sulfonamides; polymyxins; chloramphenicol; neomycin; paromomycin; colistin mesylate; bacitracin; vancomycin; tetracyclines; rifampin and its derivatives (“rifemycin”); cycloserine; β-lactams; cephalosporins; amphotericin B; fluconazole; flucytosine; natamycin; miconazole; ketoconazole; corticosteroids; diclofenac; flurbiprofen; ketorolac; sulprofen; cromoglycine; lodusamide; levocabastine; naphazoline; antazoline; feniramine; or azalide antibiotics.

[0179] One or more additional reagents may be administered to the patient simultaneously or sequentially.

[0180] IV. Formulation, Dosage Form and Administration

[0181] When used as a medicine, the salts and crystalline forms described in this application can be administered as pharmaceutical compositions. These compositions can be prepared in ways well known in the pharmaceutical field and can be administered via a variety of routes, depending on whether local or systemic treatment is required and the area to be treated. Administration can be local (including transdermal, epidermal, ophthalmic, and mucosal administration, including intranasal, vaginal, and rectal administration), pulmonary administration (e.g., by inhalation or blowing of powders or aerosols, including via nebulizers; intratracheal or intranasal administration), oral, or parenteral administration. Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular injection or infusion; or intracranial administration, such as intrathecal or intraventricular administration. Parenteral administration can be in the form of a single bolus dose or, for example, via a continuous infusion pump. Pharmaceutical compositions and formulations for local administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional drug carriers, containing aqueous, powdered, or oily bases, thickeners, etc., may be necessary or desired. The content of the active pharmaceutical compound should be 0.1% to 90% by weight, preferably 0.5% to 50% by weight, of the whole composition, which is sufficient to achieve the following specified dosage range.

[0182] This invention also includes pharmaceutical compositions comprising the salt and crystalline form of the active ingredient as described in this application, and a combination of one or more pharmaceutically acceptable carriers (excipients). In some embodiments, the compositions are suitable for topical administration. In preparing the compositions of this invention, the active ingredient is typically mixed with an excipient, diluted with the excipient, or encapsulated in such a carrier, such as a capsule, sachet, paper, or other container. When the excipient is used as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a medium, carrier, or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0183] In preparing formulations, the active compounds described in this application in the form of salts or crystals can be ground to provide an appropriate particle size before being combined with other ingredients. If the salt or crystalline form is substantially insoluble, it can be ground to a particle size of less than 200 mesh. If the salt or crystalline form is substantially water-soluble, the particle size can be adjusted, for example, to about 40 mesh, by grinding to provide a substantially uniform distribution in the formulation.

[0184] The salts and crystalline forms described in this application can be ground using known grinding procedures, such as wet milling, to obtain particle sizes suitable for tablet formation and other formulation types. Subdivided (e.g., nanoparticle) formulations of the salts and crystalline forms described in this application can be prepared using methods known in the art, see, for example, International Application No. WO 2002 / 000196.

[0185] Examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. Formulations may further include: lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methylparaben and propylparaben; sweeteners; and flavoring agents. Using methods known in the art, the salts and crystalline forms described in this application can be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a patient.

[0186] Suitable tablets can be obtained, for example, by mixing one or more active ingredients with known excipients, such as inert diluents like calcium carbonate, calcium phosphate, or lactose, disintegrants like corn starch or alginate, binders like starch or gelatin, lubricants like magnesium stearate or talc, and / or delayed-release agents like carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. Tablets may also comprise several layers.

[0187] The composition can be formulated into unit dosage forms, each dose containing about 5 to about 1,000 mg (1 g), more typically about 100 mg to about 500 mg of the active ingredient. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human subjects and other mammals, each unit containing a predetermined amount of the active substance, which is calculated to combine with suitable pharmaceutical excipients to produce the desired therapeutic effect.

[0188] In some embodiments, the compositions of the present invention comprise about 5 mg to about 50 mg of the active ingredient. Those skilled in the art will understand that this embodies a compound or composition comprising about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, or about 45 mg to about 50 mg of the active ingredient. The described dosage may be a specified amount of a particular salt or crystalline form, or an amount providing a specified dosage of a particular salt or crystalline form of the base compound (i.e., N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide).

[0189] In some embodiments, the compositions of the present invention comprise about 50 mg to about 500 mg of the active ingredient. Those skilled in the art will understand that this embodies a compound or composition comprising about 50 mg to about 100 mg, about 100 mg to about 150 mg, about 150 mg to about 200 mg, about 200 mg to about 250 mg, about 250 mg to about 300 mg, about 350 mg to about 400 mg, or about 450 mg to about 500 mg of the active ingredient. The described dosage may be a specified amount of a particular salt or crystalline form, or an amount providing a specified dosage of a particular salt or crystalline form of the base compound (i.e., N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide).

[0190] In some embodiments, the compositions of the present invention comprise about 500 mg to about 1,000 mg of the active ingredient. Those skilled in the art will understand that this embodies a compound or composition comprising about 500 mg to about 550 mg, about 550 mg to about 600 mg, about 600 mg to about 650 mg, about 650 mg to about 700 mg, about 700 mg to about 750 mg, about 750 mg to about 800 mg, about 800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg to about 950 mg, or about 950 mg to about 1,000 mg of the active ingredient. The described dose may be a specified amount of a particular salt or crystalline form, or it may provide a specified dose of a particular salt or crystalline form of a base compound (i.e., N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide).

[0191] The specified dose may be given once daily, or, if necessary, several times a day, such as twice, three, or four times a day.

[0192] Active compounds can be effective over a wide dose range and are typically administered at the effective dose. However, it will be understood that the actual dose administered will usually be determined by the physician based on relevant circumstances, including the condition to be treated, the route of administration chosen, the compound to be administered, age, weight, individual patient response, and the severity of the patient's symptoms.

[0193] To prepare solid compositions, such as tablets, a major active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition comprising a homogeneous mixture in the salt or crystalline form described in this application. When these preformulation compositions are referred to as homogeneous, the active ingredient is typically uniformly dispersed throughout the composition, thereby allowing for easy subdivision of the composition into equivalent unit dosage forms, such as tablets, pills, and capsules. The solid preformulation is then subdivided into unit dosage forms of the aforementioned type, containing, for example, from about 0.1 to about 1000 mg of the active ingredient.

[0194] Tablets or pills containing the salts or crystalline forms described in this application can be coated or otherwise formulated to provide dosage forms with the advantage of prolonged action. Coated tablets can be prepared by coating a core similarly prepared to a tablet with substances commonly used for tablet coating, such as collidone, shellac, gum arabic, talc, titanium dioxide, or sugar. To achieve delayed release or prevent incompatibility, the core can also consist of multiple layers. Similarly, tablet coatings can consist of multiple layers to achieve delayed release, possibly using the excipients described above for tablets.

[0195] For example, tablets or pills may contain an internal dose and an external dose component, the latter being a coating of the former. The two components may be separated by an enteric coating, which resists disintegration in the stomach and allows the internal component to enter the duodenum intact or with delayed release. A variety of substances can be used for this enteric coating or coating, including various polymeric acids and mixtures of polymeric acids with substances such as shellac, cetyl alcohol, and cellulose acetate.

[0196] Salts, crystalline forms, and compositions incorporated herein may be administered orally or by injection in liquid forms including aqueous solutions, suitably flavored syrups, water or oil suspensions, and flavored emulsions with edible oils (e.g., cottonseed oil, sesame oil, coconut oil, or peanut oil), as well as elixirs and similar pharmaceutical carriers. Although liquid formulations in which salts are dissolved will generally not contain the crystalline form of the salt, the salts and crystalline forms described herein may still be used to prepare liquid formulations, for example, by dissolving their salt or crystalline form in a suitable medium.

[0197] Solutions for injection and infusion can be prepared in common ways, such as by adding isotonic agents, preservatives (e.g., parabens) or stabilizers (e.g., alkali metal salts of ethylenediaminetetraacetic acid), optionally using emulsifiers and / or dispersants, while if water is used as a diluent, organic solvents, for example, can optionally be used as solvents or dissolving aids and transferred to injection bottles, ampoules or infusion bottles.

[0198] Capsules containing one or more active substances or combinations of active substances can be prepared, for example, by mixing the active substances with an inert carrier such as lactose or sorbitol and packaging them into gelatin capsules.

[0199] Compositions for inhalation or inhalation include pharmaceutically acceptable solutions and suspensions in aqueous or organic solvents or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the composition is administered orally or via nasal inhalation to produce local or systemic effects. The composition may be nebulized using an inert gas. The nebulized solution may be inhaled directly from a nebulizer, or the nebulizer may be connected to a mask, tent, or intermittent positive pressure ventilation machine. Solution, suspension, or powder compositions may be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0200] Topical formulations may contain one or more conventional carriers. In some embodiments, ointments may contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ethers, propylene glycol, white petrolatum, etc. The carrier composition of creams may be based on a combination of water and glycerin and one or more other components such as glyceryl monostearate, PEG-glyceryl monostearate, and cetylstearyl alcohol. Gels may be formulated using isopropanol and water, suitably combined with other components such as glycerin, hydroxyethyl cellulose, etc. In some embodiments, the topical formulation contains at least about 0.1 wt%, at least about 0.25 wt%, at least about 0.5 wt%, at least about 1 wt%, at least about 2 wt%, or at least about 5 wt% of the compounds of the present invention. Topical formulations may be suitably packaged in, for example, 100 g tubes, optionally in conjunction with instructions for use in treating selected indications such as psoriasis or other skin conditions.

[0201] The amount of the salt or crystalline form or composition administered to a patient will vary depending on the contents of the medication, the purpose of administration (e.g., prevention or treatment), the patient's condition, the route of administration, etc. In therapeutic applications, the composition may be administered to a patient with an existing disease in an amount sufficient to cure or at least partially stop the symptoms of the disease and its complications. The effective dose will depend on the disease condition being treated and the judgment of the attending physician based on factors such as the severity of the disease, the patient's age, weight, and general condition.

[0202] The therapeutic dose of the compounds of the present invention can vary depending on, for example, the specific purpose of treatment, the route of administration, the patient's health and condition, and the prescribing physician's judgment. The proportion or concentration of the compounds of the present invention in the pharmaceutical composition can vary depending on many factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, the compounds of the present invention can be used for parenteral administration in a physiologically buffered aqueous solution containing about 0.1% to about 10% w / v of the compound. Some typical dosage ranges are about 1 μg / kg to about 1 g / kg body weight per day. In some embodiments, the dosage range is about 0.01 mg / kg to about 100 mg / kg body weight per day. The dosage may depend on variables such as the type and progression of the disease or condition, the overall health status of the particular patient, the relative biological efficacy of the selected compound, the formulation of excipients, and the route of administration. The effective dose can be extrapolated from dose-response curves derived from in vitro or animal model testing systems.

[0203] The expected appropriate dose range for human administration will be approximately 50 mg to approximately 2000 mg, for example, approximately 100 mg to approximately 2000 mg, approximately 200 mg to approximately 2000 mg, approximately 400 mg to approximately 2000 mg, approximately 600 mg to approximately 2000 mg, approximately 800 mg to approximately 2000 mg, approximately 1000 mg to approximately 2000 mg, approximately 1200 mg to approximately 2000 mg, approximately 1400 mg to approximately 2000 mg, approximately 1500 mg to... Approximately 2000 mg, approximately 1600 mg to approximately 2000 mg, approximately 1800 mg to approximately 2000 mg, approximately 50 mg to approximately 1500 mg, approximately 100 mg to approximately 1500 mg, approximately 200 mg to approximately 1500 mg, approximately 400 mg to approximately 1500 mg, approximately 600 mg to approximately 1500 mg, approximately 800 mg to approximately 1500 mg, approximately 1000 mg to approximately 1500 mg, approximately 1200 mg to approximately 1500 mg, approximately 1250mg to about 1500mg, about 50mg to about 1000mg, about 100mg to about 1000mg, about 200mg to about 1000mg, about 400mg to about 1000mg, about 600mg to about 1000mg, about 800mg to about 1000mg, about 50mg to about 500mg, about 100mg to about 500mg, about 200mg to about 500mg, about 400mg to about 500mg, or dosage The appropriate dose may be the dose of the salt itself, or the dose of a salt providing a specified amount of the base compound (i.e., N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide).

[0204] The compositions of the present invention may further include one or more other agents, such as chemotherapeutic agents, steroids, anti-inflammatory compounds or immunosuppressants, examples of which are listed above.

[0205] The following formulation examples illustrate the present invention, but do not limit its scope:

[0206] Examples of pharmaceutical preparations

[0207]

[0208] Finely chopped active ingredient, lactose, and some corn starch are mixed together. The mixture is sieved, then moistened with an aqueous solution of polyvinylpyrrolidone, kneaded, wet-granulated, and dried. The granules, remaining corn starch, and magnesium stearate are sieved and mixed together. The mixture is then compressed into tablets of suitable shape and size.

[0209]

[0210] Finely ground active ingredients, some corn starch, lactose, microcrystalline cellulose, and polyvinylpyrrolidone are mixed together. The mixture is sieved and then processed into granules with the remaining corn starch and water. These granules are dried and sieved again. Sodium fluoromethyl starch and magnesium stearate are added and mixed. The mixture is then compressed into tablets of appropriate size.

[0211] V. Reagent Kit

[0212] The present invention also includes pharmaceutical kits for, for example, treating or preventing diseases or conditions associated with B-RAF, such as cancer, said pharmaceutical kit comprising one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of the salt or crystalline form described in this application. If desired, such kits may further include one or more of a variety of conventional pharmaceutical kit components, such as containers having one or more pharmaceutically acceptable carriers, additional containers, etc., as will be apparent to those skilled in the art. The kit may also include instructions (as inserts or labels) indicating the amount of the ingredient to be administered, dosing guidelines, and / or guidelines for mixing the ingredients.

[0213] The invention will be described in more detail through specific embodiments. The following embodiments are provided for illustrative purposes and are not intended to limit the invention in any way. Those skilled in the art will readily recognize that various non-critical parameters can be changed or modified to obtain substantially the same results.

[0214] Example

[0215] General methods

[0216] In the following embodiments, unless otherwise stated, the X-ray powder diffraction analysis was performed on a transmission-type STOE STADI powder diffractometer equipped with a position-sensitive detector (PSD) and a Cu anode as an X-ray source for monochromatic CuKα1 radiation. The general measurement conditions are:

[0217] ●Starting angle –3°

[0218] ● Stop angle – 40°

[0219] ●Sampling – 0.02 degrees.

[0220] ● Scanning speed – 10s / step.

[0221] Differential scanning calorimetry (DSC) was performed using a TA Instruments differential scanning calorimeter (model Q2000) with an injection volume of 8-10 mg. Typical experimental conditions were: 25-350℃, at a rate of 10℃ / min.

[0222] Thermogravimetric analysis (TGA) was performed on a TA-based thermogravimetric analyzer (model Q5000) under the following conditions: the temperature was increased to 350°C at a rate of 10°C / min.

[0223] Dynamic vapor adsorption (DVS) was performed in an IGASorp water adsorption analyzer from Hiden Isochema. Adsorption and desorption isotherms were constructed at 25 °C with 10% RH increments (from 0% to 90% RH).

[0224] For HPLC-MS / UV-spectroscopy, retention time / MS-ESI measurements for characterizing the example compounds according to the present invention were prepared using HPLC-MS equipment (high-performance liquid chromatography with a mass detector). + Give the retention time t of the compound eluted at the injection peak. 保留 =0.00. The method described in the following examples is as follows.

[0225] HPLC-MS Method A

[0226]

[0227] HPLC-MS Method B

[0228]

[0229]

[0230] HPLC-MS Method C

[0231]

[0232] Equilibrium solubility measurement

[0233] A saturated solution is prepared by adding an appropriate volume of the selected aqueous medium (typically in the range of 0.25–1.5 mL) to each well, containing a known amount of solid drug substance (typically in the range of 0.5–5.0 mg). The wells are shaken or stirred for a predetermined period of time (typically in the range of 2–24 h), and then filtered using a suitable filter membrane (typically a PTFE filter with a pore size of 0.45 μm). Filter absorption is avoided by discarding the first few drops of filtrate. The amount of dissolved drug substance is determined by UV spectroscopy. Additionally, the pH of the saturated aqueous solution is measured using a glass electrode pH meter.

[0234] Inherent dissolution rate measurement

[0235] The intrinsic dissolution rate of 3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide salt was determined using a rotating disk method with a constant surface area in aqueous media covering a pH range of 1.1–7.4.

[0236] The drug substance (5 mg) was compressed at 356.1 Newtons for 60 seconds to form discs. These discs were then fixed onto a sample holder installed in a small dissolution testing device. The dissolution medium was stirred at 200 rpm at 37°C. Samples were automatically removed from the dissolution vessel every two minutes and measured by ultraviolet spectrophotometry.

[0237] Preparation of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide (BI 882370)

[0238]

[0239] Step 1.4-(6-methyl-5-nitro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (3)

[0240]

[0241] DIPEA (62.82 mL, 0.435 mol) was added to a solution of 6-chloro-3-nitro-2-methylpyridine (1) (50 g, 290 mmol) and N-Boc-piperazine (2) (53.95 g, 290 mmol) in dry MeCN (200 mL), and stirred at 50 °C for 4 h. After the reaction was complete, the reaction mixture was diluted with MeCN and water and stirred for 30 min. The precipitated product was collected by filtration, washed with water, and the solid was dried under vacuum.

[0242] Step 2.4 - [6-((E)-2-dimethylamino-vinyl)-5-nitro-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester (4)

[0243]

[0244] To a stirred solution of tert-butyl 4-(6-methyl-5-nitro-pyridin-2-yl)piperazine-1-carboxylate (3) (13 g, 40.3 mmol) in DMF (35 mL), N,N-dimethylformamide dimethyl acetal (14.47 g, 121 mmol) was added, and the mixture was stirred at 90 °C for 36 h under an argon atmosphere. Another 1.5 equivalent of N,N-dimethylformamide dimethyl acetal was added, and the mixture was stirred at 90 °C for 12 h. The reaction mixture was poured into water and extracted with DCM. The combined organic layers were washed with water, dried over anhydrous Na₂SO₄, and concentrated under vacuum. The residue was ready for use in the next step without further purification.

[0245] Step 3.4 - (1H-pyrrolo[3,2-b]pyridin-5-yl)piperazine-1-carboxylic acid tert-butyl ester (5)

[0246]

[0247] 4-[6-((E)-2-dimethylamino-vinyl)-5-nitro-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester (36.4 g, 96 mmol) was dissolved in MeOH, and Pd / C (0.56 g, 10%) was added. The mixture was hydrogenated in an autoclave at 60 psi for 16 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography by NP MPLC. The products containing fraction (5) of compound were combined (HPLC-MS method B: t 保留 = 1.55 min; MS(M+H) + =303), evaporated in a vacuum.

[0248] Step 4. N-(3-amino-2,6-difluorophenyl)acetamide (7)

[0249]

[0250] Compound (6) (55.0 g, 254 mmol) was dissolved in MeOH (1.0 L). Pd / C (10.0 g, 10%) was added, and the mixture was hydrogenated in an autoclave at 200 psi for 3 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by NP-MPLC on silica gel using DCM / MeOH (96:4) as eluent. The products containing the aniline intermediate fraction were combined (HPLC-MS Method B: t). 保留=0.25 min; MS (MH) - =185), evaporation.

[0251] Step 5. N-(2,6-difluoro-3-(propylsulfonamido)phenyl)acetamide (9)

[0252]

[0253] To an aniline intermediate (35.0 g, 188 mmol) in DCM (100 mL), pyridine (6.6 mL, 75 mmol) and n-propanesulfonyl chloride (8) (29.5 mL, 263 mmol) were added, and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc (200 mL), washed with H2O and HCl (aq., 1 N), separated into layers, dried over MgSO4, and evaporated to obtain sulfonamide (9), which was ready for use without further purification.

[0254] Step 6. N-(3-amino-2,4-difluorophenyl)propane-1-sulfonamide (10)

[0255]

[0256] Sulfonated aniline (9) (38.0 g, 130 mmol) was dissolved in EtOH (250 mL), H₂O (200 mL), and concentrated hydrochloric acid (200 mL), and heated to 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure, and aqueous NaOH (4 N) was added until pH = 6 was reached. The mixture was extracted twice with DCM. The combined organic layers were washed with brine, dried over MgSO₄, filtered, and evaporated to obtain deacylated aniline (10) (HPLC-MS method B: t 保留 =0.22 min; MS(MH) - =249) is a hydrochloride salt, which can be used without further purification.

[0257] Step 7. N-(2,4-difluoro-3-iodophenyl)propane-1-sulfonamide (11)

[0258]

[0259] The hydrochloride salt of compound (10) was dissolved in DCM and extracted with NaHCO3 solution. The organic layer was dried over MgSO4, filtered, and evaporated. NaNO2 (1.96 g, 28.4 mmol) was added in small batches to free base (10) (3.55 g, 14.21 mmol) in TFA (80 mL) at 0 °C. The mixture was stirred for 30 min, and KI (23.83 g, 142 mmol) was added. The mixture was stirred for another 15 min. The reaction mixture was diluted with Et2O and stirred for 1 h. Na2S2O3 solution (semi-concentrated) was added, and the mixture was extracted three times with Et2O. The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography by NP-MPLC. The products containing the fraction of compound (11) were combined (HPLC-MS method A: t 保留 = 1.58 min; MS (MH) - =360), evaporated in a vacuum.

[0260] Step 8.4-((1-(2,6-difluoro-3-(propylsulfonamido)phenyl)-1H-pyrrolo[3,2-b]pyridin-5-yl)(methyl)amino)piperidine-1-carboxylic acid tert-butyl ester (12)

[0261]

[0262] 1H-pyrrolo[3,2-b]pyridine (5) (10.0 g, 30.27 mmol), sulfonamide (11) (16.4 g, 45.4 mmol), CuI (576 mg, 3.03 mmol), trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (1.91 mL, 12.1 mmol), and Cs₂CO₃ (29.6 g, 90.85 mmol) were dissolved in dry toluene (3 mL). The resulting mixture was purged with argon and stirred at 20 °C for 16 h. After adding the remaining CuI (576 mg, 3.03 mmol), trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (1.91 mL, 12.1 mmol), and Cs₂CO₃ (20.0 g, 60.0 mmol), the reaction mixture was stirred for another 24 h. The solvent was removed under vacuum, and the residue was dissolved in DCM and extracted with NaHCO₃ solution (semi-concentrated extraction). The organic layer was dried over MgSO4, filtered, and the solvent was removed under vacuum. The residue was purified by NP-MPLC. The products containing fractions (12) were combined (HPLC-MS method C: t). 保留 = 1.62 min; MS(M+H) + =564), the solvent is removed in a vacuum.

[0263] Step 9.4-((1-(2,6-difluoro-3-(propylsulfonamido)phenyl)-3-iodo-1H-pyrrolo[3,2-b]pyridin-5-yl)(methyl)amino)piperidine-1-carboxylic acid tert-butyl ester (13)

[0264]

[0265] To a solution of sulfonamide (12) (1.078 g, 1.9 mmol) in DMF (4 mL) / THF (100 μL), NIS (474 ​​mg, 2.1 mmol) was added, and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with 30 mL of DCM and extracted with NaHCO3 solution (semi-concentrated). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using RP HPLC. The product containing fraction (13) (HPLC-MS method B: t) 保留 = 2.035 min; MS(M+H) + =688) was freeze-dried.

[0266] Step 10.4-((1-(2,6-difluoro-3-(propylsulfonamido)phenyl)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)(methyl)amino)piperidine-1-carboxylic acid tert-butyl ester (15)

[0267]

[0268] Sulfonamide (13) (770 mg, 1.12 mmol), pyrimidin-5-yl-boronic acid (14) (194 mg, 1.57 mmol), Pd(dppf)Cl2 (82 mg, 0.11 mmol), LiCl (142 mg, 3.35 mmol), and Na2CO3 (294 mg, 2.8 mmol) were dissolved in dioxane / H2O (2:1 mixture, 12 mL). The resulting mixture was purged with argon and stirred at 100 °C for 1 h. The reaction mixture was diluted with DCM and extracted with NaHCO3 solution (semi-concentrated). The organic layer was dried over MgSO4, filtered, and then added... The solvent was removed under vacuum, and the residue was purified by RP HPLC. The product containing (15) fractions (HPLC-MS method C: t) Ret. = 2.149 min; MS(M+H) + =642) was freeze-dried.

[0269] Step 11. N-(2,4-difluoro-3-(5-(methyl(piperidin-4-yl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)phenyl)propane-1-sulfonamide

[0270]

[0271] HCl (in dioxane, 4 N, 2 mL) was added to a solution of example compound (15) (154 mg, 0.24 mmol) in DCM / MeOH (1:1, 4 mL), and the mixture was stirred at room temperature for 3 h. The solvent was removed under vacuum. The resulting compound (16) (HPLC-MS method B: t) was usable without further purification. 保留 = 1.02 min; MS(M+H) + =542).

[0272] Step 12. N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide (I)

[0273]

[0274] Compound I was obtained by reductive alkylation of compound (16) with acetaldehyde (40%, in iPrOH) in the presence of 1.5 equivalents of sodium acetoxyborohydride in iPrOH. The crude product was recrystallized from ethanol to give the title compound in 84% yield.

[0275] Scale-up synthesis of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide (BI 882370)

[0276]

[0277] Step 1. N-(2,4-difluoro-3-(5-(methyl(piperidin-4-yl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)phenyl)propane-1-sulfonamide

[0278]

[0279] Isopropanol (8.83 kg) and compound (15) (1.80 kg, 2.8 mol) were added to the reactor, and the mixture was stirred and heated to 55–60 °C. Concentrated hydrochloric acid (2.76 kg, 28 mol) was added dropwise to the reactor over more than 20 min at 60–65 °C. The reactants were then heated to 60–70 °C and maintained for 1 h. The conversion rate was monitored by HPLC and reached approximately 99.5% after about 1 h.

[0280] The reactants were cooled and distilled off the isopropanol under reduced pressure at a temperature not exceeding 50°C. A brown oil was obtained, dissolved in water (6.75 kg), and washed with ethyl acetate (2.02 kg) at 20-30°C. The aqueous phase was cooled to 15-20°C. The pH was adjusted to 8.0-8.5 at 20-30°C with a 10% NaOH aqueous solution (approximately 8.0 kg). The mixture was stirred at 20-30°C for 3-4 h, during which the pH was adjusted to 8.0-8.5 every half hour by adding 10% NaOH solution. The product was separated by filtration, and the filter cake was washed with water (3.6 kg). The solid was dried under a vacuum of 45-50°C until the water content was not greater than 5.5%. This yielded approximately 1.64 kg of crude compound (16) (108% of the theoretical yield; crude product containing water and NaCl was detected). The crude product was used directly.

[0281] Step 12. N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide (I)

[0282]

[0283]

[0284]

[0285] method:

[0286] Dichloromethane (19.88 kg) and compound (16) (1.5 kg, 2.77 mol) were added to the reactor, the mixture was stirred, and cooled to 0–10 °C under a nitrogen atmosphere. Sodium triacetoxyborohydride (95%, 0.93 kg, 4.16 mol) was added to the mixture at 0–10 °C. The mixture was stirred for 20–30 min at 0–10 °C. Acetaldehyde (40%, 1.07 kg, 9.71 mol) from DCM was slowly added to the mixture over 2 h at 0–10 °C. The reaction mixture was stirred for 0.5–1 h under a nitrogen atmosphere at 0–10 °C. The conversion was monitored by HPLC and reached approximately 99.5% after approximately 0.5–1 h.

[0287] Water (15 kg) was added to the reactants at a temperature below 15°C. The mixture was stirred at 15-30°C for 20-30 min. Ammonia (25%, 1.13 kg, 16.61 mol) was added to the mixture, and the mixture was stirred for 0.5 h. The organic phase was separated and then extracted with water (15 kg) at 20-25°C. Activated carbon (0.15 kg) was added to the organic phase. The mixture was stirred for 1 h and then filtered. The filtrate was concentrated under reduced pressure at a temperature not exceeding 40°C to give compound (I) (1.58 kg, 100% yield) as a foamy solid.

[0288] The crystallinity of the free base of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide was investigated.

[0289] The crystallinity of the free base of N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide, recrystallized from an aqueous ethanol solution, was studied. Using this base as a starting material for salt formation studies, the results indicated that the compound has low crystallinity. Figure 1 As shown.

[0290] The study investigated the salt forms of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide.

[0291] The compound N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide was combined with various acids in various solvent systems.

[0292] A 96-well master dish was filled with a stock solution of the compound in MeOH at a concentration of approximately 40 mg / mL. The dish was placed in a vacuum oven to remove liquid, thus obtaining the same amount of solid material in each well. Subsequently, different solvent / solvent mixtures and acids were added to the solid material in each well (approximately 500 μL), and the entire dish was heated to 50 °C for 2 hours while stirring (using a small stir bar added to each well).

[0293] The acids used are shown in Table 1. The solvents used are shown in Table 2. The crystallinity of the salts was determined by slurry experiments or evaporative crystallization.

[0294] To study crystal formation through slurry experiments, the dish was cooled, and the crystallinity of the salt was determined by XRPD. Figure 2A The image shown is of the main petri dish displaying the salt. Figure 2B The image shows an XRPD image of the salt from each master plate well, which shows the crystallinity of the formed salt.

[0295] To study crystal formation via evaporation experiments, the solution was filtered at the same temperature (50°C) using a preheated filter plate after a period of heating to ensure that undissolved material was not transferred to other crystallization plates. The filtrate was dispensed into an evaporation plate (approximately 200 μL). The solvent was then evaporated, and the crystallinity of the salt was determined by XRPD. Figure 3A The image shown is of the main petri dish displaying the salt. Figure 3B The image shows an XRPD image of the salt from each well of the evaporator plate, which shows the crystallinity of the formed salt.

[0296] Table 1. Salts used for salt form studies

[0297]

[0298]

[0299] Table 2. Solvents used for salt form studies

[0300] entry solvent A ethanol B 90% aqueous ethanol C 2-Propanol (iPrOH) D Water content iPrOH / (90%) E acetone F Ethyl acetate G Methyl isobutyl ketone (MIBK) H Tetrahydrofuran (THF)

[0301] Based on the initial screening, six crystalline salts were formed, namely chloride (CL), fumarate (FU), phosphate (PH), succinate (SC), sulfate (SU), and tartrate (TA), as summarized in Table 3.

[0302] Table 3. Results of preliminary salt form studies

[0303]

[0304]

[0305] XRPD images of samples performed for each salt form summarized in Table 3 are as follows: Figure 4 As shown.

[0306] Scale-up synthesis of the salt form of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide

[0307] Based on the preliminary salt form identification results, approximately 50 mg of chloride (CL), fumarate (FU), phosphate (PH), succinate (SC), sulfate (SU), and tartrate (TA) salts were resynthesized. Except for the phosphate, the crystalline forms of the chloride (CL), fumarate (FU), succinate (SC), sulfate (SU), and tartrate (TA) salts were obtained, as summarized in Table 4.

[0308] Table 4. Preliminary results of the salt form study

[0309]

[0310] Data obtained by amplification of N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride are shown in Figure 5-9 middle.

[0311] Figure 5 The image below shows the XRPD plot of N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride from pore E2, compared to the sample obtained by amplified synthesis (top image).

[0312] Figure 6 This is the DSC chromatogram of N-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride. The sample shows endothermic reaction at approximately 321 °C.

[0313] Figure 7 This is the TGA diagram of N-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride.

[0314] Figure 8 The adsorption-desorption curves are for N-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride, showing the increase and decrease in weight as the relative humidity varies between 0 and 100%. The sample showed an approximately 2.4% weight increase in the relative humidity range of 10-90%.

[0315] Figure 9 The images show the XRPD plots of N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride before (bottom) and after (top) the adsorption-desorption experiment, indicating that no significant structural changes occurred.

[0316] Data obtained by amplification of N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate are shown in Figure 10-14 middle.

[0317] Figure 10 The image below shows the XRPD plot of N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate from pore F10, compared to the sample obtained by amplified synthesis (top image).

[0318] Figure 11 This is the DSC chromatogram of N-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate. The sample shows endothermic activity at approximately 182 °C.

[0319] Figure 12 Yes, this is the TGA diagram of N-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate.

[0320] Figure 13 The adsorption-desorption curves are for N-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate, showing the increase and decrease in weight as the relative humidity varies between 0 and 100%. The sample showed an increase in weight of approximately 1.2% in the range of 10-90% relative humidity.

[0321] Figure 14The images show the XRPD plots of N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride before (bottom) and after (top) the adsorption-desorption experiment, indicating that no significant structural changes occurred.

[0322] Synthesis and Properties of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride

[0323] N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride is prepared in various solvent systems as follows: N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide (100 mg, 176 μmol) is dissolved in various solvents (10-20 mL), and HCl (10 M solution in ethanol; 1 equivalent) is added at 50 °C. The resulting solution is then heated with stirring at approximately the boiling point of the solvent for about 1 h, and then cooled to room temperature and stirred for 3 h or longer (e.g., overnight). The salt is then collected by filtration and dried at 50°C.

[0324] Table 5 provides a summary of the experiments conducted.

[0325] Table 5. Synthesis of N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride

[0326]

[0327]

[0328] #Synthesized in 1g increments

[0329] Preparative-scale synthesis of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride

[0330] N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide (1.0 g, 1.76 mmol) was heated at 60 °C with stirring to form a brown solution. HCl (10 M solution in ethanol; 1.84 mmol, 1.05 equivalents) was added. The resulting suspension was heated at 60 °C with stirring for 1 h, then at 80 °C for 1 h, then at 50 °C for 1 h, and then cooled to room temperature and stirred overnight (approximately 16 h). The salt was then collected by filtration and dried at 50 °C under reduced pressure overnight (approximately 16 h). This yielded N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride (1.023 g, 96% yield) as a grayish-white solid. Data for N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride are shown in… Figure 15-24 middle.

[0331] Figure 15 This is the XRPD diagram of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride.

[0332] Table 6 is a list of representative XRPD peaks, d values, and relative intensities for the XRPD of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride.

[0333] Table 6. XRPD peaks, d values, and relative intensities of N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride

[0334]

[0335]

[0336]

[0337] Figure 16This is the DSC chromatogram of N-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride. The sample shows endothermic activity starting at approximately 313 °C. Typically, the sample begins to endothermic in the range of 312–322 °C, corresponding to the melting point. Therefore, the melting point is measured to be approximately 317 ± 5 °C. Some samples exhibit additional endothermic activity at approximately 250 °C, corresponding to solvent loss.

[0338] Figure 17 This is the TGA chromatogram of N-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride. The sample exhibits a drying loss of approximately 1.7–2.5% at up to approximately 250 °C, corresponding to the release of water and solvent. The water content was measured to be approximately 0.9% (Karl Fischer method).

[0339] Figure 18 This is an isothermal adsorption-desorption plot of N-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride, showing the increase and decrease in weight as the relative humidity varies between 0 and 90%. The sample shows a reversible weight increase of approximately 4% in the 0–90% relative humidity range and approximately 2.5% in the 0–80% relative humidity range. It appears that the amount of absorption and desorption depends on the amount of organic solvent present in the sample.

[0340] Figure 19 The images show the XRPD plots of N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride before (bottom) and after (top) the adsorption-desorption experiment, indicating that no significant structural changes occurred.

[0341] Figure 20 This is the XRPD diagram of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride after grinding at 30 rpm for 10 min in a gyratory mill. The sample shows a significant decrease in crystallinity, but the polymorphism remains unchanged.

[0342] Figure 21This is the XRPD image of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride after pressing at 2000N for 1s to form a sheet (5 mm in diameter). The sample shows a slight decrease in crystallinity, but the polymorphism remains unchanged.

[0343] Figure 22 It is N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride 1 1H NMR spectrum (400MHz, DMSO-d6).

[0344] Figure 23 It is N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride 1 An inset of 1H NMR spectra (400 MHz, DMSO-d6) in the aliphatic region (δ -0.5–6.0).

[0345] Figure 24 It is N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride 1 An inset of 1H NMR spectra (400MHz, DMSO-d6) in the aromatic region (δ6.0–11.5).

[0346] The equilibrium solubility of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride in various media was determined. The results are summarized in Table 7.

[0347] Table 7. Solubility of N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride in various media

[0348]

[0349]

[0350] The intrinsic dissolution rates of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride in various media were measured in media at various pH values. The results are summarized in Table 8.

[0351] Table 8. Intrinsic dissolution rates of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride in aqueous media at pH 1.0–7.4

[0352] pH of the medium <![CDATA[Intrinsic dissolution rate (μg / cm 2 / min)]]> 1.0 4 2.2 121 3.0 80 4.5 38 6.8 15 7.4 3

[0353] Figure 25 This is a graph showing the dissolution rate of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride in aqueous media at pH values ​​from 1.0 to 7.4 over 0–60 min.

[0354] Synthesis and Properties of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate

[0355] N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate is prepared in various solvent systems as follows: N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide (100 mg, 176 μmol) is dissolved in various solvents (about 8-10 mL per mg of drug) under heating, and succinic acid (1 equivalent) is added. The resulting solution is heated at about 60-80 °C for about 1 h with stirring, then cooled to room temperature and stirred for 3 h or more (e.g., overnight). The salt is then collected by filtration and dried at 50°C.

[0356] Table 8 provides a summary of the experiments conducted.

[0357] Table 8. Synthesis of N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate

[0358]

[0359]

[0360] *Acetone solvate.

[0361] For N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate, crystallization from many solvents yields the same crystalline form (form A) as obtained by the above experiments, but crystallization from acetone yields a different crystalline form (form B) (acetone solvate).

[0362] Preparative-scale synthesis of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate (form A)

[0363] N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide (800 mg, 1.40 mol) in ethanol (8 mL) was heated at 60 °C with stirring to form a pale yellow solution. Succinic acid (166 mg, 1.40 mmol, 1.0 equivalent) was added. The resulting solution was heated at 60 °C for 10 min with stirring, then at 45 °C for 10 min, until a precipitate formed. The suspension was heated at 55 °C with stirring for 1 h, then cooled to room temperature and stirred overnight (approximately 16 h). The salt was then collected by filtration and dried at 50 °C under reduced pressure for 3 days. This yielded N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate (726 mg, 75% yield) as a grayish-white solid. Data for the obtained N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate (form A) are shown in... Figure 26-35 middle.

[0364] Figure 26 This is the XRPD diagram of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate (form A).

[0365] Table 9 is a list of representative XRPD peaks, d-values, and relative intensities for N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate (form A).

[0366] Table 9. XRPD peaks, d-values, and relative intensities of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate (form A)

[0367]

[0368]

[0369]

[0370] Figure 27 This is the DSC chromatogram of N-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate. The sample shows endothermic activity starting at approximately 180 °C. Typically, the sample begins to endothermic in the range of 179–182 °C, corresponding to the melting point. Therefore, the melting point is measured to be approximately 180 ± 3 °C. Some samples exhibit additional endothermic activity at approximately 160–165 °C, corresponding to solvent loss.

[0371] Figure 28 This is a TGA chromatogram of N-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate. The sample exhibits drying losses of approximately 1.4–3.7% up to about 250 °C, corresponding to water and solvent release. The water content was measured to be approximately 0.03% (Karl Fischer method). The salt tends to contain a variable amount of solvent in the crystals, which is released at temperatures above about 160 °C.

[0372] Figure 29This is an isothermal adsorption-desorption plot of N-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate, showing the increase and decrease in weight as relative humidity varies between 0 and 90%. The sample shows a reversible weight increase of approximately 4% in the 0–90% relative humidity range and approximately 2.5% in the 0–80% relative humidity range. It appears that the amount of absorption and desorption depends on the amount of organic solvent present in the sample. Adsorption and desorption are completely reversible, and there is no change in crystallinity or polycrystalline form.

[0373] Figure 30 The images show the XRPD plots of N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate before (bottom) and after (top) the adsorption-desorption experiment, indicating that no significant structural changes occurred.

[0374] Figure 31 This is the XRPD plot of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate after grinding at 30 rpm for 10 min in a gyratory mill. The sample shows a slight decrease in crystallinity, but the polymorphism remains unchanged.

[0375] Figure 32 This is the XRPD diagram of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate after being pressed at 2000N for 1 second to form tablets (5 mm in diameter). The sample shows no significant decrease in crystallinity or change in polycrystalline form.

[0376] Figure 33 It is N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate 1 1H NMR spectrum (400 MHz, DMSO-d6).

[0377] Figure 34It is N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate 1 An inset of 1H NMR spectra (400 MHz, DMSO-d6) in the aliphatic region (δ-0.5–6.0).

[0378] Figure 35 It is N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate 1 An inset of 1H NMR spectra (400 MHz, DMSO-d6) in the aromatic region (δ6.0–10.0).

[0379] The solubility of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate in various media was determined. The results are summarized in Table 10.

[0380] Table 10. Solubility of N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate in various media

[0381] medium Solubility (mg / mL) after 2 hours water >2.00 HCl (0.1 M) 0.20 HCl (0.01 M) >0.05 McIlvaine buffer (pH 2.2) >5.00 McIlvaine buffer (pH 3.0) >5.00 McIlvaine buffer (pH 4.0) >5.00 McIlvaine buffer (pH 4.5) >5.00 McIlvaine buffer (pH 5.0) >5.00 Acetate buffer (pH 5.0) >5.00 McIlvaine buffer (pH 6.0) 3.7 McIlvaine buffer (pH 6.8) >5.00 Phosphate buffer (pH 6.8) >5.00 McIlvaine buffer (pH 7.4) 0.30 Sorensen buffer (pH 9.0) 0.001 Sorensen buffer (pH 11) 0.05 0.1 M citric acid >5.00 Simulated intestinal fluid (FaSSIF) 0.003 Simulated intestinal fluid (FeSSIF) 0.40

[0382] The intrinsic dissolution rates of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate in various media were measured in media at various pH values. The results are summarized in Table 11.

[0383] Table 11. Intrinsic dissolution rates of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate in aqueous media at pH 1.0–7.4

[0384]

[0385]

[0386] Figure 36 This is a graph showing the dissolution rate of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride in aqueous media at pH values ​​from 1.0 to 7.4 over 0–60 min.

[0387] Surprisingly, the solubility of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate was significantly higher than that of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate in many of the media tested. The intrinsic dissolution rate of N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate is also significantly higher than that of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate.

[0388] Pharmacokinetics of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate and N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate in rats

[0389] Pharmacokinetics of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide hydrochloride and N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide hydrochloride were measured in HsdHan:WIST Norwegian rats after oral administration of 40 mg and 80 mg (dose based on free base). Each salt was administered to 3 animals. Results are shown in Table 12.

[0390] Table 12. Mean plasma concentrations (N = 3 ± standard deviation) of N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate in Norwegian rats after oral administration.

[0391]

[0392]

[0393] Data show that the exposure value of monosuccinate is much higher than that of monohydrochloride. Furthermore, compared to 50% of the exposure value of monosuccinate, the oral bioavailability of monohydrochloride at a dose of 40 mg / kg is only 1%.

[0394] Figure 37 shows the relationship between plasma concentrations and time in rats after oral administration of the following substances: (A) at 40 mg / kg of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monohydrochloride; (B) at 80 mg / kg of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl) (C) Propane-1-sulfonamide monosuccinate at 40 mg / kg; (D) N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate at 80 mg / kg.

[0395] Scale-up preparation of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate (form A)

[0396]

[0397] Methanol (11.26 kg) and compound (I) (1.58 kg, 2.63 mol) were added to a reactor, and the mixture was stirred and heated to 60-70 °C until the solid dissolved. Succinic acid (393 g, 3.16 mol) was added to the mixture. Stirring was continued at 60-70 °C for 0.5-1 h, and then the solution was cooled to 10-25 °C. Seed crystals of N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate (3 g) of form A were added to the mixture, and stirring was continued for another 1 h to allow the product to crystallize completely. The mixture was then cooled to 0-10 °C and maintained for 3-4 h. The precipitated product was separated by filtration and washed with cooled methanol. The solid was dried under vacuum at 45-50 °C to give N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate of form A (1.53 kg, yield 80.2%).

[0398] Characterization of further salt forms of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate

[0399] Further experiments were conducted to characterize form A of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate. Several other forms were identified during the characterization process.

[0400] Other general methods

[0401] Unless otherwise stated, the instruments and methods used in the following studies are described below.

[0402] X-ray powder diffraction

[0403] XRPD analysis was performed using a PANalytical Empyrean X-ray powder diffractometer with the parameters listed in Table 13.

[0404] Table 13. XPRD Parameters

[0405]

[0406]

[0407] Thermogravimetric analysis and differential scanning calorimetry

[0408] TGA data was acquired using the TA Q500 / Q5000 / 5500TGA from TA Instruments. DSC data was acquired using the TA Q200 / Q2000 / 2500DSC from TA Instruments. Detailed parameters used are listed in Table 14.

[0409] Table 14. XPRD Parameters

[0410] parameter TGA DSC method Ramp Ramp Sample tray Aluminum, open Aluminum, coiled temperature Ambient temperature -350℃ 25-250℃ heating rate 10℃ / min 10℃ / min purge gas Nitrogen Nitrogen

[0411] Dynamic steam adsorption

[0412] DVS was measured using SMS (Surface Measurement Systems) DVS Intrinsic. The deliquescence points of LiCl, Mg(NO3)2, and KCl were calibrated at 25°C and relative humidity. The parameters for the DVS test are listed in Table 15.

[0413] Table 15. DVS Parameters

[0414]

[0415] Nuclear magnetic resonance

[0416] 1 H₂ desorption NMR was performed using a Bruker 400MHz NMR spectrometer with DMSO-d₆ or deuterated methanol as the solvent.

[0417] polarizing microscope

[0418] Used at room temperature The Axio Lab.A1 upright microscope with a CT3 camera was used to capture PLM images.

[0419] HPLC

[0420] HPLC analysis was performed using an Agilent 1260 HPLC system. The chromatographic conditions are listed in Tables 16 and 17.

[0421] Table 16. HPLC parameters used for purity testing

[0422]

[0423] Table 17. HPLC parameters used for solubility testing

[0424]

[0425]

[0426] Polymorph screening experiments were conducted using antisolvent addition, reverse antisolvent addition, solid vapor diffusion, solution vapor diffusion, slurry, slow evaporation, slow cooling, and polymer-induced crystallization techniques. In addition to form A, four new succinate forms were identified and assigned to succinate forms C, D, E, and F. All crystal forms were analyzed by X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and proton nuclear magnetic resonance (NMR). 1 Characterized by ¹H NMR and HPLC. Two other forms are anhydrous, one a solvate, and the other could not be characterized due to limited sample quantity and difficulty in re-preparation. In terms of stability and other properties, succinate forms C, D, E, and F are all inferior to form A.

[0427] Further characterization of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate of form A

[0428] Further characterization of the N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate sample of form A.

[0429] XRPD results for two batches of form A of N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate are shown in Figure 38 middle.

[0430] The results of TGA and DSC analysis are shown in Figure 39 In the TGA curve of succinate form A, a weight loss of 1.9% was observed up to 140 °C. On the DSC curve, a step endothermic signal was observed at 159.5 °C (start), followed by significant endothermic reaction at 181.3 °C (start).

[0431] 1 The H NMR spectrum shows Figure 40 (DMSO-d6 as solvent) and Figure 41In a solution containing deuterated MeOH as solvent, the molar ratio of succinic acid to free base was determined to be 0.9:1. The molar ratio of acid to free base in type A succinate was calculated using peak integrals at 2.38 ppm (integral 3.58, hydrogen atom of succinate, 4H) and 1.78 ppm (integral 6.00, hydrogen atom of free base, 6H).

[0432] HPLC analysis confirmed that the purity of the succinate form A (810023-01-A) of the sample was 99.5% (area).

[0433] After succinate form A was heated to 170°C and then cooled to room temperature, further XRPD, TGA, DSC, and... 1 1H NMR analysis. Results are shown in Figures 42 to 45 middle.

[0434] After heating, XRPD ( Figure 42 It was confirmed that the crystal form was still type A succinate.

[0435] In the TGA curve ( Figure 43 In the study, a weight loss of up to 2.6% was observed at 140°C, which is likely due to moisture adsorbed on the surface of the heated sample when it was exposed to air prior to further TGA testing. The TGA analysis was performed approximately 4.5 hours after the heating experiment. The weight loss of the heated sample (2.6%) was higher than the initially observed weight loss (1.9%), indicating that the hygroscopicity of type A succinate can increase slightly after heat treatment.

[0436] In the DSC curve ( Figure 44 In the study, heat absorption was observed only at one point at 182.7℃ (the starting temperature).

[0437] In NMR analysis ( Figure 45 In the study, the molar ratio of succinic acid to free base was still observed to be 0.9:1.

[0438] Based on the above results, type A succinate was identified as an anhydrous substance.

[0439] equilibrium solubility

[0440] The equilibrium solubility of form A in water was measured at room temperature. The solid was suspended in H₂O (approximately 800 rpm) at room temperature. After 24 h, the suspension was centrifuged (10,000 rpm, 5 min) and then filtered (0.45 μm PTFE membrane). The supernatant was analyzed by HPLC (discarding the first few drops) and the pH was measured. Residual solids were analyzed by XRPD. The measured solubility of form A was 14.3 mg / mL.

[0441] XRPD analysis showed that form A did not change during the dissolution experiment. Figure 46 ).

[0442] Solid-state stability

[0443] The N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate sample of form A was stored at 80 °C for one day, at 25 °C at 60% RH for one week, and at 40 °C at 75% RH for one week. All samples were then characterized by XRPD and HPLC, and the results are summarized in Table 18.

[0444] No form change or decrease in HPLC purity was observed under any conditions, indicating that N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate of form A possesses good solid-state stability. XRPD analysis results are shown in... Figure 47 middle.

[0445] Table 18. Summary of solid stability evaluation of N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate of form A

[0446]

[0447] hygroscopic

[0448] To investigate the relationship between the stability of the solid form and humidity, DVS isotherms of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate in form A were collected at 25°C between 0% and 95% RH.

[0449] Shown Figure 48 The DVS plot of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate of form A shows a water absorption rate of 0.14% at 25°C / 80% RH, indicating that form A is non-hygroscopic.

[0450] Figure 49The XRPD analysis shown in the figure indicates that the DVS analysis did not result in any change in the form of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate of form A.

[0451] polarizing microscope

[0452] PLM images were recorded to study the morphology of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate in form A. Figure 50 As shown, form A consists of rod-shaped crystals.

[0453] in conclusion

[0454] Based on all the above results, it was found that N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate of form A is a stable, non-hygroscopic crystalline form suitable for pharmaceutical use.

[0455] In addition to the contents described herein, various modifications to the invention will be apparent to those skilled in the art based on the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Every reference cited in this application, including all patents, patent applications, and publications, is incorporated herein by reference in its entirety.

Claims

1. The use of crystalline N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate in the preparation of a medicament for treating cancer in patients, wherein, The crystalline N-(3-(5-(((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate has an X-ray powder diffraction pattern including the following peaks in 2θ: 15.4°±0.5°; 16.1°±0.5°; 17.2°±0.5°; 18.0°±0.5°; 20.0°±0.5°; and 21.8°±0.5°; The cancers mentioned are breast cancer, prostate cancer, colon cancer, endometrial cancer, brain cancer, bladder cancer, skin cancer, uterine cancer, ovarian cancer, lung cancer, pancreatic cancer, kidney cancer, stomach cancer, hematologic cancer, malignant melanoma, thyroid cancer, colorectal cancer, or biliary tract cancer.

2. The use according to claim 1, wherein the crystalline salt is substantially anhydrous and non-solventized.

3. The use according to claim 1, wherein the XRPD peak, d-value, and relative intensity of the crystalline salt are...

4. The use according to claim 1, wherein the crystalline salt has an X-ray powder diffraction pattern comprising the following peaks in terms of 2θ: 15.4°±0.2°; 20.0°±0.2°; and 21.8°±0.2°.

5. The use according to claim 1, wherein the crystalline salt has an X-ray powder diffraction pattern as shown in FIG10, FIG26 or FIG38.

6. The use according to claim 1, wherein the crystalline salt has a differential scanning calorimeter (DSC) as shown in FIG11, FIG27 or FIG39.

7. The use according to claim 1, wherein the crystalline salt has the thermogravimetric analysis (TGA) shown in Figure 12, Figure 28 or Figure 39.

8. Use of a composition comprising crystalline N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate and a chemotherapeutic agent in the preparation of a medicament for treating cancer in patients; wherein, The crystalline N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide monosuccinate has an X-ray powder diffraction pattern including the following peaks in 2θ: 15.4°±0.5°; 16.1°±0.5°; 17.2°±0.5°; 18.0°±0.5°; 20.0°±0.5°; and 21.8°±0.5°; the cancer being breast cancer, prostate cancer, colon cancer, endometrial cancer, brain cancer, bladder cancer, skin cancer, uterine cancer, ovarian cancer, lung cancer, pancreatic cancer, kidney cancer, stomach cancer, hematological cancer, malignant melanoma, thyroid cancer, colorectal cancer, or biliary tract cancer.

9. Use of the composition according to claim 8 in the preparation of a medicament for treating cancer in patients, wherein the chemotherapeutic agent is selected from one of the following: hormones, hormone analogs and anti-hormonal drugs, aromatase inhibitors, LHRH agonists and antagonists, growth factor inhibitors, antimetabolites, antitumor antibiotics, platinum derivatives, alkylating agents, antimitotic agents, tubulin inhibitors, PARP inhibitors, topoisomerase inhibitors, serine / threonine kinase inhibitors, tyrosine kinase inhibitors, protein-protein interaction inhibitors, MEK inhibitors, ERK inhibitors, IGF-1R inhibitors, ErbB receptor inhibitors, rapamycin analogs, amifostine, anagrelide, clodronate, filstilbene, interferon, leucovorin, rituximab, procarbazine, levamisole, mesna, mitotane, pamidronate, and porphyrin sodium.

10. Use of the composition according to claim 9 in the preparation of a medicament for treating cancer in patients, wherein the chemotherapeutic agent is a platinum derivative, an alkylating agent, a serine / threonine kinase inhibitor, a tyrosine kinase inhibitor, a MEK inhibitor, an ERK inhibitor, an ErbB receptor inhibitor, a rapamycin analog, interferon, or procarbazine.

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