Polymorphic compounds and uses thereof

Abstract

The present invention provides free base and salt forms that are useful in the treatment of various CDK4-mediated and CDK6-mediated conditions, such as cancer, by administering small molecule therapeutic agents that act as inhibitors of CDK4 and CDK6. Pharmaceutical compositions comprising the free base and salt forms and methods of use and preparation thereof are also described.

Description

Technical Field

[0001] The present disclosure relates to CDK inhibitors and methods of use thereof. Background Art

[0002] Cyclin-dependent kinases (CDKs) are a family of conserved serine / threonine kinases that play a key role in the regulation of the cell cycle and gene transcription (Malumbres 2014). Among the cell cycle CDK subfamily, CDK4 and CDK6 are the main regulators that control the entry of cells from the first interphase (G1) into the DNA synthesis phase (S). During this process, cyclin D protein levels increase, complex with CDK4 / 6 and activate their kinase activity. The activated CDK4 / 6 complex phosphorylates retinoblastoma protein (RB1) and other RB1-like proteins, reducing their binding affinity and releasing the transcriptional repressor complex containing RB1 from the E2F transcription factor, resulting in the activation of E2F-controlled cell cycle genes and progression of the cell cycle (Lapenna and Giordano 2009, Asghar, Witkiewicz et al. 2015).

[0003] Given the important role played by CDK4 / 6 in cell cycle regulation, its dysfunction is a hallmark of cancer (Hanahan and Weinberg 2011), and dysregulation of the CDK4 / 6 pathway is frequently observed in cancer, such as (epi)genetic inactivation of the endogenous CDK4 / 6 inhibitor p16INK4A and amplification / overexpression of CDK4 / 6 and cyclin D proteins (Lapenna and Giordano 2009, Malumbres and Barbacid 2009, Asghar, Witkiewicz et al. 2015, O'Leary, Finn et al. 2016). CDK4 / 6 has been intensively investigated as a potential therapeutic target for cancer treatment, and the recent approval of CDK4 / 6 selective inhibitors, palbociclib (U.S. Food and Drug Administration 2017), ribociclib (U.S. Food and Drug Administration 2017), and abemaciclib (U.S. Food and Drug Administration 2018), in combination with endocrine therapy for the treatment of hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer further validates this theme.

[0004] Central nervous system (CNS) diseases such as glioblastoma (GBM) and brain metastases are challenging malignancies with urgent unmet needs. GBM is the most common and most aggressive primary brain cancer in adults, with an overall 5-year survival rate of less than 6% (Ostrom, Gittleman et al. 2016). Large-scale genomic studies have revealed that the cyclin D-CDK4 / 6-RB1 pathway is alternating in most gliomas and represents one of the most disturbed pathways (Cancer Genome Atlas Research 2008, Brennan, Verhaak et al. 2013), suggesting that CDK4 / 6 may be a good target for GBM. On the other hand, an estimated 20% of all cancer patients may develop brain metastases, but there is still a lack of effective treatment (Achrol, Rennert et al. 2019). Interestingly, genomic studies have also identified the CDK pathway as one of the three most altered and causative genetic alterations in brain metastasis (Brastianos, Carter et al. 2015, Valiente, Ahluwalia et al. 2018). However, despite positive preclinical data supporting targeting CDK4 / 6 for the treatment of GBM (Yin, Li et al. 2018, Bronner, Merrick et al. 2019) and initial signs of brain penetration of abemaciclib in patients (Patnaik, Rosen et al. 2016, Sahebjam, Rhun et al. 2016), clinical development of CDK4 / 6 inhibitors in the clinic for GBM or brain metastases remains in early stages or unsuccessful (Anders, Rhun et al. 2019, Nguyen, Searle et al. 2019, Sahebjam, Le Rhun et al. 2019), likely due to their inability to penetrate the blood-brain barrier (BBB) ​​(deGooijer, Zhang et al. 2015, Parrish, Pokorny et al. 2015, Raub, Wishart et al. 2015).

[0005] Additional small molecule CDK4 / 6 inhibitors are needed. Summary of the invention

[0006] It has now been found that the compounds of the present invention and compositions thereof can be used to treat, prevent and / or reduce the risk of diseases, disorders or conditions in CDK4-mediated and CDK6-mediated disorders. Such compounds are represented by the following chemical structure, represented as Compound A:

[0007]

[0008] or a pharmaceutically acceptable salt thereof.

[0009] The compounds of the present invention and pharmaceutically acceptable compositions thereof can be used to treat various diseases, disorders or conditions associated with CDK4-mediated and CDK6-mediated. Such diseases, disorders or conditions include those described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Figure 1 The XRPD pattern of Compound A, free base Form A is depicted.

[0011] Figure 2 Depicted are the DSC thermograms and TGA traces of Compound A, free base Form A.

[0012] Figure 3 The XRPD pattern of Compound A, free base Form B is depicted.

[0013] Figure 4 Depicted are the DSC thermograms and TGA traces of Compound A, free base Form B.

[0014] Figure 5 The XRPD pattern of Compound A, free base Form C is depicted.

[0015] Figure 6 Depicted are the DSC thermograms and TGA traces of Compound A, free base Form C.

[0016] Figure 7 Depicted is the XRPD pattern of Compound A, succinate salt Form A.

[0017] Figure 8 Depicted are the DSC thermogram and TGA trace of Compound A, succinate salt Form A.

[0018] Fig. 9 The XRPD pattern of Compound A, succinate salt Form B is depicted.

[0019] Fig.10 Depicted are the DSC thermograms and TGA traces of Compound A, succinate salt Form B.

[0020] Fig.11 The XRPD pattern of Compound A, succinate salt Form C is depicted.

[0021] Fig.12 Depicted are the DSC thermograms and TGA traces of Compound A, succinate salt Form C.

[0022] Fig.13 The XRPD pattern of Compound A, succinate salt Form D is depicted.

[0023] Fig.14Depicted are the DSC thermogram and TGA trace of Compound A, succinate salt Form D.

[0024] Fig.15 The XRPD pattern of Compound A, succinate salt Form E is depicted.

[0025] Fig.16 Depicted are the DSC thermogram and TGA trace of Compound A, succinate salt Form E.

[0026] Fig.17 The XRPD pattern of Compound A, succinate salt Form F is depicted.

[0027] Fig.18 Depicted are the DSC thermogram and TGA trace of Compound A, succinate salt Form F.

[0028] Fig.19 Depicted are the DSC thermogram and TGA trace of Compound A, succinate salt Form F.

[0029] Fig. 20 The XRPD pattern of Compound A, succinate salt Form G is depicted.

[0030] Fig.21 Depicted are the DSC thermogram and TGA trace of Compound A, succinate salt Form G.

[0031] Fig. 22 Depicted are the DSC thermogram and TGA trace of Compound A, succinate salt Form G.

[0032] Fig.23 Single crystals of Compound A, succinate salt Form G are depicted.

[0033] Fig.24 An XRPD pattern of Compound A, hydrochloride salt Form A is depicted.

[0034] Fig.25 Depicted are the DSC thermogram and TGA trace of Compound A, hydrochloride salt Form A.

[0035] Fig.26 The XRPD pattern of Compound A, hydrochloride salt Form B is depicted.

[0036] Fig. 27 Depicted are the DSC thermograms and TGA traces of Compound A, hydrochloride salt Form B.

[0037] Fig.28 An XRPD pattern of Compound A, hydrochloride salt Form C is depicted.

[0038] Fig.29 Depicted are the DSC thermograms and TGA traces of Compound A, hydrochloride salt Form C.

[0039] Fig.30 The XRPD pattern of Compound A, hydrochloride salt Form D is depicted.

[0040] Fig.31 Depicted are the DSC thermogram and TGA trace of Compound A, hydrochloride salt Form D.

[0041] Fig.32 An XRPD pattern of Compound A, hydrochloride salt Form E is depicted.

[0042] Fig.33 Depicted are the DSC thermograms and TGA traces of Compound A, hydrochloride salt Form E.

[0043] Fig.34 An XRPD pattern of Compound A, hydrochloride salt Form F is depicted.

[0044] Fig.35 Depicted are the DSC thermogram and TGA trace of Compound A, hydrochloride salt Form F.

[0045] Fig.36 An XRPD pattern of Compound A, maleate salt Form A is depicted.

[0046] Fig.37 Depicted are the DSC thermogram and TGA trace of Compound A, maleate salt Form A.

[0047] Fig.38 An XRPD pattern of Compound A, sulfate salt Form A is depicted.

[0048] Fig.39 Depicted are the DSC thermograms and TGA traces of Compound A, Sulfate Form A.

[0049] Fig.40 The XRPD pattern of Compound A, sulfate salt Form B is depicted.

[0050] Fig.41 DSC thermograms and TGA traces of Compound A, sulfate salt Form B are depicted.

[0051] Fig.42 An XRPD pattern of Compound A, sulfate salt Form C is depicted.

[0052] Fig.43 Depicted are the DSC thermograms and TGA traces of Compound A, sulfate salt Form C.

[0053] Fig.44 An XRPD pattern of Compound A, phosphate salt Form A is depicted.

[0054] Fig.45Depicted are the DSC thermograms and TGA traces of Compound A, phosphate Form A.

[0055] Fig.46 An XRPD pattern of Compound A, L-tartrate salt Form A is depicted.

[0056] Fig.47 Depicted are the DSC thermogram and TGA trace of Compound A, L-tartrate salt Form A.

[0057] Fig.48 Depicted is the XRPD pattern of Compound A, fumarate salt Form A.

[0058] Fig.49 Depicted are the DSC thermogram and TGA trace of Compound A, fumarate salt Form A.

[0059] Fig.50 The XRPD pattern of Compound A, fumarate salt Form B is depicted.

[0060] Fig.51 Depicted are the DSC thermograms and TGA traces of Compound A, fumarate salt Form B.

[0061] Fig.52 The XRPD pattern of Compound A, fumarate salt Form C is depicted.

[0062] Fig.53 Depicted are the DSC thermograms and TGA traces of Compound A, fumarate salt Form C.

[0063] Fig.54 The XRPD pattern of Compound A, fumarate salt Form D is depicted.

[0064] Fig.55 Depicted are the DSC thermogram and TGA trace of Compound A, fumarate salt Form D.

[0065] Fig.56 An XRPD pattern of Compound A, citrate salt Form A is depicted.

[0066] Fig.57 Depicted are the DSC thermogram and TGA trace of Compound A, citrate salt Form A.

[0067] Fig.58 An XRPD pattern of Compound A, L-malate salt Form A is depicted.

[0068] Fig.59 Depicted are the DSC thermogram and TGA trace of Compound A, L-malate salt Form A.

[0069] Fig.60 Depicted is the XRPD pattern of Compound A, mesylate salt Form A.

[0070] Fig.61 Depicted are the DSC thermogram and TGA trace of Compound A, mesylate salt Form A.

[0071] Fig.62 The XRPD pattern of Compound A, mesylate salt Form B is depicted.

[0072] Fig.63 Depicted are the DSC thermograms and TGA traces of Compound A, mesylate salt Form B.

[0073] Fig.64 Depicted is the XRPD pattern of Compound A, ethanesulfonate salt Form A.

[0074] Fig.65 Depicted are the DSC thermogram and TGA trace of Compound A, esylate salt Form A.

[0075] Fig.66 The XRPD pattern of Compound A, esylate salt Form B is depicted.

[0076] Fig.67 Depicted are the DSC thermogram and TGA trace of Compound A, esylate salt Form B.

[0077] Fig.68 Depicted is the XRPD pattern of Compound A, tosylate salt Form A.

[0078] Fig.69 Depicted are the DSC thermogram and TGA trace of Compound A, tosylate salt Form A.

[0079] Fig.70 The XRPD pattern of Compound A, tosylate salt Form B is depicted.

[0080] Fig.71 Depicted are the DSC thermogram and TGA trace of Compound A, tosylate salt Form B.

[0081] Fig.72 Depicted is the XRPD pattern of Compound A, glutarate salt Form A.

[0082] Fig.73 An XRPD pattern of Compound A, acetate salt Form A is depicted.

[0083] Fig.74 Depicted are the DSC thermograms and TGA traces of Compound A, acetate salt Form A.

[0084] Fig.75 An XRPD pattern of Compound A, malonate salt Form A is depicted.

[0085] Fig.76The XRPD pattern of Compound A, malonate salt Form B is depicted.

[0086] Fig.77 Depicted is the XRPD pattern of Compound A, Sebacate Salt Form A.

[0087] Fig.78 Depicted are the DSC thermogram and TGA trace of Compound A, Sebacate Salt Form A.

[0088] Fig.79 An XRPD pattern of Compound A, acetylglycinate Form A is depicted.

[0089] Fig.80 Depicted are the DSC thermogram and TGA trace of Compound A, acetylglycinate Form A.

[0090] Fig.81 An XRPD pattern of Compound A, acetylglycinate Form B is depicted.

[0091] Fig.82 Depicted are the DSC thermograms and TGA traces of Compound A, acetylglycinate Form B. DETAILED DESCRIPTION

[0092] General Description of Certain Aspects of the Invention

[0093] Certain CDK4 inhibitors and CDK6 inhibitors are described in U.S. Patent Application Serial No. US17 / 480,323, filed on September 21, 2021 (hereinafter referred to as the "'323 Application"), the entire contents of which are hereby incorporated by reference herein. Such compounds include Compound A:

[0094]

[0095] Compound A, 2-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)-pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one, is described in Example 56 of the '323 application, and the synthesis of Compound A is described in detail at Example 56 and is reproduced herein for ease of reference.

[0096] It would be desirable to provide a solid form of Compound A (e.g., as its free base or a salt thereof) that imparts properties such as improved water solubility, stability, and ease of formulation. Accordingly, the present invention provides both the free base form and the salt form of Compound A.

[0097] Free base form of compound A

[0098] It is contemplated that Compound A free alkali can exist in various physical forms. For example, Compound A free alkali can be in solution, suspension or solid form. In certain embodiments, Compound A free alkali is in solid form. When Compound A free alkali is in solid form, the compound can be amorphous, crystalline or a mixture thereof. Exemplary solid forms are described in more detail below.

[0099] In some embodiments, the present invention provides a certain form of Compound A free base that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain a significant amount of foreign matter. Such foreign matter may include different forms of Compound A free base, residual solvents, or any other impurities that may be produced by the preparation and / or separation of Compound A. In certain embodiments, there is at least about 95% by weight of a certain form of Compound A free base. In still other embodiments of the present invention, there is at least about 99% by weight of a certain form of Compound A free base.

[0100] According to one embodiment, a certain form of Compound A free base is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent, wherein the percentage is based on the total weight of the composition. According to another embodiment, relative to the total area of ​​the HPLC chromatogram, a certain form of Compound A free base contains no more than about 3.0 area percent HPLC total organic impurities, and in certain embodiments, contains no more than about 1.5 area percent HPLC total organic impurities. In other embodiments, relative to the total area of ​​the HPLC chromatogram, a certain form of Compound A free base contains no more than about 1.0% area percent HPLC of any single impurity; contains no more than about 0.6 area percent HPLC of any single impurity, and in certain embodiments, contains no more than about 0.5 area percent HPLC of any single impurity.

[0101] A structure depicted for a certain form of Compound A free base is also meant to encompass all tautomeric forms of Compound A free base. In addition, structures depicted herein are also meant to encompass compounds that differ only in the presence of one or more isotopically enriched atoms. For example, in addition to replacing hydrogen with deuterium or tritium or replacing 13 C or 14 Compounds having the present structures other than C-enriched carbon instead of carbon are within the scope of the present invention.

[0102] It has been found that Compound A free base can exist in various solid forms. Exemplary such forms include polymorphs, such as the polymorphs described herein.

[0103] As used herein, the term "polymorph" refers to different crystal structures into which a compound or a salt or solvate thereof can crystallize.

[0104] As used herein, when used with reference to a degree 2-Theta value, the term "about" refers to the stated value ± 0.2 degrees 2-Theta.

[0105] In certain embodiments, the Compound A free base is a crystalline solid. In other embodiments, the Compound A free base is a crystalline solid substantially free of amorphous Compound A free base. As used herein, the term "substantially free of amorphous Compound A free base" means that the compound does not contain a significant amount of amorphous Compound A free base. In certain embodiments, there is at least about 95% by weight of the crystalline Compound A free base. In still other embodiments of the present invention, there is at least about 99% by weight of the crystalline Compound A free base.

[0106] It has been found that Compound A free base can exist in at least three different polymorphic forms. In certain embodiments, the present invention provides a polymorphic form of Compound A free base referred to herein as Form A. In certain embodiments, the present invention provides a polymorphic form of Compound A free base referred to herein as Form B. In certain embodiments, the present invention provides a polymorphic form of Compound A free base referred to herein as Form C.

[0107] In some embodiments, Compound A free base is amorphous. In some embodiments, Compound A free base is amorphous and is substantially free of crystalline Compound A free base.

[0108] Form A of Compound A

[0109] In some embodiments, Form A of Compound A free base has at least 1, 2, 3, 4, or 5 spectral peaks selected from the peaks listed in Table 1 below.

[0110] Table 1 - XRPD peak positions of Form A of Compound A free base

[0111] <![CDATA[Position (°2θ) 1 > Strength cps° 9.0 1057 11.5 2282 12.9 1758 16.8 1433 17.9 1752 21.2 1097 22.0 443 23.5 1823 25.7 936 28.2 1093

[0112] 1 In this and all subsequent tables, the positions 2θ are within ±0.2.

[0113] In some embodiments, Form A of Compound A is characterized in that it has one or more peaks selected from peaks at about 11.5, about 12.9, and about 23.5 degrees 2θ in its X-ray powder diffraction (XRPD) pattern. In some embodiments, Form A of Compound A free base is characterized in that it has two or more peaks selected from peaks at about 11.5, about 12.9, and about 23.5 degrees 2θ in its X-ray powder diffraction pattern. In some embodiments, Form A of Compound A free base is characterized in that it has all three peaks selected from peaks at about 11.5, about 12.9, and about 23.5 degrees 2θ in its X-ray powder diffraction pattern.

[0114] As used herein, when used with reference to a degree 2-Theta value, the term "about" refers to the stated value ± 0.2 degrees 2-Theta.

[0115] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to Figure 1 XRPD provided in.

[0116] The following is a description of a method for preparing Form A of Compound A free base.

[0117] Form B of Compound A

[0118] In some embodiments, Form B of Compound A free base has at least 1, 2, 3, 4, or 5 spectral peaks selected from the peaks listed in Table 2 below.

[0119] Table 2 - XRPD Peak Positions of Form B of Compound A Free Base

[0120] Position (°2θ) Strength cps° 11.2 1838 16.0 1234 17.8 2637 17.9 634 18.3 3016 19.1 640 20.8 5682 22.5 874 22.9 1368 31.6 1095

[0121] In some embodiments, Form B of the free base of Compound A is characterized in that it has one or more peaks selected from the peaks at about 17.8, about 18.3, and about 20.8 degrees 2θ in its X-ray powder diffraction (XRPD) pattern. In some embodiments, Form B of the free base of Compound A is characterized in that it has two or more peaks selected from the peaks at about 17.8, about 18.3, and about 20.8 degrees 2θ in its X-ray powder diffraction pattern. In some embodiments, Form B of the free base of Compound A is characterized in that it has all three peaks selected from the peaks at about 17.8, about 18.3, and about 20.8 degrees 2θ in its X-ray powder diffraction pattern. As used herein, when a reference 2θ value is used, the term "about" refers to the value ± 0.2 degrees 2θ.

[0122] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to Figure 3 XRPD provided in.

[0123] A method for preparing Form B of Compound A free base is described below.

[0124] Form C of Compound A

[0125] In some embodiments, Form C of Compound A free base has at least 1, 2, 3, 4, or 5 spectral peaks selected from the peaks listed in Table 3 below.

[0126] Table 3 - XRPD peak positions of Form C of Compound A free base

[0127] Position (°2θ) Strength cps° 13.6 1965 16.4 2483 17.2 1233 20.0 1322 20.6 1123 20.8 1744 22.6 974 22.9 2889 23.7 1384 31.6 2668

[0128] In some embodiments, the form C of the free base of compound A is characterized in that it has one or more peaks selected from the peaks at about 16.4, about 22.9 and about 31.6 degrees 2θ in its X-ray powder diffraction (XRPD) pattern. In some embodiments, the form C of the free base of compound A is characterized in that it has two or more peaks selected from the peaks at about 16.4, about 22.9 and about 31.6 degrees 2θ in its X-ray powder diffraction pattern. In some embodiments, the form C of the free base of compound A is characterized in that it has all three peaks selected from the peaks at about 16.4, about 22.9 and about 31.6 degrees 2θ in its X-ray powder diffraction pattern. As used herein, when a reference 2θ value is used, the term "about" refers to the value ± 0.2 degrees 2θ.

[0129] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to Figure 5 XRPD provided in.

[0130] A method for preparing Form C of Compound A free base is described below.

[0131] In some embodiments, the present invention provides Compound A free base:

[0132]

[0133] wherein the compound is crystalline.

[0134] In some embodiments, the present invention provides Compound A free base, wherein the compound is substantially free of amorphous Compound A free base.

[0135] In some embodiments, the present invention provides Compound A free base, wherein the compound is substantially free of impurities.

[0136] In some embodiments, the present invention provides Compound A free base, wherein the compound has one or more peaks selected from the peaks at about 11.5, about 12.9 and about 23.5 degrees 2θ in its XRPD. In some such embodiments, the present invention provides Compound A free base, wherein the compound has at least two peaks selected from the peaks at about about 11.5, about 12.9 and about 23.5 degrees 2θ in its XRPD. In some such embodiments, the present invention provides Compound A succinate, wherein the compound has at least three peaks selected from the peaks at about about 11.5, about 12.9 and about 23.5 degrees 2θ in its XRPD. In some such embodiments, the present invention provides Compound A free base, wherein the compound belongs to Form A.

[0137] In some embodiments, the present invention provides Compound A free base, wherein the XRPD of the compound is substantially similar to Figure 1 XRPD depicted in .

[0138] In some embodiments, the present invention provides a free base of Compound A, wherein the compound has one or more peaks selected from the peaks at about 17.8, about 18.3, and about 20.8 degrees 2θ in its XRPD. In some such embodiments, the present invention provides a free base of Compound A, wherein the compound has at least two peaks selected from the peaks at about 17.8, about 18.3, and about 20.8 degrees 2θ in its XRPD. In some such embodiments, the present invention provides a free base of Compound A, wherein the compound has at least three peaks selected from the peaks at about 17.8, about 18.3, and about 20.8 degrees 2θ in its XRPD. In some such embodiments, the present invention provides a free base of Compound A, wherein the compound belongs to Form B.

[0139] In some embodiments, the present invention provides Compound A free base, wherein the XRPD of the compound is substantially similar to Figure 3 XRPD depicted in .

[0140] In some embodiments, the present invention provides a free base of Compound A, wherein the compound has one or more peaks selected from the peaks at about 16.4, about 22.9, and about 31.6 degrees 2θ in its XRPD. In some such embodiments, the present invention provides a free base of Compound A, wherein the compound has at least two peaks selected from the peaks at about 16.4, about 22.9, and about 31.6 degrees 2θ in its XRPD. In some such embodiments, the present invention provides a free base of Compound A, wherein the compound has at least three peaks selected from the peaks at about 16.4, about 22.9, and about 31.6 degrees 2θ in its XRPD. In some such embodiments, the present invention provides a free base of Compound A, wherein the compound belongs to Form C.

[0141] In some embodiments, the present invention provides Compound A free base, wherein the XRPD of the compound is substantially similar to Figure 5 XRPD depicted in .

[0142] In some embodiments, the present invention provides a composition comprising Compound A free base and a pharmaceutically acceptable carrier or excipient.

[0143] In some embodiments, the present invention provides a method of treating a CDK4-mediated and CDK6-mediated disorder in a patient in need thereof, the method comprising administering Compound A free base or a composition thereof to the patient. In some embodiments, Compound A free base is in Form A. In some embodiments, Compound A free base is in Form B. In some embodiments, Compound A free base is in Form C.

[0144] In some embodiments, the CDK4-mediated and CDK6-mediated disorder is cancer. In some embodiments, the cancer is breast cancer, malignant brain tumor, colon cancer, small cell lung cancer, non-small cell lung cancer, bladder cancer, ovarian cancer, prostate cancer, chronic lymphoid leukemia, lymphoma, myeloma, acute myeloid leukemia, secondary pancreatic cancer or secondary brain metastasis.

[0145] In some embodiments, the breast cancer is HR+ / HER2- or HR+ / HER2+ advanced or metastatic breast cancer; and the malignant brain tumor is a glioblastoma, astrocytoma, or pontine glioma.

[0146] In some embodiments, a pharmaceutical composition of Compound A free base is administered to a patient. In some embodiments, the administration is oral administration of Compound A free base. In some embodiments, the administration is intravenous administration of Compound A free base.

[0147] In some embodiments, the methods described herein further include administering another therapeutic agent to the patient. In some embodiments, the other therapeutic agent is a PRMT5 inhibitor, a HER2 kinase inhibitor, an aromatase inhibitor, an estrogen receptor antagonist, or an alkylating agent. In some embodiments, the aromatase inhibitor is letrozole. In some embodiments, the estrogen receptor antagonist is fulvestrant. In some embodiments, the alkylating agent is temozolomide.

[0148] Salt form of compound A

[0149] In some embodiments, acid and Compound A ion bond to form Compound A succinate described below. It is contemplated that Compound A succinate can exist in various physical forms. For example, Compound A succinate can be in solution, suspension or solid form. In certain embodiments, Compound A succinate is in solid form. When Compound A succinate is in solid form, the compound can be amorphous, crystalline or a mixture thereof. Exemplary such solid forms of Compound A succinate are described in more detail below.

[0150] Succinate of Compound A

[0151] According to one embodiment, the present invention provides a succinate salt of compound A:

[0152]

[0153] Those of ordinary skill in the art will appreciate that succinic acid and Compound A ionically bond to form Compound A succinate. It is contemplated that Compound A succinate can exist in various physical forms. For example, Compound A succinate can be in solution, suspension, or solid form. In certain embodiments, Compound A succinate is in solid form. When Compound A succinate is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0154] In certain embodiments, the invention provides Compound A succinates that are substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain a significant amount of foreign matter. Such foreign matter may include excess succinic acid, excess Compound A, residual solvents, or any other impurities that may be produced by the preparation and / or separation of Compound A succinate. In certain embodiments, there is at least about 95% by weight of Compound A succinate. In still other embodiments of the present invention, there is at least about 99% by weight of Compound A succinate.

[0155] According to one embodiment, Compound A succinate is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8% by weight, wherein the percentage is based on the total weight of the composition. According to another embodiment, relative to the total area of ​​the HPLC chromatogram, Compound A succinate contains no more than about 3.0 area percent HPLC total organic impurities, and in certain embodiments, contains no more than about 1.5 area percent HPLC total organic impurities. In other embodiments, relative to the total area of ​​the HPLC chromatogram, Compound A succinate contains no more than about 1.0% area percent HPLC of any single impurity; contains no more than about 0.6 area percent HPLC of any single impurity, and in certain embodiments, contains no more than about 0.5 area percent HPLC of any single impurity.

[0156] The structures depicted for Compound A succinate are also meant to encompass all tautomeric forms of Compound A succinate. Additionally, the structures depicted herein are also meant to encompass compounds that differ only in the presence of one or more isotopically enriched atoms. For example, in addition to replacing hydrogen with deuterium or tritium or replacing 13 C or 14 Compounds having the present structures other than C-enriched carbon instead of carbon are within the scope of the present invention.

[0157] In certain embodiments, Compound A succinate is a crystalline solid. In other embodiments, Compound A succinate is a crystalline solid substantially free of amorphous Compound A succinate. As used herein, the term "substantially free of amorphous Compound A succinate" means that the compound does not contain a significant amount of amorphous Compound A succinate. In certain embodiments, there is at least about 95% by weight of crystalline Compound A succinate. In still other embodiments of the present invention, there is at least about 99% by weight of crystalline Compound A succinate.

[0158] It has been found that Compound A succinate can exist in at least seven different polymorphic forms. In some embodiments, the present invention provides a polymorphic form of Compound A succinate referred to herein as Form A. In certain embodiments, the present invention provides a polymorphic form of Compound A succinate referred to herein as Form B. In some embodiments, the present invention provides a polymorphic form of Compound A succinate referred to herein as Form C. In certain embodiments, the present invention provides a polymorphic form of Compound A succinate referred to herein as Form D. In some embodiments, the present invention provides a polymorphic form of Compound A succinate referred to herein as Form E. In certain embodiments, the present invention provides a polymorphic form of Compound A succinate referred to herein as Form F. In some embodiments, the present invention provides a polymorphic form of Compound A succinate referred to herein as Form G.

[0159] In some embodiments, the Compound A succinate salt is amorphous. In some embodiments, the Compound A succinate salt is amorphous and is substantially free of crystalline Compound A succinate salt.

[0160] Compound A succinate form A

[0161] In some embodiments, Form A of Compound A succinate salt has at least 1, 2, 3, 4, or 5 spectral peaks selected from the peaks listed in Table 4 below.

[0162] Table 4 - XRPD Peak Positions of Form A of Compound A Succinate Salt

[0163] Position (°2θ) Strength cps° 8.1 1598 10.8 1007 11.0 741 11.6 3424 12.0 556 13.6 860 15.8 640 17.5 872 24.4 1148 25.2 1001

[0164] In some embodiments, Form A of Compound A succinate is characterized in that it has one or more peaks selected from peaks at about 8.1, about 11.6, and about 24.4 degrees 2θ in its X-ray powder diffraction pattern. In some embodiments, Form A of Compound A succinate is characterized in that it has two or more peaks selected from peaks at about 8.1, about 11.6, and about 24.4 degrees 2θ in its X-ray powder diffraction pattern. In some embodiments, Form A of Compound A succinate is characterized in that it has all three peaks selected from peaks at about 8.1, about 11.6, and about 24.4 degrees 2θ in its X-ray powder diffraction pattern.

[0165] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to Figure 7 XRPD provided in.

[0166] A method for preparing Form A of Compound A succinate salt is described below.

[0167] Compound A succinate form B

[0168] In some embodiments, Form B of the Compound A succinate salt has at least 1, 2, 3, 4, or 5 spectral peaks selected from the peaks listed in Table 5 below.

[0169] Table 5 - XRPD Peak Positions of Form B of Compound A Succinate Salt

[0170] Position (°2θ) Strength cps° 11.9 1476 12.3 1571 14.3 388 15.1 786 18.6 2087 20.6 411 21.8 629 24.1 1904 24.6 2561 25.6 715

[0171] In some embodiments, Form B of Compound A succinate is characterized in that it has one or more peaks selected from peaks at about 18.6, about 24.1, and about 24.6 degrees 2θ in its X-ray powder diffraction pattern. In some embodiments, Form B of Compound A succinate is characterized in that it has two or more peaks selected from peaks at about 18.6, about 24.1, and about 24.6 degrees 2θ in its X-ray powder diffraction pattern. In some embodiments, Form B of Compound A succinate is characterized in that it has all three peaks selected from peaks at about 18.6, about 24.1, and about 24.6 degrees 2θ in its X-ray powder diffraction pattern.

[0172] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to Fig. 9 XRPD provided in.

[0173] A method for preparing Form B of the succinate salt of Compound A is described below.

[0174] Compound A succinate form C

[0175] In some embodiments, Form C of the Compound A succinate salt has at least 1, 2, 3, 4, or 5 spectral peaks selected from the peaks listed in Table 6 below.

[0176] Table 6 - XRPD Peak Positions of Form C of Compound A Succinate Salt

[0177] Position (°2θ) Strength cps° 9.2 3483 11.0 1956 11.9 3746 14.2 2881 15.1 3132 18.6 3295 18.9 3877 23.9 1819 24.0 2111 24.2 3363

[0178] In some embodiments, Form C of Compound A succinate is characterized in that it has one or more peaks selected from peaks at about 9.2, about 11.9, and about 18.9 degrees 2θ in its X-ray powder diffraction pattern. In some embodiments, Form C of Compound A succinate is characterized in that it has two or more peaks selected from peaks at about 9.2, about 11.9, and about 18.9 degrees 2θ in its X-ray powder diffraction pattern. In some embodiments, Form C of Compound A succinate is characterized in that it has all three peaks selected from peaks at about 9.2, about 11.9, and about 18.9 degrees 2θ in its X-ray powder diffraction pattern.

[0179] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to Fig.11 XRPD provided in.

[0180] A method for preparing Form C of the succinate salt of Compound A is described below.

[0181] Compound A succinate form D

[0182] In some embodiments, Form D of the Compound A succinate salt has at least 1, 2, 3, 4, or 5 spectral peaks selected from the peaks listed in Table 7 below.

[0183] Table 7 - XRPD Peak Positions of Form D of Compound A Succinate Salt

[0184] Position (°2θ) Strength cps° 11.3 1074 12.3 2971 15.2 378 18.5 1582 19.4 2426 21.0 692 22.7 848 24.3 2178 24.7 2637 25.4 973

[0185] In some embodiments, Form D of Compound A succinate is characterized in that it has one or more peaks selected from peaks at about 12.3, about 19.4, and about 24.7 degrees 2θ in its X-ray powder diffraction pattern. In some embodiments, Form D of Compound A succinate is characterized in that it has two or more peaks selected from peaks at about 12.3, about 19.4, about 24.7, and about 18.9 degrees 2θ in its X-ray powder diffraction pattern. In some embodiments, Form B of Compound A succinate is characterized in that it has all three peaks selected from peaks at about 12.3, about 19.4, and about 24.7 degrees 2θ in its X-ray powder diffraction pattern.

[0186] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to Fig.13 XRPD provided in.

[0187] A method for preparing Form D of the succinate salt of Compound A is described below.

[0188] Compound A succinate form E

[0189] In some embodiments, Form E of the succinate salt of Compound A has at least 1, 2, 3, 4, or 5 spectral peaks selected from the peaks listed in Table 8 below.

[0190] Table 8 - XRPD Peak Positions of Form E of Compound A Succinate Salt

[0191] Position (°2θ) Strength cps° 9.2 773 11.0 285 11.9 2806 14.2 652 15.1 1170 18.0 1309 18.6 993 18.9 1059 23.1 1781 24.1 2603

[0192] In some embodiments, Form E of Compound A succinate is characterized in that it has one or more peaks selected from peaks at about 11.9, about 23.1, and about 24.1 degrees 2θ in its X-ray powder diffraction pattern. In some embodiments, Form E of Compound A succinate is characterized in that it has two or more peaks selected from peaks at about 11.9, about 23.1, about 24.1, and about 18.9 degrees 2θ in its X-ray powder diffraction pattern. In some embodiments, Form E of Compound A succinate is characterized in that it has all three peaks selected from peaks at about 11.9, about 23.1, and about 24.1 degrees 2θ in its X-ray powder diffraction pattern.

[0193] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to Fig.15 XRPD provided in.

[0194] A method for preparing Form E of the succinate salt of Compound A is described below.

[0195] Compound A succinate salt form F

[0196] In some embodiments, Form F of the succinate salt of Compound A has at least 1, 2, 3, 4, or 5 peaks selected from the peaks listed in Table 9 below.

[0197] Table 9 - XRPD Peak Positions of Form F of Compound A Succinate Salt

[0198] Position (°2θ) Relative strength [%] 6.0 69.55 6.5 34.06 8.1 11.08 9.8 19.53 11.6 18.09 12.5 100.00 13.5 9.30 14.8 10.73 15.8 40.61 16.4 16.76 17.2 18.19 18.4 40.48 18.6 37.40 19.1 31.21 20.2 9.75 21.2 36.05 22.4 7.29 23.7 17.44 24.5 90.59 24.7 90.50 26.3 15.31 27.4 10.51 28.5 12.96 32.1 3.11 34.0 3.97 37.1 3.14

[0199] In some embodiments, Form F of Compound A succinate is characterized in that it has one or more peaks selected from peaks at about 6.0, about 12.5, and about 24.5 degrees 2θ in its X-ray powder diffraction pattern. In some embodiments, Form F of Compound A succinate is characterized in that it has two or more peaks selected from peaks at about 6.0, about 12.5, about 24.5, and about 18.9 degrees 2θ in its X-ray powder diffraction pattern. In some embodiments, Form F of Compound A succinate is characterized in that it has all three peaks selected from peaks at about 6.0, about 12.5, and about 24.5 degrees 2θ in its X-ray powder diffraction pattern.

[0200] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to Fig.17 XRPD provided in.

[0201] A method for preparing Form F of the succinate salt of Compound A is described below.

[0202] Compound A succinate form G

[0203] In some embodiments, Form G of Compound A succinate salt has at least 1, 2, 3, 4, or 5 spectral peaks selected from the peaks listed in Table 10 below.

[0204] Table 10 - XRPD Peak Positions of Form G of Compound A Succinate Salt

[0205]

[0206]

[0207]

[0208] In some embodiments, Form G of Compound A succinate is characterized in that it has one or more peaks selected from peaks at about 6.0, about 15.3, and about 23.4 degrees 2θ in its X-ray powder diffraction pattern. In some embodiments, Form G of Compound A succinate is characterized in that it has two or more peaks selected from peaks at about 6.0, about 15.3, about 23.4, and about 18.9 degrees 2θ in its X-ray powder diffraction pattern. In some embodiments, Form G of Compound A succinate is characterized in that it has all three peaks selected from peaks at about 6.0, about 15.3, and about 23.4 degrees 2θ in its X-ray powder diffraction pattern.

[0209] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to Fig. 20 XRPD provided in.

[0210] The following describes a method for preparing Form G of Compound A succinate salt.

[0211] In some embodiments, the present invention provides Compound A succinate salt:

[0212]

[0213] In some embodiments, the present invention provides Compound A succinate salt, wherein the compound is crystalline.

[0214] In some embodiments, the present invention provides Compound A succinate salt, wherein the compound is a crystalline solid substantially free of amorphous Compound A succinate salt.

[0215] In some embodiments, the present invention provides Compound A succinate salt, wherein the compound is substantially free of impurities.

[0216] In some embodiments, the present invention provides Compound A succinate, wherein the compound has one or more peaks selected from the peaks at about 8.1, about 11.6, and about 24.4 degrees 2θ in its XRPD. In some such embodiments, the present invention provides Compound A succinate, wherein the compound has at least two peaks selected from the peaks at about 8.1, about 11.6, and about 24.4 degrees 2θ in its XRPD. In some such embodiments, the present invention provides Compound A succinate, wherein the compound has at least three peaks selected from the peaks at about 8.1, about 11.6, and about 24.4 degrees 2θ in its XRPD. In some such embodiments, the present invention provides Compound A succinate, wherein the compound belongs to Form A.

[0217] In some embodiments, the present invention provides a succinate salt of Compound A, wherein the XRPD of the compound is substantially similar to Figure 7XRPD depicted in .

[0218] In some embodiments, the present invention provides Compound A succinate, wherein the compound has one or more peaks selected from the peaks at about 18.6, about 24.1, and about 24.6 degrees 2θ in its XRPD. In some such embodiments, the present invention provides Compound A succinate, wherein the compound has at least two peaks selected from the peaks at about 18.6, about 24.1, and about 24.6 degrees 2θ in its XRPD. In some such embodiments, the present invention provides Compound A succinate, wherein the compound has at least three peaks selected from the peaks at about 18.6, about 24.1, and about 24.6 degrees 2θ in its XRPD. In some such embodiments, the present invention provides Compound A succinate, wherein the compound belongs to Form B.

[0219] In some embodiments, the present invention provides a succinate salt of Compound A, wherein the XRPD of the compound is substantially similar to Fig. 9 XRPD depicted in .

[0220] In some embodiments, the present invention provides Compound A succinate, wherein the compound has one or more peaks selected from the peaks at about 9.2, about 11.9, and about 18.9 degrees 2θ in its XRPD. In some such embodiments, the present invention provides Compound A succinate, wherein the compound has at least two peaks selected from the peaks at about 9.2, about 11.9, and about 18.9 degrees 2θ in its XRPD. In some such embodiments, the present invention provides Compound A succinate, wherein the compound has at least three peaks selected from the peaks at about 9.2, about 11.9, and about 18.9 degrees 2θ in its XRPD. In some such embodiments, the present invention provides Compound A succinate, wherein the compound belongs to Form C.

[0221] In some embodiments, the present invention provides a succinate salt of Compound A, wherein the XRPD of the compound is substantially similar to Fig.11 XRPD depicted in .

[0222] In some embodiments, the present invention provides Compound A succinate, wherein the compound has one or more peaks selected from the peaks at about 12.3, about 19.4, and about 24.7 degrees 2θ in its XRPD. In some such embodiments, the present invention provides Compound A succinate, wherein the compound has at least two peaks selected from the peaks at about 12.3, about 19.4, and about 24.7 degrees 2θ in its XRPD. In some such embodiments, the present invention provides Compound A succinate, wherein the compound has at least three peaks selected from the peaks at about 12.3, about 19.4, and about 24.7 degrees 2θ in its XRPD. In some such embodiments, the present invention provides Compound A succinate, wherein the compound belongs to Form D.

[0223] In some embodiments, the present invention provides a succinate salt of Compound A, wherein the XRPD of the compound is substantially similar to Fig.13 XRPD depicted in .

[0224] In some embodiments, the present invention provides Compound A succinate, wherein the compound has one or more peaks selected from the peaks at about 11.9, about 23.1, and about 24.1 degrees 2θ in its XRPD. In some such embodiments, the present invention provides Compound A succinate, wherein the compound has at least two peaks selected from the peaks at about 11.9, about 23.1, and about 24.1 degrees 2θ in its XRPD. In some such embodiments, the present invention provides Compound A succinate, wherein the compound has at least three peaks selected from the peaks at about 11.9, about 23.1, and about 24.1 degrees 2θ in its XRPD. In some such embodiments, the present invention provides Compound A succinate, wherein the compound belongs to Form E.

[0225] In some embodiments, the present invention provides a succinate salt of Compound A, wherein the XRPD of the compound is substantially similar to Fig.15 XRPD depicted in .

[0226] In some embodiments, the present invention provides Compound A succinate, wherein the compound has one or more peaks selected from the peaks at about 6.0, about 12.5, and about 24.5 degrees 2θ in its XRPD. In some such embodiments, the present invention provides Compound A succinate, wherein the compound has at least two peaks selected from the peaks at about 6.0, about 12.5, and about 24.5 degrees 2θ in its XRPD. In some such embodiments, the present invention provides Compound A succinate, wherein the compound has at least three peaks selected from the peaks at about 6.0, about 12.5, and about 24.5 degrees 2θ in its XRPD. In some such embodiments, the present invention provides Compound A succinate, wherein the compound belongs to Form F.

[0227] In some embodiments, the present invention provides a succinate salt of Compound A, wherein the XRPD of the compound is substantially similar to Fig.17 XRPD depicted in .

[0228] In some embodiments, the present invention provides Compound A succinate, wherein the compound has one or more peaks selected from the peaks at about 6.0, about 15.3, and about 23.4 degrees 2θ in its XRPD. In some such embodiments, the present invention provides Compound A succinate, wherein the compound has at least two peaks selected from the peaks at about 6.0, about 15.3, and about 23.4 degrees 2θ in its XRPD. In some such embodiments, the present invention provides Compound A succinate, wherein the compound has at least three peaks selected from the peaks at about 6.0, about 15.3, and about 23.4 degrees 2θ in its XRPD. In some such embodiments, the present invention provides Compound A succinate, wherein the compound belongs to Form G.

[0229] In some embodiments, the present invention provides a succinate salt of Compound A, wherein the XRPD of the compound is substantially similar to Fig. 20 XRPD depicted in .

[0230] In some embodiments, the present invention provides a composition comprising Compound A succinate and a pharmaceutically acceptable carrier or excipient.

[0231] In some embodiments, the present invention provides a method of treating a CDK4-mediated and CDK6-mediated disorder in a patient in need thereof, the method comprising administering Compound A succinate or a composition thereof to the patient. In some embodiments, Compound A succinate is in Form A. In some embodiments, Compound A succinate is in Form B. In some embodiments, Compound A succinate is in Form C. In some embodiments, Compound A succinate is in Form D. In some embodiments, Compound A succinate is in Form E. In some embodiments, Compound A succinate is in Form F. In some embodiments, Compound A succinate is in Form G.

[0232] In some embodiments, the CDK4-mediated and CDK6-mediated disorder is cancer. In some embodiments, the cancer is breast cancer, malignant brain tumor, colon cancer, small cell lung cancer, non-small cell lung cancer, bladder cancer, ovarian cancer, prostate cancer, chronic lymphoid leukemia, lymphoma, myeloma, acute myeloid leukemia, secondary pancreatic cancer or secondary brain metastasis.

[0233] In some embodiments, the breast cancer is HR+ / HER2- or HR+ / HER2+ advanced or metastatic breast cancer; and the malignant brain tumor is a glioblastoma, astrocytoma, or pontine glioma.

[0234] In some embodiments, a pharmaceutical composition of Compound A succinate is administered to a patient. In some embodiments, the administration is oral administration of Compound A succinate. In some embodiments, the administration is intravenous administration of Compound A succinate.

[0235] In some embodiments, the methods described herein further include administering an additional therapeutic agent to the patient. In some embodiments, the additional therapeutic agent is a PRMT5 inhibitor, a HER2 kinase inhibitor, an aromatase inhibitor, an estrogen receptor antagonist, or an alkylating agent. In some embodiments, the aromatase inhibitor is letrozole. In some embodiments, the estrogen receptor antagonist is fulvestrant. In some embodiments, the alkylating agent is temozolomide.

[0236] Pharmaceutical salt of compound A

[0237] In some embodiments, the present disclosure relates to a pharmaceutical salt of Compound A:

[0238]

[0239] The salt is hydrochloride, sulfate, maleate, phosphate, L-tartrate, fumarate, citrate, L-malate, toluenesulfonate, succinate, methanesulfonate, ethanesulfonate, glutarate, n-acetylglycinate, acetate, malonate or sebacate.

[0240] In some embodiments, the present disclosure relates to a pharmaceutical salt of Compound A, which is a hydrochloride. In some embodiments, the pharmaceutical salt of Compound A is a hydrochloride in an amorphous form. In some embodiments, the pharmaceutical salt of Compound A is a hydrochloride in a crystalline form.

[0241] In some embodiments, the present disclosure relates to a pharmaceutical salt of Compound A, which is a sulfate salt. In some embodiments, the pharmaceutical salt of Compound A is a sulfate salt in an amorphous form. In some embodiments, the pharmaceutical salt of Compound A is a sulfate salt in a crystalline form.

[0242] In some embodiments, the present disclosure relates to a pharmaceutical salt of Compound A, which is a maleate. In some embodiments, the pharmaceutical salt of Compound A is a maleate in an amorphous form. In some embodiments, the pharmaceutical salt of Compound A is a maleate in a crystalline form.

[0243] In some embodiments, the present disclosure relates to a pharmaceutical salt of Compound A, which is a phosphate salt. In some embodiments, the pharmaceutical salt of Compound A is a phosphate salt in an amorphous form. In some embodiments, the pharmaceutical salt of Compound A is a phosphate salt in a crystalline form.

[0244] In some embodiments, the present disclosure relates to a pharmaceutical salt of Compound A, which is an L-tartrate. In some embodiments, the pharmaceutical salt of Compound A is an L-tartrate in an amorphous form. In some embodiments, the pharmaceutical salt of Compound A is an L-tartrate in a crystalline form.

[0245] In some embodiments, the present disclosure relates to a pharmaceutical salt of Compound A, which is a fumarate. In some embodiments, the pharmaceutical salt of Compound A is a fumarate in an amorphous form. In some embodiments, the pharmaceutical salt of Compound A is a fumarate in a crystalline form.

[0246] In some embodiments, the present disclosure relates to a pharmaceutical salt of Compound A, which is a citrate. In some embodiments, the pharmaceutical salt of Compound A is a citrate in an amorphous form. In some embodiments, the pharmaceutical salt of Compound A is a citrate in a crystalline form.

[0247] In some embodiments, the present disclosure relates to a pharmaceutical salt of Compound A, which is an L-malate salt. In some embodiments, the pharmaceutical salt of Compound A is an L-malate salt in an amorphous form. In some embodiments, the pharmaceutical salt of Compound A is an L-malate salt in a crystalline form.

[0248] In some embodiments, the present disclosure relates to a pharmaceutical salt of Compound A, which is a toluenesulfonate. In some embodiments, the pharmaceutical salt of Compound A is a toluenesulfonate in an amorphous form. In some embodiments, the pharmaceutical salt of Compound A is a toluenesulfonate in a crystalline form.

[0249] In some embodiments, the present disclosure relates to a pharmaceutical salt of Compound A, which is a succinate. In some embodiments, the pharmaceutical salt of Compound A is a succinate in an amorphous form. In some embodiments, the pharmaceutical salt of Compound A is a succinate in a crystalline form.

[0250] In some embodiments, the present disclosure relates to a pharmaceutical salt of Compound A, which is a mesylate. In some embodiments, the pharmaceutical salt of Compound A is a mesylate in an amorphous form. In some embodiments, the pharmaceutical salt of Compound A is a mesylate in a crystalline form.

[0251] In some embodiments, the present disclosure relates to a pharmaceutical salt of Compound A, which is an ethanesulfonate. In some embodiments, the pharmaceutical salt of Compound A is an ethanesulfonate in an amorphous form. In some embodiments, the pharmaceutical salt of Compound A is an ethanesulfonate in a crystalline form.

[0252] In some embodiments, the present disclosure relates to a pharmaceutical salt of Compound A, which is a glutarate. In some embodiments, the pharmaceutical salt of Compound A is a glutarate in an amorphous form. In some embodiments, the pharmaceutical salt of Compound A is a glutarate in a crystalline form.

[0253] In some embodiments, the present disclosure relates to a pharmaceutical salt of Compound A, which is acetylglycinate. In some embodiments, the pharmaceutical salt of Compound A is acetylglycinate in an amorphous form. In some embodiments, the pharmaceutical salt of Compound A is acetylglycinate in a crystalline form.

[0254] In some embodiments, the present disclosure relates to a pharmaceutical salt of Compound A, which is an acetate salt. In some embodiments, the pharmaceutical salt of Compound A is an acetate salt in an amorphous form. In some embodiments, the pharmaceutical salt of Compound A is an acetate salt in a crystalline form.

[0255] In some embodiments, the present disclosure relates to a pharmaceutical salt of Compound A, which is a malonate. In some embodiments, the pharmaceutical salt of Compound A is a malonate in an amorphous form. In some embodiments, the pharmaceutical salt of Compound A is a malonate in a crystalline form.

[0256] In some embodiments, the present disclosure relates to a pharmaceutical salt of Compound A, which is a sebacate. In some embodiments, the pharmaceutical salt of Compound A is a sebacate in an amorphous form. In some embodiments, the pharmaceutical salt of Compound A is a sebacate in a crystalline form.

[0257] General method for providing salt compounds

[0258] Compound A is prepared according to the method described in detail in the '323 application, the entire contents of which are hereby incorporated by reference. Salt compounds of the general formula X, which specifically encompasses the salt Compound A succinate and / or specific forms thereof, are prepared from Compound A according to the following general scheme.

[0259]

[0260] For example, Compound A succinate salt and forms thereof are prepared from Compound A by combining Compound A with an appropriate acid to form a salt of the acid. Thus, another aspect of the present invention provides a method for preparing Compound A succinate salt and forms thereof.

[0261] As generally described above, in some embodiments, the present invention provides a method for preparing a salt compound of formula X:

[0262]

[0263] The method comprises the following steps:

[0264] Compound A:

[0265]

[0266] Combined with a suitable acid and optionally a suitable solvent under conditions suitable for the formation of a salt compound of Formula X.

[0267] In some embodiments, the suitable acid is succinic acid. In some embodiments, the invention provides a method for preparing a succinate salt of Compound A. In certain embodiments, the succinate salt of Compound A is Compound A succinate salt. In certain embodiments, the succinate salt of Compound A is Form A of Compound A succinate salt. In certain embodiments, the succinate salt of Compound A is Form B of Compound A succinate salt. In certain embodiments, the succinate salt of Compound A is Form C of Compound A succinate salt. In certain embodiments, the succinate salt of Compound A is Form D of Compound A succinate salt. In certain embodiments, the succinate salt of Compound A is Form E of Compound A succinate salt. In certain embodiments, the succinate salt of Compound A is Form F of Compound A succinate salt. In certain embodiments, the succinate salt of Compound A is Form G of Compound A succinate salt.

[0268] In some embodiments, the suitable acid is hydrochloric acid. In some embodiments, the present invention provides a method for preparing the hydrochloride of Compound A. In certain embodiments, the hydrochloride of Compound A is Compound A hydrochloride. In certain embodiments, the hydrochloride of Compound A is Form A of Compound A hydrochloride. In certain embodiments, the hydrochloride of Compound A is Form B of Compound A hydrochloride. In certain embodiments, the hydrochloride of Compound A is Form C of Compound A hydrochloride. In certain embodiments, the hydrochloride of Compound A is Form D of Compound A hydrochloride. In certain embodiments, the hydrochloride of Compound A is Form E of Compound A hydrochloride. In certain embodiments, the hydrochloride of Compound A is Form F of Compound A hydrochloride.

[0269] In some embodiments, the suitable acid is maleic acid. In some embodiments, the present invention provides a method for preparing a malonate salt of Compound A. In certain embodiments, the malonate salt of Compound A is a malonate salt of Compound A. In certain embodiments, the malonate salt of Compound A is Form A of the malonate salt of Compound A.

[0270] In some embodiments, the suitable acid is sulfuric acid. In some embodiments, the present invention provides a method for preparing a sulfate salt of Compound A. In certain embodiments, the sulfate salt of Compound A is Compound A sulfate. In certain embodiments, the sulfate salt of Compound A is Form A of Compound A sulfate. In certain embodiments, the sulfate salt of Compound A is Form B of Compound A sulfate. In certain embodiments, the sulfate salt of Compound A is Form C of Compound A sulfate.

[0271] In some embodiments, the suitable acid is phosphoric acid. In some embodiments, the present invention provides a method for preparing a phosphate salt of Compound A. In certain embodiments, the phosphate salt of Compound A is Compound A phosphate. In certain embodiments, the phosphate salt of Compound A is Form A of Compound A phosphate.

[0272] In some embodiments, the suitable acid is L-tartaric acid. In some embodiments, the present invention provides a method for preparing an L-tartrate salt of Compound A. In certain embodiments, the phosphate salt of Compound A is Compound A L-tartrate salt. In certain embodiments, the L-tartrate salt of Compound A is Form A of Compound A L-tartrate salt.

[0273] In some embodiments, the suitable acid is fumaric acid. In some embodiments, the present invention provides a method for preparing a fumarate salt of Compound A. In certain embodiments, the fumarate salt of Compound A is Compound A fumarate. In certain embodiments, the fumarate salt of Compound A is Form A of Compound A fumarate. In certain embodiments, the fumarate salt of Compound A is Form B of Compound A fumarate. In certain embodiments, the fumarate salt of Compound A is Form C of Compound A fumarate. In certain embodiments, the fumarate salt of Compound A is Form D of Compound A fumarate.

[0274] In some embodiments, the suitable acid is citric acid. In some embodiments, the present invention provides a method for preparing a citrate salt of Compound A. In certain embodiments, the phosphate salt of Compound A is Compound A citrate. In certain embodiments, the citrate salt of Compound A is Form A of Compound A citrate.

[0275] In some embodiments, the suitable acid is L-malic acid. In some embodiments, the invention provides a method for preparing an L-malate salt of Compound A. In certain embodiments, the phosphate salt of Compound A is Compound A L-malate. In certain embodiments, the L-malate salt of Compound A is Form A of Compound A L-malate.

[0276] In some embodiments, the suitable acid is methanesulfonic acid. In some embodiments, the present invention provides a method for preparing a mesylate salt of Compound A. In certain embodiments, the mesylate salt of Compound A is Compound A mesylate. In certain embodiments, the mesylate salt of Compound A is Form A of Compound A mesylate. In certain embodiments, the mesylate salt of Compound A is Form B of Compound A mesylate.

[0277] In some embodiments, the suitable acid is ethanesulfonic acid. In some embodiments, the present invention provides a method for preparing an ethanesulfonate salt of Compound A. In certain embodiments, the ethanesulfonate salt of Compound A is Compound A ethanesulfonate salt. In certain embodiments, the ethanesulfonate salt of Compound A is Form A of Compound A ethanesulfonate salt. In certain embodiments, the ethanesulfonate salt of Compound A is Form B of Compound A ethanesulfonate salt.

[0278] In some embodiments, the suitable acid is toluenesulfonic acid. In some embodiments, the present invention provides a method for preparing a toluenesulfonate salt of Compound A. In certain embodiments, the toluenesulfonate salt of Compound A is Compound A toluenesulfonate salt. In certain embodiments, the toluenesulfonate salt of Compound A is Form A of Compound A toluenesulfonate salt. In certain embodiments, the toluenesulfonate salt of Compound A is Form B of Compound A toluenesulfonate salt.

[0279] In some embodiments, the suitable acid is glutaric acid. In some embodiments, the present invention provides a method for preparing a glutarate salt of Compound A. In certain embodiments, the glutarate salt of Compound A is Compound A glutarate. In certain embodiments, the glutarate salt of Compound A is Form A of Compound A glutarate.

[0280] In some embodiments, the suitable acid is acetic acid. In some embodiments, the present invention provides a method for preparing an acetate salt of Compound A. In certain embodiments, the acetate salt of Compound A is Compound A acetate. In certain embodiments, the acetate salt of Compound A is Form A of Compound A acetate.

[0281] In some embodiments, the suitable acid is malonic acid. In some embodiments, the present invention provides a method for preparing a malonate salt of Compound A. In certain embodiments, the malonate salt of Compound A is a malonate salt of Compound A. In certain embodiments, the malonate salt of Compound A is Form A of the malonate salt of Compound A. In certain embodiments, the malonate salt of Compound A is Form B of the malonate salt of Compound A.

[0282] In some embodiments, the suitable acid is sebacic acid. In some embodiments, the present invention provides a method for preparing a sebacic acid salt of Compound A. In certain embodiments, the sebacic acid salt of Compound A is a sebacic acid salt of Compound A. In certain embodiments, the sebacic acid salt of Compound A is Form A of the sebacic acid salt of Compound A.

[0283] In some embodiments, the suitable acid is acetylglycine. In some embodiments, the present invention provides a method for preparing an acetylglycine salt of Compound A. In certain embodiments, the acetylglycine salt of Compound A is Compound A acetylglycine salt. In certain embodiments, the acetylglycine salt of Compound A is Form A of Compound A acetylglycine salt. In certain embodiments, the acetylglycine salt of Compound A is Form B of Compound A acetylglycine salt.

[0284] A suitable solvent can be any solvent system (eg, one solvent or a mixture of solvents) in which Compound A and / or the acid are soluble or at least partially soluble.

[0285] Examples of suitable solvents that can be used for the present invention include but are not limited to protic solvents, aprotic solvents, polar aprotic solvents or mixtures thereof. In certain embodiments, suitable solvents include ethers, esters, alcohols, ketones or mixtures thereof. In certain embodiments, the solvent is one or more organic alcohols. In certain embodiments, the solvent is chlorinated. In certain embodiments, the solvent is an aromatic solvent.

[0286] In certain embodiments, suitable solvent is methanol, ethanol, isopropanol or acetone, wherein the solvent is anhydrous or combined with water or heptane. In certain embodiments, suitable solvent comprises tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, glycol dimethyl ether, diglyme, methyl tert-butyl ether, the tert-butyl alcohol, n-butyl alcohol and acetonitrile. In certain embodiments, suitable solvent is ethanol. In certain embodiments, suitable solvent is anhydrous ethanol. In certain embodiments, suitable solvent is MTBE.

[0287] In some embodiments, a suitable solvent is ethyl acetate. In some embodiments, a suitable solvent is a mixture of methanol and dichloromethane. In some embodiments, a suitable solvent is a mixture of acetonitrile and water. In certain embodiments, a suitable solvent is methyl acetate, isopropyl acetate, acetone or tetrahydrofuran. In certain embodiments, a suitable solvent is ether. In certain embodiments, a suitable solvent is water. In certain embodiments, a suitable solvent is methyl ethyl ketone. In certain embodiments, a suitable solvent is toluene.

[0288] In some embodiments, the present invention provides a method for preparing a salt compound of formula X, the method comprising one or more steps of removing a solvent and adding a solvent. In some embodiments, the added solvent is the same as the removed solvent. In some embodiments, the added solvent is different from the removed solvent. The means of solvent removal are known in the field of synthesis and chemistry, and include but are not limited to any of those means described herein and in the Examples.

[0289] In some embodiments, the method for preparing the salt compound of Formula X comprises one or more steps of heating or cooling the formulation.

[0290] In some embodiments, the method for preparing the salt compound of Formula X comprises one or more steps of agitating or stirring the formulation.

[0291] In some embodiments, the method for preparing the salt compound of Formula X comprises the step of adding a suitable acid to a solution or slurry of Compound A.

[0292] In some embodiments, the method for preparing the salt compound of Formula X comprises a heating step.

[0293] In certain embodiments, the salt compound of Formula X is precipitated from the mixture. In another embodiment, the salt compound of Formula X is crystallized from the mixture. In other embodiments, the salt compound of Formula X is crystallized from the solution after seeding the solution (i.e., adding crystals of the salt compound of Formula X to the solution).

[0294] The salt compound of formula X can be precipitated from the reaction mixture or produced by removing part or all of the solvent by methods such as evaporation, distillation, filtration (e.g., nanofiltration, ultrafiltration), reverse osmosis, adsorption and reaction, by adding an antisolvent such as heptane, by cooling or by various combinations of these methods.

[0295] As generally described above, the salt compound of Formula X is optionally isolated. It will be appreciated that the salt compound of Formula X can be isolated by any suitable physical means known to those of ordinary skill in the art. In certain embodiments, the precipitated solid salt compound of Formula X is separated from the supernatant by filtration. In other embodiments, the precipitated solid salt compound of Formula X is separated from the supernatant by decanting the supernatant.

[0296] In certain embodiments, the salt compound of Formula X is separated from the supernatant by filtration.

[0297] In certain embodiments, the isolated salt compound of Formula X is dried in air. In other embodiments, the isolated salt compound of Formula X is dried under reduced pressure, optionally at elevated temperature.

[0298] Pharmaceutical compositions and methods of administration

[0299] In some embodiments, the present disclosure relates to pharmaceutical compositions comprising Compound A succinate salt.

[0300] The pharmaceutical composition of the present invention is usually formulated to provide a therapeutically effective amount of the disclosed compound in the form of an active ingredient or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. Where necessary, the pharmaceutical composition contains a pharmaceutically acceptable salt and / or coordination complex thereof and one or more pharmaceutically acceptable excipients, carriers (including inert solid diluents and fillers), diluents (including sterile aqueous solutions and various organic solvents), penetration enhancers, solubilizers and adjuvants.

[0301] Pharmaceutical composition of the present invention can be used alone or in combination with one or more other medicaments, and described other medicaments are also usually used in the form of pharmaceutical composition. When necessary, one or more compounds of the present invention and other medicaments can be mixed into preparations, or two components can be formulated into independent preparations so that they can be used in combination alone or simultaneously.

[0302] In some embodiments, the concentration of one or more compounds provided in the pharmaceutical compositions of the invention is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.1% or less. 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% (or a number within a range defined by and including any two of the above numbers) w / w, w / v or v / v.

[0303] In some embodiments, the concentration of one or more compounds of the invention is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25%, 15%, 14.75%, 14.5 0%, 14.25%, 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25%, 11%, 10.75%, 10.50%, 10.25%, 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25%, 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6.25% , 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 1.25%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03 %. 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% (or a number within a range defined by and including any two of the above numbers) w / w, w / v or v / v.

[0304] In some embodiments, the concentration of one or more compounds of the invention is between about 0.0001% to about 50%, about 0.001% to about 40%, about 0.01% to about 30%, about 0.02% to about 29%, about 0.03% to about 28%, about 0.04% to about 27%, about 0.05% to about 26%, about 0.06% to about 25%, about 0.07% to about 24%, about 0.08% to about 26%, about 0.09% to about 27%, about 0.10% to about 28%, about 0.11% to about 29%, about 0.12% to about 29%, about 0.13% to about 29%, about 0.14% to about 29%, about 0.15% to about 29%, about 0.16% to about 29%, about 0.17% to about 29%, about 0.18% to about 29%, about 0.19% to about 29%, about 0.20% to about 29%, about 0.21% to about 29%, about 0.22% to about 29%, about 0.23% to about 29%, about 0.24% to about 29%, about 0.25% to about 29%, about 0.26% to about 29%, about 0.27% to about 29%, about 0.28% to about 29%, about 0. In the range of about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%, about 1% to about 10% w / w, w / v or v / v.

[0305] In some embodiments, the concentration of one or more compounds of the invention is in the range of about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, about 0.1% to about 0.9% w / w, w / v, or v / v.

[0306] In some embodiments, the amount of one or more compounds of the invention is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0. 0.002g, 0.001g, 0.0009g, 0.0008g, 0.007g, 0.006g, 0.005g, 0.004g, 0.003g, 0.002g, 0.001g, 0.0009g, 0.0008g, 0.0007g, 0.0006g, 0.0005g, 0.0004g, 0.0003g, 0.0002g or 0.0001g (or a number within a range defined by and including any two of the above numbers).

[0307] In some embodiments, the amount of one or more compounds of the invention is greater than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.003 5g, 0.004g, 0.0045g, 0.005g, 0.0055g, 0.006g, 0.0065g, 0.007g, 0.0075g, 0.008g ,0.0085g,0.009g,0.0095g,0.01g,0.015g,0.02g,0.025g,0.03g,0.035g,0.04g,0 .045g, 0.05g, 0.055g, 0.06g, 0.065g, 0.07g, 0.075g, 0.08g, 0.085g, 0.09g, 0.095 g, 0.1g, 0.15g, 0.2g, 0.25g, 0.3g, 0.35g, 0.4g, 0.45g, 0.5g, 0.55g, 0.6g, 0.65g, 0. 7g, 0.75g, 0.8g, 0.85g, 0.9g, 0.95g, 1g, 1.5g, 2g, 2.5, 3g, 3.5, 4g, 4.5g, 5g, 5.5g, 6g, 6.5g, 7g, 7.5g, 8g, 8.5g, 9g, 9.5g or 10g (or a number within the range defined by and including any two of the above numbers).

[0308] In some embodiments, the amount of one or more compounds of the invention ranges from 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.

[0309] Compounds according to the present invention are effective in a wide range of dosages. For example, when treating adults, 0.01 to 1000 mg per day, 0.5 to 100 mg per day, 1 to 50 mg per day, and 5 to 40 mg per day are examples of dosages that can be used. An exemplary dosage is 10 to 30 mg per day. Exact dosage will depend on route of administration, compound administration form, subject to be treated, subject to be treated, weight, and preference and experience of the attending physician.

[0310] The pharmaceutical compositions of the present invention generally contain an active ingredient of the present invention (i.e., a compound of the present disclosure) or a pharmaceutically acceptable salt and / or coordination complex thereof and one or more pharmaceutically acceptable excipients, carriers (including but not limited to inert solid diluents and fillers), diluents, sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers and adjuvants.

[0311] Non-limiting exemplary pharmaceutical compositions and methods for their preparation are described below.

[0312] Pharmaceutical compositions for oral administration

[0313] In some embodiments, the present invention provides a pharmaceutical composition for oral administration, which contains a compound of the present invention and a pharmaceutical excipient suitable for oral administration.

[0314] In some embodiments, the present invention provides a solid pharmaceutical composition for oral administration, which contains: (i) an effective amount of a compound of the present invention; optionally (ii) an effective amount of a second agent; and (iii) a pharmaceutical excipient suitable for oral administration. In some embodiments, the composition further contains: (iv) an effective amount of a third agent.

[0315] In some embodiments, the pharmaceutical composition can be a liquid pharmaceutical composition suitable for oral consumption. The pharmaceutical composition of the present invention suitable for oral administration can be presented in discrete dosage forms, such as capsules, cachets or tablets, or liquid or aerosol sprays, solutions, or suspensions in aqueous or non-aqueous liquids, oil-in-water emulsions or water-in-oil liquid emulsions each containing a predetermined amount of active ingredients in the form of powders or granules. Such dosage forms can be prepared by any pharmaceutical method, but all methods include the step of associating the active ingredient with a carrier, which constitutes one or more essential ingredients. Typically, the composition is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a finely powdered solid carrier or both, and then forming the product into a desired presentation form when necessary. For example, tablets can be prepared by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared by compressing in a suitable machine an active ingredient in a free-flowing form (such as a powder or granule) optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent and / or a surfactant or a dispersant. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0316] The present invention further encompasses anhydrous pharmaceutical compositions and dosage forms including active ingredients, since water may promote the degradation of some compounds. For example, in the pharmaceutical field, water (e.g., 5%) can be added as a means of simulating long-term storage to determine the properties of the formulation over time, such as shelf life or stability. The anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low-moisture ingredients and low-moisture or low-humidity conditions. If substantial contact with moisture and / or moisture is expected during manufacture, packaging and / or storage, the pharmaceutical compositions and dosage forms of the present invention containing lactose can be made water-free. Anhydrous pharmaceutical compositions can be prepared and stored in a manner that maintains the anhydrous nature of the anhydrous pharmaceutical composition. Therefore, anhydrous compositions can be packaged using materials known to prevent exposure to water so that the composition can be included in a suitable prescribed kit. Examples of suitable packaging include, but are not limited to, sealed foils, plastics, etc., unit dose containers, blister packs, and strip packs.

[0317] According to conventional pharmaceutical compounding techniques, active ingredients can be closely mixed with pharmaceutical carriers. The carrier can be in various forms depending on the desired preparation form for administration. When preparing a composition of an oral dosage form, in the case of an oral liquid preparation (such as a suspension, solution, and elixir) or an aerosol, any commonly used pharmaceutical medium can be used as a carrier, such as water, ethylene glycol, oil, alcohol, flavoring agent, preservative, colorant, etc.; or in the case of an oral solid preparation, carriers such as starch, sugar, microcrystalline cellulose, diluent, granulating agent, lubricant, binder, and disintegrant can be used, and lactose is not used in some embodiments. For example, in the case of a solid oral preparation, a suitable carrier includes powders, capsules, and tablets. If desired, tablets can be coated by standard aqueous or non-aqueous techniques.

[0318] Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch or other starches, gelatin, natural and synthetic gums (e.g., acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum), cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropyl methylcellulose, microcrystalline cellulose, and mixtures thereof.

[0319] Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powders), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0320] Disintegrants can be used in the compositions of the present invention to provide tablets that disintegrate when exposed to an aqueous environment. Too much disintegrant may produce tablets that may disintegrate in the bottle. Too little disintegrant may not be enough to cause disintegration to occur, and may therefore change the rate and extent of release of one or more active ingredients from the dosage form. Therefore, a sufficient amount of disintegrant (which will not adversely change the release of one or more active ingredients due to too little or too much) can be used to form a dosage form of the compound disclosed herein. The amount of disintegrant used can vary based on the type of formulation and the mode of administration and can be easily discerned by a person of ordinary skill in the art. About 0.5 to about 15% by weight of disintegrant or about 1 to about 5% by weight of disintegrant can be used in the pharmaceutical composition. Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starch, other starches, clays, other algins, other celluloses, gums, or mixtures thereof.

[0321] Lubricants that can be used to form pharmaceutical compositions and dosage forms of the present invention include but are not limited to calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerol, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar or a mixture thereof. Additional lubricants include, for example, a condensed aerosol of synthetic silica, synthetic silicon dioxide or a mixture thereof. Optionally, a lubricant can be added in an amount less than about 1% by weight of the pharmaceutical composition.

[0322] When aqueous suspensions and / or elixirs are required for oral administration, the active ingredient therein may be mixed with various sweetening or flavoring agents, coloring agents or dyes and, if desired, emulsifying and / or suspending agents and such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.

[0323] Tablets may be uncoated or may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide sustained action over a longer period of time. For example, time-delay materials such as glyceryl monostearate or glyceryl distearate may be used. Formulations for oral use may also be presented in the form of hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate or kaolin), or in the form of soft gelatin capsules, wherein the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin or olive oil).

[0324] Surfactants that can be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants can be used, a mixture of lipophilic surfactants can be used, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant can be used.

[0325] Suitable hydrophilic surfactants may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of or less than about 10. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of nonionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with lower HLB values ​​are more lipophilic or hydrophobic and more soluble in oils, while surfactants with higher HLB values ​​are more hydrophilic and more soluble in aqueous solutions.

[0326] Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is generally not applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10. However, the HLB value of a surfactant is only a rough guide that is commonly used to achieve the formulation of industrial, pharmaceutical, and cosmetic emulsions.

[0327] The hydrophilic surfactant can be an ionic or nonionic surfactant. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidates; fatty acid derivatives of amino acids, oligopeptides and polypeptides; glyceride derivatives of amino acids, oligopeptides and polypeptides; lecithin and hydrogenated lecithin; lysolecithin and hydrogenated lysolecithin; phospholipids and their derivatives; lysolecithin and their derivatives; carnitine fatty acid ester salts; alkyl sulfates; fatty acid salts; sodium docusate; acyl lactylates; monoacetylated and diacetylated tartaric acid esters of monoglycerides and diglycerides; succinylated monoglycerides and diglycerides; citric acid esters of monoglycerides and diglycerides; and mixtures thereof.

[0328] Within the above group, ionic surfactants include, for example: lecithin, lysolecithin, phospholipids, lysophospholipids and their derivatives; carnitine fatty acid ester salts; alkyl sulfates; fatty acid salts; sodium docusate; acyl lactylations; monoacetylated and diacetylated tartaric acid esters of monoglycerides and diglycerides; succinylated monoglycerides and diglycerides; citric acid esters of monoglycerides and diglycerides; and mixtures thereof.

[0329] The ionic surfactant can be an ionized form of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, fatty acid lactates, stearoyl-2-lactate, stearoyl lactylate, succinylated monoglycerides, monoacetylated / diacetylated tartaric acid esters of monoglycerides / diglycerides, citrate esters of monoglycerides / diglycerides, cholylsarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linolenate, stearate, dodecyl sulfate, tetradecyl sulfate, docusate, lauroyl carnitine, palmitoyl carnitine, myristoyl carnitine, and salts and mixtures thereof.

[0330] The hydrophilic nonionic surfactant may include, but is not limited to, alkyl glucosides; alkyl maltosides; alkyl thioglucosides; lauric acid polyethylene glycol glyceride; polyoxyalkylene alkyl ethers, such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols, such as polyethylene glycol alkylphenols; polyoxyalkylene alkylphenol fatty acid esters, such as polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters, such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of polyols having at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; polyoxyethylene sterols, derivatives and analogs thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters and hydrophilic transesterification products of polyols having at least one member of the group consisting of triglycerides, vegetable oils and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol or a sugar.

[0331] Other hydrophilic nonionic surfactants include, but are not limited to, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 triolein, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 capric / caprylic glycerides, PEG-8 capric / caprylic glycerides, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phytosterol, PEG-30 soybean sterol, PEG-20 trioleate, PEG-40 behenate Sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopherol PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonylphenol series, PEG 15-100 octylphenol series and poloxamer.

[0332] By way of example only, suitable lipophilic surfactants include: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acid esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and diglycerides; hydrophobic transesterification products of polyols having at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; and mixtures thereof. Within this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or hydrophobic transesterification products of polyols having at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.

[0333] In one embodiment, the composition may include a solubilizing agent to ensure good solubilization and / or dissolution of the compound of the present invention and to minimize precipitation of the compound of the present invention. This is particularly important for compositions for non-oral use (e.g., compositions for injection). A solubilizing agent may also be added to increase the solubility of hydrophilic drugs and / or other components such as surfactants or to keep the composition as a stable or uniform solution or dispersion.

[0334] Examples of suitable solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, oxyalkylene glycols, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; polyethylene glycol ethers having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycogen) or methoxy PEG; amides and other nitrogen-containing compounds, such as 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone, 2-caprolactam ... pyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and its isomers, δ-valerolactone and its isomers, β-butyrolactone and its isomers; and other solubilizers known in the art, such as dimethylacetamide, dimethyl isosorbide, N-methylpyrrolidone, caprylic acid monoglyceride, diethylene glycol monoethyl ether and water.

[0335] Mixtures of solubilizing agents can also be used. Examples include, but are not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcyclodextrin, ethanol, polyethylene glycol 200-100, glycogen, oxyalkyl alcohol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizing agents include sorbitol, glycerol, triacetin, ethanol, PEG-400, glycogen, and propylene glycol.

[0336] The amount of the solubilizing agent that can be included is not particularly limited.The amount of a given solubilizing agent can be limited to the biologically acceptable amount that can be easily determined by those skilled in the art.In some cases, it may be advantageous to include the solubilizing agent that far exceeds the biologically acceptable amount, for example, to maximize the concentration of the medicine, wherein before providing compositions to the experimenter, conventional techniques such as distillation or evaporation are used to remove excessive solubilizing agent.Therefore, based on the combined weight of medicine and other excipients, the weight ratio of solubilizing agent (if present) can be 10 % by weight, 25 % by weight, 50 % by weight, 100 % by weight or at most about 200 % by weight.If desired, a very small amount of solubilizing agent can also be used, such as 5%, 2%, 1% or even less.Typically, solubilizing agent can exist with the amount of about 1 % by weight to about 100 % by weight, more typically about 5 % by weight to about 25 % by weight.

[0337] The composition may further comprise one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, but are not limited to, anti-adherents, defoamers, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, tonicifiers, flavoring agents, colorants, flavor enhancers, opacifiers, suspending agents, adhesives, fillers, plasticizers, lubricants, and mixtures thereof.

[0338] In addition, acids or bases can be incorporated into the composition to facilitate processing, enhance stability or achieve other purposes. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium bicarbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS) and the like.

[0339] Also suitable are bases as salts of pharmaceutically acceptable acids, such as acetic acid, acrylic acid, adipic acid, alginic acid, methanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, p-bromobenzenesulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, uric acid, etc. Salts of polyprotic acids can also be used, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate. When the base is a salt, the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, etc. Examples can include but are not limited to sodium, potassium, lithium, magnesium, calcium, and ammonium.

[0340] Suitable acid is a pharmaceutically acceptable organic acid or inorganic acid. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, etc. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, methanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinonesulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, p-bromobenzenesulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, uric acid, etc.

[0341] Pharmaceutical composition for injection

[0342] In some embodiments, the present invention provides a pharmaceutical composition for injection, which contains a compound of the present invention and a pharmaceutical excipient suitable for injection. The components and amounts of the pharmaceutical agents in the composition are as described herein.

[0343] The novel compositions of the present invention may be incorporated into forms for administration by injection including aqueous or oil suspensions or emulsions with sesame oil, corn oil, cottonseed oil or peanut oil as well as elixirs, mannitol, dextrose or sterile aqueous solutions and similar pharmaceutical vehicles.

[0344] Aqueous solutions in saline are also commonly used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycols, etc. (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be used. Can be, for example, by using coatings such as lecithin, by maintaining the required particle size in the case of a dispersant and by using a surfactant to maintain appropriate fluidity. Prevention of microbial action can be achieved by various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.).

[0345] Sterile injectable solutions are prepared by incorporating the compound of the present invention in a suitable solvent as required with the various other ingredients listed above, followed by filtration sterilization. Typically, dispersions are prepared by incorporating various sterilized active ingredients into a sterile vehicle containing a basic dispersion medium and other ingredients required from the ingredients listed above. In the case of sterile powders for the preparation of sterile injectable solutions, some desirable preparation methods are vacuum drying and freeze drying techniques, which produce powders of active ingredients and produce any additional desired ingredients from their previously sterile filtered solutions.

[0346] Pharmaceutical compositions for topical (eg, transdermal) delivery .

[0347] In some embodiments, the present invention provides a pharmaceutical composition for transdermal delivery, comprising a compound of the present invention and a pharmaceutical excipient suitable for transdermal delivery.

[0348] The composition of the present invention can be formulated into a solid, semi-solid or liquid preparation suitable for local or topical application, such as gel, water-soluble jelly, cream, lotion, suspension, foam, powder, slurry, ointment, solution, oil, paste, suppository, spray, emulsion, saline solution, dimethyl sulfoxide (DMSO)-based solution. Generally, a carrier with a higher density can provide an area exposed to the active ingredient for a long time. In contrast, a solution formulation can expose the active ingredient more directly to the selected area.

[0349] The pharmaceutical composition may also include a suitable solid or gel phase carrier or excipient, which is a compound that increases the penetration of the therapeutic molecule across the stratum corneum permeability barrier of the skin or aids in delivering the therapeutic molecule across the stratum corneum permeability barrier of the skin. There are many such penetration enhancing molecules available to those trained in the art of topical formulations.

[0350] Examples of such carriers and excipients include, but are not limited to, wetting agents (e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidones, glyceryl monolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

[0351] Another exemplary formulation for use in the methods of the present invention employs a transdermal delivery device ("patch"). Such transdermal patches may be used to provide continuous or discontinuous infusion of a compound of the present invention in controlled amounts, with or without another agent.

[0352] The construction and use of transdermal patches for delivering medicaments are well known in the art. See, for example, U.S. Pat. Nos. 5,023,252, 4,992,445, and 5,001,139. ​​Such patches can be configured for continuous, pulsatile, or on-demand delivery of medicaments.

[0353] Pharmaceutical compositions for inhalation .

[0354] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, the composition is administered by oral or nasal respiratory route to produce local or systemic effects. Compositions preferably in pharmaceutically acceptable solvents may be atomized by the use of an inert gas. Atomized solutions may be inhaled directly from an atomizing device, or the atomizing device may be attached to a mask tampons or intermittent positive pressure breathing machine. Solutions, suspensions or powder compositions may be administered preferably orally or nasally from a device that delivers the formulation in an appropriate manner.

[0355] Other pharmaceutical compositions .

[0356] Pharmaceutical compositions can also be prepared from the compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural or intraspinal administration. The preparation of such pharmaceutical compositions is well known in the art. See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G., eds., Handbook of Clinical Drug Data, 10th ed., McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, 3rd ed., Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, 9th ed., McGraw-Hill, 20037ybg; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, 10th ed., McGraw-Hill, 2001; Remingtons Pharmaceutical Sciences, 13th ed., Sciences, 20th ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, 32nd ed. (The Pharmaceutical Press, London, 1999); all references are incorporated herein by reference in their entirety.

[0357] The administration of the compound or pharmaceutical composition of the present invention can be achieved by any method capable of delivering the compound to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), local (e.g., transdermal application), rectal administration, local delivery by catheter or stent, or by inhalation. The compound can also be administered intrafatally or intrathecally.

[0358] The amount of the compound administered will depend on the severity of the treated subject, the disease or condition, the rate of administration, the disposal of the compound and the judgment of the prescribing physician. However, whether in a single dose or in divided doses, the effective dose is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably in the range of about 1 to about 35 mg / kg / day. For a 70 kg person, this will be equivalent to about 0.05 to 7 g / day, preferably about 0.05 to about 2.5 g / day. In some cases, the dosage level below the lower limit of the above range may exceed a sufficient amount, and in other cases, still larger dosages can be used without causing any harmful side effects, such as by dividing such larger doses into several small doses for full-day administration.

[0359] In some embodiments, compounds of the invention are administered in a single dose.

[0360] Typically, such administration will be by injection, such as intravenous injection, to quickly introduce the agent. However, other routes may be used as appropriate. A single dose of a compound of the invention may also be used to treat acute conditions.

[0361] In some embodiments, the compounds of the present invention are administered in multiple doses. It can be administered about once a day, twice a day, three times a day, four times a day, five times a day, six times a day, or more than six times a day. It can be administered about once a month, once every two weeks, once a week, or once every other day. In another embodiment, the compounds of the present invention and another medicament are administered together about once a day to about 6 times a day. In another embodiment, the administration of the compounds of the present invention and the medicament continues for less than about 7 days. In another embodiment, the administration continues for more than about 6 days, 10 days, 14 days, 28 days, two months, six months, or one year. In some cases, continuous administration is achieved, and continuous administration continues for the required duration.

[0362] The administration of the compounds of the present invention can continue for the desired duration. In some embodiments, the administration of the compounds of the present invention continues for more than 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days or 28 days. In some embodiments, the administration of the compounds of the present invention continues for less than 28 days, 14 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days or 1 day. In some embodiments, the compounds of the present invention continue to be administered for a long time, for example to treat chronic effects.

[0363] An effective amount of the compounds of the present invention may be administered in single or multiple doses by any recognized mode of administration having similar utility, including rectal, buccal, intranasal and transdermal routes, by intraarterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topically or as an inhalant.

[0364] The composition of the present invention can also be delivered by impregnation or coating device (for example, stent) or arterial insertion cylindrical polymer. Such application methods can, for example, help prevent or improve restenosis after surgery such as balloon angioplasty. Without being bound by theory, the compound of the present invention can slow down or inhibit the migration and proliferation of smooth muscle cells in the arterial wall that help restenosis. The compound of the present invention can be applied, for example, by local delivery from the cover or sheath of the support, stent graft, graft or support of the support. In certain embodiments, the compound of the present invention is mixed with a matrix. Such a matrix can be a polymer matrix and can be used to combine the compound with the support. The polymer matrix suitable for this purpose comprises, for example, lactone polyesters or copolyesters, such as polylactide, polycaprolactonglycolide, polyorthoester, polyanhydride, polyamino acid, polysaccharide, polyphosphazene, poly(ether-ester) copolymer (e.g., PEO-PLLA), polydimethylsiloxane, poly(ethylene-vinyl acetate), acrylate polymer or copolymer (e.g., polyhydroxyethyl methyl methacrylate, polyvinyl pyrrolidone), fluorinated polymer (e.g., polytetrafluoroethylene and cellulose ester). Suitable matrix can be non-degradable or can degrade over time, thereby releasing one or more compounds. The compound of the present invention can be applied to the surface of the stent by various methods (e.g., dip coating / spin coating, spray coating, dip coating and / or brush coating). The compound can be applied in a solvent, and the solvent can be allowed to evaporate, thereby forming a compound layer on the stent. Alternatively, the compound can be positioned in the body of the stent or graft, such as in a microchannel or micropore. When implanted, the compound diffuses out from the body of the stent to contact the arterial wall. Such stents can be prepared by immersing a stent made to contain such micropores or microchannels in a solution of the compound of the present invention in a suitable solvent and then evaporating the solvent. Excess drugs on the surface of the stent can be removed by another short solvent wash. In yet other embodiments, the compound of the present invention can be covalently attached to a stent or graft. Covalent linkers can be used, which degrade in vivo to release the compound of the present invention. Any biologically unstable connection, such as ester, amide or anhydride connection, can be used for such purposes. In addition, the compound of the present invention can be administered intravascularly from the balloon used during angioplasty. Extravascular administration of the compound can also be performed by pericardial or adventitial application of the formulation of the present invention to reduce restenosis.

[0365] For example, various stent devices that can be used as described are disclosed in the following references, all of which are hereby incorporated by reference: U.S. Patent No. 5,451,233; U.S. Patent No. 5,040,548; U.S. Patent No. 5,061,273; U.S. Patent No. 5,496,346; U.S. Patent No. 5,292,331; U.S. Patent No. 5,674,278; U.S. Patent No. 3,657,744; U.S. Patent No. 4,739,762; U.S. Patent No. 5,195,984; U.S. Patent No. 5,292,331; U.S. Patent No. 5,674,278; U.S. Patent No. 5,879,382; U.S. Patent No. 6,344,053.

[0366] The compounds of the present invention can be administered in doses. It is known in the art that due to the variability of compound pharmacokinetics between subjects, individualization of dosing regimens is necessary for optimal therapy. The administration of the compounds of the present invention can be found by routine experimentation based on the present disclosure.

[0367] When the compound of the invention is administered as a composition comprising one or more agents, and the half-life of said agent is shorter than that of the compound of the invention, the unit dosage forms of said agent and the compound of the invention may be adjusted accordingly.

[0368] The pharmaceutical composition of the present invention can be, for example, suitable for oral administration in the form of tablets, capsules, pills, powders, sustained-release formulations, solutions, suspensions, suitable for parenteral administration in the form of sterile solutions, suspensions or emulsions, suitable for topical administration in the form of ointments or creams, or suitable for rectal administration in the form of suppositories. The pharmaceutical composition can be in a unit dosage form suitable for single administration of precise doses. The pharmaceutical composition will include conventional pharmaceutical carriers or excipients and the compound of the present invention as an active ingredient. In addition, the pharmaceutical composition may include other medicaments (medicinal agent or pharmaceutical agent), carriers, adjuvants, etc.

[0369] Exemplary parenteral administration forms include solutions or suspensions of the active compound in sterile aqueous solutions, for example, aqueous propylene glycol or aqueous dextrose. Such dosage forms can be suitably buffered, if necessary.

[0370] How to use

[0371] The method generally includes administering a therapeutically effective amount of the compound of the present invention to the subject. The therapeutically effective amount of the compound combination of the present invention can change according to the intended application (in vitro or in vivo) or the subject being treated and the condition (e.g., the subject's weight and age, the severity of the condition, the mode of administration, etc.) that can be easily determined by a person of ordinary skill in the art. The term is also applicable to the dosage that will induce a specific response (e.g., the proliferation of the target protein is reduced or the activity is downregulated) in the target cell. The specific dosage will change according to the specific compound selected, the dosage regimen followed, whether it is administered in combination with other compounds, the timing of administration, the administration tissue, and the physical delivery system carried by it.

[0372] As used herein, the term “IC 50 ” refers to the half-maximal inhibitory concentration of an inhibitor to inhibit a biological or biochemical function. This quantitative measure indicates how much of a particular inhibitor is needed to inhibit a given biological process (or component of a process, i.e., an enzyme, cell, cell receptor, or microorganism) by half. In other words, it is the half-maximal (50%) inhibitory concentration (IC) of a substance (50% IC or IC 50 ).EC 50 It refers to the plasma concentration required to achieve 50%>maximal effect in vivo.

[0373] In some embodiments, the methods of the invention utilize CDK inhibitors having an IC50 value of about or less than a predetermined value as determined in an in vitro assay. In some embodiments, the CDK inhibitors have an IC50 value of about or less than a predetermined value as determined in an in vitro assay. 50Values ​​for inhibiting CDK: about 1 nM or less, 2 nM or less, 5 nM or less, 7 nM or less, 10 nM or less, 20 nM or less, 30 nM or less, 40 nM or less, 50 nM or less, 60 nM or less, 70 nM or less, 80 nM or less, 90 nM or less, 100 nM or less, 120 nM or less, 140 nM or less, 150 nM or less, 160 nM or less, 170 nM or less, 0nM or less, 180nM or less, 190nM or less, 200nM or less, 225nM or less, 250nM or less, 275nM or less, 300nM or less, 325nM or less, 350nM or less, 375nM or less, 400nM or less, 425nM or less, 450nM or less, 475nM or less, 500nM or less, 550nM or less, 600nM or less, 625nM or less, 650nM or less, 675nM or less, 700nM or less, 710nM or less, 720nM or less, 730nM or less, 740nM or less, 750nM or less, 760nM or less, 775nM or less, 780nM or less, 790nM or less, 800nM or less, 810nM or less, 820nM or less, 830nM or less, 840nM or less, 850nM or less, 860nM or less M or less, 650nM or less, 700nM or less, 750nM or less, 800nM or less, 850nM or less, 900nM or less, 950nM or less, 1μΜ or less, 1.1μΜ or less, 1.2μΜ or less, 1.3μΜ or less, 1.4μΜ or less, 1.5μΜ or less, 1.6μΜ or less, 1.7μΜ or less, 1.8μΜ or less, 1.9μΜ or less , 2μΜ or less, 5μΜ or less, 10μΜ or less, 15μΜ or less, 20μΜ or less, 25μΜ or less, 30μΜ or less, 40μΜ or less, 50μΜ, 60μΜ, 70μΜ, 80μΜ, 90μΜ, 100μΜ, 200μΜ, 300μΜ, 400μΜ or 500μΜ or less (or a number within the range defined by and including any two of the above numbers).

[0374] In some embodiments, the CDK inhibitor is present at an IC 50 value selectively inhibits CDK, the IC 50 The value is its IC to one, two or three other CDKs 50 At most 1 / 2, 1 / 3, 1 / 4, 1 / 5, 1 / 6, 1 / 7, 1 / 8, 1 / 9, 1 / 10, 1 / 15, 1 / 20, 1 / 25, 1 / 30, 1 / 35, 1 / 40, 1 / 45, 1 / 50, 1 / 100 or 1 / 1000 of a value (or a number within a range defined by and including any two of the above numbers).

[0375] In some embodiments, the CDK inhibitor is present at an IC 50 value selectively inhibits CDK, the IC 50Values ​​less than about 1 nM, 2 nM, 5 nM, 7 nM, 10 nM, 20 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, 120 nM, 140 nM, 150 nM, 160 nM, 170 nM, 180 nM, 190 nM, 200 nM, 225 nM, 250 nM, 275 nM, 300 nM, 325 nM, 350 nM, 375 nM, 400 nM, 425 nM, 450 nM, 475 nM, 500 nM, 550 nM, 600 nM, 650 nM, 700 nM, 750 nM, 800 nM, 850 nM, , 1.2 μM, 1.3 μM, 1.4 μM, 1.5 μM, 1.6 μM, 1.7 μM, 1.8 μM, 1.9 μM, 2 μM, 5 μM, 10 μM, 15 μM, 20 μM, 25 μM, 30 μM, 40 μM, 50 μM, 60 μM, 70 μM, 80 μM, 90 μM, 100 μM, 200 μM, 300 μM, 400 μM or 500 μM (or a number within a range defined by and including any two of the above numbers), and the IC50 value is its IC50 against one, two or three other CDKs. 50 At most 1 / 2, 1 / 3, 1 / 4, 1 / 5, 1 / 6, 1 / 7, 1 / 8, 1 / 9, 1 / 10, 1 / 15, 1 / 20, 1 / 25, 1 / 30, 1 / 35, 1 / 40, 1 / 45, 1 / 50, 1 / 100 or 1 / 1000 of a value (or a number within a range defined by and including any two of the above numbers).

[0376] The methods of the present invention can be used to treat conditions associated with CDKs. Any condition that is caused directly or indirectly by abnormal activity or expression levels of CDKs may be a desired condition.

[0377] Different pathologies associated with CDKs have been reported. CDKs are involved, for example, in autoimmune diseases, neurodegeneration (such as Parkinson's disease, Alzheimer's disease and ischemia), inflammatory diseases, viral infections and cancers, such as colon cancer, breast cancer, small cell lung cancer, non-small cell lung cancer, bladder cancer, ovarian cancer, prostate cancer, chronic lymphatic leukemia, lymphoma, myeloma, acute myeloid leukemia or pancreatic cancer.

[0378] Non-limiting examples of such conditions include, but are not limited to, acanthoma, acinar cell carcinoma, acoustic neuroma, acral lentiginous melanoma, acrohidrosis, acute eosinophilic leukemia, acute lymphocytic leukemia, acute lymphocytic leukemia, acute megakaryocytic leukemia, acute monocytic leukemia, mature acute myeloblastic leukemia, acute myeloid dendritic cell leukemia, acute myeloid leukemia, acute myeloid leukemia, acute promyelocytic leukemia, adamantoma, adenocarcinoma, adenoid cystic carcinoma, adenoma, odontogenic adenoma tumor, adrenocortical carcinoma, adult T-cell leukemia, aggressive NK-cell leukemia, AIDS-related cancer, AIDS-related lymphoma, alveolar soft tissue sarcoma, ameloblastic fibroma, anal cancer, anaplastic large cell lymphoma, undifferentiated thyroid cancer, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, appendix cancer, astrocytoma, atypical teratoid rhabdoid tumor, basal cell carcinoma, basaloid carcinoma, B-cell leukemia, B-cell lymphoma, Bellini duct carcinoma duct carcinoma, bile duct cancer, bladder cancer, germ cell tumor, bone cancer, bone tumor, brain stem glioma, brain tumor, breast cancer, Brenner tumor, bronchiolar carcinoma, bronchioalveolar carcinoma, brown tumor, Burkitt's lymphoma, cancer of unknown primary, carcinoid tumor, carcinoma, carcinoma in situ, penile cancer, cancer of unknown primary, carcinosarcoma, Castleman's Disease, embryonal tumor of the central nervous system, cerebellar astrocytoma, cerebral astrocytoma, cervical cancer, bile duct cancer, chondroma, chondrosarcoma, chordoma, choriocarcinoma, choroid plexus papilloma, chronic lymphocytic leukemia, chronic monocytic leukemia, chronic myeloid leukemia, chronic myeloproliferative disorder, chronic neutrophilic leukemia, clear cell tumor, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, Degos disease disease), dermatofibrosarcoma protuberans, dermoid cyst, desmoplastic small round cell tumor, diffuse large B-cell lymphoma, dysembryoplastic neuroepithelioma, embryonal carcinoma, endodermal sinus tumor, endometrial carcinoma, endometrioid tumor, enteropathy-associated T-cell lymphoma, ependymoblastoma, ependymoma, epidermoid carcinoma, epithelioid sarcoma, erythroleukemia, esophageal cancer, olfactory neuroblastoma, Ewing Family of Tumor, Ewing Family Sarcoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct carcinoma, extramammary Paget's diseasedisease), fallopian tube cancer, duplication teratoma, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, gallbladder cancer, ganglioglioma, ganglioneuroma, gastric cancer, gastric lymphoma, gastrointestinal cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, gastrointestinal stromal tumor, germ cell tumor, germ tissue tumor, gestational choriocarcinoma, gestational trophoblastic tumor, giant cell tumor of bone, glioblastoma multiforme, glioma, gliomatosis, glomus tumor, glucagonoma, gonadoblastoma, granulosa cell tumor, hairy cell leukemia, head and neck cancer, head and neck cancer cancer), heart cancer, hemoglobinopathies such as beta-thalassemia and sickle cell disease (SCD), hemangioblastoma, hemangiopericytoma, angiosarcoma, hematological malignancies, hepatocellular carcinoma, hepatosplenic T-cell lymphoma, hereditary breast-ovarian cancer syndrome, Hodgkin Lymphoma, Hodgkin's lymphoma, hypopharyngeal cancer, hypothalamic glioma, inflammatory breast cancer, intraocular melanoma, islet cell carcinoma, islet cell tumor, juvenile myelomonocytic leukemia, Kaposi's sarcoma, Kaposi's sarcoma, kidney cancer, Klatskin tumor, Krukenberg tumor, Laryngeal cancer Cancer), Laryngeal cancer, Lentigo maligna, Melanoma, Leukemia, Lip and oral cancer, Liposarcoma, Lung cancer, Luteoma, Lymphangioma, Lymphangiosarcoma, Lymphoepithelioma, Lymphatic leukemia, Lymphoma, Macroglobulinemia, Malignant fibrous histiocytoma, Malignant fibrous histiocytomafibroushistiocytoma), malignant fibrous histiocytoma of bone, malignant glioma, malignant mesothelioma, malignant peripheral nerve sheath tumor, malignant rhabdoid tumor, malignant salamander tumor, MALT lymphoma, mantle cell lymphoma, mast cell leukemia, mastocytosis, mediastinal germ cell tumor, mediastinal tumor, medullary thyroid carcinoma, medulloblastoma, medulloblastoma, medulloepithelioma, melanoma, melanoma, meningioma, Merkel cell carcinoma, mesothelioma, mesothelioma, metastatic squamous neck carcinoma of unknown primary, metastatic urothelial carcinoma, mixed mullerian tumor, monocytic leukemia, oral cancer, mucinous tumor, multiple endocrine neoplasia syndrome, multiple myeloma Myeloma, Multiple myeloma, Mycosis Fungoides, Myelodysplastic disease, Myelodysplastic syndrome, Myeloid leukemia, Myeloid sarcoma, Myeloproliferative disease, Myxoma, Nasal cancer, Nasopharyngeal cancer, Nasopharyngeal carcinoma, Neoplasm, Schwannoma, Neuroblastoma, Neuroblastoma, Neurofibroma, Neuroma, Nodular melanoma, Non-Hodgkin lymphoma, Non-Hodgkin lymphoma, Non-melanoma skin cancer, Non-small cell lung cancer, Eye tumors, Oligoastrocytoma, Oligodendroglioma, Oncocytoma, Optic nerve sheath meningioma, Oral cancer, Oral cancer cancer), Oropharyngeal cancer, Osteosarcoma, Osteosarcoma, Ovarian cancer, Ovarian epithelial cancer, Ovarian germ cell tumor, Ovarian low malignant potential tumor, Paget's disease of the breast, Superior sulcus tumor, Pancreatic cancer, Pancreatic cancercancer), papillary thyroid cancer, papilloma, paraganglioma, paranasal sinus cancer, parathyroid cancer, penile cancer, perivascular epithelioid cell tumor, pharyngeal cancer, pheochromocytoma, moderately differentiated pineal parenchymal tumor, pinealoblastoma, pituitary cell tumor, pituitary adenoma, pituitary tumor, plasma cell neoplasm, pleuropulmonary blastoma, polyembryony, precursor T lymphoblastic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, primary hepatocellular carcinoma, primary liver cancer, primary peritoneal cancer, primitive neuroectodermal tumor, prostate cancer, pseudomyxoma peritonei, rectal cancer, renal cell carcinoma, respiratory tract cancer involving the NUT gene on chromosome 15, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter's transformation transformation), sacrococcygeal teratoma, salivary gland cancer, sarcoma, schwannomatosis, sebaceous gland cancer, secondary tumors, seminoma, serous tumor, Sertoli-Leydig cell tumor, sex cord-stromal tumor, Sezary syndrome Syndrome), signet ring cell carcinoma, skin cancer, small blue round cell tumor, small cell carcinoma, small cell lung cancer, small cell lymphoma, small intestinal cancer, soft tissue sarcoma, somatostatinoma, sooty warts, spinal cord tumor, spinal cord tumor, splenic marginal zone lymphoma, squamous cell carcinoma, gastric cancer, superficial spreading melanoma, supratentorial primitive neuroectodermal tumor, surface epithelial-stromal tumor, synovial sarcoma, T-cell acute lymphoblastic leukemia, T-cell large granular lymphocytic leukemia, T-cell leukemia, T-cell lymphoma, T-cell prolymphocytic leukemia, teratocarcinoma, advanced lymphoma, testicular cancer, theca cell tumor, laryngeal cancer, thymic cancer, thymoma, thyroid cancer, renal pelvis and ureter transitional cell carcinoma, transitional cell carcinoma, urachal carcinoma, urethral cancer, urogenital neoplasms, uterine sarcoma, uveal melanoma, vaginal cancer, Verner Morrison syndrome Morrison syndrome, verrucous carcinoma, optic pathway glioma, vulvar carcinoma, Waldenstrom's macroglobulinemia, Warthin's tumor, Wilms' tumor, or any combination thereof.

[0379] In some embodiments, the method is used to treat a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory diseases (such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease), skin diseases (such as psoriasis, eczema and scleroderma), diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer and epidermoid carcinoma.

[0380] In other embodiments, the method is used to treat a disease selected from breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, uterine cancer, or cervical cancer.

[0381] In other embodiments, the method is used to treat a disease selected from the group consisting of leukemias such as acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS), or epidermoid carcinoma.

[0382] The compounds of the present disclosure and pharmaceutical compositions comprising the compounds can be administered alone or in combination with medical therapy to treat any of the described diseases. Medical therapy includes, for example, surgery and radiation therapy (e.g., gamma radiation, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, systemic radioisotopes).

[0383] In other aspects, the compounds of the present disclosure and pharmaceutical compositions comprising the compounds may be administered alone or in combination with one or more other agents to treat any of the described diseases.

[0384] In other methods, compounds of the disclosure and pharmaceutical compositions comprising the compounds may be administered in combination with agonists of nuclear receptor agents.

[0385] In other methods, the compounds of the disclosure and pharmaceutical compositions comprising the compounds may be administered in combination with antagonists of nuclear receptor agents.

[0386] In other methods, the compounds of the present disclosure and pharmaceutical compositions comprising the compounds may be administered in combination with an anti-proliferative agent.

[0387] In some embodiments, the present disclosure relates to a method for treating CDK4-mediated and CDK6-mediated disorders in a patient in need thereof, comprising administering to the patient a compound of Formula I (including all subgenera described herein) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I (including all subgenera described herein).

[0388] In some embodiments, the CDK4-mediated and CDK6-mediated disorder is cancer. In some embodiments, the cancer is breast cancer, malignant brain tumor, colon cancer, small cell lung cancer, non-small cell lung cancer, bladder cancer, ovarian cancer, prostate cancer, chronic lymphoid leukemia, lymphoma, myeloma, acute myeloid leukemia, secondary pancreatic cancer or secondary brain metastasis.

[0389] In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is a malignant brain tumor. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is small cell lung cancer. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is ovarian cancer.

[0390] In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is chronic lymphoid leukemia. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is myeloma. In some embodiments, the cancer is acute myeloid leukemia. In some embodiments, the cancer is secondary pancreatic cancer. In some embodiments, the cancer is secondary brain metastasis.

[0391] In some embodiments, the breast cancer is HR+ / HER2- or HR+ / HER2+ advanced or metastatic breast cancer. In some embodiments, the breast cancer is HR+ / HER2- advanced breast cancer. In some embodiments, the breast cancer is HR+ / HER2- metastatic breast cancer. In some embodiments, the breast cancer is HR+ / HER2+ advanced breast cancer. In some embodiments, the breast cancer is HR+ / HER2+ metastatic breast cancer.

[0392] In some embodiments, the malignant brain tumor is a glioblastoma, an astrocytoma, or a pontine glioma. In some embodiments, the malignant brain tumor is a glioblastoma. In some embodiments, the malignant brain tumor is an astrocytoma. In some embodiments, the malignant brain tumor is a pontine glioma.

[0393] In some embodiments, a pharmaceutical composition comprising a compound of Formula I (including all subgenera described herein) or a pharmaceutically acceptable salt thereof is administered to a patient. In some embodiments, administration is oral administration.

[0394] Combination therapy

[0395] In order to treat cancer and other proliferative diseases, the compounds of the present invention can be used in combination with chemotherapeutic agents, agonists or antagonists of nuclear receptors or other antiproliferative agents. The compounds of the present invention can also be used in combination with medical therapies such as surgery or radiotherapy, for example gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy and systemic radioisotopes. Examples of suitable chemotherapeutic agents include any of the following: abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, all-trans retinoic acid, hexamethylmelamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bendamustine, bevacizumab, bexarotene, bleomycin, bortezombi, bortezomib, intravenous busulfan, intravenous, oral busulfan, calusterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolone propionate propionate, eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citratecitrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon α2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate acetate), levamisole, lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin CC), mitotane, mitoxantrone, nandrolone, phenpropionate, nelarabine, nofetumomab, oxaliplatin, paclitaxel, pamidronate, panobinostat, panitumumab, pegaspargase, pegfilgrastim m), pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinib malate maleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinstat, and zoledronate.

[0396] In certain embodiments, the compound of the present invention can be used in combination with the therapeutic agent of the targeted epigenetic regulator. The example of epigenetic regulator includes bromodomain inhibitors, histone lysine methyltransferase inhibitors, histone arginine methyltransferase inhibitors, histone demethylase inhibitors, histone deacetylase inhibitors, histone acetylase inhibitors and DNA methyltransferase inhibitors. Histone deacetylase inhibitors include, for example, vorinostat. Histone arginine methyltransferase inhibitors include protein arginine methyltransferase (PRMT) inhibitors such as PRMT5, PRMT1 and PRMT4. DNA methyltransferase inhibitors include inhibitors of DNMT1 and DNMT3.

[0397] For the treatment of cancer and other proliferative diseases, the compounds of the present invention can be used in combination with targeted therapies, comprising JAK kinase inhibitors (e.g., ruxolitinib), PI3 kinase inhibitors (including PI3K-δ selective and broad-spectrum PI3K inhibitors), MEK inhibitors, cyclin-dependent kinase inhibitors (including CDK4 / 6 inhibitors and CDK9 inhibitors), BRAF inhibitors, mTOR inhibitors, proteasome inhibitors (e.g., bortezomib, carfilzomib), HDAC inhibitors (e.g., panobinostat, vorinostat), DNA methyltransferase inhibitors, dexamethasone, bromo- and extra-terminal family members (BET) inhibitors, BTK inhibitors (e.g., ibrutinib, acalabrutinib), BCL2 inhibitors (e.g., venetoclax), dual BCL2 family inhibitors (e.g., BCL2 / BCLxL), PARP inhibitors, FLT3 inhibitors or LSD1 inhibitors.

[0398] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-1, such as an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475) or PDR001. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibody is pembrolizumab. In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-L1, such as an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is atezolizumab, durvalumab or BMS-935559. In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CTLA-4, such as an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab.

[0399] In some embodiments, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulator. Examples of alkylating agents include cyclophosphamide (CY), melphalan (MEL), and bendamustine. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the corticosteroid is dexamethasone (DEX). In some embodiments, the immunomodulator is lenalidomide (LEN) or pomalidomide (POM).

[0400] For the treatment of autoimmune or inflammatory conditions, the compounds of the invention may be administered in combination with a corticosteroid such as triamcinolone, dexamethasone, fluocinolone, cortisone, prednisolone or flumetholone.

[0401] For the treatment of autoimmune or inflammatory disorders, the compounds of the invention may be combined with immunosuppressants such as fluocinolone acetonide. Rimexolone (AL-2178, Vexol, Alcon) or cyclosporine Combined administration.

[0402] In some embodiments, the present disclosure relates to the methods described herein, further comprising administering an additional therapeutic agent to the patient.

[0403] Additional therapeutic agents are PRMT5 inhibitors, HER2 kinase inhibitors, aromatase inhibitors, estrogen receptor antagonists or alkylating agents.

[0404] In some embodiments, the additional therapeutic agent is a PRMT5 inhibitor. In some embodiments, the additional therapeutic agent is a HER2 kinase inhibitor. In some embodiments, the additional therapeutic agent is an aromatase inhibitor. In some embodiments, the additional therapeutic agent is an estrogen receptor antagonist. In yet other embodiments, the additional therapeutic agent is an alkylating agent.

[0405] In some embodiments, the aromatase inhibitor is letrozole. In some embodiments, the estrogen receptor antagonist is fulvestrant. In other embodiments, the alkylating agent is temozolomide.

[0406] In yet other embodiments, the PRMT5 inhibitor is a compound disclosed in U.S. Published Patent Application No. 2020 / 0148692 (filed on January 16, 2020); U.S. Published Patent Application No. 2019 / 0284193 (filed on April 5, 2019); and U.S. Published Patent Application No. 2019 / 0048014 (filed on August 9, 2018); each of the U.S. published patent applications is hereby incorporated by reference in its entirety.

[0407] In some embodiments, the PRMT5 inhibitor is:

[0408] (2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-6-chloroisochroman-1-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt or solvate thereof;

[0409] (2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-7-chloroisochroman-1-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt or solvate thereof;

[0410] (2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-5-chloroisochroman-1-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt or solvate thereof;

[0411] (2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-6,7-difluoroisochroman-1-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt or solvate thereof;

[0412] (2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-5,6-difluoroisochroman-1-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt or solvate thereof;

[0413] (2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-6-chloro-5-fluoroisochroman-1-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt or solvate thereof;

[0414] (2R,3R,4S,5S)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-6-chloroisochroman-1-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt or solvate thereof;

[0415] (2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-6,7-dichloroisochroman-1-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt or solvate thereof;

[0416] (2S,3S,4R,5R)-2-((R)-6-chloroisochroman-1-yl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt or solvate thereof;

[0417] (2S,3S,4R,5R)-2-((R)-6,7-difluoroisochroman-1-yl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt or solvate thereof;

[0418] (2S,3S,4R,5R)-2-((R)-5,6-difluoroisochroman-1-yl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt or solvate thereof;

[0419] (2S,3S,4R,5R)-2-((R)-6-chloroisochroman-1-yl)-5-(5-fluoro-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt or solvate thereof;

[0420] (2S,3S,4R,5R)-2-((R)-6,7-dichloroisochroman-1-yl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt or solvate thereof.

[0421] In some embodiments, the PRMT5 inhibitor is (2S,3S,4R,5R)-2-((R)-6-chloroisochroman-1-yl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt or solvate thereof.

[0422] All features of each of the various aspects of the invention apply mutatis mutandis to all other aspects.

[0423] In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting the present invention in any manner.

[0424] Example

[0425] As depicted in the following examples, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present invention, the following general methods and other methods known to those of ordinary skill in the art can be applied to all compounds as described herein and subclasses and species of each of these compounds.

[0426] Example A - General Preparation of Compound A

[0427]

[0428] The title compound was prepared according to the procedures and intermediates described below and in the '323 application, the entire contents of which are incorporated herein by reference.

[0429] Step 1. tert-Butyl 6-nitro-3',6'-dihydro-[3,4'-bipyridyl]-1'(2'H)-carboxylate

[0430]

[0431] N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (12.0 g, 38.8 mmol), 5-bromo-2-nitropyridine (7.80 g, 38.4 mmol), sodium carbonate (15.9 g, 115 mmol) and 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.51 g, 3.84 mmol) were suspended in 1,4-dioxane (120 mL) and water (40.0 mL) under an inert atmosphere. The reaction mixture was heated at 100 ° C for 6 hours. The reaction mixture was cooled to room temperature and diluted with water (100 mL). The mixture was extracted with EtOAc (100 mL×3). The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography using EtOAc / heptane (10%-60% with 0.1% Et3N) to give the title compound (9.20 g, 30.1 mmol, 78.4% yield) as a brown solid. 15 H 20 N3O4[M+H] + LCMS calculated value: m / z = 306.1; found value: 306.1.

[0432] Step 2. 6-Nitro-1',2',3',6'-tetrahydro-3,4'-bipyridine

[0433]

[0434] 6-Nitro-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-tert-butyl carboxylate (11.0 g, 36.0 mmol) was dissolved in DCM (30.0 mL) and cooled to 0 ° C. Trifluoroacetic acid (10.0 mL, 131 mmol) was slowly added at 0 ° C. The reaction mixture was warmed to room temperature and stirred for 5 hours. The reaction mixture was concentrated under reduced pressure and then diluted with water (10.0 mL). The solution was freeze-dried and used without further purification to give the crude TFA salt of the title compound as a yellow solid (18.6 g). 10 H 12 N3O2[M+H] + LCMS calculated value: m / z = 206.1; found value: 206.0.

[0435] Step 3. 1'-Methyl-6-nitro-1',2',3',6'-tetrahydro-3,4'-bipyridine

[0436]

[0437] Formaldehyde (24.9 mL, 335 mmol, 37 wt% in H2O) and the crude TFA salt of 6-nitro-1', 2', 3', 6'-tetrahydro-3, 4'-bipyridine (18.6 g) were dissolved in DCM (60 mL) at room temperature. The mixture was stirred for 30 minutes and the reaction was cooled to 0 ° C. Sodium triacetoxyborohydride (14.2 g, 66.9 mmol) was added in batches at 0 ° C. The resulting reaction mixture was warmed to room temperature and stirred overnight. The reaction was quenched with saturated sodium bicarbonate (aqueous solution) (60.0 mL) and sodium carbonate was added until gas evolution was no longer observed. The organic phase was separated and the aqueous layer was extracted with DCM (30.0 mL × 2). The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The reaction sequence in steps 2-3 was repeated with an additional portion of tert-butyl 6-nitro-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (2.5 mmol in step 2) and the crude material from both sequences was combined for purification. Purification by silica gel chromatography using MeOH / DCM (0-50%) afforded the free base of the title compound as a yellow solid (8.10 g, 36.9 mmol, quantitative yield for two steps). 1 H NMR (300MHz, DMSO-d6) δ8.74(d,J=2.1Hz,1H),8.29-8.16(m,2H),6.57(t,J=3.6Hz,1H),3.09-3.03(m,2H),2.60-2.52(m,4H),2.27(s,3H). C 11 H 14 N3O2[M+H] + LCMS calculated value: m / z = 220.1; found value: 220.0.

[0438] The free base was dissolved in EtOAc (50.0 mL), DCM (5.00 mL) and MeOH (5.00 mL). HCl solution (37.0 mL, 74.0 mmol, 2 N in iPrOAc) was then added. The reaction mixture was stirred at room temperature for 2 hours. The precipitate was collected by filtration and dried under reduced pressure to obtain the HCl salt of the title compound as a white solid (9.46 g, 32.4 mmol, 90.1% yield).

[0439] Step 4. 5-(1-methylpiperidin-4-yl)pyridin-2-amine

[0440]

[0441] In a 500mL reaction vessel, 1'-methyl-6-nitro-1',2',3',6'-tetrahydro-3,4'-bipyridine HCl salt (9.46g, 32.4mmol) was dissolved in MeOH (150mL). Palladium / carbon (0.875g, 0.822mmol, 10wt%) and glacial acetic acid (1.00mL, 17.5mmol) were added sequentially at room temperature. The reaction vessel was sealed in a Parr shaker, and hydrogen (60psi) was charged into the container. The reaction mixture was mixed overnight. The hydrogen atmosphere was removed, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The dark residue was dissolved in DCM (30.0mL) and neutralized with sodium hydroxide (3.39g, 84.8mmol). The organic layer was washed with water (30.0mL×2), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography using MeOH / DCM (0-50% with 0.1% Et3N) to give the title compound (6.10 g, 31.9 mmol, 98.5% yield) as an off-white solid. 1 H NMR (300MHz, DMSO-d6) δ7.74(d,J=2.2Hz,1H),7.23(dd,J=8.5,2.4Hz,1H),6.36(d,J=8.5Hz,1H),5.62 (s,2H),2.81(d,J=11.4Hz,2H),2.40-2.16(m,1H),2.15(s,3H),2.00-1.75(m,2H),1.64-1.47(m,4H). C 11 H 18 N3[M+H] + LCMS calculated value: m / z = 192.1; found value: 192.1.

[0442] Step 5. 2-(2-Chloro-5-fluoropyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one

[0443]

[0444] n-Butyl lithium (5.20 mL, 13.0 mmol, 2.5 M in hexane) was added dropwise to a solution of 2-bromo-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one (2.60 g, 8.66 mmol) at -78 ° C. The reaction mixture was stirred at -78 ° C for 20 minutes. Then 2-chloro-5-fluoropyrimidine (1.38 g, 10.4 mmol) was added once. The mixture was stirred at -78 ° C for 30 minutes. The reaction was quenched with saturated NH4Cl (aqueous solution) and diluted with DCM (30.0 mL). The mixture was warmed to room temperature and the two phases were separated. The organic layer was removed and the aqueous layer was extracted with DCM (30.0 mL × 2). The combined organic layer was washed with brine, dried over sodium sulfate and concentrated.

[0445] 2,3-dichloro-5,6-dicyano-p-benzoquinone (1.86 g, 8.20 mmol) was added to THF (30.0 mL) containing the crude residue. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with DCM (30.0 mL), washed with hot potassium carbonate (10 wt% aqueous solution) (30.0 mL × 2), dried over sodium sulfate and concentrated. The crude residue was purified by preparative HPLC using a C18 column (20%-100% MeCN / 0.1% TFA (aqueous solution)) to give the TFA salt of the title compound as an off-white solid (1.35 g, 2.90 mmol, 35.3% yield). 16 H 16 ClFN3OS[M+H] + LCMS calculated values: m / z = 352.1, 354.1; found values: 352.0, 353.9.

[0446] Step 6. 2-(5-Fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one

[0447] To a solution of 2-(2-chloro-5-fluoropyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one, TFA salt (1.20 g, 2.58 mmol) and 5-(1-methylpiperidin-4-yl)pyridin-2-amine (0.783 g, 4.09 mmol) in 1,4-dioxane (24.0 mL) was added K3PO4 (2.17 g, 10.2 mmol) and XPhos Pd G2 (268 mg, 0.341 mmol, CAS1310584-14-5). The reaction vessel was sealed and the mixture was degassed three times with N2. The reaction mixture was heated at 100 °C overnight. The reaction mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The dark residue was purified by preparative HPLC on a C18 column (10%-50% MeCN / 0.1% TFA (aqueous solution)) to give the title compound in the form of a TFA salt. The TFA salt was neutralized with saturated NaHCO (aqueous solution) (20.0 mL), and the aqueous layer was extracted with DCM (20.0 mL × 3). The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in 1N HCl (2.20 mL, 2.20 mmol, 1.05 equiv), and the solvent was removed by freeze drying to give the HCl salt of the title compound as a yellow solid (1.21 g, 2.23 mmol, 86.5% yield). 1 H NMR(300MHz,DMSO-d6)δ10.46(br s,1H),10.31(br s,1H),8.75(d,J=2.5Hz,1H),8.21(d,J=2.4Hz,1H),8.12(d,J=8.7Hz,1H),7.71(dd,J=8.8,2.4Hz,1H),7.55(s,1H),3.52(s,3H),3.4 6(s,2H),3.20-2.97(m,2H),2.95-2.84(m,2H),2.77(d,J=4.3Hz,3H),2.69(d,J=3.5Hz,3H),2.06-1.93(m,4H),1.31(d,J=6.8Hz,6H). C 27 H 32 FN6OS[M+H] + LCMS calculated value: m / z = 507.2; found value: 507.2.

[0448] General Procedure for Examples 1-8

[0449] X-ray powder diffraction (XRPD) data. XRPD data were collected using the following parameters:

[0450] Instrument: Rigaku Smart lab SE

[0451] X-ray wavelength: Cu, Kα, Kα1 1.540598, Kα2 1.544426

[0452] Kα2:Kα1 intensity ratio: 0.50

[0453] X-ray tube settings: 40kV, 15mA, scan mode 1D

[0454] Scanning range (2θ): 3°-40°, step size (2θ): 0.02°, scanning speed (2θ): 10° / min.

[0455] Thermogravimetric analysis (TGA). TGA data were collected using the following parameters:

[0456] Instrument: TA, TGA500

[0457] Method: ramp, temperature range room temperature-300°C, heating rate 10°C / min

[0458] Purge gas: N2 (>99.999%)

[0459] Pan Type: Aluminum, open ended.

[0460] Differential Scanning Calorimetry (DSC): DSC data were collected using the following parameters:

[0461] Instrument: TA, TGA500

[0462] Method: ramp, temperature range room temperature-300°C, heating rate 10°C / min

[0463] Purge gas: N2 (>99.999%)

[0464] Pan Type: Aluminum, open ended.

[0465] Polarized Light Microscopy (PLM): PLM data were collected using the following parameters:

[0466] Instrument: Olympus BX53

[0467] Method: The sample was dispersed on a glass slide with methyl silicone oil.

[0468] Example 1 - Form A of Compound A Free Base

[0469]

[0470] Form A of Compound A free base.

[0471] Table 1 above is reproduced below and lists the X-ray diffraction peaks observed for Form A of Compound A free base.

[0472] Table 1 - XRPD peak positions of Form A of Compound A free base

[0473] Position (°2θ) Strength cps° 9.0 1057 11.5 2282 12.9 1758 16.8 1433 17.9 1752 21.2 1097 22.0 443 23.5 1823 25.7 936 28.2 1093

[0474] Figure 1 Depicted is the XRPD pattern of Form A of Compound A free base.

[0475] Figure 2 Depicted are the DSC thermogram and TGA trace of Form A of Compound A free base.

[0476] The properties of Form A of Compound A free base are summarized in Table 11 below.

[0477] Table 11 - Properties of Form A of Compound A Free Base

[0478] Characterization instrument result Crystallinity XRPD Medium crystallinity Thermal weight loss TGA 0.5% at 236.4°C Melting point DSC <![CDATA[Melting points below about 189.87 ℃ and 247.86 ℃ > form PLM Fine granular Residual Solvents NMR No residual solvent purity HPLC 97.0％

[0479] Example 2 - Form B of Compound A Free Base

[0480]

[0481] Form B of Compound A free base.

[0482] Table 2 above is reproduced below and lists the X-ray diffraction peaks observed for Form B of Compound A free base.

[0483] Table 2 - XRPD peak positions of Form B of Compound A free base

[0484] Position (°2θ) Strength cps° 11.2 1838 16.0 1234 17.8 2637 17.9 634 18.3 3016 19.1 640 20.8 5682 22.5 874 22.9 1368 31.6 1095

[0485] Figure 3 Depicted is the XRPD pattern of Form B of Compound A free base.

[0486] Figure 4 Depicted are the DSC thermogram and TGA trace of Form B of Compound A free base. The properties of Form B of Compound A free base are summarized in Table 12 below.

[0487] Table 12 - Properties of Form B of Compound A Free Base

[0488]

[0489] Example 3 - Form C of Compound A Free Base

[0490]

[0491] Form C of Compound A free base.

[0492] Table 3 above is reproduced below and lists the X-ray diffraction peaks observed for Form C of Compound A free base.

[0493] Table 3 - XRPD peak positions of Form C of Compound A free base

[0494] Position (°2θ) Strength cps° 13.6 1965 16.4 2483 17.2 1233 20.0 1322 20.6 1123 20.8 1744 22.6 974 22.9 2889 23.7 1384 31.6 2668

[0495] Figure 5 Depicted is an XRPD pattern of Form C of Compound A free base.

[0496] Figure 6 Depicted are the DSC thermogram and TGA trace of Form C of Compound A free base.

[0497] The properties of Form C of Compound A free base are summarized in Table 13 below.

[0498] Table 13 - Properties of Form C of Compound A Free Base

[0499]

[0500] Example 4 - Form A of Compound A Succinate

[0501]

[0502] Form A of Compound A succinate salt.

[0503] Form A of Compound A succinate salt was prepared in a manner similar to Examples 12-41 below.

[0504] Three endothermic peaks (40.4°C, 113.1°C, and 148.6°C) were examined by DSC. When heated to 105.4°C by TGA, the mass loss of Form A of Compound A succinate was 2.7%. 1 H NMR, residual solvent of EtOH was 0.19%.

[0505] Table 4 above is reproduced below and lists the X-ray diffraction peaks observed for Form A of Compound A succinate salt.

[0506] Table 4 - XRPD Peak Positions of Form A of Compound A Succinate Salt

[0507] Position (°2θ) Strength cps° 8.1 1598 10.8 1007 11.0 741 11.6 3424 12.0 556 13.6 860 15.8 640 17.5 872 24.4 1148 25.2 1001

[0508] Figure 7 Depicted is an XRPD pattern of Form A of Compound A succinate salt.

[0509] Figure 8Depicted are the DSC thermogram and TGA trace of Form A of Compound A succinate salt.

[0510] Example 5 - Form B of Compound A Succinate Salt

[0511]

[0512] Form B of Compound A succinate salt.

[0513] Form B of Compound A succinate salt was prepared in a manner similar to Examples 12-41 below.

[0514] Form B of Compound A succinate was obtained by stirring in 2-MeTHF at 25°C. Two endothermic peaks (39.2°C and 136.6°C) were examined by DSC. When heated to 117.5°C by TGA, Form B of Compound A succinate lost 2.4% of its mass. 1 H NMR, residual solvent of 2-MeTHF was 0.11%.

[0515] Table 5 above is reproduced below and lists the X-ray diffraction peaks observed for Form B of Compound A succinate salt.

[0516] Table 5 - XRPD Peak Positions of Form B of Compound A Succinate Salt

[0517] Position (°2θ) Strength cps° 11.9 1476 12.3 1571 14.3 388 15.1 786 18.6 2087 20.61 411 21.8 629 24.1 1904 24.6 2561 25.6 715

[0518] Fig. 9 Depicted is the XRPD pattern of Form B of Compound A succinate salt.

[0519] Fig.10 Depicted are the DSC thermogram and TGA trace of Form B of Compound A succinate salt.

[0520] Example 6 - Form C of Compound A Succinate Salt

[0521]

[0522] Form C of Compound A succinate salt.

[0523] Form C of Compound A succinate salt was prepared in a manner similar to Examples 12-41 below.

[0524] Form C of Compound A succinate was obtained by stirring in a solvent system near 25°C and 50°C. One endothermic peak (144.0°C) was detected by DSC. When heated to 105.6°C by TGA, Form C of Compound A succinate lost 1.3% of its mass. 1 H NMR, the residual solvent of acetone was 0.34%.

[0525] Table 6 above is reproduced below and lists the X-ray diffraction peaks observed for Form C of Compound A succinate salt.

[0526] Table 6 - XRPD Peak Positions of Form C of Compound A Succinate Salt

[0527]

[0528]

[0529] Fig.11 Depicted is an XRPD pattern of Form C of Compound A succinate salt.

[0530] Fig.12 Depicted are the DSC thermogram and TGA trace of Form C of Compound A succinate salt.

[0531] Example 7 - Form D of Compound A Succinate Salt

[0532]

[0533] Form D of Compound A succinate salt.

[0534] Form D of Compound A succinate salt was prepared in a manner similar to Examples 12-41 below.

[0535] Form D of Compound A succinate was obtained by stirring in THF / H2O or acetone / H2O system at 25°C and 50°C. One endothermic peak (138.7°C) was detected by DSC. When heated to 131.2°C by TGA, Form D of Compound A succinate lost 4.1% of its mass. 1 H NMR, residual solvent of THF was 0.9%.

[0536] Table 7 above is reproduced below and lists the X-ray diffraction peaks observed for Form D of Compound A succinate salt.

[0537] Table 7 - XRPD Peak Positions of Form D of Compound A Succinate Salt

[0538] Position (°2θ) Strength cps° 11.3 1074 12.3 2971 15.2 378 18.5 1582 19.4 2426 21.0 692 22.7 848 24.3 2178 24.7 2637 25.4 973

[0539] Fig.13 Depicted is an XRPD pattern of Form D of Compound A succinate salt.

[0540] Fig.14 Depicted are the DSC thermogram and TGA trace of Form D of Compound A succinate salt.

[0541] Example 8 - Form E of Compound A Succinate Salt

[0542]

[0543] Form E of Compound A succinate salt.

[0544] Form E of Compound A succinate salt was prepared in a manner similar to Examples 12-41 below.

[0545] Form E of Compound A succinate was obtained by stirring in MtBE at 50°C or adding an antisolvent in a MeOH system with moderate crystallinity. One endothermic peak (134.1°C) was detected by DSC. When heated to 125.4°C by TGA, Form E of Compound A succinate lost 0.8% of its mass. 1 HNMR, residual solvent of MtBE was 0.8%.

[0546] Table 8 above is reproduced below and lists the X-ray diffraction peaks observed for Form E of Compound A succinate salt.

[0547] Table 8 - XRPD Peak Positions of Form E of Compound A Succinate Salt

[0548] Position (°2θ) Strength cps° 9.2 773 11.0 285 11.9 2806 14.2 652 15.1 1170 18.0 1309 18.6 993 18.9 1059 23.1 1781 24.1 2603

[0549] Fig.15 Depicted is an XRPD pattern of Form E of Compound A succinate salt.

[0550] Fig.16 Depicted are the DSC thermogram and TGA trace of Form E of Compound A succinate salt.

[0551] General Procedure for Examples 9, 10 and 11

[0552] X-ray powder diffraction (XRPD) data collection strategy: at room temperature, using Cu Kα radiation at 40 kV and 15 mA The XRPD patterns of the samples were recorded on an Aeris X-ray diffractometer (Almelo, the Netherlands) by a Ni monochromator. Data were collected in a continuous scan mode with a step length of 0.02° and a dwell time of 149 seconds in an angle range of 3° to 40° 2θ. The sample was loaded onto a zero background holder and gently pressed with a clean slide to ensure that the sample surface was coplanar with the surface of the holder. The diffraction patterns obtained were analyzed and mapped using HighScore Plus software (V 5.0; Almelo, the Netherlands).

[0553] Thermogravimetric analysis (TGA): Thermogravimetric analysis (TGA) was performed using a Discovery TGA 5500 (New Castle, DE, USA) operated with TRIOS software (version 5.0). TGA was performed using a TU-1000 instrument. The sample was placed in an aluminum pan. The sample cell was purged with dry nitrogen at a flow rate of 15 ml / min. A heating rate of 10°C / min from 25°C to 350°C was used in all experiments.

[0554] Differential Scanning Calorimetry (DSC): The calorimeter was used to measure the temperature of the sample using a Q100 or Discovery DSC 2500 (New Castle, DE, USA) equipped with a refrigerated cooling system (RCS90). Conventional DSC experiments were performed using a TZero instrument (TZero Instruments). The sample cell was purged with dry nitrogen at a flow rate of 50 ml / min. Accurately weighed samples (2-5 mg) placed in a TZero pan with a pin hole were scanned at a heating rate of 10°C / min over the desired temperature range.

[0555] Examples 9 and 10 were prepared by the reactive crystallization procedures described below (eg, Method I, Method II, and Method III).

[0556] Method I Compound A (about 50 mg) and succinic acid (about 13 mg) were suspended in a solvent (about 1-2 mL) and stirred at ambient temperature for about 15 hours. The resulting solid was collected by filtration and then characterized.

[0557] Method II Compound A (about 50 mg) and succinic acid (about 13 mg) were dissolved in a minimum amount of the solvent and stirred at 80 °C. ℃ If necessary, filter the hot solution using a 0.45 μm PTFE syringe filter. Keep the resulting solution at room temperature to induce precipitation of the solid.

[0558] Method III : In a separate vial, 235 mg of succinic acid was dissolved in 20 mL of ethanol and used as a stock solution. Compound A (approximately 50 mg) was dissolved in a minimal amount of solvent. One equivalent of an EtOH solution containing succinic acid was added. The resulting solid was collected by filtration and characterized.

[0559] Example 9 - Form F of Compound A Succinate Salt

[0560]

[0561] Form F of Compound A succinate salt.

[0562] Table 9 above is reproduced below and lists the X-ray diffraction peaks observed for Form F of Compound A succinate salt.

[0563] Table 9 - XRPD Peak Positions of Form F of Compound A Succinate Salt

[0564]

[0565]

[0566] Fig.17 Depicted is an XRPD pattern of Form F of Compound A succinate salt.

[0567] Fig.18 Depicted is the TGA trace of Form F of Compound A succinate salt.

[0568] Fig.19 Depicted is the DSC thermogram of Form F of Compound A succinate salt.

[0569] Example 10 - Form G of Compound A Succinate Salt

[0570]

[0571] Form G of Compound A succinate salt.

[0572] Form G of Compound A succinate salt was prepared by reactive crystallization experiments from a 1:1 v / v CHCl3-MeOH solution.

[0573] Table 10 above is reproduced below and lists the X-ray diffraction peaks observed for Form G of Compound A succinate salt.

[0574] Table 10 - XRPD Peak Positions of Form G of Compound A Succinate Salt

[0575]

[0576]

[0577]

[0578] Fig. 20 Depicted is an XRPD pattern of Form G of Compound A succinate salt.

[0579] Fig.21 Depicted is the TGA trace of Form G of Compound A succinate salt.

[0580] Fig. 22 Depicted is the DSC thermogram of Form G of Compound A succinate salt.

[0581] Example 11 - Single Crystal of Form G of Compound A Succinate Salt

[0582] Structural elucidation by single crystal X-ray diffraction (SCXRD) revealed that Form G of Compound A succinate has one equivalent of CHCl 3 molecule for each molecule of Compound A. This data, along with the TGA data, suggests that CHCl 3 plays a role in stabilizing the Form G crystal lattice.

[0583] Fig.23 Depicted is an X-ray diffraction pattern of a single crystal of Compound A succinate salt, Form G.

[0584] Examples 12-41 were prepared as follows:

[0585] Step (1): Compound A (-30 mg) was added to a reaction vessel (RV1) and charged with solvent (1 mL). The mixture was stirred at room temperature to obtain a clear solution or suspension.

[0586] Step (2): Counterion (~1.1 eq) was charged into a separate reaction vessel (RV2) along with solvent (0.5 mL) to obtain a clear solution or suspension. This solution or suspension was added dropwise into RV1 under stirring.

[0587] Step (3): Heat the mixture in RV1 at 50 ℃ The mixture was stirred for 2 hours and then cooled to 25 ℃ Lasts for 3 hours.

[0588] Step (4): The mixture was centrifuged and the filter cake was dried. The remaining solution of the filter cake was concentrated to 25 °C at atmospheric pressure. ℃ The product was evaporated to give a solid and is characterized below.

[0589] Example 12 - Form A of Compound A Hydrochloride

[0590]

[0591] Form A of Compound A hydrochloride.

[0592] Table 14 lists the X-ray diffraction peaks observed for Form A of Compound A hydrochloride.

[0593] Table 14 - XRPD Peak Positions of Form A of Compound A Hydrochloride

[0594] Position (°2θ) Strength cps° 8.3 1813 12.0 2116 12.7 628 13.9 3271 16.6 815 17.1 2095 19. 392 21.1 716 23.8 513 25.7 3593

[0595] Fig.24 Depicted is an XRPD pattern of Form A of Compound A hydrochloride.

[0596] Fig.25 Depicted are the DSC thermogram and TGA trace of Form A of Compound A hydrochloride.

[0597] Example 13 - Form B of Compound A Hydrochloride

[0598]

[0599] Form B of Compound A hydrochloride salt.

[0600] Table 15 lists the X-ray diffraction peaks observed for Form B of Compound A hydrochloride.

[0601] Table 15 - XRPD Peak Positions of Form B of Compound A Hydrochloride

[0602] Position (°2θ) Strength cps° 9.3 232 11.7 596 12.1 312 16.2 564 22.2 401 23.1 561 25.6 489 25.7 552 26.4 807 32.9 297

[0603] Fig.26 Depicted is the XRPD pattern of Form B of Compound A hydrochloride salt.

[0604] Fig. 27 Depicted are the DSC thermogram and TGA trace of Form B of Compound A hydrochloride.

[0605] Example 14 - Form C of Compound A Hydrochloride

[0606]

[0607] Form C of Compound A hydrochloride.

[0608] Table 16 lists the X-ray diffraction peaks observed for Form C of Compound A hydrochloride.

[0609] Table 16 - XRPD Peak Positions of Form C of Compound A Hydrochloride

[0610] Position (°2θ) Strength cps° 8.2 495 10.3 684 11.7 303 13.4 385 19.4 479 24.3 888 25.2 1429

[0611] Fig.28 Depicted is an XRPD pattern of Form C of Compound A hydrochloride salt.

[0612] Fig.29 Depicted are the DSC thermogram and TGA trace of Form C of Compound A hydrochloride.

[0613] Example 15 - Form D of Compound A Hydrochloride

[0614]

[0615] Form D of Compound A hydrochloride salt.

[0616] Table 17 lists the X-ray diffraction peaks observed for Form D of Compound A hydrochloride.

[0617] Table 17 - XRPD Peak Positions of Form D of Compound A Hydrochloride

[0618] Position (°2θ) Strength cps° 5.5 556 7.9 238 9.3 62 9.6 403 11.0 2200 13.2 107 13.8 274 15.9 92 16.6 178 23.8 482

[0619] Fig.30 Depicted is an XRPD pattern of Form D of Compound A hydrochloride salt.

[0620] Fig.31 Depicted are the DSC thermogram and TGA trace of Form D of Compound A hydrochloride.

[0621] Example 16 - Form E of Compound A Hydrochloride

[0622]

[0623] Form E of Compound A hydrochloride.

[0624] Table 18 lists the X-ray diffraction peaks observed for Form E of Compound A hydrochloride.

[0625] Table 18 - XRPD Peak Positions of Form E of Compound A Hydrochloride

[0626] Position (°2θ) Strength cps° 12.0 3107 14.0 3451 15.6 437 16.6 708 17.1 990 17.3 789 21.1 622 23.8 1047 25.6 1088 26.6 472

[0627] Fig.32 Depicted is an XRPD pattern of Form E of Compound A hydrochloride.

[0628] Fig.33 Depicted are the DSC thermogram and TGA trace of Form E of Compound A hydrochloride.

[0629] Example 17 - Form F of Compound A Hydrochloride

[0630]

[0631] Form F of Compound A hydrochloride.

[0632] Table 19 lists the X-ray diffraction peaks observed for Form F of Compound A hydrochloride.

[0633] Table 19 - XRPD Peak Positions of Form F of Compound A Hydrochloride

[0634] Position (°2θ) Strength cps° 8.4 599 9.7 299 12.3 2072 15.6 487 17.6 481 20.2 728 23.6 612 25.0 1078 26.1 271 34.7 151

[0635] Fig.34 Depicted is an XRPD pattern of Form F of Compound A hydrochloride.

[0636] Fig.35 Depicted are the DSC thermogram and TGA trace of Form F of Compound A hydrochloride.

[0637] Example 18 - Form A of the maleate salt of Compound A

[0638]

[0639] Form A of the maleate salt of Compound A.

[0640] Table 20 lists the X-ray diffraction peaks observed for Form A of Compound A maleate salt.

[0641] Table 20 - XRPD Peak Positions of Form A of Compound A Maleate Salt

[0642] Position (°2θ) Strength cps° 12.2 2285 17.2 1123 17.7 1056 18.4 888 21.1 1206 22.2 1216 22.8 1068 24.5 2972 26.0 1122 31.6 2362

[0643] Fig.36 Depicted is the XRPD pattern of Form A of Compound A maleate salt.

[0644] Fig.37 Depicted are the DSC thermogram and TGA trace of Form A of Compound A maleate salt.

[0645] Example 19 - Form A of Compound A Sulfate

[0646]

[0647] Form A of Compound A Sulfate.

[0648] Table 21 lists the X-ray diffraction peaks observed for Form A of Compound A Sulfate.

[0649] Table 21 - XRPD Peak Positions of Form A of Compound A Sulfate

[0650] Position (°2θ) Strength cps° 4.7 95 8.0 1131 11.7 508 14.7 770 17.6 166 20.2 953 24.7 613 26.4 2418

[0651] Fig.38 Depicted is an XRPD pattern of Form A of Compound A sulfate salt.

[0652] Fig.39 Depicted are the DSC thermogram and TGA trace of Form A of Compound A sulfate.

[0653] Example 20 - Form B of Compound A Sulfate Salt

[0654]

[0655] Form B of Compound A sulfate salt.

[0656] Table 22 lists the X-ray diffraction peaks observed for Form B of Compound A sulfate.

[0657] Table 22 - XRPD Peak Positions of Form B of Compound A Sulfate Salt

[0658] Position (°2θ) Strength cps° 12.0 3693 13.6 272 13.9 1171 15.6 656 18.9 396 22.5 370 23.8 583 31.7 1010 32.0 572 33.7 1109

[0659] Fig.40 An XRPD pattern of Form B of Compound A sulfate salt is depicted.

[0660] Fig.41 Depicted are the DSC thermogram and TGA trace of Form B of Compound A sulfate salt.

[0661] Example 21 - Form C of Compound A Sulfate Salt

[0662]

[0663] Form C of Compound A sulfate.

[0664] Table 23 lists the X-ray diffraction peaks observed for Form C of Compound A Sulfate Salt.

[0665] Table 23 - XRPD Peak Positions of Form C of Compound A Sulfate Salt

[0666] Position (°2θ) Strength cps° 7.7 202 8.1 444 9.1 421 11.4 211 11.8 377 15.7 496 18.9 176 25.3 531 25.9 629 33.7 453

[0667] Fig.42 Depicted is an XRPD pattern of Form C of Compound A sulfate salt.

[0668] Fig.43 Depicted are the DSC thermogram and TGA trace of Form C of Compound A sulfate.

[0669] Example 22 - Form A of Compound A Phosphate Salt

[0670]

[0671] Form A of Compound A phosphate salt.

[0672] Table 24 lists the X-ray diffraction peaks observed for Form A of Compound A phosphate salt.

[0673] Table 24 - XRPD Peak Positions of Form A of Compound A Phosphate Salt

[0674] Position (°2θ) Strength cps° 9.4 1620 11.1 125 13.3 766 19.0 695 22.0 330 24.6 3654 27.3 533

[0675] Fig.44 Depicted is an XRPD pattern of Form A of Compound A phosphate salt.

[0676] Fig.45 Depicted are the DSC thermogram and TGA trace of Form A of Compound A phosphate salt.

[0677] Example 23 - Form A of the L-tartrate salt of Compound A

[0678]

[0679] Compound A L-tartrate salt Form A.

[0680] Table 25 lists the X-ray diffraction peaks observed for Form A of Compound A L-tartrate salt.

[0681] Table 25 - XRPD Peak Positions of Form A of Compound A L-Tartrate Salt

[0682] Position (°2θ) Strength cps° 4.6 311 4.9 673 8.3 528 8.7 2198 9.4 908 11.6 809 15.0 756 20.6 258 24.1 926 27.1 961

[0683] Fig.46 Depicted is the XRPD pattern of Form A of the Compound A L-tartrate salt.

[0684] Fig.47 Depicted are the DSC thermogram and TGA trace of Form A of Compound A L-tartrate salt.

[0685] Example 24 - Form A of Compound A Fumarate Salt

[0686]

[0687] Form A of Compound A fumarate salt.

[0688] Table 26 lists the X-ray diffraction peaks observed for Form A of Compound A fumarate salt.

[0689] Table 26 - XRPD Peak Positions of Form A of Compound A Fumarate Salt

[0690] Position (°2θ) Strength cps° 5.6 2046 7.9 1823 10.8 303 11.5 3759 13.4 897 17.2 910 19.3 745 24.3 2241 25.2 781 26.0 1330

[0691] Fig.48 Depicted is the XRPD pattern of Form A of Compound A fumarate salt.

[0692] Fig.49 Depicted are the DSC thermogram and TGA trace of Form A of Compound A fumarate salt.

[0693] Example 25 - Form B of the Fumarate Salt of Compound A

[0694]

[0695] Form B of the fumarate salt of Compound A.

[0696] Table 27 lists the X-ray diffraction peaks observed for Form B of Compound A fumarate salt.

[0697] Table 27 - XRPD Peak Positions of Form B of Compound A Fumarate Salt

[0698] Position (°2θ) Strength cps° 5.3 2061 5.8 954 9.0 770 10.9 549 11.9 2525 18.1 1207 18.6 420 20.3 734 23.6 3515 24.3 602

[0699] Fig.50 Depicted is the XRPD pattern of Form B of Compound A fumarate salt.

[0700] Fig.51 Depicted are the DSC thermogram and TGA trace of Form B of Compound A fumarate salt.

[0701] Example 26 - Form C of Compound A Fumarate Salt

[0702]

[0703] Form C of the fumarate salt of Compound A.

[0704] Table 28 lists the X-ray diffraction peaks observed for Form C of Compound A fumarate salt.

[0705] Table 28 - XRPD Peak Positions of Form C of Compound A Fumarate Salt

[0706] Position (°2θ) Strength cps° 5.3 638 5.8 1250 7.5 1137 9.6 2075 10.4 2093 12.1 1777 14.7 686 16.1 536 22.4 936 24.5 1674

[0707] Fig.52 Depicted is the XRPD pattern of Form C of Compound A fumarate salt.

[0708] Fig.53 Depicted are the DSC thermogram and TGA trace of Form C of Compound A fumarate salt.

[0709] Example 27 - Form D of Compound A Fumarate Salt

[0710]

[0711] Compound A fumarate salt form D

[0712] Table 29 lists the X-ray diffraction peaks observed for Form D of Compound A fumarate salt.

[0713] Table 29 - XRPD Peak Positions of Form D of Compound A Fumarate Salt

[0714] Position (°2θ) Strength cps° 4.0 481 5.0 1647 5.6 1973 6.1 1191 9.4 757 11.4 1163 12.3 3245 12.7 1342 18.7 1919 24.0 3405

[0715] Fig.54 Depicted is the XRPD pattern of Form D of Compound A fumarate salt.

[0716] Fig.55 Depicted are the DSC thermogram and TGA trace of Form D of Compound A fumarate salt.

[0717] Example 28 - Form A of Compound A Citrate Salt

[0718]

[0719] Compound A citrate salt Form A.

[0720] Table 30 lists the X-ray diffraction peaks observed for Form D of Compound A citrate salt.

[0721] Table 30 - XRPD Peak Positions of Form A of Compound A Citrate Salt

[0722] Position (°2θ) Strength cps° 12.4 3192 26.3 1495

[0723] Fig.56 Depicted is an XRPD pattern of Form A of Compound A citrate salt.

[0724] Fig.57 Depicted are the DSC thermogram and TGA trace of Form A of Compound A citrate salt.

[0725] Example 29 - Compound A L-malate Form A

[0726]

[0727] Compound A L-malate salt, Form A.

[0728] Table 31 lists the X-ray diffraction peaks observed for Form A of Compound A L-malate salt.

[0729] Table 31 - XRPD Peak Positions of Form A of Compound A L-Malate Salt

[0730] Position (°2θ) Strength cps° 26.1 58801 66.0 985158

[0731] Fig.58 Depicted is the XRPD pattern of Form A of Compound A L-malate salt.

[0732] Fig.59 Depicted are the DSC thermogram and TGA trace of Form A of Compound A L-malate salt.

[0733] Example 30 - Form A of Compound A Methanesulfonate

[0734]

[0735] Form A of the mesylate salt of Compound A.

[0736] Table 32 lists the X-ray diffraction peaks observed for Form A of Compound A mesylate salt.

[0737] Table 32 - XRPD Peak Positions of Form A of Compound A Methanesulfonate

[0738] Position (°2θ) Strength cps° 10.6 322 21.7 141 23.4 323 26.1 935

[0739] Fig.60 Depicted is the XRPD pattern of Form A of the mesylate salt of Compound A.

[0740] Fig.61 Depicted are the DSC thermogram and TGA trace of Form A of Compound A mesylate salt.

[0741] Example 31 - Form B of the mesylate salt of Compound A

[0742]

[0743] Form B of the mesylate salt of Compound A.

[0744] Table 33 lists the X-ray diffraction peaks observed for Form B of Compound A mesylate salt.

[0745] Table 33 - XRPD Peak Positions of Form B of Compound A Mesylate Salt

[0746] Position (°2θ) Strength cps° 10.7 1262 11.3 411 12.0 631 15.9 255 17.0 417 18.1 694 19.3 1147 21.8 881 23.4 1196 24.3 373

[0747] Fig.62 Depicted is the XRPD pattern of Form B of the mesylate salt of Compound A.

[0748] Fig.63 Depicted are the DSC thermogram and TGA trace of Form B of Compound A mesylate salt.

[0749] Example 32 - Form A of Compound A Ethylate

[0750]

[0751] Form A of Compound A ethanesulfonate salt.

[0752] Table 34 lists the X-ray diffraction peaks observed for Form A of Compound A esylate salt.

[0753] Table 34 - XRPD Peak Positions of Form A of Compound A Ethylate Salt

[0754] Position (°2θ) Strength cps° 8.0 378 8.6 397 10.5 1452 11.2 323 12.4 547 16.5 506 19.9 1235 21.1 921 22.8 391 24.5 477

[0755] Fig.64 Depicted is the XRPD pattern of Form A of the esylate salt of Compound A.

[0756] Fig.65 Depicted are the DSC thermogram and TGA trace of Form A of Compound A ethanesulfonate salt.

[0757] Example 33 - Form B of Compound A Ethylate Salt

[0758]

[0759] Form B of Compound A ethanesulfonate salt.

[0760] Table 35 lists the X-ray diffraction peaks observed for Form B of Compound A esylate salt.

[0761] Table 35 - XRPD Peak Positions of Form B of Compound A Ethylate Salt

[0762] Position (°2θ) Strength cps° 5.3 107 7.4 598 8.3 429 10.6 919 11.7 2359 15.6 267 17.6 186 18.8 767 22.9 328

[0763] Fig.66 Depicted is the XRPD pattern of Form B of the esylate salt of Compound A.

[0764] Fig.67 Depicted are the DSC thermogram and TGA trace of Form B of the esylate salt of Compound A.

[0765] Example 34 - Form A of Compound A Tosylate Salt

[0766]

[0767] Form A of the tosylate salt of Compound A.

[0768] Table 36 lists the X-ray diffraction peaks observed for Form A of Compound A tosylate.

[0769] Table 36 - XRPD Peak Positions of Form A of Compound A Tosylate Salt

[0770] Position (°2θ) Strength cps° 5.6 1228 6.6 2832 11.4 1280 12.7 692 16.9 2123 17.2 1488 19.1 1009 20.8 1638 25.5 1661 26.3 1727

[0771] Fig.68 Depicted is the XRPD pattern of Form A of the tosylate salt of Compound A.

[0772] Fig.69 Depicted are the DSC thermogram and TGA trace of Form A of Compound A tosylate salt.

[0773] Example 35 - Form B of Compound A Tosylate Salt

[0774]

[0775] Form B of the tosylate salt of Compound A.

[0776] Table 37 lists the X-ray diffraction peaks observed for Form B of Compound A tosylate salt.

[0777] Table 37 - XRPD Peak Positions of Form B of Compound A Tosylate Salt

[0778] Position (°2θ) Strength cps° 5.6 1228 6.6 2832 11.4 1280 12.7 692 16.9 2123 17.2 1488 19.1 1009 20.8 1638 25.5 1661 26.3 1727

[0779] Fig.70Depicted is the XRPD pattern of Form B of the tosylate salt of Compound A.

[0780] Fig.71 Depicted are the DSC thermogram and TGA trace of Form B of Compound A tosylate salt.

[0781] Example 36 - Form A of Compound A Glutarate

[0782]

[0783] Form A of Compound A glutarate salt.

[0784] Table 38 lists the X-ray diffraction peaks observed for Form A of Compound A glutarate salt.

[0785] Table 38 - XRPD Peak Positions of Form A of Compound A Glutarate

[0786] Position (°2θ) Strength cps° 8.5 3509 13.3 571 14.6 209 15.7 165 16.8 401 18.2 231 20.8 219 22.8 240 25.0 620 34.9 423

[0787] Fig.72 Depicted is an XRPD pattern of Form A of Compound A glutarate salt.

[0788] Example 37 - Form A of Compound A Acetate Salt

[0789]

[0790] Form A of Compound A acetate salt.

[0791] Table 39 lists the X-ray diffraction peaks observed for Form A of Compound A acetate.

[0792] Table 39 - XRPD Peak Positions of Form A of Compound A Acetate Salt

[0793] Position (°2θ) Strength cps° 8.5 199 13.9 784 15.9 203 22.2 344 23.6 158 26.2 434

[0794] Fig.73 Depicted is an XRPD pattern of Form A of Compound A acetate salt.

[0795] Fig.74 Depicted are the DSC thermogram and TGA trace of Form A of Compound A acetate salt.

[0796] Example 38 - Form A of Compound A Malonate

[0797]

[0798] Form A of Compound A malonate salt.

[0799] Table 40 lists the X-ray diffraction peaks observed for Form A of Compound A malonate salt.

[0800] Table 40 - XRPD Peak Positions of Form A of Compound A Malonate Salt

[0801] Position (°2θ) Strength cps° 10.3 591 11.4 1530 12.6 892 14.6 464 15.2 1791 17.4 195 18.7 1485 20.0 176 21.9 662 26.9 1662

[0802] Fig.75 Depicted is the XRPD pattern of Form A of Compound A malonate salt.

[0803] Example 39 - Form B of Compound A Malonate Salt

[0804]

[0805] Form B of the malonate salt of Compound A.

[0806] Table 41 lists the X-ray diffraction peaks observed for Form B of Compound A malonate salt.

[0807] Table 41 - XRPD Peak Positions of Form B of Compound A Malonate

[0808] Position (°2θ) Strength cps° 7.8 1768 9.6 3145 10.8 853 12.2 1736 12.9 933 14.7 2858 21.2 1217 23.0 1401 24.6 721 25.6 1721

[0809] Fig.76 Depicted is the XRPD pattern of Form B of Compound A malonate salt.

[0810] Example 40 - Form A of Compound A Sebacate

[0811]

[0812] Form A of Compound A sebacate salt.

[0813] Table 42 lists the X-ray diffraction peaks observed for Form A of Compound A sebacate.

[0814] Table 42 - XRPD Peak Positions of Form A of Compound A Sebacate Salt

[0815] Position (°2θ) Strength cps° 7.5 3199 9.4 576 11.7 694 12.5 1362 13.5 982 16.9 2456 17.2 4806 19.1 1991 22.8 1186 25.6 740

[0816] Fig.77 Depicted is the XRPD pattern of Form A of Compound A sebacate salt.

[0817] Fig.78 Depicted are the DSC thermogram and TGA trace of Form A of Compound A sebacate salt.

[0818] Example 41 - Form A of Compound A Acetoglycinate

[0819]

[0820] Form A of Compound A acetylglycinate.

[0821] Table 43 lists the X-ray diffraction peaks observed for Form A of Compound A acetylglycinate.

[0822] Table 43 - XRPD Peak Positions of Form A of Compound A Aceglycinate

[0823] Position (°2θ) Strength cps° 13.3 934 14.6 544 15.7 459 16.3 556 17.1 266 18.1 482 19.9 726 21.0 611 22.8 1463 23.5 789

[0824] Fig.79 Depicted is an XRPD pattern of Form A of Compound A acetylglycinate.

[0825] Fig.80 Depicted are the DSC thermogram and TGA trace of Form A of Compound A acetylglycinate.

[0826] Example 42 - Form A of Compound A Acetoglycinate

[0827]

[0828] Form B of Compound A acetylglycinate.

[0829] Table 44 lists the X-ray diffraction peaks observed for Form B of Compound A acetylglycinate.

[0830] Table 44 - XRPD Peak Positions of Form B of Compound A Aceglycinate

[0831] Position (°2θ) Strength cps° 14.4 142 15.0 406 16.6 153 18.1 176 21.0 223 21.3 176 21.9 118 27.0 104 29.6 285 38.9 146

[0832] Fig.81 Depicted is the XRPD pattern of Form B of Compound A acetylglycinate.

[0833] Fig.82 Depicted are the DSC thermogram and TGA trace of Form B of Compound A acetylglycinate.

[0834] Although we have described several embodiments of the present invention, it is apparent that the basic examples can be altered to provide other embodiments utilizing the compounds and methods of the present invention. It will be understood, therefore, that the scope of the present invention will be defined by the claims rather than by the specific embodiments that have been shown by way of example.

Claims

1. A compound A: Its form is A, B or C.

2. The compound according to claim 1, wherein the compound is crystalline.

3. The compound of claim 1, wherein the compound is a crystalline solid substantially free of amorphous Compound A succinate.

4. The compound of claim 1, wherein the compound is substantially free of impurities.

5. The compound according to claim 1, which has one or more peaks selected from the group consisting of peaks at 11.5, 12.9 and 23.5 ± 0.2 degrees θ in its XRPD.

6. The compound according to claim 1, which has two or more peaks selected from the peaks at 11.5, 12.9 and 23.5 ± 0.2 degrees θ in its XRPD. 7 . The compound according to claim 1 , which has three or more peaks selected from the group consisting of peaks at 11.5, 12.9, and 23.5±0.2 degrees θ in its XRPD.

8. The compound of claim 5, wherein the compound is in Form A.

9. The compound of claim 1 having an XRPD substantially similar to the XRPD depicted in Figure 1.

10. The compound of claim 1, which has one or more peaks in its XRPD selected from the group consisting of peaks at 17.8, 18.3, and 20.8 ± 0.2 degrees θ.

11. The compound according to claim 1, which has two or more peaks selected from peaks at 17.8, 18.3 and 20.8 ± 0.2 degrees θ in its XRPD.

12. The compound of claim 1, having three or more peaks in its XRPD selected from the group consisting of peaks at about 17.8, 18.3, and 20.8 ± 0.2 degrees θ.

13. The compound of claim 10, wherein the compound is in Form B.

14. The compound of claim 1 having an XRPD substantially similar to the XRPD depicted in Figure 3.

15. The compound of claim 1, having one or more peaks in its XRPD selected from the group consisting of peaks at 16.4, 22.9, and 31.6 ± 0.2 degrees θ.

16. The compound of claim 1, which has two or more peaks in its XRPD selected from the group consisting of peaks at 16.4, 22.9, and 31.6 ± 0.2 degrees θ.

17. The compound according to claim 1, which has three or more peaks selected from the group consisting of peaks at 16.4, 22.9, and 31.6 ± 0.2 degrees θ in its XRPD.

18. The compound of claim 15, wherein the compound is in Form C.

19. The compound of claim 1 having an XRPD substantially similar to the XRPD depicted in Figure 5.

20. A succinate salt of compound A:

21. The compound of claim 20, wherein the compound is crystalline.

22. The compound of claim 20, wherein the compound is a crystalline solid substantially free of amorphous Compound A succinate.

23. The compound of claim 20, wherein the compound is substantially free of impurities.

24. The compound of claim 20, having one or more peaks in its XRPD selected from the group consisting of peaks at 8.1, 11.6, and 24.4 ± 0.2 degrees θ.

25. The compound of claim 20, which has at least two peaks in its XRPD selected from the group consisting of peaks at 8.1, 11.6, and 24.4 ± 0.2 degrees θ.

26. The compound of claim 20, which has at least three peaks in its XRPD selected from the group consisting of peaks at 8.1, 11.6, and 24.4 ± 0.2 degrees θ.

27. The compound of claim 26, wherein the compound is in Form A.

28. The compound of claim 20 having an XRPD substantially similar to the XRPD depicted in Figure 7.

29. The compound of claim 20, having one or more peaks in its XRPD selected from the group consisting of peaks at 18.6, 24.1, and 24.6 ± 0.2 degrees 2θ.

30. The compound of claim 20, having in its XRPD at least two peaks selected from the group consisting of peaks at 18.6, 24.1, and 24.6 ± 0.2 degrees 2θ.

31. The compound of claim 20, having in its XRPD at least three peaks selected from the group consisting of peaks at 18.6, 24.1, and 24.6 ± 0.2 degrees 2θ.

32. The compound of claim 29, wherein the compound is in Form B.

33. The compound of claim 20 having an XRPD substantially similar to the XRPD depicted in Figure 9.

34. The compound of claim 20, having one or more peaks in its XRPD selected from the group consisting of peaks at 9.2, 11.9, and 18.9 ± 0.2 degrees 2θ.

35. The compound of claim 20, having in its XRPD at least two peaks selected from the group consisting of peaks at 9.2, 11.9, and 18.9 ± 0.2 degrees 2θ.

36. The compound of claim 20, having in its XRPD at least three peaks selected from the group consisting of peaks at 9.2, 11.9, and 18.9 ± 0.2 degrees 2θ.

37. The compound of claim 34, wherein the compound is in Form C.

38. The compound of claim 20 having an XRPD substantially similar to the XRPD depicted in Figure 11.

39. The compound of claim 20, having one or more peaks in its XRPD selected from the group consisting of peaks at 12.3, 19.4, and 24.7 ± 0.2 degrees 2θ.

40. The compound of claim 20, having in its XRPD at least two peaks selected from the group consisting of peaks at 12.3, 19.4, and 24.7 ± 0.2 degrees 2θ.

41. The compound of claim 20, having in its XRPD at least three peaks selected from the group consisting of peaks at 12.3, 19.4, and 24.7 ± 0.2 degrees 2θ.

42. The compound of claim 39, wherein the compound is in Form D.

43. The compound of claim 20 having an XRPD substantially similar to the XRPD depicted in Figure 13.

44. The compound of claim 20, having one or more peaks in its XRPD selected from the group consisting of peaks at 11.9, 23.1, and 24.1 ± 0.2 degrees 2θ.

45. The compound of claim 20, having in its XRPD at least two peaks selected from the group consisting of peaks at 11.9, 23.1, and 24.1 ± 0.2 degrees 2θ.

46. ​​The compound of claim 20, having in its XRPD at least three peaks selected from the group consisting of peaks at 11.9, 23.1, and 24.1 ± 0.2 degrees 2θ.

47. The compound of claim 44, wherein the compound is in Form E.

48. The compound of claim 20 having an XRPD substantially similar to the XRPD depicted in Figure 15.

49. The compound of claim 20, having one or more peaks in its XRPD selected from the group consisting of peaks at 6.0, 12.5, and 24.5 ± 0.2 degrees 2θ.

50. The compound of claim 20, having in its XRPD at least two peaks selected from the group consisting of peaks at 6.0, 12.5, and 24.5 ± 0.2 degrees 2Θ.

51. The compound of claim 20, having in its XRPD at least three peaks selected from the group consisting of peaks at 6.0, 12.5, and 24.5 ± 0.2 degrees 2θ.

52. The compound of claim 49, wherein the compound is in Form F.

53. The compound of claim 20 having an XRPD substantially similar to the XRPD depicted in Figure 17.

54. The compound of claim 20, having one or more peaks in its XRPD selected from the group consisting of peaks at 6.0, 15.3, and 23.4 ± 0.2 degrees 2θ.

55. The compound of claim 20, having in its XRPD at least two peaks selected from the group consisting of peaks at 6.0, 15.3, and 23.4 ± 0.2 degrees 2θ.

56. The compound of claim 20, having in its XRPD at least three peaks selected from the group consisting of peaks at 6.0, 15.3, and 23.4 ± 0.2 degrees 2θ.

57. The compound of claim 54, wherein the compound is in Form G.

58. The compound of claim 20 having an XRPD substantially similar to the XRPD depicted in Figure 20.

59. A pharmaceutical composition comprising a compound according to any one of the preceding claims or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

60. A method of inhibiting CDK4 and CDK6, the method comprising a compound according to any one of claims 1 to 58 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 59.

61. A method for treating a CDK4-mediated and CDK6-mediated disorder in a patient in need thereof, the method comprising administering to the patient a compound according to any one of claims 1 to 58 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 59.

62. The method of claim 61, wherein the CDK4-mediated and CDK6-mediated disorder is cancer.

63. The method of claim 62, wherein the cancer is breast cancer, a malignant brain tumor, colon cancer, small cell lung cancer, non-small cell lung cancer, bladder cancer, ovarian cancer, prostate cancer, chronic lymphoid leukemia, lymphoma, myeloma, acute myeloid leukemia, secondary pancreatic cancer, or secondary brain metastasis.

64. The method of claim 63, wherein the breast cancer is HR+ / HER2- or HR+ / HER2+ advanced or metastatic breast cancer; and the malignant brain tumor is a glioblastoma, astrocytoma, or pontine glioma.

65. The method of any one of claims 60 to 64, wherein the patient is administered a pharmaceutical composition according to claim 59.

66. The method of any one of claims 60 to 65, wherein the administration is oral administration.

67. The method of any one of claims 60 to 66, further comprising administering an additional therapeutic agent to the patient.

68. The method of claim 67, wherein the additional therapeutic agent is a PRMT5 inhibitor, a HER2 kinase inhibitor, an aromatase inhibitor, an estrogen receptor antagonist, or an alkylating agent.

69. The method of claim 68, wherein the aromatase inhibitor is letrozole.

70. The method of claim 68, wherein the estrogen receptor antagonist is fulvestrant.

71. The method of claim 68, wherein the alkylating agent is temozolomide.

72. A method for preparing a salt compound of formula X: The method comprises the following steps: A: and combining with an acid and optionally a solvent under conditions to form a salt compound of Formula X.

73. The method of claim 72, wherein the acid is succinic acid, thereby forming a succinate salt of Compound A, and optionally causing the succinate salt to crystallize in Form A, Form B, Form C, Form D, Form E, Form F, or Form G.

74. A pharmaceutical salt of compound A: The salt is hydrochloride, sulfate, maleate, phosphate, L-tartrate, fumarate, citrate, L-malate, toluenesulfonate, succinate, methanesulfonate, ethanesulfonate, glutarate, n-acetylglycinate, acetate, malonate or sebacate.

75. The pharmaceutical salt of Compound A according to claim 74, which is a hydrochloride salt in an amorphous form.

76. The pharmaceutical salt of Compound A according to claim 74, which is a hydrochloride salt in a crystalline form.

77. The pharmaceutical salt of Compound A according to claim 74, which is a sulfate salt in an amorphous form.

78. The pharmaceutical salt of Compound A according to claim 74, which is a sulfate salt in crystalline form.

79. The pharmaceutical salt of Compound A according to claim 74, which is a maleate salt in an amorphous form.

80. The pharmaceutical salt of Compound A according to claim 74, which is a maleate salt in a crystalline form.

81. The pharmaceutical salt of Compound A according to claim 74, which is a phosphate salt in an amorphous form.

82. The pharmaceutical salt of Compound A according to claim 74, which is a phosphate salt in crystalline form.

83. The pharmaceutical salt of Compound A according to claim 74, which is L-tartrate in an amorphous form.

84. The pharmaceutical salt of Compound A according to claim 74, which is L-tartrate in crystalline form.

85. The pharmaceutical salt of Compound A according to claim 74, which is a fumarate salt in an amorphous form.

86. The pharmaceutical salt of Compound A according to claim 74, which is a fumarate salt in a crystalline form.

87. The pharmaceutical salt of Compound A according to claim 74, which is a citrate salt in an amorphous form.

88. The pharmaceutical salt of Compound A according to claim 74, which is a citrate salt in a crystalline form.

89. The pharmaceutical salt of Compound A according to claim 74, which is L-malate in an amorphous form.

90. The pharmaceutical salt of Compound A according to claim 74, which is an L-malate salt in a crystalline form.

91. The pharmaceutical salt of Compound A according to claim 74, which is a tosylate salt in an amorphous form.

92. The pharmaceutical salt of Compound A according to claim 74, which is a tosylate salt in crystalline form.

93. The pharmaceutical salt of Compound A according to claim 74, which is a succinate salt in an amorphous form.

94. The pharmaceutical salt of Compound A according to claim 74, which is a succinate salt in crystalline form.

95. The pharmaceutical salt of Compound A according to claim 74, which is a mesylate salt in an amorphous form.

96. The pharmaceutical salt of Compound A according to claim 74, which is a mesylate salt in crystalline form.

97. The pharmaceutical salt of Compound A according to claim 74, which is an ethanesulfonate salt in an amorphous form.

98. The pharmaceutical salt of Compound A according to claim 74, which is an ethanesulfonate salt in a crystalline form.

99. The pharmaceutical salt of Compound A according to claim 74, which is a glutarate salt in an amorphous form.

100. The pharmaceutical salt of Compound A according to claim 74, which is a glutarate salt in a crystalline form.

101. The pharmaceutical salt of Compound A according to claim 74, which is n-acetylglycine salt in an amorphous form.

102. The pharmaceutical salt of Compound A according to claim 74, which is n-acetylglycine salt in crystalline form.

103. The pharmaceutical salt of Compound A according to claim 74, which is an acetate salt in an amorphous form.

104. The pharmaceutical salt of Compound A according to claim 74, which is an acetate salt in a crystalline form.

105. The pharmaceutical salt of Compound A according to claim 74, which is a malonate salt in an amorphous form.

106. The pharmaceutical salt of Compound A according to claim 74, which is a malonate salt in a crystalline form.

107. The pharmaceutical salt of Compound A according to claim 74, which is a sebacate salt in an amorphous form.

108. The pharmaceutical salt of Compound A according to claim 74, which is a sebacate salt in crystalline form.

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