Polymorphic compounds and uses thereof

Abstract

The present invention provides free base and salt forms useful for treating a variety of CDK4- and CDK6-mediated disorders, such as cancer, by administration of small molecule therapeutics 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 their use. [Background technology]

[0002] Cyclin-dependent kinases (CDKs) are a family of conserved serine / threonine kinases that play key roles in cell cycle and gene transcription regulation (Malumbres 2014). Among the cell cycle CDK subfamily, CDK4 and CDK6 are master regulators that control the entry of cells from the first gap phase (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 RB1-containing transcriptional repressor complexes from E2F transcription factors, leading to the activation of E2F-regulated cell cycle genes and cell cycle progression (Lapenna and Giordano 2009, Asghar, Witkiewicz et al. 2015).

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

[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 aggressive primary brain tumor 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 alternates in the majority of gliomas and represents one of the most disrupted pathways (Cancer Genome Atlas Research 2008, Brennan, Verhaak et al. 2013), suggesting that CDK4 / 6 may be a good target for GBM. Meanwhile, brain metastases can arise from an estimated 20% of all cancer patients, yet still lack effective treatments (Achrol, Rennert et al. 2019). Interestingly, genomic studies have also identified the CDK pathway as one of the three most altered actionable genetic alterations in brain metastases (Brastianos, Carter et al. 2015, Valiente, Ahluwalia et al. 2018). However, despite positive preclinical data supporting targeting CDK4 / 6 to treat GBM (Yin, Li et al. 2018, Bronner, Merrick et al. 2019) and early 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 is still in its infancy or has failed (Anders, Rhun et al. 2019, Nguyen, Searle et al. 2019, Sahebjam, Le Rhun et al. 2019), likely due to an inability to cross the blood-brain barrier (BBB) ​​(de Gooijer, 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] The compounds of the present invention and compositions thereof have been found to be useful for treating, preventing, and / or reducing the risk of diseases, disorders, or conditions in CDK4- and CDK6-mediated disorders. Such compounds are represented by the following chemical structure, designated Compound A: [ka] A or a pharma- ceutically acceptable salt thereof.

[0007] The compounds of the present invention and pharma- ceutically acceptable compositions thereof are useful for treating a variety of diseases, disorders, or conditions associated with CDK4- and CDK6-mediation, including those described herein. [Brief description of the drawings]

[0008] [Figure 1] FIG. 1 shows the XRPD pattern of Compound A, free base form A.

[0009] [Diagram 2] FIG. 2 shows the DSC thermogram and TGA trace of Compound A, free base form A.

[0010] [Diagram 3] FIG. 3 shows the XRPD pattern of Compound A, free base form B.

[0011] [Figure 4] FIG. 4 shows the DSC thermogram and TGA trace of Compound A, free base form B.

[0012] [Diagram 5] FIG. 5 shows the XRPD pattern of Compound A, free base form C.

[0013] [Figure 6] FIG. 6 shows the DSC thermogram and TGA trace of Compound A, free base form C.

[0014] [Figure 7] FIG. 7 shows the XRPD pattern of Compound A, succinate salt Form A.

[0015] [Figure 8] FIG. 8 shows the DSC thermogram and TGA trace of Compound A, succinate salt Form A.

[0016] [Figure 9] FIG. 9 shows the XRPD pattern of Compound A, succinate salt form B.

[0017] [Figure 10] FIG. 10 shows the DSC thermogram and TGA trace of Compound A, succinate salt form B.

[0018] [Figure 11] FIG. 11 shows the XRPD pattern of Compound A, succinate salt Form C.

[0019] [Figure 12] FIG. 12 shows the DSC thermogram and TGA trace of Compound A, succinate salt Form C.

[0020] [Figure 13] FIG. 13 shows the XRPD pattern of Compound A, succinate salt Form D.

[0021] [Figure 14] FIG. 14 shows the DSC thermogram and TGA trace of Compound A, succinate salt Form D.

[0022] [Figure 15] FIG. 15 shows the XRPD pattern of Compound A, succinate salt form E.

[0023] [Figure 16] FIG. 16 shows the DSC thermogram and TGA trace of Compound A, succinate salt form E.

[0024] [Figure 17] FIG. 17 shows the XRPD pattern of Compound A, succinate salt form F.

[0025] [Figure 18] FIG. 18 shows the DSC thermogram and TGA trace of Compound A, succinate salt form F.

[0026] [Figure 19] FIG. 19 shows the DSC thermogram and TGA trace of Compound A, succinate salt form F.

[0027] [Figure 20] FIG. 20 shows the XRPD pattern of Compound A, succinate salt form G.

[0028] [Figure 21] FIG. 21 shows the DSC thermogram and TGA trace of Compound A, succinate salt form G.

[0029] [Figure 22] FIG. 22 shows the DSC thermogram and TGA trace of Compound A, succinate salt form G.

[0030] [Figure 23] FIG. 23 shows a single crystal of Compound A, succinate salt form G.

[0031] [Figure 24] FIG. 24 shows the XRPD pattern of Compound A, hydrochloride salt Form A.

[0032] [Diagram 25] FIG. 25 shows the DSC thermogram and TGA trace of Compound A, hydrochloride salt Form A.

[0033] [Figure 26] FIG. 26 shows the XRPD pattern of Compound A, hydrochloride salt form B.

[0034] [Figure 27] FIG. 27 shows the DSC thermogram and TGA trace of Compound A, hydrochloride salt form B.

[0035] [Figure 28] FIG. 28 shows the XRPD pattern of Compound A, hydrochloride salt Form C.

[0036] [Figure 29] FIG. 29 shows the DSC thermogram and TGA trace of Compound A, hydrochloride salt Form C.

[0037] [Diagram 30] FIG. 30 shows the XRPD pattern of Compound A, hydrochloride salt Form D.

[0038] [Diagram 31] FIG. 31 shows the DSC thermogram and TGA trace of Compound A, hydrochloride salt Form D.

[0039] [Diagram 32] FIG. 32 shows the XRPD pattern of Compound A, hydrochloride salt form E.

[0040] [Diagram 33] FIG. 33 shows the DSC thermogram and TGA trace of Compound A, hydrochloride salt Form E.

[0041] [Diagram 34] FIG. 34 shows the XRPD pattern of Compound A, hydrochloride salt form F.

[0042] [Diagram 35] FIG. 35 shows the DSC thermogram and TGA trace of Compound A, hydrochloride salt Form F.

[0043] [Diagram 36] FIG. 36 shows the XRPD pattern of Compound A, maleate salt form A.

[0044] [Figure 37] FIG. 37 shows the DSC thermogram and TGA trace of Compound A, maleate salt form A.

[0045] [Figure 38] FIG. 38 shows the XRPD pattern of Compound A, Sulfate Salt Form A.

[0046] [Figure 39] FIG. 39 shows the DSC thermogram and TGA trace of Compound A, sulfate salt form A.

[0047] [Diagram 40] FIG. 40 shows the XRPD pattern of Compound A, Sulfate Salt Form B.

[0048] [Diagram 41] FIG. 41 shows the DSC thermogram and TGA trace of Compound A, sulfate salt form B.

[0049] [Diagram 42] FIG. 42 shows the XRPD pattern of Compound A, Sulfate Salt Form C.

[0050] [Diagram 43] FIG. 43 shows the DSC thermogram and TGA trace of Compound A, sulfate salt form C.

[0051] [Diagram 44] FIG. 44 shows the XRPD pattern of Compound A, Phosphate Salt Form A.

[0052] [Diagram 45] FIG. 45 shows the DSC thermogram and TGA trace of Compound A, phosphate salt Form A.

[0053] [Figure 46] FIG. 46 shows the XRPD pattern of Compound A, L-tartrate salt form A.

[0054] [Figure 47] FIG. 47 shows the DSC thermogram and TGA trace of Compound A, L-tartrate salt Form A.

[0055] [Figure 48] FIG. 48 shows the XRPD pattern of Compound A, fumarate salt form A.

[0056] [Figure 49] FIG. 49 shows the DSC thermogram and TGA trace of Compound A, fumarate salt form A.

[0057] [Figure 50] FIG. 50 shows the XRPD pattern of Compound A, Fumarate Salt Form B.

[0058] [Figure 51] FIG. 51 shows the DSC thermogram and TGA trace of Compound A, fumarate salt form B.

[0059] [Figure 52] FIG. 52 shows the XRPD pattern of Compound A, fumarate salt form C.

[0060] [Figure 53] FIG. 53 shows the DSC thermogram and TGA trace of Compound A, fumarate salt Form C.

[0061] [Figure 54] FIG. 54 shows the XRPD pattern of Compound A, fumarate salt form D.

[0062] [Figure 55] FIG. 55 shows the DSC thermogram and TGA trace of Compound A, fumarate salt form D.

[0063] [Figure 56] FIG. 56 shows the XRPD pattern of Compound A, citrate salt form A.

[0064] [Figure 57] FIG. 57 shows the DSC thermogram and TGA trace of Compound A, citrate salt form A.

[0065] [Figure 58] FIG. 58 shows the XRPD pattern of Compound A, L-malate salt form A.

[0066] [Figure 59] FIG. 59 shows the DSC thermogram and TGA trace of Compound A, L-malate salt form A.

[0067] [Figure 60] FIG. 60 shows the XRPD pattern of Compound A, mesylate form A.

[0068] [Figure 61] FIG. 61 shows the DSC thermogram and TGA trace of Compound A, mesylate salt form A.

[0069] [Figure 62] FIG. 62 shows the XRPD pattern of Compound A, mesylate form B.

[0070] [Figure 63] FIG. 63 shows the DSC thermogram and TGA trace of Compound A, mesylate form B.

[0071] [Figure 64] FIG. 64 shows the XRPD pattern of Compound A, esylate salt Form A.

[0072] [Figure 65] FIG. 65 shows the DSC thermogram and TGA trace of Compound A, esylate salt Form A.

[0073] [Figure 66] FIG. 66 shows the XRPD pattern of Compound A, esylate salt form B.

[0074] [Figure 67] FIG. 67 shows the DSC thermogram and TGA trace of Compound A, esylate salt form B.

[0075] [Figure 68] FIG. 68 shows the XRPD pattern of Compound A, tosylate salt form A.

[0076] [Figure 69] FIG. 69 shows the DSC thermogram and TGA trace of Compound A, tosylate salt form A.

[0077] [Figure 70] FIG. 70 shows the XRPD pattern of Compound A, tosylate salt form B.

[0078] [Figure 71] FIG. 71 shows the DSC thermogram and TGA trace of Compound A, tosylate salt form B.

[0079] [Figure 72] FIG. 72 shows the XRPD pattern of Compound A, glutarate salt form A.

[0080] [Figure 73] FIG. 73 shows the XRPD pattern of Compound A, acetate salt form A.

[0081] [Figure 74] FIG. 74 shows the DSC thermogram and TGA trace of Compound A, acetate salt form A.

[0082] [Figure 75] FIG. 75 shows the XRPD pattern of Compound A, malonate salt form A.

[0083] [Figure 76] FIG. 76 shows the XRPD pattern of Compound A, malonate salt form B.

[0084] [Figure 77] FIG. 77 shows the XRPD pattern of Compound A, sebacate salt Form A.

[0085] [Figure 78] FIG. 78 shows the DSC thermogram and TGA trace of Compound A, sebacate salt Form A.

[0086] [Figure 79] FIG. 79 shows the XRPD pattern of Compound A, aceturate salt form A.

[0087] [Figure 80] FIG. 80 shows the DSC thermogram and TGA trace of Compound A, aceturate salt form A.

[0088] [Figure 81] FIG. 81 shows the XRPD pattern of Compound A, aceturate salt form B.

[0089] [Figure 82] FIG. 82 shows the DSC thermogram and TGA trace of Compound A, aceturate salt form B. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0090] General Description of Certain Embodiments of the Invention U.S. Patent Application No. 17 / 480,323, filed September 21, 2021 (hereinafter the "'323 Application"), which is incorporated herein by reference in its entirety, describes certain CDK4 and CDK6-inhibitors. Such compounds include Compound A. [ka] A

[0091] 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 in Example 56 and reproduced herein for ease of reference.

[0092] It would be desirable to provide a solid form of Compound A (e.g., as its free base or as a salt thereof) that imparts features such as improved water solubility, stability, and ease of formulation. Thus, the present invention provides both the free base and salt forms of Compound A.

[0093] Free base form of compound A It is contemplated that compound A free base can exist in various physical forms.For example, compound A free base can be in solution, suspension, or solid form.In certain embodiments, compound A free base is in solid form.When compound A free base is in solid form, the compound can be amorphous, crystalline, or a mixture thereof.Exemplary solid forms are described in more detail below.

[0094] In some embodiments, the present invention provides a 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 solvent, or any other impurities that may result from the preparation and / or isolation of Compound A. In certain embodiments, at least about 95% by weight of the form of Compound A free base is present. In yet other embodiments of the present invention, at least about 99% by weight of the form of Compound A free base is present.

[0095] According to one embodiment, the compound A free base form is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 percent by weight, the percentages being based on the total weight of the composition. According to another embodiment, the compound A free base form contains less than about 3.0 area percent HPLC total organic impurities, and in certain embodiments, less than about 1.5 area percent HPLC total organic impurities, based on the total area of ​​the HPLC chromatogram. In other embodiments, the compound A free base form contains less than about 1.0% area percent HPLC of any single impurity, less than about 0.6 area percent HPLC of any single impurity, and in certain embodiments, less than about 0.5 area percent HPLC of any single impurity, based on the total area of ​​the HPLC chromatogram.

[0096] Structures depicted for the form of Compound A free base are also intended to include all tautomeric forms of Compound A free base. Additionally, structures depicted herein are also intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure, except for the replacement of a carbon with a C-enriched carbon, are within the scope of this invention.

[0097] It has been found that Compound A free base can exist in various solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0098] As used herein, the term "polymorph" refers to the different crystal structures in which a compound, or a salt or solvate thereof, may crystallize.

[0099] As used herein, the term "about" when used in reference to degree 2 theta values ​​refers to the stated value ±0.2 degrees 2 theta.

[0100] In certain embodiments, Compound A free base is a crystalline solid. In other embodiments, Compound A free base is a crystalline solid that is 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 crystalline Compound A free base. In yet other embodiments of the present invention, there is at least about 99% by weight of crystalline Compound A free base.

[0101] 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, herein referred to as Form A. In certain embodiments, the present invention provides a polymorphic form of Compound A free base, herein referred to as Form B. In certain embodiments, the present invention provides a polymorphic form of Compound A free base, herein referred to as Form C.

[0102] In some embodiments, Compound A free base is amorphous. In some embodiments, Compound A free base is amorphous and substantially free of crystalline Compound A free base.

[0103] Form A of Compound A 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. [Table 1]

[0104] In some embodiments, Form A of Compound A is characterized by having one or more peaks in its X-ray powder diffraction (XRPD) pattern selected from those at about 11.5, about 12.9, and about 23.5 degrees 2-theta. In some embodiments, Form A of Compound A free base is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from those at about 11.5, about 12.9, and about 23.5 degrees 2-theta. In some embodiments, Form A of Compound A free base is characterized by having all three peaks in its X-ray powder diffraction pattern selected from those at about 11.5, about 12.9, and about 23.5 degrees 2-theta.

[0105] As used herein, the term "about" when used in reference to degree 2 theta values ​​refers to the stated value ±0.2 degrees 2 theta.

[0106] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0107] A method for preparing Form A of Compound A free base is described below.

[0108] Form B of Compound A 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. [Table 2]

[0109] In some embodiments, Form B of Compound A free base is characterized by having one or more peaks in its X-ray powder diffraction (XRPD) pattern selected from those at about 17.8, about 18.3, and about 20.8 degrees 2-theta. In some embodiments, Form B of Compound A free base is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from those at about 17.8, about 18.3, and about 20.8 degrees 2-theta. In some embodiments, Form B of Compound A free base is characterized by having all three peaks in its X-ray powder diffraction pattern selected from those at about 17.8, about 18.3, and about 20.8 degrees 2-theta. As used herein, the term "about" when used in reference to degrees 2-theta values ​​refers to the stated value ±0.2 degrees 2-theta.

[0110] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0111] A method for preparing Form B of Compound A free base is described below.

[0112] Form C of Compound A 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. [Table 3]

[0113] In some embodiments, Form C of Compound A free base is characterized by having one or more peaks in its X-ray powder diffraction (XRPD) pattern selected from those at about 16.4, about 22.9, and about 31.6 degrees 2-theta. In some embodiments, Form C of Compound A free base is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from those at about 16.4, about 22.9, and about 31.6 degrees 2-theta. In some embodiments, Form C of Compound A free base is characterized by having all three peaks in its X-ray powder diffraction pattern selected from those at about 16.4, about 22.9, and about 31.6 degrees 2-theta. As used herein, the term "about" when used in reference to a degree 2-theta value refers to the stated value ±0.2 degrees 2-theta.

[0114] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0115] A method for preparing Form C of Compound A free base is described below.

[0116] In some embodiments, the present invention provides Compound A free base, [ka] A The compound is crystalline.

[0117] In some embodiments, the present invention provides Compound A free base, wherein the compound is substantially free of amorphous Compound A free base.

[0118] In some embodiments, the present invention provides Compound A free base, which is substantially free of impurities.

[0119] In some embodiments, the present invention provides compound A free base, the compound having one or more peaks in its XRPD selected from about 11.5, about 12.9, and about 23.5 degrees 2-theta. In some such embodiments, the present invention provides compound A free base, the compound having at least two peaks in its XRPD selected from about 11.5, about 12.9, and about 23.5 degrees 2-theta. In some such embodiments, the present invention provides compound A succinate, the compound having at least three peaks in its XRPD selected from about 11.5, about 12.9, and about 23.5 degrees 2-theta. In some such embodiments, the present invention provides compound A free base, the compound being of Form A.

[0120] In some embodiments, the present invention provides Compound A free base, which has an XRPD substantially similar to that shown in FIG.

[0121] In some embodiments, the present invention provides Compound A free base, the compound having one or more peaks in its XRPD selected from about 17.8, about 18.3, and about 20.8 degrees 2-theta. In some such embodiments, the present invention provides Compound A free base, the compound having at least two peaks in its XRPD selected from about 17.8, about 18.3, and about 20.8 degrees 2-theta. In some such embodiments, the present invention provides Compound A free base, the compound having at least three peaks in its XRPD selected from about 17.8, about 18.3, and about 20.8 degrees 2-theta. In some such embodiments, the present invention provides Compound A free base, the compound being of Form B.

[0122] In some embodiments, the present invention provides Compound A free base, which has an XRPD substantially similar to that shown in FIG.

[0123] In some embodiments, the present invention provides Compound A free base, the compound having one or more peaks in its XRPD selected from about 16.4, about 22.9, and about 31.6 degrees 2-theta. In some such embodiments, the present invention provides Compound A free base, the compound having at least two peaks in its XRPD selected from about 16.4, about 22.9, and about 31.6 degrees 2-theta. In some such embodiments, the present invention provides Compound A free base, the compound having at least three peaks in its XRPD selected from about 16.4, about 22.9, and about 31.6 degrees 2-theta. In some such embodiments, the present invention provides Compound A free base, the compound being of Form C.

[0124] In some embodiments, the present invention provides Compound A free base, which has an XRPD substantially similar to that shown in FIG.

[0125] In some embodiments, the present invention provides a composition comprising Compound A free base and a pharma- ceutically acceptable carrier or excipient.

[0126] In some embodiments, the present invention provides methods of treating CDK4-mediated and CDK6-mediated disorders in a patient in need thereof, the methods comprising administering to the patient Compound A free base or a composition thereof. 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.

[0127] In some embodiments, the CDK4- and CDK6-mediated disorder is cancer, hi 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 lymphocytic leukemia, lymphoma, myeloma, acute myeloid leukemia, secondary pancreatic cancer, or secondary brain metastasis.

[0128] In some embodiments, the breast cancer is HR+ / HER2- or HR+ / HER2+ advanced or metastatic breast cancer and the malignant brain tumor is glioblastoma, astrocytoma, or pontine glioma.

[0129] In some embodiments, the patient is administered a pharmaceutical composition of Compound A free base. 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.

[0130] In some embodiments, the methods described herein further comprise administering to the patient an additional therapeutic agent. 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.

[0131] Salt form of compound A In some embodiments, the acid and compound A are ionically bonded to form compound A succinate, which is 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. Examples of such solid forms of compound A succinate are described in more detail below.

[0132] Succinate of Compound A According to one embodiment, the present invention provides a succinate salt of Compound A. [ka]

[0133] It will be understood by those skilled in the art that succinic acid and compound A are ionically bonded 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.

[0134] In some embodiments, the present invention provides a compound A succinate 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 excess succinic acid, excess compound A, residual solvent, or any other impurities that may result from the preparation and / or isolation of compound A succinate. In certain embodiments, at least about 95% by weight of compound A succinate is present. In yet other embodiments of the present invention, at least about 99% by weight of compound A succinate is present.

[0135] 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 percent by weight, the percentage being based on the total weight of the composition. According to another embodiment, compound A succinate contains less than about 3.0 area percent by HPLC of total organic impurities, and in certain embodiments, less than about 1.5 area percent by HPLC of total organic impurities, based on the total area of ​​the HPLC chromatogram. In other embodiments, compound A succinate contains less than about 1.0% area percent by HPLC of any single impurity, less than about 0.6 area percent by HPLC of any single impurity, and in certain embodiments, less than about 0.5 area percent by HPLC of any single impurity, based on the total area of ​​the HPLC chromatogram.

[0136] The structures depicted for Compound A succinate are also intended to include all tautomeric forms of Compound A succinate. Additionally, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure, except for the replacement of a carbon with a C-enriched carbon, are within the scope of this invention.

[0137] In certain embodiments, Compound A succinate is a crystalline solid. In other embodiments, Compound A succinate is a crystalline solid that is 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 yet other embodiments of the present invention, there is at least about 99% by weight of crystalline Compound A succinate.

[0138] 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.

[0139] In some embodiments, Compound A succinate is amorphous. In some embodiments, Compound A succinate is amorphous and substantially free of crystalline Compound A succinate.

[0140] Compound A succinate form A In some embodiments, Form A of Compound A succinate has at least 1, 2, 3, 4, or 5 spectral peaks selected from the peaks listed in Table 4 below. [Table 4]

[0141] In some embodiments, Form A of Compound A succinate is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from those at about 8.1, about 11.6, and about 24.4 degrees 2-theta. In some embodiments, Form A of Compound A succinate is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from those at about 8.1, about 11.6, and about 24.4 degrees 2-theta. In some embodiments, Form A of Compound A succinate is characterized by having all three peaks in its X-ray powder diffraction pattern selected from those at about 8.1, about 11.6, and about 24.4 degrees 2-theta.

[0142] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0143] A method for preparing Form A of Compound A succinate salt is described below.

[0144] Compound A succinate form B In some embodiments, Form B of Compound A succinate has at least 1, 2, 3, 4, or 5 spectral peaks selected from the peaks listed in Table 5 below. [Table 5]

[0145] In some embodiments, Form B of Compound A succinate is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from those at about 18.6, about 24.1, and about 24.6 degrees 2-theta. In some embodiments, Form B of Compound A succinate is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from those at about 18.6, about 24.1, and about 24.6 degrees 2-theta. In some embodiments, Form B of Compound A succinate is characterized by having all three peaks in its X-ray powder diffraction pattern selected from those at about 18.6, about 24.1, and about 24.6 degrees 2-theta.

[0146] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0147] A method for preparing Form B of Compound A succinate salt is described below.

[0148] Compound A succinate form C In some embodiments, Form C of Compound A succinate has at least 1, 2, 3, 4, or 5 spectral peaks selected from the peaks listed in Table 6 below. [Table 6]

[0149] In some embodiments, Form C of Compound A succinate is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from those at about 9.2, about 11.9, and about 18.9 degrees two-theta. In some embodiments, Form C of Compound A succinate is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from those at about 9.2, about 11.9, and about 18.9 degrees two-theta. In some embodiments, Form C of Compound A succinate is characterized by having all three peaks in its X-ray powder diffraction pattern selected from those at about 9.2, about 11.9, and about 18.9 degrees two-theta.

[0150] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0151] A method for preparing Form C of Compound A succinate salt is described below.

[0152] Compound A succinate form D In some embodiments, Form D of Compound A succinate has at least 1, 2, 3, 4, or 5 spectral peaks selected from the peaks listed in Table 7 below. [Table 7]

[0153] In some embodiments, Form D of Compound A succinate is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from those at about 12.3, about 19.4, and about 24.7 degrees two-theta. In some embodiments, Form D of Compound A succinate is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from those at about 12.3, about 19.4, and about 24.7 and about 18.9 degrees two-theta. In some embodiments, Form D of Compound A succinate is characterized by having all three peaks in its X-ray powder diffraction pattern selected from those at about 12.3, about 19.4, and about 24.7 degrees two-theta.

[0154] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0155] A method for preparing Form D of Compound A succinate salt is described below.

[0156] Compound A succinate form E In some embodiments, Form E of Compound A succinate has at least 1, 2, 3, 4, or 5 spectral peaks selected from the peaks listed in Table 8 below. [Table 8]

[0157] In some embodiments, Form E of Compound A succinate is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from those at about 11.9, about 23.1, and about 24.1 degrees two-theta. In some embodiments, Form E of Compound A succinate is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from those at about 11.9, about 23.1, and about 24.1, and about 18.9 degrees two-theta. In some embodiments, Form E of Compound A succinate is characterized by having all three peaks in its X-ray powder diffraction pattern selected from those at about 11.9, about 23.1, and about 24.1 degrees two-theta.

[0158] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0159] A method for preparing Form E of Compound A succinate salt is described below.

[0160] Compound A succinate form F In some embodiments, Form F of Compound A succinate has at least 1, 2, 3, 4, or 5 spectral peaks selected from the peaks listed in Table 9 below. [Table 9]

[0161] In some embodiments, Form F of Compound A succinate is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from those at about 6.0, about 12.5, and about 24.5 degrees two-theta. In some embodiments, Form F of Compound A succinate is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from those at about 6.0, about 12.5, and about 24.5, and about 18.9 degrees two-theta. In some embodiments, Form F of Compound A succinate is characterized by having all three peaks in its X-ray powder diffraction pattern selected from those at about 6.0, about 12.5, and about 24.5 degrees two-theta.

[0162] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0163] A method for preparing Form F of Compound A succinate salt is described below.

[0164] Compound A succinate form G In some embodiments, Form G of Compound A succinate has at least 1, 2, 3, 4, or 5 spectral peaks selected from the peaks listed in Table 10 below. [Table 10-1] [Table 10-2]

[0165] In some embodiments, Form G of Compound A succinate is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from those at about 6.0, about 15.3, and about 23.4 degrees 2-theta. In some embodiments, Form G of Compound A succinate is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from those at about 6.0, about 15.3, and about 23.4, and about 18.9 degrees 2-theta. In some embodiments, Form G of Compound A succinate is characterized by having all three peaks in its X-ray powder diffraction pattern selected from those at about 6.0, about 15.3, and about 23.4 degrees 2-theta.

[0166] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0167] A method for preparing Form G of Compound A succinate salt is described below.

[0168] In some embodiments, the present invention provides Compound A succinate salt. [ka]

[0169] In some embodiments, the present invention provides Compound A succinate salt, wherein the compound is crystalline.

[0170] In some embodiments, the present invention provides Compound A succinate, which is a crystalline solid that is substantially free of amorphous Compound A succinate.

[0171] In some embodiments, the present invention provides Compound A succinate salt, wherein the compound is substantially free of impurities.

[0172] In some embodiments, the present invention provides compound A succinate, the compound having one or more peaks in its XRPD selected from about 8.1, about 11.6, and about 24.4 degrees 2-theta. In some such embodiments, the present invention provides compound A succinate, the compound having at least two peaks in its XRPD selected from about 8.1, about 11.6, and about 24.4 degrees 2-theta. In some such embodiments, the present invention provides compound A succinate, the compound having at least three peaks in its XRPD selected from about 8.1, about 11.6, and about 24.4 degrees 2-theta. In some such embodiments, the present invention provides compound A succinate, the compound being of Form A.

[0173] In some embodiments, the present invention provides Compound A succinate salt, the compound having an XRPD substantially similar to that shown in FIG.

[0174] In some embodiments, the present invention provides compound A succinate, the compound having one or more peaks in its XRPD selected from about 18.6, about 24.1, and about 24.6 degrees 2-theta. In some such embodiments, the present invention provides compound A succinate, the compound having at least two peaks in its XRPD selected from about 18.6, about 24.1, and about 24.6 degrees 2-theta. In some such embodiments, the present invention provides compound A succinate, the compound having at least three peaks in its XRPD selected from about 18.6, about 24.1, and about 24.6 degrees 2-theta. In some such embodiments, the present invention provides compound A succinate, the compound being of Form B.

[0175] In some embodiments, the present invention provides Compound A succinate salt, the compound having an XRPD substantially similar to that shown in FIG.

[0176] In some embodiments, the present invention provides compound A succinate, the compound having one or more peaks in its XRPD selected from about 9.2, about 11.9, and about 18.9 degrees 2-theta. In some such embodiments, the present invention provides compound A succinate, the compound having at least two peaks in its XRPD selected from about 9.2, about 11.9, and about 18.9 degrees 2-theta. In some such embodiments, the present invention provides compound A succinate, the compound having at least three peaks in its XRPD selected from about 9.2, about 11.9, and about 18.9 degrees 2-theta. In some such embodiments, the present invention provides compound A succinate, the compound being of Form C.

[0177] In some embodiments, the present invention provides Compound A succinate salt, the compound having an XRPD substantially similar to that shown in FIG.

[0178] In some embodiments, the present invention provides a compound A succinate salt, the compound has one or more peaks in its XRPD selected from peaks at about 12.3, about 19.4, and about 24.7 degrees 2-theta. In some such embodiments, the present invention provides a compound A succinate salt, the compound has at least two peaks in its XRPD selected from peaks at about 12.3, about 19.4, and about 24.7 degrees 2-theta. In some such embodiments, the present invention provides a compound A succinate salt, the compound has at least three peaks in its XRPD selected from peaks at about 12.3, about 19.4, and about 24.7 degrees 2-theta. In some such embodiments, the present invention provides a compound A succinate salt, the compound is Form D.

[0179] In some embodiments, the present invention provides Compound A succinate salt, the compound having an XRPD substantially similar to that shown in FIG.

[0180] In some embodiments, the present invention provides a compound A succinate salt, the compound has one or more peaks in its XRPD selected from those at about 11.9, about 23.1, and about 24.1 degrees 2-theta. In some such embodiments, the present invention provides a compound A succinate salt, the compound has at least two peaks in its XRPD selected from those at about 11.9, about 23.1, and about 24.1 degrees 2-theta. In some such embodiments, the present invention provides a compound A succinate salt, the compound has at least three peaks in its XRPD selected from those at about 11.9, about 23.1, and about 24.1 degrees 2-theta. In some such embodiments, the present invention provides a compound A succinate salt, the compound is Form E.

[0181] In some embodiments, the present invention provides Compound A succinate salt, the compound having an XRPD substantially similar to that shown in FIG.

[0182] In some embodiments, the present invention provides a compound A succinate salt, the compound has one or more peaks in its XRPD selected from peaks at about 6.0, about 12.5, and about 24.5 degrees 2-theta. In some such embodiments, the present invention provides a compound A succinate salt, the compound has at least two peaks in its XRPD selected from peaks at about 6.0, about 12.5, and about 24.5 degrees 2-theta. In some such embodiments, the present invention provides a compound A succinate salt, the compound has at least three peaks in its XRPD selected from peaks at about 6.0, about 12.5, and about 24.5 degrees 2-theta. In some such embodiments, the present invention provides a compound A succinate salt, the compound is Form F.

[0183] In some embodiments, the present invention provides Compound A succinate salt, the compound having an XRPD substantially similar to that shown in FIG.

[0184] In some embodiments, the present invention provides compound A succinate, the compound has one or more peaks in its XRPD selected from about 6.0, about 15.3, and about 23.4 degrees 2-theta. In some such embodiments, the present invention provides compound A succinate, the compound has at least two peaks in its XRPD selected from about 6.0, about 15.3, and about 23.4 degrees 2-theta. In some such embodiments, the present invention provides compound A succinate, the compound has at least three peaks in its XRPD selected from about 6.0, about 15.3, and about 23.4 degrees 2-theta. In some such embodiments, the present invention provides compound A succinate, the compound is Form G.

[0185] In some embodiments, the present invention provides Compound A succinate salt, the compound having an XRPD substantially similar to that shown in FIG.

[0186] In some embodiments, the present invention provides a composition comprising Compound A succinate salt and a pharma- ceutically acceptable carrier or excipient.

[0187] In some embodiments, the present invention provides a method of treating a CDK4-mediated disorder and a CDK6-mediated disorder in a patient in need thereof, the method comprising administering to the patient Compound A succinate or a composition thereof. In some embodiments, Compound A succinate is Form A of the succinate salt. In some embodiments, Compound A succinate is Form B of the succinate salt. In some embodiments, Compound A succinate is Form C of the succinate salt. In some embodiments, Compound A succinate is Form D of the succinate salt. In some embodiments, Compound A succinate is Form E of the succinate salt. In some embodiments, Compound A succinate is Form F of the succinate salt. In some embodiments, Compound A succinate is Form G of the succinate salt.

[0188] In some embodiments, the CDK4- and CDK6-mediated disorder is cancer, hi 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 lymphocytic leukemia, lymphoma, myeloma, acute myeloid leukemia, secondary pancreatic cancer, or secondary brain metastasis.

[0189] In some embodiments, the breast cancer is HR+ / HER2- or HR+ / HER2+ advanced or metastatic breast cancer and the malignant brain tumor is glioblastoma, astrocytoma, or pontine glioma.

[0190] In some embodiments, the patient is administered a pharmaceutical composition of Compound A succinate. In some embodiments, the administration is oral administration of Compound A succinate. In some embodiments, the administration is intravenous administration of Compound A succinate.

[0191] In some embodiments, the methods described herein further comprise administering to the patient an additional therapeutic agent. 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.

[0192] Pharmaceutical Salts of Compound A In some embodiments, the present disclosure is directed to a pharmaceutical salt of Compound A, [ka] A The salts are hydrochloride, sulfate, maleate, phosphate, L-tartrate, fumarate, citrate, L-malate, tosylate, succinate, methanesulfonate, ethanesulfonate, glutarate, n-acetylglycine, acetate, malonate, or sebacate.

[0193] In some embodiments, the present disclosure is directed to a pharmaceutical salt of Compound A that is a hydrochloride salt. In some embodiments, the pharmaceutical salt of Compound A is an amorphous form of the hydrochloride salt. In some embodiments, the pharmaceutical salt of Compound A is a crystalline form of the hydrochloride salt.

[0194] In some embodiments, the present disclosure is directed to a pharmaceutical salt of Compound A that is a sulfate salt. In some embodiments, the pharmaceutical salt of Compound A is an amorphous form of the sulfate salt. In some embodiments, the pharmaceutical salt of Compound A is a crystalline form of the sulfate salt.

[0195] In some embodiments, the present disclosure is directed to a pharmaceutical salt of Compound A that is a maleate salt. In some embodiments, the pharmaceutical salt of Compound A is an amorphous form of the maleate salt. In some embodiments, the pharmaceutical salt of Compound A is a crystalline form of the maleate salt.

[0196] In some embodiments, the present disclosure is directed to a pharmaceutical salt of Compound A that is a phosphate salt. In some embodiments, the pharmaceutical salt of Compound A is an amorphous form of the phosphate salt. In some embodiments, the pharmaceutical salt of Compound A is a crystalline form of the phosphate salt.

[0197] In some embodiments, the present disclosure is directed to a pharmaceutical salt of Compound A that is an L-tartrate salt. In some embodiments, the pharmaceutical salt of Compound A is an amorphous form of the L-tartrate salt. In some embodiments, the pharmaceutical salt of Compound A is a crystalline form of the L-tartrate salt.

[0198] In some embodiments, the present disclosure is directed to a pharmaceutical salt of Compound A that is a fumarate salt. In some embodiments, the pharmaceutical salt of Compound A is an amorphous form of the fumarate salt. In some embodiments, the pharmaceutical salt of Compound A is a crystalline form of the fumarate salt.

[0199] In some embodiments, the present disclosure is directed to a pharmaceutical salt of Compound A that is a citrate salt. In some embodiments, the pharmaceutical salt of Compound A is an amorphous form of the citrate salt. In some embodiments, the pharmaceutical salt of Compound A is a crystalline form of the citrate salt.

[0200] In some embodiments, the present disclosure is directed to a pharmaceutical salt of Compound A that is an L-malate salt. In some embodiments, the pharmaceutical salt of Compound A is an amorphous form of the L-malate salt. In some embodiments, the pharmaceutical salt of Compound A is a crystalline form of the L-malate salt.

[0201] In some embodiments, the present disclosure is directed to a pharmaceutical salt of Compound A that is a tosylate salt. In some embodiments, the pharmaceutical salt of Compound A is an amorphous form of the tosylate salt. In some embodiments, the pharmaceutical salt of Compound A is a crystalline form of the tosylate salt.

[0202] In some embodiments, the present disclosure is directed to a pharmaceutical salt of Compound A that is a succinate salt. In some embodiments, the pharmaceutical salt of Compound A is an amorphous form of the succinate salt. In some embodiments, the pharmaceutical salt of Compound A is a crystalline form of the succinate salt.

[0203] In some embodiments, the present disclosure is directed to a pharmaceutical salt of Compound A that is a mesylate salt. In some embodiments, the pharmaceutical salt of Compound A is an amorphous form of the mesylate salt. In some embodiments, the pharmaceutical salt of Compound A is a crystalline form of the mesylate salt.

[0204] In some embodiments, the present disclosure is directed to a pharmaceutical salt of Compound A that is an esylate salt. In some embodiments, the pharmaceutical salt of Compound A is an amorphous form of the esylate salt. In some embodiments, the pharmaceutical salt of Compound A is a crystalline form of the esylate salt.

[0205] In some embodiments, the present disclosure is directed to a pharmaceutical salt of Compound A that is a glutarate salt. In some embodiments, the pharmaceutical salt of Compound A is an amorphous form of the glutarate salt. In some embodiments, the pharmaceutical salt of Compound A is a crystalline form of the glutarate salt.

[0206] In some embodiments, the present disclosure is directed to a pharmaceutical salt of Compound A that is an aceturate salt. In some embodiments, the pharmaceutical salt of Compound A is an amorphous form of the aceturate salt. In some embodiments, the pharmaceutical salt of Compound A is a crystalline form of the aceturate salt.

[0207] In some embodiments, the present disclosure is directed to a pharmaceutical salt of Compound A that is an acetate salt. In some embodiments, the pharmaceutical salt of Compound A is an amorphous form of the acetate salt. In some embodiments, the pharmaceutical salt of Compound A is a crystalline form of the acetate salt.

[0208] In some embodiments, the present disclosure is directed to a pharmaceutical salt of Compound A that is a malonate salt. In some embodiments, the pharmaceutical salt of Compound A is an amorphous form of the malonate salt. In some embodiments, the pharmaceutical salt of Compound A is a crystalline form of the malonate salt.

[0209] In some embodiments, the present disclosure is directed to a pharmaceutical salt of Compound A that is a sebacate salt. In some embodiments, the pharmaceutical salt of Compound A is an amorphous form of the sebacate salt. In some embodiments, the pharmaceutical salt of Compound A is a crystalline form of the sebacate salt.

[0210] General Methods for Providing Salt Compounds Compound A is prepared according to the methods detailed in the '323 application, which is incorporated herein by reference in its entirety. Salt compounds of general formula X (which formula specifically encompasses salt Compound A succinate and / or specific forms thereof) are prepared from Compound A according to the following general scheme: [ka] Compound A Salt Compound X

[0211] For example, Compound A succinate and forms thereof are prepared from Compound A by combining Compound A with a suitable acid to form a salt of the acid. Accordingly, another aspect of the present invention provides a method for preparing Compound A succinate and forms thereof.

[0212] As generally described above, in some embodiments, the present invention provides compounds having the general formula X: [ka] Salt Compound X [ka] Compound A A method for preparing a salt compound of general formula X is provided, comprising combining compound A with a suitable acid and, optionally, a suitable solvent under conditions suitable to form a salt compound of general formula X.

[0213] In some embodiments, the suitable acid is succinic acid. In some embodiments, the present invention provides a method for making a succinate salt of compound A. In certain embodiments, the succinate salt of compound A is compound A succinate. In certain embodiments, the succinate salt of compound A is form A of compound A succinate. In certain embodiments, the succinate salt of compound A is form B of compound A succinate. In certain embodiments, the succinate salt of compound A is form C of compound A succinate. In certain embodiments, the succinate salt of compound A is form D of compound A succinate. In certain embodiments, the succinate salt of compound A is form E of compound A succinate. In certain embodiments, the succinate salt of compound A is form F of compound A succinate. In certain embodiments, the succinate salt of compound A is form G of compound A succinate.

[0214] In some embodiments, the suitable acid is hydrochloric acid. In some embodiments, the present invention provides a method of making the hydrochloride salt of Compound A. In certain embodiments, the hydrochloride salt of Compound A is Compound A hydrochloride. In certain embodiments, the hydrochloride salt of Compound A is Form A of Compound A hydrochloride. In certain embodiments, the hydrochloride salt of Compound A is Form B of Compound A hydrochloride. In certain embodiments, the hydrochloride salt of Compound A is Form C of Compound A hydrochloride. In certain embodiments, the hydrochloride salt of Compound A is Form D of Compound A hydrochloride. In certain embodiments, the hydrochloride salt of Compound A is Form E of Compound A hydrochloride. In certain embodiments, the hydrochloride salt of Compound A is Form F of Compound A hydrochloride.

[0215] In some embodiments, the suitable acid is maleic acid. In some embodiments, the present invention provides a method for making a malonate salt of Compound A. In certain embodiments, the malonate salt of Compound A is Compound A malonate. In certain embodiments, the malonate salt of Compound A is Form A of Compound A malonate.

[0216] In some embodiments, the suitable acid is sulfuric acid. In some embodiments, the present invention provides a method for making 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.

[0217] In some embodiments, the suitable acid is phosphoric acid. In some embodiments, the present invention provides a method for making a phosphate salt of Compound A. In certain embodiments, the phosphate salt of Compound A is Compound A phosphate salt. In certain embodiments, the phosphate salt of Compound A is Form A of Compound A phosphate salt.

[0218] In some embodiments, the suitable acid is L-tartaric acid. In some embodiments, the present invention provides a method for making the 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.

[0219] In some embodiments, the suitable acid is fumaric acid. In some embodiments, the present invention provides a method of making 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.

[0220] In some embodiments, the suitable acid is citric acid. In some embodiments, the present invention provides a method for making a citrate salt of Compound A. In certain embodiments, the phosphate salt of Compound A is Compound A citrate salt. In certain embodiments, the citrate salt of Compound A is Form A of Compound A citrate salt.

[0221] In some embodiments, the suitable acid is L-malic acid. In some embodiments, the present invention provides a method for making an L-malate salt of Compound A. In certain embodiments, the phosphate salt of Compound A is Compound A L-malate salt. In certain embodiments, the L-malate salt of Compound A is Form A of Compound A L-malate salt.

[0222] In some embodiments, the suitable acid is methanesulfonic acid. In some embodiments, the present invention provides a method for making 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.

[0223] In some embodiments, the suitable acid is ethanesulfonic acid. In some embodiments, the present invention provides a method for making an esylate salt of Compound A. In certain embodiments, the esylate salt of Compound A is Compound A esylate salt. In certain embodiments, the esylate salt of Compound A is Form A of Compound A esylate salt. In certain embodiments, the esylate salt of Compound A is Form B of Compound A esylate salt.

[0224] In some embodiments, the suitable acid is toluenesulfonic acid. In some embodiments, the present invention provides a method for making a tosylate salt of Compound A. In certain embodiments, the tosylate salt of Compound A is Compound A tosylate salt. In certain embodiments, the tosylate salt of Compound A is Form A of Compound A tosylate salt. In certain embodiments, the tosylate salt of Compound A is Form B of Compound A tosylate salt.

[0225] In some embodiments, the suitable acid is glutaric acid. In some embodiments, the present invention provides a method for making a glutarate salt of Compound A. In certain embodiments, the glutarate salt of Compound A is Compound A glutarate salt. In certain embodiments, the glutarate salt of Compound A is Form A of Compound A glutarate salt.

[0226] In some embodiments, the suitable acid is acetic acid. In some embodiments, the present invention provides a method for making an acetate salt of Compound A. In certain embodiments, the acetate salt of Compound A is Compound A acetate salt. In certain embodiments, the acetate salt of Compound A is Form A of Compound A acetate salt.

[0227] In some embodiments, the suitable acid is malonic acid. In some embodiments, the present invention provides a method for making a malonate salt of Compound A. In certain embodiments, the malonate salt of Compound A is Compound A malonate. In certain embodiments, the malonate salt of Compound A is Form A of Compound A malonate. In certain embodiments, the malonate salt of Compound A is Form B of Compound A malonate.

[0228] In some embodiments, the suitable acid is sebacic acid. In some embodiments, the present invention provides a method for making a sebacate salt of Compound A. In certain embodiments, the sebacate salt of Compound A is Compound A sebacate salt. In certain embodiments, the sebacate salt of Compound A is Form A of Compound A sebacate salt.

[0229] In some embodiments, the suitable acid is acetophosphoric acid. In some embodiments, the present invention provides a method for making an aceturate salt of Compound A. In certain embodiments, the aceturate salt of Compound A is Compound A aceturate. In certain embodiments, the aceturate salt of Compound A is Form A of Compound A aceturate. In certain embodiments, the aceturate salt of Compound A is Form B of Compound A aceturate.

[0230] A suitable solvent may be any solvent system (eg, a solvent or mixture of solvents) in which compound A and / or the acid are soluble or at least partially soluble.

[0231] Examples of suitable solvents useful in 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 some embodiments, the solvent is one or more organic alcohols. In some embodiments, the solvent is chlorinated. In some embodiments, the solvent is an aromatic solvent.

[0232] In certain embodiments, the suitable solvent is methanol, ethanol, isopropanol, or acetone, which is anhydrous or in combination with water or heptane. In some embodiments, suitable solvents include tetrahydrofuran, dimethylformamide, dimethylsulfoxide, glyme, diglyme, methyl t-butyl ether, t-butanol, n-butanol, and acetonitrile. In some embodiments, the suitable solvent is ethanol. In some embodiments, the suitable solvent is absolute ethanol. In some embodiments, the suitable solvent is MTBE.

[0233] In some embodiments, the suitable solvent is ethyl acetate. In some embodiments, the suitable solvent is a mixture of methanol and methylene chloride. In some embodiments, the suitable solvent is a mixture of acetonitrile and water. In certain embodiments, the suitable solvent is methyl acetate, isopropyl acetate, acetone, or tetrahydrofuran. In certain embodiments, the suitable solvent is diethyl ether. In certain embodiments, the suitable solvent is water. In certain embodiments, the suitable solvent is methyl ethyl ketone. In certain embodiments, the suitable solvent is toluene.

[0234] In some embodiments, the present invention provides a method for preparing a salt compound of general formula X, 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. Means of solvent removal are known in the synthetic and chemical arts and include, but are not limited to, any of those described herein and in the Examples.

[0235] In some embodiments, the method of preparing the salt compound of general formula X includes one or more steps of heating or cooling the preparation.

[0236] In some embodiments, the method for preparing the salt compound of general formula X includes one or more steps of vigorously agitating or stirring the preparation.

[0237] In some embodiments, the method of preparing a salt compound of general formula X comprises adding a suitable acid to a solution or slurry of compound A.

[0238] In some embodiments, the method for preparing a salt compound of formula X comprises a heating step.

[0239] In certain embodiments, the salt compound of formula X precipitates from the mixture. In other embodiments, the salt compound of formula X crystallizes from the mixture. In other embodiments, the salt compound of formula X crystallizes from the solution after seeding the solution (i.e., adding crystals of the salt compound of formula X to the solution).

[0240] The salt compound of formula X can be precipitated from the reaction mixture or produced by removing some or all of the solvent through methods such as evaporation, distillation, filtration (e.g., nanofiltration, ultrafiltration), reverse osmosis, absorption, and reaction, by adding an anti-solvent such as heptane, by cooling, or by different combinations of these methods.

[0241] Generally as described above, the salt compound of formula X is optionally isolated. It will be understood that the salt compound of formula X can be isolated by any suitable physical means known to those skilled 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.

[0242] In certain embodiments, the salt compound of formula X is separated from the supernatant by filtration.

[0243] 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 and, optionally, at elevated temperature.

[0244] Pharmaceutical Compositions and Methods of Administration In some embodiments, the present disclosure is directed to a pharmaceutical composition comprising Compound A succinate salt.

[0245] The pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of the compounds of the present disclosure, or pharma- ceutically acceptable salts, esters, prodrugs, solvates, hydrates, or derivatives thereof, as an active ingredient. If desired, the pharmaceutical compositions contain pharma- ceutically acceptable salts and / or coordination complexes thereof, as well as one or more pharma- ceutically acceptable additives, carriers including inert solid diluents and excipients, diluents including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants.

[0246] The pharmaceutical composition can be administered alone or in combination with one or more other drugs, which are also typically administered in the form of a pharmaceutical composition. If desired, the compound or compounds of the present invention and the other drugs can be mixed in a formulation, or both components can be formulated in separate formulations and used in combination separately or simultaneously.

[0247] In some embodiments, the concentration of one or more compounds provided in a pharmaceutical composition of the present invention is 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%, 0.0 5%, 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 any number in a range defined by and inclusive of any two of the above numbers) w / w, w / v or v / v.

[0248] In some embodiments, the concentration of one or more compounds of the present invention is 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. 50%, 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 any number in a range defined by and inclusive of any two of the above numbers) w / w, w / v, or v / v.

[0249] In some embodiments, the concentration of one or more compounds of the present invention is from about 0.0001% to about 50%, from about 0.001% to about 40%, from about 0.01% to about 30%, from about 0.02% to about 29%, from about 0.03% to about 28%, from about 0.04% to about 27%, from about 0.05% to about 26%, from about 0.06% to about 25%, from about 0.07% to about 24%, from about 0.0 The range is from about 8% to about 23%, from about 0.09% to about 22%, from about 0.1% to about 21%, from about 0.2% to about 20%, from about 0.3% to about 19%, from about 0.4% to about 18%, from about 0.5% to about 17%, from about 0.6% to about 16%, from about 0.7% to about 15%, from about 0.8% to about 14%, from about 0.9% to about 12%, or from about 1% to about 10% w / w, w / v, or v / v.

[0250] In some embodiments, the concentration of one or more compounds of the present invention is within 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%, or about 0.1% to about 0.9% w / w, w / v or v / v.

[0251] In some embodiments, the amount of one or more compounds of the present invention is 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, 0.09 g, , 0.08g, 0.07g, 0.06g, 0.05g, 0.04g, 0.03g, 0.02g, 0.01g, 0.009g, 0.008g, 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 range defined by and including any two of the preceding figures).

[0252] In some embodiments, the amount of one or more compounds of the present invention is 0.0001g, 0.0002g, 0.0003g, 0.0004g, 0.0005g, 0.0006g, 0.0007g, 0.0008g, 0.0009g, 0.001g, 0.0015g, 0.002g, 0.0025g, 0.003g, 0.00 35g, 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, 0.04 5g, 0.05g, 0.055g, 0.06g, 0.065g, 0.07g, 0.075g, 0.08g, 0.085g, 0.09g, 0.095g, 0.1 g, 0.15g, 0.2g, 0.25g, 0.3g, 0.35g, 0.4g, 0.45g, 0.5g, 0.55g, 0.6g, 0.65g, 0.7g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g, 7.5 g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g (or any number within a range defined by and including any two of the foregoing numbers).

[0253] In some embodiments, the amount of one or more compounds of the present invention is in the range of 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.

[0254] The compounds according to the invention are effective over a wide dose range. For example, in the treatment of adults, doses of 0.01-1000 mg per day, 0.5-100 mg, 1-50 mg, and 5-40 mg per day are examples of doses that may be used. An exemplary dose is 10-30 mg per day. The exact dose depends on the route of administration, the form in which the compound is administered, the subject being treated, the weight of the subject being treated, and the preference and experience of the attending physician.

[0255] Pharmaceutical compositions of the present invention typically contain an active ingredient of the present invention (i.e., a compound of the present disclosure) or a pharma- ceutically acceptable salt and / or coordination complex thereof, as well as one or more pharma- ceutically acceptable excipients, carriers including, but not limited to, inert solid diluents and excipients, diluents, sterile aqueous solutions, and various organic solvents, permeation enhancers, solubilizers, and adjuvants.

[0256] Non-limiting exemplary pharmaceutical compositions and methods for preparing same are described below.

[0257] Pharmaceutical Composition for Oral Administration In some embodiments, the present invention provides a pharmaceutical composition for oral administration containing a compound of the present invention and a pharmaceutical excipient suitable for oral administration.

[0258] In some embodiments, the present invention provides a solid pharmaceutical composition for oral administration that contains (i) an effective amount of a compound of the present invention, optionally (ii) an effective amount of a second pharmaceutical agent, and (iii) a pharmaceutical excipient suitable for oral administration. In some embodiments, the composition further contains (iv) an effective amount of a third pharmaceutical agent.

[0259] In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral ingestion. Pharmaceutical compositions of the present invention suitable for oral administration may be provided as individual dosage forms such as capsules, cachets, or tablets, or liquids or aerosol sprays, each containing a predetermined amount of the active ingredient as a powder or granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Such dosage forms may be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient into association with a carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and thoroughly mixing the active ingredient with a liquid carrier or a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired presentation. For example, tablets can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with additives such as, but not limited to, binders, lubricants, inert diluents, and / or surfactants or dispersants. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0260] The present invention further encompasses anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, since water can accelerate the degradation of some compounds. For example, water can be added (e.g., 5%) in the pharmaceutical arts as a means of simulating long-term storage to determine characteristics such as shelf life or stability of a formulation over time. The anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. The pharmaceutical compositions and dosage forms of the present invention containing lactose can be made anhydrous if they are expected to be in substantial contact with moisture and / or humidity during manufacturing, packaging, and / or storage. The anhydrous pharmaceutical composition can be prepared and stored such that its anhydrous nature is maintained. Thus, the anhydrous composition can be packaged using materials known to prevent exposure to water such that it can be included in a suitable formulary kit. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, and the like, unit dose containers, blister packs, and strip packs.

[0261] The active ingredient can be combined in intimate mixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms, depending on the form of preparation desired for administration. In preparing compositions for oral dosage forms, any of the pharmaceutical media can be used as carriers, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc., for oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols or carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents, and in some embodiments, without the use of lactose, for oral solid preparations. For example, suitable carriers include powders, capsules, and tablets with solid oral preparations. If desired, tablets can be coated by standard aqueous or non-aqueous techniques.

[0262] 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 such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropyl methylcellulose, microcrystalline cellulose, and mixtures thereof.

[0263] Examples of excipients suitable for use in pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0264] Disintegrants may 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 may be insufficient for disintegration to occur, and thus may alter the rate and extent of release of the active ingredient from the dosage form. Thus, a dosage form of the compound disclosed herein may be formed using a sufficient amount of disintegrant that is neither too little nor too much to adversely alter the release of the active ingredient. The amount of disintegrant used may vary based on the type of formulation and mode of administration, and can be readily discerned by one of ordinary skill in the art. About 0.5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent of disintegrant may 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-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.

[0265] Lubricants that can be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, 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 mixtures thereof. Additional lubricants include, for example, syloid silica gel, coagulated aerosol of synthetic silica, or mixtures thereof. Lubricants can be added optionally in an amount of less than about 1 weight percent of the pharmaceutical composition.

[0266] When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient therein may be combined with diluents such as water, ethanol, propylene glycol, glycerin, and various combinations thereof, as well as various sweetening or flavoring agents, coloring agents or dyes, and, if desired, emulsifying and / or suspending agents.

[0267] The tablets may be uncoated or may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period.For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be used.Formulations for oral use may also be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin, or olive oil).

[0268] 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, i.e., 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.

[0269] Suitable hydrophilic surfactants will generally have an HLB value of at least 10, while suitable lipophilic surfactants will generally have an HLB value of about 10 or less. 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 have higher solubility in oil, while surfactants with higher HLB values ​​are more hydrophilic and have higher solubility in aqueous solutions.

[0270] Hydrophilic surfactants are generally considered to be 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 of about 10 or less. However, the HLB value of a surfactant is only a rough guideline that is generally used to enable the formulation of industrial, pharmaceutical, and cosmetic emulsions.

[0271] The hydrophilic surfactant may be either ionic or non-ionic.Suitable ionic surfactants include alkyl ammonium salts, fusidate salts, 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, lysophospholipids and their derivatives, carnitine fatty acid ester salts, salts of alkyl sulfates, fatty acid salts, docusate sodium, acyl lactylates, mono- and diacetylated tartaric acid esters of mono- and diglycerides, succinylated mono- and diglycerides, citrate esters of mono- and diglycerides, and mixtures thereof.

[0272] Among the aforementioned groups, ionic surfactants include, by way of example, lecithin, lysolecithin, phospholipids, lysophospholipids and their derivatives, carnitine fatty acid ester salts, salts of alkyl sulfates, fatty acid salts, docusate sodium, acyl lactylates, mono- and diacetylated tartaric acid esters of mono- and diglycerides, succinylated mono- and diglycerides, citrate esters of mono- and diglycerides, and mixtures thereof.

[0273] Ionic surfactants include lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactate esters of fatty acids, stearoyl-2-lactate, stearoyl lactate, succinyl lactate, glycer ... The ionic forms may be acetylated monoglycerides, mono / diacetylated tartaric acid esters of mono / diglycerides, citrate esters of mono / diglycerides, cholyl sarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teraceyl sulfate, docusate, lauroyl carnitine, palmitoyl carnitine, myristoyl carnitine, and salts and mixtures thereof.

[0274] Hydrophilic nonionic surfactants include, but are not limited to, alkyl glucosides, alkyl maltosides, alkyl thioglucosides, lauryl macrogol glycerides, 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 with 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 with 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.

[0275] Other hydrophilic nonionic surfactants include 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, PE G-20 Dilaurate, PEG-25 Glyceryl Trioleate, 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 Caprate / Caprylate Glycerides, PEG-8 Caprate / Caprylate Glycerides, Polyglyceryl-10 Laurate, PEG-30 Cholesterol, PEG-25 Phytosterols, PEG-30 Soy Sterols, PEG-20 Trioleate, PEG-40 Sorbitan Oleate, PEG-80 Sorbitan Laurate, Polysorbate 20, Polysorbate 80, POE-9 Lauryl Ether, These include, but are not limited to, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl L-oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonylphenol-based, PEG 15-100 octylphenol-based, and poloxamer.

[0276] Suitable lipophilic surfactants include, by way of example only, 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 with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols, fat-soluble vitamins / vitamin derivatives, 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 with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.

[0277] In one embodiment, the composition may contain a solubilizer to ensure good solubilization and / or dissolution of the compound of the present invention and minimize precipitation of the compound of the present invention. This may be particularly important for compositions for parenteral use, such as compositions for injection. Solubilizers may also be added to increase the solubility of hydrophilic drugs and / or other components (e.g., surfactants) or to maintain the composition as a stable or homogeneous solution or dispersion.

[0278] Examples of suitable solubilizers include alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and its isomers, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethylisosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropylmethylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives, ethers of polyethylene glycol having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG, amides and other nitrogen-containing compounds, such as 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-aryl ethers, ... Examples of solubilizing agents include, but are not limited to, alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide, and polyvinylpyrrolidone; citrates 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 solubilizing agents known in the art such as, but not limited to, dimethylacetamide, dimethylisosorbide, N-methylpyrrolidone, monooctanoin, diethylene glycol monoethyl ether, and water.

[0279] Mixtures of solubilizers may be used. Examples include, but are not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyalkylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcyclodextrin, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethylisosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol, and propylene glycol.

[0280] The amount of solubilizer that may be included is not particularly limited. The amount of a given solubilizer may be limited to a biologically acceptable amount, which can be easily determined by one of ordinary skill in the art. In some situations, for example, to maximize the concentration of the drug, it may be advantageous to include an amount of solubilizer that far exceeds the biologically acceptable amount, and the excess solubilizer is removed using conventional techniques such as distillation or evaporation before providing the composition to the subject. Thus, when present, the solubilizer may be in a weight ratio of 10% by weight, 25% by weight, 50% by weight, 100% by weight, or up to about 200% by weight, based on the total weight of the drug and other additives. If desired, very small amounts of solubilizer, such as 5%, 2%, 1% of solubilizer, may also be used. Typically, the solubilizer may be present in an amount of about 1% by weight to about 100% by weight, more typically about 5% by weight to about 25% by weight.

[0281] The composition may further comprise one or more pharma- ceutically acceptable additives and excipients, including, but not limited to, anti-adherents, anti-foaming agents, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, tonicity agents, flavoring agents, coloring agents, odorants, opacifying agents, suspending agents, binders, excipients, plasticizers, lubricants, and mixtures thereof.

[0282] In addition, acids or bases may be incorporated into the composition to facilitate processing, enhance stability, or for other reasons. Examples of pharma-ceutically 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, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS), and the like.

[0283] Also suitable are bases that are salts of pharma- ceutically acceptable acids (e.g., acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic 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-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, uric acid, etc.). Salts of polybasic acids such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used. When the base is a salt, the cation can be any convenient pharma-ceutically 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.

[0284] Suitable acids are pharma- ceutically acceptable organic or inorganic acids. 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, alkanesulfonic 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, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, uric acid, etc.

[0285] Injectable pharmaceutical composition In some embodiments, the present invention provides an injectable pharmaceutical composition comprising a compound of the present invention and a pharmaceutical excipient suitable for injection. The components and amounts of drugs in the composition are as described herein.

[0286] Forms in which the novel compositions of the present invention can be incorporated for administration by injection include aqueous or oily suspensions or emulsions including sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles.

[0287] Aqueous solutions in physiological saline are also commonly used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be used. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like.

[0288] Sterile injectable solution is prepared by incorporating the compound of the present invention in the required amount in a suitable solvent together with various other components as listed above as necessary, followed by filtration sterilization.Generally, dispersion is prepared by incorporating various sterilized active components into a sterile vehicle that contains a basic dispersion medium and other necessary components from those listed above.For the preparation of sterile powder for sterile injectable solution, the specific desired preparation method is vacuum drying technology and freeze-drying technology, which produces powder of active component with any additional desired components from its solution that has been previously sterile-filtered.

[0289] Pharmaceutical Compositions for Topical (e.g., Transdermal) Delivery 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.

[0290] The composition of the present invention can be formulated into solid, semi-solid or liquid form preparations suitable for topical or local administration, such as gel, water-soluble jelly, cream, lotion, suspension, foam, powder, slurry, ointment, solution, oil, paste, suppository, spray, emulsion, saline, dimethyl sulfoxide (DMSO)-based solution, etc. Generally, carriers with higher density can provide areas with prolonged exposure to active ingredient. In contrast, solution formulations can provide more rapid exposure of active ingredient to selected areas.

[0291] The pharmaceutical compositions may also include suitable solid or gel phase carriers or additives, which are compounds that allow for increased penetration or aid in the delivery of therapeutic molecules across the stratum corneum permeability barrier of the skin. There are many of these penetration enhancing molecules known to those skilled in the art of topical formulation.

[0292] Examples of such carriers and additives include, but are not limited to, humectants (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), pyrrolidone, glycerol 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 glycol.

[0293] Another exemplary formulation for use in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches can be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts, with or without another agent.

[0294] The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent Nos. 5,023,252, 4,992,445, and 5,001,139. ​​Such patches may be constructed for continuous, pulsatile, or on-demand delivery of pharmaceutical agents.

[0295] Pharmaceutical Composition for Inhalation Compositions for inhalation or insufflation include solutions and suspensions in pharma- ceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharma- ceutically acceptable additives as described above. Preferably, the compositions are administered by oral or nasal respiratory route for local or systemic effect. Compositions, preferably in pharma- ceutically acceptable solvents, may be nebulized by the use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask tent, or intermittent pressurized breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from a device that delivers the formulation in an appropriate manner.

[0296] Other Pharmaceutical Compositions Pharmaceutical compositions may also be prepared from the compositions described herein and one or more pharma- ceutical acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, ocular, intranasal, epidural, or intraspinal administration. 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, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 20037ybg; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999), all of which are incorporated herein by reference in their entireties.

[0297] The administration of the compound or pharmaceutical composition of the present invention can be carried out by any method that allows the compound to be delivered to the site of action.These methods include oral route, intraduodenal route, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical (e.g., transdermal application), rectal administration, administration via local delivery by catheter or stent, or administration via inhalation.The compound can also be administered intraadiposely or intrathecally.

[0298] The amount of compound administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the nature of the compound, and the discretion of the prescribing physician. However, effective dosages range from about 0.001 to about 100 mg / kg body weight / day, preferably about 1 to about 35 mg / kg / day, in single or divided doses. For a 70 kg human, this would be about 0.05 to 7 g / day, preferably about 0.05 to about 2.5 g / day. In some cases, dosage levels below the lower limit of the aforementioned range may be more than sufficient, while in other cases even larger doses may be used without causing adverse side effects, for example, by dividing such larger doses into several smaller doses for administration throughout the day.

[0299] In some embodiments, the compounds of the invention are administered in a single dose.

[0300] Typically, such administration is by injection, for example intravenous injection, to rapidly introduce the drug. However, other routes may be used as appropriate. A single dose of the compound of the present invention may also be used to treat acute conditions.

[0301] In some embodiments, the compound of the present invention is administered in multiple doses. Dosing can be about once, twice, three times, four times, five times, six times, or more than six times per day. Dosing can be about once a month, once every two weeks, once a week, or once every other day. In another embodiment, the compound of the present invention and another agent are administered together about once a day to about six times a day. In another embodiment, administration of the compound of the present invention and the agent continues for less than about seven days. In yet another embodiment, administration continues for more than about six days, ten days, fourteen days, twenty-eight days, two months, six months, or a year. In some cases, continuous administration is achieved and maintained as long as necessary.

[0302] Administration of the compounds of the invention may continue for as long as necessary. In some embodiments, the compounds of the invention are administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the compounds of the invention are administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the compounds of the invention are administered chronically on an ongoing basis, for example, to treat chronic effects.

[0303] An effective amount of the compounds of this invention may be administered by any of the accepted modes of administration for drugs having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intraarterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant, either in single or multiple doses.

[0304] The compositions of the present invention can also be delivered via impregnated or coated devices, such as stents, or cylindrical polymers inserted into arteries. Such administration methods can help prevent or improve restenosis after procedures such as balloon angioplasty. Without being bound by theory, the compounds of the present invention can slow or inhibit smooth muscle cell migration and proliferation in arterial walls, which contribute to restenosis. The compounds of the present invention can be administered by local delivery, for example, from the struts of a stent, from a stent graft, from a graft, or from the cover or sheath of a stent. In some embodiments, the compounds of the present invention are mixed with a matrix. Such a matrix can be a polymer matrix and can serve to bind the compound to the stent. Suitable polymer matrices for such uses include, for example, lactone-based polyesters or copolyesters (e.g., polylactides, polycaprolactone glycolides, polyorthoesters, polyanhydrides, polyamino acids, polysaccharides, polyphosphazenes, poly(ether-ester) copolymers (e.g., PEO-PLLA), polysiloxanes, poly(ethylene-vinyl acetate), acrylate-based polymers or copolymers (e.g., polyhydroxyethylmethylmethacrylate, polyvinylpyrrolidinone), fluorinated polymers such as polytetrafluoroethylene, and cellulose esters. Suitable matrices may be non-degradable or may degrade over time, allowing the compound to be transported. The compound of the present invention can be applied to the surface of the stent by various methods, such as dipping / spin coating, spray coating, dip coating, and / or brush coating. The compound may be applied in a solvent and the solvent evaporated to form a layer of the compound on the stent. Alternatively, the compound may be disposed within the body of the stent or graft, for example within microchannels or micropores. When implanted, the compound diffuses out of the stent body and contacts the arterial wall. Such a stent may be prepared by dipping a stent manufactured to contain such micropores or microchannels into a solution of the compound of the present invention in a suitable solvent, followed by evaporation of the solvent.Excess drug on the surface of the stent can be removed via an additional short solvent wash. In yet another embodiment, the compounds of the present invention can be covalently bonded to the stent or graft. Covalent linkers that degrade in vivo resulting in the release of the compounds of the present invention can be used. Any biolabile bond can be used for such purposes, such as ester, amide or anhydride bonds. The compounds of the present invention can also be administered intravascularly from a balloon used during angioplasty. Extravascular administration of the compounds by pericard or adventitial application of the formulations of the present invention can also be performed to reduce restenosis.

[0305] Various stent devices that may be used as described are disclosed, for example, in the following references, all of which are incorporated herein 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.

[0306] The compound of the present invention can be administered in doses.It is known in the art that due to the inter-subject variability in compound pharmacokinetics, individualization of dosing regimen is necessary for optimal treatment.The dosing of the compound of the present invention can be found by routine experimentation in light of the present disclosure.

[0307] When a compound of the invention is administered in a composition containing one or more other drugs, where the drug has a shorter half-life than the compound of the invention, the unit dosage form of the drug and compound of the invention may be adjusted accordingly.

[0308] The pharmaceutical composition may be in a form suitable for oral administration, for example, as a tablet, capsule, pill, powder, sustained release formulation, solution, or suspension, for parenteral injection as a sterile solution, suspension, or emulsion, for topical administration as an ointment or cream, or for rectal administration as a suppository. The pharmaceutical composition may be in a unit dosage form suitable for single administration of a precise dose. The pharmaceutical composition includes a conventional pharmaceutical carrier or additive, and a compound according to the present invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.

[0309] Exemplary parenteral administration forms include solutions or suspensions of the active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.

[0310] How to use The method typically includes administering a therapeutically effective amount of the compound of the present invention to a subject. The therapeutically effective amount of the combination of compounds of the present invention may vary depending on the intended application (in vitro or in vivo), or the subject and disease state to be treated (e.g., subject weight and age, severity of disease state, mode of administration, etc.), which can be easily determined by those skilled in the art. The term also applies to a dose that induces a specific response in target cells, such as reduced proliferation or downregulation of the activity of a target protein. The specific dose will vary depending on the particular compound selected, the dosing regimen to be followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system in which it is delivered.

[0311] As used herein, "IC 50 The term "half maximal inhibitory concentration" refers to the half maximal inhibitory concentration in inhibiting a biological or biochemical function. This quantitative measure indicates how much of a particular inhibitor is needed to half-inhibit a given biological process (or component of the process, i.e., an enzyme, cell, cellular receptor, or microorganism). In other words, it is the half maximal (50%) inhibitory concentration (IC) of a substance (50% IC, or IC50 ) EC 50 refers to the plasma concentration required to obtain >50% of the maximal effect in vivo.

[0312] In some embodiments, the subject methods utilize CDK inhibitors that have IC50 values ​​at or below about a given value, as determined in an in vitro assay. In some embodiments, the CDK inhibitor is 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, 180 nM or less, 190 nM or less, 200 nM or less, 225 nM or less, 250 nM or less, 275 nM or less, 300 nM or less, 325 nM or less, 350 nM or less, 375 nM or less, 400 nM or less, 425 nM or less, 450 nM or less, 475 nM or less, 500 nM or less, 550 nM or less, 600 nM or less IC of ≤ 650nM, ≤ 700nM, ≤ 750nM, ≤ 800nM, ≤ 850nM, ≤ 900nM, ≤ 950nM, ≤ 1μM, ≤ 1.1μM, ≤ 1.2μM, ≤ 1.3μM, ≤ 1.4μM, ≤ 1.5μM, ≤ 1.6μM, ≤ 1.7μM, ≤ 1.8μM, ≤ 1.9μM, ≤ 2μM, ≤ 5μM, ≤ 10μM, ≤ 15μM, ≤ 20μM, ≤ 25μM, ≤ 30μM, ≤ 40μM, ≤ 50μM, 60μM, 70μM, 80μM, 90μM, 100μM, 200μM, 300μM, 400μM, or 500μM or less (or within a range defined by and inclusive of any two of the foregoing numbers). 50 Inhibits CDK at low levels.

[0313] In some embodiments, the CDK inhibitor has an IC50 or IC60 inhibitor that inhibits one, two, or three other CDKs. 50 IC value that is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, or 1000 times lower (or within a range defined by and including any two of the above numbers) 50Selectively inhibits CDK at low levels.

[0314] In some embodiments, the CDK inhibitor is at or near 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 , 700nM, 750nM, 800nM, 850nM, 900nM, 950nM, 1μM, 1.1μM, 1.2μM, 1.3μM, 1.4μM, 1.5μM, 1.6μM, 1.7μM, 1.8μM, 1.9μM, 2μM, 5μM, 10μM, 15μM, 20μM, 25μM, 30μM, 40μM, 50μM, 60μM, 70μM, 80μM, 90μM, 100μM, 200μM, 300μM, 400μM, or less than 500μM (or within a range defined by and including any two of the above numbers). 50 The IC50 value is the IC50 value for one, two or three other CDKs. 50 At least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, or 1000 times (or a range defined by and inclusive of any two of the above numbers) less than the value.

[0315] The subject methods are useful for treating disease conditions associated with CDK. Any disease condition that results directly or indirectly from an abnormal activity or expression level of a CDK may be a disease condition of interest.

[0316] Various disease states associated with CDKs have been reported, including autoimmune diseases, neurodegeneration (e.g., Parkinson's disease, Alzheimer's disease, and ischemia), inflammatory diseases, viral infections, and cancer (e.g., colon cancer, breast cancer, small cell lung cancer, non-small cell lung cancer, bladder cancer, ovarian cancer, prostate cancer, chronic lymphocytic leukemia, lymphoma, myeloma, acute myeloid leukemia, or pancreatic cancer).

[0317] Non-limiting examples of such conditions include acanthoma, acinic cell carcinoma, acoustic neuroma, acral lentiginous melanoma, acrohidroma, acute eosinophilic leukemia, acute lymphoblastic leukemia, acute lymphocytic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute myeloblastic leukemia with maturation, acute myeloid dendritic cell leukemia, acute myeloid leukemia, acute myelogenous ... leukemia), acute promyelocytic leukemia, adamantinoma, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenoid odontogenic tumor, adrenal cortical carcinoma, adult T-cell leukemia, aggressive NK-cell leukemia, AIDS-related cancer, AIDS-related lymphoma, alveolar soft part sarcoma, ameloblastic fibroma, anal cancer, anaplastic large cell lymphoma, anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, appendix cancer, astrocytoma, atypical teratoid rhabdoid tumor, basal cell carcinoma, Basal-like carcinoma, B-cell leukemia, B-cell lymphoma, Bellini duct carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, bone tumor, brain stem glioma, brain tumor, breast cancer, Brenner tumor, bronchial tumor, bronchioloalveolar carcinoma, Brown tumor, Burkitt lymphoma, cancer of unknown primary site, carcinoid tumor, carcinoma, carcinoma in situ, penile cancer, cancer of unknown primary site, carcinosarcoma, Castleman disease, central nervous system embryonal tumor, cerebellar astrocytoma, cerebral astrocytoma, cervical cancer, bile duct cancer, chondroma, chondrosarcoma , chordoma, choriocarcinoma, choroid plexus papilloma, chronic lymphocytic leukemia, chronic monocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disease, chronic neutrophilic leukemia, clear cell tumor, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, Degos disease, dermatofibrosarcoma protozoa, dermoid cyst, decidual small round cell tumor, diffuse large B-cell lymphoma, decidual neuroepithelial tumor, germ cell carcinoma, endodermal sinus tumor, uterine cancer, endometrial cancer, endometrioid tumor, gut-associated T-cell lymphoma, ependymal blastoma cell tumor, ependymoma, epidermal carcinoma, parathyroid sarcoma, erythroblastic leukemia, esophageal cancer, esthesioneublastoma, Ewing family tumor, Ewing family sarcoma, Ewing sarcoma, extracranial germ cell tumor, extracarinal germ cell tumor, extrahepatic bile duct cancer, extramammary Paget's disease, fallopian tube cancer, fetal, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, gallbladder cancer, gallbladder cancer, ganglioneuroma, radiculoneuroma, gastric cancer, gastric lymphoma, gastrointestinal cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor,Gastrointestinal stromal tumor, germ cell tumor, germinoma, gestational choriocarcinoma, gestational trophoblastic tumor, giant cell tumor of bone, glioblastoma multiforme, glioma, glioma cerebrovascular disease, glomus tumor, glucagonoma, gonadoblastoma, granulosa cell tumor, hairy cell leukemia, head and neck cancer, heart cancer, b-thalassemia and sickle cell disease Hemoglobinopathies such as hemoglobinopathy (such as sarcoma, SCD), hemangioblastoma, hemangiopericytoma, hemangiosarcoma, hematologic malignancies, hepatocellular carcinoma, hepatosplenic T-cell lymphoma, hereditary breast and ovarian cancer syndrome, Hodgkin lymphoma, hypopharyngeal cancer, hypothalamic glioma, inflammatory breast cancer, intraocular melanoma, islet cell carcinoma, islet cell tumor, juvenile myelomonocytic leukemia, Kaposi's sarcoma, kidney cancer, Klatskin tumor, Krukenberg tumor, laryngeal cancer, lentigo maligna, leukemia, lip and oral cancer, liposarcoma, lung cancer, jaundice, Somatic tumor, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphocytic leukemia, lymphoma, macroglobulinemia, malignant fibrous histiocytoma, malignant fibrous histiocytoma of bone, malignant glioma, malignant mesothelioma, malignant peripheral nerve sheath tumor, malignant rhabdoid tumor, malignant triton tumor, MALT lymphoma, mantle cell lymphoma, mast cell leukemia, mastocytosis, breast germ cell tumor, breast tumor, medullary thyroid cancer, medulloblastoma, medulloepithelioma, melanoma, meningioma, Merkel cell carcinoma, mesothelioma, mesothelioma, occult squamous Epithelial cancer, metastatic urothelial carcinoma, mixed Mullerian tumor, monocytic leukemia, oral cancer, mucinous tumor, multiple endocrine neoplasia syndrome, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, myeloid leukemia, myelosarcoma, myeloproliferative disorder, myxoma, nasal cancer, nasopharyngeal cancer, neoplasm, schwannoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, non-Hodgkin's lymphoma, non-melanoma skin cancer, non-small cell lung cancer, ophthalmic tumor, oligodendroglioma, optic nerve sheath meningioma, oral cancer , oral cavity 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, Pancoast tumor, pancreatic cancer, pancreatic cancer, papillary thyroid cancer, papillomatosis, paraganglioma, paranasal sinus cancer, parathyroid cancer, penile cancer, hemangioperiepithelioma, pharyngeal cancer, pheochromocytoma, intermediate differentiation pineal tumor, pineoblastoma, pituitary cell tumor, pituitary adenoma, pituitary tumor, plasma cell neoplasm, alveolar germinoma, polygerminoma, precursor T-lymphoblastic lymphoma, primary central nervous system lymphoma,Primary pleural 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 transformation, sacral teratoma, salivary gland carcinosarcoma, Schwannomatosis, sebaceous gland carcinoma, secondary neoplasms, seminoma, serous tumor, Sertoli-Leydig cell tumor, sex cord-stromal tumor, Sezary syndrome, signet ring cell tumor, skin cancer, small blue round cell tumor, small cell carcinoma, small cell lung cancer, small cell lymphoma, small intestine cancer, soft tissue sarcoma, somatostatinoma, soot warts, spinal cord tumor, spinal cord tumor, splenic marginal zone tumor These include, but are not limited to, lymphoma, squamous cell carcinoma, gastric cancer, superficial spreading melanoma, superficial 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, teratoma, peripheral lymphatic duct carcinoma, testicular cancer, sarcoma, pharyngeal cancer, thymic carcinoma, thymoma, thyroid cancer, renal pelvis and ureter transitional cell carcinoma, transitional cell carcinoma, urethral cancer, urinary tract neoplasm, uterine sarcoma, uveal melanoma, vaginal cancer, Berner-Morrison syndrome, verruca carcinoma, visual pathway glioma, vulvar cancer, Waldenstrom's macroglobulinemia, Warthin's tumor, Wilms' tumor, and combinations thereof.

[0318] In some embodiments, the method is for treating 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 cancer.

[0319] In other embodiments, the method is for treating a disease selected from breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, uterine cancer, or cervical cancer.

[0320] In other embodiments, the method is for treating a disease selected from acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, leukemia, such as acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS), or epidermoid carcinoma.

[0321] The compounds of the present disclosure, as well as pharmaceutical compositions containing them, can be administered alone or in combination with medical therapy to treat any of the diseases described.Medical therapy includes, for example, surgery and radiation therapy (e.g., gamma irradiation, neutron radiation therapy, electron beam radiation therapy, proton radiation therapy, brachytherapy, total body radioisotopes).

[0322] In other aspects, the compounds of the present disclosure, as well as pharmaceutical compositions containing them, can be administered alone or in combination with one or more other agents to treat any of the diseases described.

[0323] In other methods, the compounds of the present disclosure, as well as pharmaceutical compositions containing them, can be administered in combination with an agonist of a nuclear receptor agent.

[0324] In other methods, the compounds of the present disclosure, as well as pharmaceutical compositions containing them, can be administered in combination with an antagonist of a nuclear receptor agent.

[0325] In other methods, the compounds of the present disclosure, as well as pharmaceutical compositions containing them, can be administered in combination with an anti-proliferative agent.

[0326] In some embodiments, the disclosure relates to a method of treating a CDK4- and CDK6-mediated disorder in a patient in need of such treatment, comprising administering to the patient a compound of formula I, including any of the subgenera described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula I, including any of the subgenera described herein.

[0327] In some embodiments, the CDK4- and CDK6-mediated disorder is cancer, hi 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 lymphocytic leukemia, lymphoma, myeloma, acute myeloid leukemia, secondary pancreatic cancer, or secondary brain metastasis.

[0328] In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is malignant brain cancer. 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.

[0329] In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is chronic lymphocytic leukemia. In some embodiments, the cancer is a leukemia or lymphoma. In some embodiments, the cancer is a 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.

[0330] 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.

[0331] 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.

[0332] In some embodiments, the patient is administered a pharmaceutical composition comprising a compound of Formula I, including any subgenera described herein, or a pharma- ceutically acceptable salt thereof, hi some embodiments, the administration is oral.

[0333] Combination therapy To treat cancer and other proliferative diseases, the compounds of the present invention can be used in combination with chemotherapeutic agents, nuclear receptor agonists or antagonists, or other antiproliferative agents. The compounds of the present invention can also be used in combination with drug therapies such as surgery or radiation therapy (e.g., gamma irradiation, neutron radiation therapy, electron beam radiation therapy, proton radiation therapy, brachytherapy, and whole body radioisotopes). Examples of suitable chemotherapeutic agents include abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, all-trans retinoic acid, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bendamustine, bevacizumab, bexarotene, bleomycin, bortezomib, bortezomib, busulfan intravenously, busulfan orally, castellon, capecitabine, carboplatin, carmustine, setuximab, ceftazidime ... Cimab, chlorambucil, cisplatin, cladribine, cloharabine, cyclophosphamide, cicarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanone propionate, eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, exemestane , fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, hisrelin acetate, ibritumomab tiuxetan acetate, idarubicin, ifosfamide, imatinib mesylate, interferon alfa-2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuproreductase acetate lolide, levamisole, lomustine, mechlorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin, paclitaxel, pamidronate, panobinostat, panitumumab, pegaspagase, pegfilgrastim, pemetrexed disodium, pentostatin,Pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, and zoledronic acid.

[0334] In some embodiments, the compounds of the present invention can be used in combination with therapeutic agents that target epigenetic regulators. Examples of epigenetic regulators include 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 inhibitors of protein arginine methyltransferases (PRMTs), such as PRMT5, PRMT1, and PRMT4. DNA methyltransferase inhibitors include inhibitors of DNMT1 and DNMT3.

[0335] For the treatment of cancer and other proliferative diseases, the compounds of the invention may be used in combination with targeted therapies including JAK kinase inhibitors (e.g., ruxolitinib), PI3 kinase inhibitors including P13K-delta selective and broad spectrum P13K inhibitors, cyclin dependent kinase inhibitors including MEK inhibitors, 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 member (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.

[0336] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1, e.g., 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 an immune checkpoint molecule is an inhibitor of PD-L1, e.g., 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 an immune checkpoint molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab.

[0337] In some embodiments, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulatory agent. 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 immunomodulatory agent is lenalidomide (LEN) or pomalidomide (POM).

[0338] For the treatment of autoimmune or inflammatory conditions, the compounds of the invention may be administered in combination with a corticosteroid (eg, triamcinolone, dexamethasone, fluocinolone, cortisone, prednisolone, or flumetholone).

[0339] To treat autoimmune or inflammatory conditions, the compounds of the invention may be administered in combination with immunosuppressants such as fluocinolone acetonide (Retisert®), rimexolone (AL-2178, Vexol, Alcon), or cyclosporine (Restasis®).

[0340] In some embodiments, the present disclosure is directed to a method described herein, further comprising administering to the patient an additional therapeutic agent.

[0341] The further therapeutic agent is a PRMT5 inhibitor, a HER2 kinase inhibitor, an aromatase inhibitor, an estrogen receptor antagonist, or an alkylating agent.

[0342] In some embodiments, the additional therapeutic agent is a PRMT5 inhibitor. In some embodiments, the additional therapeutic agent is a HER2 kinase inhibitor. In other embodiments, the additional therapeutic agent is an aromatase inhibitor. In other embodiments, the additional therapeutic agent is an estrogen receptor antagonist. In yet other embodiments, the additional therapeutic agent is an alkylating agent.

[0343] 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.

[0344] In yet other embodiments, the PRMT5 inhibitor is a compound disclosed in U.S. Published Patent Application No. 2020 / 0148692 (filed January 16, 2020), U.S. Published Patent Application No. 2019 / 0284193 (filed April 5, 2019), and U.S. Published Patent Application No. 2019 / 0048014 (filed August 9, 2018), each of which is incorporated herein in its entirety.

[0345] In some embodiments, the PRMT5 inhibitor is (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 pharma- ceutically acceptable salt or solvate thereof; (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 pharma- ceutically acceptable salt or solvate thereof; (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 pharma- ceutically acceptable salt or solvate thereof; (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 pharma- ceutically acceptable salt or solvate thereof; (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 pharma- ceutically acceptable salt or solvate thereof; (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 pharma- ceutically acceptable salt or solvate thereof; (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 pharma- ceutically acceptable salt or solvate thereof; (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 pharma- ceutically acceptable salt or solvate thereof; (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 pharma- ceutically acceptable salt or solvate thereof; (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 pharma- ceutically acceptable salt or solvate thereof; (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 pharma- ceutically acceptable salt or solvate thereof; (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 pharma- ceutically acceptable salt or solvate thereof; (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 pharma- ceutically acceptable salt or solvate thereof.

[0346] In some embodiments, the PRMT5 inhibitor is (2S,3S,4R,5R)-2-((R)-6-chloroiso-chroman-1-yl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol, or a pharma- ceutically acceptable salt or solvate thereof.

[0347] All features of each of the aspects of the invention apply to all other aspects mutatis mutandis.

[0348] 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 are not to be construed as limiting this invention in any manner. EXAMPLES

[0349] As shown in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures: It will be understood that while the general methods refer to the synthesis of specific compounds of the invention, the following general methods, and other methods known to those of skill in the art, can be applied to all compounds, as well as subclasses and species of each of these compounds, as described herein.

[0350] Example A - General Preparation of Compound A [ka] Compound A The title compound was prepared according to the steps and intermediates described below, and the '323 application, which is incorporated herein by reference in its entirety.

[0351] Step 1. tert-Butyl 6-nitro-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate [ka]

[0352] 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 inert atmosphere. The reaction mixture was heated at 100° C. for 6 h. 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 in 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 for: m / z=306.1; found: 306.1.

[0353] Step 2. 6-nitro-1',2',3',6'-tetrahydro-3,4'-bipyridine [ka]

[0354] tert-Butyl 6-nitro-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-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 added slowly at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 5 h. The reaction mixture was concentrated under reduced pressure and then diluted with water (10.0 mL). The solution was lyophilized and used without further purification to give the crude TFA salt of the title compound (18.6 g) as a yellow solid. C 10 H 12 N3O2[M+H] + LCMS calculated for: m / z=206.1; found: 206.0.

[0355] Step 3. 1'-Methyl-6-nitro-1',2',3',6'-tetrahydro-3,4'-bipyridine [ka]

[0356] 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 min and the reaction was cooled to 0 °C. Sodium triacetoxyborohydride (14.2 g, 66.9 mmol) was added in small portions at 0 °C. The resulting reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with saturated sodium bicarbonate (aq) (60.0 mL) and sodium carbonate was added until no gas evolution was observed. The organic layer was separated and the aqueous layer was extracted with DCM (30.0 mL x 2). The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The reaction sequence of steps 2-3 was repeated with the addition 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 with MeOH (0-50%) in DCM afforded the free base of the title compound (8.10 g, 36.9 mmol, quantitative yield over two steps) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.74 (d, J=2.1 Hz, 1H), 8.29-8.16 (m, 2H), 6.57 (t, J=3.6 Hz, 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 for: m / z=220.1; found: 220.0.

[0357] The free base was dissolved in EtOAc (50.0 mL), DCM (5.00 mL), and MeOH (5.00 mL). Then, HCl solution (37.0 mL, 74.0 mmol, 2N in iPrOAc) was added. The reaction mixture was stirred at room temperature for 2 h. The precipitate was collected by filtration and dried under reduced pressure to give the HCl salt of the title compound (9.46 g, 32.4 mmol, 90.1% yield) as a white solid.

[0358] Step 4. 5-(1-methylpiperidin-4-yl)pyridin-2-amine [ka]

[0359] In a 500 mL reaction vessel, 1'-methyl-6-nitro-1',2',3',6'-tetrahydro-3,4'-bipyridine, HCl salt (9.46 g, 32.4 mmol) was dissolved in MeOH (150 mL). Palladium on carbon (0.875 g, 0.822 mmol, 10 wt%) and glacial acetic acid (1.00 mL, 17.5 mmol) were added sequentially at room temperature. The reaction vessel was sealed in a Parr shaker and the vessel was charged with hydrogen (60 psi). 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 (30.0 mL) and neutralized with sodium hydroxide (3.39 g, 84.8 mmol). The organic layer was washed with water (30.0 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography using MeOH (0-50% with 0.1% Et3N) in DCM to give the title compound (6.10 g, 31.9 mmol, 98.5% yield) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 7.74 (d, J=2.2 Hz, 1H), 7.23 (dd, J=8.5, 2.4 Hz, 1H), 6.36 (d, J=8.5 Hz, 1H), 5.62 (s, 2H), 2.81 (d, J=11.4 Hz, 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 for: m / z=192.1; found: 192.1.

[0360] Step 5. 2-(2-chloro-5-fluoropyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one [ka]

[0361] n-Butyllithium (5.20 mL, 13.0 mmol, 2.5 M in hexanes) 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 min. Then, 2-chloro-5-fluoropyrimidine (1.38 g, 10.4 mmol) was added in one portion. The reaction mixture was stirred at -78 °C for 30 min. The reaction was quenched with saturated NH4Cl (aq) 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 x 2). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated.

[0362] To the crude residue in THF (30.0 mL) was added 2,3-dichloro-5,6-dicyano-p-benzoquinone (1.86 g, 8.20 mmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with DCM (30.0 mL), washed with hot potassium carbonate (10 wt% in water) (30.0 mL x 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 (aq)) to give the TFA salt of the title compound (1.35 g, 2.90 mmol, 35.3% yield) as an off-white solid. 16 H 16 ClFN3OS [M+H] + LCMS calculated for: m / z=352.1, 354.1; found: 352.0, 353.9.

[0363] 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

[0364] To a solution of 2-(2-chloro-5-fluoropyrimidin-4-yl)-7-isopropyl-3,5-dimethyl-thieno[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, CAS 1310584-14-5). The reaction vessel was sealed and the mixture was degassed with N2 three times. 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(aq)) to give the title compound as a TFA salt. The TFA salt was neutralized with saturated NaHCO3(aq) (20.0 mL) and the aqueous layer was extracted with DCM (20.0 mL x 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 lyophilization to give the HCl salt of the title compound (1.21 g, 2.23 mmol, 86.5% yield) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.46 (br s, 1H), 10.31 (br s, 1H), 8.75 (d, J=2.5 Hz, 1H), 8.21 (d, J=2.4 Hz, 1H), 8.12 (d, J=8.7 Hz, 1H), 7.71 (dd, J=8.8, 2.4 Hz, 1H), 7.55 (s, 1H), 3.52 (s, 3H), 3.46 (s, 2H), 3.20-2.97 (m, 2H), 2.95-2.84 (m, 2H), 2.77 (d, J=4.3 Hz, 3H), 2.69 (d, J=3.5 Hz, 3H), 2.06-1.93 (m, 4H), 1.31 (d, J=6.8 Hz, 6H). C 27 H 32 FN6OS [M+H] + LCMS calculated for: m / z=507.2; found: 507.2.

[0365] General Procedure for Examples 1-8 X-ray Powder Diffraction (XRPD) Data. The XRPD data was collected using the following parameters: Equipment: Rigaku Smart Lab SE X-ray wavelength: Cu, Kα, Kα1(Å): 1.540598, Kα2(Å): 1.544426 Kα2:Kα1 intensity ratio: 0.50 X-ray tube settings: 40kV, 15mA, scan mode 1D Scan range (2 theta): 3°-40°, step size (2 theta): 0.02° at scan speed (2 theta) 10° / min.

[0366] Thermogravimetric Analysis (TGA) TGA data was collected using the following parameters: Equipment: TA, TGA500 Method: Ramp, temperature range RT-300℃, heating rate 10℃ / min Purge gas: N2 (>99.999%) Pan type: Aluminum, open.

[0367] Differential Scanning Calorimetry (DSC): DSC data was collected using the following parameters: Equipment: TA, TGA500 Method: Ramp, temperature range RT-300℃, heating rate 10℃ / min Purge gas: N2 (>99.999%) Pan type: Aluminum, open.

[0368] Polarized Light Microscopy (PLM): PLM data were collected using the following parameters: Equipment: Olympus BX53 Methods: Samples were dispersed in methyl silicone oil on glass slides.

[0369] Example 1 - Compound A Free Base Form A [ka] Compound A Free Base Form A Table 1, reproduced above, sets forth the X-ray diffraction peaks observed for Form A of Compound A free base. [Table 11]

[0370] FIG. 1 shows the XRPD pattern of Form A of Compound A free base.

[0371] FIG. 2 shows the DSC thermogram and TGA trace of Form A of Compound A free base.

[0372] The properties of Form A of Compound A free base are summarized in Table 11 below. [Table 12]

[0373] Example 2 - Compound A Free Base Form B [ka] Compound A Free Base Form B Table 2, reproduced above, sets forth the X-ray diffraction peaks observed for Form B of Compound A free base. [Table 13]

[0374] FIG. 3 shows the XRPD pattern of Form B of Compound A free base.

[0375] FIG. 4 shows the DSC thermogram and TGA trace of Form B of Compound A free base.

[0376] The properties of Form B of Compound A free base are summarized in Table 12 below. [Table 14]

[0377] Example 3 - Compound A Free Base Form C [ka] Compound A Free Base Form C Table 3, reproduced above, sets forth the X-ray diffraction peaks observed for Form C of Compound A free base. [Table 15]

[0378] FIG. 5 shows the XRPD pattern of Form C of Compound A free base.

[0379] FIG. 6 shows the DSC thermogram and TGA trace of Form C of Compound A free base.

[0380] The properties of Form C of Compound A free base are summarized in Table 13 below. [Table 16]

[0381] Example 4 - Compound A succinate form A [ka] Compound A succinate form A Form A of Compound A succinate was prepared similarly to Examples 12-41 below.

[0382] Three endothermic peaks (40.4° C., 113.1° C., and 148.6° C.) were checked by DSC. Compound A succinate Form A lost 2.7% mass when heated to 105.4° C. by TGA. Residual solvent of EtOH was 1 H NMR gave it a value of 0.19%.

[0383] Table 4, reproduced above, sets forth the X-ray diffraction peaks observed for Form A of Compound A succinate salt. [Table 17]

[0384] FIG. 7 shows the XRPD pattern of Form A of Compound A succinate salt.

[0385] FIG. 8 shows the DSC thermogram and TGA trace of Form A of Compound A succinate salt.

[0386] Example 5 - Compound A succinate form B [ka] Compound A succinate form B Form B of Compound A succinate was prepared similarly to Examples 12-41 below.

[0387] Compound A succinate form B was obtained by stirring in 2-MeTHF at 25° C. Two endothermic peaks (39.2° C. and 136.6° C.) were checked by DSC. Compound A succinate form B lost 2.4% mass when heated to 117.5° C. by TGA. Residual solvent in 2-MeTHF was 1 H NMR gave it a value of 0.11%.

[0388] Table 5, supra, is reproduced below and lists the X-ray diffraction peaks observed for Form B of Compound A succinate salt. [Table 18]

[0389] FIG. 9 shows the XRPD pattern of Form B of Compound A succinate salt.

[0390] FIG. 10 shows the DSC thermogram and TGA trace of Form B of Compound A succinate salt.

[0391] Example 6 - Form C of the succinate salt of compound A [ka] Compound A succinate form C Form C of Compound A succinate was prepared similarly to Examples 12-41 below.

[0392] Compound A succinate form C was obtained by stirring at 25° C. and 50° C. in the approximate solvent system. One endothermic peak (144.0° C.) was checked by DSC. Compound A succinate form C lost 1.3% mass when heated to 105.6° C. by TGA. Residual solvent of acetone was 1 H NMR gave 0.34%.

[0393] Table 6, reproduced above, sets forth the X-ray diffraction peaks observed for Form C of Compound A succinate salt. [Table 19]

[0394] FIG. 11 shows the XRPD pattern of Form C of Compound A succinate salt.

[0395] FIG. 12 shows the DSC thermogram and TGA trace of Form C of Compound A succinate salt.

[0396] Example 7 - Form D of the succinate salt of compound A [ka] Compound A succinate form D Form D of Compound A succinate was prepared similarly to Examples 12-41 below.

[0397] Compound A succinate form D was obtained by stirring in THF / H2O or acetone / H2O systems at 25°C and 50°C. One endothermic peak (138.7°C) was checked by DSC. Compound A succinate form D lost 4.1% mass when heated to 131.2°C by TGA. The residual solvent in THF was 1 H NMR gave it a value of 0.9%.

[0398] Table 7, reproduced above, sets forth the X-ray diffraction peaks observed for Form D of Compound A succinate salt. [Table 20]

[0399] FIG. 13 shows the XRPD pattern of Form D of Compound A succinate salt.

[0400] FIG. 14 shows the DSC thermogram and TGA trace of Form D of Compound A succinate salt.

[0401] Example 8 - Form E of the succinate salt of compound A [ka] Compound A succinate form E Form E of Compound A succinate was prepared similarly to Examples 12-41 below.

[0402] Compound A succinate Form E was obtained with moderate crystallinity by stirring in MtBE at 50° C. or by adding an anti-solvent in MeOH system. One endothermic peak (134.1° C.) was checked by DSC. Compound A succinate Form E lost 0.8% mass when heated to 125.4° C. by TGA. Residual solvent in MtBE was 1 HNMR gave a value of 0.8%.

[0403] Table 8, supra, is reproduced below and lists the X-ray diffraction peaks observed for Form E of Compound A succinate salt. [Table 21]

[0404] FIG. 15 shows the XRPD pattern of Form E of Compound A succinate salt.

[0405] FIG. 16 shows the DSC thermogram and TGA trace of Form E of Compound A succinate salt.

[0406] General Procedure for Examples 9, 10 and 11 X-ray powder diffraction (XRPD) data collection strategy: XRPD patterns of samples were recorded at room temperature using an Aeris X-ray diffractometer (Almelo, The Netherlands) with Cu Kα radiation (λ = 1.54 Å), 40 kV, 15 mA, passing through a Ni monochromator. Data were collected in continuous scan mode with a step size of 0.02° and a dwell time of 149 s, over an angular range of 3° to 40° 2θ. Samples were loaded into a zero background holder and gently pressed by a clean glass slide to ensure coplanarity of the sample surface with the holder surface. Acquired diffractograms were analyzed and plotted with HighScore Plus software (V5.0; Almelo, The Netherlands).

[0407] Thermogravimetric analysis (TGA): TGA was performed using a Discovery TGA 5500 (TA® Instruments, New Castle, DE, USA) instrument running on TRIOS software (version 5.0). Samples were placed in aluminum pans. The sample cells were purged with dry nitrogen at a flow rate of 15 mL / min. A heating rate of 10 °C / min from 25–350 °C was used in all experiments.

[0408] Differential Scanning Calorimetry (DSC): Conventional DSC experiments were performed using either a Q100 or a Discovery DSC 2500 (TA® Instruments, New Castle, DE, USA) instrument equipped with a refrigerated cooling system (RCS90). Sample cells were purged with dry nitrogen at a flow rate of 50 mL / min. Precision weighed samples (2-5 mg) placed in TZero pans with a pinhole were scanned at a heating rate of 10 °C / min over the desired temperature range.

[0409] Examples 9 and 10 were prepared by the reactive crystallization procedures described below, for example, Method I, Method II, and Method III.

[0410] 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.

[0411] Method-II Compound A (approximately 50 mg) and succinic acid (approximately 13 mg) were dissolved together in a minimum amount of the specified solvent with heating at 80° C. If necessary, the hot solution was filtered using a 0.45 μm PTFE syringe filter. The resulting solution was kept at room temperature to induce precipitation of a solid.

[0412] 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 minimum amount of solvent. One equivalent of succinic acid containing EtOH solution was added. The resulting solid was collected by filtration and characterized.

[0413] Example 9 - Compound A succinate salt form F [ka] Compound A succinate form F Table 9, reproduced above, sets forth the X-ray diffraction peaks observed for Form F of Compound A succinate salt. [Table 22]

[0414] FIG. 17 shows the XRPD pattern of Form F of Compound A succinate salt.

[0415] FIG. 18 shows a TGA trace of Form F of Compound A succinate salt.

[0416] FIG. 19 shows the DSC thermogram of Form F of Compound A succinate salt.

[0417] Example 10 - Compound A succinate form G [ka] Compound A succinate form G Form G of Compound A succinate salt was prepared by a reactive crystallization experiment from a 1:1 v / v CHCl3-MeOH solution.

[0418] Table 10, reproduced above, sets forth the X-ray diffraction peaks observed for Form G of Compound A succinate salt. [Table 23-1] [Table 23-2]

[0419] FIG. 20 shows the XRPD pattern of Form G of Compound A succinate salt.

[0420] FIG. 21 shows a TGA trace of Form G of Compound A succinate salt.

[0421] FIG. 22 shows a DSC thermogram of Form G of Compound A succinate salt.

[0422] Example 11 - Single Crystal of Form G of Compound A Succinate Structural elucidation by single crystal X-ray diffraction (SCXRD) revealed that form G of Compound A succinate has one equivalent of CHCl3 molecule per molecule of Compound A. This data, together with the TGA data, suggests that CHCl3 plays a role in stabilizing the crystal lattice of form G.

[0423] FIG. 23 shows the X-ray diffraction pattern of a single crystal of Compound A succinate, Form G.

[0424] Examples 12-41 were prepared as follows.

[0425] Step (1): Compound A (approximately 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.

[0426] Step (2): Counterion (approximately 1.1 equiv.) was charged to a separate reaction vessel (RV2) with solvent (0.5 mL) to give a clear solution or suspension. This solution or suspension was added dropwise to RV1 with stirring.

[0427] Step (3): The mixture in RV1 was heated and stirred at 50° C. for 2 hours, then cooled to 25° C. for 3 hours.

[0428] Step (4): The mixture was centrifuged and the filtrate cake was dried. The remaining solution of the filtrate cake was evaporated at atmospheric pressure at 25° C. to obtain a solid product, which was characterized as follows:

[0429] Example 12 - Compound A Hydrochloride Form A [ka] Compound A Hydrochloride Form A Table 14 shows the X-ray diffraction peaks observed for Form A of Compound A hydrochloride. [Table 24]

[0430] FIG. 24 shows the XRPD pattern of Form A of Compound A hydrochloride.

[0431] FIG. 25 shows the DSC thermogram and TGA trace of Compound A hydrochloride Form A.

[0432] Example 13 - Compound A Hydrochloride Form B [ka] Compound A Hydrochloride Form B Table 15 shows the X-ray diffraction peaks observed for Form B of Compound A hydrochloride. [Table 25]

[0433] FIG. 26 shows the XRPD pattern of Form B of Compound A hydrochloride.

[0434] FIG. 27 shows the DSC thermogram and TGA trace of Form B of Compound A hydrochloride.

[0435] Example 14 - Compound A Hydrochloride Form C [ka] Compound A Hydrochloride Form C Table 16 shows the X-ray diffraction peaks observed for Form C of Compound A hydrochloride. [Table 26]

[0436] FIG. 28 shows the XRPD pattern of Form C of Compound A hydrochloride.

[0437] FIG. 29 shows the DSC thermogram and TGA trace of Form C of Compound A hydrochloride.

[0438] Example 15 - Compound A Hydrochloride Form D [ka] Compound A Hydrochloride Form D Table 17 lists the X-ray diffraction peaks observed for Form D of Compound A hydrochloride. [Table 27]

[0439] FIG. 30 shows the XRPD pattern of Form D of Compound A hydrochloride.

[0440] FIG. 31 shows the DSC thermogram and TGA trace of Form D of Compound A hydrochloride.

[0441] Example 16 - Compound A Hydrochloride Form E [ka] Compound A Hydrochloride Form E Table 18 lists the X-ray diffraction peaks observed for Form E of Compound A hydrochloride. [Table 28]

[0442] FIG. 32 shows the XRPD pattern of Form E of Compound A hydrochloride.

[0443] FIG. 33 shows the DSC thermogram and TGA trace of Form E of Compound A hydrochloride.

[0444] Example 17 - Compound A Hydrochloride Form F [ka] Compound A Hydrochloride Form F Table 19 shows the X-ray diffraction peaks observed for Form F of Compound A hydrochloride. [Table 29]

[0445] FIG. 34 shows the XRPD pattern of Form F of Compound A hydrochloride.

[0446] FIG. 35 shows the DSC thermogram and TGA trace of Form F of Compound A hydrochloride.

[0447] Example 18 - Compound A Maleate Form A [ka] Compound A Maleate Form A Table 20 shows the X-ray diffraction peaks observed for Form A of the Compound A maleate salt. [Table 30]

[0448] FIG. 36 shows the XRPD pattern of Form A of Compound A maleate salt.

[0449] FIG. 37 shows the DSC thermogram and TGA trace of Form A of the Compound A maleate salt.

[0450] Example 19 - Compound A Sulfate Form A [ka] Compound A Sulfate Form A Table 21 lists the X-ray diffraction peaks observed for Form A of Compound A Sulfate. [Table 31]

[0451] FIG. 38 shows the XRPD pattern of Form A of Compound A sulfate salt.

[0452] FIG. 39 shows the DSC thermogram and TGA trace of Form A of Compound A sulfate salt.

[0453] Example 20 - Compound A Sulfate Form B [ka] Compound A sulfate form B Table 22 shows the X-ray diffraction peaks observed for Form B of Compound A Sulfate. [Table 32]

[0454] FIG. 40 shows the XRPD pattern of Form B of Compound A sulfate salt.

[0455] FIG. 41 shows the DSC thermogram and TGA trace of Form B of Compound A sulfate salt.

[0456] Example 21 - Compound A Sulfate Form C [ka] Compound A sulfate form C Table 23 shows the X-ray diffraction peaks observed for Form C of Compound A Sulfate. [Table 33]

[0457] FIG. 42 shows the XRPD pattern of Form C of Compound A sulfate salt.

[0458] FIG. 43 shows the DSC thermogram and TGA trace of Form C of Compound A sulfate salt.

[0459] Example 22 - Compound A Phosphate Form A [ka] Compound A Phosphate Form A Table 24 shows the X-ray diffraction peaks observed for Form A of Compound A phosphate. [Table 34]

[0460] FIG. 44 shows the XRPD pattern of Form A of Compound A phosphate.

[0461] FIG. 45 shows the DSC thermogram and TGA trace of Form A of Compound A phosphate salt.

[0462] Example 23 - Compound A L-tartrate salt form A [ka] Compound A L-tartrate form A Table 25 lists the X-ray diffraction peaks observed for Form A of Compound A L-tartrate salt. [Table 35]

[0463] FIG. 46 shows the XRPD pattern of Form A of Compound A L-tartrate salt.

[0464] FIG. 47 shows the DSC thermogram and TGA trace of Form A of Compound A L-tartrate salt.

[0465] Example 24 - Compound A Fumarate Salt Form A [ka] Compound A Fumarate Form A Table 26 shows the X-ray diffraction peaks observed for Form A of Compound A fumarate salt. [Table 36]

[0466] FIG. 48 shows the XRPD pattern of Form A of Compound A fumarate salt.

[0467] FIG. 49 shows the DSC thermogram and TGA trace of Form A of Compound A fumarate salt.

[0468] Example 25 - Compound A Fumarate Salt Form B [ka] Compound A fumarate form B Table 27 shows the X-ray diffraction peaks observed for Form B of Compound A fumarate salt. [Table 37]

[0469] FIG. 50 shows the XRPD pattern of Form B of Compound A fumarate salt.

[0470] FIG. 51 shows the DSC thermogram and TGA trace of Form B of Compound A fumarate salt.

[0471] Example 26 - Compound A Fumarate Salt Form C [ka] Compound A fumarate form C Table 28 shows the X-ray diffraction peaks observed for Form C of Compound A fumarate salt. [Table 38]

[0472] FIG. 52 shows the XRPD pattern of Form C of Compound A fumarate salt.

[0473] FIG. 53 shows the DSC thermogram and TGA trace of Form C of Compound A fumarate salt.

[0474] Example 27 - Compound A Fumarate Salt Form D [ka] Compound A fumarate form D Table 29 shows the X-ray diffraction peaks observed for Form D of Compound A fumarate salt. [Table 39]

[0475] FIG. 54 shows the XRPD pattern of Form D of Compound A fumarate salt.

[0476] FIG. 55 shows the DSC thermogram and TGA trace of Form D of Compound A fumarate salt.

[0477] Example 28 - Compound A Citrate Salt Form A [ka] Compound A Citrate Form A Table 30 shows the X-ray diffraction peaks observed for Form D of Compound A Citrate Salt. [Table 40]

[0478] FIG. 56 shows the XRPD pattern of Form A of Compound A Citrate Salt.

[0479] FIG. 57 shows the DSC thermogram and TGA trace of Form A of Compound A Citrate Salt.

[0480] Example 29 - Compound A L-Malate Form A [ka] Compound A L-Malate Form A Table 31 shows the X-ray diffraction peaks observed for Form A of Compound A L-malate salt. [Table 41]

[0481] FIG. 58 shows the XRPD pattern of Form A of Compound A L-malate salt.

[0482] FIG. 59 shows the DSC thermogram and TGA trace of Form A of the Compound A L-malate salt.

[0483] Example 30 - Compound A Mesylate Form A [ka] Compound A Mesylate Form A Table 32 shows the X-ray diffraction peaks observed for Form A of Compound A mesylate. [Table 42]

[0484] FIG. 60 shows the XRPD pattern of Form A of Compound A mesylate.

[0485] FIG. 61 shows the DSC thermogram and TGA trace of Form A of Compound A mesylate.

[0486] Example 31 - Compound A Mesylate Form B [ka] Compound A mesylate form B Table 33 shows the X-ray diffraction peaks observed for Form B of Compound A mesylate. [Table 43]

[0487] FIG. 62 shows the XRPD pattern of Form B of Compound A mesylate.

[0488] FIG. 63 shows the DSC thermogram and TGA trace of Form B of Compound A mesylate.

[0489] Example 32 - Form A of the esylate salt of compound A [ka] Compound A Esylate Form A Table 34 shows the X-ray diffraction peaks observed for Form A of Compound A esylate salt. [Table 44]

[0490] FIG. 64 shows the XRPD pattern of Form A of Compound A esylate salt.

[0491] FIG. 65 shows the DSC thermogram and TGA trace of Form A of Compound A esylate salt.

[0492] Example 33 - Compound A Esylate Form B [ka] Form B of the esylate salt of compound A Table 35 lists the X-ray diffraction peaks observed for Form B of Compound A esylate salt. [Table 45]

[0493] FIG. 66 shows the XRPD pattern of Form B of Compound A esylate salt.

[0494] FIG. 67 shows the DSC thermogram and TGA trace of Form B of Compound A esylate salt.

[0495] Example 34 - Compound A Tosylate Form A [ka] Compound A Tosylate Form A Table 36 lists the X-ray diffraction peaks observed for Form A of the Compound A tosylate salt. [Table 46]

[0496] FIG. 68 shows the XRPD pattern of Form A of the Compound A tosylate salt.

[0497] FIG. 69 shows the DSC thermogram and TGA trace of Form A of the Compound A tosylate salt.

[0498] Example 35 - Compound A Tosylate Form B [ka] Compound A Tosylate Form B Table 37 lists the X-ray diffraction peaks observed for Form B of Compound A tosylate salt. [Table 47]

[0499] FIG. 70 shows the XRPD pattern of Form B of Compound A tosylate salt.

[0500] FIG. 71 shows the DSC thermogram and TGA trace of Form B of Compound A tosylate salt.

[0501] Example 36 - Compound A Glutarate Salt Form A [ka] Compound A Glutarate Form A Table 38 shows the X-ray diffraction peaks observed for Form A of Compound A glutarate salt. [Table 48]

[0502] FIG. 72 shows the XRPD pattern of Form A of Compound A glutarate salt.

[0503] Example 37 - Compound A Acetate Form A [ka] Compound A Acetate Form A Table 39 shows the X-ray diffraction peaks observed for Form A of Compound A acetate. [Table 49]

[0504] FIG. 73 shows the XRPD pattern of Form A of Compound A acetate.

[0505] FIG. 74 shows the DSC thermogram and TGA trace of Form A of Compound A acetate.

[0506] Example 38 - Compound A Malonate Form A [ka] Compound A Malonate Form A Table 40 shows the X-ray diffraction peaks observed for Form A of Compound A malonate. [Table 50]

[0507] FIG. 75 shows the XRPD pattern of Form A of Compound A malonate.

[0508] Example 39 - Compound A Malonate Form B [ka] Compound A Malonate Form B Table 41 shows the X-ray diffraction peaks observed for Form B of Compound A malonate. [Table 51]

[0509] FIG. 76 shows the XRPD pattern of Form B of Compound A malonate salt.

[0510] Example 40 - Compound A Sebacic Acid Salt Form A [ka] Compound A Sebacic Acid Salt Form A Table 42 lists the X-ray diffraction peaks observed for Form A of Compound A sebacate salt. [Table 52]

[0511] FIG. 77 shows the XRPD pattern of Form A of Compound A sebacate salt.

[0512] FIG. 78 shows the DSC thermogram and TGA trace of Form A of Compound A sebacate salt.

[0513] Example 41 - Compound A Acetate Form A [ka] Compound A Aceturate Form A Table 43 lists the X-ray diffraction peaks observed for Form A of Compound A aceturate salt. [Table 53]

[0514] FIG. 79 shows the XRPD pattern of Form A of Compound A aceturate salt.

[0515] FIG. 80 shows the DSC thermogram and TGA trace of Form A of Compound A aceturate salt.

[0516] Example 42 - Compound A Acetate Form B [ka] Compound A Acetate Form B Table 44 shows the X-ray diffraction peaks observed for Form B of Compound A aceturate salt. [Table 54]

[0517] FIG. 81 shows the XRPD pattern of Form B of Compound A aceturate salt.

[0518] FIG. 82 shows the DSC thermogram and TGA trace of Form B of Compound A aceturate salt.

[0519] Having described several embodiments of the present invention, it will be apparent that the basic examples may be modified to provide other embodiments that utilize the compounds and methods of the present invention. It will therefore be appreciated that the scope of the present invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

Claims

1. Compound A: 【Chemistry 1】 A Form A, B, or C.

2. 10. The compound of claim 1, wherein the compound is crystalline.

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

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

5. 2. The compound of claim 1, having in its XRPD one or more peaks selected from those at 11.5, 12.9 and 23.5±0.2 degrees theta.

6. 2. The compound of claim 1, having in its XRPD two or more peaks selected from those at 11.5, 12.9 and 23.5±0.2 degrees theta.

7. 2. The compound of claim 1, having in its XRPD three or more peaks selected from those at 11.5, 12.9 and 23.5±0.2 degrees theta.

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

9. 2. The compound of claim 1, having an XRPD substantially similar to that shown in FIG.

10. 2. The compound of claim 1, having in its XRPD one or more peaks selected from those at 17.8, 18.3, and 20.8±0.2 degrees theta.

11. 2. The compound of claim 1, having in its XRPD two or more peaks selected from those at 17.8, 18.3, and 20.8±0.2 degrees theta.

12. 2. The compound of claim 1, having in its XRPD three or more peaks selected from those at about 17.8, 18.3, and 20.8±0.2 degrees theta.

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

14. 4. The compound of claim 1, having an XRPD substantially similar to that shown in FIG.

15. 2. The compound of claim 1, having in its XRPD one or more peaks selected from those of 16.4, 22.9 and 31.6±0.2 degrees theta.

16. 2. The compound of claim 1, having in its XRPD two or more peaks selected from those at 16.4, 22.9 and 31.6±0.2 degrees theta.

17. 2. The compound of claim 1, having in its XRPD three or more peaks selected from those at 16.4, 22.9 and 31.6±0.2 degrees theta.

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

19. 10. The compound of claim 1, having an XRPD substantially similar to that shown in FIG.

20. Compound A succinate: 【Chemistry 2】 1。

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

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

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

24. 21. The compound of claim 20, having in its XRPD one or more peaks selected from 8.1, 11.6 and 24.4±0.2 degrees theta.

25. 21. The compound of claim 20, having in its XRPD at least two peaks selected from those of 8.1, 11.6 and 24.4±0.2 degrees theta.

26. 21. The compound of claim 20, having in its XRPD at least three peaks selected from those at 8.1, 11.6 and 24.4±0.2 degrees theta.

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

28. 21. The compound of claim 20, having an XRPD substantially similar to that shown in Figure 7.

29. 21. The compound of claim 20, having in its XRPD one or more peaks selected from 18.6, 24.1 and 24.6±0.2 degrees two-theta.

30. 21. The compound of claim 20, having in its XRPD at least two peaks selected from those of 18.6, 24.1 and 24.6±0.2 degrees two-theta.

31. 21. The compound of claim 20, having in its XRPD at least three peaks selected from those at 18.6, 24.1 and 24.6±0.2 degrees two-theta.

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

33. 21. The compound of claim 20, having an XRPD substantially similar to that shown in Figure 9.

34. 21. The compound of claim 20, having in its XRPD one or more peaks selected from 9.2, 11.9 and 18.9±0.2 degrees two-theta.

35. 21. The compound of claim 20, having in its XRPD at least two peaks selected from those of 9.2, 11.9 and 18.9±0.2 degrees two-theta.

36. 21. The compound of claim 20, having in its XRPD at least three peaks selected from those at 9.2, 11.9 and 18.9±0.2 degrees two-theta.

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

38. 21. The compound of claim 20, having an XRPD substantially similar to that shown in Figure 11.

39. 21. The compound of claim 20, having in its XRPD one or more peaks selected from those at 12.3, 19.4, and 24.7±0.2 degrees two-theta.

40. 21. The compound of claim 20, having in its XRPD at least two peaks selected from those at 12.3, 19.4, and 24.7±0.2 degrees two-theta.

41. 21. The compound of claim 20, having in its XRPD at least three peaks selected from those at 12.3, 19.4, and 24.7±0.2 degrees two-theta.

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

43. 21. The compound of claim 20, having an XRPD substantially similar to that shown in Figure 13.

44. 21. The compound of claim 20, having in its XRPD one or more peaks selected from those of 11.9, 23.1 and 24.1±0.2 degrees two-theta.

45. 21. The compound of claim 20, having in its XRPD at least two peaks selected from those of 11.9, 23.1 and 24.1±0.2 degrees two-theta.

46. 21. The compound of claim 20, having in its XRPD at least three peaks selected from those at 11.9, 23.1 and 24.1±0.2 degrees two-theta.

47. 45. The compound of claim 44, wherein the compound is of form E.

48. 21. The compound of claim 20, having an XRPD substantially similar to that shown in Figure 15.

49. 21. The compound of claim 20, having in its XRPD one or more peaks selected from 6.0, 12.5 and 24.5±0.2 degrees two-theta.

50. 21. The compound of claim 20, having in its XRPD at least two peaks selected from those at 6.0, 12.5, and 24.5±0.2 degrees two-theta.

51. 21. The compound of claim 20, having in its XRPD at least three peaks selected from those at 6.0, 12.5, and 24.5±0.2 degrees two-theta.

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

53. 21. The compound of claim 20, having an XRPD substantially similar to that shown in Figure 17.

54. 21. The compound of claim 20, having in its XRPD one or more peaks selected from 6.0, 15.3 and 23.4±0.2 degrees two-theta.

55. 21. The compound of claim 20, having in its XRPD at least two peaks selected from those of 6.0, 15.3 and 23.4±0.2 degrees two-theta.

56. 21. The compound of claim 20, having in its XRPD at least three peaks selected from those at 6.0, 15.3 and 23.4±0.2 degrees two-theta.

57. 55. The compound of claim 54, wherein the compound is of form G.

58. 21. The compound of claim 20, having an XRPD substantially similar to that shown in Figure 20.

59. 60. A pharmaceutical composition comprising a compound according to any one of claims 1 to 58, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

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

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

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

63. 63. The method of claim 62, wherein 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 lymphocytic leukemia, lymphoma, myeloma, acute myeloid leukemia, secondary pancreatic cancer, or secondary brain metastasis.

64. 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 glioblastoma, astrocytoma, or pontine glioma.

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

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

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

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

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

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

72. A process for preparing a salt compound of formula X, comprising: 【Chemistry 3】 X A: 【Chemistry 4】 A with an acid and optionally a solvent under conditions to form a salt compound of formula X.

73. 73. The method of claim 72, wherein the acid is succinic acid, thereby forming a succinate salt of compound A, and optionally crystallizing the succinate salt into Form A, Form B, Form C, Form D, Form E, Form F, or Form G.

74. A pharmaceutical salt of compound A, 【Chemistry 5】 A A pharmaceutical salt of Compound A, wherein the salt is a hydrochloride, sulfate, maleate, phosphate, L-tartrate, fumarate, citrate, L-malate, tosylate, succinate, methanesulfonate, ethanesulfonate, glutarate, n-acetylglycine, acetate, malonate, or sebacate.

75. 75. The pharmaceutical salt of compound A according to claim 74, which is the hydrochloride salt in amorphous form.

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

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

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

79. 75. The pharmaceutical salt of compound A according to claim 74, which is the maleate salt in amorphous form.

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

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

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

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

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

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

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

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

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

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

90. 75. The pharmaceutical salt of compound A according to claim 74, which is the L-malate salt in crystalline form.

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

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

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

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

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

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

97. 75. The pharmaceutical salt of compound A according to claim 74, which is an esylate salt in amorphous form.

98. 75. The pharmaceutical salt of compound A according to claim 74, which is an esylate salt in crystalline form.

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

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

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

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

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

104. 75. The pharmaceutical salt of compound A according to claim 74, which is an acetate salt in crystalline form.

105. 75. The pharmaceutical salt of compound A according to claim 74, which is a malonate salt in amorphous form.

106. 75. The pharmaceutical salt of compound A according to claim 74, which is a crystalline form of the malonate salt.

107. 75. The pharmaceutical salt of compound A according to claim 74, which is a sebacate salt in amorphous form.

108. 75. The pharmaceutical salt of compound A according to claim 74, which is a sebacate salt in crystalline form.

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