Selective inhibitor of protein arginine methyltransferase 5 (PRMT5)

Abstract

The present disclosure relates to pharmaceutically acceptable salts of compounds of formula I. [Formula 1] JPEG2022548689000030.jpg38128 Pharmaceutical compositions comprising pharmaceutically acceptable salts of compounds of Formula I, as well as methods for their use and preparation, are also described.

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application claims the benefit of priority of U.S. Provisional Patent Application No. 62 / 902,322, filed on September 18, 2019, the entire disclosure of which is incorporated herein by reference.

[0002] (Field of the Invention) This disclosure relates to PRMT5 inhibitors and methods of using the same.

Background Art

[0003] Protein arginine methylation is a common post - translational modification that regulates numerous cellular processes, including gene transcription, mRNA splicing, DNA repair, protein cellular localization, cell fate determination, and signal transduction. There are three methyl - arginine species: ωN - monomethylarginine (MMA), ωN, N - asymmetric dimethylarginine (ADMA), and ωN, N’ - symmetric dimethylarginine (SDMA). The formation of methylated arginine is catalyzed by the protein arginine methyltransferase (PRMT) family of methyltransferases. Currently, there are nine PRMTs annotated in the human genome. Most of these enzymes are type I enzymes (PRMT1, - 2, - 3, - 4, - 6, - 8) capable of mono - and asymmetric dimethylation of arginine with S - adenosylmethionine (SAM) as the methyl donor. PRMT - 5, - 7, and - 9 are thought to be type II enzymes that catalyze symmetric dimethylation of arginine. Each PRMT species means the characteristic motif of seven β - strand methyltransferases (Katz et al., 2003), as well as additional "double E" and "THW" sequence motifs specific to the PRMT sub - family.

[0004] PRMT5 functions as a general transcriptional repressor that acts on a number of transcription factors and repressor complexes, including BRG1 and hBRM, Blimp1, and Snail. Once recruited to a promoter, this enzyme symmetrically dimethylates H3R8 and H4R3. Importantly, the H4R3 site is a major target of PRMT1 methylation (ADMA), which is generally considered a transcriptional activation mark. Thus, both H4R3me2s (repressive; me2s indicates SDMA modification) and H4R3me2a (active; me2a indicates ADMA modification) are generated in vivo. The specificity of PRMT5 for H3R8 and H4R3 can be altered by interaction with COPR5, which may play an important role in determining the PRMT5 co-repressor state. The role of PRMT in cancer

[0005] Aberrant expression of PRMT has been confirmed in human cancers, and PRMT is considered a therapeutic target. Genome-wide analysis of histone modifications in prostate cancer has shown that dimethylation of histone H4R3 is positively correlated with increased malignancy, and these changes are predictive of clinical outcome.

[0006] The concentration of PRMT5 has been shown to be elevated in a panel of lymphoid cancer cell lines as well as clinical samples of mantle cell lymphoma. PRMT5 interacts with many substrates involved in various cellular processes, including RNA processing, signaling, and transcriptional regulation. PRMT5 can directly modify histones H3 and H4, resulting in repression of gene expression. Overexpression of PRMT5 may stimulate cell proliferation and induce transformation by directly suppressing tumor suppressor genes. Pal et al., Mol. Cell. Biol. 2003, 7475; Pal et al. Mol. Cell. Biol. 2004, 9630; Wang et al. Mol. Cell. Biol. 2008, 6262; Chung et al. J Biol Chem 2013, 5534. In addition to its well-established oncogenic function in transcription and translation, the transcription factor MYC also protects specific pre-messenger RNA splicing as an essential step in lymphoma formation. Koh et al. Nature 2015, 523 7558; Hsu et al. Nature 2015 525, 384.

[0007] The discovery of cancer dependencies has the potential to inform treatment strategies and identify putative drug targets. By integrating data from comprehensive genomic profiling of cancer cell lines and functional characterization of cancer dependencies, it has recently been discovered that deletion of the methylthioadenosine phosphorylase (MTAP) enzyme confers selective dependency on protein arginine methyltransferase 5 (PRMT5) and its binding partner WDR77. MTAP is frequently deleted because it is commonly located proximal to the frequently deleted tumor suppressor gene CDKN2A. Cells with MTAP deletion have increased intracellular concentrations of methylthioadenosine (MTA), a metabolite cleaved by MTAP. Furthermore, MTA specifically inhibits the enzymatic activity of PRMT5. Administration of either MTA or a small molecule PRMT5 inhibitor shows preferential reduction of cell viability in MTAP-deleted cancer cell lines compared to isogenic MTAP-expressing controls. Collectively, these findings indicate that PRMT5 is a potential vulnerability across multiple cancer lineages enhanced by common "passenger" genomic alterations. Role of PRMT5 in abnormal hemoglobinopathy

[0008] The developmental switch of human globin gene subtypes from fetus to adult, which begins at birth, is a precursor to the onset of abnormal hemoglobinopathies, β-thalassemia, and sickle cell disease (SCD). The observation that increased adult globin gene expression (in the context of hereditary persistence of fetal hemoglobin [HPFH] mutations) significantly improves the clinical severity of thalassemia and SCD has prompted the search for therapeutic strategies to abrogate gamma-globin gene silencing. Central to gamma gene silencing is DNA methylation, which marks important CpG dinucleotides adjacent to the gene transcription start site in adult bone marrow erythroid cells. These marks have been shown to be established as a result of the recruitment of DNA methyltransferase DNMT3A to the gamma-promoter by protein arginine methyltransferase PRMT5. Zhao et al. Nat Struct Mol Biol. 2009 16, 304. PRMT5-mediated methylation of histone H4R3 recruits DNMT3A and links histone and DNA methylation in gene silencing.

[0009] PRMT5 functions as a template for the direct binding of DNMT3A and induces the repressive histone mark H4R3me2s and subsequent DNA methylation. Loss of PRMT5 binding or its enzymatic activity results in demethylation of CpG dinucleotides and gene activation. In addition to the H4R3me2s mark and DNA methylation, the binding of PRMT5 to the gamma-promoter and its enzymatic activity are essential for the assembly of a multi-protein complex at the gamma-promoter, which induces extensive cooperative repressive epigenetic marks. Disruption of this complex results in reactivation of gamma gene expression. These studies provide a basis for developing PRMT5 inhibitors as a targeted therapy for thalassemia and SCD. SUMMARY OF THE INVENTION

[0010] The present disclosure relates to pharmaceutically acceptable salts of compounds of Formula I:

Chemical formula

[0011] The present disclosure also relates to hydrochloride, phosphate, and tartrate salts of formula I.

[0012] Also described are crystalline forms of such salts, as well as pharmaceutical compositions and methods of use of such salts.

Brief Description of the Drawings

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Mode for Carrying Out the Invention

[0037] The present disclosure may be more fully understood by reference to the following description, which includes the following definitions and examples. Specific features of the disclosed compositions and methods described herein in the context of separate aspects may also be provided in combination in a single aspect. Alternatively, for the sake of brevity, the various features of the disclosed compositions and methods described in the context of a single aspect may be provided separately or in any partial combination.

[0038] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or State government, or a corresponding agency in a country other than the United States, or listed in the United States Pharmacopeia or other generally recognized pharmacopeia for use in animals.

[0039] "Pharmaceutically acceptable salt" means a salt of a compound of the present disclosure that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. In particular, such salts may be non-toxic and may be addition salts of inorganic acids or organic acids and base addition salts. Specifically, such salts are (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc., or (2) salts formed when the acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion, or salts formed when coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. Examples of salts further include, but are not limited to, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc. When the compound contains a basic functional group, salts of non-toxic organic acids or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc. are further included.

[0040] "Pharmaceutically acceptable excipient" means an inert substance that is added to a pharmaceutical composition or otherwise used as a solvent, carrier, or diluent to facilitate administration of the drug and is non-toxic and within the biological acceptance range with respect to administration to a subject, and in another way, a biologically suitable substance. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol.

[0041] "Solvate" means a physical association of a compound of formula I with one or more solvent molecules.

[0042] "Subject" includes humans. The terms "human", "patient", and "subject" are used interchangeably herein.

[0043] "Treating" or "treatment" of any disease or disorder means, in one embodiment, improving the disease or disorder (i.e., arresting or reducing at least one of the disease or its clinical symptoms). In another embodiment, "treating" or "treatment" means improving at least one physical parameter, which may not be recognizable by the subject. In yet another embodiment, "treating" or "treatment" means modulating the disease or disorder physically (e.g., stabilization of recognizable symptoms), physiologically (e.g., stabilization of physical parameters), or both. In yet another embodiment, "treating" or "treatment" means delaying the onset of the disease or disorder. In some embodiments, "treating" or "treatment" means prophylactic treatment, i.e., preventing the onset of the disease or disorder.

[0044] "The compounds of the present disclosure" and corresponding expressions mean pharmaceutically acceptable salts of the compounds of formula I described herein, as well as their subgenera, and the expression includes stereoisomers (e.g., enantiomers, diastereoisomers) and constitutional isomers (e.g., tautomers) when the context permits.

[0045] As used herein, the term "isotope variant" means a compound that contains an isotope ratio in one or more of the atoms that make up such a compound in greater than natural abundance. For example, an "isotope variant" of a compound can be radiolabeled, i.e., can contain one or more radioisotopes, or can be labeled with a non-radioactive isotope such as, for example, deuterium ( 2 H or D), carbon-13 ( 13 C), nitrogen-15 ( 15 N), etc. In compounds in which such isotope substitution occurs, the following atoms, if present, may differ. For example, any hydrogen may be 2 H / D, any carbon may be 13 C, or any nitrogen may be 15 N, and it will be understood that the presence and arrangement of such atoms may be determined by those skilled in the art.

[0046] Also, it should be understood that compounds having the same molecular formula but different in the nature or sequence of the bonds of their atoms, or different in the arrangement through their primitive spaces, are referred to as "isomers". Isomers with different arrangements of their atoms in space are referred to as "stereoisomers", for example, diastereoisomers, enantiomers, and atropisomers. The compounds of the present disclosure may have one or more asymmetric centers, and thus such compounds can be produced as individual (R)- or (S)-stereoisomers at each asymmetric center, or as mixtures thereof. Unless otherwise stated, the description or name of a particular compound in this specification and the claims is intended to include all of its stereoisomers and mixtures, racemates, or others. Although one chiral center is present in the structure but the specific stereochemistry at that center is not shown, both enantiomers are individually, or as a mixture of enantiomers, included in this structure. Although two or more chiral centers are present in the structure but the specific stereochemistry at the centers is not shown, all enantiomers and diastereoisomers are individually or as a mixture included in that structure. Methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art.

[0047] In some aspects, the present disclosure relates to pharmaceutically acceptable salts of the compounds of Formula I:

Chemical formula

[0048] In some embodiments, the pharmaceutically acceptable salts are phosphoric acid, sulfuric acid, hydrochloric acid, ascorbic acid, L-tartaric acid, ethane-1,2-disulfonic acid, or 1-hydroxy-2-naphthoic acid, and oxalic acid.

[0049] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula I is a hydrochloride salt, i.e., Formula IA.

Chemical formula

[0050] In some embodiments, the pharmaceutically acceptable salt of the compound of formula I is a phosphate, i.e., of formula IB.

[0051] In other embodiments, the pharmaceutically acceptable salt of the compound of formula I is a tartrate, i.e., of formula IC.

[0052] In some embodiments, the tartrate is an L-tartrate. In other embodiments, the tartrate is a D-tartrate.

[0053] In other embodiments, the pharmaceutically acceptable salt of the compound of formula I is a sulfate, i.e., of formula ID.

[0054] In other embodiments, the pharmaceutically acceptable salt of the compound of formula I is an ascorbate, i.e., of formula IE.

[0055] In other embodiments, the pharmaceutically acceptable salt of the compound of formula I is an ethane-1,2-disulfonate, i.e., of formula IF.

[0056] In other embodiments, the pharmaceutically acceptable salt of the compound of formula I is a 1-hydroxy-2-naphthoate, i.e., of formula IG.

[0057] In other embodiments, the pharmaceutically acceptable salt of the compound of formula I is an oxalate, i.e., of formula IH.

[0058] In some aspects, the disclosure relates to crystalline forms of the pharmaceutically acceptable salts of formula I.

[0059] In some embodiments, the disclosure relates to crystalline forms of the salts of formula IA, formula IB, or formula IC.

[0060] The crystalline forms of the salts of Formula IA, Formula IB, or Formula IC according to the present disclosure may have advantageous properties including one or more of chemical or polymorphic purity, flowability, solubility, dissolution rate, bioavailability, form, or crystal habit, stability - for example, chemical stability, thermal stability, and mechanical stability with respect to polymorphic transformation, storage stability, hygroscopicity, low residual solvent content, as well as advantageous processing and handling properties such as compressibility, or bulk density.

[0061] The crystalline form may be considered herein to be characterized by graphic data “as shown in” the figures. Such data includes, for example, powder X-ray diffraction grams (XRPD), differential scanning calorimetry (DSC) thermograms, or thermogravimetric analysis (TGA) profiles. As is well known in the art, the graphic data potentially provides additional technical information to further define each solid form, which may not necessarily be described by reference to numerical values or peak positions alone. Thus, when referring to the graphic data of the figures herein, the term “substantially as shown in” means a pattern that is not necessarily identical to that shown herein, but which falls within the limits of experimental error or deviation when considered by one of ordinary skill in the art. One of ordinary skill in the art can readily compare the graphic data of the figures herein with graphic data generated for an unknown crystalline form and determine whether the two sets of graphic data characterize the same crystalline form or two different crystalline forms.

[0062] The crystalline form of a solid may be considered in this specification as "polymorphically pure" or "substantially free of any other form". As used herein in this context, the expression "substantially free of any other form" means that, when measured, for example, by XRPD, the solid form contains no more than about 20%, about 10%, about 5%, about 2%, about 1%, or 0% of any other form of the target compound. For example, when substantially free of any other solid form, the solid form of formula IA described herein will be understood to contain more than about 80% (w / w), more than about 90% (w / w), more than about 95% (w / w), more than about 98% (w / w), more than about 99% (w / w), or about 100% of the target solid form of formula IA. Thus, in some embodiments of the present disclosure, the described solid form of formula IA may contain from about 1% to about 20% (w / w), from about 5% to about 20% (w / w), or from about 5% to about 10% (w / w) of one or more other solid forms of formula IA.

[0063] As used herein, unless otherwise specified, the XRPD peaks reported herein are measured using CuK α radiation, λ = 1.54 Å.

[0064] The modifier "about" should be considered to disclose a range defined by the absolute values of the two endpoints. For example, the expression "about 2 to about 4" also discloses the range "2 to 4". When used to modify a single number, the term "about" represents plus or minus 10% of the indicated number and includes the indicated number. For example, "about 10%" indicates the range from 9% to 11%, and "about 1" means 0.9 to 1.1.

[0065] In some aspects, the present disclosure relates to the hydrochloride salt of formula I, i.e., the crystalline form of formula IA. In some embodiments, the crystalline form of formula IA is Form I (Formula IA-Form I). In some embodiments, Formula IA-Form I is substantially free of any other solid form of formula IA.

[0066] In some embodiments, Form I of Formula IA exhibits an XRPD substantially as shown in Figure 1. The XRPD of Form I of Formula IA shown in Figure 1 includes a reflection angle (degree 2θ ± 0.2 degree 2θ), a line spacing (d value), and a relative intensity as shown in Table 1. [Table 1]

[0067] In some embodiments of the present disclosure, Form I of Formula IA is characterized by an XRPD pattern that includes a peak at one of the angles listed in Table 1. In other aspects, Form I of Formula IA is characterized by an XRPD pattern that includes two or more peaks at one of the angles listed in Table 1 above. In other aspects, Form I of Formula IA is characterized by an XRPD pattern that includes two peaks selected from the angles listed in Table 1 above. In other aspects, Form I of Formula IA is characterized by an XRPD pattern that includes three peaks selected from the angles listed in Table 1 above. In other aspects, Form I of Formula IA is characterized by an XRPD pattern that includes four peaks selected from the angles listed in Table 1 above. In other aspects, Form I of Formula IA is characterized by an XRPD pattern that includes five peaks selected from the angles listed in Table 1 above. In other aspects, Form I of Formula IA is characterized by an XRPD pattern that includes six peaks selected from the angles listed in Table 1 above. In other aspects, Form I of Formula IA is characterized by an XRPD pattern that includes seven peaks selected from the angles listed in Table 1 above. In other aspects, Form I of Formula IA is characterized by an XRPD pattern that includes eight peaks selected from the angles listed in Table 1 above. In other aspects, Form I of Formula IA is characterized by an XRPD pattern that includes nine peaks selected from the angles listed in Table 1 above. In other aspects, Form I of Formula IA is characterized by an XRPD pattern that includes ten peaks selected from the angles listed in Table 1 above. In other aspects, Form I of Formula IA is characterized by an XRPD pattern that includes more than ten peaks selected from the angles listed in Table 1 above.

[0068] In some embodiments, Form I of Formula IA is characterized by an XRPD pattern comprising a peak at 23.8 degrees ± 0.2 degrees 2θ. In other embodiments, Form I of Formula IA is characterized by an XRPD pattern comprising peaks at 21.2 and 23.8 degrees ± 0.2 degrees 2θ. In other embodiments, Form I of Formula IA is characterized by an XRPD pattern comprising peaks at 21.2, 23.8, and 27.0 degrees ± 0.2 degrees 2θ. In other embodiments, Form I of Formula IA is characterized by an XRPD pattern comprising peaks at 21.2, 23.8, 27.0, and 32.5 degrees ± 0.2 degrees 2θ.

[0069] In some embodiments of the present disclosure, Form I of Formula IA is characterized by an XRPD pattern comprising peaks at two or more of 21.2, 23.8, 27.0, and 32.5 degrees ± 0.2 degrees 2θ.

[0070] In some embodiments, Form I of Formula IA can be characterized by a DSC thermogram substantially as shown in FIG. 2. As shown in FIG. 2, when heated at a rate of 10 °C / min, Form I of Formula IA produced an endothermic peak at 244.19 °C, with a peak onset temperature of 234.71 °C and a melting enthalpy of 252.8 J / g. In some embodiments of the present disclosure, Form I of Formula IA is characterized by a DSC thermogram comprising an endothermic peak at about 244 °C. In other embodiments of the present disclosure, Form I of Formula IA is characterized by a DSC melting enthalpy of about 253 J / g.

[0071] In some embodiments, Form I of Formula IA can be characterized by a TGA profile substantially as shown in FIG. 3 when heated at a rate of 20 °C / min. As shown in FIG. 3, when Form I of Formula IA was heated to about 300 °C, it lost about 18.4% of its weight.

[0072] In some embodiments of the present disclosure, Form I of Formula IA is characterized by an XRPD pattern comprising peaks at one or more of 21.2, 23.8, 27.0, and 32.5 degrees ± 0.2 degrees 2θ, and a DSC thermogram comprising an endothermic peak at about 244 °C when heated at a rate of 10 °C / min.

[0073] In some embodiments, the crystalline form of Formula IA is Form II (Formula IA-Form II). In some embodiments, Formula IA-Form II is substantially free of any other solid form of Formula IA.

[0074] In some embodiments, Formula IA-Form II exhibits substantially the XRPD as shown in Figure 4. The XRPD of Formula IA-Form II shown in Figure 4 includes the reflection angle (degrees 2θ ± 0.2 degrees 2θ), the interplanar spacing (d-value), and the relative intensity as shown in Table 2. [Table 2]

[0075] In some embodiments of the present disclosure, Form II of Formula IA is characterized by an XRPD pattern that includes a peak at one of the angles listed in Table 2. In other aspects, Form II of Formula IA is characterized by an XRPD pattern that includes two or more peaks at one of the angles listed in Table 2 above. In other aspects, Form II of Formula IA is characterized by an XRPD pattern that includes two peaks selected from the angles listed in Table 2 above. In other aspects, Form II of Formula IA is characterized by an XRPD pattern that includes three peaks selected from the angles listed in Table 2 above. In other aspects, Form II of Formula IA is characterized by an XRPD pattern that includes four peaks selected from the angles listed in Table 2 above. In other aspects, Form II of Formula IA is characterized by an XRPD pattern that includes five peaks selected from the angles listed in Table 2 above. In other aspects, Form II of Formula IA is characterized by an XRPD pattern that includes six peaks selected from the angles listed in Table 2 above. In other aspects, Form II of Formula IA is characterized by an XRPD pattern that includes seven peaks selected from the angles listed in Table 2 above. In other aspects, Form II of Formula IA is characterized by an XRPD pattern that includes eight peaks selected from the angles listed in Table 2 above. In other aspects, Form II of Formula IA is characterized by an XRPD pattern that includes nine peaks selected from the angles listed in Table 2 above. In other aspects, Form II of Formula IA is characterized by an XRPD pattern that includes ten peaks selected from the angles listed in Table 2 above. In other aspects, Form II of Formula IA is characterized by an XRPD pattern that includes more than ten peaks selected from the angles listed in Table 2 above.

[0076] In some embodiments, Form II of Formula IA is characterized by an XRPD pattern that includes a peak at 25.5 degrees ± 0.2 degrees 2θ. In other embodiments, Form II of Formula IA is characterized by an XRPD pattern that includes peaks at 14.8, 17.5, and 25.5 degrees ± 0.2 degrees 2θ. In other embodiments, Form II of Formula IA is characterized by an XRPD pattern that includes peaks at 14.8, 17.5, 18.4, 24.0, and 25.5 degrees ± 0.2 degrees 2θ. In other embodiments, Form II of Formula IA is characterized by an XRPD pattern that includes peaks at 14.8, 17.5, 18.4, 24.0, 25.5, 28.0, and 28.7 degrees ± 0.2 degrees 2θ. In other embodiments, Form II of Formula IA is characterized by an XRPD pattern that includes peaks at 17.5, 18.4, 19.8, 24.0, 25.5, 28.0, and 28.7 degrees ± 0.2 degrees 2θ.

[0077] In some embodiments of the present disclosure, Form II of Formula IA is characterized by an XRPD pattern that includes peaks at three or more of 17.5, 18.4, 19.8, 24.0, 25.5, 28.0, and 28.7 degrees ± 0.2 degrees 2θ. In some embodiments of the present disclosure, Form II of Formula IA is characterized by an XRPD pattern that includes peaks at four or more of 17.5, 18.4, 19.8, 24.0, 25.5, 28.0, and 28.7 degrees ± 0.2 degrees 2θ. In some embodiments of the present disclosure, Form II of Formula IA is characterized by an XRPD pattern that includes peaks at five or more of 17.5, 18.4, 19.8, 24.0, 25.5, 28.0, and 28.7 degrees ± 0.2 degrees 2θ. In some embodiments of the present disclosure, Form II of Formula IA is characterized by an XRPD pattern that includes peaks at six or more of 17.5, 18.4, 19.8, 24.0, 25.5, 28.0, and 28.7 degrees ± 0.2 degrees 2θ.

[0078] In some embodiments, Form II of Formula IA can be characterized by a TGA profile that is substantially as shown in FIG. 5 when heated at a rate of 20 °C / min. As shown in FIG. 5, Form II of Formula IA lost approximately 3% of its weight when heated to about 225 °C.

[0079] In some embodiments, the crystalline form of Formula IA is Form IIa (Formula IA-Form IIa). In some embodiments, Formula IA-Form IIa is substantially free of any other solid form of Formula IA.

[0080] In some embodiments, Formula IA-Form IIa exhibits substantially the XRPD as shown in Figure 6. The XRPD of Formula IA-Form IIa shown in Figure 6 includes the reflection angle (degrees 2θ ± 0.2 degrees 2θ), the interplanar spacing (d-value), and the relative intensity as shown in Table 3.

Table 3

[0081] In some embodiments of the present disclosure, Form IA - Form IIa is characterized by an XRPD pattern that includes a peak at one of the angles listed in Table 3. In other aspects, Form IA - Form IIa is characterized by an XRPD pattern that includes two or more peaks at one of the angles listed in Table 3 above. In other aspects, Form IA - Form IIa is characterized by an XRPD pattern that includes two peaks selected from the angles listed in Table 3 above. In other aspects, Form IA - Form IIa is characterized by an XRPD pattern that includes three peaks selected from the angles listed in Table 3 above. In other aspects, Form IA - Form IIa is characterized by an XRPD pattern that includes four peaks selected from the angles listed in Table 3 above. In other aspects, Form IA - Form IIa is characterized by an XRPD pattern that includes five peaks selected from the angles listed in Table 3 above. In other aspects, Form IA - Form IIa is characterized by an XRPD pattern that includes six peaks selected from the angles listed in Table 3 above. In other aspects, Form IA - Form IIa is characterized by an XRPD pattern that includes seven peaks selected from the angles listed in Table 3 above. In other aspects, Form IA - Form IIa is characterized by an XRPD pattern that includes eight peaks selected from the angles listed in Table 3 above. In other aspects, Form IA - Form IIa is characterized by an XRPD pattern that includes nine peaks selected from the angles listed in Table 3 above. In other aspects, Form IA - Form IIa is characterized by an XRPD pattern that includes ten peaks selected from the angles listed in Table 3 above. In other aspects, Form IA - Form IIa is characterized by an XRPD pattern that includes more than ten peaks selected from the angles listed in Table 3 above.

[0082] In some embodiments, Form IIa of Formula IA is characterized by an XRPD pattern that includes a peak at 26.1 degrees ± 0.2 degrees 2θ. In other embodiments, Form IIa of Formula IA is characterized by an XRPD pattern that includes peaks at 14.0, 14.9, and 26.1 degrees ± 0.2 degrees 2θ. In other embodiments, Form IIa of Formula IA is characterized by an XRPD pattern that includes peaks at 12.5, 14.0, 14.9, 18.4, and 26.1 degrees ± 0.2 degrees 2θ. In other embodiments, Form IIa of Formula IA is characterized by an XRPD pattern that includes peaks at 12.5, 14.0, 14.9, 18.4, 24.9, and 26.1 degrees ± 0.2 degrees 2θ. In other embodiments, Form IIa of Formula IA is characterized by an XRPD pattern that includes peaks at 12.5, 14.0, 14.9, 18.4, 24.9, 26.1, and 28.3 degrees ± 0.2 degrees 2θ.

[0083] In some embodiments of the present disclosure, Form IIa of Formula IA is characterized by an XRPD pattern that includes peaks at three or more of 12.5, 14.0, 14.9, 18.4, 24.9, 26.1, and 28.3 degrees ± 0.2 degrees 2θ. In some embodiments of the present disclosure, Form IIa of Formula IA is characterized by an XRPD pattern that includes peaks at four or more of 12.5, 14.0, 14.9, 18.4, 24.9, 26.1, and 28.3 degrees ± 0.2 degrees 2θ. In some embodiments of the present disclosure, Form IIa of Formula IA is characterized by an XRPD pattern that includes peaks at five or more of 12.5, 14.0, 14.9, 18.4, 24.9, 26.1, and 28.3 degrees ± 0.2 degrees 2θ. In some embodiments of the present disclosure, Form IIa of Formula IA is characterized by an XRPD pattern that includes peaks at six or more of 12.5, 14.0, 14.9, 18.4, 24.9, 26.1, and 28.3 degrees ± 0.2 degrees 2θ.

[0084] In some embodiments, Form IIa of Formula IA can be characterized by a DSC thermogram substantially as shown in FIG. 7. As shown in FIG. 7, when heated at a rate of 10° C. / min, Form IIa of Formula IA produces an endothermic peak at 199.44° C., with a peak onset temperature of 194.14° C. and a melting enthalpy of 55.02 J / g, followed by an exothermic peak, and then an endothermic peak at 244.53° C., with a peak onset temperature of 236.29° C. and a melting enthalpy of 327.1 J / g. In some embodiments of the present disclosure, Form IIa of Formula IA is characterized by a DSC thermogram that includes an endothermic peak at about 199° C. In other embodiments of the present disclosure, Form IIa of Formula IA is characterized by a DSC melting enthalpy of about 55 J / g.

[0085] In some embodiments of the present disclosure, Form IIa of Formula IA is characterized by an XRPD pattern that includes peaks at one or more of 12.5, 14.0, 14.9, 18.4, 24.9, 26.1, and 28.3 degrees ±0.2 degrees 2θ, and a DSC thermogram that includes an endothermic peak at about 199° C. when heated at a rate of 10° C. / min.

[0086] In some embodiments, the crystalline form of Formula IA is Form III (Form III of Formula IA). In some embodiments, Form III of Formula IA is substantially free of any other solid forms of Formula IA.

[0087] In some embodiments, Form III of Formula IA exhibits XRPD substantially as shown in FIG. 8. The XRPD of Form III of Formula IA shown in FIG. 8 includes a reflection angle (degrees 2θ ±0.2 degrees 2θ), an interplanar spacing (d-value), and a relative intensity as shown in Table 4.

Table 4

[0088] In some embodiments of the present disclosure, Form IA - Form III is characterized by an XRPD pattern that includes a peak at one of the angles listed in Table 4. In other aspects, Form IA - Form III is characterized by an XRPD pattern that includes two or more peaks at one of the angles listed in Table 4 above. In other aspects, Form IA - Form III is characterized by an XRPD pattern that includes two peaks selected from the angles listed in Table 4 above. In other aspects, Form IA - Form III is characterized by an XRPD pattern that includes three peaks selected from the angles listed in Table 4 above. In other aspects, Form IA - Form III is characterized by an XRPD pattern that includes four peaks selected from the angles listed in Table 4 above. In other aspects, Form IA - Form III is characterized by an XRPD pattern that includes five peaks selected from the angles listed in Table 4 above. In other aspects, Form IA - Form III is characterized by an XRPD pattern that includes six peaks selected from the angles listed in Table 4 above. In other aspects, Form IA - Form III is characterized by an XRPD pattern that includes seven peaks selected from the angles listed in Table 4 above. In other aspects, Form IA - Form III is characterized by an XRPD pattern that includes eight peaks selected from the angles listed in Table 4 above. In other aspects, Form IA - Form III is characterized by an XRPD pattern that includes nine peaks selected from the angles listed in Table 4 above. In other aspects, Form IA - Form III is characterized by an XRPD pattern that includes ten peaks selected from the angles listed in Table 4 above. In other aspects, Form IA - Form III is characterized by an XRPD pattern that includes more than ten peaks selected from the angles listed in Table 4 above.

[0089] In some embodiments, Form IA - Form III is characterized by an XRPD pattern that includes peaks at 8.1 degrees ± 0.2 degrees 2θ. In other embodiments, Form IA - Form III is characterized by an XRPD pattern that includes peaks at 8.1 and 23.3 degrees ± 0.2 degrees 2θ. In other embodiments, Form IA - Form III is characterized by an XRPD pattern that includes peaks at 8.1, 12.5, 16.2, and 23.3 degrees ± 0.2 degrees 2θ. In other embodiments, Form IA - Form III is characterized by an XRPD pattern that includes peaks at 8.1, 12.5, 16.2, 18.8, 23.3, and 24.5 degrees ± 0.2 degrees 2θ. In other embodiments, Form IA - Form III is characterized by an XRPD pattern that includes peaks at 8.1, 12.5, 13.7, 14.5, 16.2, 18.8, 23.3, and 24.5 degrees ± 0.2 degrees 2θ. In yet other embodiments, Form IA - Form III is characterized by an XRPD pattern that includes peaks at 8.1, 12.5, 13.7, 14.5, 15.3, 16.2, 18.8, 21.2, 23.3, and 24.5 degrees ± 0.2 degrees 2θ.

[0090] In some embodiments of the present disclosure, Form IA - Form III is characterized by an XRPD pattern that includes peaks at three or more of 8.1, 12.5, 13.7, 14.5, 15.3, 16.2, 18.8, 21.2, 23.3, and 24.5 degrees ± 0.2 degrees 2θ. In some embodiments of the present disclosure, Form IA - Form III is characterized by an XRPD pattern that includes peaks at four or more of 8.1, 12.5, 13.7, 14.5, 15.3, 16.2, 18.8, 21.2, 23.3, and 24.5 degrees ± 0.2 degrees 2θ. In some embodiments of the present disclosure, Form IA - Form III is characterized by an XRPD pattern that includes peaks at five or more of 8.1, 12.5, 13.7, 14.5, 15.3, 16.2, 18.8, 21.2, 23.3, and 24.5 degrees ± 0.2 degrees 2θ. In some embodiments of the present disclosure, Form IA - Form III is characterized by an XRPD pattern that includes peaks at six or more of 8.1, 12.5, 13.7, 14.5, 15.3, 16.2, 18.8, 21.2, 23.3, and 24.5 degrees ± 0.2 degrees 2θ. In some embodiments of the present disclosure, Form IA - Form III is characterized by an XRPD pattern that includes peaks at seven or more of 8.1, 12.5, 13.7, 14.5, 15.3, 16.2, 18.8, 21.2, 23.3, and 24.5 degrees ± 0.2 degrees 2θ.

[0091] In some embodiments, Form III of Formula IA can be characterized by a DSC thermogram substantially as shown in FIG. 9. As shown in FIG. 9, when heated at a rate of 10 ° C. / min, Form III of Formula IA produces an endothermic peak at 120.83 ° C., with a peak onset temperature of 113.61 ° C. and a melting enthalpy of 187.5 J / g. Subsequently, an exothermic peak is produced at 163.21 ° C., with a peak onset temperature of 158.31 ° C. and a melting enthalpy of 67.85 J / g. Subsequently, an endothermic peak is produced at 192.59 ° C., with a peak onset temperature of 190.01 ° C. and a melting enthalpy of 66.36 J / g. Subsequently, an endothermic peak is produced at 233.74 ° C., with a peak onset temperature of 227.54 ° C. and a melting enthalpy of 88.63 J / g. In some embodiments of the present disclosure, Form III of Formula IA is characterized by a DSC thermogram that includes an endothermic peak at about 121 ° C. In other embodiments of the present disclosure, Form III of Formula IA is characterized by a DSC melting enthalpy of about 187.5 J / g.

[0092] In some embodiments, Form III of Formula IA can be characterized by a TGA profile substantially as shown in FIG. 10 when heated at a rate of 20 ° C. / min. As shown in FIG. 10, when Form III of Formula IA was heated to about 125 ° C., it lost about 4.1% of its weight.

[0093] In some embodiments of the present disclosure, Form III of Formula IA is characterized by an XRPD pattern that includes peaks at one or more of 12.5, 13.7, 14.5, 15.3, 16.2, 18.8, 21.2, 23.3, and 24.5 degrees ± 0.2 degrees 2θ, and a DSC thermogram that includes an endothermic peak at about 121 ° C. when heated at a rate of 10 ° C. / min.

[0094] In some embodiments, the crystalline form of Formula IA is Form IV (Form III of Formula IA). In some embodiments, Form III of Formula IA is substantially free of any other solid forms of Formula IA.

[0095] In some embodiments, Form IA - Form IV exhibit XRPD substantially as shown in Figure 11. The XRPD of Form IA - Form IV shown in Figure 11 includes the reflection angle (degrees 2θ ± 0.2 degrees 2θ), the line spacing (d - value), and the relative intensity as shown in Table 5. [Table 5]

[0096] In some embodiments of the present disclosure, Form IA - Form IV is characterized by an XRPD pattern that includes a peak at one of the angles listed in Table 5. In other aspects, Form IA - Form IV is characterized by an XRPD pattern that includes two or more peaks at one of the angles listed in Table 5 above. In other aspects, Form IA - Form IV is characterized by an XRPD pattern that includes two peaks selected from the angles listed in Table 5 above. In other aspects, Form IA - Form IV is characterized by an XRPD pattern that includes three peaks selected from the angles listed in Table 5 above. In other aspects, Form IA - Form IV is characterized by an XRPD pattern that includes four peaks selected from the angles listed in Table 5 above. In other aspects, Form IA - Form IV is characterized by an XRPD pattern that includes five peaks selected from the angles listed in Table 5 above. In other aspects, Form IA - Form IV is characterized by an XRPD pattern that includes six peaks selected from the angles listed in Table 5 above. In other aspects, Form IA - Form IV is characterized by an XRPD pattern that includes seven peaks selected from the angles listed in Table 5 above. In other aspects, Form IA - Form IV is characterized by an XRPD pattern that includes eight peaks selected from the angles listed in Table 5 above. In other aspects, Form IA - Form IV is characterized by an XRPD pattern that includes nine peaks selected from the angles listed in Table 5 above. In other aspects, Form IA - Form IV is characterized by an XRPD pattern that includes ten peaks selected from the angles listed in Table 5 above. In other aspects, Form IA - Form IV is characterized by an XRPD pattern that includes more than ten peaks selected from the angles listed in Table 5 above.

[0097] In some embodiments, Formulas IA - IV are characterized by an XRPD pattern that includes peaks at 4.0 degrees ± 0.2 degrees 2θ. In other embodiments, Formulas IA - IV are characterized by an XRPD pattern that includes peaks at 4.0 and 22.7 degrees ± 0.2 degrees 2θ. In other embodiments, Formulas IA - IV are characterized by an XRPD pattern that includes peaks at 4.0, 22.7, and 27.8 degrees ± 0.2 degrees 2θ. In other embodiments, Formulas IA - IV are characterized by an XRPD pattern that includes peaks at 22.7, 27.8, and 30.6 degrees ± 0.2 degrees 2θ. In other embodiments, Formulas IA - IV are characterized by an XRPD pattern that includes peaks at 14.8, 22.7, 27.8, and 30.6 degrees ± 0.2 degrees 2θ. In still other embodiments, Formulas IA - IV are characterized by an XRPD pattern that includes peaks at 4.0, 14.8, 22.7, 27.8, and 30.6 degrees ± 0.2 degrees 2θ.

[0098] In some embodiments of the present disclosure, Formulas IA - IV are characterized by an XRPD pattern that includes peaks at three or more of 4.0, 14.8, 22.7, 27.8, and 30.6 degrees ± 0.2 degrees 2θ. In some embodiments of the present disclosure, Formulas IA - IV are characterized by an XRPD pattern that includes peaks at four or more of 4.0, 14.8, 22.7, 27.8, and 30.6 degrees ± 0.2 degrees 2θ.

[0099] In some embodiments, Formulas IA - IV can be characterized by a DSC thermogram substantially as shown in FIG. 12. As shown in FIG. 12, when heated at a rate of 10°C / min, Formulas IA - IV produce an endothermic peak at 169.03°C, with a peak onset temperature of 161.67°C and a melting enthalpy of 25.82 J / g, followed by an exothermic peak at 192.83°C, and then an endothermic peak at 243.32°C, with an onset temperature of 238.22°C and an enthalpy of 366.9 J / g. In some embodiments of the present disclosure, Formulas IA - IV are characterized by a DSC thermogram that includes an endothermic peak at about 169°C. In other embodiments of the present disclosure, Formulas IA - IV are characterized by a DSC melting enthalpy of about 26 J / g.

[0100] In some embodiments, Formulas IA - IV can be characterized by a TGA profile substantially as shown in FIG. 13 when heated at a rate of 20 °C / min. As shown in FIG. 13, when Formulas IA - IV are heated to about 300 °C, they lost about 12.4 (1.135% + 11.23%)% of their weight.

[0101] In some embodiments of the present disclosure, Formulas IA - IV are characterized by an XRPD pattern including peaks at one or more of 4.0, 14.8, 22.7, 27.8, and 30.6 degrees ± 0.2 degrees 2θ, and a DSC thermogram including an endothermic peak at about 169 °C when heated at a rate of 10 °C / min.

[0102] In some aspects, the present disclosure relates to a phosphate of Formula I, i.e., a crystalline form of Formula IB.

[0103] In some embodiments, the crystalline salt of Formula IB is Form IB - I and exhibits XRPD substantially as shown in FIG. 14A. The XRPD of Form IB - I shown in FIG. 14A includes the reflection angle (degrees 2θ ± 0.2 degrees 2θ), the interplanar spacing (d - value), and the relative intensity as shown in Table 6. [Table 6]

[0104] In some embodiments of the present disclosure, Form IB-I is characterized by an XRPD pattern that includes a peak at one of the angles listed in Table 6. In other aspects, Form IB-I is characterized by an XRPD pattern that includes two or more peaks at one of the angles listed in Table 6 above. In other aspects, Form IB-I is characterized by an XRPD pattern that includes two peaks selected from the angles listed in Table 6 above. In other aspects, Form IB-I is characterized by an XRPD pattern that includes three peaks selected from the angles listed in Table 6 above. In other aspects, Form IB-I is characterized by an XRPD pattern that includes four peaks selected from the angles listed in Table 6 above. In other aspects, Form IB-I is characterized by an XRPD pattern that includes five peaks selected from the angles listed in Table 6 above. In other aspects, Form IB-I is characterized by an XRPD pattern that includes six peaks selected from the angles listed in Table 6 above. In other aspects, Form IB-I is characterized by an XRPD pattern that includes seven peaks selected from the angles listed in Table 6 above. In other aspects, Form IB-I is characterized by an XRPD pattern that includes eight peaks selected from the angles listed in Table 6 above. In other aspects, Form IB-I is characterized by an XRPD pattern that includes nine peaks selected from the angles listed in Table 6 above. In other aspects, Form IB-I is characterized by an XRPD pattern that includes ten peaks selected from the angles listed in Table 6 above. In other aspects, Form IB-I is characterized by an XRPD pattern that includes more than ten peaks selected from the angles listed in Table 6 above.

[0105] In some embodiments, Form IB-I is characterized by an XRPD pattern that includes a peak at 24.9 degrees ± 0.2 degrees 2θ. In other embodiments, Form IB-I is characterized by an XRPD pattern that includes peaks at 18.2, 19.6, and 24.9 degrees ± 0.2 degrees 2θ. In other embodiments, Form IB-I is characterized by an XRPD pattern that includes peaks at 18.2, 19.6, 24.9, 25.7, and 27.0 degrees ± 0.2 degrees 2θ. In other embodiments, Form IB-I is characterized by an XRPD pattern that includes peaks at 18.2, 18.8, 19.6, 24.9, 25.7, and 27.0 degrees ± 0.2 degrees 2θ.

[0106] In some embodiments of the present disclosure, Form IB-I is characterized by an XRPD pattern that includes peaks at three or more of 18.2, 18.8, 19.6, 24.9, 25.7, and 27.0 degrees ± 0.2 degrees 2θ. In some embodiments of the present disclosure, Form IB-I is characterized by an XRPD pattern that includes peaks at four or more of 18.2, 18.8, 19.6, 24.9, 25.7, and 27.0 degrees ± 0.2 degrees 2θ. In some embodiments of the present disclosure, Form IB-I is characterized by an XRPD pattern that includes peaks at five or more of 18.2, 18.8, 19.6, 24.9, 25.7, and 27.0 degrees ± 0.2 degrees 2θ. In some embodiments of the present disclosure, Form IB-I is characterized by an XRPD pattern that includes peaks at six or more of 18.2, 18.8, 19.6, 24.9, 25.7, and 27.0 degrees ± 0.2 degrees 2θ. In some embodiments of the present disclosure, Form IB-I is characterized by an XRPD pattern that includes peaks at seven or more of 18.2, 18.8, 19.6, 24.9, 25.7, and 27.0 degrees ± 0.2 degrees 2θ.

[0107] In some embodiments, Form IB-I can be characterized by a DSC thermogram substantially as shown in FIG. 15A. As shown in FIG. 15A, when heated at a rate of 10° C. / min, Form IB-I produces an endothermic peak at 200.6° C., with a peak onset temperature of 198.96° C. and a melting enthalpy of 53.99 J / g, followed by endothermic peaks at 224.96° C. and 235.97° C. In some embodiments of the present disclosure, Form IB-I is characterized by a DSC thermogram including an endothermic peak at about 201° C. In other embodiments of the present disclosure, Form IB-I is characterized by a DSC melting enthalpy of about 54 J / g.

[0108] In some embodiments, Form IB-I can be characterized by a TGA profile substantially as shown in FIG. 16A when heated at a rate of 20° C. / min. As shown in FIG. 16A, when Form IB-I was heated to about 250° C., it lost about 6% of its weight.

[0109] In some embodiments of the present disclosure, Form IB-I is characterized by an XRPD pattern including peaks at one or more of 18.2, 18.8, 19.6, 24.9, 25.7, and 27.0 degrees ±0.2 degrees 2θ, and a DSC thermogram including an endothermic peak at about 201° C. when heated at a rate of 10° C. / min.

[0110] In some embodiments, the crystalline salt of Formula IB is Form IB-II, which exhibits XRPD substantially as shown in FIG. 14B. The XRPD of Form IB-II shown in FIG. 14B includes reflection angles (degrees 2θ ±0.2 degrees 2θ), interplanar spacings (d values), and relative intensities as shown in Table 6B. [Table 7]

[0111] In some embodiments of the present disclosure, Form II of Formula IB is characterized by an XRPD pattern that includes a peak at one of the angles listed in Table 6B. In other aspects, Form II of Formula IB is characterized by an XRPD pattern that includes two or more peaks at one of the angles listed in Table 6B above. In other aspects, Form II of Formula IB is characterized by an XRPD pattern that includes two peaks selected from the angles listed in Table 6B above. In other aspects, Form II of Formula IB is characterized by an XRPD pattern that includes three peaks selected from the angles listed in Table 6B above. In other aspects, Form II of Formula IB is characterized by an XRPD pattern that includes four peaks selected from the angles listed in Table 6B above. In other aspects, Form II of Formula IB is characterized by an XRPD pattern that includes five peaks selected from the angles listed in Table 6B above. In other aspects, Form II of Formula IB is characterized by an XRPD pattern that includes six peaks selected from the angles listed in Table 6B above. In other aspects, Form II of Formula IB is characterized by an XRPD pattern that includes seven peaks selected from the angles listed in Table 6B above. In other aspects, Form II of Formula IB is characterized by an XRPD pattern that includes eight peaks selected from the angles listed in Table 6B above. In other aspects, Form II of Formula IB is characterized by an XRPD pattern that includes nine peaks selected from the angles listed in Table 6B above. In other aspects, Form II of Formula IB is characterized by an XRPD pattern that includes ten peaks selected from the angles listed in Table 6B above. In other aspects, Form II of Formula IB is characterized by an XRPD pattern that includes more than ten peaks selected from the angles listed in Table 6B above.

[0112] In some embodiments, Form II of Formula IB is characterized by an XRPD pattern that includes a peak at 24.6 degrees ± 0.2 degrees 2θ. In other embodiments, Form II of Formula IB is characterized by an XRPD pattern that includes peaks at 19.3, 24.6, and 27.4 degrees ± 0.2 degrees 2θ. In other embodiments, Form II of Formula IB is characterized by an XRPD pattern that includes peaks at 19.3, 22.3, 23.6, 24.6, and 27.4 degrees ± 0.2 degrees 2θ. In other embodiments, Form II of Formula IB is characterized by an XRPD pattern that includes peaks at 19.3, 22.3, 23.6, 24.6, 25.6, and 27.4 degrees ± 0.2 degrees 2θ.

[0113] In some embodiments of the present disclosure, Form II of Formula IB is characterized by an XRPD pattern that includes peaks at three or more of 19.3, 22.3, 23.6, 24.6, 25.6, and 27.4 degrees ± 0.2 degrees 2θ. In some embodiments of the present disclosure, Form II of Formula IB is characterized by an XRPD pattern that includes peaks at four or more of 19.3, 22.3, 23.6, 24.6, 25.6, and 27.4 degrees ± 0.2 degrees 2θ. In some embodiments of the present disclosure, Form II of Formula IB is characterized by an XRPD pattern that includes peaks at five or more of 19.3, 22.3, 23.6, 24.6, 25.6, and 27.4 degrees ± 0.2 degrees 2θ. In some embodiments of the present disclosure, Form II of Formula IB is characterized by an XRPD pattern that includes peaks at six or more of 19.3, 22.3, 23.6, 24.6, 25.6, and 27.4 degrees ± 0.2 degrees 2θ.

[0114] In some embodiments, Form II of Formula IB can be characterized by a DSC thermogram that is substantially as shown in Figure 15B. As shown in Figure 15B, when heated at a rate of 10 °C / min, Form II of Formula IB produced an endothermic peak at 228.56 °C, with a peak onset temperature of 225.70 °C and a melting enthalpy of 140.4 J / g. In some embodiments of the present disclosure, Form II of Formula IB is characterized by a DSC thermogram that includes an endothermic peak at about 229 °C. In other embodiments of the present disclosure, Form II of Formula IB is characterized by a DSC melting enthalpy of about 140 J / g.

[0115] In some embodiments, Form IB - Form II can be characterized by a TGA profile substantially as shown in FIG. 16B when heated at a rate of 20 °C / min. As shown in FIG. 16B, Form IB - Form II lost approximately 7.3% of its weight when heated to about 275 °C.

[0116] In some embodiments of the present disclosure, Form IB - Form II is characterized by an XRPD pattern that includes peaks at one or more of 19.3, 22.3, 23.6, 24.6, 25.6, and 27.4 degrees ± 0.2 degrees 2θ, and a DSC thermogram that includes an endothermic peak at about 229 °C when heated at a rate of 10 °C / min.

[0117] In some aspects, the present disclosure relates to the tartrate salt of formula I, i.e., the crystalline form of formula IC.

[0118] In some embodiments, formula IC exhibits XRPD substantially as shown in FIG. 17. The XRPD of formula IC shown in FIG. 17 includes reflection angles (degrees 2θ ± 0.2 degrees 2θ), interplanar spacings (d - values), and relative intensities as shown in Table 7.

Table 8

[0119] In some embodiments of the present disclosure, formula IC is characterized by an XRPD pattern that includes a peak at one of the angles listed in Table 7. In other aspects, formula IC is characterized by an XRPD pattern that includes two or more peaks at one of the angles listed in Table 7 above. In other aspects, formula IC is characterized by an XRPD pattern that includes two peaks selected from the angles listed in Table 7 above. In other aspects, formula IC is characterized by an XRPD pattern that includes three peaks selected from the angles listed in Table 7 above. In other aspects, formula IC is characterized by an XRPD pattern that includes four peaks selected from the angles listed in Table 7 above. In other aspects, formula IC is characterized by an XRPD pattern that includes five peaks selected from the angles listed in Table 7 above. In other aspects, formula IC is characterized by an XRPD pattern that includes six peaks selected from the angles listed in Table 7 above. In other aspects, formula IC is characterized by an XRPD pattern that includes seven peaks selected from the angles listed in Table 7 above. In other aspects, formula IC is characterized by an XRPD pattern that includes eight peaks selected from the angles listed in Table 7 above. In other aspects, formula IC is characterized by an XRPD pattern that includes nine peaks selected from the angles listed in Table 7 above. In other aspects, formula IC is characterized by an XRPD pattern that includes ten peaks selected from the angles listed in Table 7 above. In other aspects, formula IC is characterized by an XRPD pattern that includes more than ten peaks selected from the angles listed in Table 7 above.

[0120] In some embodiments, Formula IC is characterized by an XRPD pattern that includes peaks at 18.4 degrees ± 0.2 degrees 2θ. In other embodiments, Formula IC is characterized by an XRPD pattern that includes peaks at 18.4, 19.9, and 21.5 degrees ± 0.2 degrees 2θ. In other embodiments, Formula IC is characterized by an XRPD pattern that includes peaks at 18.4, 19.4, 19.9, 21.5, and 26.3 degrees ± 0.2 degrees 2θ. In other embodiments, Formula IC is characterized by an XRPD pattern that includes peaks at 11.4, 18.4, 19.4, 19.9, 21.5, 26.3, and 30.2 degrees ± 0.2 degrees 2θ. In other embodiments, Formula IC is characterized by an XRPD pattern that includes peaks at 11.4, 18.4, 19.4, 19.9, 21.5, 26.3, 30.2, and 33.1 degrees ± 0.2 degrees 2θ.

[0121] In some embodiments of the present disclosure, Formula IC is characterized by an XRPD pattern that includes peaks at three or more of 11.4, 18.4, 19.4, 19.9, 21.5, 26.3, 30.2, and 33.1 degrees ± 0.2 degrees 2θ. In some embodiments of the present disclosure, Formula IC is characterized by an XRPD pattern that includes peaks at four or more of 11.4, 18.4, 19.4, 19.9, 21.5, 26.3, 30.2, and 33.1 degrees ± 0.2 degrees 2θ. In some embodiments of the present disclosure, Formula IC is characterized by an XRPD pattern that includes peaks at five or more of 11.4, 18.4, 19.4, 19.9, 21.5, 26.3, 30.2, and 33.1 degrees ± 0.2 degrees 2θ. In some embodiments of the present disclosure, Formula IC is characterized by an XRPD pattern that includes peaks at six or more of 11.4, 18.4, 19.4, 19.9, 21.5, 26.3, 30.2, and 33.1 degrees ± 0.2 degrees 2θ. In some embodiments of the present disclosure, Formula IC is characterized by an XRPD pattern that includes peaks at seven or more of 11.4, 18.4, 19.4, 19.9, 21.5, 26.3, 30.2, and 33.1 degrees ± 0.2 degrees 2θ.

[0122] In some embodiments, Formula IC can be characterized by a DSC thermogram substantially as shown in FIG. 18. As shown in FIG. 18, when heated at a rate of 10° C. / min, Formula IC produced an endothermic peak at 190.04° C., with a peak onset temperature of 180.70° C. and a melting enthalpy of 19.00 J / g. In some embodiments of the present disclosure, Formula IC is characterized by a DSC thermogram that includes an endothermic peak at about 190° C. In other embodiments of the present disclosure, Formula IC is characterized by a DSC melting enthalpy of about 19 J / g.

[0123] In some embodiments, Formula IC can be characterized by a TGA profile substantially as shown in FIG. 19 when heated at a rate of 20° C. / min. As shown in FIG. 19, when Formula IC was heated to about 275° C., it lost about 9.3% of its weight.

[0124] In some embodiments of the present disclosure, Formula IC is characterized by an XRPD pattern that includes peaks at one or more of 11.4, 18.4, 19.4, 19.9, 21.5, 26.3, 30.2, and 33.1 degrees ±0.2 degrees 2θ, and a DSC thermogram that includes an endothermic peak at about 190° C. when heated at a rate of 10° C. / min. Pharmaceutical Compositions and Methods of Administration

[0125] The pharmaceutical composition of interest is typically formulated to provide a therapeutically effective amount of a compound of the present disclosure as an active ingredient, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof. Optionally, the pharmaceutical composition contains a pharmaceutically acceptable salt and / or its coordination compound, and a carrier containing one or more pharmaceutically acceptable excipients, inert solid diluents, and fillers, a diluent containing sterile aqueous solutions and various organic solvents, a penetration enhancer, a solubilizer, and an adjuvant.

[0126] The pharmaceutical composition in question can be administered alone or in combination with one or more other agents, which is also typically administered in the form of a pharmaceutical composition. If desired, one or more compounds of the present invention and other agents may be mixed into a formulation, or both components may be formulated into separate formulations and used in combination, separately or simultaneously.

[0127] In some embodiments, the concentration of one or more compounds provided in the pharmaceutical composition of the present invention is, by weight ratio (w / w), weight / volume ratio (w / v), or volume ratio (v / v), less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% (or a number within the range defined by any two of the above numbers, and numbers within the ranges including those numbers).

[0128] In some embodiments, the concentration of one or more compounds of the present invention is, by weight ratio (w / w), weight / volume ratio (w / v), or volume ratio (v / v), more than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25%, 15%, 14.75%, 14.50%, 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 a number within the range defined by any two of the above numbers, and numbers within the ranges including those numbers).

[0129] In some embodiments, the concentration of one or more compounds of the present invention is in the range of about 0.0001% to about 50%, about 0.001% to about 40%, about 0.01% to about 30%, about 0.02%, about 29%, about 0.03% to about 28%, about 0.04% to about 27%, about 0.05% to about 26%, about 0.06% to about 25%, about 0.07% to about 24%, about 0.08% to about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%, about 1% to about 10% by weight ratio (w / w), weight / volume ratio (w / v), or volume ratio (v / v).

[0130] In some embodiments, the concentration of one or more compounds of the present invention is in the range of about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, about 0.1% to about 0.9% by weight ratio (w / w), weight / volume ratio (w / v), or volume ratio (v / v).

[0131] 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, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g (or a number within the range defined by any two of the above numbers, and numbers within the ranges that include those numbers) or less.

[0132] In some embodiments, the amount of one or more compounds of the present invention is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g, 0.3 g, 0.35 g, 0.4 g, 0.45 g, 0.5 g, 0.55 g, 0.6 g, 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5 g, 3 g, 3.5 g, 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 a number within a range defined by any two of the above numbers, and numbers within the ranges including those numbers).

[0133] 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.

[0134] The compounds according to the present invention are effective over a wide range of dosages. For example, in the treatment of adult humans, dosages of 0.01 - 1000 mg, 0.5 - 100 mg, 1 - 50 mg / day, and 5 - 40 mg / day are examples of dosages that may be used. An exemplary dosage is 10 - 30 mg / day. The exact dosage will depend 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.

[0135] The pharmaceutical composition of the present invention typically contains the active ingredient of the present invention (i.e., the compound of the present disclosure), or a pharmaceutically acceptable salt and / or coordination compound thereof, and one or more pharmaceutically acceptable excipients, carriers, diluents, sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers, and adjuvants including but not limited to inert solid diluents and fillers.

[0136] Non-limiting and exemplary pharmaceutical compositions and methods for their preparation are described below. Pharmaceutical compositions for oral administration.

[0137] In some embodiments, the present invention provides a pharmaceutical composition for oral administration containing the compound of the present invention and a pharmaceutical excipient suitable for oral administration.

[0138] In some embodiments, the present invention provides a solid pharmaceutical composition for oral administration containing (i) an effective amount of the compound of the present invention, optionally (ii) an effective amount of a second agent, and (iii) a pharmaceutical excipient suitable for oral administration. In some embodiments, the composition further contains (iv) an effective amount of a third agent.

[0139] In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral ingestion. The pharmaceutical composition of the present invention suitable for oral administration may exist as a separate dosage form such as a capsule, cachet, or tablet, or a predetermined amount of the active ingredient may be in the form of a powder or granules, in solution, or as a suspension in an aqueous or non-aqueous liquid, a water-in-oil emulsion, or an oil-in-water liquid emulsion, and may exist as a liquid or an aerosol spray. Such dosage forms can be prepared by any of the methods of a pharmacist, but all methods include the step of combining the active ingredient with a carrier, which constitutes one or more of the necessary ingredients. Generally, the composition is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or an ultra-fine solid carrier or both, and then, if necessary, forming the product into the desired state. For example, tablets can be prepared by compressing or molding, optionally using one or more auxiliary ingredients. Compressed tablets are prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as a powder or granules mixed with excipients such as, but not limited to, binders, lubricants, inert diluents, and / or surfactants or dispersants. Molded tablets can be produced by molding, in a suitable machine, a mixture of powdered compounds moistened with an inert liquid diluent.

[0140] The present invention further encompasses anhydrous pharmaceutical compositions and dosage forms containing an active ingredient since water can promote the decomposition of several compounds. For example, in the pharmaceutical field, water may be added (e.g., 5%) as a means of simulating long-term storage in order to determine properties such as shelf life or the stability of the 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 rendered anhydrous if they are expected to come into substantial contact with moisture and / or humidity during manufacture, packaging, and / or storage. The anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained. Thus, the anhydrous composition may be packaged using materials known to prevent exposure to water so that it can be included in a suitable dispensing kit. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, etc., unit-dose containers, blister packs, and strip packs.

[0141] The active ingredient can be combined in a homogeneous 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 the formulation desired for administration. When preparing a composition for an oral dosage form, in the case of an oral liquid formulation (suspension, solution, elixir, etc.) or an aerosol, for example, any of the usual pharmaceutical culture media such as water, glycols, oils, alcohols, flavoring additives, preservatives, coloring agents, etc. can be used as the carrier, or in the case of an oral solid formulation, carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrants can be used without the use of lactose in some embodiments. For example, suitable carriers for solid oral formulations include powders, capsules, and tablets. If desired, the tablets can be coated by standard aqueous or non-aqueous techniques.

[0142] Suitable binders for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures of these natural and synthetic gums.

[0143] Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrate, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures of these.

[0144] Disintegrants may be used in the compositions of the present invention to provide tablets that disintegrate when exposed to an aqueous environment. If there is too much disintegrant, the provided tablets may disintegrate within the container. If there is too little disintegrant, disintegration may be insufficient to occur, and thus, the release rate and release range of the active ingredient(s) from the dosage form may vary. Therefore, to form the dosage forms of the compounds disclosed herein, a sufficient amount of disintegrant that is neither too much nor too little may be used so as not to detrimentally change the release of the active ingredient(s). The amount of disintegrant used may be varied based on the type of formulation and the mode of administration i and may be readily recognizable to those skilled in the art. A disintegrant of about 0.5 to about 15% by weight, or about 1 to about 5% by weight, may be used in the pharmaceutical composition. Disintegrants that may be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, potassium polyacrylate, sodium glycolate starch, potato starch or tapioca starch, other starches, pregelatinized starch, other starches, clays, other algins, other celluloses, gums, or mixtures thereof.

[0145] Lubricants that may 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 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. The lubricant may optionally be added in an amount of less than about 1% by weight of the pharmaceutical composition.

[0146] When an aqueous suspension and / or elixir is desired for oral administration, the active ingredient therein may be combined with various sweetening or flavoring agents, coloring substances or dyes, and, if desired, the drug may be emulsified and / or precipitated with such diluents as water, ethanol, propylene glycol, glycerin, and various combinations thereof.

[0147] Tablets may be uncoated or may be coated by well-known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, time-delay materials such as glyceryl monostearate or glyceryl distearate may be used. Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

[0148] Surfactants that may be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be used, a mixture of lipophilic surfactants may be used, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be used.

[0149] Suitable hydrophilic surfactants may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of about 10 or less. The experimental parameter used to characterize the relative hydrophilicity and hydrophobicity of nonionic amphiphilic compounds is the hydrophilic-lipophilic balance (the "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.

[0150] 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 a general guideline commonly used to enable the formulation of industrial, pharmaceutical, and cosmetic emulsions.

[0151] Hydrophilic surfactants can be either ionic or nonionic. 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; lysophosphatidylcholine and hydrogenated lysophosphatidylcholine; phospholipids and their derivatives; lysophospholipids and their derivatives; carnitine fatty acid ester salts; alkyl sulfates; fatty acid salts; sodium doxsylate; acyl lactic acid; mono - and di - acetylated tartaric acid esters of mono - and di - glycerides; succinylated mono - and di - glycerides; citric acid esters of mono - and di - glycerides; and mixtures thereof, but are not limited thereto.

[0152] Within the above group, examples of ionic surfactants include lecithin, lysophosphatidylcholine, phospholipids, lysophospholipids and their derivatives; carnitine fatty acid ester salts; salts of alkyl sulfates; fatty acid salts; sodium doxsylate; acyl lactic acid; mono - and di - acetylated tartaric acid esters of mono - and di - glycerides; succinylated mono - and di - glycerides; citric acid esters of mono - and di - glycerides; and mixtures thereof.

[0153] The ionic surfactant can be the ionized form of lecithin, lysophosphatidylcholine, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactic acid esters of fatty acids, stearoyl-2-lactic acid, stearoyl lactic acid, succinylated monoglycerides, mono / diacetylated tartaric acid esters of mono / diglycerides, citric acid esters of mono / diglycerides, cholylsarcosine, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, oleic acid, ricinoleate, linoleate, linolenic acid, stearate, sodium lauryl sulfate, teracesyl sulfate, doxarate, lauroyl carnitine, palmitoyl carnitine, myristoyl carnitine, and salts and mixtures thereof.

[0154] Examples of hydrophilic nonionic surfactants include alkyl glucosides; alkyl maltosides; alkyl thioglucosides; lauryl macrogol glycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkyl phenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of polyols having at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivatives, and analogs thereof; polyoxyethylated vitamins and their derivatives; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; hydrophilic transesterification products of polyols having at least one member of the group consisting of polyethylene glycol sorbitan fatty acid esters and triglycerides, vegetable oils, and hydrogenated vegetable oils, but are not limited thereto. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.

[0155] Examples of other hydrophilic nonionic surfactants include, but are not limited to, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 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 caprylic / capric glyceride, PEG-8 caprylic / capric glyceride, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phytosterol, PEG-30 soy sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG10-100 nonylphenol type, PEG15-100 octylphenol type, and poloxamer.

[0156] Suitable lipophilic surfactants include, by way of example only, aliphatic 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 di-glycerides; hydrophobic transesterification products of polyols having at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-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 having at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.

[0157] In one embodiment, the composition may include a solubilizer to ensure good solubilization and / or dissolution of the compounds of the invention and to minimize precipitation of the compounds of the invention. This can be particularly important for compositions for parenteral use, for example, compositions for injection. Solubilizers may also be added to increase the solubility of other components such as hydrophilic drugs and / or surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.

[0158] Examples of suitable solubilizers include the following alcohols and polyols: ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and its isomers, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrin 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-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributyl citrate, triethyl acetyl citrate, tributyl acetyl citrate, triethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and its isomers, δ-valerolactone and its isomers, β-butyrolactone and its isomers; and other solubilizers such as dimethylacetamide, dimethyl isosorbide, N-methylpyrrolidone, mono-octanoin, diethylene glycol monoethyl ether, and water, but are not limited thereto.

[0159] Mixtures of solubilizing agents may also be used. Examples include, but are not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropyl cyclodextrin, ethanol, polyethylene glycol 200 - 100, glycopyrrolate, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizing agents include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycopyrrolate, and propylene glycol.

[0160] The amount of solubilizing agent that may be included is not particularly limited. The amount of a given solubilizing agent may be readily determined by one of ordinary skill in the art and may be limited to a biologically acceptable amount. Depending on the situation, it may be advantageous to include an amount of solubilizing agent that exceeds the biologically acceptable amount in order to maximize the drug concentration, for example, by removing excess solubilizing agent using conventional techniques such as distillation or evaporation before providing the composition to the subject. Thus, when present, the solubilizing agent may be in a weight ratio of 10 wt%, 25 wt%, 50 wt%, 100 wt%, or up to about 200 wt% based on the combined weight of the drug and other excipients. If desired, very small amounts of solubilizing agent, such as 5%, 2%, 1% or less, may also be used. Typically, the solubilizing agent may be present in an amount of about 1 wt% to about 100 wt%, more typically about 5 wt% to about 25 wt%.

[0161] The composition may further comprise one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, but are not limited to, antiadherents, antifoaming agents, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, tonicity agents, flavoring agents, coloring agents, odorants, opacifying agents, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0162] In addition, an acid or a base may be formulated in the composition to facilitate the treatment, improve stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, aluminum magnesium hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (Tris), and the like. Also suitable are bases that are salts of pharmaceutically acceptable acids, and these 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, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like. Salts of polybasic acids such as sodium phosphate, disodium phosphate, and sodium dihydrogen phosphate can also be used. When the base is a salt, the cation can be any convenient and pharmaceutically acceptable cation such as ammonium, an alkali metal, or an alkaline earth metal. Examples may include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, and ammonium.

[0163] Suitable acids are pharmaceutically 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, and the like. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acid, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acid, formic acid, fumaric acid, gluconic acid, hydroxynaphthalenesulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like.

[0164] In some embodiments, the pharmaceutical composition comprises a compound of formula IA, microcrystalline cellulose, crospovidone, sodium lauryl sulfate, and magnesium stearate.

[0165] In some embodiments, the pharmaceutical composition comprises a compound of formula IA, mannitol, microcrystalline cellulose, crospovidone, sodium lauryl sulfate, and magnesium stearate.

[0166] In some embodiments, the pharmaceutical composition comprises a compound of formula IA - Form I, mannitol, microcrystalline cellulose, crospovidone, sodium lauryl sulfate, and magnesium stearate.

[0167] In some embodiments, the pharmaceutical composition comprises a compound of formula IA - Form II, mannitol, microcrystalline cellulose, crospovidone, sodium lauryl sulfate, and magnesium stearate.

[0168] In some embodiments, the pharmaceutical composition comprises a compound of formula IA - Form IIa, mannitol, microcrystalline cellulose, crospovidone, sodium lauryl sulfate, and magnesium stearate.

[0169] In some embodiments, the pharmaceutical composition comprises a compound of Formula IA - Form III, mannitol, microcrystalline cellulose, crospovidone, sodium lauryl sulfate, and magnesium stearate.

[0170] In some embodiments, the pharmaceutical composition comprises a compound of Formula IA - Form IV, mannitol, microcrystalline cellulose, crospovidone, sodium lauryl sulfate, and magnesium stearate.

[0171] In some embodiments, the pharmaceutical composition comprises a compound of Formula IB, mannitol, microcrystalline cellulose, crospovidone, sodium lauryl sulfate, and magnesium stearate. Pharmaceutical composition for injection.

[0172] In some embodiments, the present invention provides a pharmaceutical composition for injection, comprising a compound of the present invention and a pharmaceutical excipient suitable for injection. The components and amounts of the drugs in the composition are as described herein.

[0173] Forms in which the novel composition of the present invention may be incorporated for administration by injection include aqueous or oily suspensions, or emulsions, including sesame oil, corn oil, cottonseed oil, or peanut oil, and elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical solvents.

[0174] Aqueous solutions in physiological saline are also commonly used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, etc. (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be used. Appropriate fluidity can be maintained, for example, by using coatings such as lecithin and by using surfactants, to maintain the required particle size in the case of dispersion. Prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.

[0175] The sterile injectable solutions are prepared by compounding the required amount of the compound of the invention in a suitable solvent, optionally with various other ingredients as enumerated above, and subsequently sterilization filtering. Generally, the dispersion is adjusted by compounding various sterilized active ingredients into a non-viable container containing a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, particular desirable preparation methods are vacuum drying and lyophilization techniques, which result in a powder of the active ingredient and any additional desired ingredients from its previously sterilization filtered solution. Pharmaceutical composition for topical (e.g., transdermal) delivery.

[0176] In some embodiments, the present invention provides a pharmaceutical composition for transdermal delivery, containing the compound of the present invention and a pharmaceutical excipient suitable for transdermal delivery.

[0177] The compositions of the present invention can be formulated into solid, semi-solid, or liquid form formulations suitable for topical or local administration, such as gels, water-soluble jellies, creams, lotions, suspensions, foams, powders, slurries, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, aqueous saline solutions, dimethyl sulfoxide (DMSO)-based solutions, etc. Generally, high-density carriers can provide areas with prolonged exposure to the active ingredient. In contrast, solution formulations may result in more immediate exposure of the active ingredient to the selected area.

[0178] The pharmaceutical composition may also include a suitable solid or gel-phase carrier or excipient, which is a compound that enables the increase or aids the delivery of the therapeutic molecule across the stratum corneum permeability barrier of the skin. Many of these penetration enhancing molecules are well known to those skilled in the art of topical formulations.

[0179] Examples of such carriers and excipients 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, starch, cellulose derivatives, gelatin, and polymers such as polyethylene glycol.

[0180] Another exemplary formulation for use in the method of the present invention employs a transdermal delivery device (“patch”). Such a transdermal patch may be used to provide a controlled amount of continuous or discontinuous infusion of the compounds of the present invention, with or without another agent.

[0181] The construction and use of transdermal patches for delivering pharmaceuticals are well known in the art. See U.S. Pat. Nos. 5,023,252, 4,992,445, and 5,001,139. Such patches may be constructed for continuous, pulsed, or as-needed delivery of pharmaceuticals. Pharmaceutical composition for inhalation.

[0182] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, the compositions are administered by the oral or nasal respiratory route for local or systemic effects. Preferably, the compositions in pharmaceutically acceptable solvents may be nebulized by the use of an inert gas. The nebulized solution may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent or intermittent positive pressure breathing machine. The solution, suspension, or powder composition may be administered preferably orally or nasally from a device that delivers the formulation in an appropriate manner. Other pharmaceutical compositions.

[0183] The pharmaceutical compositions may also be prepared from the compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intranasal administration. The preparation of such pharmaceutical compositions is well known in the art. See, for example, 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; Remington Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins, 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999).

[0184] Administration of the compounds or pharmaceutical compositions of the present invention can be effected by any method that enables delivery of the compound to the site of action. These methods include oral route, duodenal route, parenteral injection (including intravenous, arterial, subcutaneous, intramuscular, intracardiac, intraperitoneal or infusion), topical (e.g., transdermal application), rectal administration, local delivery via catheter or stent, or via inhalation. The compounds can also be administered into adipose or intrathecal.

[0185] The amount of the compound administered depends on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound, and the discretion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg of body weight per day, preferably 1 to about 35 mg / kg / day, administered in a single dose or divided doses. In a 70 kg human, this is 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 above range may be appropriate, while in other cases, for example, such higher dosages may still be used without causing any harmful side effects by dividing such higher dosages into several smaller dosages for administration over the course of a day.

[0186] In some embodiments, the compounds of the invention are administered in a single dose.

[0187] Typically, such administration can be performed by injection, such as intravenous injection, to rapidly introduce the drug. However, other routes may also be appropriately used. A single dose of the compounds of the invention may also be used for the treatment of acute conditions.

[0188] In some embodiments, the compounds of the invention are administered in multiple doses. The administration may be about 1, 2, 3, 4, 5, 6, or more than 6 times per day. The administration may be once per month, once every two weeks, once per week, or once a day. In another embodiment, the compounds of the invention and another drug are administered together about 1 to about 6 times per day. In another embodiment, the administration of the compounds of the invention and the drug continues for less than about 7 days. In yet another embodiment, the administration continues for more than about 6, 10, 14, 28 days, 2 months, 6 months, or 1 year. In some cases, continuous administration is achieved and maintained as needed.

[0189] Administration of the compounds of the present invention may be continued as long as necessary. In some embodiments, the compounds of the present invention are administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the compounds of the present invention are administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the compounds of the present invention are administered over a long period of time during progression, for example, for the treatment of chronic effects.

[0190] An effective amount of the compounds of the present invention may be administered by any of the acceptable modes of administration of agents having similar utilities, including rectal, buccal, intranasal, and transdermal routes, by intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or inhalation, either as a single dose or as multiple doses.

[0191] The compositions of the present invention may also be delivered, for example, via an impregnated or coated device such as a stent, or an arterially inserted cylindrical polymer. Such methods of administration can, for example, assist in preventing or ameliorating restenosis following a procedure such as balloon angioplasty. Without being bound by theory, the compounds of the present invention can delay or inhibit the migration and proliferation of smooth muscle cells within the arterial wall that contribute to restenosis. The compounds of the present invention may be administered, for example, by local delivery from the wall of a stent, from a graft of a stent, from a graft, or from a cover or sheath of a stent. In some embodiments, the compounds of the present invention are mixed with a matrix. Such a matrix may be a polymer matrix and can serve to bind the compound to the stent. Suitable polymer matrices for such use include, for example, lactone-based polyesters or copolyesters such as polylactide, polycaprolactone glycolide, polyorthoesters, polyanhydrides, polyamino acids, polysaccharides, polyphosphazenes, poly(ether-ester) copolymers (e.g., PEO-PLLA); fluorinated polymers such as polydimethylsiloxane, poly(ethylene-vinyl acetate), acrylate-based polymers or copolymers (e.g., polyhydroxyethyl methacrylate methyl, polyvinyl pyrrolidone), polytetrafluoroethylene, and cellulose esters. Suitable matrices may be non-degradable or may degrade over time to release the compound or compounds. The compounds of the present invention may be applied to the surface of a stent by various methods such as dip coating / spin coating, spray coating, dip coating, and / or brush coating. The compound may be applied in a solvent and the solvent may be evaporated to form a layer of the compound on the stent. Alternatively, the compound may be placed within the body of the stent or graft, for example, within microchannels or micropores. When embedded, the compound diffuses out of the body of the stent and contacts the arterial wall. Such a stent may be prepared by immersing a stent manufactured to contain such micropores or microchannels into a solution of the compound of the present invention in a suitable solvent and subsequently evaporating the solvent.Excess drug on the surface of the stent may be removed via additional simple solvent washes. In still other embodiments, the compounds of the invention may be covalently attached to the stent or graft. A biodegradable covalent linker may be used to effect release of the compounds of the invention in vivo. Any labile bond such as an ester, amide, or anhydride bond may be used. The compounds of the invention may be administered intravascularly from a balloon used during angioplasty. Extravascular administration of the compounds of the formulation of the invention through the pericardium and epicardium may also be done to reduce restenosis.

[0192] Various stent devices that may be used as described are disclosed, for example, in the following references, all of which are hereby incorporated by reference: U.S. Patent Nos. 5,451,233; 5,040,548; 5,061,273; 5,496,346; 5,292,331; 5,674,278; 3,657,744; 4,739,762; 5,195,984; 5,292,331; 5,674,278; 5,879,382; 6,344,053.

[0193] The compounds of the invention may be administered in dosages. It is well known in the art that due to inter-subject variability in the pharmacokinetics of the compounds, individualization of the dosing regimen is necessary for optimal treatment. Administration of the compounds of the invention can be found by routine experimentation in light of this disclosure.

[0194] The compounds of the invention are administered in a composition containing one or more agents, the agents having a shorter half-life than the unit dosage form of the compounds of the invention, and the compounds of the invention may be adjusted accordingly.

[0195] The pharmaceutical composition to be targeted may be in a form suitable for oral administration, such as tablets, capsules, pills, powders, sustained-release formulations, solutions, suspensions, or may be in a form suitable for parenteral injection as a sterile solution, suspension or emulsion, or may be in a form suitable for topical administration as an ointment or cream, or may be in a form suitable for rectal administration as a suppository. The pharmaceutical composition may be in a unit dosage form suitable for single administration of an exact dosage. The pharmaceutical composition will contain a conventional pharmaceutical carrier or excipient and the compound according to the present invention as an active ingredient. In addition, it may contain other drugs or pharmaceuticals, carriers, adjuvants, etc.

[0196] Exemplary parenteral dosage forms include solutions or suspensions of the active compound in sterile aqueous solutions, such as aqueous propylene glycol or dextrose solutions. If desired, such dosage forms may be suitably buffered. Method of Use

[0197] Typically, the method involves administering to a subject a therapeutically effective amount of the compound of the present invention. The therapeutically effective amount of the compound for the targeted combination may vary depending on the intended use (in vitro or in vivo), or the subject and disease state being treated, such as the weight and age of the subject, the severity of the disease state, the mode of administration, etc., but this can be readily determined by those skilled in the art. The term also applies to the dose that induces a specific response in the target cells, such as a reduction in the proliferation or downregulation of the activity of the target protein. The specific dose may vary depending on the specific compound selected, the subsequent dosing regimen, whether it is administered in combination with other compounds, the timing of administration, the tissue being administered to, and the physical delivery system by which it is carried.

[0198] As used herein, the term "IC" 50"IC50" means the maximum half - inhibitory concentration of an inhibitor that inhibits a biological or biochemical function. This quantitative measurement indicates how much of a particular inhibitor is required to inhibit a given biological process (or a component of a process, i.e., an enzyme, cell, cell receptor, or microorganism) by half. In other words, it is the maximum half - inhibitory (50%) concentration (IC) of a substance (50% IC or IC50). EC50 means the plasma concentration required to obtain 50% of the maximum effect in vivo.

[0199] In some embodiments, the subject method utilizes a PRMT5 inhibitor having an IC50 value that is approximately a predetermined value or less than a predetermined value, as confirmed in an in vitro assay. In some embodiments, the PRMT5 inhibitor inhibits PRMT5a with an IC50 value of 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, 650 nM or less, 700 nM or less, 750 nM or less, 800 nM or less, 850 nM or less, 900 nM or less, 950 nM or less, 1 μΜ or less, 1.1 μΜ or less, 1.2 μΜ or less, 1.3 μΜ or less, 1.4 μΜ or less, 1.5 μΜ or less, 1.6 μΜ or less, 1.7 μΜ or less, 1.8 μΜ or less, 1.9 μΜ or less, 2 μΜ or less, 5 μΜ or less, 10 μΜ or less, 15 μΜ or less, 20 μΜ or less, 25 μΜ or less, 30 μΜ or less, 40 μΜ or less, 50 μΜ, 60 μΜ, 70 μΜ, 80 μΜ, 90 μΜ, 100 μΜ, 200 μΜ, 300 μΜ, 400 μΜ, or 500 μΜ or less (or a number within a range defined by any two of the above numbers, and numbers within ranges that include those numbers).

[0200] In some embodiments, the PRMT5 inhibitor selectively inhibits PRMT5a with an IC50 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 a number within the range defined by any two of the above numbers, and numbers within the ranges that include those numbers) than its IC50 value for one, two, or three other PRMTs.

[0201] In some embodiments, the PRMT5 inhibitor selectively inhibits PRMT5a with an IC50 value of less than about 1 nM, 2 nM, 5 nM, 7 nM, 10 nM, 20 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, 120 nM, 140 nM, 150 nM, 160 nM, 170 nM, 180 nM, 190 nM, 200 nM, 225 nM, 250 nM, 275 nM, 300 nM, 325 nM, 350 nM, 375 nM, 400 nM, 425 nM, 450 nM, 475 nM, 500 nM, 550 nM, 600 nM, 650 nM, 700 nM, 750 nM, 800 nM, 850 nM, 900 nM, 950 nM, 1 μΜ, 1.1 μΜ, 1.2 μΜ, 1.3 μΜ, 1.4 μΜ, 1.5 μΜ, 1.6 μΜ, 1.7 μΜ, 1.8 μΜ, 1.9 μΜ, 2 μΜ, 5 μΜ, 10 μΜ, 15 μΜ, 20 μΜ, 25 μΜ, 30 μΜ, 40 μΜ, 50 μΜ, 60 μΜ, 70 μΜ, 80 μΜ, 90 μΜ, 100 μΜ, 200 μΜ, 300 μΜ, 400 μΜ, or 500 μΜ (or a number within the range defined by any two of the above numbers, and numbers within the ranges that include those numbers), and the IC50 value 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 a number within the range defined by any two of the above numbers, and numbers within the ranges that include those numbers) than its IC50 value for one, two, or three other PRMTs.

[0202] The subject methods are useful for treating disease states associated with PRMT5. Any disease state that results directly or indirectly from abnormal activity or expression levels of PRMT5 can be an intended disease state.

[0203] Different disease states associated with PRMT5 have been reported. PRMT5 is involved, for example, in various human cancers, as well as in many abnormal hemoglobinopathies.

[0204] Non-limiting examples of such conditions include acanthoma, acinar cell carcinoma, acoustic neuroma, acral lentiginous melanoma, eccrine poroma, 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, adenomatoid odontogenic tumor, adrenocortical 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 carcinoma, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, appendiceal cancer, astrocytoma, atypical teratoid / rhabdoid tumor, basal cell carcinoma, Basal-like carcinoma, B-cell leukemia, B-cell lymphoma, Bellini duct carcinoma, bile duct cancer, bladder cancer, blastoma, bone cancer, bone tumor, brainstem 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, carcinoma of unknown primary site, carcinosarcoma, Castleman disease, central nervous system germ cell tumor, cerebellar astrocytoma, cerebral astrocytoma, cervical cancer, cholangiocarcinoma, chondroma, chondrosarcoma, chordoma, choriocarcinoma, choroid plexus papilloma, chronic lymphocytic leukemia, chronic monocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorder, chronic neutrophilic leukemia, clear cell tumor, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, Degos disease, dermatofibrosarcoma protuberans, dermoid cyst, desmoplastic small round cell tumor, diffuse large B-cell lymphoma, dysplastic ganglioglioma, embryonal carcinoma, endodermal sinus tumor, endometrial cancer, endometrial carcinoma, endometrial tumor, enteropathy-associated T-cell lymphoma, epithelioblastoma, epithelioma, epidermoid carcinoma, epithelioid sarcoma, erythroleukemia, esophageal cancer,esthesioneuroblastoma, Ewing tumor, Ewing sarcoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, extramammary Paget disease, fallopian tube cancer, fetal inclusion anomaly, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid carcinoma, gallbladder cancer, gallbladder carcinoma, ganglioglioma, ganglioneuroma, 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, gliomatosis, glomus tumor, glucagonoma, gonadoblastoma, granulosa cell tumorHairy cell leukemia, head and neck cancer, head and neck cancer, heart cancer, abnormal hemoglobinopathies such as beta-thalassemia and sickle cell disease (SCD), hemangioblastoma, hemangiopericytoma, angiosarcoma, hematological malignancies, hepatocellular carcinoma, hepatosplenic T-cell lymphoma, hereditary breast and ovarian cancer syndrome, Hodgkin lymphoma, Hodgkin lymphoma, hypopharyngeal cancer, hypothalamic glioma, inflammatory breast cancer, intraocular melanoma, islet cell carcinoma, islet cell tumor, juvenile myelomonocytic leukemia, Kaposi sarcoma, Kaposi sarcoma, kidney cancer, crackling tumor, Krukenberg tumor, laryngeal cancer, laryngeal cancer, malignant melanoma, leukemia, lip and oral cavity cancer, liposarcoma, lung cancer, corpus luteum cyst, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphocytic leukemia, lymphoma, macroglobulinemia, malignant fibrous histiocytoma, 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, mediastinal germ cell tumor, mediastinal tumor, medullary thyroid cancer, medulloblastoma, medulloblastoma, medulloepithelioma, melanoma, melanoma, meningioma, Merkel cell carcinoma, mesothelioma, mesothelioma, metastatic squamous cell carcinoma of the neck of unknown primary origin, metastatic urothelial carcinoma, Müllerian duct mixed tumor, monocytic leukemia, oral cancer, mucinous tumor, multiple endocrine neoplasia syndrome, multiple myeloma, multiple myeloma, fungating polypoid tumor, fungating polypoid tumor, myelodysplasia, myelodysplastic syndrome, myeloid leukemia, myeloid sarcoma, myeloproliferative disorders, myxoma, nasal cavity cancer, nasopharyngeal cancer, nasopharyngeal cancer, neoplasm, schwannoma, neuroblastoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, non-Hodgkin lymphoma, non-Hodgkin lymphoma, non-melanoma skin cancer, non-small cell lung cancer, ophthalmic oncology, anaplastic astrocytoma, anaplastic glioma, eosinophilic adenoma, optic nerve sheath meningioma, oral cancer, oral cancer, oropharyngeal cancer, osteosarcoma, osteosarcoma, ovarian cancer, ovarian cancer, epithelial ovarian cancer, ovarian germ cell tumor, low-grade ovarian tumor, mammary Paget's disease, Pancoast tumor, pancreatic cancer, pancreatic cancer, papillary thyroid cancer, papillomatosis, paraganglioma, paranasal sinus cancer, parathyroid cancer, penile cancer, perivascular epitheloid cell tumor, pharyngeal cancer, pheochromocytoma, moderately differentiated pineal parenchymal tumor, pineoblastoma, pituitary cell tumor, pituitary adenoma, pituitary tumor, plasma cell neoplasm, pleuropulmonary blastoma, polyembryoma, precursor T-lymphoblastic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, primary hepatocellular carcinoma, primary liver cancer, primary peritoneal cancer, primitive neuroectodermal tumor, prostate cancer, peritoneal pseudomyxoma,Rectal cancer, renal cell carcinoma, respiratory carcinomas associated with the NUT gene on chromosome 15, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter transformation, sacrococcygeal teratoma, salivary gland cancer, sarcoma, schwannomatosis, sebaceous adenocarcinoma, secondary neoplasm, seminoma, serous tumor, Sertoli-Leydig cell tumor, sex cord-stromal tumor, Sézary syndrome, signet ring cell carcinoma, 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 wart, spinal cord tumor, spinal tumor, splenic marginal zone lymphoma, squamous cell carcinoma, stomach cancer, superficial spreading melanoma, primitive neuroectodermal tumor of the tentorium, surface epithelial stromal tumor, synovial sarcoma, T cell acute lymphoblastic leukemia, T cell large granular lymphocyte leukemia, T cell leukemia, T cell lymphoma, T cell prelymphocytic leukemia, teratoma, advanced lymphadenocarcinoma, testicular cancer, theca cell tumor, laryngeal cancer, thymic cancer, thymoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, transitional cell carcinoma, urachal carcinoma, urethral cancer, urogenital tumor, uterine sarcoma, choroidal melanoma, vaginal cancer, Werner-Morrison syndrome, verrucous carcinoma, optic pathway glioma, vulvar cancer, Waldenström macroglobulinemia, Warthin tumor, Wilms tumor, or any combination thereof, but not limited thereto.

[0205] 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, psoriasis, eczema, and skin diseases such as scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi sarcoma, and ovarian cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, and epidermoid cancer.

[0206] 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.

[0207] In other embodiments, the method is for treating a disease selected from leukemia, such as acute myeloid leukemia (AML), acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS), epidermoid carcinoma, or abnormal hemoglobinopathies, such as β-thalassemia and sickle cell disease (SCD).

[0208] In still other embodiments, the method is for treating a disease selected from CDKN2A deletion cancer, 9P deletion cancer, MTAP deletion cancer, spliceosome mutant cancer, glioblastoma, NSCLC, head and neck cancer, bladder cancer, or hepatocellular carcinoma.

[0209] 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, cervical cancer, leukemia, such as acute myeloid leukemia (AML), acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS), epidermoid carcinoma, abnormal hemoglobinopathies, such as β-thalassemia and sickle cell disease (SCD), CDKN2A deletion cancer, 9P deletion cancer, MTAP deletion cancer, spliceosome mutant cancer, glioblastoma, NSCLC, head and neck cancer, bladder cancer, hepatocellular carcinoma, adenoid cystic carcinoma (ACC), primary central nervous system lymphoma, fallopian tube cancer, or non-Hodgkin lymphoma.

[0210] In other embodiments, the method is for treating a disease selected from adenoid cystic carcinoma (ACC), primary central nervous system lymphoma, fallopian tube cancer, or non-Hodgkin lymphoma.

[0211] The compounds of the present disclosure, as well as pharmaceutical compositions containing them, can be administered alone or in combination with a medical therapy to treat any of the described diseases. Examples of medical therapies include, for example, surgery and radiation therapy (e.g., gamma irradiation, neutron beam radiation therapy, electron beam radiation therapy, proton beam therapy, brachytherapy, systemic radioisotopes).

[0212] In other embodiments, 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 described diseases.

[0213] In other ways, 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 agonist.

[0214] In other ways, 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 agonist.

[0215] In other ways, the compounds of the present disclosure, as well as pharmaceutical compositions containing them, can be administered in combination with an anti-proliferative agent.

[0216] 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 chemotherapeutic agents to treat any of the described diseases. Examples of other chemotherapeutic agents include, for example, abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, all-trans retinoic acid, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bendamustine, bevacizumab, bexarotene, bleomycin, bortezombi, bortezomib, busulfan intravenous, busulfan oral, calusterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, drostanolone propionate, eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alfa-2a, irinotecan, lapatinib tosylate, lenalidomide, letrozole, leucovorin, leuprorelin acetate, levamisole, lomustine, mechlorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone phenylpropionate, nelarabine, nolatrexed, oxaliplatin, paclitaxel, pamidronate, panobinostat, panitumumab, pegasparaginase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, lestaurtinib, sorafenib, streptozocin, sunitinib,Sunitinib malate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinstat, and zoledronic acid, and any combination thereof may be mentioned.

[0217] In other embodiments, the other agent is a therapeutic agent that targets an epigenetic regulator. Examples of epigenetic regulator drugs include, for example, bromodomain inhibitors, histone lysine methyltransferases, histone arginine methyltransferases, histone demethylases, histone deacetylases, histone acetylases, and DNA methyltransferases, and any combination thereof. Histone deacetylase inhibitors are preferred in some embodiments and include, for example, vorinostat.

[0218] In other methods where the disease to be treated is cancer or another proliferative disease, the compounds of the present disclosure, and pharmaceutical compositions containing them, can be administered in combination with a targeted therapy agent. Examples of targeted therapies include, for example, JAK kinase inhibitors (e.g., ruxolitinib), PI3 kinase inhibitors (including PI3K-delta selective and broad-spectrum PI3K inhibitors), MEK inhibitors, cyclin-dependent kinase inhibitors (e.g., CDK4 / 6 inhibitors), BRAF inhibitors, mTOR inhibitors, proteasome inhibitors (e.g., bortezomib, carfilzomib), HDAC inhibitors (e.g., panobinostat, vorinostat), DNA methyltransferase inhibitors, dexamethasone, bromo and extra-terminal family members, BTK inhibitors (e.g., ibrutinib, acalabrutinib), BCL2 inhibitors (e.g., venetoclax), MCL1 inhibitors, PARP inhibitors, FLT3 inhibitors, and LSD1 inhibitors, and any combination thereof.

[0219] In other methods where the disease to be treated is cancer or another proliferative disease, the compounds of the present disclosure, as well as pharmaceutical compositions containing them, can be administered in combination with immune checkpoint inhibitors. Examples of immune checkpoint inhibitors include, for example, inhibitors of PD-1, such as anti-PD-1 monoclonal antibodies. Examples of anti-PD-1 monoclonal antibodies include, for example, nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, and AMP-224, as well as combinations thereof. In some embodiments, the anti-PD1 antibody is nivolumab. In some embodiments, the anti-PD1 antibody is pembrolizumab. In some embodiments, the immune checkpoint inhibitor is an inhibitor of PD-L1, such as an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C, or any combination thereof. In some embodiments, the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736. In other embodiments, the immune checkpoint inhibitor is an inhibitor of CTLA-4, such as an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab.

[0220] In other methods where the disease to be treated is cancer or another proliferative disease, the compounds of the present disclosure, as well as pharmaceutical compositions containing them, can be administered in combination with alkylating agents (e.g., cyclophosphamide (CY), melphalan (MEL), and bendamustine), proteasome inhibitors (e.g., carfilzomib), corticosteroid agents (e.g., dexamethasone (DEX), or immunomodulatory agents (e.g., lenalidomide (LEN) or pomalidomide (POM)), or any combination thereof.

[0221] In some embodiments, the disease to be treated is an autoimmune condition or an inflammatory condition. In these aspects, the compounds of the present disclosure, and pharmaceutical compositions containing them, can be administered in combination with corticosteroid agents such as triamcinolone, dexamethasone, fluocinolone, cortisone, prednisolone, or flumetholone, etc., or any combination thereof.

[0222] In other ways in which the disease to be treated is an autoimmune condition or an inflammatory condition, the compounds of the present disclosure, and pharmaceutical compositions containing them, can be administered in combination with immunosuppressive agents such as fluocinolone acetonide (RETISERT™), rimixolone (AL-2178, VEXOL™, ALCO™), or cyclosporine (RESTASIS™), etc., or any combination thereof.

[0223] In some embodiments, the disease to be treated is beta-thalassemia or sickle cell disease. In these aspects, the compounds of the present disclosure, and pharmaceutical compositions containing them, can be administered in combination with one or more agents such as, for example, HYDREA™ (hydroxyurea).

[0224] In some aspects, the present invention relates to a method for preparing a pharmaceutically acceptable salt described herein. In some embodiments, the method for preparing a pharmaceutically acceptable salt is as described in the following examples.

[0225] The examples and formulations provided below further illustrate and exemplify the compounds of the present invention and methods for preparing such compounds. It should be understood that the scope of the present invention is in no way limited by the scope of the following examples and formulations. Experimental Procedures Example 1. Synthesis of (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 (Formula I)

Chemical formula

[0226] To a solution of 2-(2-Bromo-5-chloro-phenyl)acetic acid (20.0 g, 80.16 mmol) dissolved in THF (200 mL), borane in THF (240.49 mL, 240.49 mmol) was added, and the mixture was stirred at 40 °C for 8 h. The mixture was quenched with MeOH at 0 °C, concentrated, and extracted with EA (400 mL × 2). The combined organic layers were dried, concentrated, and purified by Combi flash eluting with CH3CN / H2O (neutral) at 5 / 95 to 95 / 5 to obtain 22b (18.1 g, 76.854 mmol, yield 95.9%) as a colorless oil. LCMS [M-18]: 217.0 / 219.0. Synthesis of 2. 2-(2-Bromo-5-chloro-phenyl)ethoxy-tert-butyl-dimethyl-silane (22b)

[0227] To a solution of 22a (18.1 g, 76.85 mmol) dissolved in DMF (200 mL), imidazole (7.85 g, 115.28 mmol) and TBDMSCl (13.9 g, 92.23 mmol) were added, and the mixture was stirred at 25 °C for 8 h. EA (800 mL) was added, and the mixture was washed with brine (400 mL × 2). The organic layer was concentrated and purified by flash column (PE) to obtain 22b (26.7 g, 76.34 mmol, yield 99.3%) as a colorless oil. Synthesis of 3. [2-[2-[tert-Butyl(dimethyl)silyl]oxyethyl]-4-chloro-phenyl]-[(3aR,4R,6S,6aS)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanone (22c)

[0228] A solution of 22b (8.91 g, 25.6 mmol) dissolved in dry THF (50 mL) was added with n-BuLi (12.8 mL, 20.48 mmol) at -78 °C, and the mixture was stirred under nitrogen for 10 minutes. A solution of 1Ad (4.0 g, 10.24 mmol) dissolved in dry THF (20 mL) was added, and the mixture was stirred at -78 °C for 5 minutes. TLC (PE:EA = 8:1) indicated the completion of the reaction. The reaction mixture was poured into dilute HCl (pH 6; maintaining pH < 8 during the quenching process). The mixture was extracted with EA (200 mL × 2), the combined organic layers were dried, concentrated, and purified by Combi-flash eluting with CH3CN / H2O (neutral) at 5 / 95 - 95 / 5 to obtain 22c (5.1 g, 8.60 mmol, 84% yield) as a yellow solid. Step 4. Synthesis of (R)-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-chloro-phenyl]methanol (22d)

[0229] To a solution of 22c (5.0 g, 8.44 mmol) dissolved in THF (30 mL), DIBAL-H (16.88 mL, 25.31 mmol) was added at -78 °C, and the mixture was stirred at -78 °C for 30 minutes. TLC (PE / EA = 8 / 1) indicated that the SM with Rf = 0.5 was completely consumed by the main product with Rf = 0.4. The reaction mixture was poured into dilute HCl (pH 6, 400 mL; maintaining pH < 8 during the quenching process). The mixture was extracted with EA (300 mL × 2), the combined organic layers were dried, concentrated, and crude 22d (5.0 g) was obtained as a yellow solid. Step 5. Synthesis of 2-[5-chloro-2-[(R)-hydroxy-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methyl]phenyl]ethanol (22e)

[0230] To a solution of 22d (3.0 g, 5.17 mmol) dissolved in THF (50 mL) was added tetrabutylammonium fluoride (5.17 mL, 5.17 mmol). The mixed solution was stirred at 25 °C for 40 minutes. The reaction mixture was poured into an aqueous NH4Cl solution and extracted with EA (100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and the solvent was concentrated under reduced pressure. The crude product was purified by flash column (PE:EA = 15:1~3:1) to obtain 22e (2 g, 4.08 mmol, 79% yield) as a white solid. LCMS [M+H]: 480.1. Step 6. Synthesis of 4-chloro-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R)-6-chloroisochroman-1-yl]-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (22f)

[0231] To a solution of 22e (2.0 g, 4.16 mmol) dissolved in THF (100 mL) were added tributylphosphine (2.1 mL, 8.33 mmol), isopropyl (NE)-N-isopropoxycarbonyliminocarbamate (1.72 mL, 8.74 mmol), and pyridine (0.34 mL, 4.16 mmol), and the reaction mixture was stirred at 25 °C for 16 hours.

[0232] TLC (PE / EA = 3 / 1, Rf = 0.4) indicated that the starting material had been consumed. The solvent was removed under reduced pressure, and the crude product was purified by column chromatography on silica gel using petroleum ether / EtOAc (10:1~5:1) as the eluent to obtain 22f (1.7 g, 3.68 mmol, 88% yield) as a yellow oil. LCMS [M+H]: 462.1. Step 7. Synthesis of 4-methyl-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R)-6-chloroisochroman-1-yl]-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (22g)

[0233] Methylmagnesium bromide (3.68 mL, 11.04 mmol) was added dropwise to a solution of ferric acetylacetonate (0.13 g, 0.37 mmol) and 22f (1.7 g, 3.68 mmol) dissolved in THF (100 mL) at 5 °C under nitrogen. The reaction mixture was warmed to room temperature and stirred for 1 h. TLC (EA:PE = 1:1, Rf = 0.3) indicated the completion of the reaction. Saturated NH4Cl was added dropwise to quench the reaction, which was then extracted with EA (200 mL × 2), dried over Na2SO4, and concentrated. The residue was purified by flash column (PE:EA = 10:1~1:1) to afford 22g (900 mg, 1.93 mmol, 52.6% yield) as a white solid. Step 8. Synthesis of (2R,3R,4S,5S)-2-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1R)-6-chloroisochroman-1-yl]tetrahydrofuran-3,4-diol (Formula I)

[0234] To a solution of HCl (6.0 mL, 12 mmol) dissolved in methanol (10 mL), 22g (900 mg, 2.04 mmol) was added and the reaction mixture was stirred at 40 °C for 2 h. The reaction mixture was concentrated, and the residue was stirred with EA (50 mL) and filtered. The solid was purified by preparative HPLC eluting with CH3CN / H2O (0.1% NH4OH) from 5 / 95 to 95 / 5. The product fraction was extracted with EA (100 mL × 2), and the extract was concentrated to afford Formula I (550 mg, 1.34 mmol, 66% yield) as a white solid. LCMS [M+H]: 402.3. 11H NMR (400 MHz, DMSO-d6): δ 8.67 (s, 1H), 7.76 (d, J = 4.0 Hz, 1H), 7.22 - 7.31 (m, 3H), 6.81 (d, J = 3.6 Hz, 1H), 6.31 (d, J = 7.6 Hz, 1H), 5.26 (d, J = 7.2 Hz, 1H), 5.13 (d, J = 4.0 Hz, 1H), 4.90 (d, J = 3.6 Hz, 1H), 4.48 - 4.54 (m, 1H), 4.42 - 4.43 (m, 1H), 4.23 - 4.27 (m, 1H), 3.84 - 3.86 (m, 1H), 3.66 - 3.72 (m, 1H), 2.91 - 2.99 (m, 1H), 2.70 - 2.74 (m, 1H), 2.67 (s, 3H). 1 1H NMR (400 MHz, DMSO-d6 + D2O): δ 8.86 (s, 1H), 7.77 (d, J = 4 Hz, 1H), 7.22 - 7.31 (m, 3H), 6.82 (d, J = 3.6 Hz, 1H), 6.31 (d, J = 7.6 Hz, 1H), 4.90 (d, J = 3.6 Hz, 1H), 4.49 - 4.53 (m, 1H), 4.42 - 4.43 (m, 1H), 4.24 - 4.28 (m, 1H), 3.83 - 3.85 (m, 1H), 3.66 - 3.72 (m, 1H), 2.91 - 2.99 (m, 1H), 2.70 - 2.75 (m, 1H), 2.69 (s, 3H). Example 2. Synthesis of (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 (Formula I)

[0235] 5.84 g of Formula IA was added to a 250 mL round-bottom flask. 60 mL of deionized water was added and stirred for 5 minutes to obtain a suspension (pH 1.6). 2.5 mL of concentrated NH4OH (37%) was added gradually with stirring to obtain a slurry (pH 10). Stirring was carried out at pH 10 for 3 hours. The batch was filtered and washed first with 200 mL of water and then with 200 mL of heptane. The product on the filter was dried in an oven under vacuum (temperature 40 °C) to obtain 5.20 g (98.0%) of Formula I. The HPLC purity was 99.7%. Formula I was crystalline by XRPD.

[0236] In some embodiments, the free base of Formula I may have the following XRPD peaks (see Figure 21). [Table 9] Example 3.

[0237] The free base of Formula I was treated with phosphoric acid, sulfuric acid, hydrochloric acid, ascorbic acid, L-tartaric acid, ethane-1,2-disulfonic acid, and 1-hydroxy-2-naphthoic acid, and oxalic acid to obtain a solid. Example 4. Synthesis of the hydrochloride salt (Formula IA) of (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 [Chemical formula]

[0238] To 60 mg of the free base of Formula I (0.150 mmol), 1.5 mL of dichloromethane (DCM) and 2.0 mL of acetonitrile were added, and the mixture was stirred to obtain a clear solution. Hydrochloric acid (1 M solution in isopropanol, 0.165 mL, 0.165 mmol, 1.10 equivalents) was added, and the resulting mixture was stirred at room temperature for 40 minutes. The DCM was removed at 40 - 45 °C to obtain a slurry. The slurry was stirred at 65 °C for 60 minutes, then cooled to room temperature and stirred for 2 hours. The mixture was filtered and washed with methyl t-butyl ether (MTBE). The filter cake was dried under vacuum at 45 - 48 °C overnight to obtain 48.0 mg of the hydrochloride salt (Formula IA).

[0239] The XRPD of the hydrochloride salt is shown in Figure 1.

[0240] The DSC of the hydrochloride salt is shown in Figure 2.

[0241] The TGA of the hydrochloride salt is shown in Figure 3.

[0242] The crystalline HCl salt formed by this procedure is in the form of Formula IA - Form I. Example 5. Synthesis of the hydrochloride salt (Formula IA) of (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

Chemical formula

[0243] To 100.3 mg of Formula I (0.25 mmol, 1.0 equivalent) was added 4.0 mL of acetone and stirred for 5 minutes. 265 μL of 1.0 M HCl in IPA (0.263 mmol, 1.06 equivalents) was added. The resulting mixture was stirred to obtain a thin slurry, which was then stirred continuously overnight. The mixture was filtered to obtain a solid, which was dried under vacuum at 40 °C overnight to obtain 98.8 mg (yield 90.0%) of the salt (Formula IA). The purity of the salt was 99.2% by HPLC. The crystallinity of the salt was confirmed by XPRD. Comparison of the HPLC peak areas of the salt and the free base showed that the ratio of the free base to hydrochloric acid was approximately 1:1. Example 6. Synthesis of the hydrochloride salt (Formula IA) of (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

Chemical formula

[0244] To a clean and dry RBF, crude PRT1063, 3476.2 g (including 1829.0 g of PRT1063 based on the theoretical yield from the previous step) and MeOH (18.3 L) were charged. After concentrated HCl (1720 mL, 5.0 equivalents) was charged into the reactor, the resulting solution was stirred at 35 - 45 °C for about 8 hours. MTBE (55.0 L) was added to the reaction mixture, and the resulting slurry was stirred at room temperature for about 2 hours. The slurry was cooled to 0 - 5 °C and stirred for about 1 hour. The slurry was filtered, and the filter cake was returned to the RBF. MTBE (9.1 L) was charged, and the slurry was stirred at room temperature for 0.5 - 1 hour. The slurry was filtered, and the filter cake was washed with MTBE (3.7 L). Next, the filter cake was dried under vacuum on the funnel for more than 2 hours.

[0245] Recrystallization of Formula IA: To a clean and dry RBF, Formula IA (1500 g) and MeOH (15 L) were charged. The mixture was heated to 50 - 60 °C and stirred to form a clear solution. The solution was cooled to 20 - 30 °C and filtered through a fritted glass funnel. The filtrate was transferred to a clean and dry reactor, and the volume of the filtrate in the reactor was recorded. The funnel was washed with MeOH (3.0 L). This washing MeOH was used to rinse the filtrate receiving flask and then added to the reactor. A distillation apparatus was assembled on the reactor. The filtered solution in the reactor was heated to reflux, and the distillate was collected. While maintaining the distillation in the reactor, IPA (15 L) was gradually added to the reactor at a rate to maintain the initially recorded volume of the solution. After the addition of IPA, while maintaining the distillation, heptane (22.5 L) was gradually added to the reactor until the internal volume reached the recorded volume. Heating was stopped, and the slurry was cooled to 15 - 25 °C. The slurry was stirred at 15 - 25 °C for about 2 hours. The batch was filtered, and the filter cake was washed with heptane (4.5 L). The product was dried on the filter for more than 2 hours by pulling air through the filter cake. The filter cake was transferred to a tray and dried to a constant weight in an oven at 50 °C under vacuum. Example 7.

[0246] The polymorphic forms of Formula IA are characterized as described below. These polymorphs - Formula IA - Form I, Formula IA - Form II, Formula IA - Form IIa, Formula IA - Form III, Formula IA - Form IV - can be prepared using the methods described below. Solubility of the HCl salt at 21 ± 1 °C and 50 ± 1 °C

[0247] 3 mL of the test solvent was added to a 4 mL vial. Formula IA was added until a turbid solution was obtained at 21 ± 1 °C. Approximately 30 mg of additional Formula IA was added to the turbid solution. The mixture was stirred at 21 ± 1 °C over the weekend, during which the temperature was controlled by an IKA® ETS-D5 temperature controller and IKA® RCT basic safety management. The mixture was filtered using a syringe filter (PTFE, 0.22 μL, 13 mm, Agela Technologies Inc.). The saturated solution was transferred to an HPLC vial, diluted with methanol, and analyzed by HPLC.

[0248] 2 mL of the test solvent was added to a 4 mL vial. Formula IA was added until a turbid solution was obtained at 50 ± 1 °C. Approximately 30 mg of additional Formula IA was added to the turbid solution. The mixture was stirred at 50 ± 1 °C for 24 hours, during which the temperature was controlled by an IKA® ETS-D5 temperature controller and IKA® RCT basic safety management. The mixture was filtered using a syringe filter (PTFE, 0.22 μL, 13 mm, Agela Technologies Inc.). The saturated solution was transferred to an HPLC vial, diluted with methanol, and analyzed by HPLC. The results are shown in Table 8.

Table 10

[0249] To provide information on the dominant crystalline form, a phase equilibrium study was designed. Formula IA was equilibrated in a solvent at 25 ± 1 °C and 50 ± 1 °C. The temperature was controlled by an IKA® ETSD5 temperature controller and IKA® RCT basic safety management.

[0250] Form IA - Polymorph I was added to about 3 mL of solvent until a turbid solution was obtained and then about 20 mg of additional Form IA - Polymorph I was added to the turbid solution. The mixture was stirred at 25 ± 1 °C and 50 ± 1 °C for 2.0 days. The solid was filtered and analyzed by XRPD.

[0251] In these tests, polymorph II (Form IA - Polymorph II) was obtained from the phase equilibrium in ethanol at 25 °C and polymorph III (Form IA - Polymorph III) was obtained from water at 21 °C (Table 2). The phase equilibrium at 50 ± 1 °C (Table 3) resulted in polymorph III from water and Form I from the other solvents. The results are shown in Table 9. [Table 11] Evaporation tests

[0252] Evaporation tests were conducted to identify the dominant crystalline form during uncontrolled evaporation. Tests that did not result in particulate solids (i.e., clear thin films and oils) were not further investigated. The solid forms of the crystalline forms of the evaporation samples at 20 °C and 50 °C were investigated using XRPD. In these tests, saturated solutions prepared from Form IA - Polymorph I were evaporated. The results are shown in Table 10. [Table 12] Anti - solvent addition tests

[0253] Saturated or nearly saturated solutions of Form IA were prepared by adding Form IA - Polymorph I to the solvent. An anti - solvent was added to induce precipitation. The anti - solvents used were hexane, heptane, methyl t - butyl ether (MTBE), toluene, ethyl acetate, acetone, methyl ethyl ketone (MEK), isopropanol (IPA), tetrahydrofuran (THF), acetonitrile, and isopropyl acetate (IPAc). Tests that did not produce particulate solids upon anti - solvent addition were not further investigated. The results are shown in Table 11 below. [Table 13] Inverse addition test

[0254] A saturated solution or a solution close to saturation of Formula IA was prepared from Form I of Formula IA in a solvent. Next, this solution was added to a larger amount of miscible antisolvent. As the antisolvent, hexane, heptane, MTBE, toluene, ethyl acetate, acetone, MEK, IPA, THF, acetonitrile, and IPAc were used. Tests that did not produce particulate solids upon addition to the antisolvent were not further investigated. The results are shown in Table 12 below. [Table 14] Cooling of saturated solution

[0255] A saturated solution or a solution close to saturation of Form I of Formula IA in methanol or ethanol was prepared at room temperature and quenched to about -40°C. A saturated solution in water was prepared at 35°C and quenched to about 5°C. Both tests were designed to induce precipitation of a higher energy form. The results of these tests are shown in Table 13 below. [Table 15] Competitive slurry test

[0256] To evaluate the conversion of the solid form of Formula IA, a competitive slurry test was carried out as follows. Formula IA was added to a solvent mixture until a saturated solution was formed. Next, an additional 8 mg of Form I of Formula IA was added, and then 8 mg each of Form IIa of Formula IA, Form III of Formula IA, and Form IV of Formula IA were added. The slurry was stirred and analyzed by XRPD at various time points including overnight and 24 hours. The results are shown in Table 14. [Table 16] Representative synthetic procedure Form II of Formula IA

[0257] To approximately 3 mL of a saturated solution of the drug substance prepared with ethanol, approximately 50 mg of the drug substance was added, followed by stirring at 25 ± 1 °C for 2 days. This was filtered and air-dried in a hood for 24 hours and analyzed by XRPD as Form II of Formula IA. See Figures 4 and 5.

[0258] 3.0 mL of the saturated solution in ethanol was quenched and cooled to -20 °C, held at this temperature for 30 minutes to obtain a slurry, which was filtered and air-dried. The solid was analyzed by XRPD and identified as Form II of Formula IA. Form IIa of Formula IA

[0259] Form IIa of Formula IA was formed by drying Form II of Formula IA under vacuum at 48 - 50 °C for 24 hours. Form III of Formula IA

[0260] To approximately 3 mL of a saturated solution of the drug substance prepared with water, approximately 50 mg of the drug substance was added, followed by stirring at 25 ± 1 °C for 2 days. This was filtered and air-dried in a hood for 24 hours and analyzed by XRPD as Form III of Formula IA. See Figures 8 and 10.

[0261] 3.0 mL of the saturated solution in water was quenched and cooled to 2 - 3 °C, held at this temperature for 1.0 hour to obtain a slurry, which was filtered and air-dried. The solid was analyzed by XRPD and identified as Form III of Formula IA. See Figure 9. Form IV of Formula IA

[0262] To 2.5 mL of ethyl acetate, 0.6 mL of a solution of the drug substance prepared with MeOH (50 mg / mL) was added, followed by stirring for approximately 5 minutes. The solid was filtered and analyzed by XRPD as Form IV of Formula IA. See Figures 12 and 13.

[0263] To 0.6 mL of a solution of the drug substance prepared with MeOH (50 mg / mL), 1.5 mL of ethyl acetate was added, followed by stirring for approximately 5 minutes. The solid was filtered and analyzed by XRPD as Form IV of Formula IA. Example 8. Synthesis of Phosphate Salt of (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 (Formula IB)

[0264] To 50 mg of the free base of Formula I (0.125 mmol), 1.5 mL of isopropanol (IPA) and 1.0 mL of dichloromethane (DCM) were added, and the mixture was stirred to obtain a clear solution. Phosphoric acid (1 M solution in IPA, 0.15 mL, 0.15 mmol, 1.20 equivalents) was added, and the resulting mixture was stirred at room temperature for 40 minutes. DCM was removed at 40 °C to obtain a slurry. The slurry was stirred at 65 °C for 60 minutes, then cooled to room temperature and stirred for 2 hours. The mixture was filtered and washed with methyl t-butyl ether (MTBE). The filter cake was dried under vacuum at 45 - 48 °C overnight to obtain the phosphate salt (Formula IB).

[0265] The XRPD of this phosphate salt is shown in Figure 14B.

[0266] The DSC of this phosphate salt is shown in Figure 15B.

[0267] The TGA of this phosphate salt is shown in Figure 16B. Example 9. Synthesis of Phosphate Salt of (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 (Formula IB)

[0268] To 100.6 mg of the free base of formula I (0.25 mmol, 1.0 equivalent), 4.0 mL of EtOH was added. The resulting mixture was stirred for 5 minutes. 263 μL of 1.0 M H3PO4 in IPA (0.263 mmol, 1.06 equivalents) was added. The resulting mixture was stirred continuously overnight and then filtered to obtain a solid. The filter cake was dried under vacuum at 40 °C overnight to obtain 86.7 mg (69.3%) of the salt. The purity of the salt was 98.5% by HPLC. Comparison of the HPLC peak areas of the salt and the free base showed that the ratio of the free base to phosphoric acid was about 2:1.

[0269] The XRPD of this phosphate is shown in Figure 14A.

[0270] The DSC of this phosphate is shown in Figure 15A.

[0271] The TGA of this phosphate is shown in Figure 16A. Example 10. Synthesis of the tartrate salt (formula IC) of (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

[0272] To 40.5 mg of L-tartaric acid (0.263 mmol, 1.05 equivalents), 100.2 mg (0.25 mmol, 1.0 equivalent) of formula I was added. 4.0 mL of 2-butanone was added and the resulting mixture was stirred continuously overnight. The mixture was filtered to obtain a solid, which was washed with 2.5 mL of MTBE. The filter cake was dried under vacuum at 40 °C overnight to obtain 68.8 mg (yield 50.0%) of the tartrate salt.

[0273] The stoichiometric ratio of the salt between formula I and tartaric acid was determined to be 2:1 by its 1 1H NMR spectrum (Figure 20) (400 MHz, DMSO-d6).

[0274] The XRPD of this tartrate is shown in Figure 17.

[0275] The DSC of this tartrate is shown in Figure 18.

[0276] The TGA of this tartrate is shown in Figure 19.

[0277] Of the tartrate 1 The 1H NMR spectrum is shown in Figure 20. Instrument method Powder X-ray diffraction (XRPD)

[0278] The XRPD pattern can also be collected using a Rigaku MiniFlex X-ray Powder Diffractometer (XRPD) instrument. The X-ray radiation is obtained from copper (Cu) at 1.54056 Å using a β K filter. X-ray power: 30 kV, 15 mA. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC)

[0279] TGA can be collected using a TGA Q500 by TA Instruments at a scanning rate of 20 °C / min.

[0280] DSC can also be obtained using a TA Instrument Differential Scanning Calorimetry, Model Q20 equipped with an autosampler at a scanning rate of 10 °C / min and a nitrogen gas flow of 50 mL / min. Biochemical assay protocol

[0281] The compound was solubilized and diluted 3-fold with 100% DMSO. These diluted compounds were in assay buffer (20 mM Tris-HCl, pH 8.0, 50 mM NaCl, 0.002% Tween 20, 1 mM TCEP, 1% DMSO) at a concentration 10-fold higher than the desired assay concentration for 10 doses of IC 50It was further diluted in the format. The standard reaction was carried out using 300 nM of histone H4-based AcH4-23 (Anaspec: AS-65002) in a total volume of 30 μL in assay buffer as a substrate. To this, the diluted PRMT5 / MEP50 complex was added to provide a final assay concentration of 2.5 nM, and the compound was pre-incubated at 37 °C for 20 minutes. The reaction was initiated by adding S-[3H-methyl]-adenosyl-L-methionine (PerkinElmer: NET155001MC) to a final concentration of 1 μM. After incubation at 37 °C for 30 minutes, the reaction was stopped by adding 25 μL of 8 M guanidine HCl. Streptavidin YSI SPA beads (Perkinelmer: RPNQ0012) were prepared at 0.3 mg / mL in assay buffer. To each reaction, 150 μL of the SPA bead suspension was added and cultured with shaking at room temperature for 30 minutes. Before reading on a scintillation counter, the plate was centrifuged at 100 xg for 30 seconds. IC 50 values were determined by fitting the data to a standard four-parameter with a Hill slope using GraphPad Prism software. See Table 15 (PRMT5 IC 50 ) below. Cell assay protocol Cell treatment and Western blotting for detecting symmetric di-methylarginine (sDMA) marks

[0282] Compound dosing and cell culture: The compound was dissolved in DMSO to prepare a 10 mM stock solution, and further serial 3-fold dilutions were performed to prepare a stock solution top at 1 mM. Granta-519 cells were maintained in RPMI 1640 (Corning Cellgro, catalog number: 10-040-Cv) supplemented with 10% (v / v) FBS (GE Healthcare, catalog number: SH30910.03), and U-87MG cells were maintained in DMEM (Corning Cellgro, catalog number: 10-013-CV) with 10% FBS and 2 mM Glutamin (Corning Cellgro, catalog number 25005CV).

[0283] Use Western blot analysis to determine the enzyme inhibition IC 50 values in Granta-519 and U-87MG cells. One day before the experiment, Granta-519 cells were passaged at a density of 0.5×10 6 cells / mL. U-87MG cells were trypsinized and seeded at 4×10 5 cells into 6-well plates and allowed to grow overnight. The next day, Granta-519 cells were spun down at 1,500 rpm for 4 minutes, resuspended in fresh medium at 0.5×10 6 cells / mL, and 3 mL of culture solution (1.5×10 6 cells) was seeded into 6-well plates. Serial three-fold dilutions of the stock solution of the compound were added to the cells (3 mL, 1:1,000 dilution, DMSO concentration was 0.1%; final maximum concentration at 1 μM), and the cells were cultured for 3 days. Cells cultured with DMSO were used as a control.

[0284] Cells were harvested after 3 days, resuspended in 15 mL of PBS, lysed with 4% SDS, and homogenized by passing through a homogenizer column (Omega Biotek, catalog number: HCR003). Total protein concentration was determined by BCA assay (ThermoFisher Scientific, catalog number: 23225). The lysate was mixed with 5x Laemmli buffer and boiled for 5 minutes. 40 mg of total protein was separated on an SDS-PAGE gel (Bio-Rad, catalog numbers: 4568083, 4568043), transferred to a PVDF membrane, blocked with 0.1% (v / v) Tween20 (TBST) containing 5% dry milk in TBS at room temperature (RT) for 1 hour, and then incubated with primary antibodies (sDMA: Cell Signaling, catalog number: 13222, 1:3,000; β-actin: Sigma, catalog number: 1:5,000) containing 5% dry milk in TBST at 4°C overnight. The next day, the membrane was washed with TBST 5×5 minutes, incubated with HRP-conjugated secondary antibodies (GE Healthcare; catalog numbers: NA934-1ML, NA931-1ML, 1:5,000) at room temperature for 2 hours, followed by washing with TBST 5×5 minutes, and then incubated with ECL substrate (Bio-Rad, catalog numbers: 1705061, 1705062). Chemiluminescence signals were captured with a Fluochem HD2 imager (Proteinsimple). The SmD3me2s band was quantified with ImageJ. Signals were normalized to β-actin and DMSO controls. IC 50 values were calculated using Graphpad Prism ([inhibitor] vs. normalized response - variable slope). See Table 15 (sDMA IC 50 ) below. Cell proliferation assay for determining IC 50 in Granta-519 and U-87MG cells

[0285] One day before the experiment, Granta-519 cells were seeded at 0.5×10 6Passaged at a density of cells / mL. U-87MG cells were trypsinized, 2,000 cells were seeded into a 96-well plate, and allowed to grow overnight. On the experimental day (day 0), Granta-519 cells were spun down at 1,500 rpm for 4 minutes, resuspended in fresh medium at 0.5×10 6 cells / mL, and 190 μL of the cells were added to a 96-well plate. For U-87MG cells, the old medium was removed and replaced with 190 μL of fresh medium. The stock solution of the compound was first diluted 1:50 with fresh medium in a 96-well plate, 10 μL of the diluted drug was added to the 96-well plate containing the cells, and the cells were cultured for 3 days. DMSO was used as a solvent control.

[0286] On day 3 (One day 3), 50 μL of Granta-519 cells were transferred to a new 96-well plate, and 140 μL of fresh medium was added. For U-87MG cells, the old medium was removed and replaced with 190 μL of fresh medium. The stock solution of the compound was freshly diluted 1:50 with medium, 10 μL of the diluted drug was added to the cells, and the cells were allowed to grow for an additional 3 days. The same process was repeated on day 6. The cells were allowed to grow for an additional 4 days.

[0287] On day 10, 100 μL of Granta-519 cells were transferred to a new 96-well plate, and 10 μL of Cell Counting Kit-8 (CCK-8, Jojindo, CK04-13) solution was added. For U-87MG cells, the old medium was removed, replaced with 100 μL of fresh medium, and 10 μL of CCK-8 solution was added. The plate was cultured in a CO2 incubator for 2 hours (Granta-519 cells) or 30 minutes (U-87MG cells), and the OD 450 value was measured using a microplate reader (iMark microplate reader, Bio-Rad). The percentage of viable cells relative to the DMSO solvent control was calculated and plotted using Graphpad Prism ([Inhibitor] vs. Normalized Response - Variable Slope) to determine the growth IC 50 value on day 10. Refer to Table 15 (Growth IC 50 ) below.

Table 17

[0288] In some embodiments, the present disclosure relates to the following aspects. Aspect 1. A pharmaceutically acceptable salt of a compound of Formula I: [Chemical Formula] Aspect 2. The pharmaceutically acceptable salt according to Aspect 1, wherein the salt is hydrochloride of Formula IA. [Chemical Formula] Aspect 3. The crystalline form of the hydrochloride salt according to Aspect 2. Aspect 4. The crystalline form according to Aspect 3, wherein the crystal is Form I of IA. Aspect 5. The crystalline form according to Aspect 3 or Aspect 4, characterized by a powder X-ray diffraction pattern substantially as shown in Figure 1. Aspect 6. The crystalline form according to any one of Aspects 3, 4, or 5, characterized by a powder X-ray diffraction pattern including a peak at 2θ of 23.8 degrees ± 0.2 degrees on the 2θ scale using λ = 1.54 Å (Cu Kα). Aspect 7. The crystalline form according to any one of Aspects 3 to 6, characterized by a powder X-ray diffraction pattern including peaks at 2θ of 21.2 and 23.8 degrees ± 0.2 degrees on the 2θ scale using λ = 1.54 Å (Cu Kα). Aspect 8. The crystalline form according to any one of Aspects 3 to 7, characterized by a powder X-ray diffraction pattern including peaks at 2θ of 21.2, 23.8, 27.0, and 32.5 degrees ± 0.2 degrees on the 2θ scale using λ = 1.54 Å (Cu Kα). Aspect 9. The crystalline form according to any one of Aspects 3 to 8, characterized by a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 2 when heated at a rate of 10 °C / min. Aspect 10. The crystalline form according to any one of Aspects 3 to 9, characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at about 244 °C when heated at a rate of 10 °C / min. Aspect 11. When heating at a rate of 20 °C / min, the crystalline form according to any one of Aspects 3 to 10, characterized by a thermogravimetric analysis profile substantially as shown in Figure 3. Aspect 12. The crystalline form according to Aspect 3, wherein the crystal is in Form II of Formula IA. Aspect 13. The crystalline form according to Aspect 3 or Aspect 12, characterized by a powder X-ray diffraction pattern substantially as shown in Figure 4. Aspect 14. The crystalline form according to any one of Aspects 3, 12, or 13, characterized by a powder X-ray diffraction pattern including a peak at 25.5 degrees ± 0.2 degrees 2θ on the 2θ scale using λ = 1.54 angstroms (Cu Kα). Aspect 15. The crystalline form according to any one of Aspects 3 or 12 to 14, characterized by a powder X-ray diffraction pattern including peaks at 14.8, 17.5, and 25.5 degrees ± 0.2 degrees 2θ on the 2θ scale using λ = 1.54 angstroms (Cu Kα). Aspect 16. The crystalline form according to any one of Aspects 3 or 12 to 15, characterized by a powder X-ray diffraction pattern including peaks at 14.8, 17.5, 18.4, 24.0, 25.5, 28.0, and 28.7 degrees ± 0.2 degrees 2θ on the 2θ scale using λ = 1.54 angstroms (Cu Kα). Aspect 17. When heating at a rate of 20 °C / min, the crystalline form according to any one of Aspects 3 or 12 to 16, characterized by a thermogravimetric analysis profile substantially as shown in Figure 5. Aspect 18. The crystalline form according to Aspect 3, wherein the crystal is in Form IIa of Formula IA. Aspect 19. The crystalline form according to Aspect 3 or Aspect 18, characterized by a powder X-ray diffraction pattern substantially as shown in Figure 6. Aspect 20. The crystalline form according to any one of Aspects 3, 18, or 19, characterized by a powder X-ray diffraction pattern including a peak at 26.1 degrees ± 0.2 degrees 2θ on the 2θ scale using λ = 1.54 angstroms (Cu Kα). Aspect 21. A crystalline form according to any one of Aspect 3 or Aspects 18 to 20, characterized by a powder X-ray diffraction pattern that includes peaks at 14.0, 14.9, and 26.1 degrees ± 0.2 degrees 2θ on the 2θ scale using λ = 1.54 angstroms (Cu Kα). Aspect 22. A crystalline form according to any one of Aspect 3 or Aspects 18 to 21, characterized by a powder X-ray diffraction pattern that includes peaks at 12.5, 14.0, 14.9, 18.4, and 26.1 degrees ± 0.2 degrees 2θ on the 2θ scale using λ = 1.54 angstroms (Cu Kα). Aspect 23. A crystalline form according to any one of Aspect 3 or Aspects 18 to 22, characterized by a differential scanning calorimetry (DSC) thermogram that is substantially as shown in FIG. 7 when heated at a rate of 10 °C / min. Aspect 24. A crystalline form according to any one of Aspect 3 or Aspects 18 to 23, characterized by a differential scanning calorimetry (DSC) thermogram that includes an endothermic peak at approximately 199 °C when heated at a rate of 10 °C / min. Aspect 25. The crystalline form according to Aspect 3, wherein the crystal is Form IA-III. Aspect 26. The crystalline form according to Aspect 3 or Aspect 25, characterized by a powder X-ray diffraction pattern that is substantially as shown in FIG. 8. Aspect 27. A crystalline form according to any one of Aspect 3, 25, or 26, characterized by a powder X-ray diffraction pattern that includes a peak at 8.1 degrees ± 0.2 degrees 2θ on the 2θ scale using λ = 1.54 angstroms (Cu Kα). Aspect 28. A crystalline form according to any one of Aspect 3 or Aspects 25 to 27, characterized by a powder X-ray diffraction pattern that includes peaks at 8.1 and 23.3 degrees ± 0.2 degrees 2θ on the 2θ scale using λ = 1.54 angstroms (Cu Kα). Aspect 29. A crystalline form according to any one of Aspect 3 or Aspects 25 to 28, characterized by a powder X-ray diffraction pattern that includes peaks at 8.1, 12.5, 13.7, 14.5, 16.2, 18.8, 23.3, and 24.5 degrees ± 0.2 degrees 2θ on the 2θ scale using λ = 1.54 angstroms (Cu Kα). Aspect 30. When heating at a rate of 10 °C / min, a crystal form according to any one of Aspect 3, or Aspects 25 to 29, characterized by a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG. 9. Aspect 31. When heating at a rate of 10 °C / min, a crystal form according to any one of Aspect 3, or Aspects 25 to 30, characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at about 121 °C. Aspect 32. When heating at a rate of 20 °C / min, a crystal form according to any one of Aspect 3, Aspects 25 to 31, characterized by a thermogravimetric analysis profile substantially as shown in FIG. 10. Aspect 33. The crystal form according to Aspect 3, wherein the crystal is of Formula IA - Form IV. Aspect 34. A crystal form according to Aspect 3 or Aspect 33, characterized by a powder X - ray diffraction pattern substantially as shown in FIG. 11. Aspect 35. A crystal form according to any one of Aspect 3, Aspect 33, or Aspect 34, characterized by a powder X - ray diffraction pattern including a peak at 4.0 degrees ± 0.2 degrees 2θ on a 2θ scale using λ = 1.54 Å (Cu Kα). Aspect 36. A crystal form according to any one of Aspect 3, or Aspect 33 to Aspect 35, characterized by a powder X - ray diffraction pattern including peaks at 4.0 and 22.7 degrees ± 0.2 degrees 2θ on a 2θ scale using λ = 1.54 Å (Cu Kα). Aspect 37. A crystal form according to any one of Aspect 3, or Aspect 33 to Aspect 36, characterized by a powder X - ray diffraction pattern including peaks at 4.0, 22.7, and 27.8 degrees ± 0.2 degrees 2θ on a 2θ scale using λ = 1.54 Å (Cu Kα). Aspect 38. When heating at a rate of 10 °C / min, a crystal form according to any one of Aspect 3, or Aspect 33 to Aspect 37, characterized by a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG. 12. Aspect 39. When heating at a rate of 10 °C / min, a crystal form according to any one of Aspect 3, or Aspect 33 to Aspect 38, characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at about 169 °C. Aspect 40. The crystalline form according to any one of Aspects 3, 33 to 39, characterized by a thermogravimetric analysis profile substantially as shown in FIG. 13 when heated at a rate of 20 °C / min. Aspect 41. The pharmaceutically acceptable salt according to Aspect 1, wherein the salt is phosphate of Formula IB. Aspect 42. The crystalline form of the phosphate according to Aspect 41. Aspect 43. The crystalline form according to Aspect 42, wherein the crystal is Form IB-I. Aspect 44. The crystalline form according to Aspect 42 or Aspect 43, characterized by a powder X-ray diffraction pattern substantially as shown in FIG. 14A. Aspect 45. The crystalline form according to any one of Aspects 42 to 44, characterized by a powder X-ray diffraction pattern including a peak at 24.9 degrees ± 0.2 degrees 2θ on a 2θ scale using λ = 1.54 Å (Cu Kα). Aspect 46. The crystalline form according to any one of Aspects 42 to 45, characterized by a powder X-ray diffraction pattern including peaks at 18.2, 19.6, 24.9 degrees ± 0.2 degrees 2θ on a 2θ scale using λ = 1.54 Å (Cu Kα). Aspect 47. The crystalline form according to any one of Aspects 42 to 46, characterized by a powder X-ray diffraction pattern including peaks at 18.2, 19.6, 24.9, 25.7, and 27.0 degrees ± 0.2 degrees 2θ on a 2θ scale using λ = 1.54 Å (Cu Kα). Aspect 48. The crystalline form according to any one of Aspects 42 to 47, characterized by a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG. 15A when heated at a rate of 10 °C / min. Aspect 49. The crystalline form according to any one of Aspects 42 to 48, characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at about 201 °C when heated at a rate of 10 °C / min. Aspect 50. The crystalline form according to any one of Aspects 42 to 49, characterized by a thermogravimetric analysis profile substantially as shown in FIG. 16A when heated at a rate of 20 °C / min. Aspect 51. The crystalline form according to Aspect 42, wherein the crystal is Form IB-II. Aspect 52. The crystalline form according to Aspect 42 or Aspect 51, characterized by a powder X-ray diffraction pattern substantially as shown in Figure 14B. Aspect 53. The crystalline form according to Aspect 42, or any one of Aspects 51 to 52, characterized by a powder X-ray diffraction pattern that includes a peak at 2θ of 24.6 degrees ± 0.2 degrees on the 2θ scale using λ = 1.54 angstroms (Cu Kα). Aspect 54. The crystalline form according to Aspect 42, or any one of Aspects 51 to 53, characterized by a powder X-ray diffraction pattern that includes peaks at 2θ of 19.3, 24.6, and 27.4 degrees ± 0.2 degrees on the 2θ scale using λ = 1.54 angstroms (Cu Kα). Aspect 55. The crystalline form according to Aspect 42, or any one of Aspects 51 to 54, characterized by a powder X-ray diffraction pattern that includes peaks at 2θ of 19.3, 22.3, 23.6, 24.6, and 27.4 degrees ± 0.2 degrees on the 2θ scale using λ = 1.54 angstroms (Cu Kα). Aspect 56. The crystalline form according to Aspect 42, or any one of Aspects 51 to 55, characterized by a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 15B when heated at a rate of 10 °C / min. Aspect 57. The crystalline form according to Aspect 42, or any one of Aspects 51 to 56, characterized by a differential scanning calorimetry (DSC) thermogram that includes an endothermic peak at approximately 229 °C when heated at a rate of 10 °C / min. Aspect 58. The crystalline form according to Aspect 42, or any one of Aspects 51 to 57, characterized by a thermogravimetric analysis profile substantially as shown in Figure 16B when heated at a rate of 20 °C / min. Aspect 59. The pharmaceutically acceptable salt according to Aspect 1, wherein the salt is tartrate of Formula IC. Aspect 60. The crystalline form according to Aspect 59, wherein the tartrate is crystalline. Aspect 61. The crystalline form according to Aspect 59 or Aspect 60, characterized by a powder X-ray diffraction pattern substantially as shown in Figure 17. Aspect 62. A crystalline form according to any one of Aspects 59 to 61, characterized by a powder X-ray diffraction pattern including a peak at 18.4 degrees ± 0.2 degrees 2θ on a 2θ scale using λ = 1.54 angstroms (Cu Kα). Aspect 63. A crystalline form according to any one of Aspects 59 to 62, characterized by a powder X-ray diffraction pattern including peaks at 18.4, 19.9, and 21.5 degrees ± 0.2 degrees 2θ on a 2θ scale using λ = 1.54 angstroms (Cu Kα). Aspect 64. A crystalline form according to any one of Aspects 59 to 63, characterized by a powder X-ray diffraction pattern including peaks at 18.4, 19.4, 19.9, 21.5, and 26.3 degrees ± 0.2 degrees 2θ on a 2θ scale using λ = 1.54 angstroms (Cu Kα). Aspect 65. A crystalline form according to any one of Aspects 59 to 64, characterized by a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG. 18 when heated at a rate of 10 °C / min. Aspect 66. A crystalline form according to any one of Aspects 59 to 65, characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at approximately 190 °C when heated at a rate of 10 °C / min. Aspect 67. A crystalline form according to any one of Aspects 59 to 66, characterized by a thermogravimetric analysis profile substantially as shown in FIG. 19 when heated at a rate of 20 °C / min. Aspect 68. A pharmaceutical composition comprising a pharmaceutically acceptable salt and / or crystalline form according to any one of Aspects 1 to 67 and a pharmaceutically acceptable excipient. Aspect 69. A method for treating a disease or disorder associated with abnormal PRMT5 activity in a subject, the method comprising administering to the subject a pharmaceutically acceptable salt and / or crystalline form according to any one of Aspects 1 to 67. Aspect 70. The method according to aspect 69, wherein the disease or disorder associated with abnormal PRMT5 activity is breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, uterine cancer, cervical cancer, leukemia, such as acute myeloid leukemia (AML), acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorder, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS), epidermoid carcinoma, abnormal hemoglobinopathy, such as β-thalassemia and sickle cell disease (SCD), CDKN2A deletion cancer, 9P deletion cancer, MTAP deletion cancer, spliceosome mutation cancer, glioblastoma, NSCLC, head and neck cancer, bladder cancer, or hepatocellular carcinoma.

Claims

1. Compound of formula IA: 【Chemical 1】

2. A crystal of the compound according to claim 1.

3. A crystal according to claim 2, characterized by a powder X-ray diffraction pattern comprising a peak at 2θ of 23.8 degrees ± 0.2 degrees on the 2θ scale using λ = 1.54 Å (Cu Kα).

4. A crystal according to any one of claims 2 to 3, characterized by a powder X-ray diffraction pattern comprising peaks at 2θ of 21.2 and 23.8 degrees ± 0.2 degrees on the 2θ scale using λ = 1.54 Å (Cu Kα).

5. A crystal according to any one of claims 2 to 4, characterized by a powder X-ray diffraction pattern comprising peaks at 2θ of 21.2, 23.8, 27.0, and 32.5 degrees ± 0.2 degrees on the 2θ scale using λ = 1.54 Å (Cu Kα).

6. A crystal according to any one of claims 2 to 5, characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 244 °C when heated at a rate of 10 °C / min.

7. A crystal according to claim 2, characterized by a powder X-ray diffraction pattern comprising a peak at 2θ of 25.5 degrees ± 0.2 degrees on the 2θ scale using λ = 1.54 Å (Cu Kα).

8. A crystal according to claim 2 or 7, characterized by a powder X-ray diffraction pattern comprising peaks at 2θ of 14.8, 17.5, and 25.5 degrees ± 0.2 degrees on the 2θ scale using λ = 1.54 Å (Cu Kα).

9. A crystal according to claim 2 or any one of claims 7 to 8, characterized by a powder X-ray diffraction pattern comprising peaks at 2θ of 14.8, 17.5, 18.4, 24.0, 25.5, 28.0, and 28.7 degrees ± 0.2 degrees on the 2θ scale using λ = 1.54 Å (Cu Kα).

10. A crystal according to claim 2, characterized by a powder X-ray diffraction pattern comprising a peak at 2θ of 26.1 degrees ± 0.2 degrees on the 2θ scale using λ = 1.54 Å (Cu Kα).

11. A crystal according to any one of claims 2 or 10, characterized by a powder X-ray diffraction pattern comprising peaks at 2θ of 14.0, 14.9, and 26.1 degrees ± 0.2 degrees on the 2θ scale using λ = 1.54 Å (Cu Kα).

12. In the 2θ scale using λ = 1.54 Å (Cu Kα), a powder X-ray diffraction pattern characterized by peaks at 12.5, 14.0, 14.9, 18.4, and 26.1 degrees ± 0.2 degrees 2θ, the crystal according to any one of claims 2 or 10 - 11.

13. When heated at a rate of 10 °C / min, a differential scanning calorimetry (DSC) thermogram characterized by an endothermic peak at about 199 °C, the crystal according to any one of claims 2 or 10 - 12.

14. In the 2θ scale using λ = 1.54 Å (Cu Kα), a powder X-ray diffraction pattern characterized by a peak at 8.1 degrees ± 0.2 degrees 2θ, the crystal according to claim 2.

15. In the 2θ scale using λ = 1.54 Å (Cu Kα), a powder X-ray diffraction pattern characterized by peaks at 8.1 and 23.3 degrees ± 0.2 degrees 2θ, the crystal according to any one of claims 2 or 14.

16. In the 2θ scale using λ = 1.54 Å (Cu Kα), a powder X-ray diffraction pattern characterized by peaks at 8.1, 12.5, 13.7, 14.5, 16.2, 18.8, 23.3, and 24.5 degrees ± 0.2 degrees 2θ, the crystal according to any one of claims 2 or 14 - 15.

17. When heated at a rate of 10 °C / min, a differential scanning calorimetry (DSC) thermogram characterized by an endothermic peak at about 121 °C, the crystal according to any one of claims 2 or 14 - 16.

18. In the 2θ scale using λ = 1.54 Å (Cu Kα), a powder X-ray diffraction pattern characterized by a peak at 4.0 degrees ± 0.2 degrees 2θ, the crystal according to claim 2.

19. In the 2θ scale using λ = 1.54 Å (Cu Kα), a powder X-ray diffraction pattern characterized by peaks at 4.0 and 22.7 degrees ± 0.2 degrees 2θ, the crystal according to any one of claims 2 or 18.

20. In the 2θ scale using λ = 1.54 Å (Cu Kα), a powder X-ray diffraction pattern characterized by peaks at 4.0, 22.7, and 27.8 degrees ± 0.2 degrees 2θ, the crystal according to any one of claims 2 or 18 - 19.

21. When heating at a rate of 10 °C / min, a crystal according to any one of claims 2 or 18 to 20, characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at about 169 °C.

22. A compound that is a phosphate of a compound of formula I:

23. A crystal of the compound according to claim 22.

24. A crystal according to claim 23, characterized by a powder X-ray diffraction pattern including a peak at 24.9 degrees ± 0.2 degrees 2θ on a 2θ scale using λ = 1.54 Å (Cu Kα).

25. A crystal according to any one of claims 23 to 24, characterized by a powder X-ray diffraction pattern including peaks at 18.2, 19.6, 24.9 degrees ± 0.2 degrees 2θ on a 2θ scale using λ = 1.54 Å (Cu Kα).

26. A crystal according to any one of claims 23 to 25, characterized by a powder X-ray diffraction pattern including peaks at 18.2, 19.6, 24.9, 25.7, and 27.0 degrees ± 0.2 degrees 2θ on a 2θ scale using λ = 1.54 Å (Cu Kα).

27. A crystal according to any one of claims 23 to 26, characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at about 201 °C when heating at a rate of 10 °C / min.

28. A crystal according to claim 23, characterized by a powder X-ray diffraction pattern including a peak at 24.6 degrees ± 0.2 degrees 2θ on a 2θ scale using λ = 1.54 Å (Cu Kα).

29. A crystal according to any one of claims 23 or 28, characterized by a powder X-ray diffraction pattern including peaks at 19.3, 24.6, and 27.4 degrees ± 0.2 degrees 2θ on a 2θ scale using λ = 1.54 Å (Cu Kα).

30. A crystal according to any one of claims 23 or 28 to 29, characterized by a powder X-ray diffraction pattern including peaks at 19.3, 22.3, 23.6, 24.6, and 27.4 degrees ± 0.2 degrees 2θ on a 2θ scale using λ = 1.54 Å (Cu Kα).

31. A crystal according to any one of claims 23 or 28 to 30, characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at about 229 °C when heating at a rate of 10 °C / min.

32. A compound that is a phosphate of a compound of formula I: A compound which is the tartrate salt of the compound.

33. A crystal of the compound according to claim 32.

34. The crystal according to claim 33, characterized by a powder X-ray diffraction pattern containing a peak at 2θ of 18.4 degrees ± 0.2 degrees on the 2θ scale using λ = 1.54 angstroms (Cu Kα).

35. The crystal according to any one of claims 33 to 34, characterized by a powder X-ray diffraction pattern containing peaks at 2θ of 18.4, 19.9, and 21.5 degrees ± 0.2 degrees on the 2θ scale using λ = 1.54 angstroms (Cu Kα).

36. The crystal according to any one of claims 33 to 35, characterized by a powder X-ray diffraction pattern containing peaks at 2θ of 18.4, 19.4, 19.9, 21.5, and 26.3 degrees ± 0.2 degrees on the 2θ scale using λ = 1.54 angstroms (Cu Kα).

37. The crystal according to any one of claims 33 to 36, characterized by a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at about 190 °C when heated at a rate of 10 °C / min.

38. A pharmaceutical composition comprising the compound and / or crystal according to any one of claims 1 to 37 and a pharmaceutically acceptable excipient.

39. A medicament for treating a disease or disorder associated with abnormal PRMT5 activity in a subject, the medicament comprising the compound and / or crystal according to any one of claims 1 to 37.

40. The medicament according to claim 39, wherein the disease or disorder associated with the abnormal PRMT5 activity is breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, uterine cancer, cervical cancer, leukemia, such as acute myeloid leukemia (AML), acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS), epidermoid carcinoma, abnormal hemoglobinopathy, such as β-thalassemia and sickle cell disease (SCD), CDKN2A deletion cancer, 9P deletion cancer, MTAP deletion cancer, spliceosome mutant cancer, glioblastoma, NSCLC, head and neck cancer, bladder cancer, hepatocellular carcinoma, adenoid cystic carcinoma (ACC), primary central nervous system lymphoma, fallopian tube cancer, or non-Hodgkin lymphoma.

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