Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)

Abstract

This disclosure relates to pharmaceutically acceptable salts of compounds of formula I (I). Pharmaceutical compositions comprising pharmaceutically acceptable salts of compounds of formula I are also described, as well as their use and methods of preparation.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of priority to U.S. Provisional Application No. 62 / 902,322, filed September 18, 2019, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This disclosure relates to PRMT5 inhibitors and methods of their use. Background Technology

[0004] Protein arginine methylation is a common post-translational modification regulating many cellular processes, including gene transcription, mRNA splicing, DNA repair, protein localization, cell fate determination, and signal transduction. Three types of methyl-arginine substances exist: ωNG monomethylarginine (MMA), ωNG,NG asymmetric dimethylarginine (ADMA), and ωNG,N'G symmetric dimethylarginine (SDMA). The formation of methylated arginine is catalyzed by the protein arginine methyltransferase (PRMT) family of methyltransferases. Currently, nine PRMTs have been annotated in the human genome. Most of these enzymes are type I enzymes (PRMT1, -2, -3, -4, -6, -8), which can perform mono- and asymmetric dimethylation of arginine using S-adenosylmethionine (SAM) as a methyl donor. PRMT-5, -7, and -9 are considered type II enzymes that catalyze the symmetric dimethylation of arginine. Each PRMT substance contains seven characteristic motifs of β-chain methyltransferases (Katz et al., 2003) as well as additional “double E” and “THW” sequence motifs specific to the PRMT subfamily.

[0005] PRMT5 is a universal transcriptional repressor that functions in conjunction with many transcription factors and repressor complexes, including BRG1 and hBRM, Blimp1, and Snail. Once recruited to the promoter, this enzyme induces symmetrical dimethylation of H3R8 and H4R3. Importantly, the H4R3 site is a major target of PRMT1 methylation (ADMA) and is generally considered a marker of transcriptional activation. Therefore, both H4R3me2s (repressive; me2s indicates SDMA modification) and H4R3me2a (active; me2a indicates ADMA modification) markers are generated in vivo. The specificity of PRMT5 for H3R8 and H4R3 can be altered by its interaction with COPR5, and this may play an important role in determining the co-repressive state of PRMT5.

[0006] The role of PRMT in cancer

[0007] Aberrant expression of PRMT has been identified in human cancers, and PRMT is considered a therapeutic target. A comprehensive analysis of histone modifications in prostate cancer showed that dimethylation of histone H4R3 was positively correlated with increased grade, and these changes predicted clinical outcomes.

[0008] Elevated PRMT5 levels have been observed in a group of lymphoma cell lines and clinical samples of mantle cell lymphoma. PRMT5 interacts with numerous substrates involved in a variety of cellular processes, including RNA processing, signal transduction, and transcriptional regulation. PRMT5 can directly modify histones H3 and H4, leading to repression of gene expression. PRMT5 overexpression can stimulate cell growth and induce transformation by directly repressing 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-documented oncogenic function in transcription and translation, the transcription factor MYC also protects proper premessenger RNA splicing, a necessary step in lymphoma formation. Koh et al., Nature 2015, 5237558; Hsu et al., Nature 2015, 525,384.

[0009] The discovery of cancer dependence holds the potential to inform treatment strategies and identify putative drug targets. Integrating comprehensive genomic profiling analysis from cancer cell lines and data from functional characterization of cancer cell dependence, it was recently discovered that the loss of the enzyme methionine phosphorylase (MTAP) confers selective dependence on the protein arginine methyltransferase 5 (PRMT5) and its binding partner WDR77. MTAP is frequently lost due to its proximity to the normally absent tumor suppressor gene CDKN2A. Cells with MTAP deficiency exhibit increased intracellular concentrations of methionine (MTA, a metabolite cleaved by MTAP). Furthermore, MTA specifically inhibits PRMT5 enzyme activity. Administration of MTA or small molecule PRMT5 inhibitors showed preferentially impaired cell viability in MTAP-insensitive cancer cell lines compared to their syngeneically expressed counterparts. In summary, these findings reveal PRMT5 as a potential vulnerability across multiple cancer lineages, a vulnerability amplified by a common “passerby” genomic alteration.

[0010] The role of PRMT5 in hemoglobinopathies

[0011] The developmental transition of human globin gene subtypes from birth to adulthood foreshadows the onset of hemoglobinopathies, β-thalassemia, and sickle cell disease (SCD). Increased adult globin gene expression (in the presence of persistent fetal hemoglobin [HPFH] mutations) has been observed to significantly improve the clinical severity of thalassemia and SCD, prompting the search for therapeutic strategies to reverse γ-globin gene silencing. At the heart of γ-gene silencing is DNA methylation, which marks key CpG dinucleotides flanking gene transcription initiation sites in adult bone marrow erythroid cells. These markers have been shown to be established by the recruitment of the DNA methyltransferase DNMT3A to the γ-promoter via the protein arginine methyltransferase PRMT5. (Zhao et al., Nat Struct Mol Biol. 2009 16, 304. PRMT5-mediated histone H4R3 methylation recruits DNMT3A, coupling histone and DNA methylation in gene silencing.)

[0012] PRMT5 induces repressive histone markers H4R3me2s, which serve as templates for direct binding to DNMT3A and subsequent DNA methylation. Loss of PRMT5 binding or its enzymatic activity leads to demethylation of CpG dinucleotides and gene activation. In addition to H4R3me2s marking and DNA methylation, PRMT5 binding to the γ-promoter and its enzymatic activity are essential for the assembly of a multi-protein complex on the γ-promoter, inducing a series of co-repressive epigenetic markers. Disruption of this complex leads to the reactivation of γ-gene expression. These studies provide a foundation for developing PRMT5 inhibitors as targeted therapies for thalassemia and SCD. Summary of the Invention

[0013] This disclosure relates to pharmaceutically acceptable salts of compounds of formula I:

[0014]

[0015] This disclosure also relates to hydrochlorides, phosphates and tartrates of Formula I.

[0016] The crystalline forms of such salts are also described, as well as pharmaceutical compositions and methods of use of such salts. Attached Figure Description

[0017] Figure 1 The XRPD of form IA-form I is shown.

[0018] Figure 2 The DSC thermogram of form IA-form I is shown.

[0019] Figure 3 The TGA curve of form IA-form I is shown.

[0020] Figure 4 The XRPD of form IA-form II is shown.

[0021] Figure 5 The TGA curve of form IA-form II is shown.

[0022] Figure 6 The XRPD of form IA-form IIa is shown.

[0023] Figure 7 The DSC thermogram of form IA-IIa is shown.

[0024] Figure 8 The XRPD of form IA-form III is shown.

[0025] Figure 9 The DSC thermogram of formula IA-form III is shown.

[0026] Figure 10 The TGA curve of form IA-form III is shown.

[0027] Figure 11 The XRPD of form IA-form IV is shown.

[0028] Figure 12 The DSC thermogram of form IA-IV is shown.

[0029] Figure 13 The TGA curve for form IA-IV is shown.

[0030] Figure 14A The XRPD of form IB-form I is shown.

[0031] Figure 14B The XRPD of form IB-form II is shown.

[0032] Figure 15A The DSC thermogram of form IB-form I is shown.

[0033] Figure 15B The DSC thermogram of form IB-form II is shown.

[0034] Figure 16A The TGA curve of form IB-form I is shown.

[0035] Figure 16B The TGA curve of form IB-form II is shown.

[0036] Figure 17 The XRPD of the IC is shown.

[0037] Figure 18The DSC thermogram of formula IC is shown.

[0038] Figure 19 The TGA curve of formula IC is shown.

[0039] Figure 20 The IC is shown 1 H NMR spectrum.

[0040] Figure 21 XRPD of free base of formula I is shown. Detailed Implementation

[0041] This disclosure can be more fully understood by referring to the following description, including the following definitions and examples. Certain features of the disclosed compositions and methods described herein in the context of individual aspects may also be provided in combination in individual aspects. Alternatively, for the sake of brevity, various features of the disclosed compositions and methods described in the context of individual aspects may also be provided individually or in any sub-combination.

[0042] "Pharmaceutical acceptable" means a drug that has been approved or recognized by a federal or state regulatory agency or a corresponding agency in a country outside the United States, or that is listed in the United States Pharmacopeia or other recognized pharmacopoeia for use in animals (e.g., humans).

[0043] "Pharmaceutically acceptable salt" refers to a salt of the compound disclosed herein that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. Specifically, such salts are non-toxic and can be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or from organic acids such as 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-en-1-carboxylic acid, glucoheponic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthenic acid, salicylic acid, stearic acid, mucoconic acid, etc.; or (2) when the acidic protons present in the parent compound are replaced by metal ions (e.g., alkali metal ions, alkaline earth metal ions or aluminum ions); or coordinated with organic bases such as ethanolamine, diethanolamine, triethanolamine, N-methylglucosamine, etc. By way of example only, salts also include sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc.; and when the compound contains a basic functional group, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, methanesulfonate, acetate, maleate, oxalate, etc.

[0044] "Pharmaceutical-acceptable excipients" refer to substances that are non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as inert substances, added to a pharmacological composition or otherwise used as a medium, carrier, or diluent to facilitate the administration of the drug and to be compatible with it. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol.

[0045] "Solvate" refers to the physical association of a compound of formula I with one or more solvent molecules.

[0046] "Subject" includes people. The terms "person," "patient," and "subject" are used interchangeably in this document.

[0047] In one implementation, “treating” any disease or disorder means improving the disease or disorder (i.e., preventing or reducing the development of at least one clinical symptom of the disease or its clinical symptoms). In another implementation, “treating” means improving at least one physical parameter that the subject may not be able to discern. In yet another implementation, “treating” means regulating a physical (e.g., stabilizing discernible symptoms), physiological (e.g., stabilizing physical parameters), or both, disease or disorder. In yet another implementation, “treating” means delaying the onset of a disease or disorder. In some implementations, “treating” means preventative treatment, i.e., preventing the onset of a disease or disorder.

[0048] "Compounds of this disclosure" and equivalent expressions are intended to cover pharmaceutically acceptable salts of compounds of formula I as described herein, as well as their subgenuses, and, where context permits, the expression includes stereoisomers (e.g., enantiomers, diastereomers) and structural isomers (e.g., tautomers).

[0049] As used herein, the term "isotope variant" refers to a compound in which the proportion of an isotope at one or more atoms in the atoms constituting the compound is greater than its natural abundance. For example, an "isotope variant" of a compound can be radiolabeled, i.e., containing one or more radioactive isotopes, or can be made using non-radioactive isotopes such as deuterium (…). 2 H or D), carbon-13 (H or D), carbon-13 13 C), Nitrogen-15 ( 15 The labeling is as follows: N). It should be understood that in the preparation of such isotopically substituted compounds, the following atoms (if present) may be varied such that, for example, any hydrogen atom can be... 2 H / D, any carbon can be 13 C, or any nitrogen can be 15 N, and the presence and placement of such atoms can be determined within the scope of the art.

[0050] It should also be understood that compounds having the same molecular formula but differing in the bonding properties or order of their atoms or in the spatial arrangement of their atoms are called "isomers." Isomers with different spatial atomic arrangements are called "stereoisomers," such as diastereomers, enantiomers, and transisomers. The compounds of this disclosure may have one or more asymmetric centers; therefore, such compounds may produce individual (R)- or (S)- stereoisomers, or mixtures thereof, at each asymmetric center. Unless otherwise specified, the description or naming of a particular compound in the specification and claims is intended to include all its racemic or other stereoisomers and mixtures thereof. In the case where a structure contains one chiral center but does not show the specific stereochemistry of that center, the structure covers two enantiomers, either individually or as a mixture of enantiomers. In the case where a structure contains more than one chiral center but does not show the specific stereochemistry of that center, the structure covers all enantiomers and diastereomers, either individually or as a mixture. Methods for determining stereochemistry and separating stereoisomers are well known in the art.

[0051] In some respects, this disclosure relates to pharmaceutically acceptable salts of compounds of formula I:

[0052]

[0053] In some implementations, 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.

[0054] In some implementations, the pharmaceutically acceptable salt of the compound of formula I is a hydrochloride salt, i.e., formula IA.

[0055]

[0056] In other embodiments, a pharmaceutically acceptable salt of the compound of formula I is a phosphate, namely formula IB.

[0057] In other embodiments, a pharmaceutically acceptable salt of the compound of formula I is a tartrate, i.e., formula IC.

[0058] In some embodiments, the tartrate is L-tartrate. In other embodiments, the tartrate is D-tartrate.

[0059] In other embodiments, the pharmaceutically acceptable salt of the compound of formula I is a sulfate, i.e., formula ID.

[0060] In other embodiments, a pharmaceutically acceptable salt of the compound of formula I is an ascorbate salt, namely formula IE.

[0061] In other embodiments, a pharmaceutically acceptable salt of the compound of formula I is ethane-1,2-disulfonate, i.e., formula IF.

[0062] In other embodiments, a pharmaceutically acceptable salt of the compound of formula I is a 1-hydroxy-2-naphthoic acid salt, namely formula IG.

[0063] In other embodiments, the pharmaceutically acceptable salt of the compound of formula I is an oxalate, namely formula IH.

[0064] In some respects, this disclosure relates to the crystalline form of a pharmaceutically acceptable salt of Formula I.

[0065] In some embodiments, this disclosure relates to the crystalline form of salts of formula IA, IB, or IC.

[0066] The crystalline form of salts according to formula IA, IB, or IC of this disclosure may have advantageous properties, including one or more of the following: chemical or polymorphic purity, fluidity, solubility, dissolution rate, bioavailability, morphology or crystal habit, stability—for example, chemical stability, thermal stability and mechanical stability relative to polymorphic transformation, storage stability; hygroscopicity, low residual solvent content, and advantageous processing and handling properties, such as compressibility or bulk density.

[0067] Crystalline forms may be characterized herein by graphical data “as shown in the figures.” Such data includes, for example, powder X-ray diffraction (XRPD), differential scanning calorimetry (DSC) thermograms, or thermogravimetric analysis (TGA) curves. As is known in the art, graphical data can potentially provide additional technical information to further define the corresponding solid form, which is not necessarily described by reference values ​​or peak positions. Therefore, when referring to the graphical data in the figures herein, the term “substantially as shown in the figures” means that it is not necessarily the same as those depicted herein, but falls within the limits of experimental error or bias when considered by one of ordinary skill in the art. One of skill in the art will be able to readily compare the graphical data in the figures herein with graphical data generated for unknown crystal forms and confirm whether the two sets of graphical data characterize the same crystal form or two different crystal forms.

[0068] The solid crystalline form may be referred to herein as “polymorphically pure” or “substantially free of any other forms.” As used herein in the context, the expression “substantially free of any other forms” will be understood to mean that the solid form contains about 20% or less, about 10% or less, about 5% or less, about 2% or less, about 1% or less, or 0% of any other form of the subject compound, as measured, for example, by XRPD. For example, a solid form of Formula IA that is substantially free of any other solid form as described herein should 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 subject solid form of Formula IA. Thus, in some embodiments of this disclosure, the solid form of Formula IA may contain about 1% to about 20% (w / w), about 5% to about 20% (w / w), or about 5% to about 10% (w / w) of one or more other solid forms of Formula IA.

[0069] As used herein, unless otherwise stated, the XRPD peaks reported herein are obtained using CuK. α For radiation measurements, λ =

[0070] The modifier “about” should be considered as disclosing a range defined by the absolute values ​​of its two endpoints. For example, the expression “about 2 to about 4” also discloses a range of “2 to 4”. When used to modify a single number, the term “about” refers to ±10% of the indicated number and includes the indicated number. For example, “about 10%” indicates a range of 9% to 11%, and “about 1” means 0.9–1.1.

[0071] In some aspects, this 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 (Form IA - Form I). In some embodiments, Formula IA - Form I substantially contains no other solid form of Formula IA.

[0072] In some implementations, form IA-form I exhibits essentially the same characteristics as... Figure 1 The XRPD shown. Figure 1 The XRPD of form IA-I shown includes the reflection angle (°2-θ ± 0.2°2-θ), line spacing (d value), and relative intensity, as shown in Table 1:

[0073] Table 1. In Figure 1 XRPD data for the crystalline form of Formula IA-Form I shown in the figure.

[0074]

[0075]

[0076] In some embodiments of this disclosure, Formula IA-Form I is characterized by an XRPD spectrum including a peak at one of the angles listed in Table 1. In other aspects, Formula IA-Form I is characterized by an XRPD spectrum including more than one peak at one of the angles listed in Table 1. In other aspects, Formula IA-Form I is characterized by an XRPD spectrum including two peaks at angles selected from those listed in Table 1. In other aspects, Formula IA-Form I is characterized by an XRPD spectrum including three peaks at angles selected from those listed in Table 1. In other aspects, Formula IA-Form I is characterized by an XRPD spectrum including four peaks at angles selected from those listed in Table 1. In other aspects, Formula IA-Form I is characterized by an XRPD spectrum including five peaks at angles selected from those listed in Table 1. In other aspects, Formula IA-Form I is characterized by an XRPD spectrum including six peaks at angles selected from those listed in Table 1. In other aspects, Formula IA-Form I is characterized by an XRPD spectrum including seven peaks at angles selected from those listed in Table 1. In other aspects, Formula IA-Form I is characterized by an XRPD spectrum comprising eight peaks at angles selected from those listed in Table 1 above. In other aspects, Formula IA-Form I is characterized by an XRPD spectrum comprising nine peaks at angles selected from those listed in Table 1 above. In other aspects, Formula IA-Form I is characterized by an XRPD spectrum comprising ten peaks at angles selected from those listed in Table 1 above. In other aspects, Formula IA-Form I is characterized by an XRPD spectrum comprising more than ten peaks at angles selected from those listed in Table 1 above.

[0077] In some embodiments, Formula IA-Form I is characterized by an XRPD spectrum including a peak at 23.8 degrees ± 0.2 degrees 2-θ. In other embodiments, Formula IA-Form I is characterized by XRPD spectra including peaks at 21.2 and 23.8 degrees ± 0.2 degrees 2-θ. In other embodiments, Formula IA-Form I is characterized by XRPD spectra including peaks at 21.2, 23.8, and 27.0 degrees ± 0.2 degrees 2-θ. In other embodiments, Formula IA-Form I is characterized by XRPD spectra including peaks at 21.2, 23.8, 27.0, and 32.5 degrees ± 0.2 degrees 2-θ.

[0078] In some embodiments of this disclosure, the XRPD spectrum of formula IA-form I is characterized by including peaks at two or more of 21.2, 23.8, 27.0 and 32.5 degrees ± 0.2 degrees 2-θ.

[0079] In some implementations, form IA-form I can be essentially as follows: Figure 2 The DSC thermogram shown is used for characterization. For example... Figure 2The results show that when heated at a rate of 10 °C / min, Formula IA-Form I produces an endothermic peak at 244.19 °C, with a peak onset temperature of 234.71 °C and a fusion enthalpy of 252.8 J / g. In some embodiments of this disclosure, Formula IA-Form I is characterized by a DSC thermogram including an endothermic peak at approximately 244 °C. In other embodiments of this disclosure, Formula IA-Form I is characterized by a DSC enthalpy of fusion of approximately 253 J / g.

[0080] In some implementations, Formula IA-Form I is characterized by being substantially as follows when heated at a rate of 20 °C / min. Figure 3 The TGA curve shown. (As shown in the image) Figure 3 As shown, when heated to approximately 300°C, Formula IA-Form I loses approximately 18.4% of its weight.

[0081] In some embodiments of this disclosure, Formula IA-Form I is characterized by an XRPD spectrum including peaks at one or more of 21.2, 23.8, 27.0, and 32.5 degrees ± 0.2 degrees 2-θ when heated at a rate of 10 °C / min, and a DSC thermogram including an endothermic peak at about 244 °C.

[0082] In some embodiments, the crystalline form of Formula IA is Form II (Form IA - Form II). In some embodiments, Formula IA - Form II substantially contains no other solid form of Formula IA.

[0083] In some implementations, Form IA-Form II exhibits essentially the same characteristics as Figure 4 The XRPD shown. Figure 4 The XRPD of form IA-II shown includes the reflection angle (°2-θ ± 0.2°2-θ), line spacing (d value), and relative intensity, as shown in Table 2:

[0084] Table 2. In Figure 4 XRPD data for the crystalline form of Formula IA-Form II shown in the figure.

[0085]

[0086] In some embodiments of this disclosure, Formula IA-Form II is characterized by an XRPD spectrum including a peak at one of the angles listed in Table 2. In other aspects, Formula IA-Form II is characterized by an XRPD spectrum including more than one peak at one of the angles listed in Table 2. In other aspects, Formula IA-Form II is characterized by an XRPD spectrum including two peaks at angles selected from those listed in Table 2. In other aspects, Formula IA-Form II is characterized by an XRPD spectrum including three peaks at angles selected from those listed in Table 2. In other aspects, Formula IA-Form II is characterized by an XRPD spectrum including four peaks at angles selected from those listed in Table 2. In other aspects, Formula IA-Form II is characterized by an XRPD spectrum including five peaks at angles selected from those listed in Table 2. In other aspects, Formula IA-Form II is characterized by an XRPD spectrum including six peaks at angles selected from those listed in Table 2. In other aspects, Formula IA-Form II is characterized by an XRPD spectrum including seven peaks at angles selected from those listed in Table 2. In other aspects, Formula IA-Form II is characterized by an XRPD spectrum comprising eight peaks at angles selected from those listed in Table 2 above. In other aspects, Formula IA-Form II is characterized by an XRPD spectrum comprising nine peaks at angles selected from those listed in Table 2 above. In other aspects, Formula IA-Form II is characterized by an XRPD spectrum comprising ten peaks at angles selected from those listed in Table 2 above. In other aspects, Formula IA-Form II is characterized by an XRPD spectrum comprising more than ten peaks at angles selected from those listed in Table 2 above.

[0087] In some embodiments, Formula IA-Form II is characterized by an XRPD spectrum including a peak at 25.5° ± 0.2° 2-θ. In other embodiments, Formula IA-Form II is characterized by XRPD spectra including peaks at 14.8, 17.5, and 25.5° ± 0.2° 2-θ. In other embodiments, Formula IA-Form II is characterized by XRPD spectra including peaks at 14.8, 17.5, 18.4, 24.0, and 25.5° ± 0.2° 2-θ. In other embodiments, Formula IA-Form II is characterized by XRPD spectra including peaks at 14.8, 17.5, 18.4, 24.0, 25.5, 28.0, and 28.7° ± 0.2° 2-θ. In other embodiments, Formula IA-Form II is characterized by XRPD spectra including peaks at 17.5, 18.4, 19.8, 24.0, 25.5, 28.0, and 28.7 degrees ± 0.2 degrees 2-θ.

[0088] In some embodiments of this disclosure, Formula IA-Form II is characterized by an XRPD spectrum comprising 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 2-θ. In some embodiments of this disclosure, Formula IA-Form II is characterized by an XRPD spectrum comprising 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 2-θ. In some embodiments of this disclosure, Formula IA-Form II is characterized by an XRPD spectrum comprising 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 2-θ. In some embodiments of this disclosure, Formula IA-Form II is characterized by an XRPD spectrum including 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 2-θ.

[0089] In some implementations, Formula IA-Form II is characterized by being substantially as follows when heated at a rate of 20 °C / min. Figure 5 The TGA curve shown. (As shown in the image) Figure 5 As shown, when heated to about 225°C, Formula IA-Form II loses about 3% of its weight.

[0090] In some embodiments, the crystalline form of Formula IA is Form IIa (Form IA - Form IIa). In some embodiments, Formula IA - Form IIa substantially contains no other solid form of Formula IA.

[0091] In some implementations, form IA-form IIa exhibits essentially the same characteristics as... Figure 6 The XRPD shown. Figure 6 The XRPD of form IA-IIa shown includes the reflection angle (°2-θ ± 0.2°2-θ), line spacing (d value), and relative intensity, as shown in Table 3:

[0092] Table 3. In Figure 6 XRPD data for the crystalline form of Formula IA-Form IIa shown in the figure.

[0093]

[0094] In some embodiments of this disclosure, Formula IA-Form IIa is characterized by an XRPD spectrum including a peak at one of the angles listed in Table 3. In other aspects, Formula IA-Form IIa is characterized by an XRPD spectrum including more than one peak at one of the angles listed in Table 3. In other aspects, Formula IA-Form IIa is characterized by an XRPD spectrum including two peaks at angles selected from those listed in Table 3. In other aspects, Formula IA-Form IIa is characterized by an XRPD spectrum including three peaks at angles selected from those listed in Table 3. In other aspects, Formula IA-Form IIa is characterized by an XRPD spectrum including four peaks at angles selected from those listed in Table 3. In other aspects, Formula IA-Form IIa is characterized by an XRPD spectrum including five peaks at angles selected from those listed in Table 3. In other aspects, Formula IA-Form IIa is characterized by an XRPD spectrum including six peaks at angles selected from those listed in Table 3. In other aspects, Formula IA-Form IIa is characterized by an XRPD spectrum comprising seven peaks at angles selected from those listed in Table 3 above. In other aspects, Formula IA-Form IIa is characterized by an XRPD spectrum comprising eight peaks at angles selected from those listed in Table 3 above. In other aspects, Formula IA-Form IIa is characterized by an XRPD spectrum comprising nine peaks at angles selected from those listed in Table 3 above. In other aspects, Formula IA-Form IIa is characterized by an XRPD spectrum comprising ten peaks at angles selected from those listed in Table 3 above. In other aspects, Formula IA-Form IIa is characterized by an XRPD spectrum comprising more than ten peaks at angles selected from those listed in Table 3 above.

[0095] In some embodiments, Formula IA-Form IIa is characterized by an XRPD spectrum including a peak at 26.1 degrees ± 0.2 degrees 2-θ. In other embodiments, Formula IA-Form IIa is characterized by XRPD spectra including peaks at 14.0, 14.9, and 26.1 degrees ± 0.2 degrees 2-θ. In other embodiments, Formula IA-Form IIa is characterized by XRPD spectra including peaks at 12.5, 14.0, 14.9, 18.4, and 26.1 degrees ± 0.2 degrees 2-θ. In other embodiments, Formula IA-Form IIa is characterized by XRPD spectra including peaks at 12.5, 14.0, 14.9, 18.4, 24.9, and 26.1 degrees ± 0.2 degrees 2-θ. In other embodiments, the XRPD spectrum of formula IA-form IIa is characterized by including peaks at 12.5, 14.0, 14.9, 18.4, 24.9, 26.1 and 28.3 degrees ± 0.2 degrees 2-θ.

[0096] In some embodiments of this disclosure, Formula IA-Form IIa is characterized by an XRPD spectrum comprising 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 2-θ. In some embodiments of this disclosure, Formula IA-Form IIa is characterized by an XRPD spectrum comprising 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 2-θ. In some embodiments of this disclosure, Formula IA-Form IIa is characterized by an XRPD spectrum comprising 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 2-θ. In some embodiments of this disclosure, the XRPD spectrum of formula IA-form IIa is characterized by including 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 2-θ.

[0097] In some implementations, form IA-IIa can be substantially as follows: Figure 7 The DSC thermogram shown is used for characterization. For example... Figure 7 The results show that when heated at a rate of 10 °C / min, Formula IA-Form IIa produces an endothermic peak at 199.44 °C, with a peak onset temperature of 194.14 °C and a fusion 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 fusion enthalpy of 327.1 J / g. In some embodiments of this disclosure, Formula IA-Form IIa is characterized by a DSC thermogram including an endothermic peak at approximately 199 °C. In other embodiments of this disclosure, Formula IA-Form IIa is characterized by a DSC enthalpy of fusion of approximately 55 J / g.

[0098] In some embodiments of this disclosure, Formula IA-Form IIa is characterized by an XRPD spectrum including 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 2-θ when heated at a rate of 10 °C / min, and a DSC thermogram including an endothermic peak at about 199 °C.

[0099] In some embodiments, the crystalline form of Formula IA is Form III (Form IA - Form III). In some embodiments, Formula IA - Form III is substantially free of any other solid form of Formula IA.

[0100] In some implementations, form IA-form III exhibits essentially the same characteristics as Figure 8 The XRPD shown. Figure 8 The XRPD of form IA-III shown includes the reflection angle (°2-θ ± 0.2°2-θ), line spacing (d value), and relative intensity, as shown in Table 4:

[0101] Table 4. In Figure 8 XRPD data for the crystalline form of Formula IA-Form III shown in the figure.

[0102]

[0103]

[0104] In some embodiments of this disclosure, Formula IA-Form III is characterized by an XRPD spectrum including a peak at one of the angles listed in Table 4. In other aspects, Formula IA-Form III is characterized by an XRPD spectrum including more than one peak at one of the angles listed in Table 4. In other aspects, Formula IA-Form III is characterized by an XRPD spectrum including two peaks at angles selected from those listed in Table 4. In other aspects, Formula IA-Form III is characterized by an XRPD spectrum including three peaks at angles selected from those listed in Table 4. In other aspects, Formula IA-Form III is characterized by an XRPD spectrum including four peaks at angles selected from those listed in Table 4. In other aspects, Formula IA-Form III is characterized by an XRPD spectrum including five peaks at angles selected from those listed in Table 4. In other aspects, Formula IA-Form III is characterized by an XRPD spectrum including six peaks at angles selected from those listed in Table 4. In other aspects, Formula IA-Form III is characterized by an XRPD spectrum including seven peaks at angles selected from those listed in Table 4. In other aspects, Formula IA-Form III is characterized by an XRPD spectrum comprising eight peaks at angles selected from those listed in Table 4 above. In other aspects, Formula IA-Form III is characterized by an XRPD spectrum comprising nine peaks at angles selected from those listed in Table 4 above. In other aspects, Formula IA-Form III is characterized by an XRPD spectrum comprising ten peaks at angles selected from those listed in Table 4 above. In other aspects, Formula IA-Form III is characterized by an XRPD spectrum comprising more than ten peaks at angles selected from those listed in Table 4 above.

[0105] In some embodiments, Formula IA-Form III is characterized by an XRPD spectrum including a peak at 8.1 degrees ± 0.2 degrees 2-θ. In other embodiments, Formula IA-Form III is characterized by XRPD spectra including peaks at 8.1 and 23.3 degrees ± 0.2 degrees 2-θ. In other embodiments, Formula IA-Form III is characterized by XRPD spectra including peaks at 8.1, 12.5, 16.2, and 23.3 degrees ± 0.2 degrees 2-θ. In other embodiments, Formula IA-Form III is characterized by XRPD spectra including peaks at 8.1, 12.5, 16.2, 18.8, 23.3, and 24.5 degrees ± 0.2 degrees 2-θ. In other embodiments, Formula IA-Form III is characterized by XRPD spectra including peaks at 8.1, 12.5, 13.7, 14.5, 16.2, 18.8, 23.3, and 24.5 degrees ± 0.2 degrees 2-θ. In other embodiments, Formula IA-Form III is characterized by XRPD spectra including 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 2-θ.

[0106] In some embodiments of this disclosure, Formula IA-Form III is characterized by an XRPD spectrum comprising peaks at three or more of the following: 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 2-θ. In some embodiments of this disclosure, Formula IA-Form III is characterized by an XRPD spectrum comprising peaks at four or more of the following: 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 2-θ.

[0107] In some embodiments of this disclosure, Formula IA-Form III is characterized by an XRPD spectrum comprising peaks at five or more of the following: 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 2-θ. In some embodiments of this disclosure, Formula IA-Form III is characterized by an XRPD spectrum comprising peaks at six or more of the following: 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 2-θ.

[0108] In some embodiments of this disclosure, Formula IA-Form III is characterized by an XRPD spectrum comprising peaks at seven or more of the following: 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 2-θ.

[0109] In some implementations, form IA-form III can be achieved essentially as follows: Figure 9 The DSC thermogram shown is used for characterization. For example... Figure 9 The results show that when heated at a rate of 10 °C / min, Formula IA-Form III produces an endothermic peak at 120.83 °C, with a peak onset temperature of 113.61 °C and a fusion enthalpy of 187.5 J / g; followed by an exothermic peak at 163.21 °C, with a peak onset temperature of 158.31 °C and a fusion enthalpy of 67.85 J / g; followed by an endothermic peak at 192.59 °C, with a peak onset temperature of 190.01 °C and a fusion enthalpy of 66.36 J / g; followed by an endothermic peak at 233.74 °C, with a peak onset temperature of 227.54 °C and a fusion enthalpy of 88.63 J / g. In some embodiments of this disclosure, Formula IA-Form III is characterized by a DSC thermogram including an endothermic peak at approximately 121 °C. In other embodiments of this disclosure, Formula IA-Form III is characterized by a DSC enthalpy of fusion of approximately 187.5 J / g.

[0110] In some implementations, Formula IA-Form III is characterized by being substantially as follows when heated at a rate of 20 °C / min. Figure 10 The TGA curve shown. (As shown in the image) Figure 10 As shown, when heated to approximately 125°C, Formula IA-Form III loses approximately 4.1% of its weight.

[0111] In some embodiments of this disclosure, Formula IA-Form III is characterized by an XRPD spectrum including 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 2-θ when heated at a rate of 10 °C / min, and a DSC thermogram including an endothermic peak at about 121 °C.

[0112] In some embodiments, the crystalline form of Formula IA is Form IV (Form IA - Form IV). In some embodiments, Formula IA - Form IV substantially contains no other solid form of Formula IA.

[0113] In some implementations, form IA-form IV exhibits essentially the same characteristics as... Figure 11 The XRPD shown. Figure 11The XRPD of form IA-IV shown includes the reflection angle (°2-θ ± 0.2°2-θ), line spacing (d value), and relative intensity, as shown in Table 5:

[0114] Table 5. In Figure 11 XRPD data for the crystalline form of Formula IA-Form IV shown in the figure.

[0115]

[0116]

[0117] In some embodiments of this disclosure, Formula IA-Form IV is characterized by an XRPD spectrum including a peak at one of the angles listed in Table 5. In other aspects, Formula IA-Form IV is characterized by an XRPD spectrum including more than one peak at one of the angles listed in Table 5. In other aspects, Formula IA-Form IV is characterized by an XRPD spectrum including two peaks at angles selected from those listed in Table 5. In other aspects, Formula IA-Form IV is characterized by an XRPD spectrum including three peaks at angles selected from those listed in Table 5. In other aspects, Formula IA-Form IV is characterized by an XRPD spectrum including four peaks at angles selected from those listed in Table 5. In other aspects, Formula IA-Form IV is characterized by an XRPD spectrum including five peaks at angles selected from those listed in Table 5. In other aspects, Formula IA-Form IV is characterized by an XRPD spectrum including six peaks at angles selected from those listed in Table 5. In other aspects, Formula IA-Form IV is characterized by an XRPD spectrum including seven peaks at angles selected from those listed in Table 5. In other aspects, Formula IA-Form IV is characterized by an XRPD spectrum comprising eight peaks at angles selected from those listed in Table 5 above. In other aspects, Formula IA-Form IV is characterized by an XRPD spectrum comprising nine peaks at angles selected from those listed in Table 5 above. In other aspects, Formula IA-Form IV is characterized by an XRPD spectrum comprising ten peaks at angles selected from those listed in Table 5 above. In other aspects, Formula IA-Form IV is characterized by an XRPD spectrum comprising more than ten peaks at angles selected from those listed in Table 5 above.

[0118] In some embodiments, Formula IA-Form IV is characterized by an XRPD spectrum including a peak at 4.0° ± 0.2° 2-θ. In other embodiments, Formula IA-Form IV is characterized by XRPD spectra including peaks at 4.0° and 22.7° ± 0.2° 2-θ. In other embodiments, Formula IA-Form IV is characterized by XRPD spectra including peaks at 4.0°, 22.7°, and 27.8° ± 0.2° 2-θ. In other embodiments, Formula IA-Form IV is characterized by XRPD spectra including peaks at 22.7°, 27.8°, and 30.6° ± 0.2° 2-θ. In other embodiments, Formula IA-Form IV is characterized by XRPD spectra including peaks at 14.8°, 22.7°, 27.8°, and 30.6° ± 0.2° 2-θ. In other embodiments, Formula IA-Form IV is characterized by XRPD spectra including peaks at 4.0, 14.8, 22.7, 27.8, and 30.6 degrees ± 0.2 degrees 2-θ.

[0119] In some embodiments of this disclosure, Formula IA-Form IV is characterized by an XRPD spectrum comprising peaks at three or more of 4.0, 14.8, 22.7, 27.8, and 30.6 degrees ± 0.2 degrees 2-θ. In some embodiments of this disclosure, Formula IA-Form IV is characterized by an XRPD spectrum comprising peaks at four or more of 4.0, 14.8, 22.7, 27.8, and 30.6 degrees ± 0.2 degrees 2-θ.

[0120] In some implementations, form IA-form IV can be achieved essentially as follows: Figure 12 The DSC thermogram shown is used for characterization. For example... Figure 12 The results show that when heated at a rate of 10 °C / min, Formula IA-form IV produces an endothermic peak at 169.03 °C, with a peak onset temperature of 161.67 °C and an enthalpy of fusion 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 this disclosure, Formula IA-form IV is characterized by a DSC thermogram including an endothermic peak at approximately 169 °C. In other embodiments of this disclosure, Formula IA-form IV is characterized by a DSC enthalpy of fusion of approximately 26 J / g.

[0121] In some implementations, form IA-IV is characterized by essentially the same properties when heated at a rate of 20°C / min. Figure 13 The TGA curve shown. (As shown in the image) Figure 13 As shown, when heated to about 300°C, Form IV of Formula IA loses about 12.4% (1.135% + 11.23%) of its weight.

[0122] In some embodiments of this disclosure, Formula IA-Form IV is characterized by an XRPD spectrum including peaks at one or more of 4.0, 14.8, 22.7, 27.8 and 30.6 degrees ± 0.2 degrees 2-θ when heated at a rate of 10 °C / min, and a DSC thermogram including an endothermic peak at about 169 °C.

[0123] In some respects, this disclosure relates to the crystalline form of the phosphate of formula I, namely formula IB.

[0124] In some embodiments, the crystalline salt of formula IB is formula IB-form I, exhibiting essentially the same characteristics as... Figure 14A The XRPD shown. Figure 14A The XRPD of form IB-I shown includes the reflection angle (°2-θ ± 0.2°2-θ), line spacing (d value), and relative intensity, as shown in Table 6:

[0125] Table 6. In Figure 14A XRPD data for the crystalline form of Formula IB-Form I shown in the figure.

[0126]

[0127] In some embodiments of this disclosure, Formula IB-Form I is characterized by an XRPD spectrum including a peak at one of the angles listed in Table 6. In other aspects, Formula IB-Form I is characterized by an XRPD spectrum including more than one peak at one of the angles listed in Table 6. In other aspects, Formula IB-Form I is characterized by an XRPD spectrum including two peaks at angles selected from those listed in Table 6. In other aspects, Formula IB-Form I is characterized by an XRPD spectrum including three peaks at angles selected from those listed in Table 6. In other aspects, Formula IB-Form I is characterized by an XRPD spectrum including four peaks at angles selected from those listed in Table 6. In other aspects, Formula IB-Form I is characterized by an XRPD spectrum including five peaks at angles selected from those listed in Table 6. In other aspects, Formula IB-Form I is characterized by an XRPD spectrum including six peaks at angles selected from those listed in Table 6. In other aspects, Formula IB-Form I is characterized by an XRPD spectrum including seven peaks at angles selected from those listed in Table 6. In other aspects, Formula IB-Form I is characterized by an XRPD spectrum comprising eight peaks at angles selected from those listed in Table 6 above. In other aspects, Formula IB-Form I is characterized by an XRPD spectrum comprising nine peaks at angles selected from those listed in Table 6 above. In other aspects, Formula IB-Form I is characterized by an XRPD spectrum comprising ten peaks at angles selected from those listed in Table 6 above. In other aspects, Formula IB-Form I is characterized by an XRPD spectrum comprising more than ten peaks at angles selected from those listed in Table 6 above.

[0128] In some embodiments, Formula IB-Form I is characterized by an XRPD spectrum including a peak at 24.9° ± 0.2° 2-θ. In other embodiments, Formula IB-Form I is characterized by XRPD spectra including peaks at 18.2, 19.6, and 24.9° ± 0.2° 2-θ. In other embodiments, Formula IB-Form I is characterized by XRPD spectra including peaks at 18.2, 19.6, 24.9, 25.7, and 27.0° ± 0.2° 2-θ. In other embodiments, Formula IB-Form I is characterized by XRPD spectra including peaks at 18.2, 18.8, 19.6, 24.9, 25.7, and 27.0° ± 0.2° 2-θ.

[0129] In some embodiments of this disclosure, Formula IB-Form I is characterized by an XRPD spectrum comprising peaks at three or more of 18.2, 18.8, 19.6, 24.9, 25.7, and 27.0° ± 0.2° 2-θ. In some embodiments of this disclosure, Formula IB-Form I is characterized by an XRPD spectrum comprising peaks at four or more of 18.2, 18.8, 19.6, 24.9, 25.7, and 27.0° ± 0.2° 2-θ. In some embodiments of this disclosure, Formula IB-Form I is characterized by an XRPD spectrum comprising peaks at five or more of 18.2, 18.8, 19.6, 24.9, 25.7, and 27.0° ± 0.2° 2-θ. In some embodiments of this disclosure, Formula IB-Form I is characterized by an XRPD spectrum comprising peaks at six or more of the following: 18.2, 18.8, 19.6, 24.9, 25.7, and 27.0° ± 0.2° 2-θ. In some embodiments of this disclosure, Formula IB-Form I is characterized by an XRPD spectrum comprising peaks at seven or more of the following: 18.2, 18.8, 19.6, 24.9, 25.7, and 27.0° ± 0.2° 2-θ.

[0130] In some implementations, form IB-form I can be essentially as follows: Figure 15A The DSC thermogram shown is used for characterization. For example... Figure 15A The results show that when heated at a rate of 10 °C / min, Formula IB-Form I produces an endothermic peak at 200.6 °C, with a peak onset temperature of 198.96 °C and a fusion enthalpy of 53.99 J / g, followed by endothermic peaks at 224.96 °C and 235.97 °C. In some embodiments of this disclosure, Formula IB-Form I is characterized by a DSC thermogram including an endothermic peak at approximately 201 °C. In other embodiments of this disclosure, Formula IB-Form I is characterized by a DSC enthalpy of fusion of approximately 54 J / g.

[0131] In some implementations, form IB is characterized by being substantially as follows when heated at a rate of 20°C / min. Figure 16A The TGA curve shown. (As shown in the image) Figure 16A As shown, when heated to approximately 250°C, Form IB-Form I loses about 6% of its weight.

[0132] In some embodiments of this disclosure, Formula IB-Form I is characterized by an XRPD spectrum including peaks at one or more of 18.2, 18.8, 19.6, 24.9, 25.7 and 27.0 degrees ± 0.2 degrees 2-θ when heated at a rate of 10 °C / min, and a DSC thermogram including an endothermic peak at about 201 °C.

[0133] In some embodiments, the crystalline salt of formula IB is formula IB-form II, which exhibits essentially the same characteristics as... Figure 14B The XRPD shown. Figure 14B The XRPD of form IB-II shown includes the reflection angle (°2-θ ± 0.2°2-θ), line spacing (d value), and relative intensity, as shown in Table 6B:

[0134] Table 6B. In Figure 14B XRPD data for the crystalline form of Formula IB-Form II shown in the figure.

[0135]

[0136] In some embodiments of this disclosure, Formula IB-Form II is characterized by an XRPD spectrum including a peak at one of the angles listed in Table 6B. In other aspects, Formula IB-Form II is characterized by an XRPD spectrum including more than one peak at one of the angles listed in Table 6B. In other aspects, Formula IB-Form II is characterized by an XRPD spectrum including two peaks selected from the angles listed in Table 6B. In other aspects, Formula IB-Form II is characterized by an XRPD spectrum including three peaks selected from the angles listed in Table 6B. In other aspects, Formula IB-Form II is characterized by an XRPD spectrum including four peaks selected from the angles listed in Table 6B. In other aspects, Formula IB-Form II is characterized by an XRPD spectrum including five peaks selected from the angles listed in Table 6B. In other aspects, Formula IB-Form II is characterized by an XRPD spectrum including six peaks selected from the angles listed in Table 6B. In other aspects, Formula IB-Form II is characterized by an XRPD spectrum including seven peaks selected from the angles listed in Table 6B. In other aspects, Formula IB-Form II is characterized by including an XRPD spectrum with eight peaks selected from the angles listed in Table 6B above. In other aspects, Formula IB-Form II is characterized by including an XRPD spectrum with nine peaks selected from the angles listed in Table 6B above. In other aspects, Formula IB-Form II is characterized by including an XRPD spectrum with ten peaks selected from the angles listed in Table 6B above. In other aspects, Formula IB-Form II is characterized by including an XRPD spectrum with more than ten peaks selected from the angles listed in Table 6B above.

[0137] In some embodiments, Formula IB-Form II is characterized by an XRPD spectrum including a peak at 24.6° ± 0.2° 2-θ. In other embodiments, Formula IB-Form II is characterized by XRPD spectra including peaks at 19.3, 24.6, and 27.4° ± 0.2° 2-θ. In other embodiments, Formula IB-Form II is characterized by XRPD spectra including peaks at 19.3, 22.3, 23.6, 24.6, and 27.4° ± 0.2° 2-θ. In other embodiments, Formula IB-Form II is characterized by XRPD spectra including peaks at 19.3, 22.3, 23.6, 24.6, 25.6, and 27.4° ± 0.2° 2-θ.

[0138] In some embodiments of this disclosure, Formula IB-Form II is characterized by an XRPD spectrum comprising peaks at three or more of the following: 19.3, 22.3, 23.6, 24.6, 25.6, and 27.4° ± 0.2° 2-θ. In some embodiments of this disclosure, Formula IB-Form II is characterized by an XRPD spectrum comprising peaks at four or more of the following: 19.3, 22.3, 23.6, 24.6, 25.6, and 27.4° ± 0.2° 2-θ. In some embodiments of this disclosure, Formula IB-Form II is characterized by an XRPD spectrum comprising peaks at five or more of the following: 19.3, 22.3, 23.6, 24.6, 25.6, and 27.4° ± 0.2° 2-θ. In some embodiments of this disclosure, the XRPD spectrum of form IB-form II is characterized by including peaks at six or more of the following: 19.3, 22.3, 23.6, 24.6, 25.6, and 27.4 degrees ± 0.2 degrees 2-θ.

[0139] In some implementations, form IB-form II can be substantially as follows Figure 15B The DSC thermogram shown is used for characterization. For example... Figure 15B The results show that when heated at a rate of 10 °C / min, Formula IB-Form II produces an endothermic peak at 228.56 °C, with a peak onset temperature of 225.70 °C and a fusion enthalpy of 140.4 J / g. In some embodiments of this disclosure, Formula IB-Form II is characterized by a DSC thermogram including an endothermic peak at approximately 229 °C. In other embodiments of this disclosure, Formula IB-Form II is characterized by a DSC enthalpy of fusion of approximately 140 J / g.

[0140] In some implementations, form IB-II is characterized by being substantially as follows when heated at a rate of 20°C / min. Figure 16B The TGA curve shown. (As shown in the image) Figure 16B As shown, when heated to approximately 275°C, Form IB-Form II loses approximately 7.3% of its weight.

[0141] In some embodiments of this disclosure, Formula IB-Form II is characterized by an XRPD spectrum including peaks at one or more of 19.3, 22.3, 23.6, 24.6, 25.6 and 27.4 degrees ± 0.2 degrees 2-θ when heated at a rate of 10 °C / min, and a DSC thermogram including an endothermic peak at about 229 °C.

[0142] In some respects, this disclosure relates to the crystalline form of tartrate of formula I, i.e., formula IC.

[0143] In some implementations, the IC exhibits essentially the same behavior as Figure 17 The XRPD shown. Figure 17 The XRPD of the IC shown includes the reflection angle (°2-θ ± 0.2°2-θ), line spacing (d value), and relative intensity, as shown in Table 7:

[0144] Table 7. In Figure 17 XRPD data for the crystalline form of IC shown in the figure.

[0145]

[0146]

[0147] In some embodiments of this disclosure, Formula IC is characterized by an XRPD spectrum including a peak at one of the angles listed in Table 7. In other aspects, Formula IC is characterized by an XRPD spectrum including more than one peak at one of the angles listed in Table 7. In other aspects, Formula IC is characterized by an XRPD spectrum including two peaks at angles selected from those listed in Table 7. In other aspects, Formula IC is characterized by an XRPD spectrum including three peaks at angles selected from those listed in Table 7. In other aspects, Formula IC is characterized by an XRPD spectrum including four peaks at angles selected from those listed in Table 7. In other aspects, Formula IC is characterized by an XRPD spectrum including five peaks at angles selected from those listed in Table 7. In other aspects, Formula IC is characterized by an XRPD spectrum including six peaks at angles selected from those listed in Table 7. In other aspects, Formula IC is characterized by an XRPD spectrum including seven peaks at angles selected from those listed in Table 7. In other aspects, Formula IC is characterized by an XRPD spectrum comprising eight peaks at angles selected from those listed in Table 7 above. In other aspects, Formula IC is characterized by an XRPD spectrum comprising nine peaks at angles selected from those listed in Table 7 above. In other aspects, Formula IC is characterized by an XRPD spectrum comprising ten peaks at angles selected from those listed in Table 7 above. In other aspects, Formula IC is characterized by an XRPD spectrum comprising more than ten peaks at angles selected from those listed in Table 7 above.

[0148] In some embodiments, Formula IC is characterized by an XRPD spectrum including a peak at 18.4° ± 0.2° 2-θ. In other embodiments, Formula IC is characterized by XRPD spectra including peaks at 18.4, 19.9, and 21.5° ± 0.2° 2-θ. In other embodiments, Formula IC is characterized by XRPD spectra including peaks at 18.4, 19.4, 19.9, 21.5, and 26.3° ± 0.2° 2-θ. In other embodiments, Formula IC is characterized by XRPD spectra including peaks at 11.4, 18.4, 19.4, 19.9, 21.5, 26.3, and 30.2° ± 0.2° 2-θ. In other embodiments, the IC is characterized by XRPD spectra including peaks at 11.4, 18.4, 19.4, 19.9, 21.5, 26.3, 30.2, and 33.1 degrees ± 0.2 degrees 2-θ.

[0149] In some embodiments of this disclosure, the formula IC is characterized by an XRPD spectrum comprising peaks at three or more of the following: 11.4, 18.4, 19.4, 19.9, 21.5, 26.3, 30.2, and 33.1 degrees ± 0.2 degrees 2-θ. In some embodiments of this disclosure, the formula IC is characterized by an XRPD spectrum comprising peaks at four or more of the following: 11.4, 18.4, 19.4, 19.9, 21.5, 26.3, 30.2, and 33.1 degrees ± 0.2 degrees 2-θ. In some embodiments of this disclosure, the formula IC is characterized by an XRPD spectrum comprising peaks at five or more of the following: 11.4, 18.4, 19.4, 19.9, 21.5, 26.3, 30.2, and 33.1 degrees ± 0.2 degrees 2-θ. In some embodiments of this disclosure, Formula IC is characterized by an XRPD spectrum comprising peaks at six or more of the following: 11.4, 18.4, 19.4, 19.9, 21.5, 26.3, 30.2, and 33.1 degrees ± 0.2 degrees 2-θ. In some embodiments of this disclosure, Formula IC is characterized by an XRPD spectrum comprising peaks at seven or more of the following: 11.4, 18.4, 19.4, 19.9, 21.5, 26.3, 30.2, and 33.1 degrees ± 0.2 degrees 2-θ.

[0150] In some implementations, the IC can be essentially as follows Figure 18 The DSC thermogram shown is used for characterization. For example... Figure 18The results show that when heated at a rate of 10 °C / min, Formula IC produces an endothermic peak at 190.04 °C, with a peak onset temperature of 180.70 °C and a fusion enthalpy of 19.00 J / g. In some embodiments of this disclosure, Formula IC is characterized by a DSC thermogram including an endothermic peak at approximately 190 °C. In other embodiments of this disclosure, Formula IC is characterized by a DSC enthalpy of fusion of approximately 19 J / g.

[0151] In some implementations, the IC is characterized by essentially acting as follows when heated at a rate of 20°C / min. Figure 19 The TGA curve shown. (As shown in the image) Figure 19 As shown, when heated to approximately 275°C, the IC loses about 9.3% of its weight.

[0152] In some embodiments of this disclosure, the IC is characterized by an XRPD spectrum including 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 2-θ when heated at a rate of 10 °C / min, and a DSC thermogram including an endothermic peak at about 190 °C.

[0153] Pharmaceutical Compositions and Administration

[0154] The subject pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of the disclosed compound as an active ingredient, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof. Where desired, the pharmaceutical composition contains a pharmaceutically acceptable salt and / or coordination complex thereof, and one or more pharmaceutically acceptable excipients, carriers including inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers, and adjuvants.

[0155] The subject pharmaceutical composition can be administered alone or in combination with one or more other pharmaceutical agents, which are also typically administered in the form of a pharmaceutical composition. Where desired, one or more compounds of the invention can be mixed with other pharmaceutical agents to form a preparation, or the two components can be formulated into separate preparations for use alone or in combination.

[0156] In some embodiments, the concentration of one or more compounds provided in the pharmaceutical compositions of the present invention is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.0%, etc. 6%, 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 numbers within a range limited by any two of the above numbers) w / w, w / v, or v / v.

[0157] In some embodiments, the concentration of one or more compounds of the present invention is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25%, 15%, 14.75%, 14 0.50%, 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 0.25%, 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 numbers within a range limited by any two of the above numbers) w / w, w / v or v / v.

[0158] 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% to about 29%, about 0.03% to about 28%, about 0.04% to about 27%, about 0.05% to about 26%, about 0.06% to about 25%, about 0.07% to about 24%, about 0.08% to about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%, about 1% to about 10% w / w, w / v, or v / v.

[0159] 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% w / w, w / v, or v / v.

[0160] In some embodiments, the amount of one or more compounds of the present invention is equal to or less than 10g, 9.5g, 9.0g, 8.5g, 8.0g, 7.5g, 7.0g, 6.5g, 6.0g, 5.5g, 5.0g, 4.5g, 4.0g, 3.5g, 3.0g, 2.5g, 2.0g, 1.5g, 1.0g, 0.95g, 0.9g, 0.85g, 0.8g, 0.75g, 0.7g, 0.65g, 0.6g, 0.55g, 0.5g, 0.45g, 0.4g, 0.35g, 0.3g, 0.25g, 0.2g, 0.15g, 0. 1g, 0.09g, 0.08g, 0.07g, 0.06g, 0.05g, 0.04g, 0.03g, 0.02g, 0.01g, 0.009g, 0.008g, 0.007g, 0.006g, 0.005g, 0.004g, 0.003g, 0.002g, 0.001g, 0.0009g, 0.0008g, 0.0007g, 0.0006g, 0.0005g, 0.0004g, 0.0003g, 0.0002g, or 0.0001g (or a number within a range limited by any two of the above numbers and including them).

[0161] In some embodiments, the amount of one or more compounds of the present invention is greater than 0.0001g, 0.0002g, 0.0003g, 0.0004g, 0.0005g, 0.0006g, 0.0007g, 0.0008g, 0.0009g, 0.001g, 0.0015g, 0.002g, 0.0025g, 0.003g, 0.0 035g, 0.004g, 0.0045g, 0.005g, 0.0055g, 0.006g, 0.0065g, 0.007g, 0.0075g, 0.0 08g, 0.0085g, 0.009g, 0.0095g, 0.01g, 0.015g, 0.02g, 0.025g, 0.03g, 0.035g, 0.0 4g, 0.045g, 0.05g, 0.055g, 0.06g, 0.065g, 0.07g, 0.075g, 0.08g, 0.085g, 0.09g, 0.095g, 0.1g, 0.15g, 0.2g, 0.25g, 0.3g, 0.35g, 0.4g, 0.45g, 0.5g, 0.55g, 0.6g, 0. 65g, 0.7g, 0.75g, 0.8g, 0.85g, 0.9g, 0.95g, 1g, 1.5g, 2g, 2.5g, 3g, 3.5g, 4g, 4.5g, 5g, 5.5g, 6g, 6.5g, 7g, 7.5g, 8g, 8.5g, 9g, 9.5g, or 10g (or a number within a range limited by any two of the above numbers and including them).

[0162] In some embodiments, the amount of one or more compounds of the present invention is in the range of 0.0001g-10g, 0.0005g-9g, 0.001g-8g, 0.005g-7g, 0.01g-6g, 0.05g-5g, 0.1g-4g, 0.5g-4g, or 1g-3g.

[0163] The compounds according to the invention are effective over a wide dose range. For example, in adult treatment, doses of 0.01 mg / day to 1000 mg / day, 0.5 mg / day to 100 mg / day, 1 mg / day to 50 mg / day, and 5 mg / day to 40 mg / day are examples of usable doses. Exemplary doses are 10 mg / day to 30 mg / day. The exact dose 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 preferences and experience of the attending physician.

[0164] The pharmaceutical compositions of the present invention typically contain the active ingredient of the present invention (i.e., the compound disclosed herein) or its pharmaceutically acceptable salt and / or coordination complex, and one or more pharmaceutically acceptable excipients, carriers, including but not limited to inert solid diluents and fillers, diluents, sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers and adjuvants.

[0165] The following describes non-limiting exemplary pharmaceutical compositions and methods for their preparation.

[0166] Pharmaceutical compositions for oral administration.

[0167] In some embodiments, the present invention provides a pharmaceutical composition for oral administration comprising the compound of the present invention and a pharmaceutical excipient suitable for oral administration.

[0168] In some embodiments, the present invention provides a solid pharmaceutical composition for oral administration comprising: (i) an effective amount of the compound of the present invention; optionally (ii) an effective amount of a second pharmaceutical agent; and (iii) a pharmaceutical excipient suitable for oral administration. In some embodiments, the composition further comprises: (iv) an effective amount of a third pharmaceutical agent.

[0169] In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral consumption. Pharmaceutical compositions of the present invention suitable for oral administration may be presented in discrete dosage forms, such as capsules, pouches, or tablets, or liquids or aerosol sprays, each containing a predetermined amount of the active ingredient as a powder or granules, solution, or suspension in an aqueous or non-aqueous liquid, oil-in-water emulsion, or water-in-oil liquid emulsion. Such dosage forms can be prepared by any pharmaceutical method, but all methods include the step of associating the active ingredient with a carrier, which constitutes one or more essential components. Typically, the composition is prepared by uniformly and tightly mixing the active ingredient with a liquid carrier or a subdivided solid carrier, or both, and then, if necessary, shaping the product into the desired presentation form. For example, tablets may be prepared by compression or molding, optionally with one or more excipients. Compressed tablets may be prepared by compressing the active ingredient in a free-flowing form, such as powder or granules, in a suitable machine, optionally mixed with excipients such as, but not limited to, binders, lubricants, inert diluents, and / or surfactants or dispersants. Molded tablets can be prepared by molding a mixture of powdered compounds wetted with an inert liquid diluent in a suitable machine.

[0170] This invention also covers anhydrous pharmaceutical compositions and dosage forms containing active ingredients, as water can promote the degradation of some compounds. For example, in the pharmaceutical field, water (e.g., 5%) may be added 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 this invention can be prepared using anhydrous or low-moisture ingredients and low-moisture or low-humidity conditions. If significant contact with moisture and / or humidity is anticipated during manufacturing, packaging, and / or storage, the lactose-containing pharmaceutical compositions and dosage forms of this invention can be made anhydrous. Anhydrous pharmaceutical compositions can be prepared and stored in ways that allow them to maintain their anhydrous properties. Therefore, anhydrous compositions can be packaged using materials known to prevent exposure to water, so that they can be included in suitable formulation kits. Examples of suitable packaging include, but are not limited to, sealing foil, plastics, etc., unit-dose containers, blister packs, and strip packs.

[0171] According to conventional pharmaceutical formulation techniques, the active ingredient can be tightly mixed with the drug carrier. The carrier can take various forms depending on the desired preparation for administration. In preparing compositions for oral dosage forms, in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols, any conventional pharmaceutical medium can be used as a carrier, such as water, ethylene glycol, oil, alcohol, flavoring agents, preservatives, coloring agents, etc.; or in the case of oral solid preparations, carriers such as starch, sugar, microcrystalline cellulose, diluents, granulators, lubricants, binders, and disintegrants can be used, although lactose is not used in some embodiments. For example, in the case of solid oral preparations, suitable carriers include powders, capsules, and tablets. Tablets can be coated using standard aqueous or non-aqueous techniques if desired.

[0172] Binders suitable for pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch or other starches, gelatin, natural and synthetic gums such as gum arabic, sodium alginate, alginic acid, other alginates, powdered tragacanth gum, 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 thereof.

[0173] Examples of suitable fillers for 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, glucose binders, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0174] Disintegrants can be used in the compositions of the present invention to provide tablets that disintegrate upon exposure to an aqueous environment. Too much disintegrant may result in tablets that may disintegrate in the bottle. Too little may be insufficient for disintegration to occur and may therefore alter the rate and extent of release of the active ingredient from the dosage form. Therefore, a dosage form of the compounds disclosed herein can be formed using a sufficient amount of disintegrant that is neither too little nor too much, thereby adversely altering the release of the active ingredient. The amount of disintegrant used may vary based on the type of formulation and the administration method and can be readily identified by those skilled in the art. About 0.5% to about 15% by weight or about 1% to about 5% by weight of disintegrant may be used in the pharmaceutical composition. Disintegrants that can 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, croscarmellose, polacrilin potassium, sodium carboxymethyl starch, potato or cassava starch, other starches, pregelatinized starches, other starches, clays, other algae, other celluloses, gums, or mixtures thereof.

[0175] Lubricants that can be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, or mixtures thereof. Additional lubricants include, for example, syloid silica gel, condensed aerosols of synthetic silica, or mixtures thereof. Optionally, a lubricant may be added in an amount less than about 1% by weight of the pharmaceutical composition.

[0176] When aqueous suspensions and / or elixirs are intended for oral administration, the active ingredients therein may be combined with various sweeteners or flavorings, coloring substances or dyes, and, if desired, emulsifiers and / or suspending agents with diluents such as water, ethanol, propylene glycol, glycerin, and various combinations thereof.

[0177] Tablets may be uncoated or coated using known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide sustained action over a longer period. For example, delay-release 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 (e.g., calcium carbonate, calcium phosphate, or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with an aqueous or oily medium (e.g., peanut oil, liquid paraffin, or olive oil).

[0178] Surfactants that can be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, mixtures of hydrophilic surfactants, mixtures of lipophilic surfactants, or mixtures of at least one hydrophilic surfactant and at least one lipophilic surfactant may be used.

[0179] Suitable hydrophilic surfactants typically have an HLB value of at least 10, while suitable lipophilic surfactants typically have an HLB value of about 10 or less. The empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of nonionic amphiphilic compounds is the hydrophilic-lipophilic balance (“HLB” value). Surfactants with lower HLB values ​​are more lipophilic or hydrophobic and have greater solubility in oils, while surfactants with higher HLB values ​​are more hydrophilic and have greater solubility in aqueous solutions.

[0180] Hydrophilic surfactants are generally considered to be compounds with HLB values ​​greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not typically applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds with HLB values ​​equal to or less than about 10. However, the HLB value of a surfactant is only a rough guideline commonly used to formulate industrial, pharmaceutical, and cosmetic emulsions.

[0181] Hydrophilic surfactants can be ionic or nonionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidates; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glycerol ester derivatives of amino acids, oligopeptides, and polypeptides; lecithin and hydrogenated lecithin; lysophosphatidylcholine and hydrogenated lysophosphatidylcholine; phospholipids and their derivatives; lysophosphatidylcholine and its derivatives; carnitine fatty acid ester salts; alkyl sulfates; fatty acid salts; sodium docusate; acyl lactates; monoacetylated tartrate esters and diacetylated tartrate esters of monoglycerides and diglycerides; succinylated monoglycerides and diglycerides; citrate esters of monoglycerides and diglycerides; and mixtures thereof.

[0182] In the foregoing group, ionic surfactants include, for example: lecithin, lysophosphatidylcholine, phospholipids, lysophosphatidylcholine and their derivatives; carnitine fatty acid ester salts; alkyl sulfates; fatty acid salts; sodium docusate; acyl lactates; monoacetylated tartrate esters and diacetylated tartrate esters of monoglycerides and diglycerides; succinylated monoglycerides and diglycerides; citrate esters of monoglycerides and diglycerides; and mixtures thereof.

[0183] Ionic surfactants can be lecithin, lysophosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, fatty acid lactate, stearoyl-2-lactic acid ester, stearoyl lactate, succinylated monoglycerides, mono / diacetylated tartrate esters of mono / diglycerides, mono / diglycerides of citrate, choylsarcosine, hexanoate, caprylate, caprate, laurate, myristate, palmitate, oleate, castor oil ester, linoleate, linolenic acid ester, stearate, dodecyl sulfate, tetraethyl sulfate, docusate, lauroylcarnitine, palmitoylcarnitine, myristoylcarnitine, and their salts and mixtures.

[0184] Hydrophilic nonionic surfactants may include, but are not limited to, alkyl glucosides; alkyl maltodextrins; alkyl thioglucosides; lauryl polyethylene glycol glycerides; polyoxyethylene alkyl ethers, such as polyethylene glycol alkyl ethers; polyoxyethylene alkylphenols, such as polyethylene glycol alkylphenols; polyoxyethylene alkylphenol fatty acid esters, such as polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyethylene dehydrated sorbitol fatty acid esters, such as polyethylene glycol dehydrated sorbitol fatty acid esters; hydrophilic transesterification products of polyols with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; polyoxyethylene sterols, their derivatives and analogs; polyoxyethylene vitamins and their derivatives; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol dehydrated sorbitol fatty acid esters and hydrophilic transesterification products of polyols with at least one member of the group consisting of triglycerides, vegetable oils and hydrogenated vegetable oils. Polyols can be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or sugars.

[0185] 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 trioleylglycerol, PEG-32 dioleate, PEG-20 laurate, PEG-30 laurate, PEG-20 stearate, PEG-20 oleate, PEG-30 oleate, PEG-30 laurate, PEG-40 laurate, and 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 / caprylic glyceryl ester, PEG-8 caprylic / caprylic glyceryl ester, polyglycerol-10 laurate, PEG-30 cholesterol, PEG-25 phytosterols, PEG-30 soybean sterols, PEG-20 trioleate, PEG-40 de-oxidized castor oil. Sorbitol oleate, PEG-80 dehydrated sorbitol laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopherol PEG-100 succinate, PEG-24 cholesterol, polyglycerol-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonylphenol series, PEG 15-100 octylphenol series, and poloxamer.

[0186] By way of example only, suitable lipophilic surfactants include: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acid esters; propylene glycol fatty acid esters; sorbitol fatty acid esters; polyethylene glycol sorbitol fatty acid esters; sterols and sterol derivatives; polyoxyethylene sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of monoglycerides and diglycerides; hydrophobic transesterification products of polyols with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; oil-soluble vitamins / vitamin derivatives; and mixtures thereof. Preferred lipophilic surfactants in this group include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or hydrophobic transesterification products of polyols with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.

[0187] In one embodiment, the composition may contain a solubilizer to ensure good solubility and / or dissolution of the compounds of the present invention and to minimize precipitation of the compounds of the present invention. This is particularly important for compositions intended for non-oral use (e.g., compositions for injection). Solubilizers may also be added to increase the solubility of hydrophilic drugs and / or other components such as surfactants or to maintain the composition as a stable or homogeneous solution or dispersion.

[0188] Examples of suitable solubilizers include, but are not limited to, the following: alcohols and polyols (such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and its isomers, glycerol, pentaerythritol, sorbitol, mannitol, ethylene glycol monoethyl ether, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol), hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; polyethylene glycol ethers with an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycogen) or methoxy PEG; amides and other nitrogen-containing compounds, such as 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkyl Pyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide, and polyvinylpyrrolidone; esters such as ethyl propionate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethyl citrate, ethyl oleate, ethyl octanoate, ethyl butyrate, glyceryl triacetate, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and its isomers, δ-valerolactone and its isomers, β-butyrolactone and its isomers; and other solubilizers known in the art, such as dimethylacetamide, dimethylisosorbide, N-methylpyrrolidone, glyceryl monooctanoate, diethylene glycol monoethyl ether, and water.

[0189] Mixtures of solubilizers may also be used. Examples include, but are not limited to, triethyl glycerol triacetate, triethyl citrate, ethyl oleate, ethyl octanoate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin, ethanol, polyethylene glycol 200-100, glycogen, ethylene glycol monoethyl ether, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triethyl glycerol triacetate, ethanol, PEG-400, glycogen, and propylene glycol.

[0190] There are no particular limitations on the amount of solubilizer that may be included. The amount of a given solubilizer may be limited to a bioacceptable amount that can be readily determined by a person skilled in the art. In some cases, it may be advantageous to include an amount of solubilizer far exceeding the bioacceptable amount, for example, to maximize the concentration of the drug, wherein excess solubilizer is removed using conventional techniques (such as distillation or evaporation) before the composition is served to the subject. Thus, if present, the weight ratio of the solubilizer may be 10%, 25%, 50%, 100%, or up to about 200% by weight, based on the combined weight of the drug and other excipients. Very small amounts of solubilizer, such as 5%, 2%, 1%, or even less, may also be used if desired. Typically, the solubilizer may be present in amounts from about 1% to about 100% by weight, and more typically from about 5% to about 25% by weight.

[0191] The composition may also contain one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, but are not limited to, anti-sticking agents, defoamers, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, tension modifiers, flavoring agents, coloring agents, taste enhancers, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0192] In addition, acids or bases can be incorporated into the composition to facilitate processing, enhance stability, or achieve other purposes. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium bicarbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tri(hydroxymethyl)aminomethane (TRIS), etc. Suitable bases are also salts of pharmaceutically acceptable acids such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulosic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinone sulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, p-bromobenzenesulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, etc. Salts of polybasic acids, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate, may also be used. When the base is a salt, the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, etc. Examples may include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, and ammonium.

[0193] 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, and phosphoric acid. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulosic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinone sulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, p-bromobenzenesulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, and uric acid.

[0194] In some embodiments, the pharmaceutical composition comprises a compound of formula IA, microcrystalline cellulose, crospovidone, sodium lauryl sulfate, and magnesium stearate.

[0195] In some embodiments, the pharmaceutical composition comprises a compound of formula IA, mannitol, microcrystalline cellulose, crospovidone, sodium lauryl sulfate, and magnesium stearate.

[0196] In some embodiments, the pharmaceutical composition comprises a compound of formula IA-form I, mannitol, microcrystalline cellulose, crospovidone, sodium lauryl sulfate, and magnesium stearate.

[0197] In some embodiments, the pharmaceutical composition comprises a compound of formula IA-form II, mannitol, microcrystalline cellulose, crospovidone, sodium lauryl sulfate, and magnesium stearate.

[0198] In some embodiments, the pharmaceutical composition comprises a compound of formula IA-form IIa, mannitol, microcrystalline cellulose, crospovidone, sodium lauryl sulfate, and magnesium stearate.

[0199] In some embodiments, the pharmaceutical composition comprises a compound of formula IA-form III, mannitol, microcrystalline cellulose, crospovidone, sodium lauryl sulfate, and magnesium stearate.

[0200] In some embodiments, the pharmaceutical composition comprises a compound of formula IA-form IV, mannitol, microcrystalline cellulose, crospovidone, sodium lauryl sulfate, and magnesium stearate.

[0201] In some embodiments, the pharmaceutical composition comprises a compound of formula IB, mannitol, microcrystalline cellulose, crospovidone, sodium lauryl sulfate, and magnesium stearate.

[0202] Pharmaceutical compositions for injection.

[0203] In some embodiments, the present invention provides an injectable pharmaceutical composition comprising the compound of the present invention and an injectable pharmaceutical excipient. The components and amounts of the pharmaceutical preparations in the composition are as described herein.

[0204] The novel compositions of the present invention that can be incorporated into the form of those for administration by injection include aqueous or oil suspensions or emulsions containing sesame oil, corn oil, cottonseed oil or peanut oil, as well as elixirs, mannitol, dextrose or sterile aqueous solutions and similar pharmaceutical mediators.

[0205] Aqueous solutions in saline solutions are also commonly used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be used. The desired particle size can be maintained, for example, by using coatings such as lecithin in the case of dispersions, and appropriate flowability can be maintained by using surfactants. Prevention of microbial action can be provided by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.

[0206] A sterile injectable solution is prepared by incorporating the required amount of the compound of the present invention, along with various other components as enumerated above, into a suitable solvent, followed by filtration and sterilization. Typically, a dispersion is prepared by incorporating various sterilized active ingredients into a sterile medium containing a basic dispersion medium and any other desired components from those enumerated above. In cases where sterile powders are used to prepare sterile injectable solutions, certain desirable preparation methods include vacuum drying and freeze-drying techniques, which produce powders of the active ingredient plus any additional desired components from their previously sterile filtered solution.

[0207] Pharmaceutical compositions for local (e.g., transdermal) delivery.

[0208] In some embodiments, the present invention provides a pharmaceutical composition for transdermal delivery comprising the compound of the present invention and a pharmaceutical excipient suitable for transdermal delivery.

[0209] The compositions of the present invention can be formulated into preparations suitable for topical or local application in solid, semi-solid, or liquid forms, such as gels, water-soluble gels, creams, lotions, suspensions, foams, powders, slurries, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, and dimethyl sulfoxide (DMSO)-based solutions. Generally, a carrier with higher density provides a longer-lasting area of ​​exposure to the active ingredient. In contrast, solution formulations allow for more direct exposure of the active ingredient to the selected area.

[0210] Pharmaceutical compositions may also contain suitable solid or gel phase carriers or excipients, which are compounds that allow for increased permeability of therapeutic molecules across the skin's stratum corneum permeability barrier or facilitate the delivery of therapeutic molecules across the skin's stratum corneum permeability barrier. Many of these permeation-enhancing molecules are known to those trained in the field of topical formulations.

[0211] Examples of such carriers and excipients include, but are not limited to, wetting agents (e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidone, glyceryl monolaurate, sulfoxide, 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.

[0212] Another exemplary formulation used in the methods of the present invention employs a transdermal delivery device (“patch”). Such transdermal patches can be used to provide a controlled amount of the compound of the present invention for continuous or discontinuous infusion, with or without another agent.

[0213] The construction and use of transdermal patches for drug delivery are well known in the art. See, for example, U.S. Patents 5,023,252, 4,992,445, and 5,001,139. ​​Such patches can be configured for continuous, pulsed, or on-demand drug delivery.

[0214] Pharmaceutical compositions for inhalation.

[0215] Compositions for inhalation or inhalation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, the composition is administered via oral or nasal inhalation to produce a local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized using an inert gas. The nebulized solution may be inhaled directly from a nebulizer, or the nebulizer may be attached to a mask plug or intermittent positive pressure ventilation machine. Solutions, suspensions, or powder compositions may preferably be administered orally or nasally from a device that delivers the formulation in a suitable manner.

[0216] Other pharmaceutical compositions.

[0217] Pharmaceutical compositions can also be prepared from the compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or spinal administration. Preparations of such pharmaceutical compositions are well known in the art. See, for example, Anderson, Philip O., Knoben, James E., Troutman, William G. (eds.), *Handbook of Clinical Drug Data*, 10th edition, McGraw-Hill, 2002; Pratt and Taylor (eds.), *Principles of Drug Action*, 3rd edition, Churchill Livingston, New York, 1990; Katzung (ed.), *Basic and Clinical Pharmacology*, 9th edition, McGraw Hill, 2003; Goodman and Gilman (eds.), *The Pharmacological Basis of Therapeutics*, 10th edition, McGraw-Hill, 2001; Remingtons Pharmaceutical Sciences*, 20th edition, Lippincott Williams & Wilkins, 2000; Martindale, *The Extra Pharmacopoeia*, 32nd edition (The Pharmaceutical Press, London, 1999); all of these references are incorporated herein by reference in full.

[0218] The administration of the compounds or pharmaceutical compositions of the present invention can be achieved by any method capable of delivering the compounds to the site of action. These methods include oral administration, intraduodenal administration, parenteral injection (including intravenous, intra-arterial, subcutaneous, intramuscular, intravascular, intraperitoneal, or infusion), local administration (e.g., percutaneous application), rectal administration, local delivery via catheter or stent, or inhalation. The compounds can also be administered intra-fatty or intrathecally.

[0219] The amount of compound administered will depend on the subject being treated, the severity of the impairment or condition, the rate of administration, the disposal of the compound, and the prescribing physician's judgment. However, the effective dose is in the range of about 0.001 mg / kg body weight / day to about 100 mg / kg body weight / day, preferably about 1 mg / kg / day to about 35 mg / kg / day, administered as a single dose or in divided doses. For a 70 kg person, this would equate to about 0.05 g / day to 7 g / day, preferably about 0.05 g / day to about 2.5 g / day. In some cases, dose levels below the lower limit of the above range may be well sufficient, while in other cases, still larger doses may be used without causing any harmful side effects, for example, by dividing such a larger dose into several smaller doses administered throughout the day.

[0220] In some embodiments, the compounds of the present invention are administered in a single dose.

[0221] Typically, such administration is performed by injection, such as intravenous injection, to rapidly deliver the drug. However, other routes may be appropriately used. A single dose of the compound of the present invention can also be used to treat acute conditions.

[0222] In some embodiments, the compounds of the present invention are administered in multiple doses. Dosing may be about once, twice, three times, four times, five times, six times, or more than six times daily. Dosing may be about once a month, once every two weeks, once a week, or once every other day. In another embodiment, the compounds of the present invention are administered together with another agent about once daily to about six times daily. In another embodiment, the administration of the compounds and agents of the present invention lasts for less than about seven days. In another embodiment, the administration lasts for more than about six days, ten days, fourteen days, twenty-eight days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as needed.

[0223] The application of the compounds of the present invention is continued as needed. In some embodiments, the application of the compounds of the present invention is continued for more than 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, or 28 days. In some embodiments, the application of the compounds of the present invention is continued for less than 28 days, 14 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day. In some embodiments, the compounds of the present invention are applied on a continuous basis for a long period of time, for example, for chronic therapeutic effects.

[0224] Effective amounts of the compounds of the present invention may be administered in single or multiple doses via any of the acceptable modes of administration of pharmaceutical agents having similar effects, including rectal, buccal, intranasal and percutaneous routes, by intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical or as an inhaler.

[0225] The compositions of the present invention can also be delivered via, for example, impregnation or coating devices (such as stents) or arterial insertion cylindrical polymers. Such methods of administration can, for example, help prevent or improve restenosis after procedures such as balloon angioplasty. Without being limited by theory, the compounds of the present invention can slow or inhibit the migration and proliferation of smooth muscle cells in the arterial wall that lead to restenosis. The compounds of the present invention can be administered, for example, by local delivery from the strut of a stent, from a stent graft, from the graft, or from the stent cover or sheath. In some embodiments, the compounds of the present invention are mixed with a matrix. Such a matrix can be a polymer matrix and can be used to bind the compounds to a stent. Suitable polymer matrices for such applications 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); polydimethylsiloxane, poly(ethylene-vinyl acetate), acrylate-based polymers or copolymers (e.g., polyhydroxyethyl methacrylate, polyvinylpyrrolidone), fluorinated polymers such as polytetrafluoroethylene, and cellulose esters. Suitable matrices may be non-degradable or degradable over time, releasing one or more compounds. The compounds of the present invention can be applied to the surface of a stent by various methods such as dip coating / spin coating, spraying, dip coating, and / or brushing. The compounds can be applied in a solvent, and the solvent can be allowed to evaporate, thereby forming a compound layer on the stent. Alternatively, the compounds can be positioned within the body of the stent or implant, such as in microchannels or micropores. When implanted, the compounds diffuse from the body of the stent to contact the arterial wall. Such stents can be prepared by immersing a stent manufactured to contain such micropores or microchannels in a solution of the compound of the present invention in a suitable solvent, followed by solvent evaporation. Excess drug on the surface of the stent can be removed by an additional brief solvent wash. In other embodiments, the compound of the present invention can be covalently attached to a stent or graft. A covalent connector can be used that degrades in vivo, thereby releasing the compound of the present invention. Any biounstable bond can be used for this purpose, such as ester, amide, or anhydride bonds. Additionally, the compound of the present invention can be administered intravascularly by a balloon used during angioplasty. Extravascular administration of the compound can also be performed via pericardial or adventitia application of the formulation of the present invention to reduce restenosis.

[0226] For example, various support devices that can be used as described are disclosed in the following references, all of which are incorporated herein by reference: U.S. Patent 5,451,233; U.S. Patent 5,040,548; U.S. Patent 5,061,273; U.S. Patent 5,496,346; U.S. Patent 5,292,331; U.S. Patent 5,674,278; U.S. Patent 3,657,744; U.S. Patent 4,739,762; U.S. Patent 5,195,984; U.S. Patent 5,292,331; U.S. Patent 5,674,278; U.S. Patent 5,879,382; U.S. Patent 6,344,053.

[0227] The compounds of the present invention can be administered in doses. It is known in the art that individualization of dosing regimens is necessary for optimal therapy due to the variability in pharmacokinetics among subjects. According to this disclosure, the dosage of the compounds of the present invention can be determined through routine experiments.

[0228] When the compound of the present invention is administered in a composition comprising one or more agents, and the agents have a shorter half-life than the compound of the present invention, the unit dosage form of the agents and the compound of the present invention may be adjusted accordingly.

[0229] The pharmaceutical composition may be in forms suitable for oral administration, such as tablets, capsules, pills, powders, sustained-release formulations, solutions, and suspensions; forms suitable for parenteral injection, such as sterile solutions, suspensions, or emulsions; forms suitable for topical application, such as ointments or creams; or forms suitable for rectal administration, such as suppositories. The pharmaceutical composition may be in a unit dosage form suitable for a single, precise dose. The pharmaceutical composition will comprise a conventional pharmaceutical carrier or excipient and the compound of the present invention as the active ingredient. Furthermore, the pharmaceutical composition may comprise other pharmaceutical agents, carriers, adjuvants, etc.

[0230] Exemplary parenteral formulations comprise a solution or suspension of the active compound in a sterile aqueous solution, such as propylene glycol or dextrose. Such dosage forms may be appropriately buffered if desired.

[0231] How to use

[0232] This method typically involves administering a therapeutically effective amount of the compounds of the present invention to a subject. The therapeutically effective amount of the combination of subject compounds may vary depending on the intended application (in vitro or in vivo) or the subject being treated and the nature of the disease, such as the subject's weight and age, the severity of the disease, the method of administration, etc., which can be readily determined by those skilled in the art. The term also applies to doses that will induce a specific response in target cells (e.g., reduced proliferation or downregulation of target protein activity). The specific dose will vary depending on the particular compound selected, the dosing regimen to be followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system carried therein.

[0233] As used in this article, the term "IC" 50 The half-maximum inhibitory concentration (IC50) refers to the concentration at which an inhibitor inhibits a biological or biochemical function. This quantitative measure indicates how much of a specific inhibitor is needed to inhibit half of a given biological process (or a component of that process, i.e., an enzyme, cell, cell receptor, or microorganism). In other words, it is the half-maximum (50%) inhibitory concentration (IC50) of a substance. The EC50 is the plasma concentration required to achieve 50% or more of the maximum effect in vivo.

[0234] In some embodiments, the method of the present invention utilizes a PRMT5 inhibitor with an IC50 value of about or less than a predetermined value, as determined in in vitro assays. In some embodiments, the PRMT5 inhibitor inhibits PRMT5 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, or 140 nM or less. 150nM or less, 160nM or less, 170nM or less, 180nM or less, 190nM or less, 200nM or less, 225nM or less, 250nM or less, 275nM or less, 300nM or less, 325nM or less, 350nM or less, 375nM or less, 400nM or less, 425nM or less, 450nM or less, 475nM or less, 500nM or less Smaller, 550nM or smaller, 600nM or smaller, 650nM or smaller, 700nM or smaller, 750nM or smaller, 800nM or smaller, 850nM or smaller, 900nM or smaller, 950nM or smaller, 1μM or smaller, 1.1μM or smaller, 1.2μM or smaller, 1.3μM or smaller, 1.4μM or smaller, 1.5μM or smaller, 1.6μM or smaller, 1.7μM or smaller, 1.8μM or smaller Smaller, 1.9 μM or smaller, 2 μM or smaller, 5 μM or smaller, 10 μM or smaller, 15 μM or smaller, 20 μM or smaller, 25 μM or smaller, 30 μM or smaller, 40 μM or smaller, 50 μM, 60 μM, 70 μM, 80 μM, 90 μM, 100 μM, 200 μM, 300 μM, 400 μM, or 500 μM or smaller g (or numbers within a range limited by any two of the above numbers and including them).

[0235] In some implementations, the PRMT5 inhibitor selectively inhibits PRMT5, and its 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 than its IC50 value for one, two, or three other PRMTs (or a number within a range defined by and including any two of the above numbers).

[0236] In some implementations, the PRMT5 inhibitor selectively inhibits PRMT5 with IC50 values ​​less than approximately 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, and 1... 90nM, 200nM, 225nM, 250nM, 275nM, 300nM, 325nM, 350nM, 375nM, 400nM, 425nM, 450nM, 475nM, 500nM, 550nM, 600nM, 650nM, 700nM, 750nM, 800nM, 850nM, 900nM, 950nM, 1μM, 1 .1μM, 1.2μM, 1.3μM, 1.4μM, 1.5μM, 1.6μM, 1.7μM, 1.8μM, 1.9μM, 2μM, 5μM, 10μM, 15μM, 20μM, 25μM, 30μM, 40μM, 50μM, 60μM, 70μM, 80μM, 90μM, 100μM, 200μM, 300μM, 400μM or 50 0 μM (or a number within the range defined by any two of the above numbers) and the IC50 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 than its IC50 value for one, two, or three other PRMTs (or a number within the range defined by any two of the above numbers).

[0237] The method of this invention can be used to treat diseases related to PRMT5. Any disease directly or indirectly caused by abnormal activity or expression levels of PRMT5 can be considered a potential disease.

[0238] Various disease symptoms associated with PRMT5 have been reported. PRMT5 is associated with, for example, a variety of human cancers and many hemoglobinopathies.

[0239] Non-limiting examples of such conditions include, but are not limited to, acanthoma, acinar cell carcinoma, acoustic neuroma, acral melanoma, acral hidradenoma, acute eosinophilic leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute myeloid leukemia with maturation, acute myeloid dendritic cell leukemia, acute myeloid leukemia, acute myeloid leukemia, acute promyelocytic leukemia, ameloblastoma, adenocarcinoma, adenoid cystic carcinoma, adenoma, odontogenic adenoid tumor, adrenocortical carcinoma, adult T-cell leukemia, aggressive NK-cell leukemia, AIDS-related cancers, AIDS-related lymphomas, acinar soft tissue sarcoma, ameloblastic fibroma, and anal cancer. Anaplastic large cell lymphoma, anaplastic thyroid carcinoma, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, appendix cancer, astrocytoma, atypical teratoid / rhabdomyosarcoma, basal cell carcinoma, basal cell carcinoma, B-cell leukemia, B-cell lymphoma, Bellini ductal carcinoma, biliary tract cancer, bladder cancer, germ cell tumor, bone cancer, bone tumor, brainstem glioma, brain tumor, breast cancer, Brunner tumor, bronchial tumor, bronchioloalveolar carcinoma, brown tumor, Burkitt lymphoma, cancer of unknown origin, carcinoid tumor, tumor, carcinoma in situ, penile cancer, cancer of unknown origin, carcinosarcoma, Castreman's disease, embryonic tumors of the central nervous system, cerebellar astrocytoma, cerebral astrocytoma, cervical cancer, bile duct cancer Chondroma, chondrosarcoma, chordoma, choriocarcinoma, choroid plexus papilloma, chronic lymphocytic leukemia, chronic monocytic leukemia, chronic myeloid leukemia, chronic myelodysplastic syndrome, chronic neutrophilic leukemia, clear cell tumor, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, Degos' disease, dermatofibrosarcoma protuberans, dermoid cyst, fibroplastic small round cell tumor, diffuse large B-cell lymphoma, dysplastic neuroepithelial tumor, embryonal carcinoma, endodermal sinus tumor, endometrial cancer, endometrial uterine cancer, endometrioid tumor, T-cell lymphoma associated with bowel disease, ependymoblastoma, ependymoma, epidermoid carcinoma, epithelioid sarcoma, erythroleukemia, esophageal cancer, sensory nerve cell... Ewing's familial tumor, Ewing's familial sarcoma, Ewing's sarcoma, extracranial germ cell tumor, gonadal germ cell tumor, extrahepatic bile duct carcinoma, extramammary Paget's disease, fallopian tube cancer, fetus in fetus, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid carcinoma, gallbladder cancer, gallbladder cancer, ganglioglioma, ganglioma, gastric cancer, gastric lymphoma, gastrointestinal cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, gastrointestinal stromal tumor, germ cell tumor, germ cell tumor, gestational choriocarcinoma, gestational trophoblastic tumor, giant cell tumor of bone, glioblastoma multiforme, glioma, gliomatosis of the brain, glomus tumor, glucagonoma, gonadal germ cell tumor, granuloma, pilocellular leukemia, head and neck cancer, head and neck cancer, heart cancer.Hemoglobinopathies (such as β-thalassemia and sickle cell disease (SCD)), angioblastoma, hemangiopericytoma, angiosarcoma, hematologic malignancies, hepatocellular carcinoma, hepatocellular T-cell lymphoma, hereditary breast-ovarian cancer syndrome, Hodgkin's lymphoma, Hodgkin's lymphoma, hypopharyngeal cancer, hypothalamic glioma, inflammatory breast cancer, intraocular melanoma, islet cell carcinoma, islet cell tumor, juvenile myelomonocytic leukemia, Kaposi's sarcoma, Kaposi's sarcoma, renal cell carcinoma, hilar cholangiocarcinoma, Kuckenberg tumor, laryngeal cancer, laryngeal cancer, malignant lentigines melanoma, leukemia, lip and oral cancer, liposarcoma, lung cancer, corpus luteum tumor, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoid leukemia, lymphoma, macroglobulinemia, malignant fibrosis Histiocytoma, Malignant fibrous histiocytoma, Malignant fibrous histiocytoma of bone, Malignant glioma, Malignant mesothelioma, Malignant peripheral nerve sheath tumor, Malignant rhabdomyosarcoma, Malignant salamander tumor, MALT lymphoma, Mantle cell lymphoma, Mast cell leukemia, Mastocytosis, Mediastinal germ cell tumor, Mediastinal tumor, Medullary thyroid carcinoma, Meningioma, Melanoma, Meningioma, McEllig cell carcinoma, Mesothelioma, Mesothelioma, Metastatic squamous cell carcinoma of the neck with unknown primary site, Metastatic bladder epithelial carcinoma, Müllerian mixed tumor, Monocytic leukemia, Oral cancer, Myxoma, Multiple endocrine neoplasia syndrome, Multiple myeloma, Multiple myeloma, Mycosis fungoides, Mycosis fungoides, Bone Myelodysplastic disorders, myelodysplastic syndromes, myeloid leukemia, myeloid sarcoma, myeloproliferative disorders, myxoma, nasal cavity carcinoma, nasopharyngeal carcinoma, neoplasm, neurocytoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, non-Hodgkin lymphoma, non-melanoma skin cancer, non-small cell lung cancer, eye tumors, oligodendroastrocytoma, oligodendroglioma, eosinophilia, optic nerve sheath meningioma, oral cancer, oral cavity cancer, oropharyngeal cancer, osteosarcoma, osteosarcoma, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, low-grade potential malignant tumor of the ovary, Paget's disease of the breast, superior sulcus tumor of the lung, pancreatic cancer, papillary thyroid carcinoma, papilloma, gangliocytosis. Pine carcinoma, sinus carcinoma, parathyroid carcinoma, penile cancer, perivascular epithelioid cell tumor, nasopharyngeal carcinoma, pheochromocytoma, moderately differentiated pineal parenchymal tumor, pineal cell carcinoma, pituitary cell tumor, pituitary adenoma, pituitary tumor, plasmacytoma, pleural pulmonary blastoma, polyembryoma, precursor T-lymphoblastic lymphoma, primary central nervous system lymphoma, primary exudative lymphoma, primary hepatocellular carcinoma, primary liver cancer, primary peritoneal carcinoma, primitive neuroectodermal tumor, prostate cancer, peritoneal pseudomyxoma, rectal cancer, renal cell carcinoma, respiratory tract cancer involving the NUT gene on chromosome 15, retinoblastoma, rhabdomyosarcoma, rhabdomyosarcoma, Richter transformation, sacrococcygeal teratoma, salivary gland carcinoma, sarcoma, Schwann cell tumor, sebaceous gland carcinomaSecondary tumors, seminomas, serous lesions, Sezery-Leigh cell tumors, sex cord-stromal tumors, Sezery syndrome, signet ring cell carcinoma, skin cancer, small round blue cell tumors, small cell carcinoma, small cell lung cancer, small cell lymphoma, small intestinal cancer, soft tissue sarcoma, somatostatinoma, somnoloma, spinal cord tumors, spinal cord tumors, marginal zone lymphoma of the spleen, squamous cell carcinoma, gastric cancer, superficial extended melanoma, supratentorial primitive neuroectodermal tumors, surface epithelial-stromal tumors, synovial sarcoma, T-cell acute lymphoblastic leukemia, large T-cell tumors Myelocytic lymphocytic leukemia, T-cell leukemia, T-cell lymphoma, T-cell prolymphocytic leukemia, teratoma, late-stage lymphoma, testicular cancer, theca cell tumor, laryngeal cancer, thymic carcinoma, thymoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, transitional cell carcinoma, urachal carcinoma, urethral cancer, urogenital tumors, uterine sarcoma, uveal melanoma, vaginal cancer, Van Murder syndrome, verrucous carcinoma, optic pathway glioma, vulvar cancer, Waldenström macroglobulinemia, Worthian tumor, Wilms tumor, or any combination thereof.

[0240] In some implementations, the method is used to treat diseases selected from the group consisting of: tumor angiogenesis, chronic inflammatory diseases (such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease), skin diseases (such as psoriasis, eczema, and scleroderma), diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma, and ovarian cancer, breast cancer, pancreatic cancer, prostate cancer, colon cancer, and epidermoid carcinoma.

[0241] In other embodiments, the method is used to treat diseases selected from: breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, uterine cancer, or cervical cancer.

[0242] In other embodiments, the method is used to treat diseases selected from: leukemia (such as acute myeloid leukemia (AML), acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia), myelodysplastic syndrome, myelodysplastic disorder, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS), epidermoid carcinoma, or hemoglobinopathies (such as β-thalassemia and sickle cell disease (SCD)).

[0243] In other embodiments, the method is used to treat diseases selected from: CDKN2A-deficient cancer; 9P-deficient cancer; MTAP-deficient cancer; spliceosomal mutant cancer, glioblastoma, NSCLC, head and neck cancer, bladder cancer, or hepatocellular carcinoma.

[0244] In other embodiments, the method is used to treat diseases 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), myelodysplastic syndrome, myelodysplastic disorder, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), mastocytosis, chronic lymphocytic leukemia. Cellular leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS), epidermoid carcinoma, hemoglobinopathies (such as β-thalassemia and sickle cell disease (SCD)), cancers with CDKN2A deletion; cancers with 9P deletion; cancers with MTAP deletion; spliceosomal mutant carcinoma, 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.

[0245] In other embodiments, the method is used to treat diseases selected from: adenoid cystic carcinoma (ACC), primary central nervous system lymphoma, fallopian tube cancer, or non-Hodgkin lymphoma.

[0246] The compounds disclosed herein, and pharmaceutical compositions comprising them, may be administered alone or in combination with medical therapies to treat any of the described diseases. Medical therapies include, for example, surgery and radiation therapy (e.g., gamma radiation, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, whole-body radioisotopes).

[0247] In other respects, the compounds disclosed herein and the pharmaceutical compositions comprising them may be administered alone or in combination with one or more other pharmaceutical agents to treat any of the described diseases.

[0248] In other methods, the compounds of this disclosure and pharmaceutical compositions comprising them may be administered in combination with agonists of nuclear receptor pharmaceutical agents.

[0249] In other methods, the compounds of this disclosure and pharmaceutical compositions comprising them may be administered in combination with antagonists of nuclear receptor agents.

[0250] In other methods, the compounds of this disclosure and pharmaceutical compositions comprising them may be administered in combination with antiproliferative agents.

[0251] In other respects, the compounds disclosed herein, and pharmaceutical compositions comprising them, may 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 abarelix, interleukin, alemtuzumab, alitretinoin, allopurinol, all-trans retinoic acid, hexamethylmelamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bendamustine, bevacizumab, bexarotene, bleomycin, and bortine. Bortezombi, bortezomib, intravenous busulfan, oral busulfan, calusterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukindiftitox, dexrazoxen, docetaxel, doxorubicin, dromostanolonepropionate, eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, fluorouracil, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, ozozumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alpha-2a, irinotecan, lapatinib dimethylbenzenesulfonateditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin, paclitaxel, pamidronate, panitumumab, panobinostat, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, procainamide, procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib, streptozotocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil Mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, zoledronate, and any combination thereof.

[0252] In other respects, other agents are therapeutic agents that target epigenetic regulators. Examples of epigenetic regulators 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 respects and include, for example, vorinostat.

[0253] In other approaches where the disease to be treated is cancer or another proliferative disease, the compounds disclosed herein, and pharmaceutical compositions comprising them, may be administered in combination with targeted therapy agents. Targeted therapies include, for example, JAK kinase inhibitors (e.g., ruxotinib), PI3 kinase inhibitors (including PI3K-δ 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., pabisostat, 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.

[0254] In other methods where the disease to be treated is cancer or another proliferative disease, the compounds of this disclosure and pharmaceutical compositions comprising them may be administered in combination with immune checkpoint inhibitors. 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, and combinations thereof. In some aspects, the anti-PD1 antibody is nivolumab. In some aspects, the anti-PD1 antibody is pembrolizumab. In some aspects, the immune checkpoint inhibitor is an inhibitor of PD-L1, for example, an anti-PD-L1 monoclonal antibody. In some respects, anti-PD-L1 monoclonal antibodies are BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C, or any combination thereof. In some respects, anti-PD-L1 monoclonal antibodies are MPDL3280A or MEDI4736. In other respects, immune checkpoint inhibitors are inhibitors of CTLA-4, such as anti-CTLA-4 antibodies. In some respects, anti-CTLA-4 antibodies are ipilimumab.

[0255] In other methods in which the disease to be treated is cancer or another proliferative disease, the compounds disclosed herein and pharmaceutical compositions comprising them may be administered in combination with alkylating agents (e.g., cyclophosphamide (CY), melphalan (MEL), and bendamustine), proteasome inhibitors (e.g., carfilzomib), corticosteroids (e.g., dexamethasone (DEX)), or immunomodulators (e.g., lenalidomide (LEN) or pomalidomide (POM)), or any combination thereof.

[0256] In some embodiments, the disease to be treated is an autoimmune condition or an inflammatory condition. In these respects, the compounds of this disclosure and pharmaceutical compositions comprising them may be administered in combination with corticosteroids such as, for example, triamcinolone, dexamethasone, fluocinolone, cortisone, prednisolone, or flumetholone, or any combination thereof.

[0257] In other methods where the disease to be treated is an autoimmune condition or an inflammatory condition, the compounds of this disclosure and pharmaceutical compositions comprising them may be administered in combination with immunosuppressants such as, for example, fluocinolone acetonide (RETISERT). TM ), Rimexolone (AL-2178, VEXOL) TM ALCO TM ) or cyclosporine (RESTASIS) TM ), or any combination thereof.

[0258] In some embodiments, the disease to be treated is β-thalassemia or sickle cell disease. In these respects, the compounds of this disclosure and pharmaceutical compositions comprising them may be combined with one or more pharmaceutical agents such as, for example, HYDREA. TM (Hydroxyurea) combined application.

[0259] In some aspects, the present invention relates to methods for preparing pharmaceutically acceptable salts as described herein. In some embodiments, the methods for preparing pharmaceutically acceptable salts are those described in the following examples.

[0260] The examples and preparations provided below further illustrate and demonstrate the compounds of the present invention and methods for preparing such compounds. It should be understood that the scope of the present invention is not limited in any way by the scope of the examples and preparations provided below.

[0261] Experimental procedures

[0262] 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)

[0263]

[0264] Step 1. Synthesis of 2-(2-bromo-5-chloro-phenyl)ethanol (22a)

[0265] Borane in THF (240.49 mL, 240.49 mmol) was added to a solution of 2-(2-bromo5-chlorophenyl)acetic acid (20.0 g, 80.16 mmol) in THF (200 mL), and the mixture was stirred at 40 °C for 8 hours. 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 elution from 5 / 95 to 95 / 5 with CH3CN / H2O (neutral) to give 22b (18.1 g, 76.854 mmol, 95.9% yield) as a colorless oil. LCMS [M-18]: 217.0 / 219.0.

[0266] Step 2. Synthesis of 2-(2-bromo-5-chloro-phenyl)ethoxy-tert-butyl-dimethyl-silane (22b)

[0267] Imidazole (7.85 g, 115.28 mmol) and TBDMSCl (13.9 g, 92.23 mmol) were added to a solution of 22a (18.1 g, 76.85 mmol) in DMF (200 mL), and the mixture was stirred at 25 °C for 8 hours. EA (800 mL) was added, and the mixture was washed with brine (400 mL × 2). The organic layer was concentrated and purified by a rapid column (PE) to give 22b (26.7 g, 76.34 mmol, 99.3% yield) as a colorless oil.

[0268] Step 3. Synthesis of [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-tetrahydrofurano[3,4-d][1,3]dioxacyclopenten-6-yl]methyl ketone (22c)

[0269] n-BuLi (12.8 mL, 20.48 mmol) was added to a solution of 22b (8.91 g, 25.6 mmol) in anhydrous THF (50 mL) at -78 °C, and the mixture was stirred under nitrogen for 10 min. 1Ad (4.0 g, 10.24 mmol) was added to a solution of anhydrous THF (20 mL), and the mixture was stirred at -78 °C for 5 min. TLC (PE:EA = 8:1) showed the reaction was complete. The reactants were poured into dilute HCl (pH 6; pH maintained <8 during quenching). The mixture was extracted with EA (200 mL × 2), the combined organic layers were dried, concentrated, and purified by combi-flash elution from 5 / 95 to 95 / 5 with CH3CN / H2O (neutral) to give 22c (5.1 g, 8.60 mmol, 84% yield) as a yellow solid.

[0270] 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-tetrahydrofurano[3,4-d][1,3]dioxacyclopenten-6-yl]-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-chloro-phenyl]methanol (22d)

[0271] DIBAL-H (16.88 mL, 25.31 mmol) was added to a solution of 22d (5.0 g, 8.44 mmol) in 30 mL of THF at -78 °C, and the mixture was stirred at -78 °C for 30 min. TLC (PE / EA = 8 / 1) showed that the SM Rf = 0.5, indicating complete consumption, with the main product Rf = 0.4. The reactants were poured into dilute HCl (pH 6, 400 mL, pH < 8 during quenching). The mixture was extracted with EA (300 mL × 2), and the combined organic layers were dried and concentrated to give crude 22d (5.0 g) as a yellow solid.

[0272] 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-tetrahydrofurano[3,4-d][1,3]dioxacyclopenten-6-yl]methyl]phenyl]ethanol (22e)

[0273] Tetrabutylammonium fluoride (5.17 mL, 5.17 mmol) was added to a solution of 22d (3.0 g, 5.17 mmol) in THF (50 mL). The mixture was stirred at 25 °C for 40 min. The reaction mixture was poured into an aqueous solution of NH4Cl 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 rapid column chromatography (PE:EA = 15:1 to 3:1) to give 22e (2 g, 4.08 mmol, 79% yield) as a white solid. LCMS [M+H]: 480.1.

[0274] Step 6. Synthesis of 4-chloro-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R)-6-chloroisochroman-1-yl]-3a,4,6,6a-tetrahydrofurano[3,4-d][1,3]dioxacyclopenten-4-yl]pyrrolo[2,3-d]pyrimidine (22f)

[0275] Tributylphosphine (2.1 mL, 8.33 mmol), (NE)-N-isopropoxycarbonyliminocarbamate isopropyl ester (1.72 mL, 8.74 mmol), and pyridine (0.34 mL, 4.16 mmol) were added to a solution of 22e (2.0 g, 4.16 mmol) in THF (100 mL), and the reaction mixture was stirred at 25 °C for 16 hours.

[0276] TLC (PE / EA = 3 / 1, Rf = 0.4) showed that the starting material was consumed. The solvent was removed under vacuum, and the crude product was purified by silica gel column chromatography using petroleum ether / EtOAc (10:1–5:1) as eluent to give 22f (1.7 g, 3.68 mmol, 88% yield) as a yellow oil. LCMS [M+H]: 462.1.

[0277] Step 7. Synthesis of 4-methyl-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R)-6-chloroisochroman-1-yl]-3a,4,6,6a-tetrahydrofurano[3,4-d][1,3]dioxacyclopenten-4-yl]pyrrolo[2,3-d]pyrimidine (22 g)

[0278] Magnesium methyl bromide (3.68 mL, 11.04 mmol) was added dropwise to a solution of ferric acetylacetone (0.13 g, 0.37 mmol) and 22f (1.7 g, 3.68 mmol) in THF (100 mL) at 5 °C under nitrogen atmosphere. The reaction mixture was heated to room temperature and stirred for 1 hour. TLC (EA:PE = 1:1, Rf = 0.3) showed that the reaction was complete. The reaction was quenched by adding saturated NH4Cl dropwise, extracted with EA (200 mL × 2), dried over Na2SO4 and concentrated. The residue was purified by rapid column chromatography (PE:EA = 10:1 to 1:1) to give 22 g (900 mg, 1.93 mmol, 52.6% yield) as a white solid.

[0279] Step 8. Synthesis of (2R,3R,4S,5S)-2-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1R)-6-chloroisocyanuran-1-yl]tetrahydrofuran-3,4-diol (Formula I)

[0280] 22 g (900 mg, 2.04 mmol) was added to a solution of HCl (6.0 mL, 12 mmol) in methanol (10 mL), and the reaction mixture was stirred at 40 °C for 2 hours. The reaction mixture was concentrated, and the residue was stirred with EA (50 mL) and filtered. The solid was purified by preparative HPLC by elution from 5 / 95 to 95 / 5 with CH3CN / H2O (0.1% NH4OH). The product fraction was extracted with EA (100 mL × 2) and the extract was concentrated to produce Formula I (550 mg, 1.34 mmol, 66% yield), a white solid. LCMS [M+H]: 402.3. 1 H NMR(400M Hz, DMSO-d6): δ8.67(s,1H),7.76(d,J=4.0Hz,1H),7.22-7.31(m,3H),6.81(d,J=3 .6Hz,1H),6.31(d,J=7.6Hz,1H),5.26(d,J=7.2Hz,1H),5.13(d,J=4.0Hz,1H),4.9 0(d,J=3.6Hz,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). 1H NMR(400M Hz, DMSO-d6+D2O): δ8.86 (s, 1H), 7.77 (d, J = 4Hz, 1H), 7.22-7.31 (m, 3H), 6.82 (d, J = 3.6Hz, 1H), 6.31 (d, J = 7.6Hz, 1H), 4.90 (d, J = 3.6Hz, 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).

[0281] 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)

[0282] 5.84 g of Formula IA was added to a 250 mL round-bottom flask. 60 mL of deionized water was added and the mixture was stirred for 5 minutes to obtain a suspension (pH 1.6). 2.5 mL of concentrated NH4OH (37%) was slowly added and stirred to obtain a slurry (pH 10). The mixture was stirred for 3 hours until pH 10. The batch was filtered, washed first with 200 mL of water, then with 200 mL of heptane. The product was dried under vacuum (40 °C) on a filter in an oven to give 5.20 g (98.0%) of Formula I. The HPLC purity was 99.7%. Formula I was crystallized by XRPD.

[0283] In some embodiments, the free base of formula I may have the following XRPD peaks (see...) Figure 21 ):

[0284]

[0285] Example 3.

[0286] The solid can be obtained by treating the free base of formula I with phosphoric acid, sulfuric acid, hydrochloric acid, ascorbic acid, L-tartaric acid, ethane-1,2-disulfonic acid and 1-hydroxy-2-naphthoic acid, as well as oxalic acid.

[0287] 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

[0288]

[0289] Add 1.5 mL of dichloromethane (DCM) and 2.0 mL of acetonitrile to 60 mg of free base of formula I (0.150 mmol) and stir the mixture to obtain a clear solution. Add hydrochloric acid (1 M isopropanol solution; 0.165 mL, 0.165 mmol, 1.10 equivalents) and stir the resulting mixture at room temperature for 40 minutes. Remove DCM at 40–45 °C to obtain a slurry. Stir the slurry at 65 °C for 60 minutes, then cool to room temperature and stir for 2 hours. Filter the mixture and wash with methyl tert-butyl ether (MTBE). Dry the filter cake under vacuum overnight at 45–48 °C to obtain 48.0 mg of hydrochloride (formula IA).

[0290] XRPD of hydrochloride in Figure 1 As shown in the image.

[0291] DSC of hydrochloride Figure 2 As shown in the image.

[0292] TGA hydrochloride in Figure 3 The middle shows

[0293] The crystalline hydrochloride formed by this procedure is of formula IA-form I.

[0294] 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

[0295]

[0296] Add 4.0 mL of acetone to 100.3 mg of formula I (0.25 mmol, 1.0 equivalent) and stir for 5 minutes. Add 265 μL of 1.0 M HCl (0.263 mmol, 1.06 equivalent) in IPA. Stir the resulting mixture to obtain a thin slurry, and then stir continuously overnight. Filter the mixture to obtain a solid, which is dried under vacuum at 40 °C overnight to give 98.8 mg (yield 90.0%) of salt (formula IA). The purity of the salt was determined to be 99.2% by HPLC. The crystallinity of the salt was confirmed by XPRD. The HPLC peak area comparison of the salt and free base showed that the ratio of free base to hydrochloric acid was approximately 1:1.

[0297] 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

[0298]

[0299] 3476.2 g of crude PRT1063 (containing 1829.0 g of PRT1063 based on the theoretical yield from the previous step) and 18.3 L of MeOH were charged into a clean and dry RBF. After adding concentrated HCl (1720 mL, 5.0 equivalents) to the reactor, the resulting solution was stirred at 35°C–45°C for approximately 8 hours. 55.0 L of MTBE was added to the reaction, and the resulting slurry was stirred at room temperature for approximately 2 hours. The slurry was cooled to 0°C–5°C and stirred for approximately 1 hour. The slurry was filtered, and the filter cake was transferred back to the RBF. 9.1 L of MTBE was added, and the slurry was stirred at room temperature for 0.5–1 hour. The slurry was filtered, and the filter cake was washed with 3.7 L of MTBE. The filter cake was then dried under vacuum on an NLT funnel for 2 hours.

[0300] Recrystallization of Formula IA: 1500 g of Formula IA and 15 L of MeOH were charged into a clean and dry RBF container. 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 sintered glass funnel. The filtrate was transferred to a clean and dry reactor, and the volume of filtrate in the reactor was recorded. The funnel was washed with 3.0 L of MeOH. This washing MeOH was used to rinse the filtrate receiving flask before adding it to the reactor. The distillation apparatus was attached to the reactor. The filtrate in the reactor was heated to reflux and the distillate was collected. While maintaining distillation in the reactor, 15 L of IPA was gradually added to the reactor at a rate that maintained the initial recorded volume of the solution. After adding IPA, heptane (22.5 L) was gradually added to the reactor while maintaining distillation 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 approximately 2 hours. The batch was filtered, and the filter cake was washed with heptane (4.5 L). The product was dried on an NLT filter for 2 hours by air-pulling the filter cake. The filter cake was transferred to a tray and vacuum-dried in an oven at 50 °C to a constant weight.

[0301] Example 7.

[0302] The polymorphs of Formula IA have been identified as follows. These polymorphs—Form I, Form II, Form IIa, Form III, and Form IV of Formula IA—can be prepared using the methods described below.

[0303] Solubility of hydrochloride at 21±1℃ and 50±1℃

[0304] Add 3 mL of test solvent to a 4 mL vial. Add Formula IA until a turbid solution is obtained at 21 ± 1 °C. Add approximately 30 mg of an additional Formula IA to the turbid solution. Stir the mixture at 21 ± 1 °C for one weekend, during which time the temperature is adjusted from... ETS-D5 temperature controller and RCT basic safety controls were used. 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.

[0305] Add 2 mL of test solvent to a 4 mL vial. Add Formula IA until a turbid solution is obtained at 50 ± 1 °C. Add approximately 30 mg of another Formula IA to the turbid solution. Stir the mixture at 50 ± 1 °C for 24 hours, during which time the temperature is adjusted from... ETS-D5 temperature controller and RCT basic safety controls were used. 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.

[0306] Table 8

[0307]

[0308] Phase equilibrium at 25±1℃ and 50±1℃

[0309] Phase equilibrium studies aim to provide information about the dominant crystal form. Formula IA reaches equilibrium in the solvent at 25±1℃ and 50±1℃. The temperature is determined by... ETSD5 temperature controller and RCT basic security control.

[0310] Add Formula IA crystal form I to approximately 3 mL of solvent until a turbid solution is obtained, then add approximately 20 mg of additional Formula IA crystal form I to the turbid solution. Stir the mixture at 25 ± 1 °C and 50 ± 1 °C for 2.0 days. Filter the solids and analyze by XRPD.

[0311] In these experiments, polymorph II (Formula IA - Crystal II) was obtained from phase equilibrium in ethanol at 25 °C, and polymorph III (Formula IA - Crystal III) was obtained from water at 21 °C (Table 2). Phase equilibrium at 50 ± 1 °C (Table 3) resulted in polymorph III from water and crystal I from other solvents. The results are shown in Table 9.

[0312] Table 9

[0313]

[0314] Evaporation Research

[0315] Evaporation studies were conducted to identify the dominant crystalline form during uncontrolled evaporation. Experiments not resulting in any particulate solids (i.e., transparent films and oils) were not further investigated. XRPD was used to investigate the solid morphology of the crystalline forms of the samples evaporated at 20 °C and 50 °C. In these studies, saturated solutions prepared by formula IA – form I were evaporated. The results are shown in Table 10.

[0316] Table 10

[0317]

[0318] Antisolvent addition experiment

[0319] Saturated or nearly saturated solutions of formula IA were prepared by adding formula IA – form I – to a solvent. Antisolvents were added to induce precipitation. Hexane, heptane, methyl tert-butyl ether (MTBE), toluene, ethyl acetate, acetone, methyl ethyl ketone (MEK), isopropanol (IPA), tetrahydrofuran (THF), acetonitrile, and isopropyl acetate (IPAc) were used as antisolvents. Experiments where no particulate solids were produced upon addition of antisolvents were not further investigated. These results are presented in Table 11 below.

[0320] Table 11

[0321]

[0322]

[0323] Reverse addition experiment

[0324] A saturated or nearly saturated solution of formula IA was prepared in a solvent from form I. This solution was then added to a larger volume of a miscible antisolvent. Hexane, heptane, MTBE, toluene, ethyl acetate, acetone, MEK, IPA, THF, acetonitrile, and IPAc were used as antisolvents. Experiments where no particulate solids were produced upon addition to the antisolvent were not further investigated. These results are presented in Table 12 below.

[0325] Table 12

[0326]

[0327]

[0328] Cooling of saturated solutions

[0329] A saturated or nearly saturated solution of form IA-I in methanol or ethanol was prepared at room temperature and quenched to approximately -40°C. A saturated solution in water was prepared at 35°C and quenched to approximately 5°C. Both experiments aimed to induce precipitation of the higher energy form. The results of these experiments are shown in Table 13 below.

[0330] Table 13

[0331] Solvent (mL) The obtained polymorphic form MeOH not applicable EtOH II water III

[0332] Competitive slurry experiment

[0333] To evaluate the conversion of the solid form of Formula IA, a competitive slurry experiment was performed as follows. Formula IA was added to a solvent mixture until a saturated solution was formed. Then, in addition to 8 mg each of Formula IA-form IIa, Formula IA-form III, and Formula IA-form IV, 8 mg of Formula IA-form I was 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.

[0334] Table 14

[0335]

[0336] Representative synthesis procedure

[0337] Form IA - Form II

[0338] Approximately 50 mg of the drug substance was added to approximately 3 mL of the drug substance prepared in ethanol, followed by stirring at 25°C ± 1°C for 2 days. The mixture was then filtered, air-dried in a fume hood for 24 hours, and analyzed by XRPD to be of formula IA – form II. See also... Figure 4 , Figure 5

[0339] A saturated solution of 3.0 mL in ethanol was quenched and cooled to -20 °C, and held at this temperature for 30 minutes to obtain a slurry. This slurry was filtered and air-dried. The solid was analyzed by XRPD and designated as Formula IA – Form II.

[0340] Form IA - Form IIa

[0341] Formula IA-Form IIa is formed by vacuum drying Formula IA-Form II at 48-50°C for 24 hours.

[0342] Form IA - Form III

[0343] Approximately 50 mg of the drug substance was added to approximately 3 mL of the drug substance prepared in water, followed by stirring at 25°C ± 1°C for 2 days. The mixture was then filtered, air-dried in a fume hood for 24 hours, and analyzed by XRPD to be of formula IA-form III. See also Figure 8 , Figure 10 .

[0344] A 3.0 mL saturated solution in water was quenched and cooled to 2-3 °C, and held at this temperature for 1.0 hour to obtain a slurry. This slurry was filtered and air-dried. The solid was analyzed by XRPD and designated as Formula IA - Form III. See also Figure 9 .

[0345] Form IA - Form IV

[0346] Add 0.6 mL of a solution of the drug substance prepared in MeOH (50 mg / mL) to 2.5 mL of ethyl acetate, then stir for approximately 5 minutes. Filter the solid and analyze by XRPD to obtain formula IA-form IV. See also Figure 12 and Figure 13 .

[0347] Add 1.5 mL of ethyl acetate to 0.6 mL of a solution of the drug substance prepared in MeOH (50 mg / mL), and stir for about 5 minutes. Filter the solid and analyze it by XRPD to obtain form IA-IV.

[0348] Example 8. Synthesis of the phosphate 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)

[0349] Add 1.5 mL of isopropanol (IPA) and 1.0 mL of dichloromethane (DCM) to 50 mg of free base of formula I (0.125 mmol) and stir to obtain a clear solution. Add phosphoric acid (1 M solution in IPA; 0.15 mL, 0.15 mmol, 1.20 equivalents) and stir the resulting mixture at room temperature for 40 minutes. Remove DCM at 40 °C to obtain a slurry. Stir the slurry at 65 °C for 60 minutes, then cool to room temperature and stir for 2 hours. Filter the mixture and wash with methyl tert-butyl ether (MTBE). Dry the filter cake under vacuum overnight at 45 °C–48 °C to obtain phosphate (formula IB).

[0350] The XRPD of this phosphate in Figure 14B As shown in the image.

[0351] The DSC of this phosphate was... Figure 15B As shown in the image.

[0352] The TGA of this phosphate Figure 16B As shown in the image.

[0353] Example 9. Synthesis of the phosphate (Formula IB) 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

[0354] Add 4.0 mL of EtOH to 100.6 mg of free base of formula I (0.25 mmol, 1.0 equivalent). Stir the resulting mixture for 5 minutes. Add 263 μL of 1.0 M H3PO4 (0.263 mmol, 1.06 equivalent) in IPA. Continue stirring the resulting mixture overnight, then filter to obtain a solid. Dry the filter cake under vacuum at 40 °C overnight to obtain 86.7 mg (69.3%) of salt. The purity of the salt was determined to be 98.5% by HPLC. The HPLC peak area comparison of the salt and free base indicated that the ratio of free base to phosphoric acid was approximately 2:1.

[0355] The XRPD of this phosphate in Figure 14A As shown in the image.

[0356] The DSC of this phosphate was... Figure 15A As shown in the image.

[0357] The TGA of this phosphate Figure 16A As shown in the image.

[0358] Example 10. Synthesis of tartrate (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

[0359] Add 100.2 mg (0.25 mmol, 1.0 equivalent) of Formula I to 40.5 mg L=L-tartaric acid (0.263 mmol, 1.05 equivalent). Add 4.0 mL of 2-butanone and stir the resulting mixture continuously overnight. Filter the mixture to obtain a solid, which is washed with 2.5 mL of MTBE. Dry the filter cake under vacuum at 40 °C overnight to give 68.8 mg (50.0% yield) of tartrate.

[0360] The stoichiometric ratio of the salts of Formula I and tartaric acid is determined by their... 1 H NMR spectroscopy ( Figure 20 The ratio was determined to be 2:1 (at 400MHz in DMSO-d6).

[0361] The XRPD of the tartrate in Figure 17 As shown in the image.

[0362] The DSC of this tartrate was... Figure 18 As shown in the image.

[0363] The tartrate TGA in Figure 19 As shown in the image.

[0364] Tartrate 1 H NMR spectroscopy in Figure 20 As shown in the image.

[0365] Instrumental Methods

[0366] X-ray powder diffraction (XRPD)

[0367] XRPD patterns can also be collected using the Rigaku MiniFlex X-ray powder diffractometer (XRPD) instrument. The X-ray radiation originates from K... β Filter Copper (Cu). X-ray power: 30KV, 15mA.

[0368] Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC)

[0369] TGA can be collected using a TGA Q500 instrument via TA at a scan rate of 20°C per minute.

[0370] Alternatively, a TA Instrument Differential Scanning Calorimeter (Q20 model, with autosampler) can be used to obtain DSC using a scan rate of 10℃ / min and a nitrogen flow rate of 50mL / min.

[0371] Biochemical assay protocol

[0372] The compound was solubilized and diluted 3-fold in 100% DMSO. These diluted compounds were then further diluted in assay buffer (20 mM Tris-HCl, pH 8.0, 50 mM NaCl, 0.002% Tween 20, 1 mM TCEP, 1% DMSO) for 10-dose IC50 assays. 50The assay was performed at a concentration 10 times higher than the desired assay concentration. A standard reaction was performed in a total volume of 30 μL in assay buffer using 300 nM histone H4-based AcH4-23 (Anaspec: AS-65002) as the substrate. The PRMT5 / MEP50 complex, diluted to provide a final assay concentration of 2.5 nM, was added, and the compound was pre-incubated at 37 °C for 20 min. 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 min, the reaction was terminated by adding 25 μL of 8 M guanidine hydrochloride. 0.3 mg / mL streptavidin YSI SPA beads (PerkinElmer: RPNQ0012) were prepared in assay buffer. 150 μL of the SPA bead suspension was added to each reaction, and the mixture was incubated with shaking at room temperature for 30 min. Centrifuge the board at 100×g for 30 seconds before taking the reading on the flash counter. IC 50 The values ​​were determined by fitting the data to four standard parameters using the Hill slope with GraphPad Prism software. See Table 15 below (PRMT5 IC). 50 ).

[0373] Cell assay protocol

[0374] Cell processing and Western blotting for detecting symmetric dimethylarginine (sDMA) labeling

[0375] Compound titration and cell culture: The compound was dissolved in DMSO to prepare a 10 mM stock solution, and further serially diluted 3-fold to prepare a working stock solution up to 1 mM. Granta-519 cells were maintained in PRMI 1640 (Corning Cellgro, catalog number: 10-040-CV) supplemented with 10% v / v FBS (GE Healthcare, catalog number: SH30910.03), and U-87 MG cells were maintained in DMEM (Corning Cellgro, catalog number: 10-013-CV) containing 10% FBS and 2 mM glutamine (Corning Cellgro, catalog number: 25005CV).

[0376] Western blot analysis was used to determine the enzyme inhibition IC50 in Granta-519 and U-87 MG cells. 50 Value. The day before the experiment, Granta-519 cells were passaged to 0.5 × 10⁻⁶ cells. 6 U-87 MG cells were digested with trypsin and then subjected to a density of 4 × 10⁻⁶ cells / mL. 5One cell line was seeded into 6-well plates and allowed to grow overnight. The next day, Granta-519 cells were centrifuged at 1,500 rpm for 4 minutes and cultured at 0.5 × 10⁻⁶ cells per well. 6 Cells / ml were resuspended in fresh culture medium, and 3 mL of culture (1.5 × 10⁻⁶ cells / ml) was added. 6 Cells were seeded into 6-well plates. Eight-point, 3-fold serially diluted working stock solutions of the compound were added to the cells (3 mL, 1:1,000 dilution, 0.1% DMSO; final maximum concentration 1 μM) and incubated for 3 days. Cells incubated with DMSO were used as a mediator control.

[0377] Cells were harvested after 3 days, resuspended in 15 mL PBS, lysed in 4% SDS, and homogenized using a homogenizer column (Omega Biotek, catalog number: HCR003). Total protein concentration was determined by BCA assay (Thermo Fisher Scientific, catalog number: 23225). The lysate was mixed with 5x Laemmli buffer and boiled for 5 minutes. Forty mg of total protein was separated on an SDS-PAGE gel (Bio-Rad, catalog number: 4568083, 4568043), transferred to a PVDF membrane, blocked at room temperature (RT) with 5% dry emulsion (Bio-Rad, catalog number: 1706404) in TBS (TBST) containing 0.1% v / v Tween 20, and incubated overnight at 4°C with primary antibodies (sDMA: cell signaling, catalog number: 13222, 1:3,000; β-actin: sigma, catalog number: 1:5,000) in 5% dry emulsion in TBST. The next day, the membrane was washed with TBST for 5 × 5 minutes and incubated with HRP-conjugated secondary antibody (GE Healthcare; catalog numbers: NA934-1ML, NA931-1ML; 1:5,000) at room temperature for 2 hours, followed by washing with TBST for 5 × 5 minutes and incubating with ECL substrate (Bio-Rad, catalog numbers: 1705061, 1705062). Chemiluminescence signals were captured using a Fluochem HD2 imager (Proteinsimple). SmD3me2s bands were quantified using ImageJ. The signal was normalized relative to β-actin and DMSO controls. IC50 was calculated using Graphpad Prism. 50 Values ​​([inhibitor] to normalized response - variable slope). See Table 15 below (sDMA IC) 50 ).

[0378] Determining IC50 in Granta-519 and U-87 MG cells 50 Cell proliferation assay

[0379] The day before the experiment, Granta-519 cells were passaged to 0.5 × 10⁻⁶ cells. 6 U-87 MG cells were digested with trypsin, and 2,000 cells were seeded into 96-well plates and allowed to grow overnight. On day 0 of the experiment, Granta-519 cells were centrifuged at 1,500 rpm for 4 minutes and resuspended in fresh medium to a density of 0.5 × 10⁻⁶ cells / ml. 6 Cells / ml, and 190 mL of cells were added to 96-well plates. For U-87 MG cells, the old medium was removed and replaced with 190 μL of fresh medium. The working stock solution of the compound was first diluted 1:50 in fresh medium in 96-well plates, and 10 μL of the diluted drug was added to the 96-well plates containing cells and incubated for 3 days. DMSO was used as a mediator control.

[0380] On day 3, 50 μL of Granta-519 cells were transferred to new 96-well plates and 140 μL of fresh medium was added. For U-87 MG cells, the old medium was removed and replaced with 190 μL of fresh medium. The working stock solution of the compound was freshly diluted 1:50 with medium, and 10 μL of the diluted drug was added to the cells and allowed to regrow for 3 days. The same procedure was repeated on day 6. Cells were allowed to regrow for 4 days.

[0381] On day 10, 100 mL of Granta-519 cells were transferred to a new 96-well plate, and 10 μL of CellCounting Kit-8 (CCK-8, Jojindo, CK04-13) solution was added. For U-87 MG cells, the old medium was removed and replaced with 100 mL of fresh medium, and 10 mL of CCK-8 solution was added. The plates were incubated in a CO2 incubator for 2 hours (Granta-519 cells) or 30 minutes (U-87 MG cells), and OD was measured using a microplate reader (iMark microplate reader, Bio-Rad). 450 Values ​​were calculated. The percentage of viable cells relative to the DMSO-mediated control was plotted in Graphpad Prism ([inhibitor] versus normalized response - variable slope) to determine the proliferation IC50 at day 10. 50 Values. See Table 15 below (Crypto-proliferation IC50 value). 50 ).

[0382] Table 15. Biochemistry and cell potency in the U-87 MG cell line [Granta-519 cell line].

[0383]

[0384] In some implementations, this disclosure relates to the following aspects:

[0385] Aspect 1. A pharmaceutically acceptable salt of a compound of formula I:

[0386]

[0387] Aspect 2. The pharmaceutically acceptable salt according to aspect 1, wherein the salt is a hydrochloride salt of formula IA.

[0388] Aspect 3. A crystalline form of the hydrochloride salt according to aspect 2.

[0389] Aspect 4. The crystalline form according to aspect 3, wherein the crystalline form is of formula IA-form I.

[0390] Aspect 5. The crystalline form according to aspect 3 or aspect 4, characterized in that it is substantially as described in aspect 3 or 4. Figure 1 The X-ray powder diffraction pattern shown is shown.

[0391] Aspect 6. The crystalline form according to any one of Aspects 3, 4 or 5, characterized by an X-ray powder diffraction pattern comprising a peak at 23.8 degrees ± 0.2 degrees 2-θ on a 2-θ scale of λ = 1.54 Å (Cu Kα).

[0392] Aspect 7. The crystalline form according to any one of Aspects 3-6, characterized by an X-ray powder diffraction pattern comprising peaks at 21.2 and 23.8 degrees ± 0.2 degrees 2-θ on a 2-θ scale of λ = 1.54 Å (Cu Kα).

[0393] Aspect 8. The crystalline form according to any one of Aspects 3-7, characterized by an X-ray powder diffraction pattern comprising peaks at 21.2, 23.8, 27.0 and 32.5 degrees ± 0.2 degrees 2-θ on a 2-θ scale of λ = 1.54 Å (Cu Kα).

[0394] Aspect 9. The crystalline form according to any one of Aspects 3-8, characterized in that it substantially reacts with heating at a rate of 10°C / min. Figure 2 The differential scanning calorimetry (DSC) thermogram shown is shown.

[0395] Aspect 10. The crystalline form according to any one of Aspects 3-9, 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.

[0396] Aspect 11. The crystalline form according to any one of Aspects 3-10, characterized in that it substantially reacts when heated at a rate of 20°C / min. Figure 3 The thermogravimetric analysis curves are shown.

[0397] Aspect 12. The crystalline form according to aspect 3, wherein the crystalline form is of formula IA - form II.

[0398] Aspect 13. The crystalline form according to aspect 3 or aspect 12, characterized in that it is substantially as described in aspect 3. Figure 4 The X-ray powder diffraction pattern shown is shown.

[0399] Aspect 14. The crystalline form according to any one of Aspects 3, 12 or 13, characterized by an X-ray powder diffraction pattern comprising a peak at 25.5 degrees ± 0.2 degrees 2-θ on a 2-θ scale of λ = 1.54 Å (Cu Kα).

[0400] Aspect 15. The crystalline form according to any one of Aspect 3 or 12-14, characterized by an X-ray powder diffraction pattern comprising peaks at 14.8, 17.5 and 25.5 degrees ± 0.2 degrees 2-θ on a 2-θ scale of λ = 1.54 Å (Cu Kα).

[0401] Aspect 16. The crystalline form according to any one of Aspect 3 or 12-15, characterized by an X-ray powder diffraction pattern comprising peaks at 14.8, 17.5, 18.4, 24.0, 25.5, 28.0 and 28.7 degrees ± 0.2 degrees 2-θ on a 2-θ scale of λ = 1.54 Å (Cu Kα).

[0402] Aspect 17. The crystalline form according to any one of Aspect 3 or 12-16, characterized in that it substantially reacts with the following reaction when heated at a rate of 20°C / min: Figure 5 The thermogravimetric analysis curves are shown.

[0403] Aspect 18. The crystalline form according to aspect 3, wherein the crystalline form is of formula IA-form IIa.

[0404] Aspect 19. The crystalline form according to aspect 3 or aspect 18, characterized in that it is substantially as follows Figure 6 The X-ray powder diffraction pattern shown is shown.

[0405] Aspect 20. The crystalline form according to any one of Aspects 3, 18 or 19, characterized by an X-ray powder diffraction pattern comprising a peak at 26.1 degrees ± 0.2 degrees 2-θ on a 2-θ scale of λ = 1.54 Å (Cu Kα).

[0406] Aspect 21. The crystalline form according to any one of Aspect 3 or 18-20, characterized by an X-ray powder diffraction pattern comprising peaks at 14.0, 14.9 and 26.1 degrees ± 0.2 degrees 2-θ on a 2-θ scale of λ = 1.54 Å (Cu Kα).

[0407] Aspect 22. The crystalline form according to any one of Aspect 3 or 18-21, characterized by an X-ray powder diffraction pattern comprising peaks at 12.5, 14.0, 14.9, 18.4 and 26.1 degrees ± 0.2 degrees 2-θ on a 2-θ scale of λ = 1.54 Å (Cu Kα).

[0408] Aspect 23. The crystalline form according to any one of Aspect 3 or 18-22, characterized in that it substantially reacts with the following reaction when heated at a rate of 10°C / min: Figure 7 The differential scanning calorimetry (DSC) thermogram shown is shown.

[0409] Aspect 24. The crystalline form according to any one of Aspect 3 or 18-23, characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at about 199°C when heated at a rate of 10°C / min.

[0410] Aspect 25. The crystalline form according to aspect 3, wherein the crystalline form is of formula IA-form III.

[0411] Aspect 26. The crystalline form according to aspect 3 or aspect 25, characterized in that it is substantially as described in aspect 3 or aspect 25. Figure 8 The X-ray powder diffraction pattern shown is shown.

[0412] Aspect 27. The crystalline form according to any one of Aspects 3, 25 or 26, characterized by an X-ray powder diffraction pattern comprising a peak at 8.1 degrees ± 0.2 degrees 2-θ on a 2-θ scale of λ = 1.54 Å (Cu Kα).

[0413] Aspect 28. The crystalline form according to any one of Aspect 3 or 25-27, characterized by an X-ray powder diffraction pattern comprising peaks at 8.1 and 23.3 degrees ± 0.2 degrees 2-θ on a 2-θ scale of λ = 1.54 Å (Cu Kα).

[0414] Aspect 29. The crystalline form according to any one of Aspect 3 or 25-28, characterized by an X-ray powder diffraction pattern comprising peaks at 8.1, 12.5, 13.7, 14.5, 16.2, 18.8, 23.3 and 24.5 degrees ± 0.2 degrees 2-θ on a 2-θ scale of λ = 1.54 Å (Cu Kα).

[0415] Aspect 30. The crystalline form according to any one of Aspect 3 or 25-29, characterized in that it substantially reacts with the following reaction when heated at a rate of 10°C / min: Figure 9 The differential scanning calorimetry (DSC) thermogram shown is shown.

[0416] Aspect 31. The crystalline form according to any one of Aspect 3 or 25-30, characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at about 121°C when heated at a rate of 10°C / min.

[0417] Aspect 32. The crystalline form according to any one of Aspects 3, 25-31, characterized in that it substantially reacts with the following reaction when heated at a rate of 20°C / min: Figure 10 The thermogravimetric analysis curves are shown.

[0418] Aspect 33. The crystalline form according to aspect 3, wherein the crystalline form is of formula IA-form IV.

[0419] Aspect 34. The crystalline form according to aspect 3 or aspect 33, characterized in that it is substantially as described in aspect 3. Figure 11 The X-ray powder diffraction pattern shown is shown.

[0420] Aspect 35. The crystalline form according to any one of Aspects 3, 33 or 34, characterized by an X-ray powder diffraction pattern comprising a peak at 4.0 degrees ± 0.2 degrees 2-θ on a 2-θ scale of λ = 1.54 Å (Cu Kα).

[0421] Aspect 36. The crystalline form according to any one of Aspect 3 or 33-35, characterized by an X-ray powder diffraction pattern comprising peaks at 4.0 and 22.7 degrees ± 0.2 degrees 2-θ on a 2-θ scale of λ = 1.54 Å (Cu Kα).

[0422] Aspect 37. The crystalline form according to any one of Aspect 3 or 33-36, characterized by an X-ray powder diffraction pattern comprising peaks at 4.0, 22.7 and 27.8 degrees ± 0.2 degrees 2-θ on a 2-θ scale of λ = 1.54 Å (Cu Kα).

[0423] Aspect 38. The crystalline form according to any one of Aspect 3 or 33-37, characterized in that it substantially reacts with the following reaction when heated at a rate of 10°C / min: Figure 12 The differential scanning calorimetry (DSC) thermogram shown is shown.

[0424] Aspect 39. The crystalline form according to any one of Aspect 3 or 33-38, characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at about 169°C when heated at a rate of 10°C / min.

[0425] Aspect 40. The crystalline form according to any one of Aspects 3, 33-39, characterized in that it substantially reacts with the following reaction when heated at a rate of 20°C / min: Figure 13 The thermogravimetric analysis curves are shown.

[0426] Aspect 41. The pharmaceutically acceptable salt according to aspect 1, wherein the salt is a phosphate of formula IB.

[0427] Aspect 42. A crystalline form of the phosphate according to aspect 41.

[0428] Aspect 43. The crystalline form according to aspect 42, wherein the crystal is of form IB-form I.

[0429] Aspect 44. The crystalline form according to aspect 42 or aspect 43, characterized in that it is substantially as described in aspect 42 or aspect 43. Figure 14A The X-ray powder diffraction pattern shown is shown.

[0430] Aspect 45. The crystalline form according to any one of Aspects 42-44, characterized by an X-ray powder diffraction pattern comprising a peak at 24.9 degrees ± 0.2 degrees 2-θ on a 2-θ scale of λ = 1.54 Å (Cu Kα).

[0431] Aspect 46. The crystalline form according to any one of Aspects 42-45, characterized by an X-ray powder diffraction pattern comprising peaks at 18.2, 19.6, and 24.9 degrees ± 0.2 degrees 2-θ on a 2-θ scale of λ = 1.54 Å (Cu Kα).

[0432] Aspect 47. The crystalline form according to any one of Aspects 42-46, characterized by an X-ray powder diffraction pattern comprising peaks at 18.2, 19.6, 24.9, 25.7 and 27.0 degrees ± 0.2 degrees 2-θ on a 2-θ scale of λ = 1.54 Å (Cu Kα).

[0433] Aspect 48. The crystalline form according to any one of aspects 42-47, characterized in that it substantially reacts when heated at a rate of 10°C / min. Figure 15A The differential scanning calorimetry (DSC) thermogram shown is shown.

[0434] Aspect 49. The crystalline form according to any one of Aspects 42-48, 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.

[0435] Aspect 50. The crystalline form according to any one of Aspects 42-49, characterized in that it substantially reacts with the following reaction when heated at a rate of 20°C / min: Figure 16A The thermogravimetric analysis curves are shown.

[0436] Aspect 51. The crystalline form according to aspect 42, wherein the crystalline form is of form IB-II.

[0437] Aspect 52. The crystalline form according to aspect 42 or aspect 51, characterized in that it is substantially as described in aspect 42 or aspect 51. Figure 14B The X-ray powder diffraction pattern shown is shown.

[0438] Aspect 53. The crystalline form according to any one of Aspects 42 or 51-52, characterized by an X-ray powder diffraction pattern comprising a peak at 24.6 degrees ± 0.2 degrees 2-θ on a 2-θ scale of λ = 1.54 Å (Cu Kα).

[0439] Aspect 54. The crystalline form according to any one of Aspects 42 or 51-53, characterized by an X-ray powder diffraction pattern comprising peaks at 19.3, 24.6 and 27.4 degrees ± 0.2 degrees 2-θ on a 2-θ scale of λ = 1.54 Å (Cu Kα).

[0440] Aspect 55. The crystalline form according to any one of Aspects 42 or 51-54, characterized by an X-ray powder diffraction pattern comprising peaks at 19.3, 22.3, 23.6, 24.6 and 27.4 degrees ± 0.2 degrees 2-θ on a 2-θ scale of λ = 1.54 Å (Cu Kα).

[0441] Aspect 56. The crystalline form according to any one of Aspect 42 or 51-55, characterized in that it substantially reacts with the following reaction when heated at a rate of 10 °C / min: Figure 15B The differential scanning calorimetry (DSC) thermogram shown is shown.

[0442] Aspect 57. The crystalline form according to any one of Aspect 42 or 51-56, characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at about 229°C when heated at a rate of 10°C / min.

[0443] Aspect 58. The crystalline form according to any one of Aspect 42 or 51-57, characterized in that it substantially reacts with the following reaction when heated at a rate of 20°C / min: Figure 16B The thermogravimetric analysis curves are shown.

[0444] Aspect 59. The pharmaceutically acceptable salt according to aspect 1, wherein the salt is a tartrate salt of formula IC.

[0445] Aspect 60. The crystalline form according to aspect 59, wherein the tartrate is crystalline.

[0446] Aspect 61. The crystalline form according to aspect 59 or aspect 60, characterized in that it is substantially as described in aspect 60. Figure 17 The X-ray powder diffraction pattern shown is shown.

[0447] Aspect 62. The crystalline form according to any one of Aspects 59-61, characterized by an X-ray powder diffraction pattern comprising a peak at 18.4 degrees ± 0.2 degrees 2-θ on a 2-θ scale of λ = 1.54 Å (Cu Kα).

[0448] Aspect 63. The crystalline form according to any one of Aspects 59-62, characterized by an X-ray powder diffraction pattern comprising peaks at 18.4, 19.9 and 21.5 degrees ± 0.2 degrees 2-θ on a 2-θ scale of λ = 1.54 Å (Cu Kα).

[0449] Aspect 64. The crystalline form according to any one of Aspects 59-63, characterized by an X-ray powder diffraction pattern comprising peaks at 18.4, 19.4, 19.9, 21.5 and 26.3 degrees ± 0.2 degrees 2-θ on a 2-θ scale of λ = 1.54 Å (Cu Kα).

[0450] Aspect 65. The crystalline form according to any one of aspects 59-64, characterized in that it substantially reacts when heated at a rate of 10°C / min. Figure 18 The differential scanning calorimetry (DSC) thermogram shown is shown.

[0451] Aspect 66. The crystalline form according to any one of Aspects 59-65, characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at about 190°C when heated at a rate of 10°C / min.

[0452] Aspect 67. The crystalline form according to any one of aspects 59-66, characterized in that it substantially reacts when heated at a rate of 20°C / min. Figure 19 The thermogravimetric analysis curves are shown.

[0453] Aspect 68. A pharmaceutical composition comprising a pharmaceutically acceptable salt and / or crystalline form according to any one of Aspects 1-67 and a pharmaceutically acceptable excipient.

[0454] 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 1-67.

[0455] 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, myelodysplastic syndrome, myelodysplastic disorder, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS), epidermoid carcinoma, hemoglobinopathies such as β-thalassemia and sickle cell disease (SCD), CDKN2A-deficient cancer; 9P-deficient cancer; MTAP-deficient cancer; spliceosomal mutant cancer, glioblastoma, NSCLC, head and neck cancer, bladder cancer, or hepatocellular carcinoma.

Claims

1. A pharmaceutically acceptable salt of a compound, wherein the salt is a hydrochloride salt represented by formula IA. The hydrochloride thereon is a crystalline form of formula IA-form I, characterized in that... X-ray powder diffraction patterns using Cu Kα radiation, including peaks at 21.2, 23.8, 27.0, and 32.5 degrees ± 0.2 degrees 2-θ on a 2-θ scale of λ = 1.54 Å.

2. The pharmaceutically acceptable salt according to claim 1, wherein the crystalline form is characterized by the X-ray powder diffraction pattern shown in FIG1.

3. The pharmaceutically acceptable salt according to claim 1 or 2, wherein the crystalline form is characterized by the differential scanning calorimetry (DSC) thermogram shown in Figure 2 when heated at a rate of 10 °C / min.

4. The pharmaceutically acceptable salt according to claim 1 or 2, wherein the crystalline form is characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at 244 °C ± 10% when heated at a rate of 10 °C / min.

5. The pharmaceutically acceptable salt according to claim 1 or 2, wherein the crystalline form is characterized by the thermogravimetric analysis curve shown in Figure 3 when heated at a rate of 20°C / min.

6. The pharmaceutically acceptable salt according to claim 1, wherein the hydrochloride is the crystalline form of formula IA-form II, characterized in that... X-ray powder diffraction patterns using Cu Kα radiation, including peaks at 14.8, 17.5, 18.4, 24.0, 25.5, 28.0, and 28.7 degrees ± 0.2 degrees 2-θ on a 2-θ scale of λ = 1.54 Å.

7. The pharmaceutically acceptable salt according to claim 6, wherein the crystalline form is characterized by the X-ray powder diffraction pattern shown in FIG4.

8. The pharmaceutically acceptable salt according to claim 6 or 7, wherein the crystalline form is characterized by the thermogravimetric analysis curve shown in Figure 5 when heated at a rate of 20°C / min.

9. The pharmaceutically acceptable salt according to claim 1, wherein the hydrochloride is the crystalline form of formula IA-form IIa, characterized in that... X-ray powder diffraction patterns using Cu Kα radiation, including peaks at 12.5, 14.0, 14.9, 18.4, and 26.1 degrees ± 0.2 degrees 2-θ on a 2-θ scale of λ = 1.54 Å.

10. The pharmaceutically acceptable salt according to claim 9, wherein the crystalline form is characterized by the X-ray powder diffraction pattern shown in FIG6.

11. The pharmaceutically acceptable salt according to claim 9 or 10, wherein the crystalline form is characterized by a differential scanning calorimetry (DSC) thermogram as shown in FIG7 when heated at a rate of 10 °C / min.

12. The pharmaceutically acceptable salt according to claim 9 or 10, wherein the crystalline form is characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at 199°C ± 10% when heated at a rate of 10°C / min.

13. The pharmaceutically acceptable salt according to claim 1, wherein the hydrochloride is the crystalline form of formula IA-form III, characterized in that... X-ray powder diffraction patterns using Cu Kα radiation, including peaks at 8.1, 12.5, 13.7, 14.5, 16.2, 18.8, 23.3, and 24.5 degrees ± 0.2 degrees 2-θ on a 2-θ scale of λ = 1.54 Å.

14. The pharmaceutically acceptable salt according to claim 13, wherein the crystalline form is characterized by the X-ray powder diffraction pattern shown in FIG8.

15. The pharmaceutically acceptable salt according to claim 13 or 14, wherein the crystalline form is characterized by a differential scanning calorimetry (DSC) thermogram as shown in FIG9 when heated at a rate of 10 °C / min.

16. The pharmaceutically acceptable salt according to claim 13 or 14, wherein the crystalline form is characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at 121°C ± 10% when heated at a rate of 10°C / min.

17. The pharmaceutically acceptable salt according to claim 13 or 14, wherein the crystalline form is characterized by the thermogravimetric analysis curve shown in Figure 10 when heated at a rate of 20°C / min.

18. The pharmaceutically acceptable salt according to claim 1, wherein the hydrochloride is the crystalline form of formula IA-form IV, characterized in that... X-ray powder diffraction patterns using Cu Kα radiation, including peaks at 4.0, 22.7, and 27.8 degrees ± 0.2 degrees 2-θ on a 2-θ scale of λ = 1.54 Å.

19. The pharmaceutically acceptable salt according to claim 18, wherein the crystalline form is characterized by the X-ray powder diffraction pattern shown in FIG11.

20. The pharmaceutically acceptable salt according to claim 18 or 19, wherein the crystalline form is characterized by a differential scanning calorimetry (DSC) thermogram as shown in Figure 12 when heated at a rate of 10 °C / min.

21. The pharmaceutically acceptable salt according to claim 18 or 19, wherein the crystalline form is characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at 169 °C ± 10% when heated at a rate of 10 °C / min.

22. The pharmaceutically acceptable salt according to claim 18 or 19, wherein the crystalline form is characterized by the thermogravimetric analysis curve shown in Figure 13 when heated at a rate of 20°C / min.

23. The pharmaceutically acceptable salt according to claim 1, wherein the salt is a phosphate of formula I.

24. A pharmaceutically acceptable salt according to claim 23, wherein the phosphate is in crystalline form, characterized in that... X-ray powder diffraction patterns using Cu Kα radiation, including peaks at 18.2, 19.6, 24.9, 25.7, and 27.0 degrees ± 0.2 degrees 2-θ on a 2-θ scale of λ = 1.54 Å.

25. The pharmaceutically acceptable salt according to claim 24, wherein the crystalline form is characterized by the X-ray powder diffraction pattern shown in FIG14A.

26. The pharmaceutically acceptable salt according to claim 23 or 24, wherein the crystalline form is characterized by a differential scanning calorimetry (DSC) thermogram as shown in FIG15A when heated at a rate of 10 °C / min.

27. The pharmaceutically acceptable salt according to claim 23 or 24, wherein the crystalline form is characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at 201 °C ± 10% when heated at a rate of 10 °C / min.

28. The pharmaceutically acceptable salt according to claim 23 or 24, wherein the crystalline form is characterized by the thermogravimetric analysis curve shown in Figure 16A when heated at a rate of 20°C / min.

29. The pharmaceutically acceptable salt according to claim 23, wherein the phosphate is in crystalline form, characterized in that... X-ray powder diffraction patterns using Cu Kα radiation, including peaks at 19.3, 22.3, 23.6, 24.6, and 27.4 degrees ± 0.2 degrees 2-θ on a 2-θ scale of λ = 1.54 Å.

30. The pharmaceutically acceptable salt according to claim 29, wherein the crystalline form is characterized by the X-ray powder diffraction pattern shown in FIG14B.

31. The pharmaceutically acceptable salt according to claim 29 or 30, wherein the crystalline form is characterized by a differential scanning calorimetry (DSC) thermogram as shown in FIG15B when heated at a rate of 10 °C / min.

32. The pharmaceutically acceptable salt according to claim 29 or 30, wherein the crystalline form is characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at 229 °C ± 10% when heated at a rate of 10 °C / min.

33. The pharmaceutically acceptable salt according to claim 29 or 30, wherein the crystalline form is characterized by the thermogravimetric analysis curve shown in Figure 16B when heated at a rate of 20°C / min.

34. The pharmaceutically acceptable salt according to claim 1, wherein the salt is a tartrate salt of formula I.

35. The pharmaceutically acceptable salt according to claim 34, wherein the tartrate is in crystalline form, characterized in that... X-ray powder diffraction patterns using Cu Kα radiation, including peaks at 18.4, 19.4, 19.9, 21.5, and 26.3 degrees ± 0.2 degrees 2-θ on a 2-θ scale of λ = 1.54 Å.

36. The pharmaceutically acceptable salt according to claim 35, wherein the crystalline form is characterized by the X-ray powder diffraction pattern shown in FIG17.

37. The pharmaceutically acceptable salt according to claim 34 or 35, wherein the crystalline form is characterized by a differential scanning calorimetry (DSC) thermogram as shown in Figure 18 when heated at a rate of 10 °C / min.

38. The pharmaceutically acceptable salt according to claim 34 or 35, wherein the crystalline form is characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at 190 °C ± 10% when heated at a rate of 10 °C / min.

39. The pharmaceutically acceptable salt according to claim 34 or 35, wherein the crystalline form is characterized by the thermogravimetric analysis curve shown in Figure 19 when heated at a rate of 20°C / min.

40. A pharmaceutical composition comprising a pharmaceutically acceptable salt and a pharmaceutically acceptable excipient according to any one of claims 1-39.

41. Use of a pharmaceutically acceptable salt according to any one of claims 1-39 in the preparation of a medicament for treating a disease or disorder associated with abnormal PRMT5 activity in a subject, wherein said 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, myelodysplastic disorder, mastocytosis, multiple myeloma (MM), epidermoid carcinoma, hemoglobinopathies, glioblastoma, head and neck cancer, bladder cancer, hepatocellular carcinoma, adenoid cystic carcinoma (ACC), primary central nervous system lymphoma, fallopian tube cancer, or non-Hodgkin's lymphoma.

42. The use according to claim 41, wherein the leukemia is acute myeloid leukemia (AML), acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, or hairy cell leukemia, and the hemoglobinopathies are β-thalassemia or sickle cell disease (SCD).

43. The use according to claim 41, wherein the disease or disorder associated with abnormal PRMT5 activity is myeloproliferative disorder.

44. The use according to claim 43, wherein the myeloproliferative disorder is myelodysplastic syndrome (MDS).

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