EA043295B1 - SELECTIVE PROTEIN-ARGININE-METHYLTRANSFERASE 5 (PRMT5) INHIBITOR - Google Patents

Description

Cross-reference to related applications

This application claims priority over U.S. Provisional Application No.

62/805175, filed Feb. 13, 2019, and U.S. Provisional Application No. 62/805,726, filed Feb. 14, 2019. The entire contents of each of these applications are incorporated herein by reference.

Technical field

The present disclosure relates to PRMT5 inhibitors and methods for their use.

State of the art

Arginine protein methylation is a common post-translational modification that regulates many cellular processes, including gene transcription, mRNA splicing, DNA repair, cellular protein localization, cell fate determination, and signaling. There are three types of methyl-arginine molecules: ω NG monomethylarginine (MMA), ω NG, asymmetric NG dimethylarginine (ADMA), and ω NG, symmetrical N'G dimethylarginine (SDMA). The formation of methylated arginines is catalyzed by a family of methyltransferases, protein arginine methyltransferases (PRMTs). There are currently nine PRMTs annotated in the human genome. Most of these enzymes are type I enzymes (PRMT1, -2, -3, 4, -6, -8) that are capable of mono- and asymmetric dimethylation of arginine using Sadenosine Methionine (SAM) as a methyl donor. PRMT-5, -7 and -9 are considered type II enzymes that catalyze the symmetrical dimethylation of arginines. Each PRMT species contains characteristic motifs of seven beta-chain methyltransferases (Katz et al., 2003), as well as additional double E and THW sequence motifs characteristic of the PRMT subfamily.

PRMT5 is a general transcriptional repressor that functions with numerous transcription factors and repressor complexes, including BRG1 and hBRM, Blimp1 and Snail. This enzyme, being recruited to the promoter, symmetrically dimethylates H3R8 and H4R3. It is important to note that the H4R3 site is the main target for PRMT1 (ADMA) methylation and is generally regarded as a marker for transcriptional activation. Thus, both H4R3me2s (repressive; me2s indicates SDMA modification) and H4R3me2a (active; me2a indicates ADMA modification) are labeled in vivo. The specificity of PRMT5 for H3R8 and H4R3 may be altered as a result of its interaction with COPR5, and this may play an important role in determining the status of a PRMT5 corepressor.

The role of PRMT in cancer

Aberrant PRMT expression has been identified in human cancer, and PRMTs are considered therapeutic targets. A general analysis of histone modifications in prostate cancer has shown that H4R3 histone dimethylation is positively correlated with increasing stage, and such changes predict clinical outcome. PRMT5 levels have been shown to be elevated in a panel of lymphoid cancer cell lines as well as in mantle cell lymphoma clinical specimens. PRMT5 interacts with a number of substrates that are involved in many cellular processes, including RNA processing, signaling, and transcriptional regulation. PRMT5 can directly modify H3 and H4 histones, resulting in downregulation of gene expression. Overexpression of PRMT5 can stimulate cell growth and induce transformation by directly suppressing tumor suppressor genes. Pal et al., Mol. cell. Biol. 2003, 7475; Pal et al. Mol. cell. Biol. 2004, 9630; Wang et al. Mol. cell. Biol. 2008, 6262; Chung et al. J Biol Chem 2013, 5534. In addition to its well-documented oncogenic functions in transcription and translation, transcription factor MYC also ensures proper splicing of the messenger RNA precursor as an important step in lymphomagenesis. Koh et al. Nature 2015, 523 7558; Hsu et al. Nature 2015 525, 384.

The discovery of the factors on which cancer depends can inform therapeutic strategies and reveal putative drug targets. In summarizing data from complex genomic profiling of cancer cell lines and functional characterization of cancer cell dependencies, it was recently found that the loss of the enzyme methylthioadenosine phosphorylase (MTAP) causes selective dependence on protein arginine methyltransferase 5 (PRMT5) and its binding partner WDR77. MTAP is often lost due to its proximity to the commonly deleted tumor suppressor gene, CDKN2A. Cells bearing MTAP deletions have elevated intracellular concentrations of methylthioadenosine (MTA, a metabolite cleaved by MTAP). In addition, MTA specifically inhibits the enzymatic activity of PRMT5. Administration of either MTA or a small molecule inhibitor of PRMT5 demonstrates a preferential disruption of the viability of MTAP-null cancer cell lines compared to isogenic counterparts expressing MTAP. Taken together, the findings indicate that PRMT5 is a potential vulnerable side for several cancer lineages, enhanced by a shared passenger genomic change.

The role of PRMT5 in hemoglobinopathies

The switch of the human globin gene subtype from embryonic to adult during development, which begins at birth, marks the onset of hemoglobinopathies, b-thalassemia, and sickle cell anemia (SCD). The finding that increased expression of the adult globin gene (in the setting of inherited persistence of fetal hemoglobin [HPFH] mutations) significantly alleviates the clinical severity of thalassemia and SCD prompted the search for therapeutic strategies to reverse gamma globin gene silencing. The central point in gamma gene silencing is DNA methylation, which marks the critical CpG dinucleotides flanking the gene transcription start site in adult human bone marrow erythroid cells. These marks have been shown to be established as a consequence of the recruitment of a DNA methyltransferase, DNMT3A, to the gamma promoter by the protein arginine methyltransferase PRMT5. Zhao et al. Nat Struct Mol Biol. 2009 16, 304. PRMT5-mediated histone methylation H4R3 recruits DNMT3A by binding histone and DNA methylation during gene silencing.

PRMT5 induces the repressive histone mark H4R3me2s, which serves as a template for direct DNMT3A binding and subsequent DNA methylation. Loss of PRMT5 binding or enzymatic activity leads to demethylation of CpG dinucleotides and gene activation. In addition to the H4R3me2s tag and DNA methylation, PRMT5 binding to the gamma promoter and its enzymatic activity are important for the assembly of a multiprotein complex at the gamma promoter that induces a series of coordinated repressive epigenetic marks. Violation of this complex leads to reactivation of the expression of the gamma gene. The presented studies provide the basis for the development of PRMT5 inhibitors as targeted therapies for thalassemia and SCD.

Brief description of the essence of the invention

This description relates to pharmaceutically acceptable salts of (2R,3S,4R,5R)-5-(4-amino7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((R)-(3,4 -dichlorophenyl)(hydroxy)methyl)-3-methyltetrahydrofuran3,4-diol, i.e. compounds of formula I

The present description also relates to the maleate, hydrochloride, oxalate, phosphate and bisulfate salts of formula I.

Crystalline forms of such salts are also described, as well as pharmaceutical compositions containing said salts and methods of using said salts.

The present description also relates to crystalline forms of the compound of formula I, as well as to pharmaceutical compositions containing these forms, and methods of using these forms are also described.

Brief description of graphic materials

In FIG. 1 shows the RPD profile of the maleate salt having formula IA.

In FIG. 2 shows the RPD profile of the maleate salt having formula IA.

In FIG. 3 is a DSC thermogram of a maleate salt having formula IA.

In FIG. 4 shows the TGA profile of the maleate salt having formula IA.

In FIG. 5 shows the TGA profile and DSC thermogram of a maleate salt having formula IA.

In FIG. 6 shows the RPD profile of the hydrochloride salt having formula IB.

In FIG. 7 shows the RPD profile of the hydrochloride salt having the formula IB.

In FIG. 8 shows the RPD profile of the hydrochloride salt having formula IB.

In FIG. 9 is a DSC thermogram of a hydrochloride salt having formula IB.

In FIG. 10 shows the TGA profile of the hydrochloride salt having formula IB.

In FIG. 11 shows the TGA profile and DSC thermogram of a hyrochloride salt having the formula IB.

In FIG. 12 shows the RPD profile of an oxalate salt having the formula IC.

In FIG. 13 shows the RPD profile of a phosphate salt having the formula ID.

In FIG. 14 shows the RPD profile of the maleate salt having formula IA.

In FIG. 15 is a DSC thermogram of a maleate salt having formula IA.

In FIG. 16 shows the TGA profile of the maleate salt having formula IA.

In FIG. 17 shows the RPD profile of the hydrochloride salt having formula IB.

In FIG. 18 is a DSC thermogram of a hydrochloride salt having formula IB.

In FIG. 19 shows the TGA profile of the hydrochloride salt having formula IB.

In FIG. 20 shows the profile of the RPD formula IB, form I.

In FIG. 21 shows a DSC thermogram of formula IB, form I.

In FIG. 22 shows the TGA profile of Formula IB, Form I.

In FIG. 23 shows the profile of a chipboard of formula IB, form I.

In FIG. 24 shows a comparison of RPD formula IB, form I, before (top) and after (bottom) DSP.

In FIG. 25 shows 1H NMR (400 MHz; DMSO-d ₆ ) of Formula IB, Form I.

In FIG. 26 shows the profile of the RPD formula IB, form II.

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In FIG. 27 is a DSC thermogram of Formula IB, Form II.

In FIG. 28 shows the TGA profile of Formula IB, Form II.

In FIG. 29 shows Ή NMR (400 MHz; MeOH-d ₄ ) of formula IB, form II.

In FIG. 30 shows the profile of a chipboard of formula IB, form II.

In FIG. 31 shows a comparison of the RPD of formula IB, form II, before (top) and after (bottom) DSP.

In FIG. 32 shows the profile of the RPD formula IB, form III.

In FIG. 33 is a DSC thermogram of formula IB, form III.

In FIG. 34 shows the TGA profile of formula IB, form III.

In FIG. 35 shows 1H NMR (400 MHz; DMSO-d ₆ ) of formula IB, form III.

In FIG. 36 shows the profile of a chipboard of formula IB, form III.

In FIG. 37 shows a comparison of RPD formula IB, form III, before (top) and after (bottom) DSP.

In FIG. 38 shows the profile of the RPD formula IB, form IV.

In FIG. 39 shows a DSC thermogram of formula IB, form IV.

In FIG. 40 shows the TGA profile of Formula IB, Form IV.

In FIG. 41 shows 1H NMR (400 MHz; DMCO-d ₆ ) of formula IB, form IV.

In FIG. 42 shows the RPD profile of the crystalline form of Formula IB.

In FIG. 43 is a DSC thermogram of the crystalline form of formula IB.

In FIG. 44 shows the TGA profile of the crystalline form of formula IB.

In FIG. 45 shows the RPD profile of a phosphate salt having the formula ID.

In FIG. 46 is a DSC thermogram of a phosphate salt having the formula ID.

In FIG. 47 shows the TGA profile of a phosphate salt having formula ID.

In FIG. 48 shows the RPD profile of the crystalline form of the compound having Formula I, Form I.

In FIG. 49 is a DSC thermogram of a crystalline form of the compound having Formula I, Form I.

In FIG. 50 shows the TGA profile of Formula I, Form I.

In FIG. 51 shows 1H NMR (400 MHz; MeOH-d ₄ ) of Formula I, Form I.

In FIG. 52 shows the profile of a chipboard of formula I, form I.

In FIG. 53 shows a comparison of the RPD before (top) and after (bottom) EAF for Formula I, Form I.

In FIG. 54 shows the profile of the RPD formula I, form II.

In FIG. 55 shows a DSC thermogram of formula I, form II.

In FIG. 56 shows the profile of the RPD formula I, form III.

In FIG. 57 shows a DSC thermogram of formula I, form III.

In FIG. 58 shows the profile of the RPD formula I, form II.

In FIG. 59 shows a DSC thermogram of formula I, form II.

In FIG. 60 shows the profile of the RPD formula I, form II.

In FIG. 61 shows a DSC thermogram of formula I, form II.

In FIG. 62 shows the profile of the RPD formula I, form II.

In FIG. 63 shows a DSC thermogram of formula I, form II.

Detailed description of illustrative embodiments of the invention

The present invention may be better understood with reference to the following description, including the following definitions and examples. Some features of the described compositions and methods, which are described herein in the context of separate aspects, may also be presented in combination, in one aspect. Alternatively, the various features of the described compositions and methods, which for brevity are described in the context of one aspect, can also be presented individually or in any subcombination.

Pharmaceutically acceptable means approved or subject to approval by a federal or state government regulatory agency, or by an appropriate authority in countries outside the United States, or listed in the USP or other known pharmacopoeias for use in animals, such as humans.

A pharmaceutically acceptable salt refers to a salt of a compound of the present disclosure that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic, can be addition salts of inorganic or organic acids, as well as addition salts of bases. In particular, such salts include: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentane propionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzene sulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-en-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, laurylsulfuric acid, gluconic acid, glutamic acid , hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed by replacing an acidic proton present in the parent compound with a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or when it is coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium salts, and the like; and if the compound contains a basic functionality, non-toxic organic or inorganic acid salts such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, phosphate, sulfate, bisulfate, and the like.

A pharmaceutically acceptable excipient refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of the agent, and which is compatible with it. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

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

The subject includes people. The terms human, patient, and subject are used interchangeably in this context.

Treating or treating any disease or disorder refers, in one embodiment, to alleviating the disease or disorder (ie, stopping or reducing the development of the disease or at least one of its clinical symptoms). In another implementation, to treat or treatment refers to the improvement of at least one physical parameter, which may not be noticeable to the subject. In other embodiments, treating or treating refers to modulating a disease or disorder, either physically (eg, stabilizing a noticeable symptom), physiologically (eg, stabilizing a physical parameter), or both. In another embodiment, treating or treating refers to delaying the onset of a disease or disorder.

The compounds of the present disclosure and equivalent expressions include the pharmaceutically acceptable salts of the compounds of formula I described herein as well as subtypes thereof, and these expressions include stereoisomers (e.g. enantiomers, diastereomers) and structural isomers (e.g. tautomers) as permitted by law. context.

As used herein, the term isotopic variant refers to a compound that has a relative isotopic abundance of one or more of the atoms that form said compound that is above natural abundance. For example, an isotopic variant of a compound may be radioactively labeled, i. e. contain one or more radioactive isotopes, or may be labeled with non-radioactive isotopes such as, for example, deuterium ( ² H or D), carbon-13 ( ¹³ C), nitrogen-15 ( ¹⁵ N), or the like. It should be understood that in a compound in which an isotopic substitution is made, the following atoms, if present, may vary, so that, for example, any hydrogen atom may be 2H/D, any carbon atom may be ¹³ C, or any nitrogen atom may represent ¹⁵ N, and that the presence and substitution of such atoms can be detected by a person skilled in the art.

It should also be understood that compounds that have the same molecular formula but a different nature or sequence of bonding of their atoms or arrangement of their atoms in space are called isomers. Isomers that differ in the arrangement of atoms in space are called stereoisomers, such as diastereomers, enantiomers, and atropisomers. Compounds according to the present description may have one or more asymmetric centers; thus, such compounds can be obtained as individual (R)- or (S)-stereoisomers at each asymmetric center, or in the form of mixtures thereof. Unless otherwise indicated, the description or name of a particular compound in this specification and claims includes all stereoisomers and mixtures thereof, racemic or otherwise. If there is one chiral center in a structure, but no specific stereochemistry is specified for that center, then such a structure includes both enantiomers individually or as a mixture of enantiomers. If there is more than one chiral center in a structure, but no specific stereochemistry is specified for these centers, then such a structure includes all enantiomers and diastereomers individually or as a mixture. Methods for determining stereochemistry and separating stereoisomers are well known in the art.

In some aspects, the present description relates to pharmaceutically acceptable salts of the compounds of formula I:

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In some embodiments, the pharmaceutically acceptable is the maleate salt which is of formula IA salt of the compound of formula I

In some embodiments, the pharmaceutically acceptable is the hydrochloride salt which is of formula IB salt of the compound of formula I

In some embodiments, the pharmaceutically acceptable salt is an oxalate salt which has the formula IC of a compound of formula I

In some embodiments, the pharmaceutically acceptable salt is a phosphate salt that has the formula I compound ID

In some embodiments, the pharmaceutically acceptable salt is the bisulfate salt which has the formula IE of the compound of formula I

In some aspects, the present description relates to crystalline forms of pharmaceutically acceptable salts of the compounds of formula I.

In some embodiments, the present description relates to crystalline forms of salts of formula IA, IB, IC, ID or IE.

In other aspects, the present description relates to crystalline forms of the compounds of formula I.

The crystalline forms of salts of formula IA, IB, IC, ID or IE and the crystalline forms of formula I according to the present description may have advantageous properties, including one or more of chemical or polymorphic purity, flowability, solubility, dissolution rate, bioavailability, morphology or crystal structure, stability, such as chemical stability, thermal stability and mechanical stability in relation to polymorphic transformation, storage stability; hygroscopicity, low content of residual solvents and advantageous characteristics for processing and transportation, such as compressibility or bulk density.

The crystalline form may be referred to herein as characterized by the graphical data presented in the figure. Such data include, for example, X-ray powder diffraction (XRD) patterns, differential scanning calorimetry (DSC) thermograms, or thermogravimetric analysis (TGA) profiles. As is known in the art, graphical data potentially provides additional technical information for remote

- 5 043295 further specification of the corresponding solid form, which may not necessarily be described only with reference to numerical values or peak positions. Thus, the term essentially as shown in relation to the graphical data in the figure means in this context a profile that is not necessarily identical to that depicted, but which is within the experimental error or deviations, as interpreted by a person skilled in the art. Those skilled in the art can easily compare the plots in the figures provided herein with plots obtained for an unknown crystal form and confirm that the two sets of plots describe the same crystal form or two different crystal forms.

The solid crystalline form may be referred to herein as being polymorphically pure or substantially free of other forms. When used in this context, the expression essentially free of other forms means that said 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 forms of the compound in question when measured, for example, using RPD. For example, it should be understood that the solid form of formula IA, described herein as essentially free of other solid forms, contains more than about 80% (wt./wt.), more than about 90% (wt./wt.), more about 95% (w/w), more than about 98% (w/w), more than about 99% (w/w), or about 100% of the considered solid form of formula IA. Accordingly, in some embodiments of this document, the described solid forms of formula IA may contain from about 1% to about 20% (w/w), from about 5 to about 20% (w/w), or from about 5% to about 10% (w/w) of one or more other solid forms of formula IA.

In this context, unless otherwise indicated, the recorded RPD peaks are measured using CuKa radiation, λ=1.54Α.

The modifier should be roughly understood as describing the range defined by the absolute values of the two endpoints. For example, the expression from about 2 to about 4 also describes the range from 2 to 4. When used to modify a single number, the term roughly refers to plus or minus 10% of the specified number and includes the specified number itself. For example, about 10% means the range from 9 to 11%, and about 1 means 0.9-1.1.

Formula IA (maleate salt of formula I).

In some aspects, the present description relates to the crystalline form of the maleate salt of formula I, i. to formula IA. In some embodiments, the crystalline form of Formula IA is substantially free of other solid forms of Formula IA.

In some embodiments, the crystalline form of Formula IA has an RPD profile substantially as shown in FIG. 1. The RPD profile of the formula IA crystalline form shown in FIG. 1 contains reflection angles (degrees 2-theta ± 0.2 degrees 2-theta), distances between lines (values of d) and relative intensities shown in Table 1. 1:

Table 1. RPD data for the crystalline form of formula IA shown in FIG. 1

Angle (degrees 2-theta ± 0.2 degrees 2-theta) d value (A) Relative intensity 5.479 16.1157 5 6.68 13.2205 50.3 10.441 8.4659 8.5 10.959 8.0664 13.4

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13.72 6.4489 32.4 14.879 5.9489 31.8 16.319 5.4271 100 16.839 5.2606 59.6 17.679 5.0126 20.9 18.762 4.7256 26.1 19.379 4.5765 39.8 20.419 4.3457 53.7 21.441 4.1408 28.4 22.04 4.0296 9.1 23.12 3.8438 22.5 23.862 3.726 9.2 25.4 3.5037 51 25.859 3.4426 27.4 26.619 3.3459 46.7 27.057 3.2928 27 27.9 3.1952 31.8 29.08 3.0681 38.2 30.741 2.9061 21.1 31.358 2.8503 12.6 32.738 2.7332 AND 33.539 2.6697 16.3 34.917 2.5675 4.3 36.499 2.4597 14.8 37.3 2.4087 19.4 38.401 2.3422 3.8 39.72 2.2674 12 41.16 2.1913 10.5 41.618 2.1683 9.6 42.817 2.1103 3.8 43.56 2.076 13.8

In some embodiments of the present description, the crystalline form of formula IA is characterized by an RPD profile containing a peak at one of the angles indicated in table. 1. In other aspects, the crystalline form of formula IA is characterized by an RPD profile containing more than one peak at one of the angles indicated above in table. 1. In other aspects, the crystalline form of formula IA is characterized by an RPD profile containing two peaks selected from the angles indicated above in table. 1. In other aspects, the crystalline form of formula IA is characterized by an RPD profile containing three peaks selected from the angles indicated above in table. 1. In other aspects, the crystalline form of formula IA is characterized by an RPD profile containing four peaks selected from the angles indicated above in table. 1. In other aspects, the crystalline form of formula IA is characterized by an RPD profile containing five peaks selected from the angles indicated above in table. 1. In other aspects, the crystalline form of formula IA is characterized by an RPD profile containing six peaks selected from the angles indicated above in table. 1. In other aspects, the crystalline form of formula IA is characterized by an RPD profile containing seven peaks selected from the angles indicated above in table. 1. In other aspects, the crystalline form of formula IA is characterized by an RPD profile containing eight peaks selected from the angles indicated above in table. 1. In other aspects, the crystalline form of formula IA is characterized by an RPD profile containing nine peaks selected from the angles indicated above in table. 1. In other aspects, the crystalline form of formula IA is characterized by an RPD profile containing ten peaks selected from the angles indicated above in table. 1. In other aspects, the crystalline form of formula IA is characterized by an RPD profile containing more than ten peaks selected from the angles indicated above in table. 1. In some embodiments, the crystalline form of Formula IA has an RPD profile containing a peak at 16.3° ± 0.2° 2-theta. In other embodiments, the crystalline form of formula IA has an RPD profile containing peaks at 6.7, 11.0, and 16.3° ± 0.2° 2-theta. In other embodiments, the crystalline form of formula IA has an RPD profile containing peaks at 6.7, 16.3, 20.4, and 30.7° ± 0.2° 2-theta. In other embodiments, the crystalline form of formula IA has an RPD profile containing peaks at 6.7, 14.9, 16.3, and 20.4° ± 0.2° 2-theta. In other embodiments, the crystalline form of formula IA is characterized by an RPD profile containing peaks at 6.7, 11.0, 14.9, 16.3, 16.8, 20.4, 25.4° ± 0.2° 2- theta. In other embodiments, the crystalline form of Formula IA has an RPD profile containing peaks at 6.7, 16.3, 20.4, 25.4, and 30.7° ± 0.2° 2-theta. In other embodiments, the crystalline form of Formula IA is characterized by an RPD profile containing peaks at 6.7, 11.0, 14.9, 16.3, 16.8, 20.4, 25.4, 25.9, 27.9 , 29.1 and 30.7° ± 0.2° 2-theta.

In some embodiments of the present description, the crystalline form of formula IA xa

- 7 043295 is characterized by an RPD profile containing peaks at three or more of 6.7, 11.0, 14.9, 16.3, 16.8, 20.4, 25.4, 25.9, 27.9, 29.1 and 30.7° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula IA is characterized by an RPD profile containing peaks at four or more of 6.7, 11.0, 14.9, 16.3, 16.8, 20.4, 25.4, 25 .9, 27.9, 29.1 and 30.7° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula IA is characterized by an RPD profile containing peaks at five or more of 6.7, 11.0, 14.9, 16.3, 16.8, 20.4, 25.4, 25 .9, 27.9, 29.1 and 30.7° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula IA is characterized by an RPD profile containing peaks at six or more of 6.7, 11.0, 14.9, 16.3, 16.8, 20.4, 25.4, 25 .9, 27.9, 29.1 and 30.7° ± 0.2° 2-theta.

In some embodiments of the present description, the crystalline form of formula IA is characterized by an RPD profile containing peaks at seven or more of 6.7, 11.0, 14.9, 16.3, 16.8, 20.4, 25.4, 25 .9, 27.9, 29.1 and 30.7° ± 0.2° 2-theta. In some embodiments, the crystalline form of Formula IA has an RPD profile substantially as shown in FIG. 2. RPD profile of the formula IA crystalline form shown in FIG. 2 contains reflection angles (degrees 2-theta ± 0.2 degrees 2-theta), distances between lines (d-values), and relative intensities shown in Table 2. 2:

Table 2. RPD data for the crystalline form of formula IA shown in FIG. 2

Angle (degrees 2-theta ± 0.2 degrees 2-theta) d value (A) Relative intensity 3.10 28.439 34 8.29 10.656 45 9.36 9.443 13 10.23 8.639 18 11.00 8.038 18 13.03 6.789 40 13.53 6.538 AND 14.12 6.266 AND 14.56 6.080 100 15.33 5.777 32 15.77 5.615 14 16.30 5.434 70 16.66 5.317 24 17.81 4.977 18 18.22 4.865 12 18.45 4.805 28 18.83 4,710 7 19.32 4.592 16 19.66 4.511 13 19.84 4.471 10 20.19 4,394 7 20.60 4.308 6 20.96 4.234 7 21.67 4.098 8 21.90 4.055 8 22.12 4.015 13 22.57 3.936 10 22.96 3,870 AND 23.66 3.757 AND 24.73 3.597 7 25.11 3.543 15 25.48 3.493 17 25.66 3.469 19 25.97 3.428 10 26.26 3.392 33 26.53 3.356 23 27.01 3.298 36 27.19 3.277 31 27.52 3.239 10 27.82 3.204 8 28.27 3.155 12 28.55 3.124 17 29.36 3.040 AND 29.79 2.997 AND

In some embodiments of the present description, the crystalline form of formula IA is characterized by an RPD profile containing a peak at one of the angles indicated in table. 2. In other aspects, the crystalline form of formula IA is characterized by an RPD profile containing more than one peak at one of the angles indicated above in table. 2. In other aspects, the crystalline form of the formula

- 8 043295

IA is characterized by an RPD profile containing two peaks selected from the angles indicated in Table 1 above. 2. In other aspects, the crystalline form of formula IA is characterized by an RPD profile containing three peaks selected from the angles indicated above in table. 2. In other aspects, the crystalline form of formula IA is characterized by an RPD profile containing four peaks selected from the angles indicated above in table. 2. In other aspects, the crystalline form of formula IA is characterized by an RPD profile containing five peaks selected from the angles indicated above in table. 2. In other aspects, the crystalline form of formula IA is characterized by an RPD profile containing six peaks selected from the angles indicated above in table. 2. In other aspects, the crystalline form of formula IA is characterized by an RPD profile containing seven peaks selected from the angles indicated above in table. 2. In other aspects, the crystalline form of formula IA is characterized by an RPD profile containing eight peaks selected from the angles indicated above in table. 2. In other aspects, the crystalline form of formula IA is characterized by an RPD profile containing nine peaks selected from the angles indicated above in table. 2. In other aspects, the crystalline form of formula IA is characterized by an RPD profile containing ten peaks selected from the angles indicated above in table. 2. In other aspects, the crystalline form of formula IA is characterized by an RPD profile containing more than ten peaks selected from the angles indicated above in table. 2.

In some embodiments, the crystalline form of formula IA is characterized by an RPD profile containing a peak at 14.6° ± 0.2° 2-theta. In other embodiments, the crystalline form of formula IA has an RPD profile containing peaks at 13.0, 14.6, and 16.3° ± 0.2° 2-theta. In other embodiments, the crystalline form of Formula IA has an RPD profile containing peaks at 8.3, 13.0, 14.6, 16.3, 26.3, and 27.0° ± 0.2° 2-theta. In other embodiments, the crystalline form of formula IA is characterized by an RPD profile containing peaks at 8.3, 13.0, 14.6, 15.3, 16.3, 16.7, 27.0, and 27.2° ± 0, 2° 2-theta. In other embodiments, the crystalline form of formula IA has an RPD profile containing peaks at 3.1, 8.3, 13.0, 14.6, 15.3, and 16.3° ± 0.2° 2theta. In other embodiments, the crystalline form of formula IA is characterized by an RPD profile containing peaks at 14.6, 15.3, 16.3, 16.7, 18.4, 26.3, 27.0, and 27.2°±0, 2° 2-theta. In other embodiments, the crystalline form of formula IA is characterized by an RPD profile containing peaks at 3.1, 8.3, 13.0, 14.6, 15.3, 16.3, 16.7, 18.4, 26.3 , 26.5, 27.0 and 27.2° ± 0.2° 2-theta.

In some embodiments of the present description, the crystalline form of formula IA is characterized by an RPD profile containing peaks at three or more of 3.1, 8.3, 13.0, 14.6, 15.3, 16.3, 16.7, 18 .4, 26.3, 26.5, 27.0 and 27.2° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula IA is characterized by an RPD profile containing peaks at four or more of 3.1, 8.3, 13.0, 14.6, 15.3, 16.3, 16.7, 18 .4, 26.3, 26.5, 27.0 and 27.2° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula IA is characterized by an RPD profile containing peaks at five or more of 3.1, 8.3, 13.0, 14.6, 15.3, 16.3, 16.7, 18 .4, 26.3, 26.5, 27.0 and 27.2° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula IA is characterized by an RPD profile containing peaks at six or more of 3.1, 8.3, 13.0, 14.6, 15.3, 16.3, 16.7, 18 .4, 26.3, 26.5, 27.0 and 27.2° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula IA is characterized by an RPD profile containing peaks at seven or more of 3.1, 8.3, 13.0, 14.6, 15.3, 16.3, 16.7, 18 .4, 26.3, 26.5, 27.0 and 27.2° ± 0.2° 2-theta.

In some embodiments, the crystalline form of Formula IA may be characterized substantially by a DSC thermogram as shown in FIG. 3. In FIG. 3 shows that the crystalline form of formula IA forms an endothermic peak at 206.69° C. with a peak onset temperature of 204.70° C. and a fusion enthalpy of 137.1 J/g when heated at a rate of 10° C./min. In some embodiments of the present description, the crystalline form of formula IA is characterized by a DSC thermogram containing an endothermic peak at about 207°C. In other embodiments of the present disclosure, the crystalline form of formula IA has a DSC fusion enthalpy of about 137 J/g.

In some embodiments, the crystalline form of Formula IA may be characterized substantially by a TGA profile as shown in FIG. 4, when heated at a rate of 20°C/min. In FIG. 4 shows that the crystalline form of Formula IA loses about 0.03% by weight when heated to about 150°C.

In some embodiments, the crystalline form of Formula IA may be characterized by a substantially DSC thermogram and TGA profile as shown in FIG. 5. In FIG. 5 shows that the crystalline form of formula IA forms an endothermic peak at 184.92° C. with a peak onset temperature of 179.82° C. when heated at a rate of 10 K/min.

In some embodiments of the present description, the crystalline form of formula IA is characterized by a DSC thermogram containing an endothermic peak at about 185°C when heated at a rate of 10 K/min. In FIG. 5 shows that the crystalline form of formula IA loses about 12.3% weight when heated to about 210°C.

In some embodiments of the present description, the crystalline form of formula IA is characterized by an RPD profile containing peaks at 6.7, 14.9, 16.3 and 20.4° ± 0.2° 2-theta and a thermogram

DSC containing an endothermic peak at about 207°C when heated at a rate of 10°C/min.

In some embodiments, the crystalline form of Formula IA has an RPD profile substantially as shown in FIG. 14.

In some embodiments, the crystalline form of formula IA has a substantially DSC thermogram as shown in FIG. 15.

In some embodiments, the crystalline form of Formula IA has a TGA profile substantially as shown in FIG. 16.

Formula IB (HCl salt of formula I).

In some aspects, the present description refers to the crystalline form of the hydrochloride salt, i. to the IB formula. In some embodiments, the crystalline form of Formula IB is substantially free of other solid forms of Formula IB.

In some embodiments, the crystalline form of Formula IB has an RPD profile substantially as shown in FIG. 6. RPD profile of the crystalline form of formula IB shown in FIG. 6 contains reflection angles (degrees 2-theta ± 0.2° 2-theta), distances between lines (d-values), and relative intensities shown in Table 1. 3.

Table 3. RPD data for

Angle (degrees 2-theta ± 0.2 degrees 2-theta) Value d(A) Relative intensity 5.439 16.2337 33.7 10.901 8.1096 32.7 15.159 5.8399 19.7 15.58 5.6829 9.3 16.4 5.4005 100 17.2 5.1512 5.1 21.2 4.1874 21.1 21.941 4.0477 7.5 22.798 3.8974 4 24.2 3.6746 26 25.802 3.4501 5.8 26.26 3.3909 7.7 27.521 3.2384 36.3 28 3.184 13.8 30.521 2.9265 4.6 33.259 2.6916 8 34.642 2.5873 5.7 35.96 2.4954 5.8 40.019 2.2511 4.1

IB shown in Fig. 6

In some embodiments of the present disclosure, the crystalline form of formula IB is characterized by an RPD profile containing a peak at one of the angles shown in Table 1. 3. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing more than one peak at one of the angles indicated above in table. 3. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing two peaks selected from the angles indicated above in table. 3. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing three peaks selected from the angles indicated above in table. 3. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing four peaks selected from the angles indicated above in table. 3. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing five peaks selected from the angles indicated above in table. 3. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing six peaks selected from the angles indicated above in table. 3. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing seven peaks selected from the angles indicated above in table. 3. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing eight peaks selected from the angles indicated above in table. 3. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing nine peaks selected from the angles indicated above in table. 3. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing ten peaks selected from the angles indicated above in table. 3. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing more than ten peaks selected from the angles indicated above in table. 3.

In some embodiments, the crystalline form of Formula IB has an RPD profile containing a peak at 5.4° ± 0.2° 2-theta. In other embodiments, the crystalline form of formula IB has an RPD profile containing peaks at 5.4, 10.9, and 16.4° ± 0.2° 2-theta. In other embodiments, the crystalline form of formula IB has an RPD profile containing peaks at 5.4, 10.9, 21.2, and 24.2° ± 0.2° 2-theta. In other embodiments, the crystalline form of formula IB is characterized by an RPD profile containing peaks at 5.4, 10.9, 16.4, 21.2 and 24.2°±

0.2° 2-theta. In other embodiments, the crystalline form of formula IB has an RPD profile containing peaks at 5.4, 10.9, 16.4, 21.2, 24.2, and 27.5° ± 0.2° 2-theta.

In some embodiments of the present description, the crystalline form of formula IB is characterized by an RPD profile containing peaks at three or more of 5.4, 10.9, 16.4, 21.2, 24.2 and 27.5° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula IB is characterized by an RPD profile containing peaks at four or more of 5.4, 10.9, 16.4, 21.2, 24.2 and 27.5° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula IB is characterized by an RPD profile containing peaks at five or more of 5.4, 10.9, 16.4, 21.2, 24.2 and 27.5° ± 0.2° 2-theta.

In some embodiments, the crystalline form of Formula IB may be characterized by a substantially DSC thermogram as shown in FIG. 9. In FIG. 9 shows that the crystalline form of formula IB forms an endothermic peak at 191.42°C (beginning at 179.71°C; 37.63 J/g), then an exothermic peak at 209.27°C (beginning at 200.36° C; 79.45 J/g), then another endothermic peak at 268.11°C (beginning at 261.51°C; 93.73 J/g), while heating at 10°C/min. In some embodiments of the present description, the crystalline form of formula IB is characterized by a DSC thermogram containing an endothermic peak at about 191°C when heated at a rate of 10°C/min. In other embodiments of the present description, the crystalline form of formula IB is characterized by a DSC thermogram containing an endothermic peak at about 268°C, when heated at a rate of 10°C/min.

In some embodiments, the crystalline form of Formula IB may be characterized substantially by the TGA profile as shown in FIG. 10, when heated at a rate of 20°C/min. In FIG. 10 shows that the crystalline form of formula IB loses about 0.8% by weight when heated to about 150°C. In some embodiments, the crystalline form of Formula IB has an RPD profile substantially as shown in FIG. 7. RPD profile of the crystalline form of formula IB shown in FIG. 7 contains reflection angles (degrees 2-theta ± 0.2° 2-theta), distances between lines (d-values), and relative intensities shown in Table 1. 4.

Table 4. RPD data for the crystalline form of formula IB shown in FIG. 7

Angle (degrees 2theta ± 0.2 degrees 2theta) Value d(A) Relative intensity 4.979 17.732 64.3 10.06 8.7856 12 13.72 6.4491 I,1 15.2 5.8241 100 17.153 5.165 12.4 19.099 4.643 7.3 20.359 4.3585 14.5 21.319 4.1642 13.3 24.28 3.6628 25.6 25.659 3.4689 14.5 27.919 3.1931 7.9 30.8 2.9006 33.1

In some embodiments of the present description, the crystalline form of formula IB is characterized by an RPD profile containing a peak at one of the angles indicated in table. 4. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing more than one peak at one of the angles indicated above in table. 4. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing two peaks selected from the angles indicated above in table. 4. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing three peaks selected from the angles indicated above in table. 4. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing four peaks selected from the angles indicated above in table. 4. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing five peaks selected from the angles indicated above in table. 4. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing six peaks selected from the angles indicated above in table. 4. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing seven peaks selected from the angles indicated above in table. 4. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing eight peaks selected from the angles indicated above in table. 4. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing nine peaks selected from the angles indicated above in table. 4. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing ten peaks selected from the angles indicated above in table. 4.

- 11 043295

In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing more than ten peaks selected from the angles indicated above in table. 4. In other embodiments, the crystalline form of formula IB has an RPD profile containing a peak at 5.0 degrees±0.2 degrees 2-theta. In other embodiments, the crystalline form of formula IB has an RPD profile containing peaks at 5.0, 15.2, and 24.3° ± 0.2° 2-theta. In other embodiments, the crystalline form of formula IB has an RPD profile containing peaks at 5.0, 15.2, 24.3, and 30.8° ± 0.2° 2-theta. In other embodiments, the crystalline form of formula IB is characterized by an RPD profile containing peaks at 5.0, 10.1, 13.7, 15.2, 17.1, 24.3, and 30.8° ± 0.2° 2- theta. In other embodiments, the crystalline form of formula IB has an RPD profile containing peaks at 17.1, 24.3, and 30.8° ± 0.2° 2-theta.

In some embodiments of the present description, the crystalline form of formula IB is characterized by an RPD profile containing peaks at three or more of 5.0, 10.1, 13.7, 15.2, 17.1, 24.3 and 30.8° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula IB is characterized by an RPD profile containing peaks at four or more of 5.0, 10.1, 13.7,

15.2, 17.1, 24.3 and 30.8° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula IB is characterized by an RPD profile containing peaks at five or more of 5.0, 10.1, 13.7, 15.2, 17.1, 24.3 and 30.8° ± 0.2° 2-theta.

In some embodiments, the crystalline form of Formula IB has an RPD profile substantially as shown in FIG. 8. The RPD profile of the crystalline form of formula IB shown in FIG. 8 contains reflection angles (degrees 2-theta ± 0.2° 2-theta), line spacings (d-values), and relative intensities shown in Table 8. 5.

Table 5. Data

In some embodiments of the present disclosure, the crystalline form of Khan's formula IB of FIG. 8

- 12 043295 is characterized by a RPD profile containing a peak at one of the angles indicated in Table. 5. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing more than one peak at one of the angles indicated above in table. 5. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing two peaks selected from the angles indicated above in table. 5. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing three peaks selected from the angles indicated above in table. 5. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing four peaks selected from the angles indicated above in table. 5. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing five peaks selected from the angles indicated above in table. 5. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing six peaks selected from the angles indicated above in table. 5. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing seven peaks selected from the angles indicated above in table. 5. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing eight peaks selected from the angles indicated above in table. 5. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing nine peaks selected from the angles indicated above in table. 5. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing ten peaks selected from the angles indicated above in table. 5. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing more than ten peaks selected from the angles indicated above in table. 5.

In some embodiments, the crystalline form of Formula IB has an RPD profile containing a peak at 11.4° ± 0.2° 2-theta. In other embodiments, the crystalline form of formula IB has an RPD profile containing peaks at 11.4, 11.6, 15.1, and 16.7°±0.2° 2-theta. In other embodiments, the crystalline form of formula IB has an RPD profile containing peaks at 4.9, 11.4, 11.6, and 15.1 degrees±0.2 degrees 2-theta. In other embodiments, the crystalline form of formula IB has an RPD profile containing peaks at 4.9, 11.4, 11.6, 15.1, and 16.7° ± 0.2° 2-theta. In other embodiments, the crystalline form of formula IB has an RPD profile containing peaks at 4.9, 11.4, 11.6, 15.1, 16.7, and 21.0° ± 0.2° 2-theta. In other embodiments, the crystalline form of formula IB is characterized by an RPD profile containing peaks at 4.9, 11.4, 11.6, 15.1, 16.7, 21.0, and 22.4° ± 0.2° 2- theta. In other embodiments, the crystalline form of formula IB has an RPD profile containing peaks at 4.9, 7.1, 11.4, 11.6, 12.4, 13.6, 14.3, 15.1, 16.5 , 16.7, 16.9, 17.0, 20.3, 21.0, 22.4, 23.0, 23.5 and 23.8° ± 0.2° 2-theta.

In some embodiments of the present description, the crystalline form of formula IB is characterized by an RPD profile containing peaks at three or more of 4.9, 7.1, 11.4, 11.6, 12.4, 13.6, 14.3, 15 .1, 16.5, 16.7, 16.9, 17.0, 20.3, 21.0, 22.4, 23.0, 23.5 and 23.8° ± 0.2° 2- theta. In some embodiments of the present description, the crystalline form of formula IB is characterized by an RPD profile containing peaks at four or more of 4.9, 7.1, 11.4, 11.6, 12.4, 13.6, 14.3, 15 .1, 16.5, 16.7, 16.9, 17.0, 20.3, 21.0, 22.4, 23.0, 23.5 and 23.8° ± 0.2° 2- theta. In some embodiments of the present description, the crystalline form of formula IB is characterized by an RPD profile containing peaks at five or more of 4.9, 7.1, 11.4, 11.6, 12.4, 13.6, 14.3, 15 .1, 16.5, 16.7, 16.9, 17.0, 20.3, 21.0, 22.4, 23.0, 23.5 and 23.8° ± 0.2° 2- theta. In some embodiments of the present description, the crystalline form of formula IB is characterized by an RPD profile containing peaks at six or more of 4.9, 7.1, 11.4, 11.6, 12.4, 13.6, 14.3, 15 .1, 16.5, 16.7, 16.9, 17.0, 20.3, 21.0, 22.4, 23.0, 23.5 and 23.8° ± 0.2° 2- theta. In some embodiments of the present description, the crystalline form of formula IB is characterized by an RPD profile containing peaks at seven or more of 4.9, 7.1, 11.4, 11.6, 12.4, 13.6, 14.3, 15 .1, 16.5, 16.7, 16.9, 17.0, 20.3, 21.0, 22.4, 23.0, 23.5 and 23.8° ± 0.2° 2- theta.

In some embodiments, the crystalline form of Formula IB may be characterized by a substantially DSC thermogram and TGA profile as shown in FIG. 11. In FIG. 11 shows that the crystalline form of formula IB forms an endothermic peak at 195.92°C with a peak onset temperature of 185.27°C, then an endothermic peak at 260.97°C with an onset peak at 252.35°C, on heating at a rate of 10 °C/min. In some embodiments of the present description, the crystalline form of formula IB is characterized by a DSC thermogram containing an endothermic peak at about 196°C when heated at a rate of 10°C. In other embodiments of the present description, the crystalline form of formula IB is characterized by a DSC thermogram containing an endothermic peak at about 261°C when heated at a rate of 10°C/min. In FIG. 11 shows that the crystalline form of formula IB loses about 4.9% by weight when heated to about 150°C.

In some embodiments, the crystalline form of Formula IB has an RPD profile substantially as shown in FIG. 17. The RPD profile of the crystalline form of formula IB shown in FIG. 17 contains reflection angles (degrees 2-theta ± 0.2° 2-theta), line spacings (d-values), and relative intensities shown in Table 1. 5A:

- 13 043295

Table 5A. The RPD data for the crystalline form of formula IB shown in FIG. 17

Angle (degrees 2-theta ± 0.2 degrees 2-theta) d value (A) Relative intensity 5.301 16.6585 38.4 11.779 7.5067 18.3 14.04 6.3026 20.4 15.48 5.7193 100 17.261 5.1331 52.3 19.238 4.6098 12.7 20.56 4.3164 28.5 21.541 4.122 39.1 22.9 3.8803 19.9 24.5 3.6304 72.5 25.82 3.4476 24.1 27.999 3.1841 26.6 28.797 3.0977 10.9 30.98 2.8841 47 33.279 2.69 9.7

In some embodiments of the present description, the crystalline form of formula IB is characterized by an RPD profile containing a peak at one of the angles indicated in table. 5A. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing more than one peak at one of the angles listed above in table. 5A. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing two peaks selected from the angles indicated above in table. 5A. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing three peaks selected from the angles indicated above in table. 5A. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing four peaks selected from the angles indicated in Table 1 above. 5A. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing five peaks selected from the angles indicated above in table. 5A. In other aspects, the crystalline form of Formula IB is characterized by an RPD profile containing six peaks selected from the angles indicated in Table 1 above. 5A. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing seven peaks selected from the angles indicated above in table. 5A. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing eight peaks selected from the angles indicated above in table. 5A. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing nine peaks selected from the angles listed above in table. 5A. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing ten peaks selected from the angles listed above in table. 5A. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing more than ten peaks selected from the angles indicated above in table. 5A.

In some embodiments, the crystalline form of formula IB has an RPD profile containing peaks at 5.3 and 15.5° ± 0.2° 2-theta. In other embodiments, the crystalline form of formula IB has an RPD profile containing peaks at 15.5 and 31.0° ± 0.2° 2-theta. In other embodiments, the crystalline form of formula IB has an RPD profile containing peaks at 15.5 and 24.5° ± 0.2° 2-theta. In other embodiments, the crystalline form of formula IB has an RPD profile containing peaks at 15.5, 24.5, and 31.0° ± 0.2° 2-theta. In other embodiments, the crystalline form of formula IB has an RPD profile containing peaks at 5.3, 15.5, 17.3, 24.5, and 31.0° ± 0.2° 2-theta. In other embodiments, the crystalline form of Formula IB has an RPD profile containing peaks at 5.3, 15.5, 17.3, 24.5, 28.0, and 31.0°±0.2 degrees 2-theta. In other embodiments, the crystalline form of Formula IB has an RPD profile containing peaks at 5.3, 15.5, 17.3, 21.5, 24.5, 28.0, and 31.0° ± 0.2° 2theta.

In some embodiments of the present description, the crystalline form of formula IB is characterized by an RPD profile containing peaks at three or more of 5.3, 15.5, 17.3, 21.5, 24.5, 28.0 and 31.0° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula IB is characterized by an RPD profile containing peaks at four or more of 5.3, 15.5, 17.3, 21.5, 24.5, 28.0 and 31.0° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula IB is characterized by an RPD profile containing peaks at five or more of 5.3, 15.5, 17.3, 21.5, 24.5, 28.0 and 31.0° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula IB is characterized by an RPD profile containing peaks at six or more of 5.3, 15.5, 17.3, 21.5, 24.5, 28.0 and 31.0° ± 0.2° 2-theta.

In some embodiments, the crystalline form of Formula IB may be characterized by a substantially DSC thermogram as shown in FIG. 18. In FIG. 18 shows that the crystalline form of formula IB forms an endothermic peak at 188.22°C (beginning at 179.07°C;

- 14043295

20.35 J/g), then an exothermic peak at 211.79°C (beginning at 205.18°C; 47.98 J/g), then another endothermic peak at 266.76°C (beginning at 260, 76°C; 45.59 J/g), when heated at 10°C/min. In some embodiments of the present description, the crystalline form of formula IB is characterized by a DSC thermogram containing an endothermic peak at about 188°C when heated at a rate of 10°C/min. In other embodiments of the present description, the crystalline form of formula IB is characterized by a DSC thermogram containing an endothermic peak at about 267°C, when heated at a rate of 10°C/min.

In some embodiments, the crystalline form of Formula IB may be characterized substantially by a TGA profile as shown in FIG. 19, when heated at a rate of 20°C/min.

In some embodiments, the crystalline form of Formula IB (Form I) has an RPD profile substantially as shown in FIG. 20. The RPD Form I formula IB profile shown in FIG. 20 contains reflection angles (degrees 2-theta ± 0.2° 2-theta), line spacings (d-values), and relative intensities shown in Table 2. 5V.

Table 5B. The RPD data for the crystalline form of Formula IB, Form I shown in FIG. 20

Angle (degrees 2-theta ± 0.2 degrees 2-theta) d value (A) Relative intensity 4.558 19.3693 11.3 8.819 10.0189 12.2 13.159 6.7223 100 14.302 6.1879 17D 16.138 5.4877 10.9 17.46 5.075 57.6 18.239 4.86 17.1 18.84 4.7063 16.7 19.539 4.5394 23.3 20.241 4.3837 21 20.896 4.2477 9.6 22.48 3.9517 10.7 24.28 3.6628 16.1 24.86 3.5785 31.7 26.28 3.3883 28.9 27.741 3.2132 21.6 28.34 3.1466 39.4 29.68 3.0075 Yu,1 30.76 2.9043 13.9 31.78 2.8134 7.7 32.999 2.7122 11.3 34.64 2.5874 8.8 35.919 2.4981 9.9 37.142 2.4186 15.4 40.24 2.2392 12.4 41.178 2.1904 9.2

In some embodiments of the present description, the crystalline form of formula IB, form I, is characterized by an RPD profile containing a peak at one of the angles indicated in table. 5V. In other aspects, the crystalline form of formula IB, form I, is characterized by an RPD profile containing more than one peak at one of the angles indicated above in table. 5V. In other aspects, the crystalline form of formula IB, form I, is characterized by an RPD profile containing two peaks selected from the angles indicated above in table. 5V. In other aspects, the crystalline form of formula IB, form I, is characterized by an RPD profile containing three peaks selected from the angles indicated above in table. 5V. In other aspects, the crystalline form of formula IB, form I, is characterized by an RPD profile containing four peaks selected from the angles indicated above in table. 5V. In other aspects, the crystalline form of formula IB, form I, is characterized by an RPD profile containing five peaks selected from the angles indicated above in table. 5V. In other aspects, the crystalline form of formula IB, form I, is characterized by an RPD profile containing six peaks selected from the angles indicated above in table. 5V. In other aspects, the crystalline form of formula IB, form I, is characterized by an RPD profile containing seven peaks selected from the angles indicated above in table. 5V. In other aspects, the crystalline form of formula IB, form I, is characterized by an RPD profile containing eight peaks selected from the angles indicated above in table. 5V. In other aspects, the crystalline form of formula IB, form I, is characterized by an RPD profile containing nine peaks selected from the angles indicated above in table. 5V. In other aspects, the crystalline form of formula IB, form I, is characterized by an RPD profile containing ten peaks selected from the angles indicated above in table. 5V. In other aspects, the crystalline form of formula IB, form I, is characterized by an RPD profile containing more than ten peaks selected from the angles indicated above in table. 5V.

In some embodiments, the crystalline form of Formula IB, Form I, has an RPD profile containing peaks at 13.2 and 17.5° ± 0.2° 2-theta. In other implementations of Cree

-15043295 the steel form of formula IB, form I, has an RPD profile containing peaks at 13.2, 17.5, 26.3 and 28.3° ± 0.2° 2-theta. In other embodiments, the crystalline form of Formula IB, Form I, has an RPD profile containing peaks at 13.2, 17.5, 18.8, 19.5, and 20.2° ± 0.2° 2-theta. In other embodiments, the crystalline form of Formula IB, Form I, has an RPD profile containing peaks at 13.2, 17.5, 24.9, 26.3, and 28.3° ± 0.2° 2-theta. In other embodiments, the crystalline form of Formula IB, Form I, has an RPD profile containing peaks at 13.2, 17.5, 18.8, 19.5, 20.2, 24.9, 26.3, and 28.3 ° ± 0.2° 2-theta.

In some embodiments of the present description, the crystalline form of formula IB, form I, is characterized by an RPD profile containing peaks at three or more of 13.2, 17.5, 18.8, 19.5, 20.2, 24.9, 26 ,3 and 28.3° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula IB, form I, is characterized by an RPD profile containing peaks at four or more of 13.2, 17.5, 18.8, 19.5, 20.2, 24.9, 26 ,3 and 28.3° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula IB, form I, is characterized by an RPD profile containing peaks at five or more of 13.2, 17.5, 18.8, 19.5, 20.2, 24.9, 26 ,3 and 28.3° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula IB, form I, is characterized by an RPD profile containing peaks at six or more of 13.2, 17.5, 18.8, 19.5, 20.2, 24.9, 26 ,3 and 28.3° ± 0.2° 2-theta.

In some embodiments, the crystalline form of Formula IB may be characterized by a substantially DSC thermogram as shown in FIG. 21. In FIG. 21 shows that the crystalline form of formula IB forms an endothermic peak at 271.44°C (onset at 265.22°C; 156.4 J/g) when heated at a rate of 10°C/min. In some embodiments of the present description, the crystalline form of formula IB is characterized by a DSC thermogram containing an endothermic peak at about 271°C when heated at a rate of 10°C/min.

In some embodiments, the crystalline form of Formula IB, Form I, may be characterized substantially by a TGA profile as shown in FIG. 22, when heated at a rate of 20°C/min.

In some embodiments, the crystalline form of Formula IB (Form II) has an RPD profile substantially as shown in FIG. 26. The RPD Form I formula IB profile shown in FIG. 26 contains reflection angles (degrees 2-theta ± 0.2° 2-theta), distances between lines (d-values), and relative intensities shown in Table 2. 5C.

Table 5C. The RPD data for the crystalline form of Formula IB, Form II shown in FIG. 26

Angle (degrees 2- d value Relative theta ± 0.2 (A) intensity degrees 2-theta) 5.499 16.0566 ID 10.799 8.186 I,6 11.84 7.4685 14.2 14.3 6.1887 28.4 16.12 5.4938 100 17.38 5.0983 34.3 19.059 4.6528 7.8 19.938 4.4494 9.5 20.919 4.243 20.8 21.86 4.0625 49.6 23.359 3.8051 25.2 24.98 3.5617 97.2 26.9 3.3117 30.5 28.536 3.1254 14.4 30.659 2.9136 13.1 32.32 2.7676 22.3 33.118 2.7027 AND 33.738 2.6545 12.5 35.3 2.5405 AND 36.581 2.4544 8.3 37.141 2.4187 9.3 37.88 2.3732 14.4

In some embodiments of the present description, the crystalline form of formula IB, form II, is characterized by an RPD profile containing a peak at one of the angles indicated in table. 5C. In other aspects, the crystalline form of formula IB, form II, is characterized by an RPD profile containing more than one peak at one of the angles indicated above in table. 5C. In other aspects, the crystalline form of formula IB, form II, is characterized by an RPD profile containing two peaks selected from the angles indicated above in table. 5C. In other aspects, the crystalline form of formula IB, form II, is characterized by an RPD profile containing three peaks selected from the angles indicated above in table. 5C. In other aspects, the crystalline form of Formula IB, Form II, is characterized by an RPD profile,

- 16 043295 containing four peaks selected from the angles indicated above in the table. 5C. In other aspects, the crystalline form of formula IB, form II, is characterized by an RPD profile containing five peaks selected from the angles indicated above in table. 5C. In other aspects, the crystalline form of formula IB, form II, is characterized by an RPD profile containing six peaks selected from the angles indicated above in table. 5C. In other aspects, the crystalline form of formula IB, form II, is characterized by an RPD profile containing seven peaks selected from the angles indicated above in table. 5C. In other aspects, the crystalline form of formula IB, form II, is characterized by an RPD profile containing eight peaks selected from the angles indicated above in table. 5C. In other aspects, the crystalline form of formula IB, form II, is characterized by an RPD profile containing nine peaks selected from the angles indicated above in table. 5C. In other aspects, the crystalline form of formula IB, form II, is characterized by an RPD profile containing ten peaks selected from the angles indicated above in table. 5C. In other aspects, the crystalline form of formula IB, form II, is characterized by an RPD profile containing more than ten peaks selected from the angles indicated above in table. 5C.

In some embodiments, the crystalline form of Formula IB, Form II, has an RPD profile containing peaks at 16.1 and 25.0° ± 0.2° 2-theta. In other embodiments, the crystalline form of Formula IB, Form II, has an RPD profile containing peaks at 14.3, 16.1, 17.4, and 21.9° ± 0.2° 2-theta. In other embodiments, the crystalline form of Formula IB, Form II, has an RPD profile containing peaks at 14.3, 16.1, 17.4, 21.9, and 25.0°±0.2° 2-theta. In other embodiments, the crystalline form of Formula IB, Form II, has an RPD profile containing peaks at 14.3, 16.1, 17.4, 21.9, 25.0, and 26.9° ± 0.2° 2- theta. In other embodiments, the crystalline form of Formula IB, Form II, has an RPD profile containing peaks at 14.3, 16.1, 17.4, 21.9, 25.0, 26.9, and 32.3°±0, 2° 2-theta. In some embodiments of the present description, the crystalline form of formula IB, form II, is characterized by an RPD profile containing peaks at three or more of 14.3, 16.1, 17.4, 21.9, 25.0, 26.9 and 32 .3° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula IB, form II, is characterized by an RPD profile containing peaks at four or more of 14.3, 16.1, 17.4, 21.9, 25.0, 26.9 and 32 .3° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula IB, form II, is characterized by an RPD profile containing peaks at five or more of 14.3, 16.1, 17.4, 21.9, 25.0, 26.9 and 32 .3° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula IB, form II, is characterized by an RPD profile containing peaks at six or more of 14.3, 16.1, 17.4, 21.9, 25.0, 26.9 and 32 .3° ± 0.2° 2-theta.

In some embodiments, the crystalline form of Formula IB, Form II, can be characterized substantially by a DSC thermogram as shown in FIG. 27. In FIG. 27 shows that the crystalline form of Formula IB, Form II, forms an endothermic peak at 270.14°C (starting at 265.48°C; 163.2 J/g) when heated at a rate of 10°C/min. In some embodiments of the present description, the crystalline form of formula IB is characterized by a DSC thermogram containing an endothermic peak at about 270°C when heated at a rate of 10°C/min. In some embodiments, the crystalline form of Formula IB, Form II, may be characterized substantially by a TGA profile as shown in FIG. 28, when heated at a rate of 20°C/min.

In some embodiments, the crystalline form of Formula IB has an RPD profile substantially as shown in FIG. 32. The RPD profile of the crystalline form of formula IB, form III shown in FIG. 32 contains reflection angles (degrees 2-theta ± 0.2° 2-theta), distances between lines (d-values), and relative intensities shown in Table 32. 5D.

- 17 043295

Table 5D. RPD data for . crystalline form of formula IB, form . III shown in Fig. 32

Angle (degrees 2-theta ± 0.2 degrees 2-theta) d value (A) Relative intensity 5.399 16.3551 16.5 10.5 8.4181 9.9 11.859 7.4563 13.5 12.8 6.9105 7.6 14.159 6.2498 18.8 15.68 5.6469 100 17.258 5.134 31.2 19.64 4.5164 I,4 20.778 4.2714 16.9 21.739 4.0847 27.9 22.9 3.8802 14.6 23.659 3.7574 9.7 24.62 3.6129 47.1 26.059 3.4165 22.2 28.238 3.1577 16.2 31.321 2.8536 30.4 33.542 2.6695 9.3 36.097 2.4862 8.9 36.782 2.4415 8.4

In some embodiments of the present description, the crystalline form of formula IB, form III, is characterized by an RPD profile containing a peak at one of the angles indicated in table. 5D. In other aspects, the crystalline form of formula IB, form III, is characterized by an RPD profile containing more than one peak at one of the angles indicated above in table. 5D. In other aspects, the crystalline form of formula IB, form III, is characterized by an RPD profile containing two peaks selected from the angles indicated above in table. 5D. In other aspects, the crystalline form of formula IB, form III, is characterized by an RPD profile containing three peaks selected from the angles indicated above in table. 5D. In other aspects, the crystalline form of formula IB, form III, is characterized by an RPD profile containing four peaks selected from the angles indicated above in table. 5D. In other aspects, the crystalline form of formula IB, form III, is characterized by an RPD profile containing five peaks selected from the angles indicated above in table. 5D. In other aspects, the crystalline form of formula IB, form III, is characterized by an RPD profile containing six peaks selected from the angles indicated above in table. 5D. In other aspects, the crystalline form of formula IB, form III, is characterized by an RPD profile containing seven peaks selected from the angles indicated above in table. 5D. In other aspects, the crystalline form of formula IB, form III, is characterized by an RPD profile containing eight peaks selected from the angles indicated above in table. 5D. In other aspects, the crystalline form of formula IB, form III, is characterized by an RPD profile containing nine peaks selected from the angles indicated above in table. 5D. In other aspects, the crystalline form of formula IB, form III, is characterized by an RPD profile containing ten peaks selected from the angles indicated above in table. 5D. In other aspects, the crystalline form of formula IB, form III, is characterized by an RPD profile containing more than ten peaks selected from the angles indicated above in table. 5D.

In some embodiments, the crystalline form of Formula IB, Form III, has an RPD profile containing peaks at 15.7, 24.6, and 31.3 degrees±0.2 degrees 2-theta. In other embodiments, the crystalline form of Formula IB, Form III, has an RPD profile containing peaks at 15.7, 17.3, 24.6, and 31.3° ± 0.2° 2-theta. In other embodiments, the crystalline form of Formula IB, Form III, has an RPD profile containing peaks at 15.7, 17.3, 21.7, 24.6, and 31.3° ± 0.2° 2-theta. In other embodiments, the crystalline form of Formula IB, Form III, has an RPD profile containing peaks at 15.7, 17.3, 21.7, 24.6, 26.1, 28.2, and 31.3°±0, 2° 2-theta. In other embodiments, the crystalline form of Formula IB, Form III, has an RPD profile containing peaks at 5.4, 15.7, 17.3, 21.7, 24.6, 26.1, 28.2, and 31.3 ° ± 0.2° 2-theta.

In some embodiments of the present description, the crystalline form of formula IB, form III, is characterized by an RPD profile containing peaks at three or more of 5.4, 15.7, 17.3, 21.7, 24.6, 26.1, 28 ,2 and 31.3° ± 0.2° g 2-theta. In some embodiments of the present description, the crystalline form of formula IB, form III, is characterized by an RPD profile containing peaks at four or more of 5.4, 15.7, 17.3, 21.7, 24.6, 26.1, 28 ,2 and 31.3° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula IB, form III, is characterized by an RPD profile containing peaks at five or more of 5.4, 15.7, 17.3, 21.7, 24.6, 26.1, 28 ,2 and 31.3° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula IB, form III, is characterized by an RPD profile containing peaks at six or more of 5.4, 15.7, 17.3, 21.7, 24.6, 26.1, 28 ,2 and 31.3° ± 0.2° 2-theta.

In some embodiments, the crystalline form of Formula IB, Form III, may be characterized by a substantially DSC thermogram as shown in FIG. 33. In FIG. 33 shows that the crystalline form of formula IB, form III, forms an endothermic peak at 208.48° C. (onset at 198.06° C.; 74.21 J/g) when heated at a rate of 10° C./min. . In some embodiments of the present description, the crystalline form of formula IB, form III, is characterized by a DSC thermogram containing an endothermic peak at about 208°C when heated at a rate

10°C/min.

In some embodiments, the crystalline form of Formula IB, Form III, may be characterized substantially by a TGA profile as shown in FIG. 34 when heated at a rate of 20°C/min.

In some embodiments, the crystalline form of Formula IB has an RPD profile substantially as shown in FIG. 38. The RPD profile of the crystalline form of formula IB, form IV shown in FIG. 38 contains reflection angles (degrees 2-theta ± 0.2° 2-theta), distances between lines (d-values), and relative intensities shown in Table 38. 5E:

Table 5E. The RPD data for the .crystal form of formula IB, form IV shown in FIG. 38

Angle (degrees 2-theta ± 0.2 degrees 2-theta) d value (A) Relative intensity 11.319 7.8109 I,8 12.461 7.0977 9.1 13.061 6.7727 21.1 15.459 5.727 42.1 15.919 5.5626 35.9 16.7 5.3042 59.4 17.46 5.0749 28.3 18.28 4.8493 22.6 19.357 4.5818 Yu,1 21.48 4.1334 100 22.96 3.8702 27.9 23.84 3.7293 29.8 24.5 3.6304 81.6 25.94 3.432 26.2 26.557 3.3536 22.4 28.34 3.1466 48 28.98 3.0785 34.2 30.681 2.9116 14 31.882 2.8046 15 33.558 2.6682 I,6 34.918 2.5674 14.4 36.258 2.4755 12.1 40.181 2.2424 I,8

In some embodiments of the present description, the crystalline form of formula IB, form IV, is characterized by an RPD profile containing a peak at one of the angles indicated in table. 5E. In other aspects, the crystalline form of formula IB, form IV, is characterized by an RPD profile containing more than one peak at one of the angles indicated above in table. 5E. In other aspects, the crystalline form of formula IB, form IV, is characterized by an RPD profile containing two peaks selected from the angles indicated above in table. 5E. In other aspects, the crystalline form of formula IB, form IV, is characterized by an RPD profile containing three peaks selected from the angles indicated above in table. 5E. In other aspects, the crystalline form of formula IB, form IV, is characterized by an RPD profile containing four peaks selected from the angles indicated above in table. 5E. In other aspects, the crystalline form of formula IB, form IV, is characterized by an RPD profile containing five peaks selected from the angles indicated above in table. 5E. In other aspects, the crystalline form of formula IB, form IV, is characterized by an RPD profile containing six peaks selected from the angles indicated above in table. 5E. In other aspects, the crystalline form of formula IB, form IV, is characterized by an RPD profile containing seven peaks selected from the angles indicated above in table. 5E. In other aspects, the crystalline form of formula IB, form IV, is characterized by an RPD profile containing eight peaks selected from the angles indicated above in table. 5E. In other aspects, the crystalline form of formula IB, form IV, is characterized by an RPD profile containing nine peaks selected from the angles indicated above in table. 5E. In other aspects, the crystalline form of formula IB, form IV, is characterized by an RPD profile containing ten peaks selected from the angles indicated above in table. 5E. In other aspects, the crystalline form of formula IB, form IV, is characterized by an RPD profile containing more than ten peaks selected from the angles indicated above in table. 5E.

In some embodiments, the crystalline form of Formula IB, Form IV, has an RPD profile containing peaks at 15.9, 21.5, and 24.5° ± 0.2° 2-theta. In other embodiments, the crystalline form of Formula IB, Form IV, has an RPD profile containing peaks at 15.5, 15.9, 16.7, 17.5, and 21.5° ± 0.2° 2-theta. In other embodiments, the crystalline form of Formula IB, Form IV, has an RPD profile containing peaks at 15.5, 15.9, 16.7, 17.5, 21.5, 23.0, and

- 19 043295

24.5° ± 0.2° 2-theta. In other embodiments, the crystalline form of Formula IB, Form IV, has an RPD profile containing peaks at 13.1, 15.5, 15.9, 16.7, 17.5, 21.5, 23.0, 24.5 and 28.3° ±

0.2° 2-theta. In other embodiments, the crystalline form of Formula IB, Form IV, has an RPD profile containing peaks at 13.1, 15.5, 15.9, 16.7, 17.5, 21.5, 23.0, 24.5 , 28.3 and 29.0° ± 0.2°

2-theta.

In some embodiments of the present description, the crystalline form of formula IB, form IV, is characterized by an RPD profile containing peaks at three or more of 13.1, 15.5, 15.9, 16.7, 17.5, 21.5, 23 .0, 24.5, 28.3 and 29.0° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula IB, form IV, is characterized by an RPD profile containing peaks at four or more of 13.1, 15.5, 15.9, 16.7, 17.5, 21.5, 23 .0, 24.5, 28.3 and 29.0° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula IB, form IV, is characterized by an RPD profile containing peaks at five or more of 13.1, 15.5, 15.9, 16.7, 17.5, 21.5, 23 .0, 24.5, 28.3 and 29.0° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula IB, form IV, is characterized by an RPD profile containing peaks at six or more of 13.1, 15.5, 15.9, 16.7, 17.5, 21.5, 23 .0, 24.5, 28.3 and 29.0° ± 0.2° 2-theta.

In some embodiments, the crystalline form of Formula IB, Form IV, may be characterized by a substantially DSC thermogram as shown in FIG. 39. In FIG. 39 shows that the crystalline form of Formula IB, Form IV, forms an endothermic peak at 220.59°C (onset at 214.32°C; 1.323 J/g) when heated at a rate of 10°C/min. In some embodiments of the present description, the crystalline form of formula IB, form IV, is characterized by a DSC thermogram containing an endothermic peak at about 221°C when heated at a rate of 10°C/min.

In some embodiments, the crystalline form of Formula IB, Form IV, may be characterized substantially by a TGA profile as shown in FIG. 40, when heated at a rate of 20°C/min.

In some embodiments, the crystalline form of Formula IB has an RPD profile substantially as shown in FIG. 42. The RPD profile of the formula IB crystalline form shown in FIG. 42 contains reflection angles (degrees 2-theta ± 0.2° 2-theta), distances between lines (d-values), and relative intensities shown in Table 2. 5F.

Table 5F. The RPD data for the crystalline form of formula IB shown in FIG. 42

Angle (degrees 2-theta ± 0.2 degrees 2-theta) d value (A) Relative intensity 5.34 16.5357 33.8 11.962 7.3924 21.3 14.118 6.268 25.9 15.581 5.6827 100 17.4 5.0924 51.6 19.039 4.6575 I,4 19.46 4.5578 12 20.88 4.2508 19 21.641 4.1031 41.7 22.823 3.8933 16.3 23.083 3.85 18.1 23.48 3.7857 16 23.516 3.78 14.3 24.6 3.6159 60.6 28.219 3.1597 16.6 30.54 2.9247 15.2 31.3 2.8554 20.7 33.357 2.6839 15.2 35.459 2.5295 I,4 37.037 2.4252 10.2

In some embodiments of the present description, the crystalline form of formula IB is characterized by an RPD profile containing a peak at one of the angles indicated in table. 5F. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing more than one peak at one of the angles listed above in table. 5F. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing two peaks selected from the angles indicated above in table. 5F. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing three peaks selected from the angles indicated above in table. 5F. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing four peaks selected from the angles indicated in Table 1 above. 5F. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing five peaks selected from the angles indicated above in table. 5F. In other aspects, the crystalline form of Formula IB is characterized by an RPD profile containing six peaks selected from the angles indicated in Table 1 above. 5F. In other aspects, the crystalline form of formula IB is

- 20 043295 is terized by the RPD profile containing seven peaks selected from the angles indicated in Table 1 above. 5F. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing eight peaks selected from the angles indicated above in table. 5F. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing nine peaks selected from the angles listed above in table. 5F. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing ten peaks selected from the angles listed above in table. 5F. In other aspects, the crystalline form of formula IB is characterized by an RPD profile containing more than ten peaks selected from the angles indicated above in table. 5F.

In some embodiments, the crystalline form of formula IB has an RPD profile containing peaks at 15.6 and 24.6° ± 0.2° 2-theta. In other embodiments, the crystalline form of Formula IB has an RPD profile containing peaks at 15.6, 17.4, and 21.6° ± 0.2° 2theta. In other embodiments, the crystalline form of formula IB has an RPD profile containing peaks at 15.6, 17.4, 21.6, and 24.6° ± 0.2° 2-theta. In other embodiments, the crystalline form of formula IB has an RPD profile containing peaks at 14.1, 15.6, 17.4, 21.6, and 24.6° ± 0.2° 2-theta. In other embodiments, the crystalline form of Formula IB has an RPD profile containing peaks at 5.3, 14.1, 15.6, 17.4, 21.6, and 24.6° ± 0.2° 2-theta.

In some embodiments of the present description, the crystalline form of formula IB is characterized by an RPD profile containing peaks at two or more of 5.3, 14.1, 15.6, 17.4, 21.6 and 24.6° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula IB is characterized by an RPD profile containing peaks at three or more of 5.3, 14.1, 15.6, 17.4, 21.6 and 24.6° ±0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula IB is characterized by an RPD profile containing peaks at four or more of 5.3, 14.1, 15.6, 17.4, 21.6 and 24.6° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula IB is characterized by an RPD profile containing peaks at five or more of 5.3, 14.1, 15.6, 17.4, 21.6 and 24.6° ± 0.2° 2-theta.

In some embodiments, the crystalline form of Formula IB may be characterized by a substantially DSC thermogram as shown in FIG. 43. In FIG. 43 shows that the crystalline form of formula IB forms an endothermic peak at 188.08°C (beginning at 175.78°C; 42.19 J/g), then an exothermic peak at 219.29°C (beginning at 217.41°C). C; 16.86 J/g), then an endothermic peak at 270.66°C (beginning at 266.29°C; 272.5 J/g), with heating at 10°C/min. In some embodiments of the present description, the crystalline form of formula IB is characterized by a DSC thermogram containing an endothermic peak at about 188°C when heated at a rate of 10°C/min. In some embodiments of the present description, the crystalline form of formula IB is characterized by a DSC thermogram containing an endothermic peak at about 271°C, when heated at a rate of 10°C/min.

In some embodiments, the crystalline form of Formula IB may be characterized substantially by a TGA profile as shown in FIG. 44 when heated at a rate of 20°C/min.

Formula IC (oxalate salt of formula I).

In some aspects, the present description refers to the crystalline form of the oxalate salt, i. IC formulas. In other aspects, the crystalline form of Formula IC is substantially free of other solid forms of Formula IC.

In some embodiments, the crystalline form of Formula IC has an RPD profile substantially as shown in FIG. 12. The RPD profile of the crystalline form of formula IC shown in FIG. 12 contains the angles of reflection (degrees 2-theta ± 0.2° 2-theta), line spacings (d-values), and relative intensities shown in Table 12. 6.

- 21 043295

Table 6. Data

in fig. 12

In some embodiments of the present description, the crystalline form of formula IC is characterized by an RPD profile containing a peak at one of the angles indicated in table. 6. In other aspects, the crystalline form of formula IC is characterized by an RPD profile containing more than one peak at one of the angles indicated above in table. 6. In other aspects, the crystalline form of formula IC is characterized by an RPD profile containing two peaks selected from the angles indicated above in table. 6. In other aspects, the crystalline form of formula IC is characterized by an RPD profile containing three peaks selected from the angles indicated above in table. 6. In other aspects, the crystalline form of formula IC is characterized by an RPD profile containing four peaks selected from the angles indicated above in table. 6. In other aspects, the crystalline form of formula IC is characterized by an RPD profile containing five peaks selected from the angles indicated above in table. 6. In other aspects, the crystalline form of formula IC is characterized by an RPD profile containing six peaks selected from the angles indicated above in table. 6. In other aspects, the crystalline form of formula IC is characterized by an RPD profile containing seven peaks selected from the angles indicated above in table. 6. In other aspects, the crystalline form of formula IC is characterized by an RPD profile containing eight peaks selected from the angles indicated above in table. 6. In other aspects, the crystalline form of formula IC is characterized by an RPD profile containing nine selected from the angles listed above in table. 6. In other aspects, the crystalline form of formula IC is characterized by an RPD profile containing ten peaks selected from the angles indicated above in table. 6. In other aspects, the crystalline form of formula IC is characterized by an RPD profile containing more than ten peaks selected from the angles indicated above in table. 6.

In some embodiments, the crystalline form of Formula IC has an RPD profile containing a peak at 10.5° ± 0.2° 2-theta. In other embodiments, the crystalline form

- 22 043295 formula IC is characterized by an RPD profile containing peaks at 10.5, 14.7, 16.2° ± 0.2° 2-theta. In other embodiments, the crystalline form of formula IC has an RPD profile containing peaks at 10.5, 14.7, 16.2, and 28.7° ± 0.2° 2-theta. In other embodiments, the crystalline form of formula IC is characterized by an RPD profile containing peaks at 10.5, 14.7, 16.2, 17.6, 17.7, 19.6, 28.7, and 28.9°±0, 2° 2-theta. In other embodiments, the crystalline form of Formula IC has an RPD profile containing peaks at 10.5, 14.2, 14.7, 28.7, and 28.9° ± 0.2° 2-theta. In other embodiments, the crystalline form of Formula IC has an RPD profile containing peaks at 10.5, 11.6, 13.1, 14.2, and 14.7° ± 0.2° 2-theta. In other embodiments, the crystalline form of formula IC is characterized by an RPD profile containing peaks at 10.5, 11.6, 13.1, 14.2, 14.7, 14.9, 16.2, 17.6, 17.7 , 19.6, 28.7 and 28.9° ± 0.2° 2-theta.

In some embodiments of the present description, the crystalline form of formula IC is characterized by an RPD profile containing peaks at three or more of 10.5, 11.6, 13.1, 14.2, 14.7, 14.9, 16.2, 17 .6, 17.7, 19.6, 28.7 and 28.9° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula IC is characterized by an RPD profile containing peaks at four or more of 10.5, 11.6, 13.1, 14.2, 14.7, 14.9, 16.2, 17 .6, 17.7, 19.6, 28.7 and 28.9° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula IC is characterized by an RPD profile containing peaks at five or more of 10.5, 11.6, 13.1, 14.2, 14.7, 14.9, 16.2, 17 .6, 17.7, 19.6, 28.7 and 28.9° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula IC is characterized by an RPD profile containing peaks at six or more of 10.5, 11.6, 13.1, 14.2, 14.7, 14.9, 16.2, 17 .6, 17.7, 19.6, 28.7 and 28.9° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula IC is characterized by an RPD profile containing peaks at seven or more of 10.5, 11.6, 13.1, 14.2, 14.7, 14.9, 16.2, 17 .6, 17.7, 19.6, 28.7 and 28.9 ± 0.2° 2-theta.

Formula ID (phosphate salt of formula I).

In some aspects, the present description refers to the crystalline form of the phosphate salt, i. to Formula III. In other aspects, the crystalline form of Formula ID is substantially free of other solid forms of Formula ID.

In some embodiments, the crystalline form of Formula ID has a substantially RPD profile as shown in FIG. 13. The RPD profile of the crystalline form of formula ID shown in FIG. 13 contains reflection angles (degrees 2-theta ± 0.2° 2-theta), line spacings (d-values), and relative intensities shown in Table 13. 7.

- 23 043295

Table 7. RPD data for the crystalline form of formula ID shown in FIG. 13

Angle (degrees 2-theta ± 0.2 degrees 2-theta) d value (A) Relative intensity 3.56 24.804 100 10.72 8.246 55 11.53 7.671 7 11.99 7.378 13 12.64 7,000 5 13.50 6.552 12 13.69 6.463 9 14.04 6.302 AND 14.60 6.060 15 15.03 5,889 7 15.56 5.691 27 16.28 5.442 12 17.33 5.112 7 17.73 5,000 6 17.93 4.943 22 18.54 4.783 AND 18.68 4.747 21 18.94 4.682 9 19.36 4,580 AND 20.66 4.295 6 21.12 4.202 7 21.52 4.125 5 21.82 4.070 7 22.49 3,950 6 23.13 3.843 AND 23.56 3.773 8 24.07 3.694 7 24.54 3.625 9 24.74 3.596 19 25.21 3.529 AND 25.43 3,500 5 25.85 3.444 10 26.30 3.386 AND 27.42 3,250 14 27.59 3.230 12 27.90 3.195 9 28.28 3.154 10 29.20 3.056 5 29.46 3.029 6 29.67 3.008 5 30.35 2.943 7

In some embodiments of the present description, the crystalline form of formula ID is characterized by an RPD profile containing a peak at one of the angles indicated in table. 7. In other aspects, the crystalline form of formula ID is characterized by an RPD profile containing more than one peak at one of the angles indicated above in table. 7. In other aspects, the crystalline form of formula ID is characterized by an RPD profile containing two peaks selected from the angles indicated above in table. 7. In other aspects, the crystalline form of formula ID is characterized by an RPD profile containing three peaks selected from the angles indicated above in table. 7. In other aspects, the crystalline form of formula ID is characterized by an RPD profile containing four peaks selected from the angles indicated above in table. 7. In other aspects, the crystalline form of formula ID is characterized by an RPD profile containing five peaks selected from the angles indicated above in table. 7. In other aspects, the crystalline form of formula ID is characterized by an RPD profile containing six peaks selected from the angles indicated above in table. 7. In other aspects, the crystalline form of formula ID is characterized by an RPD profile containing seven peaks selected from the angles indicated above in table. 7. In other aspects, the crystalline form of formula ID is characterized by an RPD profile containing eight peaks selected from the angles indicated above in table. 7. In other aspects, the crystalline form of formula ID is characterized by an RPD profile containing nine peaks selected from the angles indicated above in table. 7. In other aspects, the crystalline form of formula ID is characterized by an RPD profile containing ten peaks selected from the angles indicated above in table. 7. In other aspects, the crystalline form of formula ID is characterized by an RPD profile containing more than ten peaks selected from the angles indicated above in table. 7. In some embodiments, the crystalline form of formula ID

- 24 043295 is characterized by a RPD profile containing a peak at 3.6° ± 0.2 degrees 2-theta. In other embodiments, the crystalline form of Formula ID has an RPD profile containing peaks at 3.6 and 10.7° ± 0.2° 2-theta. In other embodiments, the crystalline form of formula ID has an RPD profile containing peaks at 3.6, 10.7, and 15.6° ± 0.2° 2-theta. In other embodiments, the crystalline form of formula ID has an RPD profile containing peaks at 3.6, 10.7, 15.6, and 17.9° ± 0.2° 2-theta. In other embodiments, the crystalline form of formula ID has an RPD profile containing peaks at 3.6, 10.7, 15.6, 17.9, and 18.7° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula ID is characterized by an RPD profile containing peaks at two or more of 3.6, 10.7, 15.6, 17.9 and 18.7° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula ID is characterized by an RPD profile containing peaks at three or more of 3.6, 10.7, 15.6, 17.9 and 18.7° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula ID is characterized by an RPD profile containing peaks at four or more of 3.6, 10.7, 15.6, 17.9 and 18.7° ± 0.2° 2-theta.

In some embodiments, the crystalline form of Formula ID has a substantially RPD profile as shown in FIG. 45. The RPD profile of the crystalline form of formula ID shown in FIG. 45 contains reflection angles (degrees 2-theta ± 0.2° 2-theta), distances between lines (d-values), and relative intensities shown in Table 1. 7A.

Table 7A. The RPD data for the crystalline form of formula ID shown in FIG. 45

Angle (degrees 2-theta ± 0.2 degrees 2-theta) d value (A) Relative intensity 10.64 8.3078 25.2 15.14 5,847 12.4 17.08 5.1871 57.8 18.14 4.8863 100 20.04 4.4271 79.9 21.54 4.122 28.3 22.44 3.9587 36.2 24.62 3.613 18.7 26.18 3.4011 98.7 27.278 3.2666 32.7 28.1 3.1729 72.5 29.04 3.0723 16.5 30.3 2.9473 16 33.377 2.6824 ID 34.277 2.6139 8.3 37.24 2.4125 9.5 38.057 2.3625 9.5 39.557 2.2763 14.7 40.14 2.2446 19.5 44.06 2.0536 I,6 44.06 2.0536 I,6

In some embodiments of the present description, the crystalline form of formula ID is characterized by an RPD profile containing a peak at one of the angles indicated in table. 7A. In other aspects, the crystalline form of formula ID is characterized by an RPD profile containing more than one peak at one of the angles indicated above in table. 7A. In other aspects, the crystalline form of formula ID is characterized by an RPD profile containing two peaks selected from the angles indicated above in table. 7A. In other aspects, the crystalline form of formula ID is characterized by an RPD profile containing three peaks selected from the angles indicated above in table. 7A. In other aspects, the crystalline form of formula ID is characterized by an RPD profile containing four peaks selected from the angles indicated above in table. 7A. In other aspects, the crystalline form of formula ID is characterized by an RPD profile containing five peaks selected from the angles indicated above in table. 7A. In other aspects, the crystalline form of formula ID is characterized by an RPD profile containing six peaks selected from the angles indicated above in table. 7A. In other aspects, the crystalline form of formula ID is characterized by an RPD profile containing seven peaks selected from the angles indicated above in table. 7A. In other aspects, the crystalline form of formula ID is characterized by an RPD profile containing eight peaks selected from the angles indicated above in table. 7A. In other aspects, the crystalline form of formula ID is characterized by an RPD profile containing nine peaks selected from the angles indicated above in table. 7A. In other aspects, the crystalline form of formula ID is characterized by an RPD profile containing ten peaks selected from the angles listed above in table. 7A. In other aspects, the crystalline form of formula ID is characterized by an RPD profile containing more than ten peaks selected from the angles indicated above in table. 7A.

In some embodiments, the crystalline form of Formula ID has a profile

- 25 043295

RPD containing a peak at 18.1, 20.0, 26.2 and 28.1° ± 0.2° 2-theta. In other embodiments, the crystalline form of Formula ID has an RPD profile containing peaks at 18.1, 20.0, 21.5, 22.4, 26.2, and 28.1° ± 0.2° 2-theta. In other embodiments, the crystalline form of formula ID has an RPD profile containing peaks at 17.1, 18.1, 20.0, 26.2, and 28.1° ± 0.2° 2-theta. In other embodiments, the crystalline form of Formula ID has an RPD profile containing peaks at 10.6, 17.1, 18.1, 20.0, 26.2, and 28.1° ± 0.2° 2-theta. In other embodiments, the crystalline form of formula ID is characterized by an RPD profile containing peaks at 10.6, 17.1, 18.1, 20.0, 21.5, 22.4, 26.2, and 28.1° ± 0, 2° 2-theta.

In some embodiments of the present description, the crystalline form of formula ID is characterized by an RPD profile containing peaks at two or more of 10.6, 17.1, 18.1, 20.0, 21.5, 22.4, 26.2 and 28 .1° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula ID is characterized by an RPD profile containing peaks at three or more of 10.6, 17.1, 18.1, 20.0, 21.5, 22.4, 26.2 and 28 .1° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula ID is characterized by an RPD profile containing peaks at four or more of 10.6, 17.1, 18.1, 20.0, 21.5, 22.4, 26.2 and 28 .1° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula ID is characterized by an RPD profile containing peaks at five or more of 10.6, 17.1, 18.1, 20.0, 21.5, 22.4, 26.2 and 28 .1° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula ID is characterized by an RPD profile containing peaks at six or more of 10.6, 17.1, 18.1, 20.0, 21.5, 22.4, 26.2 and 28 .1° ± 0.2° 2-theta.

In some embodiments, the crystalline form of Formula ID may be characterized substantially by a DSC thermogram as shown in FIG. 46. In FIG. 46 shows that the crystalline form of formula ID forms an endothermic peak at 160.66°C (beginning at 154.41°C; 48.38 J/g), then another endothermic peak at 221.37°C (beginning at 201. 43°C; 99.14 J/g), when heated at 10°C/min. In some embodiments of the present description, the crystalline form of formula ID is characterized by a DSC thermogram containing an endothermic peak at about 161°C when heated at a rate of 10°C/min. In other embodiments of the present description, the crystalline form of formula ID is characterized by a DSC thermogram containing an endothermic peak at about 221°C, when heated at a rate of 10°C/min.

In some embodiments, the crystalline form of Formula ID may be characterized substantially by the TGA profile as shown in FIG. 47 when heated at a rate of 20°C/min. In FIG. 47 shows that the crystalline form of formula ID loses about 3.2% by weight when heated to about 150°C.

Formula IE (bisulfate salt of formula I).

In some aspects, the present description refers to the crystalline form of the bisulfate salt, i. IE formulas. In other aspects, the crystalline form of Formula IE is substantially free of other solid forms of Formula IE.

Formula I - free base

In some aspects, the present description relates to crystalline forms of the compounds of formula I

In some embodiments, the crystalline form of formula I is crystalline form I (Formula I, Form I). In some embodiments, the crystalline form of Formula I, Form I, has an RPD profile substantially as shown in FIG. 48. The RPD profile of the crystalline form of Formula I, Form I shown in FIG. 48 contains reflection angles (degrees 2-theta ± 0.2° 2-theta), distances between lines (d-values), and relative intensities shown in Table 1. 7B.

- 26 043295

Table 7B. The RPD data for the crystalline form of Formula I, Form I shown in FIG. 48

Angle (degrees 2-theta ± 0.2 degrees 2-theta) d value (A) Relative intensity 9.299 9.5031 20.6 11.82 7.4809 9.6 12.8 6.9105 12.8 14.981 5.9089 29.4 15.58 5.683 40.4 17.341 5.1097 100 18.1 4.8971 78.2 19.66 4.5118 37.9 20.42 4.3456 56.9 21.818 4.0701 27.4 23.341 3.808 22.9 24.2 3.6747 38.4 25.2 3.5311 62.1 27.08 3.2901 53.1 28.32 3.1487 46.8 28.799 3.0974 34.5 29.959 2.9801 35.4 30.959 2.8861 14.3 31.839 2.8083 16.8 33.06 2.7073 22.4 33.96 2.6376 16.8 34.74 2.5801 8.8 35.9 2.4994 17.3 36.419 2.4649 29.1 38.06 2.3624 13.7 39.08 2.303 9 39.999 2.2522 21.8 41.681 2.1651 29.4 42.417 2.1292 12.8

In some embodiments of the present description, the crystalline form of formula I, form I, is characterized by an RPD profile containing a peak at one of the angles indicated in table. 7B. In other aspects, the crystalline form of formula I, form I, is characterized by an RPD profile containing more than one peak at one of the angles indicated above in table. 7B. In other aspects, the crystalline form of formula I, form I, is characterized by an RPD profile containing two peaks selected from the angles indicated above in table. 7B. In other aspects, the crystalline form of formula I, form I, is characterized by an RPD profile containing three peaks selected from the angles indicated above in table. 7B. In other aspects, the crystalline form of formula I, form I, is characterized by an RPD profile containing four peaks selected from the angles indicated above in table. 7B. In other aspects, the crystalline form of formula I, form I, is characterized by an RPD profile containing five peaks selected from the angles indicated above in table. 7B. In other aspects, the crystalline form of formula I, form I, is characterized by an RPD profile containing six peaks selected from the angles indicated above in table. 7B. In other aspects, the crystalline form of formula I, form I, is characterized by an RPD profile containing seven peaks selected from the angles indicated above in table. 7B. In other aspects, the crystalline form of formula I, form I, is characterized by an RPD profile containing eight peaks selected from the angles indicated above in table. 7B. In other aspects, the crystalline form of Formula I, Form I, is characterized by an RPD profile containing nine peaks selected from the angles indicated in Table 1 above. 7B. In other aspects, the crystalline form of formula I, form I, is characterized by an RPD profile containing ten peaks selected from the angles indicated above in table. 7B. In other aspects, the crystalline form of formula I, form I, is characterized by an RPD profile containing more than ten peaks selected from the angles indicated above in table. 7B.

In some embodiments, the crystalline form of Formula I, Form I, has an RPD profile containing peaks at 17.3 and 18.1° ± 0.2° 2-theta. In other embodiments, the crystalline form of Formula I, Form I, has an RPD profile containing peaks at 17.3, 18.1, 25.2, and 27.1° ± 0.2° 2-theta. In other embodiments, the crystalline form of Formula I, Form I, has an RPD profile containing peaks at 17.3, 18.1, 25.2, 27.1, 28.3, 28.8, and 30.0°±0, 2° 2theta. In other embodiments, the crystalline form of Formula I, Form I, has an RPD profile containing peaks at 17.3, 18.1, 20.4, 24.2, 25.2, 27.1, 28.3, 28.8 and 30.0° ± 0.2° 2-theta. In other embodiments, the crystalline form of Formula I, Form I, has an RPD profile containing peaks at 15.0, 17.3, 18.1, 20.4, 24.2, 25.2, 27.1, 28.3 , 28.8 and 30.0° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula I, form I, is characterized by an RPD profile containing peaks at two or more of 15.0, 17.3, 18.1, 20.4, 24.2, 25.2, 27 .1, 28.3, 28.8 and 30.0° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula I, form I, is characterized by an RPD profile containing peaks at three or more of 15.0, 17.3,

- 27 043295 .1, 20.4, 24.2, 25.2, 27.1, 28.3, 28.8 and 30.0° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula I, form I, is characterized by an RPD profile containing peaks at four or more of 15.0, 17.3, 18.1, 20.4, 24.2, 25.2, 27 .1, 28.3, 28.8 and 30.0° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula I, form I, is characterized by an RPD profile containing peaks at five or more of 15.0, 17.3, 18.1, 20.4, 24.2, 25.2, 27 .1, 28.3, 28.8 and 30.0° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula I, form I, is characterized by an RPD profile containing peaks at six or more of 15.0, 17.3, 18.1, 20.4, 24.2, 25.2, 27 .1, 28.3, 28.8 and 30.0° ± 0.2° 2-theta.

In some embodiments, the crystalline form of Formula I, Form I, can be characterized substantially by a DSC thermogram as shown in FIG. 49. In FIG. 49 shows that the crystalline form of Formula I, Form I, forms an endothermic peak at 140.30°C (onset at 136.36°C; 152.7 J/g) when heated at 10°C/min. In some embodiments of the present description, the crystalline form of formula I, form I, is characterized by a DSC thermogram containing an endothermic peak at about 140°C when heated at a rate of 10°C/min.

In some embodiments, Form I of Formula I may be characterized substantially by a TGA profile as shown in FIG. 50 when heated at a rate of 20°C/min. In FIG. 50 shows that the crystalline form of Formula I, Form I, loses about 10.9% weight when heated to about 150°C.

In some embodiments, Form I of Formula I may be characterized essentially by a chipboard profile as shown in FIG. 52. In FIG. 53 shows that DSP does not lead to a change in the polymorphic form.

In some embodiments, the crystalline form of Formula I is the crystalline Form II (Formula I, Form II). In some embodiments, the crystalline form of Formula I, Form II, has an RPD profile substantially as shown in FIG. 54. The RPD profile of the crystalline form of formula I, form II shown in FIG. 54 contains reflection angles (degrees 2-theta ± 0.2° 2-theta), distances between lines (d-values), and relative intensities shown in Table 54. 7C:

Table 7C. RPD data for

I

Angle (degrees 2-theta ± 0.2 degrees 2-theta) d value (A) Relative intensity 4.039 21.8576 9.6 11.54 7.6618 15 12.54 7.0528 37.5 15.14 5.8471 100 17.36 5.1042 15 18.92 4.6866 46.9 19.54 4.5393 15.6 20.56 4.3163 15.1 21.099 4.2072 9.2 21.898 4.0554 7.4 23.46 3.7889 20.3 24.34 3.6539 47.4 24.86 3.5786 47.8 25.46 3.4956 67.3 26.24 3.3934 41.2 27.221 3.2734 20.3 28.481 3.1313 11.6 29.501 3.0254 13.6 30.28 2.9493 44.9 32.22 2.776 19 34.22 2.6182 P,9 34.739 2.5802 17.8 35.74 2.5102 14.1 36.42 2.4649 15.3 37.46 2.3988 9.2 38.299 2.3482 10.7 39.12 2.3008 6.9 40.08 2.2478 18.4 41.661 2.1661 7.7 42.58 2.1215 6.4 43.36 2.0851 7.5 44.079 2.0527 12.1

II shown in Fig. 54

In some embodiments of the present description, the crystalline form of formula I, the form

- 28 043295

II, is characterized by a RPD profile containing a peak at one of the angles indicated in Table. 7C. In other aspects, the crystalline form of formula I, form II, is characterized by an RPD profile containing more than one peak at one of the angles indicated above in table. 7C. In other aspects, the crystalline form of formula I, form II, is characterized by an RPD profile containing two peaks selected from the angles indicated above in table. 7C. In other aspects, the crystalline form of formula I, form II, is characterized by an RPD profile containing three peaks selected from the angles indicated above in table. 7C. In other aspects, the crystalline form of formula I, form II, is characterized by an RPD profile containing four peaks selected from the angles indicated above in table. 7C. In other aspects, the crystalline form of formula I, form II, is characterized by an RPD profile containing five peaks selected from the angles indicated above in table. 7C. In other aspects, the crystalline form of formula I, form II, is characterized by an RPD profile containing six peaks selected from the angles indicated above in table. 7C. In other aspects, the crystalline form of formula I, form II, is characterized by an RPD profile containing seven peaks selected from the angles indicated above in table. 7C. In other aspects, the crystalline form of formula I, form II, is characterized by an RPD profile containing eight peaks selected from the angles indicated above in table. 7C. In other aspects, the crystalline form of formula I, form II, is characterized by an RPD profile containing nine peaks selected from the angles indicated above in table. 7C. In other aspects, the crystalline form of formula I, form II, is characterized by an RPD profile containing ten peaks selected from the angles indicated above in table. 7C. In other aspects, the crystalline form of formula I, form II, is characterized by an RPD profile containing more than ten peaks selected from the angles indicated above in table. 7C.

In some embodiments, the crystalline form of Formula I, Form II, has an RPD profile containing peaks at 23.5 and 24.9° ± 0.2° 2-theta. In other embodiments, the crystalline form of Formula I, Form II, has an RPD profile containing peaks at 18.9, 23.5, 24.3, and 24.9° ± 0.2° 2-theta. In other embodiments, the crystalline form of Formula I, Form II, has an RPD profile containing peaks at 17.4, 18.9, 23.5, 24.3, and 24.9, 25.5, and 30.3°±0, 2° 2-theta. In other embodiments, the crystalline form of Formula I, Form II, has an RPD profile containing peaks at 15.1, 17.4, 18.9, 23.5, 24.3, and 24.9° ± 0.2° 2- theta. In other embodiments, the crystalline form of Formula I, Form II, has an RPD profile containing peaks at 15.1, 17.4, 18.9, 23.5, 24.3, 24.9, and 25.5°±0, 2° 2-theta. In other embodiments, the crystalline form of Formula I, Form II, has an RPD profile containing peaks at 15.1, 17.4, 18.9, 23.5, 24.3, 24.9, 25.5, and 30.3 ° ± 0.2° 2-theta.

In some embodiments of the present description, the crystalline form of formula I, form II, is characterized by an RPD profile containing peaks at two or more of 15.1, 17.4, 18.9, 23.5, 24.3, 24.9, 25 .5 and 30.3° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula I, form II, is characterized by an RPD profile containing peaks at three or more of 15.1, 17.4, 18.9, 23.5, 24.3, 24.9, 25 .5 and 30.3° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula I, form II, is characterized by an RPD profile containing peaks at four or more of 15.1, 17.4, 18.9, 23.5, 24.3, 24.9, 25 .5 and 30.3° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula I, form II, is characterized by an RPD profile containing peaks at five or more of 15.1, 17.4, 18.9, 23.5, 24.3, 24.9, 25 .5 and 30.3° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula I, form II, is characterized by an RPD profile containing peaks at six or more of 15.1, 17.4, 18.9, 23.5, 24.3, 24.9, 25 .5 and 30.3° ± 0.2° 2-theta.

In some embodiments, the crystalline form of Formula I, Form II, may be characterized by a substantially DSC thermogram as shown in FIG. 55. In FIG. 55 shows that the crystalline form of Formula I, Form II, forms an endothermic peak at 137.01°C (onset at 133.28°C; 252.7 J/g) when heated at 10°C/min. In some embodiments of the present description, the crystalline form of formula I, form II, is characterized by a DSC thermogram containing an endothermic peak at about 137°C when heated at a rate of 10°C/min.

In some embodiments, the crystalline form of Formula I, Form II, has an RPD profile substantially as shown in FIG. 58.

In some embodiments, the crystalline form of Formula I, Form II, has a substantially DSC thermogram as shown in FIG. 59.

In some embodiments, the crystalline form of Formula I, Form II, has an RPD profile substantially as shown in FIG. 60.

In some embodiments, the crystalline form of Formula I, Form II, has a substantially DSC thermogram as shown in FIG. 61.

In some embodiments, the crystalline form of Formula I, Form II, has an RPD profile substantially as shown in FIG. 62.

In some embodiments, the crystalline form of Formula I, Form II, has a substantially DSC thermogram as shown in FIG. 63.

- 29 043295

In some embodiments, the crystalline form of formula I is a crystalline form III (formula I, form III). In some embodiments, the crystalline form of Formula I, Form III, has an RPD profile substantially as shown in FIG. 56. The RPD profile of the crystalline form of formula I, form III shown in FIG. 56 contains reflection angles (degrees 2-theta ± 0.2° 2-theta), line spacings (d-values), and relative intensities shown in Table 56. 7D:

Table 7D. RPD data for crystalline . Forms of Formula I, Forms III of FIG. 56

Angle (degrees 2- d value Relative theta ± 0.2 degrees (A) intensity 2-theta) 6.263 14.1012 18.5 9.621 9.1857 96.2 11,399 7.756 36.5 12.299 7.1907 25.6 13.24 6.6814 49.3 13.861 6.3836 45 15.56 5.6902 38.9 16.64 5.3231 95.7 17.44 5.0808 99.5 18.1 4,897 27.5 19 4.6671 42.7 20.38 4.354 65.9 20.96 4.2348 62.6 23.381 3.8014 44.1 24.92 3.5702 100 25.78 3.4529 86.3 26.3 3.3858 89.6 27 3.2997 33.2 27.66 3.2223 63 28.44 3.1357 39.3 29.28 3.0477 38.9 30.86 2.8951 28.4 32.142 2.7825 23.2 32.94 2.7169 24.2 36.299 2.4729 25.1 41.519 2.1732 58.8 42.2 2.1397 33.2

In some embodiments of the present description, the crystalline form of formula I, form III, is characterized by an RPD profile containing a peak at one of the angles indicated in table. 7D. In other aspects, the crystalline form of formula I, form III, is characterized by an RPD profile containing more than one peak at one of the angles indicated above in table. 7D. In other aspects, the crystalline form of formula I, form III, is characterized by an RPD profile containing two peaks selected from the angles indicated above in table. 7D. In other aspects, the crystalline form of formula I, form III, is characterized by an RPD profile containing three peaks selected from the angles indicated above in table. 7D. In other aspects, the crystalline form of formula I, form III, is characterized by an RPD profile containing four peaks selected from the angles indicated above in table. 7D. In other aspects, the crystalline form of formula I, form III, is characterized by an RPD profile containing five peaks selected from the angles indicated above in table. 7D. In other aspects, the crystalline form of formula I, form III, is characterized by an RPD profile containing six peaks selected from the angles indicated above in table. 7D. In other aspects, the crystalline form of formula I, form III, is characterized by an RPD profile containing seven peaks selected from the angles indicated above in table. 7D. In other aspects, the crystalline form of formula I, form III, is characterized by an RPD profile containing eight peaks selected from the angles indicated above in table. 7D. In other aspects, the crystalline form of formula I, form III, is characterized by an RPD profile containing nine peaks selected from the angles indicated above in table. 7D. In other aspects, the crystalline form of formula I, form III, is characterized by an RPD profile containing ten peaks selected from the angles indicated above in table. 7D. In other aspects, the crystalline form of formula I, form III, is characterized by an RPD profile containing more than ten peaks selected from the angles indicated above in table. 7D.

In some embodiments, the crystalline form of Formula I, Form III, has an RPD profile containing peaks at 16.6 and 17.4° ± 0.2° 2-theta. In other embodiments, the crystalline form of Formula I, Form III, has an RPD profile containing peaks at 17.4, 20.4, and 25.8° ± 0.2° 2-theta. In other embodiments, the crystalline form of Formula I, Form III, has an RPD profile containing peaks at 17.4, 20.4, 24.9, 25.8, and 26.3° ± 0.2° 2-theta. In other embodiments, the crystalline form of Formula I, Form III, has an RPD profile containing peaks at 16.6, 17.4, 20.4, 24.9, 25.8, 26.3, and 27.7°±0, 2° 2-theta. In other embodiments, the crystalline form of formula I, form III, is characterized by an RPD profile containing peaks

- 30 043295 at 9.2, 16.6, 17.4, 20.4, 24.9, 25.8, 26.3, 27.7 and 41.5° ± 0.2° 2-theta.

In some embodiments of the present description, the crystalline form of formula I, form III, is characterized by an RPD profile containing peaks at two or more of 9.2, 16.6, 17.4, 20.4, 24.9, 25.8, 26 .3, 27.7 and 41.5° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula I, form III, is characterized by an RPD profile containing peaks at three or more of 9.2, 16.6, 17.4, 20.4, 24.9, 25.8, 26 .3, 27.7 and 41.5° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula I, form III, is characterized by an RPD profile containing peaks at four or more of 9.2, 16.6, 17.4, 20.4, 24.9, 25.8, 26 .3, 27.7 and 41.5° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula I, form III, is characterized by an RPD profile containing peaks at five or more of 9.2, 16.6, 17.4, 20.4, 24.9, 25.8, 26 .3, 27.7 and 41.5° ± 0.2° 2-theta. In some embodiments of the present description, the crystalline form of formula I, form III, is characterized by an RPD profile containing peaks at six or more of 9.2, 16.6, 17.4, 20.4, 24.9, 25.8, 26 .3, 27.7 and 41.5° ± 0.2° 2-theta.

In some embodiments, the crystalline form of Formula I, Form III, may be characterized by a substantially DSC thermogram as shown in FIG. 57. In FIG. 57 shows that the crystalline form of Formula I, Form III forms an endothermic peak at 124.92°C (onset at 106.28°C; 113.2 J/g) when heated at 10°C/min. In some embodiments of the present description, the crystalline form of formula I, form III, is characterized by a DSC thermogram containing an endothermic peak at about 125°C when heated at a rate of 10°C/min.

Pharmaceutical compositions and routes of administration

The proposed pharmaceutical compositions are usually formulated to provide a therapeutically effective amount of a compound of the present invention as an active ingredient or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. If necessary, these pharmaceutical compositions contain its pharmaceutically acceptable salt and/or coordination complex and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and excipients, diluents, including a sterile aqueous solution and various organic solvents, penetration enhancers, solubilizers and adjuvants. . The proposed pharmaceutical compositions can be administered alone or in combination with one or more other agents, which are also usually administered in the form of pharmaceutical compositions. If desired, one or more of the compounds of the present invention and the other agent(s) may be mixed into a single preparation, or both components may be formulated into separate preparations for their combined use, either alone or at the same time.

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%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004% , 0.0003%, 0.0002% or 0.0001% (or a value in the range defined by and including any two of the above), wt./wt., wt./about. or rev./rev.

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%, 14.50%, 14.25% 14%, 13.75%, 13.50 %, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25% 8%, 7.75 %, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5% , 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25 %, 2%, 1.75%, 1.50%, 1.25%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0, 4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0, 03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% (or a value in the range defined by and including any two of the above), wt./wt., wt./about. or rev./rev.

In some embodiments, the concentration of one or more compounds of the present invention is in the range of from about 0.0001% to about 50%, from about 0.001% to about 40%, from about 0.01% to about 30%, from about 0. 02% to about 29%, about 0.03% to about 28%, about 0.04% to about 27%, about 0.05% to about 26%, about 0.06% to about 25% , from about 0.07% to about 24%, from about 0.08% to about 23%, from about 0.09% to about 22%, from about 0.1% to about 21%, from about 0.2 % to about 20%, from about 0.3% to about 19%, from about 0.4% to about 18%, from about 0.5% to about 17%, from about 0.6% to about 16%, from about 0.7% to about

- 31 043295

15%, from about 0.8% to about 14%, from about 0.9% to about 12%, from about 1% to about 10% w/w, w/v. or rev./rev. In some embodiments, the concentration of one or more compounds of the present invention is in the range of from about 0.001% to about 10%, from about 0.01% to about 5%, from about 0.02% to about 4.5%, from about 0.03% to about 4%, from about 0.04% to about 3.5%, from about 0.05% to about 3%, from about 0.06% to about 2.5%, from 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, wt ./rev, or rev/rev.

In some embodiments, the amount of one or more compounds of the present invention is exactly or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6 .5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1 .5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0 .55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0 09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g 0.006 g 0.005 g 0.004 g 0.003 g 0.002 g 0.001 g 0.0009 g 0.0008 g 0.0007 g 0.0006 g 0.0005 g 0.0004 g , 0.0003 g, 0.0002 g, or 0.0001 g (or a value in the range defined by and including any two of the above values).

In some embodiments, the amount of one or more compounds of the present invention is greater than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0 .0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g, 0.3 g, 0.35 g, 0.4 g, 0.45 g, 0.5 g, 0, 55 g, 0.6 g, 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g , 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g, 7.5 g, 8 g, 8.5 g, 9 g, 9.5 g or 10 g (or a value in the range defined by and including any two of the above values).

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

The compounds of the present invention are effective over a wide dosage range. For example, for the treatment of adults, examples of doses that can be used are doses of 0.01 to 1000 mg, 0.5 to 100 mg, 1 to 50 mg per day, and 5 to 40 mg per day. An exemplary dose is 10 to 30 mg per day. The exact dose depends on the route of administration, the form in which the proposed connection is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.

The pharmaceutical composition according to the present invention usually contains the active ingredient (i.e. the compound according to the present description) according to the present invention 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 excipients, diluents, sterile aqueous solution and various organic solvents, penetration enhancers, solubilizers and adjuvants. Non-limiting illustrative pharmaceutical compositions and methods for their preparation are described below.

Pharmaceutical compositions for oral administration.

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

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

In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral administration. Pharmaceutical compositions of the present invention suitable for oral administration may be presented as single dosage forms such as capsules, cachets or tablets, or as liquids or aerosol sprays, each containing a predetermined amount of the active ingredient, in the form of a powder or in granules, in solution or in suspension in an aqueous or non-aqueous liquid, oil-in-water emulsion or water-in-oil liquid emulsion. Such dosage forms may be prepared by any of the pharmaceutical methods, but all methods include the step of bringing the active ingredient into contact with the carrier which contains one or more of the required ingredients. In general, compositions are prepared by uniformly and intimately mixing the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired product. For example, a tablet may be obtained by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be obtained

- 32 043295 by compressing in an appropriate machine the active ingredient in free flowing form, such as powder or granules, optionally mixed with an excipient, such as, but not limited to, a binder, a lubricant, an inert diluent and/or a surfactant, or dispersing agent. Molded tablets can be obtained by molding in a suitable machine a mixture of a powdered compound moistened with an inert liquid diluent.

The present invention further includes anhydrous pharmaceutical compositions and dosage forms containing the active ingredient, since water may promote the destruction of some compounds. For example, water can be added (eg, 5%) to pharmaceutical products as a means to simulate long shelf life to determine characteristics such as shelf life or stability of dosage forms over time. Anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low moisture ingredients and under low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms of the present invention that contain lactose can be prepared in an anhydrous form if significant contact with moisture and/or moisture is expected during manufacture, packaging and/or storage. The anhydrous pharmaceutical composition can be prepared and stored so as to maintain its anhydrous form. Accordingly, anhydrous compositions can be packaged using known materials to prevent exposure to water, so that they can be included in appropriate prescription kits. Examples of suitable packages include, but are not limited to, hermetically sealed films of plastic or similar material, single dose containers, blister packs, and strip packs.

The active ingredient can be combined in a homogeneous mixture with a pharmaceutical carrier in accordance with conventional pharmaceutical compounding techniques. The carrier may take various forms depending on the form of preparation required for administration. When preparing compositions for oral dosage form, any of the usual pharmaceutical vehicles can be used as carriers, such as, for example, water, glycols, oils, alcohols, flavors, preservatives, coloring agents, and the like. in the case of oral liquid preparations (such as suspensions, solutions and elixirs) or aerosols; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrants may be used in the case of oral solid preparations, in some embodiments lactose-free. For example, suitable carriers include solid oral powders, capsules and tablets. If necessary, the tablets may be coated by standard aqueous or non-aqueous methods.

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

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

Disintegrants can be used in the compositions of the present invention to provide tablets that disintegrate when exposed to aqueous media. Too much disintegrant may result in tablets that may break in the vial. Too small an amount may not be sufficient to break down and this may alter the rate and extent of release of the active ingredient(s) from the dosage form. Thus, a sufficient amount of disintegrant, which is neither too small nor too large, should be used to adversely alter the release of the active ingredient(s) when preparing dosage forms for the compounds described herein. The amount of disintegrant used may vary depending on the type of dosage form and method of administration, and can be easily determined by a person skilled in the art. About 0.5% to about 15% by weight of disintegrant, or from about 1% to about 5% by weight of disintegrant, may be used in the pharmaceutical composition. Disintegrants that can be used to prepare pharmaceutical compositions and dosage forms according to the present invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crosprovidone, potassium polacrilin, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starch, other starches, clays,

- 33 043295 other algins, other celluloses, gums or mixtures thereof.

Lubricants that can be used to prepare pharmaceutical compositions and dosage forms according to 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 oil (eg, 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, colloidal silica gel, coagulated synthetic silica aerosol, or mixtures thereof. The lubricant may optionally be added in an amount of less than about 1% by weight of the pharmaceutical composition.

If aqueous suspensions and/or elixirs are required for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring or coloring agents, if necessary, with emulsifying and/or suspending agents, together with diluents such as water, ethanol , propylene glycol, glycerin and various combinations thereof.

Tablets may be uncoated or coated by known techniques to slow down breakdown and absorption in the gastrointestinal tract and thus provide sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be used. Oral dosage forms may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium such as peanut butter, liquid paraffin or olive oil.

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

A suitable hydrophilic surfactant may have an HLB value of at least 10, while suitable lipophilic surfactants may typically have an HLB value equal to or less than about 10. An empirical parameter used to describe the relative hydrophilicity and hydrophobicity of nonionic amphiphilic compounds is hydrophilic-lipophilic balance (HLB value). Surfactants with lower HLB values are more lipophilic or hydrophobic and have higher oil solubility, while surfactants with higher HLB values are more hydrophilic and have higher solubility in aqueous solutions.

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

Hydrophilic surfactants may be ionic or non-ionic. Suitable ionic surfactants include, but are not limited to, alkyl ammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides and polypeptides; glyceride derivatives of amino acids, oligopeptides and polypeptides; lecithins and hydrogenated lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and their derivatives; lysophospholipids and their derivatives; salts of esters of carnitine and fatty acids; alkyl sulfate salts; salts of fatty acids; docusate sodium; acylactylates; mono- and diacetylated tartaric acid esters of mono- and diglycerides; succinylated mono- and diglycerides; citric acid esters of mono- and diglycerides; and their mixtures.

In the above group, ionic surfactants include, for example: lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; salts of esters of carnitine and fatty acids; alkyl sulfate salts; salts of fatty acids; docusate sodium; acylactylates; mono- and diacetylated tartaric acid esters of mono- and diglycerides; succinylated mono- and diglycerides; citric acid esters of mono- and diglycerides; and their mixtures.

Ionic surfactants can be ionized forms of lecithin

- 34 043295 tin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerin, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, mol fatty acid esters, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated mono/diglyceride tartaric esters, mono/diglyceride citric acid esters, cholyl sarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teracetyl sulfate, docusate , lauroylcarnitines, palmitoylcarnitines, myristoylcarnitines and their salts and mixtures.

Hydrophilic nonionic surfactants may include, but are not limited to, alkylglucosides; alkyl maltosides; alkylthioglucosides; luaryl macrogol glycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkylphenols; polyoxyalkylene alkylphenol fatty acid esters such as polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid diesters; esters of polyethylene glycol and glyceric fatty acids; esters of polyglycerol and fatty acids; esters of polyoxyalkylene sorbitol and fatty acids, such as esters of polyethylene glycol sorbitol and fatty acids; hydrophilic trans-esterification 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 analogues; polyoxyethylated vitamins and their derivatives; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; esters of polyethylene glycol sorbitol and fatty acids; and hydrophilic trans-esterification products of polyols with at least one member of the group consisting of triglycerides, vegetable oils and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol or saccharide.

Other hydrophilic nonionic surfactants include, without limitation, PEG-10-laurate, PEG-12-laurate, PEG-20-laurate, PEG-32-laurate, PEG-32-dilaurate, PEG-12-oleate, PEG15- oleate, PEG-20-oleate, PEG-20-dioleate, PEG-32-oleate, PEG-200-oleate, PEG-400-oleate, PEG-15stearate, PEG-32-distearate, PEG-40-stearate, PEG- 100-stearate, PEG-20-dilaurate, PEG-25glyceryl trioleate, PEG-32-dioleate, PEG-20-glyceryl laurate, PEG-30-glyceryl laurate, PEG-20 glyceryl stearate, PEG-20-glyceryl oleate, PEG-30-glyceryl oleate, PEG- 30-Glyceryl Laurate, PEG-40 Glyceryl Laurate, PEG-40 Palm Kernel Oil, PEG-50 Hydrogenated Castor Oil, PEG-40 Castor Oil, PEG-35 Castor Oil, PEG-60 Castor Oil, PEG-40 Hydrogenated Castor Oil, PEG Hydrogenated Castor Oil -60, PEG-60 corn oil, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, polyglyceryl-10-laurate, PEG-30 cholesterol, PEG-25 phytosterol, PEG-30 soy sterol, PEG-20 trioleate, PEG-40 sorbitanoleate, PEG-80 sorbitan laurate, Polysorbate 20, Polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, PEG-100-tocopheryl ether succinate, PEG-24 cholesterol, polyglyceryl-10-oleate, tween 40, tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonylphenol series, PEG 15-100 octylphenol series and poloxamers.

Suitable lipophilic surfactants include, by way of example only: fatty alcohols; glycerol esters of fatty acids; acetylated esters of glycerol and fatty acids; esters of lower alcohols and fatty acids; propylene glycol esters of fatty acids; esters of sorbitol and fatty acids; esters of polyethylene glycol sorbitol and fatty acids; derivatives of sterols and sterol; derivatives of polyoxyethylated sterols and sterol; alkyl ethers of polyethylene glycol; sugar esters; sugar ethers; lactic acid derivatives of mono- and diglycerides; hydrophobic trans-esterification 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 their mixtures. In this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof; or hydrophobic transesterification products of polyols with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils and triglycerides.

In one embodiment, the composition may contain a solubilizer to ensure good solubilization and/or dissolution of the compound of the present invention and to minimize precipitation of the compound of the present invention. This may be especially important for compositions for non-oral administration, for example compositions for injection. A solubilizer may also be added to enhance the solubility of hydrophilic drug compounds and/or other components such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.

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,

- 35 043295 butanediols and their isomers, glycerin, pentaerythritol, sorbitol, mannitol, transcutol, dimethylisosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols having an average molecular weight of from about 200 to about 6000, such as PEG tetrahydrofurfuryl alcohol PEG (glycofurol) or methoxy-PEG; amides and other nitrogen compounds such as 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and its isomers, δ-valerolactone and its isomers, β-butyrolactone and its isomers; and other solubilizers known in the art such as dimethylacetamide, dimethylisosorbide, N-methylpyrrolidones, monooctanoin, diethylene glycol monoethyl ether and water.

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

The amount of the solubilizer to be included is not particularly limited. The amount of a given solubilizer may be limited to a bioacceptable amount, which can be readily ascertained by a person skilled in the art. In some circumstances, it may be advantageous to include amounts of solubilizers far in excess of bioacceptable amounts, for example, to maximize the concentration of the drug compound, with excess solubilizer removed prior to administration of the composition to the subject using standard techniques such as distillation or evaporation. Thus, if present, the solubilizer may have a weight content of 10%, 25%, 50%, 100%, or up to about 200% by weight based on the total weight of the drug compound and other excipients. If necessary, very small amounts of solubilizer can also be used, such as 5%, 2%, 1% or even less. Typically, the solubilizer may be present in an amount of from about 1% to about 100%, more typically from about 5% to about 25% by weight.

The composition may further contain one or more pharmaceutically acceptable additives and excipients. Such additives and adjuvants include, without limitation, viscosity-lowering agents, defoamers, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscosity regulators, tonicity regulators, flavoring agents, coloring agents, flavoring agents, opacifying agents, suspending agents, binders. , fillers, plasticizers, lubricants and mixtures thereof.

In addition, an acid or base may be included in the composition to facilitate processing, improve stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS) and the like. Also suitable are bases which are salts of pharmaceutically acceptable acids such as acetic acid, acrylic acid, adipic acid, alginic acid, alkane sulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, p-bromophenyl sulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannin acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like. It is also possible to use salts of polybasic acids such as sodium phosphate, disodium hydrogen phosphate and sodium dihydrogen phosphate. If the base is a salt, then the cation may be any suitable and pharmaceutically acceptable cation such as ammonium, alkali metals, alkaline earth metals, and the like. Examples may include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, and ammonium.

Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkane sulfonic acid,

- 36 043295 amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like.

In some embodiments, the pharmaceutical composition contains a Formula IA compound, mannitol, microcrystalline cellulose, crospovidone, and magnesium stearate.

In some embodiments, the pharmaceutical composition comprises a Formula IB compound, mannitol, microcrystalline cellulose, crospovidone, and magnesium stearate.

In some embodiments, the pharmaceutical composition comprises a Formula IC compound, mannitol, microcrystalline cellulose, crospovidone, and magnesium stearate.

In some embodiments, the pharmaceutical composition contains a compound of Formula ID, mannitol, microcrystalline cellulose, crospovidone, and magnesium stearate.

In some embodiments, the pharmaceutical composition contains a compound of Formula IE, mannitol, microcrystalline cellulose, crospovidone, and magnesium stearate.

Pharmaceutical compositions for injection

In some embodiments, the present invention provides an injectable pharmaceutical composition comprising a compound of the present invention and an injectable pharmaceutical excipient. The components and amounts of agents in the compositions are described herein.

Forms in which the novel compositions of the present invention may be presented for administration by injection include aqueous or oily suspensions or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, solutions with mannitol, dextrose, or sterile solutions. in water and similar pharmaceutical carriers.

For injection, aqueous solutions in saline are also commonly used. Ethanol, glycerin, propylene glycol, liquid polyethylene glycol, and the like can also be used. (and their respective mixtures), cyclodextrin derivatives and vegetable oils.

The necessary fluidity can be maintained, for example, by using a coating such as lecithin to maintain the desired particle size in the case of a dispersion, as well as by using surfactants. Infection by microorganisms can be prevented by adding various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

Sterile injectable solutions are prepared by incorporating the compound of the present invention in the required amount in an appropriate solvent with various other ingredients listed above, if necessary, followed by filtered sterilization. In general, dispersions are prepared by incorporating the various sterile active ingredients into a sterile vehicle containing a basic dispersion medium and the other necessary components listed above. In the case of sterile powders for the preparation of sterile injectable solutions, some desirable methods of preparation are vacuum drying and freeze-drying, which provide a powder of the active ingredient and any additional required ingredient from their pre-sterile filtered solution.

Pharmaceutical compositions for topical (eg, transdermal) delivery

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

The compositions of the present invention may be formulated in solid, semi-solid or liquid forms suitable for topical or topical administration, such as gels, water-soluble gels, creams, lotions, suspensions, foams, powders, slurries, ointments, solutions, oils, pastes , suppositories, sprays, emulsions, saline solutions, solutions based on dimethyl sulfoxide (DMSO). In general, carriers with higher density can provide prolonged exposure of the active ingredients in a given area. On the contrary, the solution composition may provide a more rapid effect of the active ingredient on the selected area.

The pharmaceutical compositions may also contain suitable solid or gel-like carriers or excipients which are compounds that provide improved permeability or facilitate the delivery of therapeutic molecules across the stratum corneum, which is a permeability barrier. There are many such penetration enhancing molecules that are known to those skilled in the art of topical dosage forms.

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

In another exemplary dosage form for use in the methods of the present invention, transdermal delivery devices (patches) are used. Such transdermal patches can be used to provide continuous or intermittent infusion of a compound of the present compound in controlled amounts, with or without another agent.

The design and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, for example, US Pat.

Pharmaceutical compositions for inhalation

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, such compositions are administered via the oral or nasal airways to provide a local or systemic effect. Compositions in preferred pharmaceutically acceptable solvents can be sprayed with inert gases. Nebulized solutions can be inhaled directly from the nebulizing device, or the nebulizing device can be connected to a face mask, awning, or intermittent positive pressure breathing apparatus. Solution, suspension or powder formulations may be administered, preferably via the mouth or nose, from devices that deliver the dosage form in an appropriate manner.

Other pharmaceutical compositions

Pharmaceutical compositions may also be prepared from the compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. The preparation of such pharmaceutical compositions is well known in the art. See, for example, Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 20037ybg; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999); the entire contents of each are incorporated herein by reference.

Administration of the compounds or pharmaceutical compositions of the present invention may be by any means that delivers the compounds to their site of action. Such methods include oral routes, intraduodenal route, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal, or infusion), topical administration (e.g., transdermal application), rectal administration, via a catheter or stent for local delivery, or via inhalation. . The compounds can also be administered intrafatty or intrathecally.

The amount of compound administered will depend on the subject to be treated, the severity of the disorder or condition, the rate of administration, the pharmacokinetics of the compound, and the judgment of the attending physician. However, an effective dosage ranges from about 0.001 to about 100 mg per kg of body weight per day, preferably from about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human this is from about 0.05 to 7 g/day, preferably from about 0.05 to about 2.5 g/day. In some cases, dose levels below the lower end of the above range may be more appropriate, while in other cases higher doses may be used without causing harmful side effects, for example, by dividing such higher doses into several smaller doses to be administered over a period of time. day.

In some embodiments, a compound of the present invention is administered in a single dose.

Typically, such administration is by injection, eg, intravenous injection, to rapidly administer the agent. However, other methods can be used if necessary. A single dose of a compound of the present invention may be used to treat an acute condition.

- 38 043295

In some embodiments, a compound of the present invention is administered in multiple doses. Dosing can be about once, twice, three times, four times, five times, six times, or more than six times per day. Dosing can be done about once a month, once every two weeks, once a week or every other day. In another embodiment, a compound of the present invention and another agent are administered together, from about once a day to about 6 times a day. In another embodiment, administration of a compound of the present invention and any agent is continued for less than about 7 days. In another embodiment, administration is continued for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is provided and maintained for as long as necessary.

Administration of the compounds of the present invention may be continued for as long as necessary. In some embodiments, a compound of the present invention is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, a compound of the present invention is administered for less than 28, 14, 7, 6, 5, 4, 3, 2 days, or 1 day. In some embodiments, a compound of the present invention is administered continuously on a continuous basis, such as for the treatment of chronic diseases.

An effective amount of a compound of the present invention may be administered in a single dose or in multiple doses using any conventional route of administration of agents having a similar effect, including rectal, buccal, intranasal and transdermal routes, intra-arterial injections, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, orally, topically or by inhalation.

Compositions of the present invention may also be delivered by impregnated or coated devices such as a stent, for example, or a polymeric cylinder inserted into an artery. Such a route of administration may, for example, help prevent or alleviate restenosis after procedures such as balloon angioplasty. Without being limited by theory, the compounds of the present invention can slow down or inhibit the migration and proliferation of smooth muscle cells in arterial walls that promote restenosis. The compound of the present invention may be administered, for example, by local delivery from a stent scaffold, from a stent graft, from grafts, or from a stent cover or sheath. In some embodiments, a compound of the present invention is mixed with a matrix. Such a matrix may be a polymeric matrix and may serve to bind the compound to the 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 polymers or copolymers (eg polyhydroxyethyl methacrylate, polyvinyl pyrrolidinone), fluorinated polymers such as polytetrafluoroethylene, and cellulose esters. Suitable matrices may be non-degradable or may degrade over time, releasing the compound or compounds. The compounds of the present invention can be applied to the surface of the stent in a variety of ways, such as dip/roll coating, spray coating, dip coating, and/or brush coating. Compounds may be applied in a solvent and the solvent may then be allowed to evaporate, resulting in a layer of compound on the stent. Alternatively, the compound may reside within the body of the stent or implant, such as microchannels or micropores. Upon implantation, the compound diffuses out of the stent mass and interacts with the arterial wall. Such stents can be prepared by immersing a stent prepared such that it contains such micropores or microchannels in a solution of a compound of the present invention in a suitable solvent, followed by evaporation of the solvent. Excess drug on the stent surface can be removed by an additional quick rinse in solvent. In other embodiments, the compounds of the present invention may be covalently linked to a stent or implant. You can use a covalent linker that degrades in vivo, resulting in the release of the compounds according to the present invention. Any biolabile linker can be used for this purpose, such as an ester, amide or anhydride linker. The compounds of the present invention can also be administered intravascularly from an angioplasty balloon. Extravascular administration of compounds through the pericardium or via adventitious administration of dosage forms according to the present invention can also be carried out to reduce restenosis.

Various stent devices that can be used as described herein are described, for example, in the following references, which are incorporated herein by reference: US Pat. No. 5,451,233; US patent No. 5040548; US patent No. 5061273; US Patent No.

5496346; US patent No. 5292331; US patent No. 5674278; US patent No. 3657744; US Patent No.

4739762; US patent No. 5195984; US patent No. 5292331; US patent No. 5674278; US Patent No.

5879382; US patent No. 6344053.

- 39 043295

Compounds according to the present invention can be administered doses. It is known in the art that, due to inter-individual variability in the pharmacokinetics of a compound, individualization of the dosage regimen is necessary for optimal treatment. The introduction of the compounds according to the present invention can be established using standard experiments in view of the present description.

When a compound of the present invention is administered in a composition that contains one or more agents, and if said agent has a shorter half-life than the compound of the present invention, the unit dosage forms of said agent and the compound of the present invention can be adjusted accordingly.

The pharmaceutical composition in question may, for example, be in a form suitable for oral administration, such as a tablet, capsule, pill, powder, sustained release formulation, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration. as an ointment or cream, or for rectal administration as a suppository. The pharmaceutical composition may be in unit dosage forms suitable for single administration of precise doses. The pharmaceutical composition contains a standard pharmaceutical carrier or excipient, as well as a compound according to the present invention as an active ingredient. In addition, it may contain other medical or pharmaceutical agents, carriers, adjuvants, etc.

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

Application methods

The method typically comprises administering to a subject a therapeutically effective amount of a compound of the present invention. A therapeutically effective amount of the combination of compounds in question may vary depending on the intended use (in vitro or in vivo) or on the subject and disease state being treated, for example, the weight and age of the subject, the severity of the disease state, the route of administration, etc., and can be easily installed by a person skilled in the art. This term also refers to a dose that causes a specific response in target cells, such as reduced proliferation or down-regulation of target protein activity. The specific dosage will vary depending on the specific compounds selected, the administration schedules followed, the possibility of administration in combination with other compounds, the time of administration, the tissue being administered, and the physical delivery system in which it is located.

In this context, the term IC50 refers to the half-maximal inhibitory concentration of an inhibitor when inhibiting a biological or biochemical function. The specified quantitative value means how much of a particular inhibitor is needed to inhibit a given biological process (or component of the process, i.e. enzyme, cell, cell receptor or microorganism) by half. In other words, it represents the half-maximal (50%) inhibitory concentration (IC) of the substance (50% IC or IC50). EC50 refers to the plasma concentration required to achieve 50% of the maximum effect in vivo.

In some embodiments, the proposed methods use a PRMT5 inhibitor with an IC50 value that is approximately equal to or less than a predetermined value set in an in vitro assay. 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 than, 50 nM or less, 60 nM or less, 70 nM or less, 80 nM or less, 90 nM or less, 100 nM or less, 120 nM or less, 140 nM or less, 150 nM or less, 160 nM or less less, 170 nM or less, 180 nM or less, 190 nM or less, 200 nM or less, 225 nM or less, 250 nM or less, 275 nM or less, 300 nM or less, 325 nM or less, 350 nM or less less, 375 nM or less, 400 nM or less, 425 nM or less, 450 nM or less, 475 nM or less, 500 nM or less, 550 nM or less, 600 nM or less, 650 nM or less, 700 nM or less less, 750 nM or less, 800 nM or less, 850 nM or less, 900 nM or less, 950 nM or less, 1 μM or less, 1.1 μM or less, 1.2 μM or less, 1.3 μM or less, 1.4 μM or less, 1.5 μM or less, 1.6 μM or less, 1.7 μM or less, 1.8 μM or less, 1.9 μM or less, 2 μM or less, 5 µM or less, 10 µM or less, 15 µM or less, 20 µM or less, 25 µM or less, 30 µM or less, 40 µM or less, 50 µM, 60 µM, 70 µM, 80 µM, 90 µM, 100 μM, 200 μM, 300 μM, 400 μM, or 500 μM or less (or a value in the range defined by and including any two of the above).

In some embodiments, the PRMT5 inhibitor selectively inhibits PRMT5 with an IC50 value that is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100 or 1000 times less (or with a value in the range defined by and including any two of the above values) than its IC50 value against one, two or three other PRMTs.

In some embodiments, the PRMT5 inhibitor selectively inhibits PRMT5 with a value

- 40 043295

IC50 that is less than about 1 nM, 2 nM, 5 nM, 7 nM, 10 nM, 20 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, 120 nM 140nM, 150nM, 160nM, 170nM, 180nM, 190nM, 200nM, 225nM, 250nM, 275nM, 300nM, 325nM, 350nM, 375nM, 400nM 425 nM, 450 nM, 475 nM, 500 nM, 550 nM, 600 nM, 650 nM, 700 nM, 750 nM, 800 nM, 850 nM, 900 nM, 950 nM, 1 µM, 1.1 µM, 1.2 µM, 1, 3 µM, 1.4 µM, 1.5 µM, 1.6 µM, 1.7 µM, 1.8 µM, 1.9 µM, 2 µM, 5 µM, 10 µM, 15 µM, 20 µM, 25 µM , 30 µM, 40 µM, 50 µM, 60 µM, 70 µM, 80 µM, 90 µM, 100 µM, 200 µM, 300 µM, 400 µM, or 500 µM (or in the range defined by and including any two of the above values) , and a specified IC50 value of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, or 1000 times less (or value in the range defined by and including any two of the above values) than its IC50 value for one, two or three other PRMTs.

The proposed methods are suitable for the treatment of a disease state associated with PRMT5. Any disease state that directly or indirectly results from pathological activity or expression level of PRMT5 may be an envisaged disease state.

Various disease states associated with PRMT5 have been described. For example, PRMT5 is involved in various human cancers, as well as in many hemoglobinopathies.

Non-limiting examples of such conditions include, but are not limited to, acanthoma, acinar cell carcinoma, acoustic neuroma, acral lentiginous melanoma, acrospiroma, acute eosinophilic leukemia, acute lymphoblastic leukemia, acute lymphocytic leukemia, acute megakaryoblastic leukemia, maturation acute myeloblast leukemia, acute myeloid dendritic cell leukemia, acute myeloid leukemia, acute myelogenous leukemia, acute promyelocytic leukemia, adamantine, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adrenocortical carcinoma, adult T-cell leukemia, aggressive NK-cell leukemia, cancers AIDS-associated lymphoma, alveolar soft tissue sarcoma, ameloblastic fibroma, anal cancer, anaplastic large cell lymphoma, anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, appendix cancer, astrocytoma, atypical teratoid rhabdoid tumor, basal cellular carcinoma, basal-like carcinoma, B-cell leukemia, B-cell lymphoma, Bellini duct carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, bone tumor, brainstem glioma, brain tumor, breast cancer, Brenner tumor, bronchial tumor , bronchial alveolar carcinoma, brown tumor, Burkitt's lymphoma, cancer without identified primary focus, carcinoid tumor, carcinoma, carcinoma in situ, penile carcinoma, carcinoma without identified primary focus, carcinosarcoma, Castleman's disease, embryonic tumor of the central nervous system, cerebellar astrocytoma, cerebral astrocytoma , cervical cancer, cholangiocarcinoma, chondroma, chondrosarcoma, chordoma, choriocarcinoma, choroid plexus papilloma, chronic lymphocytic leukemia, chronic monocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorder, chronic neutrophilic leukemia, clear cell tumor, colon cancer, colon cancer and colon, craniopharyngeoma, leather t-cell lymphoma, dermatofibrosarcoma, a dermoid cyst, a desmoplastic small-blade tumor, diffuser b-circuelic lymphoma, dizambotic neuroepithelial tumor, an embryo-elastic tumor, an embryo-elastic tumor. dermal sinus, endometrial cancer, endometrial uterine cancer, endometrioid tumor , enteropathic T-cell lymphoma, ependymoblastoma, ependymoma, epidermoid carcinoma, epithelioid sarcoma, erythroleukemia, esophageal cancer, esthesioneuroblastoma, Ewing family tumor, Ewing family sarcoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, extramammary Paget's disease, fallopian tube cancer, fetal fetus in fetus, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, gallbladder cancer, gallbladder cancer, ganglioglioma, ganglioneuroma, gastric cancer, gastric lymphoma, gastrointestinal cancer, carcinoid gastrointestinal tract tumor, gastrointestinal stromal tumor, gastrointestinal stromal tumor, germ cell tumor, germ cell tumor, uterine choriocarcinoma, gestational trophoblastic tumor, giant cell glomus tumor, glucagonoma, gonadoblastoma, granulosa cell tumor, hairy cell leukemia, head cancer and neck, head and neck cancer, heart cancer, hemoglobinopathies such as b-thalassemia and sickle cell disease (SCD), hemangioblastoma, hemangiopericytoma, hemangiosarcoma, hematologic malignancies, hepatocellular carcinoma, hepatosplenic T-cell lymphoma, hereditary breast cancer syndrome and ovary, Hodgkin's lymphoma, Hodgkin's lymphoma, hypopharyngeal cancer, hypothalamic glioma, edematous infiltrative breast cancer, intraocular melanomahypopharynoma, islet cell carcinoma, islet cell tumor, juvenile myelomonocytic leukemia, Kaposi's sarcoma, Kaposi's sarcoma, kidney cancer, Klatskin's tumor, Krukenberg's tumor, laryngeal cancer, laryngeal cancer, melano

- 41 043295 mu-type malignant lentigo, leukemia, cancer of the lip and mouth, liposarcoma, lung cancer, luteoma, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphocytic leukemia, lymphoma, macroglobulinemia, malignant fibrous histiocytoma, malignant fibrous histiocytoma, malignant fibrous histiocytoma of bone, malignant glioma , malignant mesothelioma, malignant peripheral nerve sheath tumor, malignant rhabdoid tumor, malignant newt tumor, MALT lymphoma, mantle cell lymphoma, mast cell leukemia, mastocytosis, mediastinal germ cell tumor, mediastinal tumor, medullary thyroid cancer, medulloblastoma, medulloblastoma, medulloepithelioma, melanoma, melanoma, meningioma, Merkel cell carcinoma, mesothelioma, mesothelioma, metastatic squamous cell carcinoma of the neck of unknown origin, metastatic urothelial carcinoma, mixed Muller's tumor, monocytic leukemia, cancer of the mouth, mucoid tumor, multiple endocrine neoplasia syndrome, multiple myeloma, multiple myeloma, mycosis fungoides , fungoid mycosis, myelodysplasia disease, myelodysplasia syndromes, myeloid leukemia, myeloid sarcoma, myeloproliferative disease, myxoma, nasal cavity cancer, nasopharyngeal cancer, nasopharyngeal carcinoma, neoplasm, neurinoma, neuroblastoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, non-Hodgkin's lymphoma, non-Hodgkin lymphoma, non-melanoma skin cancer, non-small cell lung cancer, ocular oncology, oligoastrocytoma, oligodendroglioma, oncocytoma, optic nerve sheath meningioma, oral cavity cancer, oral cavity cancer, oropharyngeal cancer, osteosarcoma, osteosarcoma, ovarian cancer, ovarian cancer, epithelial ovarian cancer, embryonic Ovarian cell tumor, borderline ovarian tumor, Paget's disease of the breast, Pancoast tumor, pancreatic cancer, pancreatic cancer, papillary thyroid cancer, papillomatosis, paraganglioma, paranasal sinus cancer, parathyroid cancer, penis cancer, perivascular tumor of epithelioid cells , pharyngeal cancer, pheochromocytoma, pineal parenchymal tumor of intermediate differentiation, pineoblastoma, pituicytoma, pituitary adenoma, pituitary tumor, plasma cell neoplasms, pleuropulmonary blastoma, polyembryoma, progenitor T-cell lymphoblastic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, primary hepatocellular carcinoma, primary liver cancer, primary peritoneal carcinoma, primitive neuroectodermal tumor, prostate cancer, peritoneal pseudomyxoma, rectal cancer, renal cell carcinoma, respiratory tract carcinoma with the NUT gene on chromosome 15, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, transformation Richter, sacrococcygeal teratoma, salivary gland cancer, sarcoma, schwannomatosis, sebaceous carcinoma, secondary neoplasm, seminoma, serous tumor, Sertoli Leydig cell tumor, ovarian sex cord stromal tumor, Cesari syndrome, cricoid cell carcinoma, small cell lymphoma, cancer small intestine, soft tissue sarcoma, somatostatinoma, chimney sweep cancer, spinal cord tumor, spinal tumor, splenic marginal zone lymphoma, squamous cell carcinoma, gastric cancer, superficial spreading melanoma, supratentorial primitive neuroectodermal tumor, superficial epithelial-stromal tumor, synovial sarcoma, T- cellular acute lymphoblastic leukemia, large granular lymphocyte T-cell leukemia, T-cell leukemia, T-cell lymphoma, T-cell prolymphocytic leukemia, teratoma, terminal lymphatic carcinoma, testicular cancer, tecoma, throat cancer, thymus carcinoma, thymoma, thyroid cancer glands, transitional cell carcinoma of the renal pelvis and ureter, transitional cell carcinoma, urethral cancer, urethral cancer, urogenital neoplasm, uterine sarcoma, uveal melanoma, vaginal cancer, Werner-Morrison syndrome, verrucous carcinoma, optic pathway carcinoma, vulvar cancer, Waldenstrom's macroglobulinemia, Wartin's tumor, Wilms' tumor, or any combination thereof.

In some embodiments, said method is for the treatment of a disease selected from the group consisting of tumor angiogenesis, a chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema and scleroderma, diabetes mellitus, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and cancer of the ovary, breast, lung, pancreas, prostate, colon and epidermoid cancer.

In some embodiments, said method is for the treatment of a disease selected from breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, uterine cancer, cervical cancer, leukemia such as acute myeloid leukemia ( AML), acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM ), myelodysplastic syndrome (MDS), epidermoid cancer, or hemoglobinopathies such as b-thalassemia and sickle cell disease (SCD).

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

In other embodiments, said method is for the treatment of a disease selected from leukemia, such as acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, acute myelogenous leukemia (AML) , chronic myelogenous leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS), epidermoid cancer, or hemoglobinopathies such as b-thalassemia and sickle cell disease (SCD).

In other embodiments, said method is for the treatment of a disease selected from cancer with a CDKN2A deletion; cancer with a 9P deletion; MTAP deletion cancer; glioblastoma, NSCLC, head and neck cancer, bladder cancer, or hepatocellular carcinoma.

Compounds according to the present description, as well as pharmaceutical compositions containing them, can be entered for the treatment of any of the diseases described above, alone or in combination with medical treatments. Medical treatments include, for example, surgery and radiation therapy (eg, gamma irradiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, systemic administration of radioactive isotopes).

In other aspects, the compounds of the present invention, as well as pharmaceutical compositions containing them, can be administered for the treatment of any of the diseases described, alone or in combination with one or more other agents. In other ways, the compounds of the present disclosure, as well as pharmaceutical compositions containing them, may be administered in combination with nuclear receptor agent agonists.

In other ways, the compounds of the present disclosure, as well as pharmaceutical compositions containing them, may be administered in combination with nuclear receptor antagonists.

In other ways, compounds according to the present description, as well as pharmaceutical compositions containing them, can be administered in combination with an antiproliferative agent.

In other aspects, the compounds of the present invention, as well as pharmaceutical compositions containing them, can be administered to treat any of the diseases described, alone or in combination with one or more other chemotherapeutic agents. Examples of other chemotherapeutic agents include, for example, abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, all-trans retinoic acid, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bendamustine, bevacizumab, bexarotene, bleomycin, bortezomib, intravenous busulf en, oral busulfan , calusterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabin, denileukin, denileukin diftitox, dexrazoxane, docetaxel , doxorubicin, dromostanolone propionate, eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxet an, idarubicin, ifosfamide, imatinib mesylate , interferon alfa 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, mechlorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxalene, mitomycin C, mitotane, mitoxantrone, nandrolone fenpropio nat, nelarabine, nofetumomab, oxaliplatin, paclitaxel, pamidronate, panobinostat, panitumumab, pegaspargasa, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine, quinacridine, rasburicase, rituximab, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen, tem ozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat and zoledronate, as well as any combination thereof.

In other aspects, the other agent is a therapeutic agent that targets an epigenetic regulator. Examples of agents acting on the epigenetic regulator include, for example, bromodomain inhibitors, histone lysine methyltransferases, histone arginine methyltransferases, histone demethylases, histone deacetylases, histone acetylases, and DNA methyltransferases, as well as any combinations thereof. In some aspects, histone deacetylase inhibitors are preferred and include, for example, vorinostat.

In other methods in which the disease being treated is cancer or other proliferative disease, the compounds of the present disclosure, as well as pharmaceutical compositions containing them, may be administered in combination with targeted therapeutic agents. Targeted therapeutic agents include, for example, JAK kinase inhibitors (eg, ruxolitinib), PI3 kinase inhibitors (including PI3K-delta selective inhibitors and broad-spectrum PI3K inhibitors), MEK inhibitors, cyclin-dependent kinase inhibitors (eg, CDK4/ 6), BRAF inhibitors, mTOR inhibitors, proteasome inhibitors (on

- 43 043295 example, bortezomib, carfilzomib), HDAC inhibitors (eg panobinostat, vorinostat), DNA methyltransferase inhibitors, dexamethasone, bromine and extraterminal family members, BTK inhibitors (eg ibrutinib, acalabrutinib), BCL2 inhibitors (eg venetoclax ), MCL1 inhibitors, PARP inhibitors, FLT3 inhibitors, and LSD1 inhibitors, and any combination thereof. In other methods in which the disease being treated is cancer or other proliferative disease, the compounds of the present invention, as well as pharmaceutical compositions containing them, can be administered in combination with immune checkpoint inhibitor agents. Immune checkpoint inhibitors include, for example, PD-1 inhibitors, such as an anti-PD-1 monoclonal antibody. 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 a PD-L1 inhibitor, such as an anti-PD-L1 monoclonal antibody. In some aspects, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C, or any combination thereof. In some aspects, the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736. In other aspects, the immune checkpoint inhibitor is a CTLA-4 inhibitor, such as an anti-CTLA-4 antibody. In some aspects, the anti-CTLA-4 antibody is ipilimumab.

In other methods in which the disease being treated is cancer or other proliferative disease, the compounds of the present disclosure, as well as pharmaceutical compositions containing them, may be administered in combination with an alkylating agent (e.g., cyclophosphamide (CY), melphalan (MEL ) and bendamustine), a proteasome inhibitor agent (eg, carfilozmib), a corticosteroid agent (eg, dexamethasone (DEX) or an immunomodulatory agent (eg, lenalidomide (LEN) or pomalidomide (POM)), or any combination thereof.

In some embodiments, the disease being treated is an autoimmune condition or an inflammatory condition. In such aspects, the compounds of the present invention, as well as pharmaceutical compositions containing them, may be administered in combination with a corticosteroid agent such as, for example, triamcinolone, dexamethasone, fluocinolone, cortisone, prednisolone, or flumetholone, or any combination thereof.

In other embodiments in which the disease being treated is an autoimmune condition or an inflammatory condition, the compounds of the present invention, as well as pharmaceutical compositions containing them, can be administered in combination with an immunosuppressant such as fluocinolone acetonide (RETISERT™), rimexolone (AL-2178, VEXOL™, ALCO™) or cyclosporine (RESTASIS™), or any combination thereof.

In some embodiments, the disease being treated is betathalassemia or sickle cell disease. In such aspects, the compounds of the present invention, as well as pharmaceutical compositions containing them, can be administered in combination with one or more agents such as, for example, HYDREA™ (hydroxyurea).

The examples and preparations below further illustrate and exemplify the compounds of the present invention and methods for preparing such compounds. It should be understood that the scope of the present invention is in no way limited by the scope of the following examples and preparations. In the following examples, molecules with a single chiral center, unless otherwise noted, exist as a racemic mixture. Molecules with two or more chiral centers, unless otherwise noted, exist as a racemic mixture of diastereomers. The individual enantiomers/diastereomers can be prepared by methods known to those skilled in the art.

The compound of formula I and its pharmaceutically acceptable salts can be obtained, for example, with reference to the following schemes and methods.

- 44 043295

⁰ OH but'

But

Scheme 1 /\PhCOCI -----BzO TEA, DCM

TEMPO, NaCIO

,.Ό

DXM 'Oh

D-Xylose ^C 5 ^H iqO ₅

MM: 150.13

SdN ₁₄ O ₅

MM: 190.20

HO J ^C 15 ^H 13OE

MM 294.30

C15H ₁₆ O ₆

MM: 292.29

MeMdVg,

S _1E N ₁₃ S1M ₃ O ₅

MM: 403.82

HE

1M HCI

ΌΗ--- ^C 13 ^H 16°E

MM: 268.27

С16Н20О6

MM: 308.33

TsOH, acetone

CI

C22H22CIN3O5

MM: 443.88

C ₁₅ H ₁₃ CIN ₃ O ₄

MM 339.78

Scheme 2

CI

Phl(OAc) ₂ , TEMPO, H ₂ O / acetonitrile o ° c - o ° C

CI

propylphosphonic anhydride

Pyridine, EtOAc

15°С-30°С

95.1%

S

C ₁₅ H ₁₈ C1Y ₃ O ₄

MM: 339.78

Oh 'o^on

C ₁₅ H _1E CIN ₃ O ₅

MM 353.76

90.8-91.3%

CI

-US-25

95.1%

C ₁₇ H ₂₁ CIN ₄ O ₅

MM: 396.83

C2iHi@CI ₃ N ₃ O ₄

MM: 482.74

Scheme 3

CI

MM: 484.76

CONC. _n.h.4oh

1,4-dioxane c ₂₁ h _1e ci _e n ₃ О ₄

MM: 482.74

80°C -100'C >100% (impure)

CI

C^CIzN^

MM:465.33

3, H ₂ 0, NH ₄ OH

-80%

1, MeON, EUN

2, maleic acid/EtOH

1, conc. HCI, MeOH

O'S-zol

2, MeOH, MTBE

BUT

BUT he is

Formula IA

Ο22Η22ΟΙ ₂ Ν ₄ Ο _Ε

MM: 541.34

Formula I

Ο _1Ε Η _1Ε ΟΙ ₂ Ν ₄ Ο ₄

MM: 425.27

- 45 043295

Scheme 4

Scheme 5 ((3aR,5R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5 Experimental methods

Synthesis of compound 3

Stage 1. Synthesis of yl)methyl benzoate (2)

To a mixture of compound 1 (40.00 g, 210.31 mmol, 1 eq.) in DCM (400 ml) was added TEA (63.84 g, 630.94 mmol, 87.82 ml, 3 eq.) dropwise at 0°C in N ₂ atmosphere. BzCl (32.52 g, 231.34 mmol, 26.88 ml, 1.1 eq.) was added dropwise to the mixture at 0° C. under N ₂ atmosphere. The mixture was stirred at 0° C. for 1 h under N ₂ atmosphere. The mixture was combined with another reaction mixture with 10 g of compound 1. The combined mixture was quenched with water (600 ml). The organic layer was separated. The aqueous layer was extracted with DCM DCM (300 mlx3). The combined organic layers were washed with saturated NaHCO ₃ solution (400 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/ethyl acetate=50/1 to 2/1) to give compound 2 (67.00 g, 227.66 mmol, 86.60% yield) as a yellow solid.

1H NMR (400 MHz, chloroform-d) δ 8.12-7.95 (m, 2H), 7.66-7.53 (m, 1H), 7.51-7.41 (m, 2H), 5.97 (d, J=3.7 Hz, 1H), 4.87-4.75 (m, 1H), 4.60 (d, J=3.5 Hz, 1H), 4.47-4 .35 (m, 2H), 4.19 (dd, J=2.2, 4.0 Hz, 1H), 3.27 (d, J=4.0 Hz, 1H), 1.52 (s, 3H), 1.33 (s, 3H).

Stage 2. Synthesis of ((3aR,5R,6aS)-2,2-dimethyl-6-oxotetrahydrofuro[2,3-d][1,3]dioxol-5-yl)methylbenzoate (3)

In parallel, two batches: To a mixture of compound 2 (10.00 g, 33.98 mmol, 1 eq.) in DCM (100 ml) was added DMP (43.24 g, 101.94 mmol, 31.56 ml, 3 eq. ) at 0°C. Stir the mixture at 15° C. for 4 hours. Filter the mixture and concentrate the filtrate. The residue was diluted with EtOAc (500 ml) and the mixture was filtered. The filtered mixture was diluted with saturated NaHCO3 solution (300 ml). The mixture was extracted with EtOAc (200 mlx3). The combined organic layers were washed with brine (300 ml), dried over Na ₂ SO ₄ , filtered and concentrated. Purify the residue by column chromatography (SiO2, petroleum ether/ethyl acetate=20/1 to 3/1) to give compound 3 (17.00 g, 58.16 mmol, 85.59% yield) as a white solid. H NMR (400 MHz, chloroform-d) δ 8.00-7.91 (m, 2H), 7.65-7.53 (m, 1H), 7.50-7.40 (m, 2H), 6.15 (d, J=4.4 Hz, 1H), 4.78-4.67 (m, 2H), 4.54-4.41 (m, 2H), 1.53 (s, 3H) , 1.44 (s, 3H)

Synthesis of Int-6

To a solution of Mg (979.09 mg, 40.28 mmol, 1.3 eq.) was added compound Int-6-1 (7 g, 30.99 mmol, 1 eq.) in THF (26 ml) at 40°C in N ₂ atmosphere. The mixture was stirred at 40° C. for 0.5 hours. The Mg was consumed. Compound Int-6 (7.75 g, crude) in THF (26 ml) as a yellow liquid was used in the next step without further purification.

- 46 043295

Preparation of ((3aR,5R,6R,6aR)-6-hydroxy-2,2,6-trimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)methylbenzoate (4)

CiaHjoOfi

MM: 308.33

To a mixture of compound 3 (17.00 g, 58.16 mmol, 1 eq.) in THF (200 ml) was added dropwise MeMgBr (3 M, 58.16 ml, 3 eq.) at -78°C under N ₂ . The mixture was stirred at -78°C for 1 h under N ₂ atmosphere. The combined mixture was quenched with saturated NH4Cl solution (200 ml), extracted with EtOAc (50 mlx3). The combined organic layers were washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=15/1 to 5/1) to give compound 4 as a white solid.

1H NMR (400 MHz, chloroform-d) δ 8.13-8.01 (m, 2H), 7.64-7.51 (m, 1H), 7.48-7.38 (m, 2H), 5.83 (d, J=4.0 Hz, 1H), 4.57 (dd, J=3.1, 11.9 Hz, 1H), 4.38 (dd, J=8.2, 11, 9 Hz, 1H), 4.21-4.06 (m, 2H), 2.71 (s, 1H), 1.60 (s, 3H), 1.37 (s, 3H), 1.26 ( s, 3H).

Preparation of ((3αR,4R,6R,6αR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3α-trimethyltetrahydrofuro[3,4-d] [1,3]dioxol-4-yl)methylbenzoate (7)

TsOH-H ₂ O ( 141.31 mg, 742.91 µmol, 0.3 eq.). The mixture was stirred at 25° C. for 12 hours. LC-MS indicated that compound 6 remained. Several new peaks were observed in the LC-MS profile and the desired compound was found. The reaction mixture was stirred at 60° C. for 2 hours. TLC showed that compound 6 was completely consumed and new spots formed. The reaction was complete, according to TLC. The reaction was quenched with NaHCO ₃ (20 ml) and extracted with EtOAc (10 mlx3). The organic layer was concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1 to 4:1). Compound 7 (730 mg, crude) was obtained as a yellow oil. TLC (petroleum ether:ethyl acetate=1:1) Rf=0.79.

Preparation of ((3aR,4R,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3α-trimethyltetrahydrofuro[3,4-d] [ 1,3]dioxol-4-yl)methanol (8)

V

C ₂₂ H ₂₂ CIN ₃ O ₅ Ci ₅ Hi _S CIN ₃ O4

MM: 443.33 MM: 339.73

A mixture of compound 7 (600 mg, 1.35 mmol, 1 eq.) and NH ₃ in MeOH (7 M, 10 ml, 51.79 eq.) was stirred at 25° C. for 12 h. LCMS showed the desired MS. The mixture was concentrated. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 to 3:1). Compound 8 (450 mg, 1.32 mmol, 97.98% yield) was obtained as a white solid.

1H NMR (400 MHz, chloroform-d) δ 8.60 (s, 1H), 7.29 (d, J=3.7 Hz, 1H), 6.60 (d, J=3.7 Hz, 1H ), 6.17 (d, J=3.2 Hz, 1H), 4.74 (d, J=3.1 Hz, 1H), 4.20 (dd, J=3.5, 5.6 Hz , 1H), 3.89-3.71 (m, 2H), 1.61 (s, 3H), 1.57 (s, 3H), 1.38 (s, 3H); LCMS: (M+H+): 340.1.

Preparation of (3aS,4S,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3α-trimethyltetrahydrofuro[3,4-d][ 1,3]dioxol-4-carboxylic acid (9)

To a mixture of compound 8 (500 mg, 1.47 mmol, 1 eq.), diacetoxyiodobenzene (DAIB) (1.04 g, 3.24 mmol, 2.2 eq.) in MeCN (2 ml) and H ₂ O ( 2 ml) was added TEMPO (46.28 mg, 294.31 μmol, 0.2 eq.) at 0°C. The mixture was stirred at 25° C. for 1 h. TLC showed that compound 8 was consumed. The mixture was concentrated. The residue was dissolved in toluene (10 ml). The mixture was concentrated. The crude product was used in the next step without further purification. Compound 9 (520 mg, crude) was obtained as a brown oil. TLC (SiO ₂ , ethyl acetate/ethanol=1/1): Rf=0.5.

Preparation of (3aS,4S,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-N-methoxy-N,2,2,3a-tetramethyltetrahydrofuro[3 ,4-d] [ 1,3]dioxol-4-carboxamide(10)

To a mixture of compound 9 (520 mg, 1.47 mmol, 1 eq.), N-methoxymethanamine (215.07 mg, 2.20 mmol, 1.5 eq., HCl), pyridine (348.82 mg, 4, 41 mmol, 355.93 μl, 3 eq) in EtOAc (5 ml) was added T3P (1.87 g, 2.94 mmol, 1.75 ml, 50% purity, 2 eq) at 25°C. The mixture was stirred at 25° C. for 12 hours. TLC indicated that compound 9 was consumed. The mixture was quenched with water (50 ml) and extracted with EtOAc (25 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative TLC (SiO2, petroleum ether/ethyl acetate=1/1). Compound 10 (450 mg, 1.13 mmol, 77.15% yield) was obtained as a colorless oil.

1H NMR (400 MHz, chloroform-d) δ 8.67 (s, 1H), 8.21 (d, J=3.7 Hz, 1H), 6.69-6.63 (m, 2H), 5 .26 (s, 1H), 4.60 (d, J=1.3 Hz, 1H), 3.79 (s, 3H), 3.28 (s, 3H), 1.70 (s, 3H) , 1.46 (d, J=3.5 Hz, 6H); LCMS: (M+H+): 397.2; TLC (SiO ₂ , petroleum ether/ethyl acetate=1/1): R _f =0.6.

Preparation of ((3aS,4S,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyltetrahydrofuro[3,4-d] [ 1,3]dioxol-4-yl)(3,4-dichlorophenyl)methanone (11)

eleven

Ci ₇ H ₂ iClM4O ₅ ^iHigCljNjOd

MM: 396.S3 MM: 4S2.74

To a solution of compound 10 (1 g, 2.52 mmol, 1 eq.) in THF (15 ml) was added the compound Int-6 (1 M, 10.08 ml, 4 eq.) at -10°C under N ₂ . The mixture was stirred at 0°C for 5 min. TLC showed that compound 10 was completely consumed and many new spots formed. The reaction was complete by TLC (petroleum ether:ethyl acetate=3:1 Rf=0.48). Saturated aqueous NH ₄ Cl solution (15 ml) was added to the solution and extracted with DCM (10 mlx2). The combined organic layers were washed with brine (20 mlx2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 to 15/1) and based on TLC (petroleum ether:ethyl acetate=3:1 Rf=0.48). Compound 11 (660 mg, 1.27 mmol, 50.42% yield, 92.94% purity by LCMS) was obtained as a white solid.

¹ H NMR (400 MHz, chloroform-d) δ=8.64 - 8.73 (m, 1H), 8.28 (d, J=2.19 Hz, 1H), 7.99 (dd, J= 8.33, 2.19 Hz, 1H), 7.89 (d, J=3.95 Hz, 1H), 7.63 (d, J=8.33 Hz, 1H), 6.72 (d, J=3.95Hz, 1H), 6.59(d, J=1.32Hz, 1H), 5.54(s, 1H), 4.70(d, J=1.32Hz, 1H) , 1.83 (s, 3H), 1.47 (s, 3H), 1.36 (s, 3H); LCMS: (M+H+): 483.9, LCMS purity 92.94%; TLC (petroleum ether:ethyl acetate=3:1) Rf=0.48.

Preparation of (R)-((3aR,4R,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyltetrahydrofuro[3, 4-d] [ 1,3]dioxol-4-yl)(3,4-dichlorophenyl)methanol (12)

12

C2iHisGl3N ₃ O4 CjiHjqCIjNsOj

MM: 482.74- MM: 484.76

To a solution of compound 11 (660 mg, 1.37 mmol, 1 eq.) in toluene (10 ml) was added DIBAL-H (1 M, 2.73 ml, 2 eq.) at -70°C under N ₂ atmosphere. The mixture was stirred at -70°C for 5 min. TLC showed that compound 11 was completely consumed and one new spot was formed. The reaction was complete by TLC (petroleum ether:ethyl acetate=3:1 Rf=0.30). A saturated aqueous solution of Rochelle's salt (30 ml) and MTBE (20 ml) was added to the reaction solution, stirred at 25°C for

0.5 h and extracted with MTBE (10 mlx4), washed with brine (10 mlx2), dried with Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 to 1/1) and based on TLC (petroleum ether:ethyl acetate=3:1 R _f =0.30). Compound 12 (310 mg, 513.06 µmol, 37.53% yield, 80.23% purity by LCMS) was obtained as a white solid.

1H NMR (400 MHz, chloroform-d) δ=8.67 (s, 1H), 7.52 (d, J=1.75 Hz, 1H), 7.40 (d, J=8.33 Hz, 1H), 7.31 (d, J=3.51 Hz, 1H), 7.22 (dd, J=8.33, 1.75 Hz, 1H), 6.69 (d, J=3.95 Hz, 1H), 6.17 (d, J=2.63 Hz, 1H), 4.83 (d, J=8.33 Hz, 1H), 4.76 (d, J=2.63 Hz, 1H), 4.05-4.18(m, 1H), 2.94(brs, 1H), 1.84(s, 3H), 1.67(s, 3H), 1.43(s, 3H ); LCMS: (M+H+): 484.3. Purity by LCMS 80.23%; TLC (petroleum ether:ethyl acetate=3:1) Rf=0.30.

Preparation of (R)-((3aR,4R,6R,6aR)-6-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyltetrahydrofuro[3, 4-d] [ 1,3]dioxol-4-yl)(3,4-dichlorophenyl)methanol (13)

13

CsiHaoCIsNaOji C ₂₁ H ₃₂ Cl ₂ N ₄ O ₄

MM: 484.76 MM: 465.33

To a solution of compound 12 (90 mg, 185.66 µmol, 1 eq.) in dioxane (5 ml) was added NH3-H2O (26.03 mg, 185.66 µmol, 28.60 µl, 25% purity, 1 eq. ) at 25°C. The mixture was closed and stirred at 100° C. for 12 hours (30 psi (206.8 kPa)). LC-MS indicated that compound 12 was completely consumed and one major peak of the desired product was found. The reaction mixture was concentrated under reduced pressure to remove the solvent. Compound 13 (80 mg, crude) was used in the next step without further purification as a yellow solid.

Preparation of (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((R)-(3,4-dichlorophenyl)( hydroxy)methyl)-3-methyltetrahydrofuran-3,4-diol (formula I)

To a solution of compound 13 (80 mg, 171.92 µmol, 1 eq.) was added HCl/MeOH (4 M, 4.26 ml, 99.07 eq.) at 0°C. The mixture was stirred at 25°C for 10 min. LC-MS showed that compound 13 was gone. Several new peaks were observed in the LC-MS profile and the desired compound was found. The reaction mixture was concentrated under reduced pressure to remove the solvent. NH ₃ *H ₂ O was added to the residue to adjust the pH to about 8. The residue was purified by preparative HPLC (basic column: Waters Xbridge 150x25.5 µm; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH4HCO3)-ACN]; B%: 15%-45%, 10 min). The compound of formula I (29.83 mg, 69.48 µmol, 40.41% yield, 99.05% purity by LCMS) was obtained as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ=8.04 (s, 1H), 7.61 (d, J=1.75 Hz, 1H), 7.51 (d, J=8.77 Hz , 1H), 7.42 (d, J=3.51 Hz, 1H), 7.38 (dd, J=8.33, 1.75 Hz, 1H), 7.07 (brs, 2H), 6 .55-6.64 (m, 2H), 5.85 (d, J=8.33 Hz, 1H), 5.27 (d, J=7.45 Hz, 1H), 4.78 - 4, 86 (m, 2H), 4.43 (t, J=7.89 Hz, 1H), 4.01 (d, J=6.14 Hz, 1H), 1.18 (s, 3H);

1H NMR (400 MHz, DMSO-d ₆ +D ₂ O) δ=8.03 (s, 1H), 7.58 (d, J=1.54 Hz, 1H), 7.50 (d, J= 8.16 Hz, 1H), 7.34-7.41 (m, 2H), 6.58 (d, J=3.53 Hz, 1H), 5.84 (d, J=8.16 Hz, 1H), 4.80 (d, J=6.39 Hz, 1H), 4.41 (d, J=8.16 Hz, 1H), 4.00 (d, J=6.39 Hz, 1H) , 1.18 (s, 3H); LCMS: (M+H+): 425.1, LCMS purity 99.05%; HPLC purity: 100.00%.

Formula I.A. (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((R)-(3,4-dichlorophenyl)(hydroxy )methyl)-3-methyltetrahydrofuran-3,4-diol, maleate salt (IA)

- 49 043295

Method 1:

(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-2-[(R)-(3,4-dichlorophenyl)hydroxymethyl]3-methyltetrahydrofuran- 3,4-diol (formula I; 0.95 g, 2.24 mmol) was dissolved in 120 ml of ACN:eoga (50:50) and heated to dissolve the solid. A solution of maleic acid (260.1 mg, 2.24 mmol) in ACN:water (10 ml) was added and the resulting solution was slowly cooled. After 3 hours, a small amount of solid formed, and therefore the solution was concentrated to about 80 ml, slowly cooled and left to stand overnight. A small amount of solid was filtered off (approximately 14 mg). The filtrate was concentrated to approximately 50 ml (the ratio of ACN:water (50:50) was changed towards an increase in the concentration of water), the collected seed crystals were added, left to cool slowly. Left to stand for 3 hours and filtered off the solid (approximately 3.2 g after drying for 1 hour (mp=201.2-201.5° C.). Dry in vacuum at room temperature overnight.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.19 (s, 1H), 7.81 (s, 1H), 7.61 (dd, J=2.8, 17.5 Hz, 2H) , 7.50 (d, J=8.3 Hz, 1H), 7.36 (dd, J=2.0, 8.4 Hz, 1H), 6.76 (d, J=3.5 Hz, 1H), 6.35-6.19 (m, 1H), 6.14 (s, 2H), 5.92 (d, J=8.2 Hz, 1H), 5.40-5.23 (m , 1H), 4.88 (s, 1H), 4.79 (d, J=7.2 Hz, 1H), 4.37 (d, J=8.2 Hz, 1H), 3.97 (d , J=7.2 Hz, 1H), 1.23 (s, 3H).

Crystals are long thin needles.

LCMS: RT=1.98 (424.8/428.8).

So pl. 201.6-202.7°C.

Method 2:

A compound of formula I (100.0 g, 1 eq.) was added to a clear container followed by a mixed solution of acetonitrile (450 ml) and deionized water (315 ml). Heated the mixture to about 50°C to obtain a solution. Filter through a filter to obtain a filtrate as a clear solution A. The resulting solution A was transferred to a 5 L clear round bottom flask equipped with a mechanical stirrer, a thermocouple and a nitrogen inlet. The container used to prepare the solution of the compound of formula I was washed with a mixed solution of acetonitrile (50 ml) and deionized water (35 ml). The wash solution was filtered through the same filter and the filtrate was transferred to the indicated 5 L round bottom flask. The mixture in a 5 L round bottom flask was heated to about 58°C. To a 5 L round bottom flask was added a pre-filtered solution of maleic acid (30 g, 1.1 eq.) in deionized water (100 ml) at such a rate as to maintain the internal temperature at 40-60°C. Then, deionized water filtered through a fine filter (2000 ml) was added to a 5 L round bottom flask at such a rate as to maintain an internal temperature of at least 40°C. The mixture in a 5 L round bottom flask was allowed to cool to 15-25° C. and stirred overnight. The mixture in the 5 L round bottom flask was cooled to 0-10° C. and stirred for about 2 hours. The mixture in the 5 L round bottom flask was filtered and the filter cake was washed with deionized water filtered through a fine filter (1000 ml). The filter cake was dried on the filter for about 3.5 hours. The product was transferred to a tray and dried in an oven under vacuum at 40° C. to constant weight (110 g). The product yield was 86.5%.

Method 3:

The free base of formula I was dissolved in methanol (12 volumes) at 20-45°C. The solution was filtered through a fine filter loaded with celite (~1 wt). Additional methanol (4 volumes) was used for washing. The filtrate and washing solution were transferred to a rotary evaporator through an inline filter and concentrated on a rotary evaporator until distillation ceased. Filtered ethanol (3.5 volumes) was charged to a rotary evaporator and concentrated until distillation ceased. The solid (formula I) was mixed in a rotary evaporator with filtered ethanol (10 volumes), then the mixture was transferred to the reactor and heated to 35-50°C. Then a solution of maleic acid (1.1 eq.) in ethanol (3.5 volumes), filtered through a fine filter, was added at 35-50°C. Stir the mixture at 35-50° C. for >30 min, cool to 15-30° C., then stir at the same temperature for >3 h. The solid is filtered off and the filter cake is washed with filtered ethanol (3.5 volumes). The product was dried by passing air through the filter cake, then the product was transferred to drying trays and further air dried. The product was further dried under vacuum at <45° C. until constant weight was reached. The product was crushed with a spatula and passed through a 60 mesh sieve. The product was further dried in a vacuum oven at <45° C. until constant weight was reached. The resulting solid is a compound of formula IA.

The RPD profile is shown in Fig. 1. The DSC profile is shown in FIG. 3. The TGA profile is shown in FIG. 4.

Method 4:

The compound of formula IA was prepared by adding the free base of formula I to acetonitrile at an initial concentration of approximately 20 mg/ml. The sample was heated to approx.

- 50 043295

55°C and added one equivalent of maleic acid. The sample instantly turned into a gel. Additional acetonitrile was added and finally a small amount of water (final concentration in a solution of approximately 9 mg/ml in 8:1 ACN/H2O (v/v)). When water was added, the sample immediately became transparent. The sample was allowed to cool slowly. No solid was isolated from the solution. The volume of the sample was substantially reduced and then sonicated. A white solid precipitated out of the solution. The solid was collected by filtration.

The RPD profile is shown in Fig. 2. Below in the table. 8 shows crystal data.

Table 8 Crystal data shown in FIG. 2

Brave type Primitive monoclinic a [A] 12.298 b [A] 6.993 with [A] 28.585 os [deg] 90 β [deg] 98.30 γ [deg] 90 Volume [A ³ /cell] 2432.5 Content of chiral particles? Chiral Symbol degeneracy R 1 21 1 Space group(s) R21 (4)

DSC and TGA are shown in Fig. 5.

This material was gravimetrically evaluated for solubility in water, which was approximately 1.1 g/l.

Method 5:

To 30.5 mg of maleic acid (0.263 mmol, 1.05 eq.) was added 106.6 mg (0.25 mmol, 1.0 eq.) of the compound of formula I. 4.0 ml of EtOH was added and the resulting mixture was continuously stirred in during the night. The mixture was filtered to give a solid which was washed with 2.5 ml MTBE and then dried (40° C. under vacuum overnight) to give a compound of formula IA.

The RPD profile is shown in Fig. 14.

The DSC profile is shown in Fig. 15.

The TGA profile is shown in Fig. 16.

IB formula. (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((R)-(3,4-dichlorophenyl)(hydroxy )methyl)-3-methyltetrahydrofuran-3,4-diol, hydrochloride salt (IB)

Method 1:

A crystalline compound of formula IB was obtained in an experiment in which a compound of formula I and an aqueous solution of HCl (1 eq.) in acetonitrile (ACN) were combined at elevated temperature. The reagents were used in a molar ratio of 1:1, and after obtaining a clear solution, the solution was left to cool to room temperature. The solid was collected and characterized after drying at ambient conditions.

The RPD profile is shown in Fig. 8. Below in the table. 9 shows crystal data.

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Table .9. The crystal data presented in Fig. 8

Brave type Primitive orthorhombic a [A] 9.597 b[A] 13.189 C [A] 35.618 a [deg] 90 β [deg] 90 γ[deg] 90 Volume [A ³ /cell] 4508.3 Content of chiral particles? Chiral Symbol degeneracy R 21 21 21 Space group(s) Ρ2ι2ι2ι(19)

DSC and TGA are shown in Fig. eleven.

This material was gravimetrically evaluated for solubility in water, which was approximately 0.8 g/l.

Method 2:

(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-2-[(R)-(3,4-dichlorophenyl)hydroxymethyl]3-methyltetrahydrofuran- 3,4-diol (formula I; 201.0 mg, 0.47 mmol) was dissolved in ACN (5 ml) and the mixture was heated until the solid dissolved. A solution of hydrochloric acid (0.03 ml, 0.47 mmol) in 1 ml ACN was added and the solution was slowly cooled. The solid was filtered off, dried in vacuo.

Mp: darkens and shrinks at 210.6-212.8°C, melts at 216.9-217.9°C.

Cl content by titration: 23.13%, theoretical value 23.03%

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.35 (s, 1H), 7.85 (d, J=3.7 Hz, 1H), 7.58 (d, J=2.0 Hz, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.35 (dd, J=2.0, 8.4 Hz, 1H), 7.01 (d, J=3.7 Hz, 1H), 6.00 (d, J=8.2 Hz, 1H), 5.92 (s, 1H), 4.78 (d, J=7.9 Hz, 1H), 4.33 ( d, J=8.2 Hz, 1H), 3.93 (d, J=7.9 Hz, 1H), 2.06 (s, 1H), 1.29 (s, 3H).

The RPD profile is shown in Fig. 6.

The DSC profile is shown in Fig. 9.

The TGA profile is shown in Fig. 10.

Method 3:

IB Formula

Concentrated hydrochloric acid (36.5-38.0%, 15 eq.) was added to a pre-cooled (0-10°C) solution of compound 13 in methanol (10 volumes), maintaining the temperature at <10°C. The bath was heated to 20-30° C. and stirred at the same temperature for >6 hours. The reaction was continued until the progress control criterion was violated (<1.0% of compound 13 relative to the compound of formula IB, as determined by HPLC). Filter the mixture and wash the filter cake (compound of formula IB) with ethanol. The filter cake was dried on a funnel by passing air through the filter cake for >1 h.

The RPD profile is shown in Fig. 7.

Method 4. Formula IB Form I:

A suspension of about 40 mg of a compound of formula IB in 0.6 ml of ethyl formate was stirred at 55° C. over the weekend and then filtered and washed with 0.6 MTBE to give crystalline form I of formula IB, which was dried in an oven at 47- 48°C during the night.

The RPD profile is shown in Fig. 20.

The DSC profile is shown in Fig. 21.

The TGA profile is shown in Fig. 22.

Karl Fischer titration showed that Form I of formula IB contains about 0.21% water.

The adsorption/desorption isotherms of form I of formula IB shown in FIG. 23 indicate that

- 52 043295 that it can adsorb ~0.5% water at about 95% humidity and can adsorb ~0.1% water at room temperature and normal humidity range (OB 40-50%).

Comparison of RPD profiles before and after EAF showed no change in shape. See fig. 24.

The 1H NMR profile is shown in FIG. 25.

Method 5: Formula IB Form II

A suspension of 60 mg of a compound of formula IB in 1.2 ml of ethanol was stirred at 55° C. for 16 h, filtered and the solid washed with 1.0 ml of MTBE. The solid was dried in an oven at 47-48° C. overnight to give form II of formula IB.

The RPD profile is shown in Fig. 26.

The DSC profile is shown in Fig. 27

The TGA profile is shown in Fig. 28.

The 1H NMR profile is shown in FIG. 29.

Karl Fischer titration indicated that Form II of formula IB contained approximately 0.54% water.

The chipboard profile is shown in Fig. 30. Adsorption/desorption isotherms of form II of formula IB indicate that it can adsorb ~6% water at about 95% humidity and can adsorb ~3% water at room temperature and normal humidity range (OB 40-50%).

Comparison of RPD profiles before and after EAF showed no change in shape. See fig. 31.

Method 6: Formula IB Form III

A suspension of about 35 mg of a compound of formula IB in 0.4 ml of acetone was stirred at 55° C. over the weekend and then washed with 0.5 MTBE to give crystalline form III of formula IB, which was dried in an oven at 47-48° C during the night.

The RPD profile is shown in Fig. 32.

The DSC profile is shown in Fig. 33.

The TGA profile is shown in Fig. 34. The sample showed a loss of approximately 0.01% of the mass to approximately 100°C.

The 1H NMR profile is shown in FIG. 35.

The chipboard profile is shown in Fig. 36. Adsorption/desorption isotherms of form III of formula IB indicate that it can adsorb ~2.8% water at about 95% humidity and can adsorb ~1% water at room temperature and normal humidity range (OB 40-50%) .

Fig. 37. The RPD profile before and after EAF showed no shape change.

Method 7: Formula IB Form IV

A suspension of 40 mg of a compound of formula IB in 0.6 ml of n-propanol was stirred at 55°C over the weekend, filtered, washed with 0.5 ml of MTBE and dried in an oven at 47-48°C overnight with obtaining form IV of formula IB.

The RPD profile is shown in Fig. 38.

The DSC profile is shown in Fig. 39. The DSC profile shows an onset temperature at 214.32°C and a peak at 220.59°C.

The TGA profile is shown in Fig. 40. The TGA profile shows a loss of approximately 0.02% weight to 130°C.

The 1H NMR profile is shown in FIG. 41.

Method 8:

To 106.3 mg of the compound of formula I (0.25 mmol, 1.0 eq.) was added 4.0 ml of 2-butanone and the resulting mixture was stirred for 5 minutes. 263 μl of 1.0 M HCl solution in IPA (0.263 mmol, 1.06 eq.) was added. The mixture was stirred to obtain a fine suspension, which was continuously stirred overnight. The mixture was filtered to give a solid which was dried (40° C. under vacuum overnight) to give the compound of formula IB (97 mg, 85.8% yield).

The RPD profile is shown in Fig. 17.

The DSC profile is shown in Fig. 18.

The TGA profile is shown in Fig. 19.

Method 9:

210 mg of the free base of formula I (0.494 mmol, 1.0 eq.) and 5.0 ml of methanol were stirred to obtain a clear solution. Hydrochloric acid (0.51 ml, 1.03 eq., in IPA from 37% aqueous solution) was added and the mixture stirred for about 1.0 minutes to form a slurry. The suspension was stirred continuously for 2.0 h, then at 50°C for 1.0 h, then at room temperature for 1.0 h. Filter the mixture and wash with MTBE (4.0 ml) and dry the solid at 45-48°C under vacuum for 24 hours.

The RPD profile is shown in Fig. 42.

The DSC profile is shown in Fig. 43.

The TGA profile is shown in Fig. 44.

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IC formula. (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((R)-(3,4-dichlorophenyl)(hydroxy )methyl)-3-methyltetrahydrofuran-3,4-diol, oxalate salt (IC)

A crystalline compound of formula IC was obtained in an experiment in which a compound of formula I and oxalic acid (1 eq) were combined in ethanol at elevated temperature. The solution was left to cool and then allowed to evaporate the ethanol. The solid was collected and characterized after drying at ambient conditions.

The RPD profile is shown in Fig. 12. Below in the table. 10 shows crystal data. Table 10. Chip data shown in FIG. 12

Brave type Primitive orthorhombic a [A] 7.373 b [A] 11,580 C [A] 50.309 a [deg] 90 β [deg] 90 γ [deg] 90 Volume [A ³ /cell] 4295.3 Content of chiral particles? Chiral Degeneracy symbol R 2t 21 21 Space group(s) Ρ2ι2ι2ι(19)

This material was gravimetrically evaluated for solubility in water and found to have no solubility (<0.3 g/l).

Formula ID. (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((R)-(3,4-dichlorophenyl)(hydroxy )methyl)-3-methyltetrahydrofuran-3,4-diol, phosphate salt (ID)

Method 1:

A crystalline compound of formula ID was obtained in an experiment in which a compound of formula I and phosphoric acid (1 eq) were combined in ethanol at elevated temperature. The sample was allowed to cool and a solid precipitated out of solution. The solid was collected and characterized after drying at ambient conditions.

The RPD profile is shown in Fig. 13. Below in the table. 11 shows crystal data.

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Table 11 Crystal data shown in FIG. 13

Brave type Primitive orthorhombic a [A] 7.730 b [A] 12.120 C [A] 49.420 a [deg] 90 β [deg] 90 γ [deg] 90 Volume [A ³ /cell] 4630.0 Content of chiral particles? Chiral Symbol R21 21 21 degeneracy Space group(s) Ρ2ι2ι2ι(19)

This material was gravimetrically evaluated for solubility in water and found to have no solubility (<0.3 g/l).

Method 2:

To 106.7 mg of the compound of formula I (0.25 mmol, 1.0 eq.) was added 4.0 ml of MeOH and the resulting mixture was stirred to obtain a clear solution. 265 µl of 1.0 M H ₃ PO ₄ solution in IPA (0.265 mmol, 1.06 eq.) was added. The mixture was stirred continuously overnight and then filtered to give a solid which was dried (40° C. under vacuum overnight) to give a compound of formula IC. The RPD profile is shown in Fig. 45.

The DSC profile is shown in Fig. 46.

The TGA profile is shown in Fig. 47.

IE formula. (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((R)-(3,4-dichlorophenyl)(hydroxy )methyl)-3-methyltetrahydrofuran-3,4-diol, bisulfate (IE)

(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-2-[(R)-(3,4-dichlorophenyl)hydroxymethyl]3-methyltetrahydrofuran- 3,4-diol (100 mg, 0.24 mmol) in IPA (5 ml) was sonicated at 50°C to give a clear solution and then sulfuric acid (2.14 ml, 0.24 mmol) was added and sonicated again at 50°C for 5 min. The mixture was allowed to cool slowly and the resulting solid was centrifuged, washed with minimal water and dried under high vacuum to give 95 mg of needles; So pl. 216-219°C.

1H NMR (500 MHz, DMSO-d6) δ 8.21 (s, 1H), 7.65 (d, J=3.7 Hz, 1H), 7.60 (d, J=1.9 Hz, 1H ), 7.51 (d, J=8.3 Hz, 1H), 7.37 (dd, J=1.9, 8.3 Hz, 1H), 6.79 (d, J=3.6 Hz , 1H), 6.24(brs, 1H), 5.94(d, J=8.2Hz, 1H), 5.33(brs, 1H), 4.90(brs, 1H), 4.80 (d, J=7.2 Hz, 1H), 4.44 - 4.33 (m, 1H), 3.98 (d, J=7.2 Hz, 1H), 1.25 (s, 3H) .

Formula I. (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((R)-(3,4-dichlorophenyl )(hydroxy)methyl)-3-methyltetrahydrofuran-3,4-diol

Method 1: Formula I, Form I

The free base of formula I (56 mg, 0.132 mmol) and 1.0 ml of isopropanol were stirred for 10 minutes to obtain a clear solution, which was stirred at 55°C for 2.0 h and then at room temperature for 4.0 h The resulting solid was filtered, washed with MTBE (1.0 ml) and then dried at 46-48° C. under vacuum overnight to give 48.7 mg (86.96% yield) of crystalline form I of formula I.

The RPD profile is shown in Fig. 48.

The DSC profile is shown in Fig. 49.

The TGA profile is shown in Fig. 50.

- 55 043295

The 1H NMR profile shown in FIG. 51 demonstrates that Form I of formula I is a mono-isopropanol solvate.

The chipboard profile is shown in Fig. 52.

The RPD profiles before and after EAF shown in Fig. 53 show no shape change.

Karl Fischer titration indicates that Form I of formula I contains about 1.3% water.

Adsorption/desorption isotherms of form I of formula I from IPA (Fig. 52) indicate that this crystalline form can adsorb ~0.5% water at about 95% humidity and can adsorb ~0.8% water at room temperature and normal humidity range (OB 40-50%).

Method 2: Formula I Form 1

The free base of formula I (175 mg, 0.412 mmol) and 2.5 ml of isopropanol were stirred for 6 minutes to obtain a clear creamy substance, which after continuous stirring for 10 minutes turned into a suspension. The resulting suspension was stirred at 50°C for 2.5 h and then at room temperature for 1.0 h. The mixture was filtered, washed with MTBE (2.0 ml) and then dried at 46-48°C under vacuum overnight to obtain 157 mg (yield 89.71%) of Form 1 of Formula I.

Method 3: Formula I, Form II

A suspension of the free base of formula I (about 50 mg) in THF was stirred for 4 hours, then stirred continuously at 55°C for 2 hours and then stirred at 25°C for 4 hours. The resulting mixture was filtered, washed with MTBE and dried in oven at 45-46°C for 24 hours to obtain form II of formula I.

The RPD profile is shown in Fig. 58.

The DSC profile is shown in Fig. 59.

Method 4: Formula I, Form II

A suspension of the free base of formula I (about 50 mg) in Me-THF was stirred for 4 hours, then stirred continuously at 55°C for 2 hours and then stirred at 25°C for 4 hours. The resulting mixture was filtered, washed with MTBE and dried in an oven at 45-46°C for 24 hours to obtain form II of formula I.

The RPD profile is shown in Fig. 60.

The DSC profile is shown in Fig. 61.

Method 5: Formula I, Form II

A suspension of the free base of formula I (about 50 mg) in acetone was stirred for 4 hours, then stirred continuously at 55°C for 2 hours and then stirred at 25°C for 4 hours. The resulting mixture was filtered, washed with MTBE and dried in oven at 45-46°C for 24 hours to obtain form II of formula I.

The RPD profile is shown in Fig. 54.

The DSC profile is shown in Fig. 55.

Method 6: Formula I, Form II

The free base of formula I (150 mg, 0.353 mmol) and 2.0 ml of ethanol were stirred for about 1.0 minutes to give a clear solution which became a suspension after 3 minutes. The resulting suspension was stirred continuously for 5 min, then at 55°C for 2.5 h, then at room temperature for 1.0 h. Filter the mixture and wash with MTBE (2.0 ml) and dry the solid at 46- 48° C. under vacuum overnight to give 121 mg (80.7% yield) of Form II of Formula I.

The RPD profile is shown in Fig. 62.

The DSC profile is shown in Fig. 63.

Method 7: Formula I, Form III

A suspension of the free base of formula I in methanol/water (1/5) was stirred for 10 min, then at 55° C. for 2 h, and then at room temperature for 1 h. Filter the mixture and wash the solid with MTBE, and then dried under vacuum at 47-48° C. overnight to give form III of formula I.

The RPD profile is shown in Fig. 56.

The DSC profile is shown in Fig. 57.

Instrumental methods X-ray powder diffraction (RPD)

RPD profiles can be recorded on a PANalytical X'Pert PRO MPD diffractometer using an incident Cu radiation beam obtained using a long-focus source with precise focusing Optix. An elliptically graded multilayer mirror is used to focus the Cu Ka x-rays through the sample and onto the detector. Prior to analysis, a silicon sample (NIST SRM 640e) is analyzed to ensure that the observed position of the Si 111 peak corresponds to the position

- 56 043295 certified by NIST (National Institute for Standards and Technology). A sample sample is placed between 3 µm thick films and analyzed in transmission geometry. A beam limiter, a short anti-scatter extension, and an anti-scatter knife collimator are used to minimize the background created by the air. Soller slits are used for the incident and diffracted beams to minimize broadening due to axial divergence. Diffraction profiles are recorded using a scanning position sensitive detector (X'Celerator) located 240 mm from the sample and Data Collector software version 2.2b.

RPD profiles can also be recorded on an X-ray powder diffractometer (RPD) Rigaku MiniFlex. X-rays are obtained from copper (Cu) at 1.5405 bA with a K _b filter. X-ray power: 30 kV, 15 mA.

Thermogravimetric Analysis (TGA) and Differential Scanning Calorimetry (DSC)

Thermal analysis can be performed on a Mettler Toledo TGA/DSC3+ analyzer. Temperature calibration is carried out using phenyl salicylate, indium, tin and zinc. The sample is placed in an aluminum crucible. The sample is closed, the lid is pierced, then inserted into the TG oven. The furnace is heated under a nitrogen atmosphere. The DSC profile can also be recorded on a TA Instrument model Q20 differential scanning calorimeter with an autosampler using a scan rate of 10° C./min and a nitrogen gas flow rate of 50 ml/min.

The TGA profile can be recorded on a TA Instruments TGA Q500 at a scan rate of 20°C per minute.

Dynamic Vapor Sorption (DSP)

Dynamic vapor sorption experiments can be performed on a symmetrical vapor sorption analyzer VTI SGA-Cx100. The moisture absorption profile is recorded in three cycles in 10% OB steps with adsorption from 5 to 95% OB, followed by desorption in 10% steps from 95 to 5%. The equilibration criterion is 0.0050 wt% in 5 minutes with a maximum equilibration time of 180 minutes. All adsorption and desorption experiments are carried out at room temperature (21-22°C). The samples do not use the pre-drying step.

Biochemical study protocol

Compounds are solubilized and diluted 3-fold in 100% DMSO. The resulting diluted compounds are further diluted in assay buffer (50 mM Tris-HCl, pH 8.5, 50 mM NaCl, 5 mM MgCl ₂ , 0.01% Brij35, 1 mM DTT, 1% DMSO) for an IC ₅₀ in 10 scheme. doses at a concentration 10 times higher than the required analytical concentration. Standard reactions are carried out in a total volume of 50 µl of assay buffer using histone H2A (final concentration 5 µM) as substrate. The PRMT5/MEP50 complex, diluted to provide a final analytical concentration of 5 nM, is added to this mixture, and the compounds are left for pre-incubation for 15-20 min at room temperature. The reaction is initiated by adding S-[3H-methyl]adenosyl-L-methionine (PerkinElmer) to a final concentration of 1 μM. After 60 min incubation at 30°C, the reaction is stopped by adding 100 μl of 20% TCA. Each reaction mixture was applied to a filter plate (MultiScreen FB Filter Plate, Millipore) and washed 5 times with PBS buffer. Scintillation fluid is added to the filter plate and counted on a scintillation counter. IC ₅₀ values are determined by fitting the data to a standard 4-parameter Hill slope using GraphPad Prism software.

Cellular Analysis Protocol

Cell processing and Western blotting to detect symmetrical dimethylarginine (sDMA) and symmetrical H3R8 histone dimethyl marks (H3R8me2s)

Initial Screening of Compounds in A549 Cells: Compounds were dissolved in DMSO to make a 10 mM stock solution and further diluted to 0.1 and 1 mM. A549 cells were maintained in PRMI 1640 medium (Corning Cellgro, cat. no.: 10-040-CV) supplemented with 10% v/v. fetal bovine serum (GE Healthcare cat. no.: SH30910.03). The day before the experiment, 1.25x105 cells were seeded in a 6-well plate in 3 ml of medium and incubated overnight. The next day, the medium was changed and 3 μl of compound solution (1:1,000 dilution, final concentration 0.1 and 1 μM; DMSO concentration: 0.1%) was added and incubated for 3 days. Cells were incubated with DMSO and used as a vehicle control. Cells were washed once with PBC, trypsinized in 150 μl of 0.25% trypsin (Corning, cat. no: 25-053-CI), neutralized with 1 ml of complete medium, transferred to microcentrifuge tubes and harvested. The cell pellet was then resuspended in 15 μl of PBS, lysed in 4% CSN and homogenized by passing through a homogenizer column (Omega Biotek, Cat No: HCR003). Total protein concentrations were determined by BCA analysis (ThermoFisher Scientific, cat. no.: 23225). The lysates were mixed with 5x Laemmli's buffer and boiled for 5 min. Forty μg of total protein was isolated on a DNS-PAGE gel (Bio-Rad, cat. no.: 4568083, 4568043), transferred to a PVDF membrane, blocked with 5% milk powder (Bio-Rad, cat. no.: 1706404) in TBS with 0.1% v/v Tween 20 (TBST) for 1 h at room temperature (RT) and incubated with primary antibodies (sDMA: Cell signaling, cat. no: 13222, 1:3,000; H3R8me2s: Epigentek, cat. no.: A-3706-100, 1:2000; β-actin:

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Abcam, cat. no: ab8227, 1:10000) in 5% milk powder in TBST at 4°C overnight. The next day, the membranes were washed with TBST, 5x5 min, and incubated with a secondary antibody conjugated to HRP (GE Healthcare; cat. no: NA934-1ML; 1:5000) for 2 h at room temperature, then washed with TBST 5x5 min, and incubated with ECL substrates (Bio-Rad, cat. no.: 1705061, 1705062). The chemiluminescent signal was captured on a Fluochem HD2 (Proteinsimple) visualizer and analyzed using ImageJ.

To determine the IC ₅₀ values of enzyme inhibition, Granta cells were seeded at a density of 5x105 cells/ml in 3 ml of medium (PRMI+10% v/v FBS) using Western blotting. Nine-point 3-fold serial dilutions of the compound (3 μl, dilution 1:1000, DMSO concentration 0.1%; maximum final concentration 10 or 1 μM, depending on the potency of the compounds) were added to the cells and incubated for 3 days. Cells were incubated with DMSO and used as a vehicle control. Cells were harvested and analyzed by Western blotting as described above. The SmD3me2s and H3R8me2s bands were quantified using ImageJ. Signals were normalized for β-actin and DMSO control. IC ₅₀ values were calculated in Graphpad Prism.

Cell Proliferation Assay to Determine IC ₅₀ on Granta-519 Cells

Granta-519 cells were maintained in PRMI 1640 medium (Corning Cellgro, cat. no.: 10-040-CV) supplemented with 10% v/v. fetal bovine serum (GE Healthcare cat. no.: SH30910.03).

The compound of formula I was dissolved in DMSO to give 10 mM stock solutions and stored at -20°C. Received nine-point 3-fold serial dilutions in DMSO with a maximum concentration of 1 mm (working stock solutions).

On the day of the experiment, the working stock solutions were further diluted 1:50 with fresh medium in a 96-well plate and 10 μl of diluted drug compounds were added to a new 96-well proliferation assay plate. Cells growing in exponential phase were centrifuged at 1500 rpm for 4 min and resuspended in fresh medium until a density of 0.5x106 cells/ml was reached. 200 μl cells were added to a 96-well plate containing diluted drug compounds and incubated for 3 days. DMSO was used as a vehicle control.

On day 3, 10 μl of the solution from the Cell Counting Kit-8 (CCK-8, Jojindo, CK04-13) was added to a new 96-well plate. Cells were incubated with drug compounds for 3 days and resuspended with pipetting, and 100 μl of cells were transferred to a 96-well plate containing CCK-8 reagent to measure viable cells. Plates were incubated in a CO2 incubator for 2 h and OD450 values were measured on a microplate reader (iMark microplate reader, Bio-Rad).

For re-plating, the compound stock solutions were diluted 1:50 with fresh medium and 10 μl of the diluted drug compounds were added to a new 96-well plate. Cells from the plate obtained on day 3 (50 μl) were added to a 96-well plate containing fresh drug compound, and another 150 μl of fresh medium was added to reach a volume of 200 μl. The plate was returned to the CO2 incubator and incubated for another 3 days. The viable cell measurement and re-plating was repeated on day 6, and the final viable cell measurement was performed on day 10.

The percentage of viable cells compared to the DMSO vehicle control was calculated and plotted (Normalized Response vs. [Inhibitor] - Variable Slope) plotted in Graphpad Prism to determine proliferation IC ₅₀ values at day 10.

Table A. Biochemical and cellular activity (in the Granta-519 cell line)

Example No. 1С ₅₀ PRMT5, μM IC ₅₀ _N PRMT5 1С ₅₀ sDMA, μM _{IC50_NsDMA} 1C ₅₀ proliferation, μM IC ₅₀ _N proliferation II Formula I 0.0015 3 0.031 3 0.075 3

Solubility of compound of formula IE in FaSSIF

First, the compounds were dispersed in freshly prepared FaSSIF buffer (http://biorelevant.com/site_media/upload/documents/How_to_make_FaSSIF_FeSSIF_and_FaSSGF.pdf) at 1 mg/ml, respectively, and standard samples were prepared by preparing 1 mg/ml experimental compounds in DMSO. The compounds were then subjected to sufficient mixing by vortexing for 30 s and stirred at 25°C at 300 rpm in a thermal mixer for 4 h. After incubation, the obtained samples were centrifuged at 10,000 rpm for 10 min to remove undissolved solid and analyzed the obtained supernatant solutions using HPLC. The actual concentrations of the compounds were determined by measuring the peak area, and the solubility (S) of the compounds was calculated using the following equation:

where C is the sample concentration in µg/mL, A is the peak area and V

- 58 043295 represents the volume of injection of the sample.

Warfarin (10-25 µg/ml), atovaquone (<2 µg/ml) and nimesulide (100-200 µg/ml) were used as positive controls in this experiment.

The measured solubility of the compound of formula IE in FaSSIF was 206 μg/ml.

Pharmacokinetic properties of the compound of formula I in vivo

In a non-crossover study of PK, rats (SD, male, not fasted) were dosed at 1 mg/kg (DMA: 20% HPBCD=5:95, solution) via intravenous (iv) administration (N=3) and 1 mg/kg (0 5% Na-CMC + 0.5% Tween 80, solution) via gavage (p.o.) (N=3). The mean T _1/2 was 4.1 h, Vss 3.1 l/kg, blood clearance 8.8 mg/min/kg in group iv; mean dose-normalized AUC was 3246 ng*h*kg/mL/mg and oral bioavailability >100% in the po group.

In vivo pharmacodynamic effect and tumor growth inhibition by the compound of formula I in the Granta-519 xenograft mouse model

Granta-519 cells were maintained in DMEM supplemented with 10% fetal bovine serum and 2 mM L-glutamine at 37° C. in 5% CO ₂ in air. Cells in the exponential growth phase were harvested and injected 1 x 10 ⁷ cells in 0.1 ml PBS with Matrigel (1:1) by subcutaneous injection into the lower right flank of each mouse for tumor development. Treatment was started when the average tumor size reached approximately 300-400 mm ³ . Mice were divided into groups using StudyDirector™ software (Studylog Systems, Inc., CA, USA) and one optimal randomization design (designed by paired allocation or striped allocation) was selected that provided the minimum variation in tumor volume between groups for group assignment. . Compound of formula I or vehicle (0.5% Na-CMC + 0.5% Tween 80, suspension) was administered orally (QD for formula I, QD for vehicle) at a dose of 30 and 50 mg/kg for 19 and 16 days, respectively . Body weight and tumor size were measured every 3-4 days after randomization. Animals were euthanized 12 hours after the last dose and blood and tumor samples were collected for analysis.

To measure the levels of sDMA in tumor samples, the tumor of each mouse was weighed and homogenized in RIPA buffer with the addition of a protease inhibitor (cOmplete™, protease inhibitor cocktail without EDTA, Roche). The lysate was centrifuged at 14,000 rpm. for 30 min at 4°C to remove debris. Total protein concentrations in the lysate were determined by BCA analysis (ThermoFisher Scientific, cat. no. 23225). Equal amounts of total protein from each tumor were isolated on a DNS-PAGE gel and sDMA levels were determined by Western blotting as described previously.

In accordance with the described protocol, the compound of formula I showed an average inhibition of tumor growth of 46% (N=5) at 30 mg/kg with a loss of body weight of 1%; mean tumor growth inhibition 79% at 50 mg/kg with 8% body weight loss. Also demonstrated >90% inhibition of sDMA at 30 mg/kg and no detectable sDMA at 50 mg/kg.

This description also applies to the following aspects:

Aspect 1 A pharmaceutically acceptable salt of a compound of formula I

Aspect 2. A pharmaceutically acceptable salt according to aspect 1, characterized in that said salt is a maleate salt having the formula IA nh ₂

L 1 7 no^o

Cl -[ U ⁿ °ChxxU ^C| ^ ^But NOIA.

Aspect 3. A crystalline form of the pharmaceutically acceptable salt of Aspect 2.

Aspect 4 The crystalline form of Aspect 3 having substantially the X-ray powder diffraction profile as shown in FIG. 1.

Aspect 5 The crystalline form of Aspect 3 having substantially the X-ray powder diffraction profile as shown in FIG. 2.

Aspect 6 The crystalline form of aspect 3, characterized by an X-ray powder diffraction profile containing a peak at 16.3° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka).

Aspect 7. The crystalline form of aspect 3, characterized by an X-ray powder diffraction profile containing peaks at 6.7, 11.0 and 16.3° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstrom (Cu Ka).

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Aspect 8. The crystalline form of aspect 3, characterized by an X-ray powder diffraction profile containing peaks at 6.7, 16.3, 20.4 and 30.7° ± 0.2° 2-theta, on a 2-theta scale with λ =1.54 angstroms (Cu Ka).

Aspect 9 The crystalline form of Aspect 3, characterized by an X-ray powder diffraction profile containing peaks at 6.7, 11.0, 14.9, 16.3, 16.8, 20.4, 25.4°±0.2 ° 2-theta, on the 2-theta scale with λ=1.54 angstroms (Cu Ka).

Aspect 10. A crystalline form according to aspect 3, characterized by an X-ray powder diffraction profile containing peaks at three or more 6.7, 11.0, 14.9, 16.3, 16.8, 20.4, 25.4, 25 .8, 27.9, 29.1 and 30.7° ± 0.2° 2-theta, 2-theta with λ=1.54 angstroms (Cu Ka).

Aspect 11 A crystalline form according to any one of aspects 3, 4, or 6-10, having substantially a differential scanning calorimetry (DSC) thermogram as shown in FIG. 3 when heated at a rate of 10°C/min.

Aspect 12 A crystalline form according to any one of aspects 3, 4 or 6-11, characterized by a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at about 207°C when heated at a rate of 10°C/min.

Aspect 13 The crystalline form of aspect 3, characterized by an X-ray powder diffraction profile containing a peak at 14.6° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka).

Aspect 14 The crystalline form of aspect 3, characterized by an X-ray powder diffraction profile containing peaks at 13.0, 14.6 and 16.3° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstrom (Cu Ka).

Aspect 15 The crystalline form of Aspect 3, characterized by an X-ray powder diffraction profile containing peaks at 8.3, 13.0, 14.6, 16.3, 26.3 and 27.0° ± 0.2° 2-theta , on the 2theta scale with λ=1.54 angstroms (Cu Ka).

Aspect 16 The crystalline form of Aspect 3, characterized by an X-ray powder diffraction profile containing peaks at 8.3, 13.0, 14.6, 15.3, 16.3, 16.7, 27.0 and 27.2° ± 0.2° 2-theta, on the 2-theta scale with λ=1.54 angstroms (Cu Ka).

Aspect 17. The crystalline form of aspect 3, characterized by an X-ray powder diffraction profile containing peaks at three or more 3.1, 8.3, 13.0, 14.6, 15.3, 16.3, 16.7, 18 .4, 26.3, 26.5, 27.0 and 27.2° ± 0.2° 2-theta, 2-theta with λ=1.54 angstroms (Cu Ka).

Aspect 18 A crystalline form according to any one of aspects 3, 5, or 13-17, having substantially a differential scanning calorimetry (DSC) thermogram as shown in FIG. 5, when heated at a rate of 10°K/min.

Aspect 19 A crystalline form according to any one of aspects 3, 5, or 13-18, characterized by a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at about 185°C when heated at a rate of 10°K/min.

Aspect 20 A crystalline form according to any one of aspects 3, 4, or 6-12, having substantially the thermogravimetric analysis profile as shown in FIG. 4, when heated at a rate of 20°C/min.

Aspect 21 A crystalline form according to any one of aspects 3, 5, or 13-19, having substantially the thermogravimetric analysis profile as shown in FIG. 5, when heated at a rate of 10°K/min.

Aspect 22. A pharmaceutically acceptable salt according to aspect 1, characterized in that said salt is a hydrochloride salt having the formula IB

Aspect 23 A crystalline form of the pharmaceutically acceptable salt of Aspect 22.

Aspect 24 The crystalline form of aspect 23 having substantially the X-ray powder diffraction profile as shown in FIG. 6.

Aspect 25 A crystalline form according to any of Aspect 23 or Aspect 24, characterized by an X-ray powder diffraction profile containing a peak at 5.4° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka) .

Aspect 26 A crystalline form according to any one of Aspect 23 or Aspect 24, characterized by an X-ray powder diffraction profile containing peaks at 5.4, 10.9, and 16.4° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka).

Aspect 27 A crystalline form according to any of Aspect 23 or Aspect 24, characterized by an X-ray powder diffraction profile containing peaks at 5.4, 10.9, 21.2 and 24.2° ± 0.2° 2-60 043295 theta, on the 2-theta scale with λ=1.54 angstroms (Cu Ka).

Aspect 28 A crystalline form according to any one of Aspect 23 or Aspect 24, characterized by an X-ray powder diffraction profile containing peaks at 5.4, 10.9, 16.4, 21.2 and 24.2°±

0.2° 2-theta, on the 2-theta scale with λ=1.54 angstroms (Cu Ka).

Aspect 29 A crystalline form according to any of Aspect 23 or Aspect 24, characterized by an X-ray powder diffraction profile containing peaks at three or more of 5.4, 10.9, 16.4, 21.2, 24.2, and 27.5 ° ± 0.2° 2-theta, on the 2-theta scale with λ=1.54 angstroms (Cu Ka).

Aspect 30 The crystalline form of aspect 23 having substantially the X-ray powder diffraction profile as shown in FIG. 7.

Aspect 31 A crystalline form according to any one of Aspect 23 or Aspect 30, characterized by an X-ray powder diffraction profile containing a peak at 5.0° ± 0.2° 2-theta on a 2-theta scale with λ=1.54 angstroms (Cu Ka) .

Aspect 32 A crystalline form according to any of Aspect 23 or Aspect 30, characterized by an X-ray powder diffraction profile containing peaks at 5.0, 15.2 and 24.3° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka).

Aspect 33 A crystalline form according to any of Aspect 23 or Aspect 30, characterized by an X-ray powder diffraction profile containing peaks at 5.0, 15.2, 24.3 and 30.8° ± 0.2° 2theta, on a scale of 2- theta with λ=1.54 angstroms (Cu Ka).

Aspect 34 A crystalline form according to any one of Aspect 23 or Aspect 30, characterized by an X-ray powder diffraction profile containing peaks at 5.0, 10.1, 13.7, 15.2, 17.1, 24.3, and 30.8 ° ± 0.2° 2-theta, on the 2-theta scale with λ=1.54 angstroms (Cu Ka).

Aspect 35 The crystalline form of aspect 23, having substantially the same X-ray powder diffraction profile as shown in FIG. 8.

Aspect 36 A crystalline form according to any one of Aspect 23 or Aspect 35, characterized by an X-ray powder diffraction profile containing a peak at 11.4° ± 0.2° 2-theta, on a 2theta scale with λ=1.54 angstroms (Cu Ka) .

Aspect 37 A crystalline form according to any one of Aspect 23 or Aspect 35, characterized by an X-ray powder diffraction profile containing peaks at 11.4, 11.6, 15.1 and 16.7° ± 0.2° 2theta, on a scale of 2- theta with λ=1.54 angstroms (Cu Ka).

Aspect 38 A crystalline form according to any of Aspect 23 or Aspect 35, characterized by an X-ray powder diffraction profile containing peaks at 4.9, 11.4, 11.6, 15.1 and 16.7° ± 0.2° 2- theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka).

Aspect 39 A crystalline form according to any of Aspect 23 or Aspect 35, characterized by an X-ray powder diffraction profile containing peaks at 4.9, 11.4, 11.6, 15.1, 16.7, 21.0, and 22.4 ° ± 0.2° 2-theta, on the 2-theta scale with λ=1.54 angstroms (Cu Ka).

Aspect 40. A crystalline form according to any one of aspect 23 or aspect 35, characterized by an X-ray powder diffraction profile containing peaks at three or more of 4.9, 7.1, 11.4, 11.6, 12.4, 13.6 , 14.3, 15.1, 16.5, 16.7, 16.9, 17.0, 20.3, 21.0, 22.4, 23.0, 23.5 and 23.8° ± 0.2° 2-theta, on the 2theta scale with λ=1.54 angstroms (Cu Ka).

Aspect 41 A crystalline form according to any one of aspects 23-29, characterized essentially by a differential scanning calorimetry (DSC) thermogram as shown in FIG. 9 when heated at a rate of 10°C/min.

Aspect 42 A crystalline form according to any one of aspects 23 or 35-40, having substantially a differential scanning calorimetry (DSC) thermogram as shown in FIG. 11 when heated at a rate of 10°C/min.

Aspect 43 A crystalline form according to any one of aspects 23-29 or 41, characterized by a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at about 268°C when heated at a rate of 10°C/min.

Aspect 44 A crystalline form according to any one of aspects 23-29, 41, or 43, characterized by a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at about 191°C when heated at a rate of 10°C/min.

Aspect 45 A crystalline form according to any one of aspects 23, 35-40, or 42, characterized by a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at about 196°C when heated at a rate of 10°C/min.

Aspect 46 A crystalline form according to any one of aspects 23-29, 41, or 43, or 44, having substantially the thermogravimetric analysis profile as shown in FIG. 10, when heated at a rate of 20°C/min.

Aspect 47 A crystalline form according to any one of aspects 23, 35-40, or 42, having substantially the thermogravimetric analysis profile as shown in FIG. 11 when heated at a rate of 10°C/min.

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Aspect 48. A pharmaceutically acceptable salt according to aspect 1, characterized in that said salt is an oxalate salt having the formula IC

Aspect 49 A crystalline form of the pharmaceutically acceptable salt of Aspect 48.

Aspect 50 The crystalline form of aspect 49 having substantially the X-ray powder diffraction profile as shown in FIG. 12.

Aspect 51 A crystalline form according to any one of Aspect 49 or Aspect 50, characterized by an X-ray powder diffraction profile containing a peak at 10.5° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka) .

Aspect 52 A crystalline form according to any one of Aspect 49 or Aspect 50, characterized by an X-ray powder diffraction profile containing peaks at 10.5, 14.7 and 16.2° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka).

Aspect 53 A crystalline form according to any one of Aspect 49 or Aspect 50, characterized by an X-ray powder diffraction profile containing peaks at 10.5, 14.7, 16.2 and 28.7° ± 0.2° 2theta, on a scale of 2- theta with λ=1.54 angstroms (Cu Ka).

Aspect 54 A crystalline form according to any of Aspect 49 or Aspect 50, characterized by an X-ray powder diffraction profile containing peaks at 10.5, 14.7, 16.2, 17.6, 17.7, 19.6, 28.7 and 28.9° ± 0.2° 2-theta, on the 2-theta scale with λ=1.54 angstroms (Cu Ka).

Aspect 55 A crystalline form according to any of Aspect 49 or Aspect 50, characterized by an X-ray powder diffraction profile containing peaks at three or more of 10.5, 11.6, 13.1, 14.2, 14.7, 14.9 , 16.2, 17.6, 17.7, 19.6, 28.7 and 28.9° ± 0.2° 2-theta, 2-theta scale with λ=1.54 angstroms (Cu Ka) .

Aspect 56. A pharmaceutically acceptable salt according to aspect 1, characterized in that said salt is a phosphate salt having the formula ID

Aspect 57 A crystalline form of the pharmaceutically acceptable salt of Aspect 56.

Aspect 58 The crystalline form of aspect 57 having substantially the X-ray powder diffraction profile as shown in FIG. 13.

Aspect 59 A crystalline form according to any one of Aspect 57 or Aspect 58, characterized by an X-ray powder diffraction profile containing a peak at 3.6° ± 0.2° 2-theta on a 2-theta scale with λ=1.54 angstroms (Cu Ka) .

Aspect 60 A crystalline form according to any one of Aspect 57 or Aspect 58, characterized by an X-ray powder diffraction profile containing peaks at 3.6 and 10.7° ± 0.2° 2-theta, on a 2-theta scale with λ=1, 54 angstroms (Cu Ka).

Aspect 61 A crystalline form according to any one of Aspect 57 or Aspect 58, characterized by an X-ray powder diffraction profile containing peaks at 3.6, 10.7 and 15.6° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka).

Aspect 62 A crystalline form according to any one of Aspect 57 or Aspect 58, characterized by an X-ray powder diffraction profile containing peaks at three or more of 3.6, 10.7, 15.6, 17.9, and 18.7°±0.2 ° 2-theta, on the 2-theta scale with λ=1.54 angstroms (Cu Ka).

Aspect 63. A pharmaceutically acceptable salt according to aspect 1, characterized in that said salt is a bisulfate salt having the formula IE

Aspect 64 A crystalline form of the pharmaceutically acceptable salt of Aspect 63.

Aspect 65. A pharmaceutical composition comprising a pharmaceutically acceptable salt according to any one of aspects 1-64 and a pharmaceutically acceptable excipient.

Aspect 66 A method of inhibiting the protein arginine methyltransferase 5 (PRMT5) enzyme, comprising: contacting the PRMT5 enzyme with an effective amount of a compound according to any one of aspects 1-64.

Aspect 67: A method of treating a disease or disorder associated with aberrant activity

PRMT5, in a subject, comprising administering to said subject a compound according to any one of aspects 164.

Aspect 68. The method of aspect 67, wherein said disease or disorder associated with aberrant 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 lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), mastocytosis , chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS), epidermoid cancer, or hemoglobinopathies such as b-thalassemia and sickle cell disease (SCD).

Aspect 69. The method of aspect 67 or aspect 68, wherein said compound or a pharmaceutically acceptable salt thereof is administered in combination with one or more other agents.

Claims (35)

1. A pharmaceutically acceptable salt of a compound of formula I ^H0 NO I 2. A pharmaceutically acceptable salt according to claim 1, characterized in that said salt is a maleate salt having the formula IA 3. A crystalline form of a pharmaceutically acceptable salt according to claim 2. 4. A crystalline form according to claim 3, characterized essentially by the X-ray powder diffraction profile as shown in FIG. 1; or an X-ray powder diffraction profile containing a peak at 16.3° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at 6.7, 11.0 and 16.3° ± 0.2° 2theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at 6.7, 16.3, 20.4 and 30.7° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka) ; or an X-ray powder diffraction profile containing peaks at 6.7, 11.0, 14.9, 16.3, 16.8, 20.4, 25.4° ± 0.2° 2-theta, on a scale of 2- theta with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at three or more of 6.7, 11.0, 14.9, 16.3, 16.8, 20.4, 25.4, 25.9, 27.9, 29 .1 and 30.7° ± 0.2° 2-theta, on the 2-theta scale with λ=1.54 angstroms (Cu Ka); or essentially such a differential scanning calorimetry (DSC) thermogram as shown in FIG. 3, when heated at a rate of 10°C/min; or a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at about 207°C when heated at a rate of 10°C/min; or essentially such a thermogravimetric analysis profile as shown in FIG. 4, when heated at a rate of 20°C/min. 5. A crystalline form according to claim 3, characterized essentially by an X-ray powder diffraction profile as shown in FIG. 2; or an X-ray powder diffraction profile containing a peak at 14.6° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at 13.0, 14.6 and 16.3° ± 0.2° 2theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at 8.3, 13.0, 14.6, 16.3, 26.3 and - 63 043295 27.0° ± 0.2° 2-theta, 2-theta with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at 8.3, 13.0, 14.6, 15.3, 16.3, 16.7, 27.0 and 27.2° ± 0.2° 2-theta, 2-theta with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at three or more of 3.1, 8.3, 13.0, 14.6, 15.3, 16.3, 16.7, 18.4, 26.3, 26 .5, 27.0 and 27.2° ± 0.2° 2-theta, 2-theta with λ=1.54 angstroms (Cu Ka); or essentially such a differential scanning calorimetry (DSC) thermogram as shown in FIG. 5, when heated at a rate of 10°K/min; or a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at about 185°C when heated at a rate of 10°K/min; or essentially such a thermogravimetric analysis profile as shown in FIG. 5, when heated at a rate of 10°K/min. 6. A crystalline form according to claim 3, characterized essentially by an X-ray powder diffraction profile as shown in FIG. 14; or essentially such a differential scanning calorimetry (DSC) thermogram as shown in FIG. 15, when heated at a rate of 10°C/min; or essentially such a thermogravimetric analysis profile as shown in FIG. 16 when heated at a rate of 20°C/min. 7. A pharmaceutically acceptable salt according to claim 1, characterized in that said salt is a hydrochloride salt having the formula IB 8. A crystalline form of a pharmaceutically acceptable salt according to claim 7. 9. A crystalline form according to claim 8, characterized essentially by an X-ray powder diffraction profile as shown in FIG. 6; or an X-ray powder diffraction profile containing a peak at 5.4° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at 5.4, 10.9 and 16.4° ± 0.2° 2theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at 5.4, 10.9, 21.2 and 24.2° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka) ; or an X-ray powder diffraction profile containing peaks at 5.4, 10.9, 16.4, 21.2 and 24.2° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at three or more of 5.4, 10.9, 16.4, 21.2, 24.2 and 27.5° ± 0.2° 2-theta, 2-theta with λ=1.54 angstroms (Cu Ka); or essentially such a differential scanning calorimetry (DSC) thermogram as shown in FIG. 9, when heated at a rate of 10°C/min; or a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at about 268°C when heated at a rate of 10°C/min; or essentially such a thermogravimetric analysis profile as shown in FIG. 10, when heated at a rate of 20°C/min. 10. A crystalline form according to claim 8, characterized essentially by an X-ray powder diffraction profile as shown in FIG. 7; or an X-ray powder diffraction profile containing a peak at 5.0° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at 5.0, 15.2 and 24.3° ± 0.2° 2theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at 5.0, 15.2, 24.3 and 30.8° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka) ; or an X-ray powder diffraction profile containing peaks at 5.0, 10.1, 13.7, 15.2, 17.1, 24.3 and 30.8° ± 0.2° 2-theta, 2-theta with λ=1.54 angstroms (Cu Ka). 11. A crystalline form according to claim 8, characterized essentially by an X-ray powder diffraction profile as shown in FIG. 8; or an X-ray powder diffraction profile containing a peak at 11.4° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka); or - 64 043295 X-ray powder diffraction profile containing peaks at 11.4, 11.6, 15.1 and 16.7° ± 0.2° 2-theta, on the 2-theta scale with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at 4.9, 11.4, 11.6, 15.1 and 16.7° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at 4.9, 11.4, 11.6, 15.1, 16.7, 21.0 and 22.4° ± 0.2° 2-theta, on a scale of 2- theta with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at three or more of 4.9, 7.1, 11.4, 11.6, 12.4, 13.6, 14.3, 15.1, 16.5, 16 .7, 16.9, 17.0, 20.3, 21.0, 22.4, 23.0, 23.5 and 23.8° ± 0.2° 2-theta, 2-theta c λ=1.54 angstroms (Cu Ka); or essentially such a differential scanning calorimetry (DSC) thermogram as shown in FIG. 11, when heated at a rate of 10°C/min; or a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at about 196°C when heated at a rate of 10°C/min; or essentially such a thermogravimetric analysis profile as shown in FIG. 11 when heated at a rate of 10°C/min. 12. A crystalline form according to claim 8, characterized essentially by an X-ray powder diffraction profile as shown in FIG. 17; or an X-ray powder diffraction profile containing a peak at 5.3 and 15.5° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at 15.5 and 31.0° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at 15.5 and 24.5° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at 5.3, 15.5, 17.3, 24.5 and 31.0° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at three or more of 5.3, 15.5, 17.3, 21.5, 24.5, 28.0 and 31.0° ± 0.2° 2-theta, on the 2-theta scale with λ=1.54 angstroms (Cu Ka); or essentially such a differential scanning calorimetry (DSC) thermogram as shown in FIG. 18, when heated at a rate of 10°C/min; or a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at about 188°C when heated at a rate of 10°C/min; or a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at about 267°C when heated at a rate of 10°C/min; or essentially such a thermogravimetric analysis profile as shown in FIG. 19, when heated at a rate of 20°C/min. 13. A crystalline form according to claim 8, characterized essentially by an X-ray powder diffraction profile as shown in FIG. 20; or an X-ray powder diffraction profile containing a peak at 13.2 and 17.5° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at 13.2, 17.5, 26.3 and 28.3° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka) ; or an X-ray powder diffraction profile containing peaks at 13.2, 17.5, 18.8, 19.5 and 20.2° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at 13.2, 17.5, 24.9, 26.3 and 28.3° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at three or more of 13.2, 17.5, 18.8, 19.5, 20.2, 24.9, 26.3 and 28.3° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka); or essentially such a differential scanning calorimetry (DSC) thermogram as shown in FIG. 21, when heated at a rate of 10°C/min; or a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at about 271°C when heated at a rate of 10°C/min; or essentially such a thermogravimetric analysis profile as shown in FIG. 22, when heated at a rate of 20°C/min. 14. A crystalline form according to claim 8, characterized essentially by an X-ray powder diffraction profile as shown in FIG. 26; or an X-ray powder diffraction profile containing a peak at 16.1 and 25.0° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka); or - 65 043295 X-ray powder diffraction profile containing peaks at 14.3, 16.1, 17.4 and 21.9° ± 0.2° 2-theta, on the 2-theta scale with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at 14.3, 16.1, 17.4, 21.9 and 25.0° ± 0.2° 2-theta, 2-theta with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at 14.3, 16.1, 17.4, 21.9, 25.0 and 26.9° ± 0.2° 2-theta, on a 2-theta scale with λ= 1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at three or more of 14.3, 16.1, 17.4, 21.9, 25.0, 26.9 and 32.3° ± 0.2° 2-theta, on the 2-theta scale with λ=1.54 angstroms (Cu Ka); or essentially such a differential scanning calorimetry (DSC) thermogram as shown in FIG. 27, when heated at a rate of 10°C/min; or a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at about 270°C when heated at a rate of 10°C/min; or essentially such a thermogravimetric analysis profile as shown in FIG. 28, when heated at a rate of 20°C/min. 15. A crystalline form according to claim 8, characterized essentially by an X-ray powder diffraction profile as shown in FIG. 32; or an X-ray powder diffraction profile containing peaks at 15.7, 24.6 and 31.3° ± 0.2° 2theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at 15.7, 17.3, 24.6 and 31.3° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka) ; or an X-ray powder diffraction profile containing peaks at 15.7, 17.3, 21.7, 24.6 and 31.3° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at 15.7, 17.3, 21.7, 24.6, 26.1, 28.2 and 31.3° ± 0.2° 2-theta, on a scale of 2- theta with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at three or more of 5.4, 15.7, 17.3, 21.7, 24.6, 26.1, 28.2 and 31.3° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka); or essentially such a differential scanning calorimetry (DSC) thermogram as shown in FIG. 33, when heated at a rate of 10°C/min; or a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at about 208°C when heated at a rate of 10°C/min; or essentially such a thermogravimetric analysis profile as shown in FIG. 34 when heated at a rate of 20°C/min. 16. A crystalline form according to claim 8, characterized essentially by an X-ray powder diffraction profile as shown in FIG. 38; or an X-ray powder diffraction profile containing peaks at 15.9, 21.5 and 24.5° ± 0.2° 2theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at 15.5, 15.9, 16.7, 17.5 and 21.5° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at 15.5, 15.9, 16.7, 17.5, 21.5, 23.0 and 24.5° ± 0.2° 2-theta, on a scale of 2- theta with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at 13.1, 15.5, 15.9, 16.7, 17.5, 21.5, 23.0, 24.5 and 28.3° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at three or more of 13.1, 15.5, 15.9, 16.7, 17.5, 21.5, 23.0, 24.5, 28.3, and 29 .0° ± 0.2° 2-theta, 2-theta scale with λ=1.54 angstroms (Cu Ka); or essentially such a differential scanning calorimetry (DSC) thermogram as shown in FIG. 39, when heated at a rate of 10°C/min; or a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at about 221°C when heated at a rate of 10°C/min; or essentially such a thermogravimetric analysis profile as shown in FIG. 40, when heated at a rate of 20°C/min. 17. A crystalline form according to claim 8, characterized essentially by an X-ray powder diffraction profile as shown in FIG. 42; or an X-ray powder diffraction profile containing peaks at 15.6 and 24.6° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at 15.6, 17.4 and 21.6° ± 0.2° 2theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka); or - 66 043295 X-ray powder diffraction profile containing peaks at 15.6, 17.4, 21.6 and 24.6° ± 0.2° 2-theta, on the 2-theta scale with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at 14.1, 15.6, 17.4, 21.6 and 24.6° ± 0.2° 2-theta, 2-theta with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at three or more of 5.3, 14.1, 15.6, 17.4, 21.6 and 24.6° ± 0.2° 2-theta, on a scale of 2- theta with λ=1.54 angstroms (Cu Ka); or essentially such a differential scanning calorimetry (DSC) thermogram as shown in FIG. 43, when heated at a rate of 10°C/min; or a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at about 188°C when heated at a rate of 10°C/min; or a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at about 271°C when heated at a rate of 10°C/min; or essentially such a thermogravimetric analysis profile as shown in FIG. 44 when heated at a rate of 20°C/min. 18. A pharmaceutically acceptable salt according to claim 1, characterized in that said salt is an oxalate salt having the formula IC 19. A crystalline form of a pharmaceutically acceptable salt according to claim 18. 20. A crystalline form according to claim 19, characterized essentially by an X-ray powder diffraction profile as shown in FIG. 12; or an X-ray powder diffraction profile containing a peak at 10.5° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at 10.5, 14.7 and 16.2° ± 0.2° 2theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at 10.5, 14.7, 16.2 and 28.7° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka) ; or an X-ray powder diffraction profile containing peaks at 10.5, 14.7, 16.2, 17.6, 17.7, 19.6, 28.7 and 28.9° ± 0.2° 2-theta, on the 2-theta scale with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at three or more of 10.5, 11.6, 13.1, 14.2, 14.7, 14.9, 16.2, 17.6, 17.7, 19 .6, 28.7 and 28.9° ± 0.2° 2-theta, on the 2-theta scale with λ=1.54 angstroms (Cu Ka). 21. A pharmaceutically acceptable salt according to claim 1, characterized in that said salt is a phosphate salt having the formula ID 22. A crystalline form of a pharmaceutically acceptable salt according to claim 21. 23. A crystalline form according to claim 22, characterized essentially by an X-ray powder diffraction profile as shown in FIG. 13; or an X-ray powder diffraction profile containing a peak at 3.6° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at 3.6 and 10.7° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at 3.6, 10.7 and 15.6° ± 0.2° 2theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at three or more of 3.6, 10.7, 15.6, 17.9 and 18.7° ± 0.2° 2-theta, 2-theta with λ=1.54 angstroms (Cu Ka). 24. A crystalline form according to claim 22, characterized essentially by an X-ray powder diffraction profile as shown in FIG. 45; or an X-ray powder diffraction profile containing peaks at 18.1, 20.0, 26.2 and 28.1° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka) ; or - 67 043295 X-ray powder diffraction profile containing peaks at 17.1, 18.1, 20.0, 26.2 and 28.1° ± 0.2° 2-theta, 2-theta with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at 10.6, 17.1, 18.1, 20.0, 26.2 and 28.1° ± 0.2° 2-theta, on a 2-theta scale with λ= 1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at three or more of 10.6, 17.1, 18.1, 20.0, 21.5, 22.4, 26.2 and 28.1° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka); or essentially such a differential scanning calorimetry (DSC) thermogram as shown in FIG. 46, when heated at a rate of 10°C/min; or a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at about 161°C when heated at a rate of 10°C/min; or a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at about 221°C when heated at a rate of 10°C/min; or essentially such a thermogravimetric analysis profile as shown in FIG. 47 when heated at a rate of 20°C/min. 25. A pharmaceutically acceptable salt according to claim 1, characterized in that said salt is a bisulfate salt having the formula IE 26. A crystalline form of a pharmaceutically acceptable salt according to claim 25. 27. Crystal form of the compound of formula I 28. A crystalline form according to claim 27, characterized essentially by an X-ray powder diffraction profile as shown in FIG. 48; or an X-ray powder diffraction profile containing peaks at 17.3 and 18.1° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at 17.3, 18.1, 25.2 and 27.1° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka) ; or an X-ray powder diffraction profile containing peaks at 17.3, 18.1, 25.2, 27.1, 28.3, 28.8 and 30.0° ± 0.2° 2-theta, on a scale of 2- theta with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at 17.3, 18.1, 20.4, 24.2, 25.2, 27.1, 28.3, 28.8 and 30.0° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at three or more of 15.0, 17.3, 18.1, 20.4, 24.2, 25.2, 27.1, 28.3, 28.8, and 30 .0° ± 0.2° 2-theta, 2-theta scale with λ=1.54 angstroms (Cu Ka); or essentially such a differential scanning calorimetry (DSC) thermogram as shown in FIG. 49, when heated at a rate of 10°C/min; or a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at about 140°C when heated at a rate of 10°C/min; or essentially such a thermogravimetric analysis profile as shown in FIG. 50 when heated at a rate of 20°C/min. 29. A crystalline form according to claim 27, characterized essentially by an X-ray powder diffraction profile as shown in FIG. 54; or an X-ray powder diffraction profile containing a peak at 23.5 and 24.9° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at 18.9, 23.5, 24.3 and 24.9° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka) ; or an X-ray powder diffraction profile containing peaks at 15.1, 17.4, 18.9, 23.5, 24.3 and 24.9° ± 0.2° 2-theta, on a 2-theta scale with λ= 1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at 15.1, 17.4, 18.9, 23.5, 24.3, 24.9 and 25.5° ± 0.2° 2-theta, on a scale of 2- theta with λ=1.54 angstroms (Cu Ka); or - 68 043295 X-ray powder diffraction profile containing peaks at three or more of 15.1, 17.4, 18.9, 23.5, 24.3, 24.9, 25.5 and 30.3° ± 0.2° 2-theta, 2-theta with λ=1.54 angstroms ( CuKa); or essentially such a differential scanning calorimetry (DSC) thermogram as shown in FIG. 55, when heated at a rate of 10°C/min; or a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at about 137° C. when heated at a rate of 10° C./min. 30. A crystalline form according to claim 27, characterized essentially by an X-ray powder diffraction profile as shown in FIG. 56; or an X-ray powder diffraction profile containing peaks at 16.6 and 17.4° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at 17.4, 20.4 and 25.8° ± 0.2° 2theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at 17.4, 20.4, 24.9, 25.8 and 26.3° ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at 16.6, 17.4, 20.4, 24.9, 25.8, 26.3 and 27.7 ± 0.2° 2-theta, on a 2-theta scale with λ=1.54 angstroms (Cu Ka); or an X-ray powder diffraction profile containing peaks at three or more of 9.2, 16.6, 17.4, 20.4, 24.9, 25.8, 26.3, 27.7, and 41.5° ± 0.2° 2-theta, on the 2-theta scale with λ=1.54 angstroms (Cu Ka); or essentially such a differential scanning calorimetry (DSC) thermogram as shown in FIG. 57, when heated at a rate of 10°C/min; or a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at about 125° C. when heated at a rate of 10° C./min. 31. A pharmaceutical composition containing a compound according to any one of claims 1 to 30 and a pharmaceutically acceptable excipient. 32. A method for inhibiting the protein arginine methyltransferase 5 (PRMT5) enzyme, comprising contacting the PRMT5 enzyme with an effective amount of a compound according to any one of claims 1-30. 33. A method of treating a disease or disorder associated with aberrant PRMT5 activity in a subject, comprising administering to said subject a compound according to any one of claims 1-30. 34. The method of claim 33, wherein said disease or disorder associated with aberrant PRMT5 activity is adenoid cystic carcinoma (ACC), breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, uterine cancer, cervical cancer, leukemia, preferably acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS), epidermoid cancer or hemoglobinopathies, preferably b-thalassemia and sickle cell disease (SCD). 35. The method according to claim 33 or 34, characterized in that said compound or a pharmaceutically acceptable salt thereof is administered in combination with one or more other agents.