Crystalline forms of 6-(6-(((1r,2r,3s,5s)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-2-methylbenzo[d]oxazol-5-ol, a splicing modulator for the treatment of huntington's disease

Abstract

Described herein are crystalline forms of 6-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-2-methylbenzo[d]oxazol-5-ol (compound A), a small molecule splicing modulator (SMSM) of mRNA, such as pre-mRNA, encoded by genes, for the treatment of Huntington's disease.

Description

WSGR Docket No.51503-768.601 COMPOSITIONS FOR MODULATING SPLICING CROSS REFERENCE

[0001] This application claims the benefit of priority to U.S. Provisional Application No.63 / 511,325, filed June 30, 2023, which is incorporated herein by reference in its entirety. SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted in electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on June 17, 2024, is named 51503-768_601_SL.xml and is 1,885 bytes in size. FIELD OF THE INVENTION

[0003] Described herein are solid state forms of splicing modulator Compound A, as well as pharmaceutical compositions thereof, and methods of use thereof in the treatment of diseases or conditions that would benefit from treatment with Compound A. BACKGROUND

[0004] The majority of protein-coding genes in the human genome are composed of multiple exons (coding regions) that are separated by introns (non-coding regions). Gene expression results in a single precursor messenger RNA (pre-mRNA). The intron sequences are subsequently removed from the pre-mRNA by a process called splicing, which results in the mature messenger RNA (mRNA). By including different combinations of exons, alternative splicing gives rise to multiple mRNAs encoding distinct protein isoforms. The spliceosome, an intracellular complex of multiple proteins and ribonucleoproteins, catalyzes splicing.

[0005] Small molecule splicing modulators (SMSMs) overcome many of the problems associated with therapies such as oligonucleotide technologies (antisense, RNA interference, etc.), including lack of oral bioavailability, and lack of blood-brain-barrier penetration, with the latter precluding delivery to the brain or spinal cord after parenteral drug administration for the treatment of diseases (e.g., neurological diseases, brain cancers, etc.).

[0006] Many compounds can exist in different crystal forms, or polymorphs, which exhibit different physical, chemical, and spectroscopic properties. For example, certain polymorphs of a compound may be more readily soluble in particular solvents, may flow more readily, or may compress more easily than others. In the case of drugs, certain solid forms may be more bioavailable than others, while others may be more stable under certain manufacturing, storage, and biological conditions. This is particularly important from a regulatory standpoint, since drugs are approved by agencies such as the U.S. Food and Drug Administration only if they meet exacting purity and characterization standards. Indeed, the regulatory approval of one polymorph of a compound, which exhibits certainDocket No.51503-768.601 solubility and physico-chemical (including spectroscopic) properties, typically does not imply the ready approval of other polymorphs of that same compound.

[0007] Polymorphic forms of a compound are known in the pharmaceutical arts to affect, for example, the solubility, stability, flowability, fractability, and compressibility of the compound, as well as the safety and efficacy of drug products comprising it. Therefore, the discovery of new polymorphs of a drug can provide a variety of advantages.

[0008] WO2020 / 163541 discloses 6-(6-{[(1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3- yl](methyl)amino}pyridazin-3-yl)-2-methyl-1,3-benzoxazol-5-ol, which is useful in treating and preventing a wide range of diseases and conditions through modulating splicing of pre-mRNA, including, but not limited to, neurodegenerative diseases, such as Huntington’s Disease. SMSMs, however, can also have challenges, such as metabolic profiles in patients, clearance rates, the amount of compound available to exert an effect (e.g., fraction unbound in plasma, half-life of the compound in circulation, etc.).

[0009] Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder. It is caused by an increase in the number of trinucleotide CAG repeats (36 repeats or more) on the short arm of chromosome 4p16.3. Huntington's disease can have a wide impact on the patient’s functional abilities and can cause movement, cognitive, and psychiatric disorders. The prevalence of Huntington's disease is estimated to be about 1 / 10,000 to about 1 / 20,000. Current treatments can alleviate certain symptoms but cannot slow or reverse the progression of Huntington’s disease. SUMMARY

[0010] The present disclosure relates to various solid state forms of the small molecule splicing modulator Compound A. Such forms of Compound A are useful for modulating the activity of splicing in mammals that would benefit from such activity.

[0011] As mentioned above, WO2020 / 163541 discloses 6-(6-{[(1R,2R,3S,5S)-2-fluoro-8- azabicyclo[3.2.1]octan-3-yl](methyl)amino}pyridazin-3-yl)-2-methyl-1,3-benzoxazol-5-ol, which is useful in treating and preventing a wide range of diseases and conditions through modulating splicing of pre-mRNAs, including, but not limited to, neurodegenerative diseases, such as Huntington’s Disease. Certain parameters for SMSMs such as metabolic profiles in patients, clearance rates, the amount of compound available to exert an effect (e.g., fraction unbound in plasma, half-life of the compound in circulation, etc.) can be affected by small changes between two similar compounds.

[0012] Thus, compounds similar to 6-(6-{[(1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3- yl](methyl)amino}pyridazin-3-yl)-2-methyl-1,3-benzoxazol-5-ol, but with improved metabolic profiles are useful in developing therapies for neurodegenerative diseases, such as Huntington’s Disease. Further, new polymorphic forms of compounds similar to 6-(6-{[(1R,2R,3S,5S)-2-fluoro-8- azabicyclo[3.2.1]octan-3-yl](methyl)amino}pyridazin-3-yl)-2-methyl-1,3-benzoxazol-5-ol can furtherDocket No.51503-768.601 the development of formulations for the treatment of these chronic illnesses, and may yield numerous formulation, manufacturing and therapeutic benefits.

[0013] Described herein is a solid state form of 6-(6-(((1R,2R,3S,5S)-2-fluoro-9- azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-2-methylbenzo[d]oxazol-5-ol (Compound A) or a stereoisomer thereof. In one aspect, provided herein is a solid state form of Compound A, having a structure

[0014] In one aspect, provided herein is a solid state form of Compound A, or a stereoisomer thereof. In some embodiments, described herein is a solid state form of Compound A, wherein the solid state form is a crystalline form. In some embodiments, described herein is a solid state form of Compound A, wherein the solid state form is crystalline form A of Compound A. In some embodiments, described herein is a solid state form of Compound A, wherein the solid state form is crystalline form B of Compound A. In some embodiments, described herein is a solid state form of Compound A, wherein the solid state form is crystalline form C of Compound A. In some embodiments, described herein is a solid state form of Compound A, wherein the solid state form is crystalline form D of Compound A. In some embodiments, described herein is a solid state form of Compound A, wherein the solid state form is crystalline form E of Compound A. In some embodiments, described herein is a solid state form of Compound A, wherein the solid state form is crystalline form F of Compound A. In some embodiments, described herein is a solid state form of Compound A, wherein the solid state form is crystalline form G of Compound A. In some embodiments, described herein is a solid state form of Compound A, wherein the solid state form is crystalline form H of Compound A.

[0015] In some embodiments, described herein is a solid state form of Compound A, or a stereoisomer thereof, wherein the solid state form is a crystalline form. In some embodiments, described herein is a solid state form of Compound A, or a stereoisomer thereof, wherein the solid state form is crystalline form A. In some embodiments, described herein is a solid state form of Compound A, or a stereoisomer thereof, wherein the solid state form is crystalline form B. In some embodiments, described herein is a solid state form of Compound A, or a stereoisomer thereof, wherein the solid state form is crystalline form C. In some embodiments, described herein is a solid state form of Compound A, or a stereoisomer thereof, wherein the solid state form is crystalline form D. In some embodiments, described herein is a solid state form of Compound A, or a stereoisomer thereof, wherein the solid state form is crystalline form E. In some embodiments, described herein is a solid state form of Compound A, or a stereoisomer thereof, wherein the solid state form is crystalline form F. In some embodiments, described herein is a solid state form of Compound A, or aDocket No.51503-768.601 stereoisomer thereof, wherein the solid state form is crystalline form G of Compound A. In some embodiments, described herein is a solid state form of Compound A, or a stereoisomer thereof, wherein the solid state form is crystalline form H.

[0016] Described herein is a crystalline form of 6-(6-(((1R,2R,3S,5S)-2-fluoro-9- azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-2-methylbenzo[d]oxazol-5-ol (Compound A), wherein the crystalline form is characterized as exhibiting: an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG.1A, FIG.1B, or FIG.1C as measured using Cu Kα radiation; an XRPD pattern with one or more peaks at 11.1 ±0.2 º2-Theta, 12.4 ±0.2 º2-Theta, and 17.5 ±0.2 º2-Theta as measured using Cu Kα radiation; an XRPD pattern with at least three, at least four, at least five, or all of the peaks at 7.1 ±0.2 º2-Theta, 11.1 ±0.2 º2-Theta, 12.4 ±0.2 º2-Theta, 14.8 ±0.2 º2-Theta, 17.5 ±0.2 º2-Theta, and 26.1 ±0.2 º2-Theta as measured using Cu Kα radiation; an XRPD pattern with at least three, at least six, at least nine, or all of the peaks at 7.1 ±0.2 º2-Theta, 7.6 ±0.2 º2-Theta, 11.1 ±0.2 º2-Theta, 12.4 ±0.2 º2-Theta, 14.8 ±0.2 º2-Theta, 15.2 ±0.2 º2-Theta, 16.0 ±0.2 º2-Theta, 16.3 ±0.2 º2-Theta, 17.5 ±0.2 º2-Theta, 19.3 ±0.2 º2-Theta, 25.3 ±0.2 º2-Theta, 26.1 ±0.2 º2-Theta and 27.1 ±0.2 º2-Theta as measured using Cu Kα radiation; a Differential Scanning Calorimetry (DSC) thermogram substantially the same as shown in FIG.10; a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak having an onset temperature at about 178 °C; a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak at about 192 °C; a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as shown in FIG.15; or a Thermogravimetric Thermal Analysis (TGA) thermogram exhibiting a mass loss of about 5.7 % from the onset of heating up to approximately 160 °C. In some embodiments, the crystalline form is characterized as exhibiting an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG.1A, FIG.1B, FIG.1C, or FIG. 1D, as measured using Cu Kα radiation. In some embodiments, the crystalline form is characterized as exhibiting an XRPD pattern with peaks at 11.1 ±0.2 º2-Theta, 12.4 ±0.2 º2-Theta, and 17.5 ±0.2 º2- Theta as measured using Cu Kα radiation. In some embodiments, the crystalline form is characterized as exhibiting an XRPD pattern with at least three, at least four, at least five, or all of the peaks at 7.1 ±0.2 º2-Theta, 11.1 ±0.2 º2-Theta, 12.4 ±0.2 º2-Theta, 14.8 ±0.2 º2-Theta, 17.5 ±0.2 º2-Theta, and 26.1 ±0.2 º2-Theta as measured using Cu Kα radiation. In some embodiments, the crystalline form is characterized as exhibiting an XRPD pattern with at least three, at least six, at least nine, or all of the peaks at 7.1 ±0.2 º2-Theta, 7.6 ±0.2 º2-Theta, 11.1 ±0.2 º2-Theta, 12.4 ±0.2 º2-Theta, 14.8 ±0.2 º2- Theta, 15.2 ±0.2 º2-Theta, 16.0 ±0.2 º2-Theta, 16.3 ±0.2 º2-Theta, 17.5 ±0.2 º2-Theta, 19.3 ±0.2 º2- Theta, 25.3 ±0.2 º2-Theta, 26.1 ±0.2 º2-Theta, and 27.1 ±0.2 º2-Theta as measured using Cu Kα radiation. In some embodiments, the crystalline form is characterized as exhibiting a Differential Scanning Calorimetry (DSC) thermogram substantially the same as shown in FIG.10. In some embodiments, the crystalline form is characterized as exhibiting a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as shown in FIG.15. In some embodiments, theDocket No.51503-768.601 crystalline form is characterized as exhibiting a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak having an onset temperature at about 178 °C. In some embodiments, the crystalline form is characterized as exhibiting a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak at about 192 °C. In some embodiments, the crystalline form is characterized as exhibiting a Thermogravimetric Thermal Analysis (TGA) thermogram that shows a mass loss of about 5.7 % from the onset of heating up to approximately 160 °C. In some embodiments, the crystalline form is anhydrous.

[0017] Described herein is a pharmaceutical composition comprising the crystalline form of Compound A or the solid state form of Compound A described herein and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is formulated in the form of a solid form pharmaceutical composition for oral administration to a mammal.

[0018] Described herein is a method of treating a condition or a disorder in a subject in need thereof, the method comprising administering to the subject the crystalline form of Compound A or the solid state form of Compound A described herein, or the pharmaceutical composition described herein.

[0019] Described herein is a method of treating Huntington's disease in a subject in need thereof, comprising administering to the subject the crystalline form of Compound A or the solid state form of Compound A described herein, or the pharmaceutical composition described herein.

[0020] Described herein is a method of modulating splicing comprising administering to cells the crystalline form of Compound A or the solid state form of Compound A described herein, or the pharmaceutical composition described herein, wherein the compound modulates splicing at a splice site sequence of a pre-mRNA that encodes an mRNA, and wherein the mRNA encodes a target protein or a functional RNA.

[0021] Described herein is use of the crystalline form of Compound A or the solid state form of Compound A described herein, or the pharmaceutical composition described herein, in the manufacture of a medicament for the treatment of a condition or disease.

[0022] Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the instant disclosure will become apparent to those skilled in the art from this detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] The features of the invention are set forth with particularity in the appended claims. A better understanding of the features of the present invention will be obtained by reference to the followingDocket No.51503-768.601 detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0024] FIG.1A displays the X-Ray Powder Diffraction (XRPD) pattern of crystalline form A of Compound A, batch AM-1.

[0025] FIG.1B displays the X-Ray Powder Diffraction (XRPD) pattern of crystalline form A of Compound A, batch AM-2.

[0026] FIG.1C displays the X-Ray Powder Diffraction (XRPD) pattern of crystalline form A of Compound A, batch AM-4.

[0027] FIG.1D displays the X-Ray Powder Diffraction (XRPD) patterns of Compound A, batch AM- 3 (dried batch of AM-2), before the DVS measurement.

[0028] FIG.1E displays the X-Ray Powder Diffraction (XRPD) patterns of Compound A in an amorphous form.

[0029] FIG.2 displays the X-Ray Powder Diffraction (XRPD) pattern of crystalline form B of Compound A.

[0030] FIG.3 displays the X-Ray Powder Diffraction (XRPD) pattern of crystalline form C of Compound A.

[0031] FIG.4 displays the X-Ray Powder Diffraction (XRPD) pattern of crystalline form D of Compound A.

[0032] FIG.5 displays the X-Ray Powder Diffraction (XRPD) pattern of crystalline form E of Compound A.

[0033] FIG.6 displays the X-Ray Powder Diffraction (XRPD) pattern of crystalline form F of Compound A.

[0034] FIG.7 displays the X-Ray Powder Diffraction (XRPD) pattern of crystalline form G of Compound A.

[0035] FIG.8 displays the X-Ray Powder Diffraction (XRPD) pattern of crystalline form H of Compound A.

[0036] FIG.9 displays the overlay of X-Ray Powder Diffraction (XRPD) patterns of the different crystalline forms, forms A, B, C, D, E, F, G, and H, obtained in the anti-solvent crystallization experiments.

[0037] FIG.10 displays the Differential Scanning Calorimetry (DSC) thermogram of crystalline form A of Compound A.

[0038] FIG.11 displays the Differential Scanning Calorimetry (DSC) thermogram of crystalline form B of Compound A.

[0039] FIG.12 displays the Differential Scanning Calorimetry (DSC) thermogram of crystalline form D of Compound A.

[0040] FIG.13 displays the Differential Scanning Calorimetry (DSC) thermogram of crystalline form G of Compound A.Docket No.51503-768.601

[0041] FIG.14 displays the Differential Scanning Calorimetry (DSC) thermogram of crystalline form H of Compound A.

[0042] FIG.15 displays the Thermogravimetric Analysis (TGA) thermogram of crystalline form A of Compound A. The x-axis displays the temperature, and the y-axis depicts (from top to bottom) the change in mass, the heat flow, and the temperature. The top graph displays the change in mass of the sample, the middle graph shows the energy, and the bottom graph displays the temperature profile.

[0043] FIG.16 displays the Thermogravimetric Analysis (TGA) thermogram of crystalline form B of Compound A. The x-axis displays the temperature, and the y-axis depicts (from top to bottom) the change in mass, the heat flow, and the temperature. The top graph displays the change in mass of the sample, the middle graph shows the energy profile), and the bottom graph displays the temperature profile.

[0044] FIG.17 displays the Thermogravimetric Analysis (TGA) thermogram of crystalline form D of Compound A. The x-axis displays the temperature, and the y-axis depicts (from top to bottom) the change in mass, the heat flow, and the temperature. The top graph displays the change in mass of the sample, the middle graph shows the energy profile, and the bottom graph displays the temperature profile.

[0045] FIG.18 displays the Thermogravimetric Analysis (TGA) thermogram of crystalline form G of Compound A. The x-axis displays the temperature, and the y-axis depicts (from top to bottom) the change in mass, the heat flow, and the temperature. The top graph displays the change in mass of the sample, the middle graph shows the energy profile, and the bottom graph displays the temperature profile.

[0046] FIG.19 displays the Thermogravimetric Analysis (TGA) thermogram of crystalline form H of Compound A. The x-axis displays the temperature, and the y-axis depicts (from top to bottom) the change in mass, the heat flow, and the temperature. The top graph displays the change in mass of the sample, the middle graph shows the energy profile, and the bottom graph displays the temperature profile. DETAILED DESCRIPTION

[0047] While small molecule inhibitors are often initially evaluated for their activity when dissolved in solution, solid state characteristics such as polymorphism are also important. Polymorphic forms of a drug substance can have different physical properties, including melting point, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure, and density. These properties can have a direct effect on the ability to process or manufacture a drug substance and the drug product. Moreover, differences in these properties can and often lead to different pharmacokinetics profiles for different polymorphic forms of a drug. Therefore, polymorphism is often an important factor under regulatory review of the ‘sameness’ of drug products from various manufacturers.Docket No.51503-768.601 Small Molecule Splicing Modulators (SMSMs)

[0048] Described herein are compounds or solid state forms thereof modifying splicing of gene products for use in the treatment, prevention and / or delay of progression of diseases or conditions.

[0049] Compounds modifying splicing of gene products include Compound A, or 6-(6- (((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-2- methylbenzo[d]oxazol-5-ol, has the chemical formula of C21H24FN5O2and a molecular weight of 397.45 g / mol. Compound A has the following chemical structure:

[0050] The absolute stereochemistry for Compound A is not identified, but relative stereochemistry is known and indicated.

[0051] Described herein are solid state forms of Compound A or a stereoisomer thereof for use in the treatment, prevention and / or delay of progression of diseases or conditions. Solid state forms can include crystalline forms, salts, solvates, and co-crystals.

[0052] In some embodiments, described herein are solid state forms of Compound A for modifying splicing of gene products, such as HTT pre-m RNA for use in the treatment, prevention, and / or delay of progression of diseases or conditions (e.g., Huntington’s disease). In some embodiments, the present disclosure relates to a pharmaceutical composition comprising solid state forms of Compound A described herein for use in the treatment, prevention, and / or delay of progression of Huntington’s disease. In some embodiments, solid state forms of Compound A described herein can be administered for treatment, prevention, and / or delay of progression of Huntington’s disease.

[0053] Described herein is a composition comprising a solid state form for modifying splicing of gene products, wherein the composition induces a post-transcriptionally unstable variant or transcript of a gene product. Described herein is a solid state form of Compound A for modifying splicing of gene products, wherein the solid state form of Compound A represses a transcript of a gene product.

[0054] In some embodiments, Compound A is amorphous. As used herein, the term “amorphous” or “amorphous solid form” or “amorphous phase” refers to a solid form lacking crystallinity.

[0055] In some embodiments, Compound A is crystalline. In some embodiments, crystallinity is determined by methods known in the art.

[0056] In some embodiments, crystallinity of a solid form is determined by X-Ray Powder Diffraction (XRPD). In some embodiments, crystallinity of a solid form is determined by solid state NMR. In some embodiments, crystallinity of a solid form is determined by Fourier Transform IR Spectroscopy (FTIR).Docket No.51503-768.601

[0057] Provided herein is a solid state form of 6-(6-(((1R,2R,3S,5S)-2-fluoro-9- azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-2-methylbenzo[d]oxazol-5-ol (Compound A) or a pharmaceutically acceptable salt or stereoisomer thereof. In one aspect, described herein is a solid state form of 6-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3- yl)(methyl)amino)pyridazin-3-yl)-2-methylbenzo[d]oxazol-5-ol. Amorphous Compound A

[0058] In one aspect, provided herein is a solid state form of Compound A in an amorphous form. In some embodiments, provide herein a composition comprising Compound A in an amorphous form.

[0059] In some embodiments, amorphous Compound A is characterized as having an X-Ray powder diffraction (XRPD) pattern showing a lack of crystallinity. In some embodiments, amorphous Compound A is characterized as having an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG.1E as measured using Cu Kα radiation.

[0060] In one aspect, described herein is a method of synthesizing an amorphous Compound A, wherein the amorphous Compound A is characterized as having an X-Ray powder diffraction (XRPD) pattern showing a lack of crystallinity.

[0061] In some embodiments, the method comprises converting Compound A of form A into an amorphous form. In some embodiments, the method comprises drying Compound A hydrate. Crystalline form of Compound A

[0062] In one aspect, provided herein is a solid state form of 6-(6-(((1R,2R,3S,5S)-2-fluoro-9- azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-2-methylbenzo[d]oxazol-5-ol (Compound A).

[0063] In one aspect, provided herein is a solid state form of Compound A, having a structure of

[0064] In some embodiments, the solid state form is a crystalline form. In some embodiments, the solid state form is crystalline form A of Compound A. In some embodiments, the solid state form is crystalline form B of Compound A. In some embodiments, the solid state form is crystalline form C of Compound A. In some embodiments, the solid state form is crystalline form D of Compound A. In some embodiments, the solid state form is crystalline form E of Compound A. In some embodiments, the solid state form is crystalline form F of Compound A. In some embodiments, the solid state form is crystalline form G of Compound A. In some embodiments, the solid state form is crystalline form H of Compound A.Docket No.51503-768.601

[0065] In some embodiments, the crystalline Compound A is unsolvated. In some embodiments, the crystalline Compound A is solvated. In some embodiments, the crystalline Compound A is a hydrate. Crystalline Form A of Compound A

[0066] In some embodiments, provided herein is crystalline form A of Compound A. In some embodiments, provided herein is a composition comprising crystalline form A of Compound A.

[0067] In some embodiments, crystalline form A of Compound A is anhydrous. In some embodiments, crystalline form A of Compound A is not solvated. In some embodiments, crystalline form A of Compound A is not hydrated.

[0068] In some embodiments, crystalline form A of Compound A is formed from the other solid-state forms described herein. In some embodiments, crystalline form A of Compound A is the thermodynamically favored solid state form of Compound A.

[0069] In some embodiments, crystalline form A of Compound A is characterized as having an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG.1A as measured using Cu Kα radiation. In some embodiments, crystalline form A of Compound A is characterized as having an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG.1B as measured using Cu Kα radiation. In some embodiments, crystalline form A of Compound A is characterized as having an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG.1C as measured using Cu Kα radiation. In some embodiments, crystalline form A of Compound A is characterized as having an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG.1D as measured using Cu Kα radiation.

[0070] In some embodiments, crystalline form A of Compound A is characterized as exhibiting an XRPD pattern with one or more peaks at 11.1 ±0.2 º2-Theta, 12.4 ±0.2 º2-Theta, and 17.5 ±0.2 º2- Theta as measured using Cu Kα radiation. In some embodiments, described herein is a crystalline form of Compound A characterized as exhibiting an XRPD pattern with one or more peaks at 11.1 ±0.2 º2-Theta, 12.4 ±0.2 º2-Theta, and 17.5 ±0.2 º2-Theta as measured using Cu Kα radiation.

[0071] In some embodiments, crystalline form A of Compound A is characterized as exhibiting an XRPD pattern with one or more peaks at 7.1 ±0.2 º2-Theta, 7.6 ±0.2 º2-Theta, and 26.1 ±0.2 º2-Theta as measured using Cu Kα radiation. In some embodiments, crystalline form A of Compound A is characterized as exhibiting an XRPD pattern with all three peaks at 7.1 ±0.2 º2-Theta, 7.6 ±0.2 º2- Theta, and 26.1 ±0.2 º2-Theta as measured using Cu Kα radiation. In some embodiments, described herein is a crystalline form of Compound A characterized as exhibiting an XRPD pattern with one or more peaks at 7.1 ±0.2 º2-Theta, 7.6 ±0.2 º2-Theta, and 26.1 ±0.2 º2-Theta as measured using Cu Kα radiation. In some embodiments, described herein is a crystalline form of Compound A characterized as exhibiting an XRPD pattern with all three peaks at 7.1 ±0.2 º2-Theta, 7.6 ±0.2 º2-Theta, and 26.1 ±0.2 º2-Theta as measured using Cu Kα radiation.

[0072] In some embodiments, crystalline form A of Compound A is characterized as exhibiting an XRPD pattern with at least three, at least four, at least five, or all of the peaks at 7.1 ±0.2 º2-Theta,Docket No.51503-768.601 11.1 ±0.2 º2-Theta, 12.4 ±0.2 º2-Theta, 14.8 ±0.2 º2-Theta, 17.5 ±0.2 º2-Theta, and 26.1 ±0.2 º2- Theta as measured using Cu Kα radiation. In some embodiments, described herein is a crystalline form of Compound A characterized as exhibiting an XRPD pattern with at least one, at least two, at least three, at least four, at least five, or all of the peaks selected from 7.1 ±0.2 º2-Theta, 11.1 ±0.2 º2- Theta, 12.4 ±0.2 º2-Theta, 14.8 ±0.2 º2-Theta, 17.5 ±0.2 º2-Theta, and 26.1 ±0.2 º2-Theta as measured using Cu Kα radiation. In some embodiments, described herein is a crystalline form of Compound A characterized as exhibiting an XRPD pattern with at least one, at least two, at least three, at least four, at least five, or all of the peaks selected from 7.1 ±0.2 º2-Theta, 8.4 ±0.2 º2-Theta, 11.1 ±0.2 º2-Theta, 12.4 ±0.2 º2-Theta, 14.8 ±0.2 º2-Theta, 17.5 ±0.2 º2-Theta, and 26.1 ±0.2 º2-Theta as measured using Cu Kα radiation.

[0073] In some embodiments, crystalline form A of Compound A is characterized as exhibiting an XRPD pattern with at least three, at least six, at least nine, or all of the peaks at 7.1 ±0.2 º2-Theta, 7.6 ±0.2 º2-Theta, 11.1 ±0.2 º2-Theta, 12.4 ±0.2 º2-Theta, 14.8 ±0.2 º2-Theta, 15.2 ±0.2 º2-Theta, 16.0 ±0.2 º2-Theta, 16.3 ±0.2 º2-Theta, 17.5 ±0.2 º2-Theta, 19.3 ±0.2 º2-Theta, 25.3 ±0.2 º2-Theta, 26.1 ±0.2 º2-Theta and 27.1 ±0.2 º2-Theta as measured using Cu Kα radiation. In some embodiments, described herein is a crystalline form of Compound A characterized as exhibiting an XRPD pattern with at least three, at least six, at least nine, or all of the peaks selected from 7.1 ±0.2 º2-Theta, 7.6 ±0.2 º2-Theta, 11.1 ±0.2 º2-Theta, 12.4 ±0.2 º2-Theta, 14.8 ±0.2 º2-Theta, 15.2 ±0.2 º2-Theta, 16.0 ±0.2 º2-Theta, 16.3 ±0.2 º2-Theta, 17.5 ±0.2 º2-Theta, 19.3 ±0.2 º2-Theta, 25.3 ±0.2 º2-Theta, 26.1 ±0.2 º2-Theta and 27.1 ±0.2 º2-Theta as measured using Cu Kα radiation. In some embodiments, crystalline form A of Compound A is characterized as exhibiting an XRPD pattern with at least three, at least six, at least nine, or all of the peaks at 7.1 ±0.2 º2-Theta, 7.6 ±0.2 º2-Theta, 8.4 ±0.2 º2-Theta, 11.1 ±0.2 º2-Theta, 12.4 ±0.2 º2-Theta, 14.8 ±0.2 º2-Theta, 15.2 ±0.2 º2-Theta, 16.0 ±0.2 º2-Theta, 16.3 ±0.2 º2-Theta, 17.5 ±0.2 º2-Theta, 19.3 ±0.2 º2-Theta, 25.3 ±0.2 º2-Theta, 26.1 ±0.2 º2-Theta and 27.1 ±0.2 º2-Theta as measured using Cu Kα radiation. In some embodiments, crystalline form A of Compound A is characterized as exhibiting an XRPD pattern comprising a peak at 8.4 ±0.2 º2- Theta.

[0074] In some embodiments, crystalline form A of Compound A is characterized as exhibiting a Differential Scanning Calorimetry (DSC) thermogram substantially the same as shown in FIG.10.

[0075] In some embodiments, crystalline form A of Compound A is characterized as exhibiting a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak having an onset temperature at about 178 °C.

[0076] In some embodiments, crystalline form A of Compound A is characterized as exhibiting a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak at about 192 °C.

[0077] In some embodiments, crystalline form A of Compound A is characterized as exhibiting a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as shown in FIG. 15.Docket No.51503-768.601

[0078] In some embodiments, crystalline form A of Compound A is characterized as exhibiting a Thermogravimetric Thermal Analysis (TGA) thermogram exhibiting a mass loss of about 5.7 % from the onset of heating up to approximately 160 °C. In some embodiments, crystalline form A of Compound A is characterized as exhibiting a Thermogravimetric Thermal Analysis (TGA) thermogram exhibiting a mass loss of at most 8 %, at most 7 %, at most 6 %, or at most 5 % from the onset of heating up to approximately 160 °C.

[0079] In some embodiments, crystalline form A of Compound A is characterized as having: a reversible water uptake of at most 16% (w / w) between 0% and 90% Relative Humidity (RH). In some embodiments, crystalline form A of Compound A is characterized as having: a reversible water uptake of at most 25% (w / w), at most 20% (w / w), at most 18% (w / w), at most 16% (w / w), or at most 15% (w / w) between 0% and 90% Relative Humidity (RH).

[0080] In some embodiments, crystalline form A of Compound A is characterized as exhibiting one or more of the following: (a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG.1A, FIG.1B, FIG.1C, or FIG.1D as measured using Cu Kα radiation; (b) an XRPD pattern with one or more (e.g., all three) peaks at 7.1 ±0.2 º2-Theta, 7.6 ±0.2 º2-Theta, and 26.1 ±0.2 º2-Theta as measured using Cu Kα radiation; (c) an XRPD pattern with one or more peaks at 11.1 ±0.2 º2-Theta, 12.4 ±0.2 º2-Theta, and 17.5 ±0.2 º2-Theta as measured using Cu Kα radiation; (d) an XRPD pattern with at least three, at least four, at least five, or all of the peaks at 7.1 ±0.2 º2-Theta, 11.1 ±0.2 º2-Theta, 12.4 ±0.2 º2-Theta, 14.8 ±0.2 º2-Theta, 17.5 ±0.2 º2-Theta, and 26.1 ±0.2 º2- Theta as measured using Cu Kα radiation; (e) an XRPD pattern with at least three, at least six, at least nine, or all of the peaks at 7.1 ±0.2 º2-Theta, 7.6 ±0.2 º2-Theta, 11.1 ±0.2 º2-Theta, 12.4 ±0.2 º2- Theta, 14.8 ±0.2 º2-Theta, 15.2 ±0.2 º2-Theta, 16.0 ±0.2 º2-Theta, 16.3 ±0.2 º2-Theta, 17.5 ±0.2 º2- Theta, 19.3 ±0.2 º2-Theta, 25.3 ±0.2 º2-Theta, 26.1 ±0.2 º2-Theta and 27.1 ±0.2 º2-Theta as measured using Cu Kα radiation; (f) a Differential Scanning Calorimetry (DSC) thermogram substantially the same as shown in FIG.10; (g) a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak having an onset temperature at about 178 °C; (h) a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak at about 192 °C; (i) a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as shown in FIG.15; and / or (j) a Thermogravimetric Thermal Analysis (TGA) thermogram exhibiting a mass loss of about 5.7 % from the onset of heating up to approximately 160 °C. In some embodiments, the crystalline form exhibits characteristics (b) and (c). In some embodiments, the crystalline form exhibits characteristics (a) and (f). In some embodiments, the crystalline form exhibits characteristics (a) and (g). In some embodiments, the crystalline form exhibits characteristics (a) and (h). In some embodiments, the crystalline form exhibits characteristics (a) and (i). In some embodiments, the crystalline form exhibits characteristics (a) and (j). In some embodiments, the crystalline form exhibits characteristics (b) and (f). In some embodiments, the crystalline form exhibits characteristics (b) and (g). In some embodiments, the crystalline form exhibits characteristics (b) and (h). In some embodiments, theDocket No.51503-768.601 crystalline form exhibits characteristics (b) and (i). In some embodiments, the crystalline form exhibits characteristics (b) and (j). In some embodiments, the crystalline form exhibits characteristics (c) and (f). In some embodiments, the crystalline form exhibits characteristics (c) and (g). In some embodiments, the crystalline form exhibits characteristics (c) and (h). In some embodiments, the crystalline form exhibits characteristics (c) and (i). In some embodiments, the crystalline form exhibits characteristics (c) and (j). In some embodiments, the crystalline form exhibits characteristics (d) and (f). In some embodiments, the crystalline form exhibits characteristics (d) and (g). In some embodiments, the crystalline form exhibits characteristics (d) and (h). In some embodiments, the crystalline form exhibits characteristics (d) and (i). In some embodiments, the crystalline form exhibits characteristics (d) and (j). In some embodiments, the crystalline form exhibits characteristics (e) and (f). In some embodiments, the crystalline form exhibits characteristics (e) and (g). In some embodiments, the crystalline form exhibits characteristics (e) and (h). In some embodiments, the crystalline form exhibits characteristics (e) and (i). In some embodiments, the crystalline form exhibits characteristics (e) and (j).

[0081] In some embodiments, crystalline form A of Compound A is characterized as exhibiting an XRPD pattern with one or more peaks listed in the following Table 1 as measured using Cu Kα radiation: Table 1

[0082] In some embodiments, crystalline form A of Compound A is characterized as exhibiting a reversible water uptake of at most 16% (w / w) between 0% and 90% Relative Humidity (RH) as determined by Dynamic Vapour Sorption (DVS).

[0083] In some embodiments, crystalline form A of Compound A is characterized as adsorbing between 2 and 15 w% of water at 25 °C and 80 % relative humidity. In some embodiments, crystalline form A of Compound A is characterized as a moderately hygroscopic material according to classification by the European Pharmacopeia.Docket No.51503-768.601

[0084] In some embodiments, crystalline form A of Compound A converts to an amorphous form after Dynamic Vapour Sorption (DVS) analysis between 0% and 90% RH.

[0085] In some embodiments, crystalline form A of Compound A converts to crystalline form B of Compound A when saturated in 1-propanol and left to slurry for one day, such as in the competitive slurry experiment as described in Example 3.

[0086] In some embodiments, crystalline form A of Compound A converts to crystalline form B of Compound A when saturated in 2-methyl THF and left to slurry for one day, such as in the competitive slurry experiment as described in Example 3. Crystalline Form B of Compound A

[0087] In some embodiments, provided herein is crystalline form B of Compound A. In some embodiments, provided herein is a composition comprising crystalline form B of Compound A.

[0088] In some embodiments, crystalline form B of Compound A is formed from the other solid-state forms described herein, such as form A. In some embodiments, crystalline form B of Compound A is the thermodynamically favored solid state form of Compound A.

[0089] In some embodiments, crystalline form B of Compound A is anhydrous. In some embodiments, crystalline form B of Compound A is not solvated. In some embodiments, crystalline form B of Compound A is not hydrated.

[0090] In some embodiments, crystalline form B of Compound A is characterized as having an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG.2 as measured using Cu Kα radiation.

[0091] In some embodiments, crystalline form B of Compound A is characterized as exhibiting an XRPD pattern with one or more peaks at 9.3 ±0.2 º2-Theta, 27.5 ±0.2 º2-Theta, and 31.0 ±0.2 º2- Theta as measured using Cu Kα radiation. In some embodiments, crystalline form B of Compound A is characterized as exhibiting an XRPD pattern with peaks at 9.3 ±0.2 º2-Theta, 27.5 ±0.2 º2-Theta, and 31.0 ±0.2 º2-Theta as measured using Cu Kα radiation. In some embodiments, crystalline form B of Compound A is characterized as exhibiting an XRPD pattern with one or more peaks at 9.3 ±0.2 º2-Theta, 27.5 ±0.2 º2-Theta, and 32.6 ±0.2 º2-Theta as measured using Cu Kα radiation. In some embodiments, crystalline form B of Compound A is characterized as exhibiting an XRPD pattern with peaks at 9.3 ±0.2 º2-Theta, 27.5 ±0.2 º2-Theta, and 32.6 ±0.2 º2-Theta as measured using Cu Kα radiation.

[0092] In some embodiments, crystalline form B of Compound A is characterized as exhibiting an XRPD pattern with at least three, at least four, at least five, or all of the peaks at 9.3 ±0.2 º2-Theta, 16.9 ±0.2 º2-Theta, 20.7 ±0.2 º2-Theta, 27.5 ±0.2 º2-Theta, 31.0 ±0.2 º2-Theta, and 32.6 ±0.2 º2- Theta. In some embodiments, crystalline form B of Compound A is characterized as exhibiting an XRPD pattern with at least three, at least four, at least five, at least six, or all of the peaks at 9.3 ±0.2 º2-Theta, 11.1 ±0.2 º2-Theta, 16.9 ±0.2 º2-Theta, 20.7 ±0.2 º2-Theta, 27.5 ±0.2 º2-Theta, 31.0 ±0.2 º2- Theta, and 32.6 ±0.2 º2-Theta. In some embodiments, crystalline form B of Compound A isDocket No.51503-768.601 characterized as exhibiting an XRPD pattern with at least three, at least four, at least five, at least six, at least seven, or all of the peaks at 9.3 ±0.2 º2-Theta, 16.9 ±0.2 º2-Theta, 20.7 ±0.2 º2-Theta, 27.5 ±0.2 º2-Theta, 31.0 ±0.2 º2-Theta, 32.6 ±0.2 º2-Theta, and 39.4 ±0.2 º2-Theta.

[0093] In some embodiments, crystalline form B of Compound A is characterized as exhibiting an XRPD pattern with one or more peaks at 4.7 ±0.2 º2-Theta, 9.3 ±0.2 º2-Theta, and 27.5 ±0.2 º2-Theta as measured using Cu Kα radiation.

[0094] In some embodiments, crystalline form B of Compound A is characterized as exhibiting an XRPD pattern with at least three, at least four, at least five, or all of the peaks at 4.7 ±0.2 º2-Theta, 9.3 ±0.2 º2-Theta, 11.1 ±0.2 º2-Theta, 22.9 ±0.2 º2-Theta, 25.8 ±0.2 º2-Theta, and 27.5 ±0.2 º2-Theta as measured using Cu Kα radiation.

[0095] In some embodiments, crystalline form B of Compound A is characterized as exhibiting an XRPD pattern with at least three, at least six, at least nine, or all of the peaks at 4.7 ±0.2 º2-Theta, 9.3 ±0.2 º2-Theta, 11.1 ±0.2 º2-Theta, 12.0 ±0.2 º2-Theta, 13.0 ±0.2 º2-Theta, 16.0 ±0.2 º2-Theta, 16.9 ±0.2 º2-Theta, 17.8 ±0.2 º2-Theta, 20.7 ±0.2 º2-Theta, 22.9 ±0.2 º2-Theta, 25.8 ±0.2 º2-Theta, 26.3 ±0.2 º2-Theta, 27.5 ±0.2 º2-Theta, 30.6 ±0.2 º2-Theta, and 39.4 ±0.2 º2-Theta as measured using Cu Kα radiation.

[0096] In some embodiments, crystalline form B of Compound A is characterized as exhibiting a Differential Scanning Calorimetry (DSC) thermogram substantially the same as shown in FIG.11.

[0097] In some embodiments, crystalline form B of Compound A is characterized as exhibiting a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak having an onset temperature between about 69 °C and about 79 °C.

[0098] In some embodiments, crystalline form B of Compound A is characterized as exhibiting a Differential Scanning Calorimetry (DSC) thermogram with a broad exothermic event having an onset at about 160 °C.

[0099] In some embodiments, crystalline form B of Compound A is characterized as exhibiting a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as shown in FIG. 16.

[0100] In some embodiments, crystalline form B of Compound A is characterized as exhibiting a Thermogravimetric Thermal Analysis (TGA) thermogram exhibiting a mass loss of about 10.7 % from the onset of heating up to approximately 160 °C.

[0101] In some embodiments, crystalline form B of Compound A is characterized as exhibiting one or more of the following: (a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG.2 as measured using Cu Kα radiation; (b) an XRPD pattern with one or more peaks at 4.7 ±0.2 º2-Theta, 9.3 ±0.2 º2-Theta, and 27.5 ±0.2 º2-Theta as measured using Cu Kα radiation; (c) an XRPD pattern with one or more peaks at 9.3 ±0.2 º2-Theta, 27.5 ±0.2 º2-Theta, and 31.0 ±0.2 º2- Theta as measured using Cu Kα radiation (d) an XRPD pattern with one or more peaks at 9.3 ±0.2 º2- Theta, 27.5 ±0.2 º2-Theta, and 32.6 ±0.2 º2-Theta as measured using Cu Kα radiation (e) an XRPDDocket No.51503-768.601 pattern with one or more peaks at 27.5 ±0.2 º2-Theta, 31.0 ±0.2 º2-Theta, and 32.6 ±0.2 º2-Theta as measured using Cu Kα radiation (f) an XRPD pattern with at least three, at least four, at least five, or all of the peaks at 4.7 ±0.2 º2-Theta, 9.3 ±0.2 º2-Theta, 11.1 ±0.2 º2-Theta, 22.9 ±0.2 º2-Theta, 25.8 ±0.2 º2-Theta, and 27.5 ±0.2 º2-Theta as measured using Cu Kα radiation; (g) an XRPD pattern with at least three, at least six, at least nine, or all of the peaks at 4.7 ±0.2 º2-Theta, 9.3 ±0.2 º2-Theta, 11.1 ±0.2 º2-Theta, 12.0 ±0.2 º2-Theta, 13.0 ±0.2 º2-Theta, 16.0 ±0.2 º2-Theta, 16.9 ±0.2 º2-Theta, 17.8 ±0.2 º2-Theta, 20.7 ±0.2 º2-Theta, 22.9 ±0.2 º2-Theta, 25.8 ±0.2 º2-Theta, 26.3 ±0.2 º2-Theta, 27.5 ±0.2 º2-Theta, 30.6 ±0.2 º2-Theta, and 39.4 ±0.2 º2-Theta as measured using Cu Kα radiation; (h) a Differential Scanning Calorimetry (DSC) thermogram substantially the same as shown in FIG.11; (i) a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak having an onset temperature between about 69 °C and about 79 °C; (j) a Differential Scanning Calorimetry (DSC) thermogram with a broad exothermic event having an onset at about 160 °C; (k) a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as shown in FIG.16; and / or (l) a Thermogravimetric Thermal Analysis (TGA) thermogram exhibiting a mass loss of about 10.7 % from the onset of heating up to approximately 160 °C.

[0102] In some embodiments, crystalline form B of Compound A is characterized as exhibiting an XRPD pattern with one or more peaks listed in the following Table 2 as measured using Cu Kα radiation: Table 2Docket No.51503-768.601

[0103] In some embodiments, crystalline form B of Compound A is characterized as exhibiting an XRPD that is converted from crystalline form A of Compound A when saturated in 1-propanol and left to slurry for one day, such as in the competitive slurry experiment as described in Example 3.

[0104] In some embodiments, crystalline form B of Compound A is characterized as exhibiting an XRPD that is converted from crystalline form A of Compound A when saturated in 2-methyl THF and left to slurry for one day, such as in the competitive slurry experiment as described in Example 3. Crystalline Form C of Compound A

[0105] In some embodiments, provided herein is crystalline form C of Compound A. In some embodiments, provided herein is a composition comprising crystalline form C of Compound A.

[0106] In some embodiments, crystalline form C of Compound A is formed from the other solid- state forms described herein, such as form A.

[0107] In some embodiments, crystalline form C of Compound A is anhydrous. In some embodiments, crystalline form C of Compound A is not solvated. In some embodiments, crystalline form C of Compound A is not hydrated.

[0108] In some embodiments, crystalline form C of Compound A is characterized as having an X- Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG.3 as measured using Cu Kα radiation.

[0109] In some embodiments, crystalline form C of Compound A is characterized as exhibiting an XRPD pattern with one or more peaks at 13.1 ±0.2 º2-Theta, 25.5 ±0.2 º2-Theta, and 28.5 ±0.2 º2- Theta as measured using Cu Kα radiation. In some embodiments, crystalline form C of Compound A is characterized as exhibiting an XRPD pattern with peaks at 13.1 ±0.2 º2-Theta, 25.5 ±0.2 º2-Theta, and 28.5 ±0.2 º2-Theta as measured using Cu Kα radiation.

[0110] In some embodiments, crystalline form C of Compound A is characterized as exhibiting an XRPD pattern with one or more peaks at 6.5 ±0.2 º2-Theta, 25.5 ±0.2 º2-Theta, and 28.5 ±0.2 º2- Theta as measured using Cu Kα radiation. In some embodiments, crystalline form C of Compound A is characterized as exhibiting an XRPD pattern with peaks at 6.5 ±0.2 º2-Theta, 25.5 ±0.2 º2-Theta, and 28.5 ±0.2 º2-Theta as measured using Cu Kα radiation. In some embodiments, crystalline form C of Compound A is characterized as exhibiting an XRPD pattern comprising a peak at 6.5 ±0.2 º2- Theta.

[0111] In some embodiments, crystalline form C of Compound A is characterized as exhibiting an XRPD pattern with one or more peaks at 17.7 ±0.2 º2-Theta, 25.5 ±0.2 º2-Theta, and 28.5 ±0.2 º2- Theta as measured using Cu Kα radiation.

[0112] In some embodiments, crystalline form C of Compound A is characterized as exhibiting an XRPD pattern with at least three, at least four, at least five, or all of the peaks at 13.1 ±0.2 º2-Theta, 15.4 ±0.2 º2-Theta, 17.7 ±0.2 º2-Theta, 25.5 ±0.2 º2-Theta, 26.4 ±0.2 º2-Theta, and 28.5 ±0.2 º2- Theta as measured using Cu Kα radiation. In some embodiments, crystalline form C of Compound A is characterized as exhibiting an XRPD pattern with all of the peaks at 13.1 ±0.2 º2-Theta, 15.4 ±0.2Docket No.51503-768.601 º2-Theta, 17.7 ±0.2 º2-Theta, 25.5 ±0.2 º2-Theta, 26.4 ±0.2 º2-Theta, and 28.5 ±0.2 º2-Theta as measured using Cu Kα radiation.

[0113] In some embodiments, crystalline form C of Compound A is characterized as exhibiting an XRPD pattern with at least three, at least four, at least five, or all of the peaks at 6.5 ±0.2 º2-Theta, 15.4 ±0.2 º2-Theta, 17.7 ±0.2 º2-Theta, 25.5 ±0.2 º2-Theta, 26.4 ±0.2 º2-Theta, and 28.5 ±0.2 º2- Theta as measured using Cu Kα radiation. In some embodiments, crystalline form C of Compound A is characterized as exhibiting an XRPD pattern with all of the peaks at 6.5 ±0.2 º2-Theta, 15.4 ±0.2 º2- Theta, 17.7 ±0.2 º2-Theta, 25.5 ±0.2 º2-Theta, 26.4 ±0.2 º2-Theta, and 28.5 ±0.2 º2-Theta as measured using Cu Kα radiation.

[0114] In some embodiments, crystalline form C of Compound A is characterized as exhibiting an XRPD pattern with at least three, at least six, at least nine, or all of the peaks at 6.5 ±0.2 º2-Theta, 12.4 ±0.2 º2-Theta, 13.1 ±0.2 º2-Theta, 14.8 ±0.2 º2-Theta, 15.4 ±0.2 º2-Theta, 17.7 ±0.2 º2-Theta, 23.8 ±0.2 º2-Theta, 25.5 ±0.2 º2-Theta, 26.4 ±0.2 º2-Theta, and 28.5 ±0.2 º2-Theta as measured using Cu Kα radiation.

[0115] In some embodiments, crystalline form C of Compound A is characterized as exhibiting one or more of the following: (a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. as measured using Cu Kα radiation; (b) an XRPD pattern with one or more peaks at 17.7 ±0.2 º2-Theta, 25.5 ±0.2 º2-Theta, and 28.5 ±0.2 º2-Theta as measured using Cu Kα radiation; (c) an XRPD pattern with one or more (e.g., all three) peaks at 13.1 ±0.2 º2-Theta, 25.5 ±0.2 º2-Theta, and 28.5 ±0.2 º2-Theta as measured using Cu Kα radiation; (d) an XRPD pattern with one or more (e.g., all three) peaks at 6.5 ±0.2 º2-Theta, 25.5 ±0.2 º2-Theta, and 28.5 ±0.2 º2-Theta as measured using Cu Kα radiation; (e) an XRPD pattern with at least three, at least four, at least five, or all of the peaks at 13.1 ±0.2 º2-Theta, 15.4 ±0.2 º2-Theta, 17.7 ±0.2 º2-Theta, 25.5 ±0.2 º2-Theta, 26.4 ±0.2 º2- Theta, and 28.5 ±0.2 º2-Theta as measured using Cu Kα radiation; and / or (f) an XRPD pattern with at least three, at least six, at least nine, or all of the peaks at 6.5 ±0.2 º2-Theta, 12.4 ±0.2 º2-Theta, 13.1 ±0.2 º2-Theta, 14.8 ±0.2 º2-Theta, 15.4 ±0.2 º2-Theta, 17.7 ±0.2 º2-Theta, 23.8 ±0.2 º2-Theta, 25.5 ±0.2 º2-Theta, 26.4 ±0.2 º2-Theta, and 28.5 ±0.2 º2-Theta as measured using Cu Kα radiation.

[0116] In some embodiments, crystalline form C of Compound A is characterized as exhibiting an XRPD pattern with one or more peaks listed in the following Table 3 as measured using Cu Kα radiation.Docket No.51503-768.601 Table 3Crystalline Form D of Compound A

[0117] In some embodiments, provided herein is crystalline form D of Compound A. In some embodiments, provided herein is a composition comprising crystalline form D of Compound A.

[0118] In some embodiments, crystalline form D of Compound A is formed from the other solid- state forms described herein, such as form A. In some embodiments, crystalline form D of Compound A is the thermodynamically favored solid state form of Compound A.

[0119] In some embodiments, crystalline form D of Compound A is formed from the other solid- state forms described herein, such as form A. In some embodiments, crystalline form D of Compound A is the thermodynamically favored solid state form of Compound A.

[0120] In some embodiments, crystalline form D of Compound A is anhydrous. In some embodiments, crystalline form D of Compound A is not solvated. In some embodiments, crystalline form D of Compound A is not hydrated.

[0121] In some embodiments, crystalline form D of Compound A is characterized as having an X- Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG.4 as measured using Cu Kα radiation.

[0122] In some embodiments, crystalline form D of Compound A is characterized as exhibiting an XRPD pattern with at least three, at least four, at least five, or all of the peaks at 9.8 ±0.2 º2-Theta, 12.5 ±0.2 º2-Theta, 15.7 ±0.2 º2-Theta, 17.7 ±0.2 º2-Theta, 19.7±0.2 º2-Theta, and 26.4 ±0.2 º2-ThetaDocket No.51503-768.601 as measured using Cu Kα radiation. In some embodiments, crystalline form D of Compound A is characterized as exhibiting an XRPD pattern with all of the peaks at 9.8 ±0.2 º2-Theta, 12.5 ±0.2 º2- Theta, 15.7 ±0.2 º2-Theta, 17.7 ±0.2 º2-Theta, 19.7±0.2 º2-Theta, and 26.4 ±0.2 º2-Theta as measured using Cu Kα radiation.

[0123] In some embodiments, crystalline form D of Compound A is characterized as exhibiting an XRPD pattern with one or more peaks at 9.8 ±0.2 º2-Theta, 15.7 ±0.2 º2-Theta, and 26.4 ±0.2 º2- Theta as measured using Cu Kα radiation.

[0124] In some embodiments, crystalline form D of Compound A is characterized as exhibiting an XRPD pattern with at least three, at least four, at least five, or all of the peaks at 9.8 ±0.2 º2-Theta, 11.2 ±0.2 º2-Theta, 15.7 ±0.2 º2-Theta, 17.7 ±0.2 º2-Theta, 18.5 ±0.2 º2-Theta, 21.7 ±0.2 º2-Theta, and 26.4 ±0.2 º2-Theta as measured using Cu Kα radiation.

[0125] In some embodiments, crystalline form D of Compound A is characterized as exhibiting an XRPD pattern with at least three, at least six, at least nine, or all of the peaks at 9.8 ±0.2 º2-Theta, 11.2 ±0.2 º2-Theta, 15.7 ±0.2 º2-Theta, 17.7 ±0.2 º2-Theta, 18.5 ±0.2 º2-Theta, 21.7 ±0.2 º2-Theta, 22.4 ±0.2 º2-Theta, 26.4 ±0.2 º2-Theta, 27.2 ±0.2 º2-Theta, and 29.3 ±0.2 º2-Theta as measured using Cu Kα radiation.

[0126] In some embodiments, crystalline form D of Compound A is characterized as exhibiting a Differential Scanning Calorimetry (DSC) thermogram substantially the same as shown in FIG.12.

[0127] In some embodiments, crystalline form D of Compound A is characterized as exhibiting a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak having an onset temperature at about 79 °C.

[0128] In some embodiments, crystalline form D of Compound A is characterized as exhibiting a Differential Scanning Calorimetry (DSC) thermogram with a weak endothermic event having an onset temperature at about 113 °C.

[0129] In some embodiments, crystalline form D of Compound A is characterized as exhibiting a Differential Scanning Calorimetry (DSC) thermogram with an endothermic event having an onset temperature at about 151 °C.

[0130] In some embodiments, crystalline form D of Compound A is characterized as exhibiting a Differential Scanning Calorimetry (DSC) thermogram with a broad exothermic event having an onset at about 175 °C.

[0131] In some embodiments, crystalline form D of Compound A is characterized as exhibiting a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as shown in FIG. 17.

[0132] In some embodiments, crystalline form D of Compound A is characterized as exhibiting a Thermogravimetric Thermal Analysis (TGA) thermogram exhibiting a mass loss of about 6.5 % from the onset of heating up to approximately 148 °C.Docket No.51503-768.601

[0133] In some embodiments, crystalline form D of Compound A is characterized as exhibiting one or more of the following: (a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG.4 as measured using Cu Kα radiation; (b) an XRPD pattern with one or more peaks at 9.8 ±0.2 º2-Theta, 15.7 ±0.2 º2-Theta, and 26.4 ±0.2 º2-Theta as measured using Cu Kα radiation; (c) an XRPD pattern with at least three, at least four, at least five, or all of the peaks at 9.8 ±0.2 º2-Theta, 11.2 ±0.2 º2-Theta, 15.7 ±0.2 º2-Theta, 17.7 ±0.2 º2-Theta, 18.5 ±0.2 º2-Theta, 21.7 ±0.2 º2-Theta, and 26.4 ±0.2 º2-Theta as measured using Cu Kα radiation; (d) an XRPD pattern with at least three, at least six, at least nine, or all of the peaks at 9.8 ±0.2 º2-Theta, 11.2 ±0.2 º2-Theta, 15.7 ±0.2 º2-Theta, 17.7 ±0.2 º2-Theta, 18.5 ±0.2 º2-Theta, 21.7 ±0.2 º2-Theta, 22.4 ±0.2 º2-Theta, 26.4 ±0.2 º2-Theta, 27.2 ±0.2 º2-Theta, and 29.3 ±0.2 º2-Theta as measured using Cu Kα radiation; (e) a Differential Scanning Calorimetry (DSC) thermogram substantially the same as shown in FIG.12; (f) a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak having an onset temperature at about 79 °C; (g) a Differential Scanning Calorimetry (DSC) thermogram with a weak endothermic event having an onset temperature at about 113 °C; (h) a Differential Scanning Calorimetry (DSC) thermogram with an endothermic event having an onset temperature at about 151 °C; (i) a Differential Scanning Calorimetry (DSC) thermogram with a broad exothermic event having an onset at about 175 °C; (j) a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as shown in FIG.17; and / or (k) a Thermogravimetric Thermal Analysis (TGA) thermogram exhibiting a mass loss of about 6.5 % from the onset of heating up to approximately 148 °C.

[0134] In some embodiments, crystalline form D of Compound A is characterized as exhibiting an XRPD pattern with one or more peaks listed in the following Table 4 as measured using Cu Kα radiation. Table 4Docket No.51503-768.601

[0135] In some embodiments, crystalline form D of Compound A is characterized as exhibiting an XRPD that is converted from crystalline form B of Compound A when stirred in 2-methyl THF and left to slurry for 2 days, 3 days, or 4 days, such as in the competitive slurry experiment as described in Example 3. Crystalline Form E of Compound A

[0136] In some embodiments, provided herein is crystalline form E of Compound A. In some embodiments, provided herein is a composition comprising crystalline form E of Compound A.

[0137] In some embodiments, crystalline form E of Compound A is formed from the other solid- state forms described herein, such as form A.

[0138] In some embodiments, crystalline form E of Compound A is anhydrous. In some embodiments, crystalline form E of Compound A is not solvated. In some embodiments, crystalline form E of Compound A is not hydrated.

[0139] In some embodiments, crystalline form E of Compound A is characterized as having an X- Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG.5 as measured using Cu Kα radiation.

[0140] In some embodiments, crystalline form E of Compound A is characterized as exhibiting an XRPD pattern with one or more peaks at 13.9 ±0.2 º2-Theta, 27.1 ±0.2 º2-Theta, and 33.6 ±0.2 º2- Theta as measured using Cu Kα radiation. In some embodiments, crystalline form E of Compound A is characterized as exhibiting an XRPD pattern with peaks at 13.9 ±0.2 º2-Theta, 27.1 ±0.2 º2-Theta, and 33.6 ±0.2 º2-Theta as measured using Cu Kα radiation. In some embodiments, crystalline form EDocket No.51503-768.601 of Compound A is characterized as exhibiting an XRPD pattern with one or more peaks at 9.4 ±0.2 º2-Theta, 27.6 ±0.2 º2-Theta, and 33.6 ±0.2 º2-Theta as measured using Cu Kα radiation.

[0141] In some embodiments, crystalline form E of Compound A is characterized as exhibiting an XRPD pattern with one or more peaks at 9.4 ±0.2 º2-Theta, 12.1 ±0.2 º2-Theta, and 27.6 ±0.2 º2- Theta as measured using Cu Kα radiation.

[0142] In some embodiments, crystalline form E of Compound A is characterized as exhibiting an XRPD pattern with at least three, at least four, at least five, or all of the peaks at 4.8 ±0.2 º2-Theta, 9.4 ±0.2 º2-Theta, 11.1 ±0.2 º2-Theta, 12.1 ±0.2 º2-Theta, 25.9 ±0.2 º2-Theta, and 27.6 ±0.2 º2-Theta as measured using Cu Kα radiation.

[0143] In some embodiments, crystalline form E of Compound A is characterized as exhibiting an XRPD pattern with at least three, at least six, at least nine, or all of the peaks at 4.8 ±0.2 º2-Theta, 5.3 ±0.2 º2-Theta, 9.4 ±0.2 º2-Theta, 11.1 ±0.2 º2-Theta, 12.1 ±0.2 º2-Theta, 12.8 ±0.2 º2-Theta, 13.9 ±0.2 º2-Theta, 16.2 ±0.2 º2-Theta, 16.7 ±0.2 º2-Theta, 20.7 ±0.2 º2-Theta, 22.9 ±0.2 º2-Theta, 25.4 ±0.2 º2-Theta, 25.9 ±0.2 º2-Theta, 26.4 ±0.2 º2-Theta, 27.1 ±0.2 º2-Theta, and 27.6 ±0.2 º2-Theta as measured using Cu Kα radiation.

[0144] In some embodiments, crystalline form E of Compound A is characterized as exhibiting one or more of the following: (a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG.5 as measured using Cu Kα radiation; (b) an XRPD pattern with one or more peaks at 9.4 ±0.2 º2-Theta, 12.1 ±0.2 º2-Theta, and 27.6 ±0.2 º2-Theta as measured using Cu Kα radiation; (c) an XRPD pattern with one or more peaks at 13.9 ±0.2 º2-Theta, 27.1 ±0.2 º2-Theta, and 33.6 ±0.2 º2- Theta as measured using Cu Kα radiation (d) an XRPD pattern with one or more peaks at 9.4 ±0.2 º2- Theta, 27.6 ±0.2 º2-Theta, and 33.6 ±0.2 º2-Theta as measured using Cu Kα radiation (e) an XRPD pattern with at least three, at least four, at least five, or all of the peaks at 4.8 ±0.2 º2-Theta, 9.4 ±0.2 º2-Theta, 11.1 ±0.2 º2-Theta, 12.1 ±0.2 º2-Theta, 25.9 ±0.2 º2-Theta, and 27.6 ±0.2 º2-Theta as measured using Cu Kα radiation; and / or (f) an XRPD pattern with at least three, at least six, at least nine, or all of the peaks at 4.8 ±0.2 º2-Theta, 5.3 ±0.2 º2-Theta, 9.4 ±0.2 º2-Theta, 11.1 ±0.2 º2-Theta, 12.1 ±0.2 º2-Theta, 12.8 ±0.2 º2-Theta, 13.9 ±0.2 º2-Theta, 16.2 ±0.2 º2-Theta, 16.7 ±0.2 º2-Theta, 20.7 ±0.2 º2-Theta, 22.9 ±0.2 º2-Theta, 25.4 ±0.2 º2-Theta, 25.9 ±0.2 º2-Theta, 26.4 ±0.2 º2-Theta, 27.1 ±0.2 º2-Theta, and 27.6 ±0.2 º2-Theta as measured using Cu Kα radiation.

[0145] In some embodiments, crystalline form E of Compound A is characterized as exhibiting an XRPD pattern with one or more peaks listed in the following Table 5 as measured using Cu Kα radiation.Docket No.51503-768.601 Table 5Crystalline Form F of Compound A

[0146] In some embodiments, provided herein is crystalline form F of Compound A. In some embodiments, provided herein is a composition comprising crystalline form F of Compound A.

[0147] In some embodiments, crystalline form F of Compound A is formed from the other solid- state forms described herein, such as form A.

[0148] In some embodiments, crystalline form F of Compound A is anhydrous. In some embodiments, crystalline form F of Compound A is not solvated. In some embodiments, crystalline form F of Compound A is not hydrated.

[0149] In some embodiments, crystalline form F of Compound A is characterized as having an X- Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG.6 as measured using Cu Kα radiation.Docket No.51503-768.601

[0150] In some embodiments, crystalline form F of Compound A is characterized as exhibiting an XRPD pattern with one or more peaks at 7.5 ±0.2 º2-Theta, 9.8 ±0.2 º2-Theta, and 15.0 ±0.2 º2-Theta as measured using Cu Kα radiation. In some embodiments, crystalline form F of Compound A is characterized as exhibiting an XRPD pattern with peaks at 7.5 ±0.2 º2-Theta, 9.8 ±0.2 º2-Theta, and 15.0 ±0.2 º2-Theta as measured using Cu Kα radiation. In some embodiments, crystalline form F of Compound A is characterized as exhibiting an XRPD pattern with peaks at 7.5 ±0.2 º2-Theta, 9.8 ±0.2 º2-Theta, 15.0 ±0.2 º2-Theta, and 27.2 ±0.2 º2-Theta as measured using Cu Kα radiation. In some embodiments, crystalline form F of Compound A is characterized as exhibiting an XRPD pattern with peaks at 15.0 ±0.2 º2-Theta, 27.2 ±0.2 º2-Theta, and 31.9 ±0.2 º2-Theta as measured using Cu Kα radiation. In some embodiments, crystalline form F of Compound A is characterized as exhibiting an XRPD pattern with peaks at 15.0 ±0.2 º2-Theta, 16.1 ±0.2 º2-Theta, and 27.2 ±0.2 º2-Theta as measured using Cu Kα radiation.

[0151] In some embodiments, crystalline form F of Compound A is characterized as exhibiting an XRPD pattern with at least three, at least four, at least five, or all of the peaks at 7.5 ±0.2 º2-Theta, 9.8 ±0.2 º2-Theta, 15.0 ±0.2 º2-Theta, 27.2 ±0.2 º2-Theta, 27.5 ±0.2 º2-Theta, and 31.9 ±0.2 º2-Theta as measured using Cu Kα radiation. In some embodiments, crystalline form F of Compound A is characterized as exhibiting an XRPD pattern with all of the peaks at 7.5 ±0.2 º2-Theta, 9.8 ±0.2 º2- Theta, 15.0 ±0.2 º2-Theta, 27.2 ±0.2 º2-Theta, 27.5 ±0.2 º2-Theta, and 31.9 ±0.2 º2-Theta as measured using Cu Kα radiation.

[0152] In some embodiments, crystalline form F of Compound A is characterized as exhibiting an XRPD pattern with one or more peaks at 9.8 ±0.2 º2-Theta, 26.4 ±0.2 º2-Theta, and 27.5 ±0.2 º2- Theta as measured using Cu Kα radiation.

[0153] In some embodiments, crystalline form F of Compound A is characterized as exhibiting an XRPD pattern with at least three, at least four, at least five, or all of the peaks at 4.7 ±0.2 º2-Theta, 9.8 ±0.2 º2-Theta, 15.7 ±0.2 º2-Theta, 26.4 ±0.2 º2-Theta, 27.5 ±0.2 º2-Theta, and 28.0 ±0.2 º2-Theta as measured using Cu Kα radiation.

[0154] In some embodiments, crystalline form F of Compound A is characterized as exhibiting an XRPD pattern with at least three, at least six, at least nine, or all of the peaks at 4.7 ±0.2 º2-Theta, 5.3 ±0.2 º2-Theta, 7.5 ±0.2 º2-Theta, 9.4 ±0.2 º2-Theta, 9.8 ±0.2 º2-Theta, 11.1 ±0.2 º2-Theta, 14.7 ±0.2 º2-Theta, 15.0 ±0.2 º2-Theta, 15.7 ±0.2 º2-Theta, 16.1 ±0.2 º2-Theta, 16.8 ±0.2 º2-Theta, 17.7 ±0.2 º2- Theta, 21.7 ±0.2 º2-Theta, 26.4 ±0.2 º2-Theta, 27.2 ±0.2 º2-Theta, 27.5 ±0.2 º2-Theta, and 28.0 ±0.2 º2-Theta as measured using Cu Kα radiation.

[0155] In some embodiments, crystalline form F of Compound A is characterized as exhibiting one or more of the following: (a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG.6 as measured using Cu Kα radiation; (b) an XRPD pattern with one or more peaks at 9.8 ±0.2 º2-Theta, 26.4 ±0.2 º2-Theta, and 27.5 ±0.2 º2-Theta as measured using Cu Kα radiation; (c) An XRPD pattern with one or more peaks at 7.5 ±0.2 º2-Theta, 9.8 ±0.2 º2-Theta, and 15.0 ±0.2 º2-Docket No.51503-768.601 Theta as measured using Cu Kα radiation; (d) an XRPD pattern with one or more peaks at 7.5 ±0.2 º2- Theta, 9.8 ±0.2 º2-Theta, 15.0 ±0.2 º2-Theta, and 27.2 ±0.2 º2-Theta as measured using Cu Kα radiation (e) an XRPD pattern with one or more peaks at 15.0 ±0.2 º2-Theta, 16.1 ±0.2 º2-Theta, and 27.2 ±0.2 º2-Theta as measured using Cu Kα radiation (f) an XRPD pattern with peaks at 15.0 ±0.2 º2-Theta, 27.2 ±0.2 º2-Theta, and 31.9 ±0.2 º2-Theta as measured using Cu Kα radiation (c) an XRPD pattern with at least three, at least four, at least five, or all of the peaks at 4.7 ±0.2 º2-Theta, 9.8 ±0.2 º2-Theta, 15.7 ±0.2 º2-Theta, 26.4 ±0.2 º2-Theta, 27.5 ±0.2 º2-Theta, and 28.0 ±0.2 º2-Theta as measured using Cu Kα radiation; and / or (d) an XRPD pattern with at least three, at least six, at least nine, or all of the peaks at 4.7 ±0.2 º2-Theta, 5.3 ±0.2 º2-Theta, 7.5 ±0.2 º2-Theta, 9.4 ±0.2 º2-Theta, 9.8 ±0.2 º2-Theta, 11.1 ±0.2 º2-Theta, 14.7 ±0.2 º2-Theta, 15.0 ±0.2 º2-Theta, 15.7 ±0.2 º2-Theta, 16.1 ±0.2 º2-Theta, 16.8 ±0.2 º2-Theta, 17.7 ±0.2 º2-Theta, 21.7 ±0.2 º2-Theta, 26.4 ±0.2 º2-Theta, 27.2 ±0.2 º2-Theta, 27.5 ±0.2 º2-Theta, and 28.0 ±0.2 º2-Theta as measured using Cu Kα radiation.

[0156] In some embodiments, crystalline form F of Compound A is characterized as exhibiting an XRPD pattern with one or more peaks listed in the following Table 6 as measured using Cu Kα radiation. Table 6Docket No.51503-768.601Crystalline Form G of Compound A

[0157] In some embodiments, provided herein is crystalline form G of Compound A. In some embodiments, provided herein is a composition comprising crystalline form G of Compound A.

[0158] In some embodiments, crystalline form G of Compound A is formed from the other solid- state forms described herein, such as form A.

[0159] In some embodiments, crystalline form G of Compound A is formed from the other solid- state forms described herein, such as form A. In some embodiments, crystalline form G of Compound A is the thermodynamically favored solid state form of Compound A.

[0160] In some embodiments, crystalline form G of Compound A is anhydrous. In some embodiments, crystalline form G of Compound A is not solvated. In some embodiments, crystalline form G of Compound A is not hydrated.

[0161] In some embodiments, crystalline form G of Compound A is characterized as having an X- Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG.7 as measured using Cu Kα radiation.

[0162] In some embodiments, crystalline form G of Compound A is characterized as exhibiting an XRPD pattern with one or more peaks at 10.9 ±0.2 º2-Theta, 13.7 ±0.2 º2-Theta, and 23.3 ±0.2 º2- Theta as measured using Cu Kα radiation. In some embodiments, crystalline form G of Compound A is characterized as exhibiting an XRPD pattern with peaks at 10.9 ±0.2 º2-Theta, 13.7 ±0.2 º2-Theta, and 23.3 ±0.2 º2-Theta as measured using Cu Kα radiation. In some embodiments, crystalline form G of Compound A is characterized as exhibiting an XRPD pattern with one or more peaks at 10.9 ±0.2 º2-Theta, 13.7 ±0.2 º2-Theta, and 19.1 ±0.2 º2-Theta as measured using Cu Kα radiation. In some embodiments, crystalline form G of Compound A is characterized as exhibiting an XRPD pattern with peaks at 10.9 ±0.2 º2-Theta, 13.7 ±0.2 º2-Theta, and 19.1 ±0.2 º2-Theta as measured using Cu KαDocket No.51503-768.601 radiation. In some embodiments, crystalline form G of Compound A is characterized as exhibiting an XRPD pattern with one or more peaks at 18.0 ±0.2 º2-Theta, 27.5 ±0.2 º2-Theta, and 28.1 ±0.2 º2- Theta as measured using Cu Kα radiation. In some embodiments, crystalline form G of Compound A is characterized as exhibiting an XRPD pattern with peaks at 18.0 ±0.2 º2-Theta, 27.5 ±0.2 º2-Theta, and 28.1 ±0.2 º2-Theta as measured using Cu Kα radiation.

[0163] In some embodiments, crystalline form G of Compound A is characterized as exhibiting an XRPD pattern with at least three, at least four, at least five, or all of the peaks at 10.9 ±0.2 º2-Theta, 13.7 ±0.2 º2-Theta, 18.0 ±0.2 º2-Theta, 23.3 ±0.2 º2-Theta, 27.5 ±0.2 º2-Theta, and 28.1 ±0.2 º2- Theta as measured using Cu Kα radiation. In some embodiments, crystalline form G of Compound A is characterized as exhibiting an XRPD pattern with all of the peaks at 10.9 ±0.2 º2-Theta, 13.7 ±0.2 º2-Theta, 18.0 ±0.2 º2-Theta, 23.3 ±0.2 º2-Theta, 27.5 ±0.2 º2-Theta, and 28.1 ±0.2 º2-Theta as measured using Cu Kα radiation. In some embodiments, crystalline form G of Compound A is characterized as exhibiting an XRPD pattern with at least three, at least four, at least five, at least six, or all of the peaks at 10.9 ±0.2 º2-Theta, 13.7 ±0.2 º2-Theta, 18.0 ±0.2 º2-Theta, 19.1 ±0.2 º2-Theta 23.3 ±0.2 º2-Theta, 27.5 ±0.2 º2-Theta, and 28.1 ±0.2 º2-Theta as measured using Cu Kα radiation. In some embodiments, crystalline form G of Compound A is characterized as exhibiting an XRPD pattern with all of the peaks at 10.9 ±0.2 º2-Theta, 13.7 ±0.2 º2-Theta, 18.0 ±0.2 º2-Theta, 19.1 ±0.2 º2-Theta 23.3 ±0.2 º2-Theta, 27.5 ±0.2 º2-Theta, and 28.1 ±0.2 º2-Theta as measured using Cu Kα radiation.

[0164] In some embodiments, crystalline form G of Compound A is characterized as exhibiting an XRPD pattern with one or more peaks at 13.7 ±0.2 º2-Theta, 23.3 ±0.2 º2-Theta, and 27.5 ±0.2 º2- Theta as measured using Cu Kα radiation.

[0165] In some embodiments, crystalline form G of Compound A is characterized as exhibiting an XRPD pattern with at least three, at least four, at least five, or all of the peaks at 13.7 ±0.2 º2-Theta, 16.0 ±0.2 º2-Theta, 18.0 ±0.2 º2-Theta, 23.3 ±0.2 º2-Theta, 25.9 ±0.2 º2-Theta, and 27.5 ±0.2 º2- Theta as measured using Cu Kα radiation.

[0166] In some embodiments, crystalline form G of Compound A is characterized as exhibiting an XRPD pattern with at least three, at least six, at least nine, or all of the peaks at 9.1 ±0.2 º2-Theta, 10.9 ±0.2 º2-Theta, 13.7 ±0.2 º2-Theta, 16.0 ±0.2 º2-Theta, 18.0 ±0.2 º2-Theta, 19.1 ±0.2 º2-Theta, 23.3 ±0.2 º2-Theta, 25.9 ±0.2 º2-Theta, 27.5 ±0.2 º2-Theta, 28.1 ±0.2 º2-Theta, 29.7 ±0.2 º2-Theta, and 30.5 ±0.2 º2-Theta as measured using Cu Kα radiation.

[0167] In some embodiments, crystalline form G of Compound A is characterized as exhibiting a Differential Scanning Calorimetry (DSC) thermogram substantially the same as shown in FIG.13.

[0168] In some embodiments, crystalline form G of Compound A is characterized as exhibiting a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak having an onset temperature at about 66 °C.Docket No.51503-768.601

[0169] In some embodiments, crystalline form G of Compound A is characterized as exhibiting a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak at about 95 °C.

[0170] In some embodiments, crystalline form G of Compound A is characterized as exhibiting a Differential Scanning Calorimetry (DSC) thermogram with a broad exothermic event having an onset at about 137 °C.

[0171] In some embodiments, crystalline form G of Compound A is characterized as exhibiting a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as shown in FIG. 18.

[0172] In some embodiments, crystalline form G of Compound A is characterized as exhibiting a Thermogravimetric Thermal Analysis (TGA) thermogram exhibiting a mass loss of about 7.9 % from the onset of heating up to approximately 160 °C.

[0173] In some embodiments, crystalline form G of Compound A is characterized as exhibiting one or more of the following: (a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG.7 as measured using Cu Kα radiation; an XRPD pattern with one or more peaks at 13.7 ±0.2 º2-Theta, 23.3 ±0.2 º2-Theta, and 27.5 ±0.2 º2-Theta as measured using Cu Kα radiation; (b) an XRPD pattern with at least three, at least four, at least five, or all of the peaks at 13.7 ±0.2 º2-Theta, 16.0 ±0.2 º2-Theta, 18.0 ±0.2 º2-Theta, 23.3 ±0.2 º2-Theta, 25.9 ±0.2 º2-Theta, and 27.5 ±0.2 º2- Theta as measured using Cu Kα radiation; (c) an XRPD pattern with peaks at 10.9 ±0.2 º2-Theta, 13.7 ±0.2 º2-Theta, and 23.3 ±0.2 º2-Theta as measured using Cu Kα radiation (d) an XRPD pattern with peaks at 10.9 ±0.2 º2-Theta, 13.7 ±0.2 º2-Theta, and 19.1 ±0.2 º2-Theta as measured using Cu Kα radiation (e) an XRPD pattern with one or more peaks (e.g., all three peaks) at 18.0 ±0.2 º2-Theta, 27.5 ±0.2 º2-Theta, and 28.1 ±0.2 º2-Theta as measured using Cu Kα radiation (f) an XRPD pattern with at least three, at least six, at least nine, or all of the peaks at 9.1 ±0.2 º2-Theta, 10.9 ±0.2 º2- Theta, 13.7 ±0.2 º2-Theta, 16.0 ±0.2 º2-Theta, 18.0 ±0.2 º2-Theta, 19.1 ±0.2 º2-Theta, 23.3 ±0.2 º2- Theta, 25.9 ±0.2 º2-Theta, 27.5 ±0.2 º2-Theta, 28.1 ±0.2 º2-Theta, 29.7 ±0.2 º2-Theta, and 30.5 ±0.2 º2-Theta as measured using Cu Kα radiation; (g) a Differential Scanning Calorimetry (DSC) thermogram substantially the same as shown in FIG.13; (h) a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak having an onset temperature at about 66 °C; (i) a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak at about 95 °C; (j) a Differential Scanning Calorimetry (DSC) thermogram with a broad exothermic event having an onset at about 137 °C; (k) a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as shown in FIG.18; and / or (l) a Thermogravimetric Thermal Analysis (TGA) thermogram exhibiting a mass loss of about 7.9 % from the onset of heating up to approximately 160 °C.

[0174] In some embodiments, crystalline form G of Compound A is characterized as exhibiting an XRPD pattern with one or more peaks listed in the following Table 7 as measured using Cu Kα radiation.Docket No.51503-768.601 Table 7Crystalline Form H of Compound A

[0175] In some embodiments, provided herein is crystalline form H of Compound A. In some embodiments, provided herein is a composition comprising crystalline form H of Compound A.

[0176] In some embodiments, crystalline form H of Compound A is formed from the other solid- state forms described herein, such as form A.

[0177] In some embodiments, crystalline form H of Compound A is formed from the other solid- state forms described herein, such as form A. In some embodiments, crystalline form H of Compound A is the thermodynamically favored solid state form of Compound A.

[0178] In some embodiments, crystalline form H of Compound A is anhydrous. In some embodiments, crystalline form H of Compound A is not solvated. In some embodiments, crystalline form H of Compound A is not hydrated.

[0179] In some embodiments, crystalline form H of Compound A is characterized as having an X- Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG.8 as measured using Cu Kα radiation.

[0180] In some embodiments, crystalline form H of Compound A is characterized as exhibiting an XRPD pattern with one or more peaks at 9.8 ±0.2 º2-Theta, 13.1 ±0.2 º2-Theta, and 27.2 ±0.2 º2- Theta as measured using Cu Kα radiation. In some embodiments, crystalline form H of Compound A is characterized as exhibiting an XRPD pattern with peaks at 9.8 ±0.2 º2-Theta, 13.1 ±0.2 º2-Theta, and 27.2 ±0.2 º2-Theta as measured using Cu Kα radiation.

[0181] In some embodiments, crystalline form H of Compound A is characterized as exhibiting an XRPD pattern with one or more peaks at 4.7 ±0.2 º2-Theta, 9.8 ±0.2 º2-Theta, and 26.5 ±0.2 º2-Theta as measured using Cu Kα radiation.

[0182] In some embodiments, crystalline form H of Compound A is characterized as exhibiting an XRPD pattern with at least three, at least four, at least five, or all of the peaks at 4.2 ±0.2 º2-Theta, 4.7Docket No.51503-768.601 ±0.2 º2-Theta, 9.8 ±0.2 º2-Theta, 13.1 ±0.2 º2-Theta, 15.7 ±0.2 º2-Theta, and 26.5 ±0.2 º2-Theta as measured using Cu Kα radiation.

[0183] In some embodiments, crystalline form H of Compound A is characterized as exhibiting an XRPD pattern with at least three, at least six, at least nine, or all of the peaks at 4.2 ±0.2 º2-Theta, 4.7 ±0.2 º2-Theta, 9.8 ±0.2 º2-Theta, 11.1 ±0.2 º2-Theta, 12.4 ±0.2 º2-Theta, 13.1 ±0.2 º2-Theta, 14.9 ±0.2 º2-Theta, 15.7 ±0.2 º2-Theta, 17.5 ±0.2 º2-Theta, 18.5 ±0.2 º2-Theta, 25.7 ±0.2 º2-Theta, 26.1 ±0.2 º2-Theta, 26.5 ±0.2 º2-Theta, and 27.2 ±0.2 º2-Theta as measured using Cu Kα radiation.

[0184] In some embodiments, crystalline form H of Compound A is characterized as exhibiting a Differential Scanning Calorimetry (DSC) thermogram substantially the same as shown in FIG.14.

[0185] In some embodiments, crystalline form H of Compound A is characterized as exhibiting a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak having an onset temperature at about 73 °C.

[0186] In some embodiments, crystalline form H of Compound A is characterized as exhibiting a Differential Scanning Calorimetry (DSC) thermogram with a weak endothermic event having an onset temperature at about 101 °C.

[0187] In some embodiments, crystalline form H of Compound A is characterized as exhibiting a Differential Scanning Calorimetry (DSC) thermogram with an endothermic event having an onset temperature at about 148 °C.

[0188] In some embodiments, crystalline form H of Compound A is characterized as exhibiting a Differential Scanning Calorimetry (DSC) thermogram with a broad exothermic event having an onset at about 168 °C.

[0189] In some embodiments, crystalline form H of Compound A is characterized as exhibiting a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as shown in FIG. 19.

[0190] In some embodiments, crystalline form H of Compound A is characterized as exhibiting a Thermogravimetric Thermal Analysis (TGA) thermogram exhibiting a mass loss of about 10.0 % from the onset of heating up to approximately 160 °C.

[0191] In some embodiments, crystalline form H of Compound A is characterized as exhibiting one or more of the following: (a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG.8 as measured using Cu Kα radiation; (b) an XRPD pattern with one or more peaks at 4.7 ±0.2 º2-Theta, 9.8 ±0.2 º2-Theta, and 26.5 ±0.2 º2-Theta as measured using Cu Kα radiation; (c) an XRPD pattern with one or more peaks at 9.8 ±0.2 º2-Theta, 13.1 ±0.2 º2-Theta, and 27.2 ±0.2 º2- Theta as measured using Cu Kα radiation (d) 26.1 ±0.2 º2-Theta, 27.2 ±0.2 º2-Theta, and 29.4 ±0.2 º2-Theta (e) 26.1 ±0.2 º2-Theta, 27.2 ±0.2 º2-Theta, and 29.4 ±0.2 º2-Theta (f) an XRPD pattern with at least three, at least four, at least five, or all of the peaks at 4.2 ±0.2 º2-Theta, 4.7 ±0.2 º2-Theta, 9.8 ±0.2 º2-Theta, 13.1 ±0.2 º2-Theta, 15.7 ±0.2 º2-Theta, and 26.5 ±0.2 º2-Theta as measured using Cu Kα radiation; (g) an XRPD pattern with at least three, at least six, at least nine, or all of the peaks atDocket No.51503-768.601 4.2 ±0.2 º2-Theta, 4.7 ±0.2 º2-Theta, 9.8 ±0.2 º2-Theta, 11.1 ±0.2 º2-Theta, 12.4 ±0.2 º2-Theta, 13.1 ±0.2 º2-Theta, 14.9 ±0.2 º2-Theta, 15.7 ±0.2 º2-Theta, 17.5 ±0.2 º2-Theta, 18.5 ±0.2 º2-Theta, 25.7 ±0.2 º2-Theta, 26.1 ±0.2 º2-Theta, 26.5 ±0.2 º2-Theta, and 27.2 ±0.2 º2-Theta as measured using Cu Kα radiation; (h) a Differential Scanning Calorimetry (DSC) thermogram substantially the same as shown in FIG.14; (i) a Differential Scanning Calorimetry (DSC) thermogram with an endothermic event having an onset temperature at about 73 °C; (j) a Differential Scanning Calorimetry (DSC) thermogram with a weak endothermic event having an onset temperature at about 101 °C; (k) a Differential Scanning Calorimetry (DSC) thermogram with an endothermic event having an onset temperature at about 148 °C; (l) a Differential Scanning Calorimetry (DSC) thermogram with a broad exothermic event having an onset at about 168 °C; (m) a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as shown in FIG.19; and / or (n) a Thermogravimetric Thermal Analysis (TGA) thermogram exhibiting a mass loss of about 10.0 % from the onset of heating up to approximately 160 °C.

[0192] In some embodiments, crystalline form H of Compound A is characterized as exhibiting an XRPD pattern with one or more peaks listed in the following Table 8 as measured using Cu Kα radiation. Table 8Docket No.51503-768.601Pharmaceutical Compositions

[0193] In some embodiments, disclosed herein is a pharmaceutical composition comprising a crystalline form of Compound A described herein and at least one pharmaceutically acceptable carrier or excipient.

[0194] In some embodiments, solid state forms of Compound A described herein are formulated into pharmaceutical compositions. In some embodiments, the pharmaceutical composition is formulated in the form of a solid form pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration to a mammal. In some cases, the mammal is human.

[0195] Pharmaceutical compositions can be formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999), herein incorporated by reference for such disclosure.

[0196] In some embodiments, the solid state forms of Compound A described herein are administered either alone or in combination with at least one pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition. Administration of the compounds and compositions described herein can be effected by any method that enables delivery of the compounds to the site of action. Methods of Dosing and Treatment Regimens

[0197] In some embodiments, disclosed herein is a method of treating a condition or a disorder in a subject in need thereof, comprising administering to the subject a crystalline form of Compound A, or a pharmaceutical composition comprising the same. In some embodiments, the crystalline form of Compound A is Form A. In some embodiments, the crystalline form of Compound A is Form B. In some embodiments, the crystalline form of Compound A is Form C. In some embodiments, the crystalline form of Compound A is Form D. In some embodiments, the crystalline form of Compound A is Form E. In some embodiments, the crystalline form of Compound A is Form F. In someDocket No.51503-768.601 embodiments, the crystalline form of Compound A is Form G. In some embodiments, the crystalline form of Compound A is Form H.

[0198] In some embodiments, the subject can benefit from modulation of a small molecule splicing modulator. Methods for treating any of the diseases or conditions described herein in a subject in need of such treatment, involves administration of pharmaceutical compositions that include at least one solid state form of Compound A disclosed herein, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said subject. In some cases, the subject is a mammal. In some cases, the subject is human.

[0199] In some embodiments, Compound A, such as solid state forms of Compound A disclosed herein, are used in the manufacture of a medicament for the treatment of a condition or disease. In some embodiments, the condition or disorder comprises Huntington's disease.

[0200] In some embodiments, disclosed herein is a method of treating Huntington's disease in a subject in need thereof, comprising administering to the subject the solid state form of Compound A (e.g., crystalline form of Compound A or amorphous Compound A) described herein, or the pharmaceutical composition described herein. The crystalline forms of Compound A disclosed herein are useful in the treatment of Huntington’s disease and symptoms thereof. Symptoms of Huntington's disease include choreatic movements, behavioral and psychiatric disturbances and dementia (Roos RA., Orphanet J Rare Dis.2010;5:40.). Huntington’s disease can be associated with a splicing product of the HTT pre-mRNA. In some embodiments, the splicing product of the HTT pre-mRNA is an aberrant splicing product. In some embodiments, the splicing product of the HTT pre-mRNA encodes an aberrant polypeptide. In some embodiments, the splicing product of the HTT pre-mRNA is an aberrant splicing product resulted from a mutation in the HTT gene. In some embodiments, the splicing product of the HTT pre-mRNA may comprise a string of CAG repeats. In some embodiments, the splicing product of the HTT pre-mRNA may comprise an aberrant expansion of a string of CAG repeats. In some embodiments, the splicing product of the HTT pre-mRNA may comprise an aberrant expansion of a string of CAG repeats resulted from a mutation in the HTT gene.

[0201] In one aspect, disclosed herein is a method of modulating splicing comprising contacting the crystalline forms of Compound A of the present disclosure to cells, wherein the compound modulates splicing at a splice site sequence of a pre-mRNA that encodes an mRNA, wherein the mRNA encodes a target protein or a functional RNA. In some cases, the cells are from a subject, such as human.

[0202] In some embodiments, a subject is affected by Huntington’s disease associated with the HTT gene. In some embodiments, a subject is affected by Huntington’s disease associated with a splicing product of the HTT pre-mRNA. In some embodiments, the splicing product of the HTT pre-mRNA is an aberrant splicing product. In some embodiments, the splicing product of the HTT pre-mRNA encodes an aberrant polypeptide. In some embodiments, the splicing product of the HTT pre-mRNA is an aberrant splicing product resulted from a mutation in the HTT gene. In some embodiments, the splicing product of the HTT pre-mRNA may comprise a string of CAG repeats. In someDocket No.51503-768.601 embodiments, the splicing product of the HTT pre-mRNA may comprise an aberrant expansion of a string of CAG repeats. In some embodiments, the splicing product of the HTT pre-mRNA may comprise an aberrant expansion of a string of CAG repeats resulted from a mutation in the HTT gene.

[0203] In some embodiments, described herein is solid state forms of Compound A modifying splicing of gene products, such as HTT pre-m RNA for use in the treatment, prevention, and / or delay of progression of diseases or conditions (e.g., Huntington’s disease). In some embodiments, the present disclosure relates to a pharmaceutical composition comprising solid state forms of Compound A described herein for use in the treatment, prevention, and / or delay of progression of Huntington’s disease. In some embodiments, solid state forms of Compound A described herein can be administered for treatment, prevention, and / or delay of progression of Huntington’s disease.

[0204] Described herein is a composition comprising solid state forms of Compound A modifying splicing of gene products wherein the composition induces a post-transcriptionally unstable variant or transcript of a gene product. Described herein is a solid state form of Compound A modifying splicing of gene products wherein the solid state form of Compound A represses a transcript of a gene product. In some embodiments, an HTT transcript harbors a poison exon. In some embodiments, the poison exon results in a frame-shift in a downstream exon, for example in an exon immediately following the poison exon. In some embodiments, the frame-shift in a downstream exon contains an in-frame stop codon that would not be in frame in the absence of inclusion of the poison exon. In some embodiments, the poison exon comprises an in-frame premature termination codon (PTC). In some embodiments, the poison exon triggers nonsense-mediated decay (NMD) and degradation of the transcript. In some embodiments, the gene product is HTT.

[0205] In some embodiments, Compound A, e.g., the solid state forms of Compound A and methods of use described herein can modulate splicing, such as alternative splicing of a polynucleotide encoded by HTT gene. In some embodiments, alternative splicing of the HTT pre-mRNA may lead to the expression of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 isoforms of the huntingtin protein. In some embodiments, the HTT gene may comprise a mutation. In some embodiments, the HTT gene may comprise a mutation associated with expansion of a CAG repeat. In some embodiments, the splice modulating compounds and methods of use described herein can modulate splicing of the HTT pre- mRNA that lead to inclusion of a cryptic exon (e.g., a poison exon) that is normally not included in the HTT spliced product, e.g., mRNA. In some embodiments, the cryptic exon (e.g., a poison exon) included in the HTT spliced product may lead to degradation of the HTT spliced product through nonsense-mediated decay (NMD) mediated RNA degradation. In some embodiments, alternative splicing of the HTT pre-mRNA can lead to inclusion of a cryptic exon that is not normally included in between exon 49 and exon 50 of the HTT mRNA. In some embodiments, alternative splicing of the HTT pre-mRNA can promote the inclusion of a poison exon 49b. In some embodiments, the HTT pre-mRNA comprises the sequence AGAguaaggg (SEQ ID NO: 1). In a preferred embodiment, the compounds described herein bind to the 5’ss sequence AGAguaaggg (SEQ ID NO: 1).Docket No.51503-768.601

[0206] In some embodiments, the compositions containing the solid state forms of Compound A described herein are administered for prophylactic and / or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and / or dose ranging clinical trial.

[0207] The amount suitable for administration of the solid state forms of Compound A or compositions described herein to a subject in need thereof corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.

[0208] In various embodiments, the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

[0209] Other embodiments and uses will be apparent to one skilled in the art in light of the present disclosures. The following examples are provided merely as illustrative of various embodiments and shall not be construed to limit the invention in any way. Definitions

[0210] Unless otherwise stated, the following terms used in this application have the definitions given below.

[0211] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study.

[0212] The terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms,Docket No.51503-768.601 inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition.

[0213] If multiple diffraction patterns are available, then assessments of particle statistics (PS) and / or preferred orientation (PO) are possible. Consistency of relative intensity among XRPD patterns from multiple diffractometers indicates good orientation statistics. Alternatively, the observed XRPD pattern may be compared with a calculated XRPD pattern based upon a single crystal structure, if available. Two-dimensional scattering patterns using area detectors can also be used to evaluate PS / PO. If the effects of both PS and PO are determined to be negligible, then the XRPD pattern is representative of the powder average intensity for the sample and prominent peaks may be identified as “Representative Peaks.” In general, the more data collected to determine Representative Peaks, the more confident one can be of the classification of those peaks.

[0214] “Characteristic peaks,” to the extent they exist, are a subset of representative peaks and are used to differentiate one crystalline polymorph from another crystalline polymorph (polymorphs being crystalline forms having the same chemical composition). Characteristic peaks are determined by evaluating which representative peaks, if any, are present in one crystalline polymorph of a compound against all other known crystalline polymorphs of that compound to within ±0.2 º2-Theta. Not all crystalline polymorphs of a compound necessarily have at least one characteristic peak.

[0215] The term “preferred orientation” as used herein refers to an extreme case of non-random distribution of the crystallites of a solid state form. In XRPD, the ideal sample is homogenous and the crystallites are randomly distributed in the bulk solid. In a truly random sample, each possible reflection from a given set of planes will have and equal number of crystallites contributing to it. However, when the solid state form is in a preferred orientation this is not the case. Accordingly, comparing the intensity between a randomly oriented diffraction pattern and a preferred oriented diffraction pattern can look entirely different. Quantitative analysis depending on intensity ratios are greatly distorted by preferred orientation. Careful sample preparation is important for decreasing the incidence of a preferred orientation.

[0216] The term “substantially the same,” as used herein to reference a figure is intended to mean that the figure is considered representative of the type and kind of characteristic data that is obtained by a skilled artisan in view of deviations acceptable in the art. Such deviations may be caused by factors related to sample size, sample preparation, particular instrument used, operation conditions, and other experimental condition variations known in the art. For example, one skilled in the art can appreciate that the endotherm onset and peak temperatures as measured by differential scanning calorimetry (DSC) may vary significantly from experiment to experiment. For example, one skilled in the art can readily identify whether two X-ray diffraction patterns or two DSC thermograms are substantially the same. In some embodiments, when characteristic peaks of two X-ray diffractionDocket No.51503-768.601 patterns do not vary more than ±0.2° 2-Theta, it is deemed that the X-ray diffraction patterns are substantially the same.

[0217] The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary e.g., no more than 15% of the stated number or numerical range. EXAMPLES

[0218] Abbreviations: HPLC-UV = High Performance Liquid Chromatography-Ultraviolet Detection NMR = nuclear magnetic resonance NS = no solids RH = relative humidity TLM = too little material v / v = volume ratio w / w = weight ratio 1-PrOH = 1-propanol 2-methyl THF = 2-methyltetrahydrofuran ACN = acetonitrile DCM = dichloromethane, methylene chloride DIPE = diisopropyl ether DMAc = N,N-dimethylacetamide DMF = N,N-dimethylformamide DMSO = dimethylsulfoxide EtOAc = ethyl acetate EtOH = ethanol IPAc = isopropyl acetate MEK = methylethyl ketone MeOH = methanol MIBK = methylisobutyl ketone MTBE = methyl tert-butyl ether NMP = N-Methyl-2-pyrrolidon t-BuOH = tert-butanol THF = tetrahydrofuran tol = toluene mL = milliliter(s) μL = microliter(s)Docket No.51503-768.601

[0219] The following examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein. Stereochemistry

[0220] (±) or racemic indicates that the product is a racemic mixture of enantiomers. For example (±) (1S,2S,3R,5R) or racemic (1S,2S,3R,5R) indicates that the relative product stereochemistry shown is based on known stereochemistry of similar compounds and or reactions and the product is a racemic mixture of enantiomers of both (1S,2S,3R,5R) and (1R,2R,3S,5S) stereoisomers. A compound in which the absolute stereochemistry of separated enantiomers is undetermined is represented as being either of the single enantiomers, for example (1S,2S,3R,5R) or (1R,2R,3S,5S) or drawn as being either possible single enantiomer. In such cases, the product is pure and a single enantiomer, but absolute stereochemistry is not identified, but relative stereochemistry is known and indicated. Example 1: Synthesis of Compound A

[0221] Compound A (also shown as Structure B) can be made by the process described as follows.

[0222] Synthesis of 2-amino-4-methoxyphenol.

[0223] A mixture of 4-methoxy-2-nitrophenol (25.0 g, 0.15 mol) and Pd / C (2.5 g) in MeOH (500 mL) was stirred, degassed with hydrogen 3 times and then held with stirring at 20oC under hydrogen for 2 d. The reaction mixture was filtered and the cake was washed with MeOH (350 mL*3). TheDocket No.51503-768.601 filtrated was combined and concentrated in vacuum to afford the product 2-amino-4-methoxyphenol as brown solid (20.0 g, yield 97.2 %). LCMS: m / z 140.1 [M+H]+; tR= 0.93 min.

[0224] Synthesis of 5-methoxy-2-methylbenzo[d]oxazole.

[0225] A mixture of 2-amino-4-methoxyphenol (20.0 g, 0.14 mol) in trimethyl orthoacetate (50 mL) was heated to 100oC with stirring and held for 1 h. The mixture was concentrated and the residue was purified by combi-flash (Biotage, Silica gel column, 330 g, 60 mL / min, EA in PE 0 % ~ 35 %, 30 min, 35 %, 12 min, UV 254280) to give the desired product 5-methoxy-2-methylbenzo[d]oxazole as orange oil (17.5 g, yield 74.6 %). LCMS: m / z 164.1 [M+H]+;= 1.41 min.

[0226] Synthesis of 6-bromo-5-methoxy-2-methylbenzo[d]oxazole.

[0227] NBS (19.6 g, 0.11 mol) was added to a mixture of 5-methoxy-2-methylbenzo[d]oxazole (17.5 g, 0.11 mol) in AcOH (150 mL). This resulting mixture was stirred at 20oC for 18 h. The mixture was quenched with ice water, neutralized with Na2CO3 aqueous, extracted with EtOAc (200 mL*3). The extracts were concentrated and the residue was purified by combi-flash (Biotage, Silica gel column, 330 g, 60 mL / min, EA in PE 0 % ~ 10 %, 30 min, 20 %, 15 min, UV 254280) to give the desired product 6-bromo-5-methoxy-2-methylbenzo[d]oxazole as pink solid (20.5 g, yield 77.0 %). LCMS: m / z 242.1; 243.9 [M+H]+; tR = 1.70 min.1H NMR (500 MHz, CDCl3-d3) δ 7.68 (s, 1H), 7.17 (s, 1H), 3.93 (s, 3H), 2.61 (s, 3H).

[0228] Synthesis of 6-bromo-2-methylbenzo[d]oxazol-5-ol.

[0229] BBr3 (210 mL, 1 mol / l, 0.21 mol) was added to a mixture of 6-bromo-5-methoxy-2- methylbenzo[d]oxazole (20.5 g, 0.085 mol) in DCM (30 mL) at 0oC. This resulting mixture was stirred at 0oC for 10 min and then warmed to 20oC with stirring and held for 3 d. The mixture was quenched with ice water, neutralized with NaHCO3 aqueous, extracted with EtOAc (360 mL*3). The extracts were concentrated and the residue was purified by combi-flash (Biotage, Silica gel column, 330 g, 80 mL / min, EA in PE 0 % ~ 50 %, 30 min, 40 %, 10 min, then MeOH in DCM 20% UV 254 280) to give the desired product 6-bromo-2-methylbenzo[d]oxazol-5-ol as grey solid (19.0 g, yield 98.6230.0 [M+H]+; tR = 1.50 min.

[0230] Synthesis of 6-bromo-5-(methoxymethoxy)-2-methylbenzo[d]oxazole.Docket No.51503-768.601

[0231] MOMBr (15.6 g, 0.12 mol) was added drop wise to a mixture of 6-bromo-2- methylbenzo[d]oxazol-5-ol (19.0 g, 0.08 mol) and DIPEA (37.7 g, 0.19 mol) in ACN (300 mL) at 5oC. This resulting mixture was stirred at 5oC and held for 30 min. The mixture was quenched with ice water, extracted with EtOAc (200 mL*3). The extracts were washed with brine (300 mL) and concentrated. The residue was purified by combi-flash (Biotage, Silica gel column, 330 g, 60 mL / min, EA in PE 0 % ~ 15 %, 20 min, 15 %, 5 min, 15 % ~ 25 %, 10 min, 25 %, 15 min, UV 254280) to give the desired product 6-bromo-5-(methoxymethoxy)-2-methylbenzo[d]oxazole as pink solid (18.0 g, yield 79.5 %). LCMS:274.0 [M+H]+; tR= 1.77 min.

[0232] Synthesis of 5-(methoxymethoxy)-2-methyl-6-(4, 4, 5, 5-tetramethyl-1, 3, 2- dioxaborolan-2-yl)benzo[d]oxazole.

[0233] A mixture of 6-bromo-5-(methoxymethoxy)-2-methylbenzo[d]oxazole (50 g, 0.02 mol), pinaolboron (28.0 g, 0.11 mol), PdCl2dppf (1.1 g, 1.5 mmol)and KOAc (10.8 g, 0.11 mol) in 1, 4- dioxane (300 mL) was heated to 100oC with stirring and held for 50 h. The mixture was quenched with ice water, extracted with EtOAc (200 mL*3). The extracts were washed with brine (200 mL) and concentrated. The residue was purified by combi-flash (Biotage, Silica gel column, 20 g, 30 mL / min, EA in PE 0 % ~ 15 %, 20 min, 15 %, 6 min, 15 % ~ 25 %, 15 min, 25 %, 10 min , UV 254280) to give the desired product 5-(methoxymethoxy)-2-methyl-6-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan- 2-yl)benzo[d]oxazole as pink solid (4.0 g, yield 68.2 %). LCMS: m / z 320.2 [M+H]+; tR = 1.86 min.

[0234] Synthesis of tert-butyl (1S,2S,5R)-2-fluoro-3-oxo-9-azabicyclo[3.3.1]nonane-9- carboxylate.

[0235] LHMDS (94 mL, 94 mmol, 1 N solution in THF) was added to a stirred solution of tert-butyl 3-oxo-9-azabicyclo[3.3.1]nonane-9-carboxylate (15 g, 62.8 mmol) in 150 mL of anhydrous THF at - 78oC under nitrogen atmosphere. After stirring for 30 min, NFSI (26.6 g, 75 mmol) in 100 mL of anhydrous THF was added dropwise. The mixture was then stirred at -78oC for 4 h, quenchend with saturated NH4Cl aqueous solution (30 mL), estracted with EtOAc (80 mL X 3). The combined organic phases were dried over anhydrous Na2SO4, conentrated and purified by silica gel chromatography (0- 5% EtOAc / petroleum ether) to give 6.5 g of tert-butyl (1S,2S,5R)-2-fluoro-3-oxo-9- azabicyclo[3.3.1]nonane-9-carboxylate as a white solid (40% yield). LCMS: m / z 202.1 [M-55]+; tR= 1.75 min.Docket No.51503-768.601

[0236] Synthesis of tert-butyl (1S,2S,5R)-2-fluoro-3-(methylimino)-9-azabicyclo[3.3.1]nonane-9- carboxylate.

[0237] Methylamine (58.5 mL, 117 mmol, 2N solution in THF) and Ti(iPrO)4(32.8 g, 117 mmol) were added to a stirred solution of tert-butyl (1S,2S,5R)-2-fluoro-3-oxo-9-azabicyclo[3.3.1]nonane-9- carboxylate (20 g, 77 mmol) in THF (1 L) under N2protection. The reaction mixture was stirred at room temperature for 2 h. Water (1 L) was added to quench the reaction. The mixture was extracted with EtOAc (1L X 3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4and concentrated to give the crude product (1S,2S,5R)-2-fluoro-3-(methylimino)-9- azabicyclo[3.3.1]nonane-9-carboxylate (20 g, 95% yield), which was directly used in next step. LCMS: m / z 271.2 [M+H]+; tR = 1.58, 1.80 min.

[0238] Synthesis of tert-butyl (1S,2R,3R,5R)-2-fluoro-3-(methylamino)-9- azabicyclo[3.3.1]nonane-9-carboxylate.

[0239] NaBH4 (4 g, 104 mmol) was added to a stirred solution of (1S,2S,5R)-2-fluoro-3- (methylimino)-9-azabicyclo[3.3.1]nonane-9-carboxylate (7 g, 26 mmol) and MgCl2 (2.46 g, 26 mmol) in 30 mL of MeOH. After the addition, the mixture was stirred at room temperature for 2 h. Additional NaBH4 may be needed till LCMS indicated the imine was consumed completely.100 mL of water was added to quench the reaction. The resulting mixture was extracted with EtOAc (180 mL X 3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, concentrated and purified by silica gel chromatography (0-5% MeOH / CH2Cl2) give 2 g of tert-butyl (1S,2R,3R,5R)-2-fluoro-3-(methylamino)-9-azabicyclo[3.3.1]nonane-9-carboxylate as colorless oil (40% yield), (high polar isomer). LCMS: m / z 273.2 [M+H]+; tR = 1.42 min.

[0240] Synthesis of tert-butyl (1S,2R,3R,5R)-3-((6-chloropyridazin-3-yl)(methyl)amino)-2- fluoro-9-azabicyclo[3.3.1]nonane-9-carboxylate.

[0241] A mixture of tert-butyl (1S,2R,3R,5R)-2-fluoro-3-(methylamino)-9-azabicyclo[3.3.1]nonane- 9-carboxylate (2 g, 7.35 mmol), 3,6-dichloropyridazine (2.19 g, 14.7 mmol) and DIPEA (3.8 g, 29.4 mmol) in DMSO (10 ml) was stirred at 1200C for 12 h. After cooling to room temperature, theDocket No.51503-768.601 mixture was quenched with H2O (100 mL) and extracted with EtOAc (150 mL X 3). The combined organic layers were concentrated and purified with silica gel chromatography (0-50% EtOAc / petroleum ether) to give 1.5 g of tert-butyl (1S,2R,3R,5R)-3-((6-chloropyridazin-3- yl)(methyl)amino)-2-fluoro-9-azabicyclo[3.3.1]nonane-9-carboxylate white solid (54% yield). LCMS: m / z 385.2 [M+H]+; tR= 1.93 min.

[0242] Chiral separation of tert-butyl (1S,2R,3R,5R)-3-((6-chloropyridazin-3- yl)(methyl)amino)-2-fluoro-9-azabicyclo[3.3.1]nonane-9-carboxylate.

[0243] 1500 mg of racemic intermediate was separated by below chiral condition to give 630 mg of P1 isomer (1.596 min) and 630 mg of P2 isomer (4.811 min).

[0244] Instrument: SFC-150 (Waters) Column: AD 20*250mm, 10um (Daicel) Column temperature: 35 ºC Mobile phase: CO2 / MEOH(0.2%Methanol Ammonia) = 65 / 35 Flow rate: 100 g / min Back pressure: 100 bar Detection wavelength: 214 nm Cycle time: 3.5min Sample solution: 1500mg dissolved in 100ml Methanol Injection volume: 3ml

[0245] Synthesis of tert-butyl (1S,2R,3R,5R)-2-fluoro-3-((6-(5-(methoxymethoxy)-2- methylbenzo[d]oxazol-6-yl)pyridazin-3-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9- carboxylate.

[0246] A mixture of tert-butyl (1S,2R,3R,5R)-3-((6-chloropyridazin-3-yl)(methyl)amino)-2-fluoro-9- azabicyclo[3.3.1]nonane-9-carboxylate (450 mg, 1.17 mmol), 5-(methoxymethoxy)-2-methyl-6-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)benzo[d]oxazole (560 mg, 1.76 mmol), Pd(dppf)Cl2(86 mg ， 0.117 mmol) and K2CO3 (324 mg, 2.34 mmol) in 1,4-Dioxane (15 mL), water (5 ml) was stirred at 1100C for 2 h under N2 atmosphere. After cooling to room temperature, the mixture was concentratedDocket No.51503-768.601 and purified by silica gel chromatography (0-50% EtOAc / petroleum ether) to give 550 mg of tert- butyl (1S,2R,3R,5R)-2-fluoro-3-((6-(5-(methoxymethoxy)-2-methylbenzo[d]oxazol-6-yl)pyridazin-3- yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate (86% yield). LCMS: m / z 541.9 [M+H]+; tR= 1.98 min.

[0247] Synthesis of 6-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3- yl)(methyl)amino)pyridazin-3-yl)-2-methylbenzo[d]oxazol-5-ol.

[0248] To a solution of tert-butyl (1S,2R,3R,5R)-2-fluoro-3-((6-(5-(methoxymethoxy)-2- methylbenzo[d]oxazol-6-yl)pyridazin-3-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate (550 mg, 1.02 mmol) in CH2Cl2(7 mL) was added TFA (3 mL) and the mixture was stirred at room temperature for 2 h, monitored by LCMS. Then the mixture was concentrated and water (10 mL) was added. pH value was adjusted to 8-9 with saturated K2CO3aqueous solution. The product was collected，concentrated and purified by C18 reversed phase column (0-70% 0.01% NH4HCO3in H2O / CH3OH) to give 166 mg of 6-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3- yl)(methyl)amino)pyridazin-3-yl)-2-methylbenzo[d]oxazol-5-ol (41% yield).1H NMR (400 MHz, MeOD –d4) δ 8.17 (d, J = 9.9 Hz, 1H), 7.98 (s, 1H), 7.32 (d, J = 9.9 Hz, 1H), 7.10 (s, 1H), 6.01 – 5.86 (m, 1H), 5.07 – 4.90 (m, 1H), 3.57 – 3.47 (m, 2H), 3.11 (s, 3H), 2.71 – 2.64 (m, 1H), 2.62 (s, 3H), 2.15 – 2.02 (m, 3H), 1.97 – 1.78 (m, 4H). LCMS: m / z 398.1 [M+H]+; tR= 1.40 min.

[0249] Synthesis of tert-butyl (1R,2S,3S,5S)-2-fluoro-3-((6-(5-(methoxymethoxy)-2- methylbenzo[d]oxazol-6-yl)pyridazin-3-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9- carboxylate.

[0250] A mixture of tert-butyl (1R,2S,3S,5S)-3-((6-chloropyridazin-3-yl)(methyl)amino)-2-fluoro-9- azabicyclo[3.3.1]nonane-9-carboxylate (450 mg, 1.17 mmol), 5-(methoxymethoxy)-2-methyl-6-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)benzo[d]oxazole (560 mg, 1.76 mmol), Pd(dppf)Cl2 (86 mg ， 0.117 mmol) and K2CO3(324 mg, 2.34 mmol) in 1,4-Dioxane (15 mL), water (5 ml) was stirred at 1100C for 2 h under N2atmosphere. After cooling to room temperature, the mixture was concentrated and purified by silica gel chromatography (0-50% EtOAc / petroleum ether) to give 500 mg of tert- butyl (1R,2S,3S,5S)-2-fluoro-3-((6-(5-(methoxymethoxy)-2-methylbenzo[d]oxazol-6-yl)pyridazin-3-Docket No.51503-768.601 yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate (79% yield). LCMS: m / z 541.9 [M+H]+;(Compound A)

[0252] To a solution of tert-butyl (1R,2S,3S,5S)-2-fluoro-3-((6-(5-(methoxymethoxy)-2- methylbenzo[d]oxazol-6-yl)pyridazin-3-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate (500 mg, 0.92 mmol) in CH2Cl2(7 mL) was added TFA (3 mL) and the mixture was stirred at room temperature for 2 h, monitored by LCMS. Then the mixture was concentrated and water (10 mL) was added. pH value was adjusted to 8-9 with saturated K2CO3aqueous solution. The product was collected，concentrated and purified by C18 reversed phase column (0-70% 0.01% NH4HCO3in H2O / CH3OH) to give 133 mg of 6-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3- yl)(methyl)amino)pyridazin-3-yl)-2-methylbenzo[d]oxazol-5-ol (36% yield).1H NMR (400 MHz, MeOD –d4) δ 8.17 (d, J = 9.9 Hz, 1H), 7.98 (s, 1H), 7.32 (d, J = 9.9 Hz, 1H), 7.10 (s, 1H), 6.01 – 5.86 (m, 1H), 5.07 – 4.90 (m, 1H), 3.57 – 3.47 (m, 2H), 3.11 (s, 3H), 2.71 – 2.64 (m, 1H), 2.62 (s, 3H), 2.15 – 2.02 (m, 3H), 1.97 – 1.78 (m, 4H). LCMS: m / z 398.1 [M+H]+; tR= 1.40 min. Example 2: Solvent Solubility Study of Compound A

[0253] The starting material Compound A was provided in three batches, batch AM-1 (1 g), batch AM-2 (7 g, or AM-3, the dried batch of AM-2), and batch AM-4 (10 g) respectively.

[0254] In this study, the solubility of Compound A was manunally assessed in solvents that are relevant to potential process scale-up and toxicity of the solvents were considered as well. The investigations to the solubility were limited to range between 5 mg / mL and 200 mg / mL, which is the relevant range for production. To assess the solubility of Compound A, a small amount of starting material (AM-3) was weighed in (~10 mg) and discrete amounts of solvent was added in sequential steps. The vials were then analysed optically to determine whether Compound A had dissolved. The results are listed in Table 9.

[0255] The pharmacopeial definitions of solubility are as follows; Practically insoluble (<0.1 mg / mL) Very slightly soluble (0.1-1 mg / mL) Slightly soluble (1-10 mg / mL) Sparingly soluble (10-33.3 mg / mL)Docket No.51503-768.601 Soluble (33.3-100 mg / mL) Freely soluble (100 mg-1 g / mL) Very soluble (>1 g / mL)

[0256] Solvents in which the solubility is classified as sparingly soluble are generally suitable for recrystallization. Those that are classified as slightly soluble are suitable for slurry experiments. Those with a lower solubility of the Compound A molecule are suitable antisolvents. Table 9. Soluibility of Compound A in different solventsDocket No.51503-768.601

[0257] The solubility was found to depend on the batch that was investigated, which is likely relating to residual solvent. The batch that was used for the solubility study contained relatively much water, even after drying. A batch with less residual water present had a lower solubility in methanol, for example. Example 3: Polymorph Screen of Compound A

[0258] A polymorph screen was performed to determine whether different forms of Compound A could be produced and the relative stability of the different forms. The new forms were also analysed to find out whether they are new polymorphs or solvates. The relative stabilities of the different forms and their interconversion was determined, by way of competitive slurry experiments. The polymorph screen consisted of antisolvent crystallization experiments using three different solvents (methanol, 1- propanol, and dichloromethane) and a range of antisolvents that were investigated in the solubility study and have a suitably low Compound A solubility. Only combinations were used where solvent and antisolvent mix. Subsequently, solvents were evaporated, either to dry the sample, or induce crystallization if nothing had crystallized. Additionally, in those experiments where crystallization took place, cooling crystallization was employed using the same mixture of ingredients. Solids were characterized using XRPD. New forms were scaled-up and analysed further using DSC, and TGA. Antisolvent Crystallization

[0259] In the antisolvent crystallization experiments, a saturated solution of Compound A was prepared and antisolvent was added to alter the solubility. In those experiments where the solubility decreases (despite of the increasing volume), solids will precipitate immediately, or crystallize over time. Experiments were allowed to crystallize for a maximum of 24 hours. Due to the different chemical environments (different solvents used) other forms can be obtained. The experiments are listed in Table 10. The combinations without an entry are of solvent combinations that do not mix, hence these experiments were not conducted.Docket No.51503-768.601 Table 10. Antisolvent experiments conducted in the polymorph screening of Compound A

[0260] The experiments conducted with methanol as a solvent used 300 µL of saturated solution and 1.5 mL of antisolvent, in the remaining experiments, 2 mL of solvent as well as antisolvent were used. In two experiments, immediate precipitation was observed, in 18 experiments crystallization was observed within one day, and in the remaining experiments, solids were obtained through evaporation. The solids were analysed using XRPD and the results are listed in Table 11. The starting material (and its XRPD pattern) has been defined as form A. In cases where the result is unclear, there are several (weak) diffraction peaks present in the XRPD pattern. A / o signifies that there are diffraction peaks present that overlap with form A, as well as peaks that do not overlap. The combinations without an entry are of solvent combinations that do not mix, hence these experiments were not conducted.Docket No.51503-768.601 Table 11. XRPD results from the antisolvent / evaporative crystallization analysis of Compound A

[0261] The XRPD patterns of all new forms that were found in the polymorph screen are shown in FIG.9.

[0262] Several experiments were scaled up, i.e., those where a new crystalline form was detected, or in case the outcome of the crystallization experiment might have produced a new form (in case of an unclear outcome). These conditions are listed in Table 12. The obtained solids were analysed using XRPD, TGA, and DSC to determine whether a new crystalline form has been produced and whether this is a solvate or not. Table 12 shows the crystalline form that was observed in both the small-scale and scaled-up experiments. Table 12. XRPD results of various crystalline forms of Compound A obtained from both small- scale (shown in normal font) and scale up experiments (shown in italic and bold font)Docket No.51503-768.601

[0263] Table 13 shows the results of the TGA experiments of the materials that were obtained in the scale-up experiments. The first column shows the solvent and antisolvent that were used in the scale- up experiment. The obtained crystalline form is indicated and the mole equivalents of each solvent / antisolvent that corresponds to the mass loss observed in the TGA experiment is shown as well. A second step indicates that the weight loss of the material occurred in two distinct regimes during heating in the TGA experiment. The mole equivalents of solvent and antisolvent that correspond to the weight loss are provided in the table. Table 13. TGA results of various crystalline forms of Compound A obtained from scale up experimentsDocket No.51503-768.601Cooling crystallization

[0264] Cooling crystallization experiments were conducted using the solvent combinations that produced precipitates in the antisolvent crystallization experiments. The solutions were placed in HPLC vials and transferred into a Crystal-16. The temperature ramp was as follows; heating to 40 °C in the cases of methanol and 1-propanol, and 35 °C in the cases where dichloromethane was used as a solvent. This temperature was kept for 30 minutes, after which the temperature was decreased to -25 °C with a cooling rate of 10 °C / h, after which the samples were heated to 20 °C in an hour. Table 14 shows the crystalline forms that were obtained in the cooling crystallization experiments. Empty fields correspond to conditions that were not tested. Table 14. Cooling crystallization experimental resultsDocket No.51503-768.601 Competitive slurry experiments

[0265] Competitive slurry experiments were conducted to find the most stable crystalline form. The starting material in most of these experiments was form A (from the provided material). A saturated solution of this material (a slurry) was prepared. Subsequently, several milligrams of solids from scale-up experiments (column 2 in Table 15) were added and left to equilibrate for at least one day (column 4).

[0266] The influence of solvent on the obtained final form was investigated in several initial experiments, to select a suitable solvent for the competitive slurry experiments. Saturated solutions were prepared in methanol, dichloromethane, and 1-propanol with form A (starting material) and left to slurry for one day. The solvents were then evaporated at ambient atmospheric conditions and the solids were analysed using XRPD. In each case, the crystalline form was altered. In 1-propanol, the material transformed into form B, in methanol, the material became mostly amorphous, while the material lost some of its crystallinity in dichloromethane.

[0267] Then, how long a form conversion took was further investigated. The first four entries of Table 15 and the second four differ only in that the solids were extracted one day later. It can be seen that the material that was stirred in 2-methyl THF underwent a transformation from form B into form D. Table 15. Crystalline forms obtained in the competitive slurry experiments.Docket No.51503-768.601Am = amorphousDocket No.51503-768.601

[0268] These new crystalline forms were identified using XRPD and analysed with optical microscopy. In case the same crystalline form was obtained in scale-up experiments, they were also analysed with DSC and TGA. Form F was analysed using single-crystal X-ray diffraction, which revealed a tetrahydrate structure of Compound A. Form A

[0269] Compound A as received is a crystalline solid with a yellow / brown colour. The material was designated as polymorphic form A. Compound A was found to reversibly form a hydrate at higher relative humidity levels (>70 % RH). However, the material becomes amorphous when the hydrate reverts back into the anhydrate upon drying or after DVS analysis between 0% and 90% RH (FIG. 1E). Compound A decomposes before it melts starting at approximately 170 °C. Form B

[0270] Form B was produced under a wide variety of conditions (see Table 11 and Table 12).

[0271] The solubility of form B was determined in aqueous buffer solutions (H3PO4 buffer at pH 6.8 and H2CO3 buffer at pH 10.8) to be <1 mg / mL. Form C

[0272] Form C was only produced in one experiment, using dichloromethane as a solvent and heptane as antisolvent. This crystalline form was not obtained in the scale-up experiment, or in the scale-up experiment where the experiment was seeded with crystals from the small-scale experiment. Form D

[0273] Form D was produced under a wide variety of conditions (see Table 11 and Table 12).

[0274] The solubility of form D was determined in aqueous buffer solutions (H3PO4 buffer at pH 6.8 and H2CO3 buffer at pH 10.8) to be <1 mg / mL. Form E

[0275] Form E was only produced in one experiment, using methanol as a solvent and water as antisolvent. This crystalline form was not obtained in the scale-up experiment. Since the material precipitated immediately on adding the antisolvent, seed crystallization was not considered. Form F

[0276] Form F was obtained in the cooling crystallization experiments, under two conditions, using dichloromethane as a solvent and 2-methyl THF as antisolvent, and using 1-propanol as solvent and isopropyl acetate as antisolvent. Single-crystal X-ray diffraction indicates that this form is a tetrahydrate. The scale-up experiment conducted to try to produce larger quantities of form F produced form B. Form G

[0277] Form G was produced in one of the scale-up experiments, using 1-propanol as solvent and methyl isobutyl ketone as an antisolvent.Docket No.51503-768.601 Form H

[0278] Form H was produced in one of the scale-up experiments, using methanol as solvent and tert- butanol as an antisolvent. Example 4: X-Ray Powder Diffraction (XRPD)

[0279] Although the following diffractometers were used, other types of diffractometers could be used. Furthermore, other wavelengths could be used and converted to the Cu Kα. In some embodiments, Synchrotron Radiation X-Ray Powder Diffraction (SR-XRPD) can be used to characterize the crystalline forms.

[0280] Diffraction patterns were measured using a Thermo Fisher Scientific ARL Equinox 1000 powder diffractometer. The diffractometer is equipped with a copper source and a germanium (111) monochromator providing monochromatic Cu-Kα1 radiation, and a position sensitive gas-ionization detector.

[0281] Samples were measured in reflection mode using capillaries with a diameter of 1 mm without any further preparation (i.e., grinding). The detector measures over the entire angle range from approx.2° (2θ) to 120° (2θ) via continuous sampling. The temperature in the diffractometer was typically around 30 °C during measurements. The exposure time was one hour. The voltage and current for the measurements were 40 kV and 40 mA. Symphonix software was used for data collection. Data analysis was performed using the program Match! Version 3.15 build 247. Characterization of crystalline form A of Compound A

[0282] The X-Ray powder diffraction pattern for crystalline form A of Compound A is displayed in FIGs.1A-1D. All three batches of the starting material have the same crystalline form—batch AM-1 in FIG.1A, AM-2 in FIG.1B, AM-3 (the dried batch of AM-2) in FIG.1D, and AM-4 in FIG.1C. XRPD peaks of Form A include the peaks listed in Table 1. Characterization of crystalline form B of Compound A

[0283] The X-Ray powder diffraction pattern for crystalline form B of Compound A is displayed in FIG.2. XRPD peaks of Form B include the peaks listed in Table 2. Characterization of crystalline form C of Compound A

[0284] The X-Ray powder diffraction pattern for crystalline form C of Compound A is displayed in FIG.3. XRPD peaks of Form C include the peaks listed in Table 3. Characterization of crystalline form D of Compound A

[0285] The X-Ray powder diffraction pattern for crystalline form D of Compound A is displayed in FIG.4. XRPD peaks of Form D include the peaks listed in Table 4.

[0286] Characterization of crystalline form E of Compound A

[0287] The X-Ray powder diffraction pattern for crystalline form E of Compound A is displayed in FIG.5. XRPD peaks of Form E include the peaks listed in Table 5.Docket No.51503-768.601 Characterization of crystalline form F of Compound A

[0288] The X-Ray powder diffraction pattern for crystalline form F of Compound A is displayed in FIG.6. XRPD peaks of Form F include the peaks listed in Table 6. Characterization of crystalline form G of Compound A

[0289] The X-Ray powder diffraction pattern for crystalline form G of Compound A is displayed in FIG.7. XRPD peaks of Form G include the peaks listed in Table 7. Characterization of crystalline form H of Compound A

[0290] The X-Ray powder diffraction pattern for crystalline form H of Compound A is displayed in FIG.8. XRPD peaks of Form H include the peaks listed in Table 8. Characterization of Amorphous Compound A

[0291] The X-Ray powder diffraction pattern for amorphous Compound A is produced in Example 3, after DVS was conducted for crystalline form A, which is displayed in FIG.1E. The XRPD shows a lack of crystallinity. Example 5: Melting Point Determination (MP)

[0292] The melting temperature (or temperature range) was evaluated using a Stuart automatic melting point |SMP50| (Cole-Parmer) device. The melting point is automatically determined by the software of the equipment based on the change of light intensity which passes through three capillary tubes (SMP 10 / 1) filled with the sample. The height of the samples inside the capillaries was approx. 5-7 mm.

[0293] Only one capillary was filled for melting point analysis. The capillaries have one end open to the atmosphere. The capillaries were typically heated with 1 K min-1 starting at 180 °C. In some cases, the initial temperature turned out to be too high, and a lower initial temperature was selected accordingly.

[0294] Form A does not show a melting point prior to decomposition. The material discolours around 170 °C and turns black around 205 °C.

[0295] The melting point of form B and form D were also determined, however, as with the starting material, chemical degradation precedes the melting point and starts at approximately 150 °C. Example 6: Differential Scanning Calorimetry (DSC)

[0296] The difference in the amount of heat necessary to increase the temperature of the sample as compared to a reference is measured as a function of temperature using Differential Scanning Calorimetry (DSC) (DSC3, Mettler Toledo).

[0297] For the measurement, a small quantity of sample (typically 1-10 mg) was placed inside a closed aluminum crucible. The starting temperature was 0 °C and the sample was heated with 5.00 K min-1 up to 200 °C or 300 °C using a 50.0 mL min-1 N2 flow. The thermograms were evaluated using the STARe SW 16.20 software from Mettler Toledo.

[0298] For Form A, the differential scanning calorimetry experiment was conducted using standard settings, that is, measured over the temperature range of 0-200 °C with a heating rate of 5 °C / minute.Docket No.51503-768.601 Exothermic events are deviations from the baseline going upwards and endothermic events are peaks going down. The DSC thermogram for crystalline form A of Compound A is displayed in FIG.10, which shows an endothermic peak starting at 178 °C, with a minimum at 192 °C.

[0299] Typical DSC for form B is shown in FIG. 11. The first endotherm in the DSC of form B has been observed to start between about 69 °C and about 79 °C. In some cases, an additional endotherm was observed at 140 °C, which might be the onset of degradation, which is followed by exothermic degradation around 160 °C.

[0300] The DSC of form D is shown in FIG.12. The first two endotherms in the DSC have an onset temperature at about 79 °C and about 113 °C, respectively. The third and final endotherm has an onset temperature at about 151 °C, followed by exothermic degradation starting at 175 °C.

[0301] The DSC of form G is shown in FIG.13.

[0302] The DSC of form H is shown in FIG.14. The first endotherm in the DSC has an onset temperature at about 66 °C and peak at about 95 °C. The second endotherm is a broad exothermic event having an onset at about 137 °C. The third and final endotherm has an onset temperature at about 148 °C, followed by exothermic degradation starting at 168 °C. Example 7: Thermogravimetric Analysis Coupled Mass Spectrometry (TGA-MS)

[0303] The change in the mass of the sample as a function of temperature increase was measured using Thermogravimetric Analysis (TGA) (TGA / DSC3+, Mettler Toledo).

[0304] A small quantity of sample (typically 5-15 mg) was placed inside an aluminum crucible with a pierced lid. The starting temperature was 25 °C and the sample was heated with 5.00 K min-1 up a few degrees below the observed melting point of the material using a 40.0 mL min-1 N2 flow. The change in the mass of the sample (in percentage relative to the initial mass) and the thermogram were evaluated using the STARe SW 16.40 software from Mettler Toledo.

[0305] The results from the thermogravimetric analysis of Compound A form A is depicted in FIG. 15. The sample was heated to 165 °C starting at 20 °C, with a heating rate of 5 °C / min, then cooled down to 20 °C with a heating rate of -10 °C / min, and heated again to 165 °C using a heating rate of 5 °C / min. The top graph in FIG.15 shows a mass loss of about 5.7 % from the onset of heating up to approximately 160 °C. The observed mass loss corresponds to 1.32 mole equivalents of water being lost.

[0306] Typical TGA measurements for Compound A form B is shown in FIG.16. The top graph in FIG.16 shows a mass loss of about 10.7 % from the onset of heating up to approximately 160 °C. The first endotherm in the DSC of form B has been observed to start between 69 °C and 79 °C.

[0307] The TGA measurements of Compound A form D are shown in FIG.17. The top graph in FIG.17 shows a mass loss of about 6.5 % from the onset of heating up to approximately 148 °C.

[0308] The TGA measurements of Compound A form G are shown in FIG.18. The top graph in FIG.18 shows a mass loss of about 7.9 % from the onset of heating up to approximately 160 °C.Docket No.51503-768.601

[0309] The TGA measurements of Compound A form H are shown in FIG.19. The top graph in FIG.19 shows a mass loss of about 10.0 % from the onset of heating up to approximately 160 °C. Example 8: Dynamic Vapour Sorption (DVS)

[0310] Determination of the mass changes occurring when the sample is exposed isothermally (25 °C) at different relative humidity was monitored using Dynamic Vapour Sorption (DVS) utilizing a DVS RESOLUTION (Surface Measurement Systems). The system is equipped with an ultrasensitive microbalance which allows for measuring changes in the sample mass lower than 1 part in 10 million. The microbalance is housed in an incubator which facilitates measuring a temperature range from 5 to 85 °C and a water (or solvent) relative vapor pressure ranging from 0 to 95%.

[0311] The samples were exposed to a 10% stepwise variation of relative humidity (RH) using Reservoir A filled with deionized water. For each cycle, the RH was varied from 0 to 90% and back to 0% at a constant temperature of 25 °C. The value of the RH within one humidity step has been held until the relative mass change (dm / dt) stabilized at a value lower than 0.01 % per minute, with the exception of the steps around RH = 0 and 90%, which have been held constant until dm / dt reached a value lower than 0.001 % per minute, or, if the sample does not stabilize within 360 minutes, the next step is initiated after this time elapses. Three cycles of RH changes were performed and any mass changes were recorded as a function of time.

[0312] XRPD analysis was then carried out on any solid retained.

[0313] The water sorption behavior of Compound A crystalline form A was plotted based on the change in mass, the relative humidity, and the time lapsed. The amount of water adsorbed by a material at 25 °C and 80 % relative humidity determines the classification by the European Pharmacopeia.

[0314] Form A takes on a maximum of 1.03 mg of water, corresponding to 15.5 %wt corresponding to 3.41 mole equivalents. XRPD was performed to exclude the possibility that a hydrate has formed (FIG.1E). NMR was subsequently performed to determine if there had been a chemical reaction. The NMR spectrum shows no change compared to the starting material. The XRPD pattern does show that the material has become amorphous. Crystalline form A of Compound A is characterized as having a reversible water uptake of at most 16% (w / w) between 0% and 90% Relative Humidity (RH) as determined by DVS.

[0315] The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims.

Claims

Docket No.51503-768.601 CLAIMS WHAT IS CLAIMED IS:

1. A solid state form of 6-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3- yl)(methyl)amino)pyridazin-3-yl)-2-methylbenzo[d]oxazol-5-ol (Compound A) or a stereoisomer thereof.

2. A solid state form of Compound A, having a structure of3. The solid state form of claim 1 or 2, wherein the solid state form is a crystalline form.

4. The solid state form of claim 1 or 2, wherein the solid state form is crystalline form A of Compound A.

5. The solid state form of claim 1 or 2, wherein the solid state form is crystalline form B of Compound A.

6. The solid state form of claim 1 or 2, wherein the solid state form is crystalline form C of Compound A.

7. The solid state form of claim 1 or 2, wherein the solid state form is crystalline form D of Compound A.

8. The solid state form of claim 1 or 2, wherein the solid state form is crystalline form E of Compound A.

9. The solid state form of claim 1 or 2, wherein the solid state form is crystalline form F of Compound A.

10. The solid state form of claim 1 or 2, wherein the solid state form is crystalline form G of Compound A.

11. The solid state form of claim 1 or 2, wherein the solid state form is crystalline form H of Compound A.

12. A crystalline form of 6-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3- yl)(methyl)amino)pyridazin-3-yl)-2-methylbenzo[d]oxazol-5-ol (Compound A), wherein the crystalline form is characterized as exhibiting: (a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG.1A, FIG.1B, or FIG.1C as measured using Cu Kα radiation; (b) an XRPD pattern with peaks at 7.1 ±0.2 º2-Theta, 7.6 ±0.2 º2-Theta, and 26.1 ±0.2 º2-Theta as measured using Cu Kα radiation;Docket No.51503-768.601 (c) an XRPD pattern with one or more peaks at 11.1 ±0.2 º2-Theta, 12.4 ±0.2 º2-Theta, and 17.5 ±0.2 º2-Theta as measured using Cu Kα radiation; (d) an XRPD pattern with at least three, at least four, at least five, or all of the peaks at 7.1 ±0.2 º2-Theta, 11.1 ±0.2 º2-Theta, 12.4 ±0.2 º2-Theta, 14.8 ±0.2 º2-Theta, 17.5 ±0.2 º2-Theta, and 26.1 ±0.2 º2-Theta as measured using Cu Kα radiation; (e) an XRPD pattern with at least three, at least six, at least nine, or all of the peaks at 7.1 ±0.2 º2-Theta, 7.6 ±0.2 º2-Theta, 11.1 ±0.2 º2-Theta, 12.4 ±0.2 º2-Theta, 14.8 ±0.2 º2-Theta, 15.2 ±0.2 º2-Theta, 16.0 ±0.2 º2-Theta, 16.3 ±0.2 º2-Theta, 17.5 ±0.2 º2- Theta, 19.3 ±0.2 º2-Theta, 25.3 ±0.2 º2-Theta, 26.1 ±0.2 º2-Theta and 27.1 ±0.2 º2- Theta as measured using Cu Kα radiation; (f) a Differential Scanning Calorimetry (DSC) thermogram substantially the same as shown in FIG.10; (g) a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak having an onset temperature at about 178 °C; (h) a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak at about 192 °C; (i) a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as shown in FIG.15; or (j) a Thermogravimetric Thermal Analysis (TGA) thermogram exhibiting a mass loss of about 5.7 % from the onset of heating up to approximately 160 °C.

13. The crystalline form of Compound A according to claim 12, wherein the crystalline form is characterized as exhibiting an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG.1A, FIG.1B, FIG. 1C, or FIG.1D, as measured using Cu Kα radiation.

14. The crystalline form of Compound A according to claim 12, wherein the crystalline form is characterized as exhibiting an XRPD pattern with peaks at 11.1 ±0.2 º2-Theta, 12.4 ±0.2 º2- Theta, and 17.5 ±0.2 º2-Theta as measured using Cu Kα radiation.

15. The crystalline form of Compound A according to claim 12, wherein the crystalline form is characterized as exhibiting an XRPD pattern with at least three, at least four, at least five, or all of the peaks at 7.1 ±0.2 º2-Theta, 11.1 ±0.2 º2-Theta, 12.4 ±0.2 º2-Theta, 14.8 ±0.2 º2- Theta, 17.5 ±0.2 º2-Theta, and 26.1 ±0.2 º2-Theta as measured using Cu Kα radiation.

16. The crystalline form of Compound A according to claim 12, wherein the crystalline form is characterized as exhibiting an XRPD pattern with at least three, at least six, at least nine, or all of the peaks at 7.1 ±0.2 º2-Theta, 7.6 ±0.2 º2-Theta, 11.1 ±0.2 º2-Theta, 12.4 ±0.2 º2- Theta, 14.8 ±0.2 º2-Theta, 15.2 ±0.2 º2-Theta, 16.0 ±0.2 º2-Theta, 16.3 ±0.2 º2-Theta, 17.5 ±0.2 º2-Theta, 19.3 ±0.2 º2-Theta, 25.3 ±0.2 º2-Theta, 26.1 ±0.2 º2-Theta, and 27.1 ±0.2 º2- Theta as measured using Cu Kα radiation.Docket No.51503-768.601 17. The crystalline form of Compound A according to claim 12, wherein the crystalline form is characterized as exhibiting a Differential Scanning Calorimetry (DSC) thermogram substantially the same as shown in FIG.

10.

18. The crystalline form of Compound A according to claim 12, wherein the crystalline form is characterized as exhibiting a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as shown in FIG.

15.

19. The crystalline form of Compound A according to claim 12, wherein the crystalline form is characterized as exhibiting a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak having an onset temperature at about 178 °C.

20. The crystalline form of Compound A according to claim 12, wherein the crystalline form is characterized as exhibiting a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak at about 192 °C.

21. The crystalline form of Compound A according to claim 12, wherein the crystalline form is characterized as exhibiting a Thermogravimetric Thermal Analysis (TGA) thermogram that shows a mass loss of about 5.7 % from the onset of heating up to approximately 160 °C.

22. The crystalline form of Compound A according to claim 12 , wherein the crystalline form is anhydrous.

23. A pharmaceutical composition comprising the crystalline form of Compound A or the solid state form of Compound A of any one of claims 1-22 and at least one pharmaceutically acceptable excipient.

24. The pharmaceutical composition of claim 23, wherein the pharmaceutical composition is formulated in the form of a solid form pharmaceutical composition for oral administration to a mammal.

25. A method of treating a condition or a disorder in a subject in need thereof, the method comprising administering to the subject the crystalline form of Compound A or the solid state form of Compound A according to any one of claims 1-22, or the pharmaceutical composition of claim 23 or 24.

26. The method of claim 25, wherein the condition or disorder comprises Huntington's disease.

27. A method of treating Huntington's disease in a subject in need thereof, comprising administering to the subject the crystalline form of Compound A or the solid state form of Compound A according to any one of claims 1-22 or the pharmaceutical composition of claim 23 or 24.

28. A method of modulating splicing comprising administering to cells the crystalline form of Compound A or the solid state form of Compound A according to any one of claims 1-22, or a pharmaceutical composition of claim 23 or 24, wherein the the crystalline form of Compound A or the solid state form of Compound A modulates splicing at a splice siteDocket No.51503-768.601 sequence of a pre-mRNA that encodes an mRNA, and wherein the mRNA encodes a target protein or a functional RNA.

29. Use of the crystalline form of Compound A or the solid state form of Compound A according to any one of claims 1-22, or the pharmaceutical composition of claim 23 or 24, in the manufacture of a medicament for the treatment of a condition or disease.

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