Formulations of BCR-ABL tyrosine kinase inhibitor

Abstract

The present disclosure relates generally to crystalline forms of (1S,2S)-N-(2-(4,6- bis(methoxy-d 3)pyrimidin-5-yl)-1-methyl-1H-pyrrolo[2, 3-c]pyridin-5-yl)-2- fluorocyclopropane-1-carboxamide (Compound 1), compositions thereof, and methods of using any of the foregoing.

Description

FORMULATIONS OF BCR-ABL TYROSINE KINASE INHIBITORCROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to and the benefit of United States Provisional Patent Application No. 63 / 708,223, filed on October 16, 2024, the disclosure of which is incorporated herein by reference in its entirety.FIELD

[0002] The present disclosure relates generally to crystalline forms of (1S,2S)- N-(2-(4,6- bis(methoxy-d / 3)pyrimidin-5-yl)-l -methyl-d / 3 -pyrrolo[2, 3-c]pyri din-5-yl)-2- fluorocyclopropane-l -carboxamide (Compound 1), compositions thereof, and methods of using any of the foregoing.BACKGROUND

[0003] The cytogenetic abnormality known as the Philadelphia chromosome is highly associated with the occurrence of a number of hematological malignancies, including a majority of chronic myeloid leukemias (CML) and a subset of acute lymphoblastic leukemias (Ph+ ALL). The Philadelphia chromosome is a product of a translocation between the breakpoint cluster region (BCR) gene on chromosome 22 and the Abelson (ABL) tyrosine kinase gene on chromosome 9, resulting in the oncogenic fusion gene product Bcr-Abl. The resultant fusion protein is both overexpressed and harbors constitutive kinase activity that then drives the activation of a number of intracellular signaling cascades to induce the uncontrolled cell growth, division and survival associated with oncogenic transformation. Accordingly, therapeutic intervention employing inhibitors of the Bcr-Abl tyrosine kinase represents a cornerstone of the current treatment paradigm for patients with Philadelphiapositive neoplastic disorders.

[0004] Imatinib (STI-571), a small molecule Bcr-Abl tyrosine kinase inhibitor (Bcr-Abl TKI), was developed as a highly effective treatment for CML in the early 1990s and is still employed today as a first line treatment for CML. However, in more aggressive cases of CML, patients often relapse due to the emergence of resistance. The primary mechanism of this resistance derives from a variety of on-target genetic alterations that drives either aberrant overexpression of the Bcr-Abl fusion or, more commonly, introduce amino acid mutations within the Abl kinase domain that reduce imatinib ’s binding affinity for the active site thereby markedly reducing its inhibitory activity. These alterations can either appearstochastically and represent a sub-population within the initial tumor cell population or arise under the selective pressure of inhibitor treatment. One of the predominant on-target Bcr-Abl resistance mutations derives from point mutations that introduce an isoleucine residue for a threonine at position 315 within the Abl kinase domain (T3151) also known as the ‘gatekeeper’ position. In addition to imatinib, this mutant form of BCR-Abl is profoundly resistant to all second generation Bcr-Abl TKIs (Nilotinib, Dasatinib, Bosutinib, Radotinib). Currently, there exists only one therapeutic option for patients harboring a T3151 mutation — the third line Bcr-Abl TKI, Ponatinib. While effective at treating patients with T3151 CML, ponatinib suffers from poor selectivity for Bcr-Abl versus a number of other protein kinases. Accordingly, ponatinib has been reported to elicit significant dose-limiting toxicities, which then limits its ability to effectively engage the target to achieve clinical efficacy.

[0005] Besides on- or off-target resistance, intolerance to Bcr-Abl TKIs also represents a major clinical challenge. The doses of more than 50% of Ph+ leukemia patients require modification due to adverse events. In fact, approximately 30% of patients are compelled to dose reduce within the first 6 months of treatment. These drug-related side effects appear early in the course of treatment and, while manageable in most cases, toxicities persist, significantly impacting the patients’ quality of life, resulting in decreased compliance. Accordingly, around 40% of patients discontinue first and second generation Bcr-Abl TKIs within the first 5 years of treatment. All of the currently approved Bcr-Abl targeted therapies inhibit other tyrosine kinases, which can lead to potentially debilitating side effects. Specifically, potent inhibition of VEGFRs, PDGFRs, c-Kit and / or the c-Src family can lead to dose-limiting side effects in patients. To address these adverse effects, dose reductions, dose interruptions, and even dose discontinuations are often required during the course of therapy, however such treatment regimens ultimately result in suboptimal therapeutic benefit.

[0006] Accordingly, there remains a substantial unmet medical need for Bcr-Abl TKIs with improved selectivity to improve tolerability and enhanced potency against the wide array of resistance mechanisms in Philadelphia-positive disorders.BRIEF SUMMARY

[0007] In one aspect, provided herein is a crystalline form of (15,25)-A-(2-(4,6- bis(methoxy-t / 3)pyrimidin-5-yl)-l -methyl- U / -pyrrolo[2, 3-c]pyri din-5-yl)-2-fluorocyclopropane- 1 -carboxamide (Compound 1) or a pharmaceutically acceptable salt thereof.Compound 1

[0008] In some embodiments, the crystalline form is a crystalline form of Compound 1 as freebase. In some embodiments, the crystalline form is Freebase Form 1 and is characterized as having an XRPD pattern substantially as shown in FIG. 65; an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 1; and / or a TGA / DSC thermogram substantially as shown in FIG. 66. In some embodiments, the crystalline form is Freebase Form 3 and is characterized as having an XRPD pattern substantially as shown in FIG. 67; and / or an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 2. In some embodiments, the crystalline form is Freebase Form 4 and is characterized as having an XRPD pattern substantially as shown in FIG. 68; and / or an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 3.

[0009] In some embodiments, the crystalline form is a crystalline form of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the crystalline form is a crystalline form of a HC1, HBr, naphthalene-l,5-disulfonic acid, sulfuric acid, ethane-1,2- disulfonic acid, esylate, 2-hydroxyethanesulfonic acid, tosylate, methanesulfonic acid, napthalene-2-sulfonic acid, benzenesulfonic acid, maleic acid, phosphoric acid, or (+)- camphor- 10-sulfonic acid salt of Compound 1.

[0010] In some embodiments, the crystalline form is HC1 Form 1, a crystalline form of a HC1 salt of Compound 1, and is characterized as having an XRPD pattern substantially as shown in FIG. 1; an XRPD pattern comprising one or more peaks as assigned at angles 2- theta in degrees as recited in Table 4; and / or a TGA / DSC thermogram substantially as shown in FIG. 2. In some embodiments, the crystalline form is HC1 Form 2, a crystalline form of aHC1 salt of Compound 1, and is characterized as having an XRPD pattern substantially as shown in FIG. 3; and / or an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 5. In some embodiments, the crystalline form is HC1 Form 3, a crystalline form of a HC1 salt of Compound 1, and is characterized as having an XRPD pattern substantially as shown in FIG. 4; and / or an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 6. In some embodiments, the crystalline form is HC1 Form 4, a crystalline form of a HC1 salt of Compound 1, and is characterized as having an XRPD pattern substantially as shown in FIG. 5; an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 7; and / or a TGA / DSC thermogram substantially as shown in FIG. 6. In some embodiments, the crystalline form is HC1 Form 5, a crystalline form of a HC1 salt of Compound 1, and is characterized as having an XRPD pattern substantially as shown in FIG. 7; and / or an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 8. In some embodiments, the crystalline form is HC1 Form 6, a crystalline form of a HC1 salt of Compound 1, and is characterized as having an XRPD pattern substantially as shown in FIG. 8; and / or an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 9.

[0011] In some embodiments, the crystalline form is HBr Form 1, a crystalline form of a HBr salt of Compound 1, and is characterized as having an XRPD pattern substantially as shown in FIG. 9; an XRPD pattern comprising one or more peaks as assigned at angles 2- theta in degrees as recited in Table 10; and / or a TGA / DSC thermogram substantially as shown in FIG. 10. In some embodiments, the crystalline form is HBr Form 2, a crystalline form of a HBr salt of Compound 1, and is characterized as having an XRPD pattern substantially as shown in FIG. 11; an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 11; and / or a TGA / DSC thermogram substantially as shown in FIG. 12. In some embodiments, the crystalline form is HBr Form 3, a crystalline form of a HBr salt of Compound 1, and is characterized as having an XRPD pattern substantially as shown in FIG. 13; and / or an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 12. In some embodiments, the crystalline form is HBr Form 4, a crystalline form of a HBr salt of Compound 1, and is characterized as having an XRPD pattern substantially as shown in FIG. 14; an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 13; and / or a TGA / DSC thermogram substantially as shown in FIG. 15.

[0012] In some embodiments, the crystalline form is Naphthal ene-l,5-disulfonic Acid Form 1, a crystalline form of a naphthalene-l,5-disulfonic acid salt of Compound 1, and is characterized as having an XRPD pattern substantially as shown in FIG. 16; an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 14; and / or a TGA / DSC thermogram substantially as shown in FIG. 17. In some embodiments, the crystalline form is Naphthalene-l,5-disulfonic Acid Form 2, a crystalline form of a naphthalene-l,5-disulfonic acid salt of Compound 1, and is characterized as having an XRPD pattern substantially as shown in FIG. 18; an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 15; and / or a TGA / DSC thermogram substantially as shown in FIG. 19.

[0013] In some embodiments, the crystalline form is Sulfuric Acid Form 1, a crystalline form of a sulfuric acid salt of Compound 1, and is characterized as having: an XRPD pattern substantially as shown in FIG. 20; an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 16; and / or a TGA / DSC thermogram substantially as shown in FIG. 21. In some embodiments, the crystalline form is Sulfuric Acid Form 2, a crystalline form of a sulfuric acid salt of Compound 1, and is characterized as having an XRPD pattern substantially as shown in FIG. 22; an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 17; and / or a TGA / DSC thermogram substantially as shown in FIG. 23. In some embodiments, the crystalline form is Sulfuric Acid Form 3, a crystalline form of a sulfuric acid salt of Compound 1, and is characterized as having an XRPD pattern substantially as shown in FIG. 24; an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 18; and / or a TGA / DSC thermogram substantially as shown in FIG. 25. In some embodiments, the crystalline form is Sulfuric Acid Form 4, a crystalline form of a sulfuric acid salt of Compound 1, and is characterized as having an XRPD pattern substantially as shown in FIG. 26; and / or an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 19. In some embodiments, the crystalline form is Sulfuric Acid Form 5, a crystalline form of a sulfuric acid salt of Compound 1, and is characterized as having an XRPD pattern substantially as shown in FIG. 27; and / or an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 20.

[0014] In some embodiments, the crystalline form is Ethane-l,2-disulfonic Acid Form 1, a crystalline form of an ethane- 1,2-disulfonic acid salt of Compound 1, and is characterized as having an XRPD pattern substantially as shown in FIG. 28; an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 21; and / or a TGA / DSC thermogram substantially as shown in FIG. 29.

[0015] In some embodiments, the crystalline form is Esylate Form 1, a crystalline form of an esylate salt of Compound 1, and is characterized as having an XRPD pattern substantially as shown in FIG. 30; an XRPD pattern comprising one or more peaks as assigned at angles 2- theta in degrees as recited in Table 22; and / or a TGA / DSC thermogram substantially as shown in FIG. 31.

[0016] In some embodiments, the crystalline form is 2-Hydroxyethanesulfonic Acid Form 1, a crystalline form of a 2-hydroxyethanesulfonic acid salt of Compound 1 and is characterized as having an XRPD pattern substantially as shown in FIG. 32; an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 23; and / or a TGA / DSC thermogram substantially as shown in FIG. 33.

[0017] In some embodiments, the crystalline form is Methanesulfonic Acid Form 1, a crystalline form of a methanesulfonic acid salt of Compound 1, and is characterized as having an XRPD pattern substantially as shown in FIG. 48; an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 30; and / or a TGA / DSC thermogram substantially as shown in FIG. 49.

[0018] In some embodiments, the crystalline form is Napthalene-2-sulfonic Acid Form 1, a crystalline form of a napthalene-2-sulfonic acid salt of Compound 1, and is characterized as having an XRPD pattern substantially as shown in FIG. 50; an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 31; and / or a TGA / DSC thermogram substantially as shown in FIG. 51. In some embodiments, the crystalline form is Napthalene-2-sulfonic Acid Form 2, a crystalline form of a napthalene-2- sulfonic acid salt of Compound 1, and is characterized as having an XRPD pattern substantially as shown in FIG. 52; an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 32; and / or a TGA / DSC thermogram substantially as shown in FIG. 53. In some embodiments, the crystalline form is Napthalene- 2-sulfonic Acid Form 3, a crystalline form of a napthalene-2-sulfonic acid salt of Compound1, and is characterized as having an XRPD pattern substantially as shown in FIG. 54; an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 33; and / or a TGA / DSC thermogram substantially as shown in FIG. 55.

[0019] In some embodiments, the crystalline form is Benzenesulfonic Acid Form 1, a crystalline form of a benzenesulfonic acid salt of Compound 1, and is characterized as having an XRPD pattern substantially as shown in FIG. 56; an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 34; and / or a TGA / DSC thermogram substantially as shown in FIG. 57. In some embodiments, the crystalline form is Benzenesulfonic Acid Form 2, a crystalline form of a benzenesulfonic acid salt of Compound 1, and is characterized as having an XRPD pattern substantially as shown in FIG. 58; an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 35; and / or a TGA / DSC thermogram substantially as shown in FIG. 59.

[0020] In some embodiments, the crystalline form is Maleic Acid Form 1, a crystalline form of a maleic acid salt of Compound 1, and is characterized as having an XRPD pattern substantially as shown in FIG. 60; and / or an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 36.

[0021] In some embodiments, the crystalline form is Phosphoric Acid Form 1, a crystalline form of a phosphoric acid salt of Compound 1, and is characterized as having an XRPD pattern substantially as shown in FIG. 61; and / or an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 37. In some embodiments, the crystalline form is Phosphoric Acid Form 2, a crystalline form of a phosphoric acid salt of Compound 1, and is characterized as having an XRPD pattern substantially as shown in FIG. 62; and / or an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 38.

[0022] In some embodiments, the crystalline form is (+)-Camphor-10-sulfonic acid Form 1, a crystalline form of a (+)-camphor-10-sulfonic acid salt of Compound 1, and is characterized as having an XRPD pattern substantially as shown in FIG. 63; an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 39; and / or a TGA / DSC thermogram substantially as shown in FIG. 64.

[0023] In some embodiments, the crystalline form is a crystalline form of a tosylate salt of Compound 1. In some embodiments, the tosylate salt is a mono-tosylate salt. In some embodiments, the crystalline form is a hydrate. In some embodiments, the crystalline form is a monohydrate. In some embodiments, the crystalline form is a hemihydrate. In some embodiments, the crystalline form is anhydrous.

[0024] In some embodiments, the crystalline form is Tosylate Form 1, a crystalline form of a tosylate salt of Compound 1, and is characterized as having an XRPD pattern substantially as shown in FIG. 34; an XRPD pattern comprising one or more peaks as assigned at angles 2 -theta in degrees as recited in Table 24; and / or a TGA / DSC thermogram substantially as shown in FIG. 35. In some embodiments, the crystalline form is characterized as having an X-ray powder diffraction (XRPD) pattern comprising a peak at an angle 2 -theta of about 17.65. In some embodiments, the XRPD pattern further comprises a peak at an angle 2 -theta of about 24.47. In some embodiments, the XRPD pattern further comprises peaks at angles 2 -theta of about 21.74, about 16.55, and about 14.30. In some embodiments, the XRPD pattern further comprises peaks at angles 2-theta of about 23.95, about 25.29, about 15.29, about 28.77, and about 28.65. In some embodiments, the XRPD pattern further comprises peaks at angles 2-theta of about 13.77, about 21.55, about 22.65, about 19.43, about 13.47, about 29.21, about 22.70, about 9.14, about 26.40, and about 23.86. In some embodiments, the crystalline form is characterized as having endothermic transitions at about 71.2 °C and about 127.9 °C, as measured by DSC. In some embodiments, the crystalline form is characterized as showing a weight loss of about 3.2% from about 37 °C to about 139 °C, and a weight loss of about 0.66% from about 139 °C to about 265 °C as determined by TGA. In some embodiments, the crystalline form is characterized as having an XRPD pattern substantially as shown in FIG. 34. In some embodiments, the crystalline form is characterized as having an TGA / DSC thermogram substantially as shown in FIG. 35.

[0025] In some embodiments, the crystalline form is Tosylate Form 2, a crystalline form of a tosylate salt of Compound 1, and is characterized as having an XRPD pattern substantially as shown in FIG. 36; and / or a TGA / DSC thermogram substantially as shown in FIG. 37.

[0026] In some embodiments, the crystalline form is Tosylate Form 3, a crystalline form of a tosylate salt of Compound 1, and is characterized as having an XRPD pattern substantially as shown in FIG. 38; an XRPD pattern comprising one or more peaks as8assigned at angles 2-theta in degrees as recited in Table 25; and / or a TGA / DSC thermogram substantially as shown in FIG. 39.

[0027] In some embodiments, the crystalline form is Tosylate Form 4, a crystalline form of a tosylate salt of Compound 1, and is characterized as having an XRPD pattern substantially as shown in FIG. 40; an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 26; and / or a TGA / DSC thermogram substantially as shown in FIG. 41. In some embodiments, the crystalline form is characterized as having an XRPD pattern comprising a peak at an angle 2-theta of about 24.80. In some embodiments, the XRPD pattern further comprises a peak at an angle 2-theta of about 17.38. In some embodiments, the XRPD pattern further comprises peaks at angles 2-theta of about 17.72, about 14.45, and about 16.97. In some embodiments, the XRPD pattern further comprises peaks at angles 2-theta of about 24.12, about 21.31, about 5.56, about 14.05, and about 28.84. In some embodiments, the XRPD pattern further comprises peaks at angles 2- theta of about 22.34, about 29.15, about 18.63, about 19.48, about 18.81, about 22.56, about 21.71, about 10.72, about 23.79, and about 10.61. In some embodiments, the crystalline form is characterized as having endothermic transitions at about 72.4 °C and about 131.5 °C, as measured by DSC. In some embodiments, the crystalline form is characterized as showing a weight loss of about 3.1% from about 31 °C to about 158 °C and a weight loss of about 1.2% from about 158 °C to about 198 °C, as determined by TGA. In some embodiments, the crystalline form is characterized as having an XRPD pattern substantially as shown in FIG. 40. In some embodiments, the crystalline form is characterized as having an TGA / DSC thermogram substantially as shown in FIG. 41.

[0028] In some embodiments, the crystalline form is Tosylate Form 5, a crystalline form of a tosylate salt of Compound 1, and is characterized as having an XRPD pattern substantially as shown in FIG. 42; an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 27; and / or a TGA / DSC thermogram substantially as shown in FIG. 43.

[0029] In some embodiments, the crystalline form is Tosylate Form 6, a crystalline form of a tosylate salt of Compound 1, and is characterized as having an XRPD pattern substantially as shown in FIG. 44; an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 28; and / or a TGA / DSC thermogram substantially as shown in FIG. 45.

[0030] In some embodiments, the crystalline form is Tosylate Form 7, a crystalline form of a tosylate salt of Compound 1, and is characterized as having: an XRPD pattern substantially as shown in FIG. 46; an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 29; and / or a TGA / DSC thermogram substantially as shown in FIG. 47. In some embodiments, the crystalline form is characterized as having an XRPD pattern comprising a peak at an angle 2-theta of about 7.48. In some embodiments, the XRPD pattern further comprises a peak at an angle 2-theta of about 23.24. In some embodiments, the XRPD pattern further comprises peaks at angles 2-theta of about 9.49, about 14.04, and about 18.07. In some embodiments, the XRPD pattern further comprises peaks at angles 2-theta of about 25.96, about 13.88, about 27.31, about 12.51, and about 22.56. In some embodiments, the XRPD pattern further comprises peaks at angles 2- theta of about 21.69, about 11.34, about 18.39, about 27.58, about 21.22, about 22.75, about 10.23, about 19.90, about 21.95, and about 13.21. In some embodiments, the crystalline form is characterized as having an endothermic transition at about 216.6 °C, as measured by DSC. In some embodiments, the crystalline form is characterized as having an XRPD pattern substantially as shown in FIG. 46. In some embodiments, the crystalline form is characterized as having an TGA / DSC thermogram substantially as shown in FIG. 47.

[0031] In another aspect, provided herein is a pharmaceutical composition comprising a crystalline form as described herein and one or more pharmaceutically acceptable excipients.

[0032] In some embodiments, the composition comprises one or more intra-granular ingredients and one or more extra-granular ingredients. In some embodiments, the one or more intra-granular ingredients comprise a crystalline form as described herein. In some embodiments, the crystalline form is Tosylate Form 1 as described herein. In some embodiments, the composition comprises Compound 1 or a pharmaceutically acceptable salt thereof in the amount equivalent to about 40 mg, 80 mg, or 120 mg of Compound 1 in the freebase form. In some embodiments, the composition comprises Compound 1 or a pharmaceutically acceptable salt thereof in the amount equivalent to between about 35 mg to 45 mg of Compound 1 in the freebase form. In some embodiments, the composition comprises Compound 1 or a pharmaceutically acceptable salt thereof in the amount equivalent to about 40 mg of Compound 1 in the freebase form. In some embodiments, the composition comprises Compound 1 or a pharmaceutically acceptable salt thereof in the amount of about 106 micromoles.

[0033] In some embodiments, the one or more intra-granular ingredients comprise or further comprise a filler. In some embodiments, the filler comprises microcrystalline cellulose or dicalcium phosphate, or both. In some embodiments, the composition comprises the filler in the amount of between about 50 wt.% and about 60 wt.%. In some embodiments, the composition comprises the filler in the amount of about 55 wt.%. In some embodiments, the composition comprises microcrystalline cellulose in the amount of about 40 wt.%. In some embodiments, the composition comprises dicalcium phosphate in the amount of about 13 wt.%.

[0034] In some embodiments, the one or more intra-granular ingredients comprise or further comprise a binder. In some embodiments, the binder comprises Plasdone K 29 / 32 or hydroxypropyl cellulose, or both. In some embodiments, the composition comprises the binder in the amount of between about 5 wt.% and about 10 wt.%. In some embodiments, the composition comprises Plasdone K 29 / 32 in the amount of about 8 wt.%. In some embodiments, the composition comprises hydroxypropyl cellulose in the amount of about 8 wt.%.

[0035] In some embodiments, the one or more intra-granular ingredients comprise or further comprise an intra-granular lubricant. In some embodiments, the intra-granular lubricant is magnesium stearate. In some embodiments, the composition comprises the intra- granular lubricant in the amount of between about 0.1 wt.% and about 1 wt.%. In some embodiments, the composition comprises the intra-granular lubricant in the amount of about 0.5 wt.%. In some embodiments, the one or more extra-granular ingredients comprise an extra-granular lubricant. In some embodiments, the extra-granular lubricant is magnesium stearate. In some embodiments, the composition comprises the extra-granular lubricant in the amount of between about 0.1 wt.% and about 1 wt.%. In some embodiments, the extra- granular lubricant in the amount of about 0.5 wt.%. In some embodiments, the composition comprises magnesium stearate in the amount of about 1 wt.%.

[0036] In some embodiments, the one or more extra-granular ingredients comprise or further comprise a disintegrant. In some embodiments, the disintegrant comprises croscarmellose sodium or sodium starch glycolate, or both. In some embodiments, the composition comprises the disintegrant in the amount of between about 4 wt.% and about 10 wt.%. In some embodiments, the composition comprises croscarmellose sodium in the11amount of about 8 wt.%. In some embodiments, the composition comprises sodium starch glycolate in the amount of about 6 wt.%.

[0037] In some embodiments, the composition comprises Tosylate Form 1 as described herein; microcrystalline cellulose; dicalcium phosphate; plasdone K 29 / 32; magnesium stearate; and crocarmellose sodium. In some embodiments, the composition comprises about 30 wt.% of the crystalline form, or Compound 1 or a pharmaceutically acceptable salt thereof in the amount equivalent to about 40 mg of Compound 1 in the freebase form; about 40 wt.% of microcrystalline cellulose; about 13 wt.% of dicalcium phosphate; about 8 wt.% of plasdone K 29 / 32; about 1 wt.% of magnesium stearate; and about 8 wt.% of crocarmellose sodium. In some embodiments, the composition comprises Tosylate Form 1 as described herein; microcrystalline cellulose; dicalcium phosphate; hydroxypropyl cellulose; magnesium stearate; and sodium starch glycolate. In some embodiments, the composition comprises about 30 wt.% of the crystalline form, or Compound 1 or a pharmaceutically acceptable salt thereof in the amount equivalent to about 40 mg of Compound 1 in the freebase form; about 40 wt.% of microcrystalline cellulose; about 13 wt.% of dicalcium phosphate; about 8 wt.% of hydroxypropyl cellulose; about 1 wt.% of magnesium stearate; and about 6 wt.% of sodium starch glycolate.

[0038] In some embodiments, the composition is formulated for oral delivery. In some embodiments, the composition is a tablet.

[0039] In another aspect, provided herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient a crystalline form as described herein, or a pharmaceutical composition as described herein. In some embodiments, the cancer is chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or a mixed phenotype acute leukemia.

[0040] In another aspect, provided herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient (15,25)-A-(2-(4,6-bis(methoxy- t / 3)pyrimidin-5-yl)-l-methyl-lJ / -pyrrolo[2,3-c]pyridin-5-yl)-2-fluorocyclopropane-l- carboxamide (Compound 1) or a pharmaceutically acceptable salt thereof at a once daily dose of an amount equivalent to about 10 mg, about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, or about 120 mg of Compound 1 in the freebase form; or at a twice daily dose of an amount equivalent to about 60 mg each or about 80 mg each of Compound 1 in thefreebase form. In some embodiments, the cancer is chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or a mixed phenotype acute leukemia. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered to the patient at a twice daily dose of an amount equivalent to about 60 mg each or about 80 mg each of Compound 1 in the freebase form.

[0041] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered to the patient as the crystalline form as described herein, or a pharmaceutical composition as described herein, at any of the doses provided herein.

[0042] In some embodiments, the leukemia is refractory leukemia. In some embodiments, the patient has one or more mutations in the Bcr-Abl tyrosine kinase gene resulting in M244V, L248V, G250E, G250A, Q252H, Q252R, Y253F, Y253H, E255K, E255V, D276G, F311L, T315N, T315A, F317V, F317L, M343T, M351T, E355G, F359A, F359V, V379I, F382L, L387M, H396P, H396R, S417Y, E459K, F486S, T315I, A337T, F359C, or P465S, or any combination of these amino acid substitutions in leukemia cells. In some embodiments, the patient has one or more mutations in the Bcr-Abl tyrosine kinase gene resulting in T3151 amino acid substitution in leukemia cells. In some embodiments, the patient has one or more mutations in the Bcr-Abl tyrosine kinase gene resulting in T315I, M244V, A337T, E355G, F359C, F359V, or P465S, or any combination of these amino acid substitutions in leukemia cells. In some embodiments, the patient has one or more mutations in the Bcr-Abl tyrosine kinase gene resulting in A337T amino acid substitution in leukemia cells. In some embodiments, the method further comprises detecting mutations in the Bcr-Abl tyrosine kinase gene of the patient. In some embodiments, the patient was previously treated with 1, 2, 3, 4, 5, or more tyrosine kinase inhibitors.

[0043] In some embodiments, the patient was previously treated with dasatinib, imatinib, asciminib, ponatinib, nilotinib, or bosutinib, or any combination thereof. In some embodiments, the patient was previously treated with asciminib and / or ponatinib. In some embodiments, the patient was previously treated with asciminib. In some embodiments, the method further comprises administering one or more pharmaceutical agents including including anti -microtubular therapies, topoisomerase inhibitors, alkylating agents, nucleotide synthesis inhibitors, DNA synthesis inhibtiors, protein synthesis inhibitors, developmental signaling pathway inhibitors, pro-apoptotic agents, Abl myristoyl-pocket binding inhibitors, MEK1 / 2 inhibitors, AKT inhibitors, PI3K inhibitors and / or radiation.

[0044] In some embodiments, the crystalline form or pharmaceutical composition is administered to the patient without fasting. In some embodiments, the crystalline form or pharmaceutical composition is administered to the patient less than about 2 hours after the patient ate food. In some embodiments, the crystalline form or pharmaceutical composition is administered to the patient less than about 1 hour before the patient eats food. In some embodiments, the crystalline form or pharmaceutical composition is orally administered to the patient daily.

[0045] In another aspect, provided herein is a method of inhibiting Bcr-Abl enzymatic activity in a cell, comprising exposing the cell with an effective amount of a crystalline form as described herein, or a pharmaceutical composition as described herein. In some embodiments, the cell has one or more mutations in the Bcr-Abl tyrosine kinase gene resulting in M244V, L248V, G250E, G250A, Q252H, Q252R, Y253F, Y253H, E255K, E255V, D276G, F311L, T315N, T315A, F317V, F317L, M343T, M351T, E355G, F359A, F359V, V379I, F382L, L387M, H396P, H396R, S417Y, E459K, F486S, T315I, A337T, F359C, or P465S, or any combination of these amino acid substitutions. In some embodiments, the cell has one or more mutations in the Bcr-Abl tyrosine kinase gene resulting in T315I amino acid substitution. In some embodiments, the cell has one or more mutations in the Bcr-Abl tyrosine kinase gene resulting in T315I, M244V, A337T, E355G, F359C, F359V, or P465S, or any combination of these amino acid substitutions. In some embodiments, the cell has one or more mutations in the Bcr-Abl tyrosine kinase gene resulting in A337T amino acid substitution. In some embodiments, the method further comprises detecting mutations in the Bcr-Abl tyrosine kinase gene of the cell.DESCRIPTION OF THE FIGURES

[0046] The present application can be understood by reference to the following description taken in conjunction with the accompanying figures.

[0047] FIG. 1 depicts an experimental XRPD pattern of a crystalline form of a HC1 salt of Compound 1, HC1 Form 1.

[0048] FIG. 2 depicts an experimental TGA / DSC thermogram of a crystalline form of a HC1 salt of Compound 1, HC1 Form 1.

[0049] FIG. 3 depicts an experimental XRPD pattern of a crystalline form of a HC1 salt of Compound 1, HC1 Form 2.

[0050] FIG. 4 depicts an experimental XRPD pattern of a crystalline form of a HC1 salt of Compound 1, HC1 Form 3.

[0051] FIG. 5 depicts an experimental XRPD pattern of a crystalline form of a HC1 salt of Compound 1, HC1 Form 4.

[0052] FIG. 6 depicts an experimental TGA / DSC thermogram of a crystalline form of a HC1 salt of Compound 1, HC1 Form 4.

[0053] FIG. 7 depicts an experimental XRPD pattern of a crystalline form of a HC1 salt of Compound 1, HC1 Form 5.

[0054] FIG. 8 depicts an experimental XRPD pattern of a crystalline form of a HC1 salt of Compound 1, HC1 Form 6.

[0055] FIG. 9 depicts an experimental XRPD pattern of a crystalline form of a HBr salt of Compound 1, HBr Form 1.

[0056] FIG. 10 depicts an experimental TGA / DSC thermogram of a crystalline form of a HBr salt of Compound 1, HBr Form 1.

[0057] FIG. 11 depicts an experimental XRPD pattern of a crystalline form of a HBr salt of Compound 1, HBr Form 2.

[0058] FIG. 12 depicts an experimental TGA / DSC thermogram of a crystalline form of a HBr salt of Compound 1, HBr Form 2.

[0059] FIG. 13 depicts an experimental XRPD pattern of a crystalline form of a HBr salt of Compound 1, HBr Form 3.

[0060] FIG. 14 depicts an experimental XRPD pattern of a crystalline form of a HBr salt of Compound 1, HBr Form 4.

[0061] FIG. 15 depicts an experimental TGA / DSC thermogram of a crystalline form of a HBr salt of Compound 1, HBr Form 4.

[0062] FIG. 16 depicts an experimental XRPD pattern of a crystalline form of a naphthalene-l,5-disulfonic acid salt of Compound 1, Naphthalene-l,5-disulfonic Acid Form 1.

[0063] FIG. 17 depicts an experimental TGA / DSC thermogram of a crystalline form of a naphthalene-l,5-disulfonic acid salt of Compound 1, Naphthalene-l,5-disulfonic Acid Form 1.

[0064] FIG. 18 depicts an experimental XRPD pattern of a crystalline form of a naphthalene-l,5-disulfonic acid salt of Compound 1, Naphthalene-l,5-disulfonic Acid Form 2.

[0065] FIG. 19 depicts an experimental TGA / DSC thermogram of a crystalline form of a naphthalene-l,5-disulfonic acid salt of Compound 1, Naphthalene-l,5-disulfonic Acid Form 2.

[0066] FIG. 20 depicts an experimental XRPD pattern of a crystalline form of a sulfuric acid salt of Compound 1, Sulfuric Acid Form 1.

[0067] FIG. 21 depicts an experimental TGA / DSC thermogram of a crystalline form of a sulfuric acid salt of Compound 1, Sulfuric Acid Form 1.

[0068] FIG. 22 depicts an experimental XRPD pattern of a crystalline form of a sulfuric acid salt of Compound 1, Sulfuric Acid Form 2.

[0069] FIG. 23 depicts an experimental TGA / DSC thermogram of a crystalline form of a sulfuric acid salt of Compound 1, Sulfuric Acid Form 2.

[0070] FIG. 24 depicts an experimental XRPD pattern of a crystalline form of a sulfuric acid salt of Compound 1, Sulfuric Acid Form 3.

[0071] FIG. 25 depicts an experimental TGA / DSC thermogram of a crystalline form of a sulfuric acid salt of Compound 1, Sulfuric Acid Form 3.

[0072] FIG. 26 depicts an experimental XRPD pattern of a crystalline form of a sulfuric acid salt of Compound 1, Sulfuric Acid Form 4.

[0073] FIG. 27 depicts an experimental XRPD pattern of a crystalline form of a sulfuric acid salt of Compound 1, Sulfuric Acid Form 5.

[0074] FIG. 28 depicts an experimental XRPD pattern of a crystalline form of an ethane- 1,2-disulfonic acid salt of Compound 1, Ethane- 1,2-disulfonic Acid Form 1.

[0075] FIG. 29 depicts an experimental TGA / DSC thermogram of a crystalline form of an ethane- 1,2-disulfonic acid salt of Compound 1, Ethane- 1,2-disulfonic Acid Form 1.

[0076] FIG. 30 depicts an experimental XRPD pattern of a crystalline form of an esylate salt of Compound 1, Esylate Form 1.

[0077] FIG. 31 depicts an experimental TGA / DSC thermogram of a crystalline form of an esylate salt of Compound 1, Esylate Form 1.

[0078] FIG. 32 depicts an experimental XRPD pattern of a crystalline form of a 2- hydroxyethanesulfonic acid salt of Compound 1, 2-Hydroxyethanesulfonic Acid Form 1.

[0079] FIG. 33 depicts an experimental TGA / DSC thermogram of a crystalline form of a 2-hydroxy ethanesulfonic acid salt of Compound 1, 2-Hydroxyethanesulfonic Acid Form 1.

[0080] FIG. 34 depicts an experimental XRPD pattern of a crystalline form of a tosylate salt of Compound 1, Tosylate Form 1.

[0081] FIG. 35 depicts an experimental TGA / DSC thermogram of a crystalline form of a tosylate salt of Compound 1, Tosylate Form 1.

[0082] FIG. 36 depicts an experimental XRPD pattern of a crystalline form of a tosylate salt of Compound 1, Tosylate Form 2.

[0083] FIG. 37 depicts an experimental TGA / DSC thermogram of a crystalline form of a tosylate salt of Compound 1, Tosylate Form 2.

[0084] FIG. 38 depicts an experimental XRPD pattern of a crystalline form of a tosylate salt of Compound 1, Tosylate Form 3.

[0085] FIG. 39 depicts an experimental TGA / DSC thermogram of a crystalline form of a tosylate salt of Compound 1, Tosylate Form 3.

[0086] FIG. 40 depicts an experimental XRPD pattern of a crystalline form of a tosylate salt of Compound 1, Tosylate Form 4.

[0087] FIG. 41 depicts an experimental TGA / DSC thermogram of a crystalline form of a tosylate salt of Compound 1, Tosylate Form 4.

[0088] FIG. 42 depicts an experimental XRPD pattern of a crystalline form of a tosylate salt of Compound 1, Tosylate Form 5.

[0089] FIG. 43 depicts an experimental TGA / DSC thermogram of a crystalline form of a tosylate salt of Compound 1, Tosylate Form 5.

[0090] FIG. 44 depicts an experimental XRPD pattern of a crystalline form of a tosylate salt of Compound 1, Tosylate Form 6.

[0091] FIG. 45 depicts an experimental TGA / DSC thermogram of a crystalline form of a tosylate salt of Compound 1, Tosylate Form 6.

[0092] FIG. 46 depicts an experimental XRPD pattern of a crystalline form of a tosylate salt of Compound 1, Tosylate Form 7.

[0093] FIG. 47 depicts an experimental TGA / DSC thermogram of a crystalline form of a tosylate salt of Compound 1, Tosylate Form 7.

[0094] FIG. 48 depicts an experimental XRPD pattern of a crystalline form of a methanesulfonic acid salt of Compound 1, Methanesulfonic Acid Form 1.

[0095] FIG. 49 depicts an experimental TGA / DSC thermogram of a crystalline form of a methanesulfonic acid salt of Compound 1, Methanesulfonic Acid Form 1.

[0096] FIG. 50 depicts an experimental XRPD pattern of a crystalline form of a napthalene-2-sulfonic acid salt of Compound 1, Napthalene-2-sulfonic Acid Form 1.

[0097] FIG. 51 depicts an experimental TGA / DSC thermogram of a crystalline form of a napthalene-2-sulfonic acid salt of Compound 1, Napthalene-2-sulfonic Acid Form 1.

[0098] FIG. 52 depicts an experimental XRPD pattern of a crystalline form of a napthalene-2-sulfonic acid salt of Compound 1, Napthalene-2-sulfonic Acid Form 2.

[0099] FIG. 53 depicts an experimental TGA / DSC thermogram of a crystalline form of a napthalene-2-sulfonic acid salt of Compound 1, Napthalene-2-sulfonic Acid Form 2.

[0100] FIG. 54 depicts an experimental XRPD pattern of a crystalline form of a napthalene-2-sulfonic acid salt of Compound 1, Napthalene-2-sulfonic Acid Form 3.

[0101] FIG. 55 depicts an experimental TGA / DSC thermogram of a crystalline form of a napthalene-2-sulfonic acid salt of Compound 1, Napthalene-2-sulfonic Acid Form 3.

[0102] FIG. 56 depicts an experimental XRPD pattern of a crystalline form of a benzenesulfonic acid salt of Compound 1, Benzenesulfonic Acid Form 1.

[0103] FIG. 57 depicts an experimental TGA / DSC thermogram of a crystalline form of a benzenesulfonic acid salt of Compound 1, Benzenesulfonic Acid Form 1.

[0104] FIG. 58 depicts an experimental XRPD pattern of a crystalline form of a benzenesulfonic acid salt of Compound 1, Benzenesulfonic Acid Form 2.

[0105] FIG. 59 depicts an experimental TGA / DSC thermogram of a crystalline form of a benzenesulfonic acid salt of Compound 1, Benzenesulfonic Acid Form 2.

[0106] FIG. 60 depicts an experimental XRPD pattern of a crystalline form of a maleic acid salt of Compound 1, Maleic Acid Form 1.

[0107] FIG. 61 depicts an experimental XRPD pattern of a crystalline form of a phosphoric acid salt of Compound 1, Phosphoric Acid Form 1.

[0108] FIG. 62 depicts an experimental XRPD pattern of a crystalline form of a phosphoric acid salt of Compound 1, Phosphoric Acid Form 2.

[0109] FIG. 63 depicts an experimental XRPD pattern of a crystalline form of a (+)- camphor- 10-sulfonic acid salt of Compound 1, (+)-Camphor-10-sulfonic Acid Form 1.

[0110] FIG. 64 depicts an experimental TGA / DSC thermogram of a crystalline form of a (+)-camphor- 10-sulfonic acid salt of Compound 1, (+)-Camphor- 10-sulfonic Acid Form 1.

[0111] FIG. 65 depicts an experimental XRPD pattern of a crystalline freebase form of Compound 1, Freebase Form 1.

[0112] FIG. 66 depicts an experimental TGA / DSC pattern of a crystalline freebase form of Compound 1, Freebase Form 1.

[0113] FIG. 67 depicts an experimental XRPD pattern of a crystalline freebase form of Compound 1, Freebase Form 3.

[0114] FIG. 68 depicts an experimental XRPD pattern of a crystalline freebase form of Compound 1, Freebase Form 4.

[0115] FIG. 69 depicts plasma concentration of Compound 1 in healthy volunteers over time after administration of 120 mg single dose at time zero, under fasted and fed conditions.DETAILED DESCRIPTION

[0116] The following description sets forth exemplary methods, parameters and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.

[0117] As used herein, reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”. In some embodiments, “about”, when used before a list of values or parameters, applies to each of the following such values or parameters. For example, in some embodiments, “about 40 mg, 80 mg, or 120 mg” is equivalent to “about 40 mg, about 80 mg, or about 120 mg”.

[0118] In some embodiments, the term “about” indicates that the recited value or parameter can vary by ±5% of that value or parameter. In some embodiments, the term “about” indicates that the recited value or parameter can vary by ±1%, ±2%, ±3%, ±4%, ±5%, ±10%, ±15%, ±20%, or ±50% of that value or parameter. In some embodiments, the term “about”, when used in reference to the 2-theta angle assigned to an XRPD pattern peak, indicates that the recited peak can vary by ± 0.2 °29. In some embodiments, the term “about”, when used in reference to the 2-theta angle assigned to an XRPD pattern peak, indicates that the recited peak can vary by ± 0.1 °29, ± 0.2 °29, ± 0.3 °29, ± 0.4 °29, ± 0.5 °29, ± 0.6 °29, ± 0.7 °29, ± 0.8 °29, ± 0.9 °29, ± 1.0 °29, ± 1.5 °29, or ± 2.0 °29. In some embodiments, the term “about”, when used in reference to a temperature, indicates that the recited temperature can vary by ± 3 °C. In some embodiments, the term “about”, when used in reference to awt.%, indicates that the recited wt.% can vary by ±1 wt.%. In some embodiments, the term “about”, when used in reference to a wt.%, indicates that the recited wt.% can vary by ±0.1 wt.%, ±0.5 wt.%, ±1 wt.%, ±2 wt.%, ±3 wt.%, ±4 wt.%, or ±5 wt.%.

[0119] The term “excipient” as used herein means an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound of the present disclosure as an active ingredient. Various substances may be embraced by the term excipient, including without limitation any substance used as a binder, disintegrant, coating, compression / encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending / gelling agent, or wet granulation agent. Binders include, e.g., carbomers, povidone, xanthan gum, etc.; coatings include, e.g., cellulose acetate phthalate, ethylcellulose, gellan gum, maltodextrin, enteric coatings, etc.; compression / encapsulation aids include, e.g., calcium carbonate, dextrose, fructose de (de = “directly compressible”), honey de, lactose (anhydrate or monohydrate; optionally in combination with aspartame, cellulose, or microcrystalline cellulose), starch de, sucrose, etc.; disintegrants include, e.g., croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, e.g., maltodextrin, carrageenans, etc.; lubricants include, e.g., magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; materials for chewable tablets include, e.g., dextrose, fructose de, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; suspending / gelling agents include, e.g., carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame, dextrose, fructose de, sorbitol, sucrose de, etc.; and wet granulation agents include, e.g., calcium carbonate, maltodextrin, microcrystalline cellulose, etc.

[0120] The terms “individual”, “subject” and “patient” refer to mammals and includes humans and non-human mammals. Examples of patients include, but are not limited to, mice, rats, hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cows, and humans. In some embodiments, patient refers to a human.

[0121] As used herein, the term “mammal” includes, but is not limited to, humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows, pigs, and sheep.

[0122] “Pharmaceutically acceptable” refers to safe and non-toxic, and suitable for in vivo or for human administration.

[0123] As used herein, the term “pharmaceutically acceptable salts” is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, N,N'- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge, S. M., et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0124] “Treating” or “treatment” of a disease in a patient refers to inhibiting the disease or arresting its development; or ameliorating or causing regression of the disease. As used herein, “treatment” or “treating” is an approach for obtaining beneficial or desired resultsincluding clinical results. For purposes of this disclosure, beneficial or desired results include, but are not limited to, one or more of the following: decreasing one more symptoms resulting from the disease or disorder, diminishing the extent of the disease or disorder, stabilizing the disease or disorder (e.g., preventing or delaying the worsening of the disease or disorder), delaying the occurrence or recurrence of the disease or disorder, delay or slowing the progression of the disease or disorder, ameliorating the disease or disorder state, providing a remission (whether partial or total) of the disease or disorder, decreasing the dose of one or more other medications required to treat the disease or disorder, enhancing the effect of another medication used to treat the disease or disorder, delaying the progression of the disease or disorder, increasing the quality of life, and / or prolonging survival of a patient. Also encompassed by “treatment” is a reduction of pathological consequence of the disease or disorder. The methods of the present disclosure contemplate any one or more of these aspects of treatment.

[0125] “Preventing”, “prevention”, or “prophylaxis” of a disease in a patient refers to preventing the disease from occurring in a patient that is predisposed or does not yet display symptoms of the disease.

[0126] The phrase “therapeutically effective amount” means an amount of a compound of the present disclosure that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.

[0127] The terms “cancer” and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.

[0128] Where individual embodiments are disclosed, it should be appreciated that this disclosure is not limiting and that all embodiments may be combined. It should also be noted that references to methods of treatment herein should be read as equivalent to compounds and / or compositions for use in said methods of treatment.Crystalline Forms

[0129] In one aspect, provided herein is a crystalline form of (15,25)-A-(2-(4,6- bis(methoxy-t / 3)pyrimidin-5-yl)-l -methyl- 17 / -pyrrolo[2, 3-c]pyri din-5-yl)-2-fluorocyclopropane- 1 -carboxamide (Compound 1) or a pharmaceutically acceptable salt thereof. Compound 1 or a pharmaceutically acceptable salt thereof may be prepared by a variety of procedures known in the art. Exemplary methods of making Compound 1 are described in International Patent Application Publication No. WO2022 / 076975, which is incorporated herein by reference in its entirety.Compound 1

[0130] In some embodiments, the crystalline form is a crystalline form of a freebase of Compound 1.

[0131] In some embodiments, the crystalline form is a crystalline form of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the crystalline form is a crystalline form of a HC1, HBr, naphthalene-l,5-disulfonic acid, sulfuric acid, ethane-1,2- disulfonic acid, esylate, 2-hydroxyethanesulfonic acid, tosylate, methanesulfonic acid, napthalene-2-sulfonic acid, benzenesulfonic acid, maleic acid, phosphoric acid, or (+)- camphor- 10-sulfonic acid salt of Compound 1. In some embodiments, the crystalline form is a crystalline form of an esylate salt of Compound 1. In some embodiments, the crystalline form is a crystalline form of a tosylate salt of Compound 1. In some embodiments, the tosylate salt is a mono-tosylate salt. In some embodiments, the crystalline form is a crystalline form of a hydrate of a tosylate salt of Compound 1. In some embodiments, the crystalline form is a hydrate. In some embodiments, the crystalline form is a monohydrate. In some embodiments, the crystalline form is a hemihydrate. In some embodiments, the crystalline form is anhydrous.

[0132] In the following section, it should be understood that, where embodiments are recited in which a crystalline form is characterized as having an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in a Table (for example, Table 1), embodiments are also provided in which the crystalline form is characterized ashaving an XRPD pattern comprising a peak assigned at an angle corresponding to the peak of greatest intensity as recited in the table (for example, a peak assigned at an angle 2-theta of 26.9742 for Table 1). Also provided are embodiments in which the crystalline form is characterized as having an XRPD pattern comprising peaks assigned at the angles corresponding to the 2 peaks of greatest intensity as recited in the table (for example, peaks assigned at angles 2-theta of 26.9742 and 21.8651 for Table 1). Also provided are embodiments in which the crystalline form is characterized as having an XRPD pattern comprising peaks assigned at the angles corresponding to the 5 peaks of greatest intensity as recited in the table (for example, peaks assigned at angles 2-theta of 26.7432, 21.8651, 22.0309, 20.5224, and 12.1926 for Table 1). Also provided are embodiments in which the crystalline form is characterized as having an XRPD pattern comprising peaks assigned at the angles corresponding to the 10 peaks of greatest intensity as recited in the table. Also provided are embodiments in which the crystalline form is characterized as having an XRPD pattern comprising peaks assigned at the angles corresponding to the 20 peaks of greatest intensity as recited in the table.

[0133] Also provided are embodiments in which the crystalline form is characterized as having an XRPD pattern comprising a peak assigned at an angle within ± 0.2 degrees 2-theta of the angle of the peak of greatest intensity as recited in the table (for example, a peak assigned at an angle 2-theta of 26.97 ± 0.2 °29 for Table 1). Also provided are embodiments in which the crystalline form is characterized as having an XRPD pattern comprising peaks assigned at the angles each within ± 0.2 degrees 2-theta of the 2 peaks of greatest intensity as recited in the table (for example, peaks assigned at angles 2-theta of 26.97 ± 0.2 and 21.87 ± 0.2 for Table 1). Also provided are embodiments in which the crystalline form is characterized as having an XRPD pattern comprising peaks assigned at the angles each within ± 0.2 degrees 2-theta of the 5 peaks of greatest intensity as recited in the table (for example, peaks assigned at angles 2-theta of 26.74 ± 0.2, 21.87 ± 0.2, 22.03 ± 0.2, 20.52 ± 0.2, and 12.19 ± 0.2 for Table 1). Also provided are embodiments in which the crystalline form is characterized as having an XRPD pattern comprising peaks assigned at the angles each within ± 0.2 degrees 2-theta of the 10 peaks of greatest intensity as recited in the table. Also provided are embodiments in which the crystalline form is characterized as having an XRPD pattern comprising peaks assigned at the angles each within ± 0.2 degrees 2-theta of the 20 peaks of greatest intensity as recited in the table. Also provided are embodiments in which the crystalline form is characterized as having an XRPD pattern comprising one ormore peaks, each assigned at an angle within ± 0.2 degrees 2-theta of a peak recited in the table.Freebase Form 1

[0134] In some embodiments, the crystalline form is Freebase Form 1. In some embodiments, the crystalline form is characterized as having an XRPD pattern substantially as shown in FIG. 65. In some embodiments, the crystalline form is characterized as having an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 1. In some embodiments, the crystalline form is characterized as having a TGA / DSC thermogram substantially as shown in FIG. 66.Table 1Freebase Form 3

[0135] In some embodiments, the crystalline form is Freebase Form 3. In some embodiments, the crystalline form is characterized as having an XRPD pattern substantially as shown in FIG. 67. In some embodiments, the crystalline form is characterized as having an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 2.Table 2Freebase Form 4

[0136] In some embodiments, the crystalline form is Freebase Form 4. In some embodiments, the crystalline form is characterized as having an XRPD pattern substantially as shown in FIG. 68. In some embodiments, the crystalline form is characterized as having an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 3.Table 3HCl Form 1

[0137] In some embodiments, the crystalline form is HCl Form 1. In some embodiments, the crystalline form is characterized as having an XRPD pattern substantially as shown in FIG. 1. In some embodiments, the crystalline form is characterized as having an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 4. In some embodiments, the crystalline form is characterized as having a TGA / DSC thermogram substantially as shown in FIG. 2.

[0138] In some embodiments, the crystalline form is characterized as having an endothermic event with an onset at about 228 °C.Table 4No. Pos. [°20] d-spacing [Al Rel. Int. [%]9 12.8457 6.8860 21.0410 13.2957 6.6539 16.9711 13.8000 6.4118 37.4712 14.4363 6.1306 17.8313 14.9322 5.9281 9.0214 15.4070 5.7465 2.4115 15.7606 5.6184 3.6216 15.9804 5.5416 8.9217 16.1602 5.4803 5.3618 16.7051 5.3028 20.6119 17.1707 5.1600 10.0720 17.6514 5.0206 2.8621 18.3945 4.8194 21.1022 18.8995 4.6917 10.1723 19.2501 4.6071 5.6824 19.4620 4.5574 19.8525 19.6832 4.5067 16.1626 20.2159 4.3891 13.7327 20.5423 4.3201 13.6028 21.0367 4.2197 12.2529 21.5087 4.1281 17.8230 21.9245 4.0508 61.8931 22.8862 3.8827 17.1132 23.1223 3.8435 19.2733 23.6013 3.7666 41.6834 24.6494 3.6088 22.7035 25.3334 3.5129 21.7236 25.6369 3.4720 22.6937 26.4001 3.3733 10.5738 26.9369 3.3073 6.3239 27.3212 3.2616 9.7840 27.5518 3.2349 11.9841 27.8100 3.2054 36.1742 28.5349 3.1256 3.7143 28.8150 3.0959 3.5444 29.6028 3.0152 5.0245 29.9559 2.9805 10.0446 31.1371 2.8701 12.1847 31.7041 2.8200 5.2748 32.0603 2.7895 7.1249 34.0022 2.6345 3.68HCl Form 230

[0139] In some embodiments, the crystalline form is HC1 Form 2. In some embodiments, the crystalline form is characterized as having an XRPD pattern substantially as shown inFIG. 3. In some embodiments, the crystalline form is characterized as having an XRPD pattern comprising one or more peaks as assigned at angles 2 -theta in degrees as recited inTable 5.Table 5No. Pos. [°20] d-spacing [A] Rel. Int. [%]1 3.2663 27.0278 2.272 7.7088 11.4592 18.113 8.4347 10.4745 2.954 8.6959 10.1605 13.245 10.0797 8.7685 27.626 10.5380 8.3882 4.807 10.8234 8.1676 10.408 11.8383 7.4696 3.409 12.5617 7.0410 6.6210 12.9318 6.8403 5.9111 13.6480 6.4829 100.0012 14.5017 6.1031 8.0913 16.3407 5.4202 11.9914 16.7377 5.2925 10.9715 17.0209 5.2051 2.4916 17.3456 5.1084 5.3517 17.9620 4.9344 4.1418 18.4344 4.8090 4.3419 19.0097 4.6648 63.7820 19.2614 4.6044 81.1621 20.0852 4.4174 2.9922 20.2156 4.3892 7.2523 20.9865 4.2296 6.9424 21.2396 4.1798 8.1125 21.6358 4.1041 10.9026 22.1595 4.0083 15.3527 23.0510 3.8553 8.0728 23.5191 3.7796 5.9429 24.3989 3.6453 14.2330 24.7562 3.5935 25.7731 25.4706 3.4943 69.9032 26.2303 3.3948 13.5533 27.0143 3.2980 3.0734 27.4897 3.2420 62.7135 29.3918 3.0364 3.3436 29.9355 2.9825 0.4637 30.6800 2.9118 23.9531No. Pos. [°20] d-spacing [A] Rel. Int. [%]38 31.2883 2.8565 5.0739 32.0578 2.7897 5.5040 32.4659 2.7556 11.0341 32.8334 2.7256 11.1742 33.0808 2.7057 9.4843 33.7561 2.6531 2.67HCl Form 3

[0140] In some embodiments, the crystalline form is HC1 Form 3. In some embodiments, the crystalline form is characterized as having an XRPD pattern substantially as shown inFIG. 4. In some embodiments, the crystalline form is characterized as having an XRPD pattern comprising one or more peaks as assigned at angles 2 -theta in degrees as recited inTable 6.Table 6No. Pos. [°20] d-spacing [Al Rel. Int. [%]1 7.7511 11.3967 5.812 8.6862 10.1718 2.563 9.1160 9.6932 4.214 9.4181 9.3829 73.575 10.0760 8.7717 75.966 10.2089 8.6578 100.007 10.5366 8.3893 7.998 10.7984 8.1864 7.469 11.8239 7.4786 3.1310 12.2433 7.2234 1.5411 12.8165 6.9016 2.6712 13.0233 6.7925 2.5913 13.3951 6.6047 5.5914 13.6555 6.4794 14.0415 14.0318 6.3064 4.0216 14.6329 6.0487 2.2317 15.0747 5.8724 0.7518 16.2171 5.4612 5.3019 16.7867 5.2772 6.2420 17.2856 5.1260 3.7321 18.4427 4.8069 2.3422 19.0527 4.6544 2.4223 19.2423 4.6089 8.3024 19.4098 4.5695 6.2625 20.1160 4.4107 2.6732HCl Form 4

[0141] In some embodiments, the crystalline form is HCl Form 4. In some embodiments, the crystalline form is characterized as having an XRPD pattern substantially as shown in FIG. 5. In some embodiments, the crystalline form is characterized as having an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 7. In some embodiments, the crystalline form is characterized as having a TGA / DSC thermogram substantially as shown in FIG. 6.

[0142] In some embodiments, the crystalline form is characterized as having an endothermic event with an onset at about 198 °C. In some embodiments, the crystalline form is characterized as having an endothermic event with an onset at about 220 °C.Table 7HCl Form 5

[0143] In some embodiments, the crystalline form is HCl Form 5. In some embodiments, the crystalline form is characterized as having an XRPD pattern substantially as shown in FIG. 7. In some embodiments, the crystalline form is characterized as having an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 8.Table 8HCl Form 6

[0144] In some embodiments, the crystalline form is HCl Form 6. In some embodiments, the crystalline form is characterized as having an XRPD pattern substantially as shown in FIG. 8. In some embodiments, the crystalline form is characterized as having an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 9.Table 9HBr Form 1

[0145] In some embodiments, the crystalline form is HBr Form 1. In some embodiments, the crystalline form is characterized as having an XRPD pattern substantially as shown in FIG. 9. In some embodiments, the crystalline form is characterized as having an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 10. In some embodiments, the crystalline form is characterized as having a TGA / DSC thermogram substantially as shown in FIG. 10.

[0146] In some embodiments, the crystalline form is characterized as having an endothermic event at about 175 °C.HBr Form 2

[0147] In some embodiments, the crystalline form is HBr Form 2. In some embodiments, the crystalline form is characterized as having an XRPD pattern substantially as shown in FIG. 11. In some embodiments, the crystalline form is characterized as having an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 11. In some embodiments, the crystalline form is characterized as having a TGA / DSC thermogram substantially as shown in FIG. 12.

[0148] In some embodiments, the crystalline form is characterized as having an endothermic event with an onset at about 142 °C. In some embodiments, the crystalline form is characterized as having an endothermic event with an onset at about 211 °C.Table 11HBr Form 3

[0149] In some embodiments, the crystalline form is HBr Form 3. In some embodiments, the crystalline form is characterized as having an XRPD pattern substantially as shown in FIG. 13. In some embodiments, the crystalline form is characterized as having an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 12.Table 12HBr Form 4

[0150] In some embodiments, the crystalline form is HBr Form 4. In some embodiments, the crystalline form is characterized as having an XRPD pattern substantially as shown in FIG. 14. In some embodiments, the crystalline form is characterized as having an XRPDpattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 13. In some embodiments, the crystalline form is characterized as having a TGA / DSC thermogram substantially as shown in FIG. 15.

[0151] In some embodiments, the crystalline form is characterized as having an endothermic event with an onset at about 132 °C. In some embodiments, the crystalline form is characterized as having an endothermic event with an onset at about 203 °C.Table 13Naphthalene-1 ,5-disulfonic Acid Form 1

[0152] In some embodiments, the crystalline form is Naphthal ene-l,5-disulfonic Acid Form 1. In some embodiments, the crystalline form is characterized as having an XRPD pattern substantially as shown in FIG. 16. In some embodiments, the crystalline form is characterized as having an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 14. In some embodiments, the crystalline form is characterized as having a TGA / DSC thermogram substantially as shown in FIG. 17.

[0153] In some embodiments, the crystalline form is characterized as having an exothermic event with an onset at about 254 °C. In some embodiments, the crystalline form is characterized as having an exothermic event with an onset at about 299 °C.Table 14Naphthalene-1 ,5-disulfonic Acid Form 2

[0154] In some embodiments, the crystalline form is Naphthal ene-l,5-disulfonic Acid Form 2. In some embodiments, the crystalline form is characterized as having an XRPD pattern substantially as shown in FIG. 18. In some embodiments, the crystalline form is characterized as having an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 15. In some embodiments, the crystalline form is characterized as having a TGA / DSC thermogram substantially as shown in FIG. 19.Table 15Sulfuric Acid Form 1

[0155] In some embodiments, the crystalline form is Sulfuric Acid Form 1. In some embodiments, the crystalline form is characterized as having an XRPD pattern substantially as shown in FIG. 20. In some embodiments, the crystalline form is characterized as having an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 16. In some embodiments, the crystalline form is characterized as having a TGA / DSC thermogram substantially as shown in FIG. 21.Table 16Sulfuric Acid Form 2

[0156] In some embodiments, the crystalline form is Sulfuric Acid Form 2. In some embodiments, the crystalline form is characterized as having an XRPD pattern substantially as shown in FIG. 22. In some embodiments, the crystalline form is characterized as having an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 17. In some embodiments, the crystalline form is characterized as having a TGA / DSC thermogram substantially as shown in FIG. 23.Table 17Sulfuric Acid Form 3

[0157] In some embodiments, the crystalline form is Sulfuric Acid Form 3. In some embodiments, the crystalline form is characterized as having an XRPD pattern substantially as shown in FIG. 24. In some embodiments, the crystalline form is characterized as having an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 18. In some embodiments, the crystalline form is characterized as having a TGA / DSC thermogram substantially as shown in FIG. 25.

[0158] In some embodiments, the crystalline form is characterized as having an endothermic event with an onset at about 165 °C. In some embodiments, the crystalline form is characterized as having an exothermic event with an onset at about 223 °C.

[0159] In some embodiments, the crystalline form is characterized as having an endothermic event with an onset at about 128 °C. In some embodiments, the crystalline form is characterized as having an endothermic event with an onset at about 163 °C. In some embodiments, the crystalline form is characterized as having an endothermic event with an onset at about 246 °C.Table 18Sulfuric Acid Form 4

[0160] In some embodiments, the crystalline form is Sulfuric Acid Form 4. In some embodiments, the crystalline form is characterized as having an XRPD pattern substantially as shown in FIG. 26. In some embodiments, the crystalline form is characterized as having an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 19.Table 19Sulfuric Acid Form 5

[0161] In some embodiments, the crystalline form is Sulfuric Acid Form 5. In some embodiments, the crystalline form is characterized as having an XRPD pattern substantially as shown in FIG. 27. In some embodiments, the crystalline form is characterized as having an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 20.Table 20Ethane- 1,2-disulfonic Acid Form 1

[0162] In some embodiments, the crystalline form is Ethane-l,2-disulfonic acid Form 1. In some embodiments, the crystalline form is characterized as having an XRPD pattern substantially as shown in FIG. 28. In some embodiments, the crystalline form is characterized as having an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 21. In some embodiments, the crystalline form is characterized as having a TGA / DSC thermogram substantially as shown in FIG. 29.

[0163] In some embodiments, the crystalline form is characterized as having an endothermic event with an onset at about 217 °C.Table 21Esylate Form 1

[0164] In some embodiments, the crystalline form is Esylate Form 1. In some embodiments, the crystalline form is characterized as having an XRPD pattern substantially as shown in FIG. 30. In some embodiments, the crystalline form is characterized as having an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 22. In some embodiments, the crystalline form is characterized as having a TGA / DSC thermogram substantially as shown in FIG. 31.

[0165] In some embodiments, the crystalline form is characterized as having an endothermic event with an onset at about 227 °C. In some embodiments, the crystalline form is characterized as having an exothermic event with an onset at about 237 °C.

[0166] In some embodiments, the crystalline form is characterized as having a weight loss of about 0.3% between about 32 °C and about 194 °C. In some embodiments, the crystalline form is characterized as having a weight loss of about 2.7% between about 193 °C and about 256 °C.Table 222-Hydroxyethanesulfonic Acid Form 1

[0167] In some embodiments, the crystalline form is 2-Hydroxyethanesulfonic Acid Form 1. In some embodiments, the crystalline form is characterized as having an XRPD pattern substantially as shown in FIG. 32. In some embodiments, the crystalline form is characterized as having an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 23. In some embodiments, the crystalline form is characterized as having a TGA / DSC thermogram substantially as shown in FIG. 33.

[0168] In some embodiments, the crystalline form is characterized as having an endothermic event with an onset at about 207 °C. In some embodiments, the crystalline form is characterized as having an endothermic event with an onset at about 244 °C.Table 23Tosylate Form 1

[0169] In some embodiments, the crystalline form is Tosylate Form 1. In some embodiments, the crystalline form is characterized as having an XRPD pattern substantially as shown in FIG. 34. In some embodiments, the crystalline form is characterized as having an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 24. In some embodiments, the crystalline form is characterized as having an X-ray powder diffraction (XRPD) pattern comprising a peak at an angle 2-theta of about 17.65. In some embodiments, the crystalline form is characterized as having an X-ray powder diffraction (XRPD) pattern comprising peaks at angles 2-theta of about 17.65 and about 24.47. In some embodiments, the crystalline form is characterized as having an X-ray powder diffraction (XRPD) pattern comprising peaks at angles 2-theta of about 17.65, about 24.47, about 21.74, about 16.55, and about 14.30. In some embodiments, the crystalline form is characterized as having an X-ray powder diffraction (XRPD) pattern comprising peaks at angles 2-theta of about 17.65, about 24.47, about 21.74, about 16.55, about 14.30, about23.95, about 25.29, about 15.29, about 28.77, and about 28.65. In some embodiments, the crystalline form is characterized as having an X-ray powder diffraction (XRPD) pattern comprising peaks at angles 2-theta of about 17.65, about 24.47, about 21.74, about 16.55, about 14.30, about 23.95, about 25.29, about 15.29, about 28.77, about 28.65, about 13.77, about 21.55, about 22.65, about 19.43, about 13.47, about 29.21, about 22.70, about 9.14, about 26.40, and about 23.86.

[0170] In some embodiments, the crystalline form is characterized as having a TGA / DSC thermogram substantially as shown in FIG. 35. In some embodiments, the crystalline form is characterized as having endothermic transitions at about 71.2 °C and about 127.9 °C, as measured by DSC. In some embodiments, the crystalline form is characterized as showing a weight loss of about 3.2% from about 37 °C to about 139 °C, and a weight loss of about 0.66% from about 139 °C to about 265 °C as determined by TGA.

[0171] In some embodiments, the crystalline form is characterized as having an endothermic event with an onset at about 66 °C. In some embodiments, the crystalline form is characterized as having an endothermic event with an onset at about 144 °C. In some embodiments, the crystalline form is characterized as having an endothermic event with an onset at about 264 °C.

[0172] In some embodiments, the crystalline form is characterized as having a weight loss of about 3.1% between about 37 °C and about 140 °C. In some embodiments, the crystalline form is characterized as having a weight loss of about 1% between about 139 °C and about 267 °C.Table 24Tosylate Form 2

[0173] In some embodiments, the crystalline form is Tosylate Form 2. In some embodiments, the crystalline form is characterized as having an XRPD pattern substantiallyas shown in FIG. 36. In some embodiments, the crystalline form is characterized as having a TGA / DSC thermogram substantially as shown in FIG. 37.Tosylate Form 3

[0174] In some embodiments, the crystalline form is Tosylate Form 3. In some embodiments, the crystalline form is characterized as having an XRPD pattern substantially as shown in FIG. 38. In some embodiments, the crystalline form is characterized as having an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 25. In some embodiments, the crystalline form is characterized as having a TGA / DSC thermogram substantially as shown in FIG. 39.Table 25Tosylate Form 4

[0175] In some embodiments, the crystalline form is Tosylate Form 4. In some embodiments, the crystalline form is characterized as having an XRPD pattern substantially as shown in FIG. 40. In some embodiments, the crystalline form is characterized as having an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 26. In some embodiments, the crystalline form is characterized as having an X-ray powder diffraction (XRPD) pattern comprising a peak at an angle 2-theta of about 24.80. In some embodiments, the crystalline form is characterized as having an X-ray powder diffraction (XRPD) pattern comprising peaks at angles 2-theta of about 24.80 and about 17.38. In some embodiments, the crystalline form is characterized as having an X-ray powder diffraction (XRPD) pattern comprising peaks at angles 2-theta of about 24.80, about 17.38, about 17.72, about 14.45, and about 16.97. In some embodiments, the crystalline form is characterized as having an X-ray powder diffraction (XRPD) pattern comprising peaks at angles 2-theta of about 24.80, about 17.38, about 17.72, about 14.45, about 16.97, about 24.12, about 21.31, about 5.56, about 14.05, and about 28.84. In some embodiments, the crystalline form is characterized as having an X-ray powder diffraction (XRPD) pattern comprising peaks at angles 2-theta of about 24.80, about 17.38, about 17.72, about 14.45, about 16.97, about 24.12, about 21.31, about 5.56, about 14.05, about 28.84, about 22.34, about 29.15, about 18.63, about 19.48, about 18.81, about 22.56, about 21.71, about 10.72, about 23.79, and about 10.61.

[0176] In some embodiments, the crystalline form is characterized as having a TGA / DSC thermogram substantially as shown in FIG. 41. In some embodiments, the crystalline form ischaracterized as having endothermic transitions at about 72.4 °C and about 131.5 °C, as measured by DSC. In some embodiments, the crystalline form is characterized as showing a weight loss of about 3.1% from about 31 °C to about 158 °C and a weight loss of about 1.2% from about 158 °C to about 198 °C, as determined by TGA.

[0177] In some embodiments, the crystalline form is characterized as having an endothermic event with an onset at about 72 °C. In some embodiments, the crystalline form is characterized as having an endothermic event with an onset at about 132 °C. In some embodiments, the crystalline form is characterized as having an endothermic event with an onset at about 260 °C.

[0178] In some embodiments, the crystalline form is characterized as having a weight loss of about 3.1% between about 31 °C and about 159 °C. In some embodiments, the crystalline form is characterized as having a weight loss of about 1% between about 158 °C and about 199 °C.Table 26Tosylate Form 5

[0179] In some embodiments, the crystalline form is Tosylate Form 5. In some embodiments, the crystalline form is characterized as having an XRPD pattern substantially as shown in FIG. 42. In some embodiments, the crystalline form is characterized as having an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 27. In some embodiments, the crystalline form is characterized as having a TGA / DSC thermogram substantially as shown in FIG. 43.

[0180] In some embodiments, the crystalline form is characterized as having an endothermic event with an onset at about 80 °C. In some embodiments, the crystalline form is characterized as having an exothermic event with an onset at about 124 °C.

[0181] In some embodiments, the crystalline form is characterized as having a weight loss of about 2.4% between about 48 °C and about 154 °C. In some embodiments, the crystalline form is characterized as having a weight loss of about 0.7% between about 154 °C and about 272 °C.Table 27Tosylate Form 6

[0182] In some embodiments, the crystalline form is Tosylate Form 6. In some embodiments, the crystalline form is characterized as having an XRPD pattern substantially as shown in FIG. 44. In some embodiments, the crystalline form is characterized as having an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 28. In some embodiments, the crystalline form is characterized as having a TGA / DSC thermogram substantially as shown in FIG. 45.

[0183] In some embodiments, the crystalline form is characterized as having an endothermic event with an onset at about 77 °C. In some embodiments, the crystalline form is characterized as having an exothermic event with an onset at about 130 °C. In some embodiments, the crystalline form is characterized as having an exothermic event with an onset at about 239 °C.

[0184] In some embodiments, the crystalline form is characterized as having a weight loss of about 3.3% between about 32 °C and about 111 °C. In some embodiments, the crystalline form is characterized as having a weight loss of about 1.3% between about 110 °C and about 269 °C.Table 28Tosylate Form 7

[0185] In some embodiments, the crystalline form is Tosylate Form 7. In some embodiments, the crystalline form is characterized as having an XRPD pattern substantially as shown in FIG. 46. In some embodiments, the crystalline form is characterized as having an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 29. In some embodiments, the crystalline form is characterized as having an X-ray powder diffraction (XRPD) pattern comprising a peak at an angle 2-theta of about 7.48. In some embodiments, the crystalline form is characterized as having an X-ray powder diffraction (XRPD) pattern comprising peaks at angles 2-theta of about 7.48 and about 23.24. In some embodiments, the crystalline form is characterized as having an X-ray powder diffraction (XRPD) pattern comprising peaks at angles 2-theta of about 7.48, about 23.24, about 9.49, about 14.04, and about 18.07. In some embodiments, the crystalline form is characterized as having an X-ray powder diffraction (XRPD) pattern comprising peaks at angles 2-theta of about 7.48, about 23.24, about 9.49, about 14.04, about 18.07, about 25.96, about 13.88, about 27.31, about 12.51, and about 22.56. In some embodiments, the crystalline form is characterized as having an X-ray powder diffraction (XRPD) pattern comprising peaks at angles 2-theta of about 7.48, about 23.24, about 9.49, about 14.04, about 18.07, about 25.96, about 13.88, about 27.31, about 12.51, about 22.56, about 21.69, about 11.34, about 18.39, about 27.58, about 21.22, about 22.75, about 10.23, about 19.90, about 21.95, and about 13.21.

[0186] In some embodiments, the crystalline form is characterized as having a TGA / DSC thermogram substantially as shown in FIG. 47. In some embodiments, the crystalline form is characterized as having an endothermic transition at about 216.6 °C, as measured by DSC.

[0187] In some embodiments, the crystalline form is characterized as having an endothermic event with an onset at about 217 °C. In some embodiments, the crystalline form is characterized as having an endothermic event with an onset at about 260 °C.

[0188] In some embodiments, the crystalline form is characterized as having a weight loss of about 1% between about 160 °C and about 283 °C.Table 29Methane sulfonic Acid Form 1

[0189] In some embodiments, the crystalline form is Methanesulfonic Acid Form 1. In some embodiments, the crystalline form is characterized as having an XRPD pattern substantially as shown in FIG. 48. In some embodiments, the crystalline form is characterized as having an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 30. In some embodiments, the crystalline form is characterized as having a TGA / DSC thermogram substantially as shown in FIG. 49.

[0190] In some embodiments, the crystalline form is characterized as having an endothermic event with an onset at about 232 °C. In some embodiments, the crystalline form is characterized as having an exothermic event with an onset at about 244 °C.Table 30Napthalene -2 -sulfonic Acid Form 1

[0191] In some embodiments, the crystalline form is Napthalene-2-sulfonic Acid Form 1. In some embodiments, the crystalline form is characterized as having an XRPD pattern substantially as shown in FIG. 50. In some embodiments, the crystalline form is characterized as having an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 31. In some embodiments, the crystalline form is characterized as having a TGA / DSC thermogram substantially as shown in FIG. 51.Table 31Napthalene -2 -sulfonic Acid Form 2

[0192] In some embodiments, the crystalline form is Napthalene-2-sulfonic Acid Form 2. In some embodiments, the crystalline form is characterized as having an XRPD pattern substantially as shown in FIG. 52. In some embodiments, the crystalline form is characterized as having an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 32. In some embodiments, the crystalline form is characterized as having a TGA / DSC thermogram substantially as shown in FIG. 53.

[0193] In some embodiments, the crystalline form is characterized as having an exothermic event with an onset at about 128 °C. In some embodiments, the crystalline form is characterized as having an exothermic event with an onset at about 233 °C.Table 32Napthalene -2 -sulfonic Acid Form 3

[0194] In some embodiments, the crystalline form is Napthalene-2-sulfonic Acid Form 3.In some embodiments, the crystalline form is characterized as having an XRPD pattern substantially as shown in FIG. 54. In some embodiments, the crystalline form is characterizedas having an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 33. In some embodiments, the crystalline form is characterized as having a TGA / DSC thermogram substantially as shown in FIG. 55.Table 33Benzene sulfonic Acid Form 1

[0195] In some embodiments, the crystalline is Benzenesulfonic Acid Form 1. In some embodiments, the crystalline form is characterized as having an XRPD pattern substantially as shown in FIG. 57. In some embodiments, the crystalline form is characterized as having an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 34. In some embodiments, the crystalline form is characterized as having a TGA / DSC thermogram substantially as shown in FIG. 57.Table 34Benzene sulfonic Acid Form 2

[0196] In some embodiments, the crystalline form is Benzenesulfonic acid Form 2. In some embodiments, the crystalline form is characterized as having an XRPD pattern substantially as shown in FIG. 58. In some embodiments, the crystalline form is characterized as having an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 35. In some embodiments, the crystalline form is characterized as having a TGA / DSC thermogram substantially as shown in FIG. 59.Table 35Maleic Acid Form 1

[0197] In some embodiments, the crystalline form is Maleic Acid Form 1. In some embodiments, the crystalline form is characterized as having an XRPD pattern substantially as shown in FIG. 60. In some embodiments, the crystalline form is characterized as having an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 36.Table 36Phosphoric Acid Form 1

[0198] In some embodiments, the crystalline form is Phosphoric Acid Form 1. In some embodiments, the crystalline form is characterized as having an XRPD pattern substantially as shown in FIG. 61. In some embodiments, the crystalline form is characterized as having an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 37.Phosphoric Acid Form 2

[0199] In some embodiments, the crystalline form is Phosphoric Acid Form 2. In some embodiments, the crystalline form is characterized as having an XRPD pattern substantially as shown in FIG. 62. In some embodiments, the crystalline form is characterized as having an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 38.Table 38( + )-Camphor-10-sulfonic Acid Form 1

[0200] In some embodiments, the crystalline form is (+)-Camphor-10-sulfonic Acid Form 1. In some embodiments, the crystalline form is characterized as having an XRPD pattern substantially as shown in FIG. 63. In some embodiments, the crystalline form is characterized as having an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 39. In some embodiments, the crystalline form is characterized as having a TGA / DSC thermogram substantially as shown in FIG. 64.

[0201] In some embodiments, the crystalline form is characterized as having an endothermic event with an onset at about 221 °C.Table 39Pharmaceutical Compositions

[0202] In one aspect, provided herein is a pharmaceutical composition comprising a crystalline form as described herein and one or more pharmaceutically acceptable excipients.

[0203] In some embodiments, the composition comprises one or more intra-granular ingredients and one or more extra-granular ingredients. In some embodiments, the one or more intra-granular ingredients comprise a crystalline form as described herein. In some embodiments, the crystalline form is a crystalline form of a mono-tosylate salt of Compound 1. In some embodiments, the crystalline form is a crystalline form of a hydrate of a mono- tosylate salt of Compound 1. In some embodiments, the crystalline form is a crystalline form of a monohydrate of a mono-tosylate salt of Compound 1. In some embodiments, the crystalline form is Tosylate Form 1 as described herein.

[0204] In some embodiments, the composition comprises Compound 1 or a pharmaceutically acceptable salt thereof in the amount equivalent to between about 40 mg and about 120 mg of Compound 1 in the freebase form. In some embodiments, the composition comprises Compound 1 or a pharmaceutically acceptable salt thereof in the amount equivalent to between about 30 mg and about 130 mg of Compound 1 in the freebase form. In some embodiments, the composition comprises Compound 1 or a pharmaceutically acceptable salt thereof in the amount equivalent to about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, or about 130 mg of Compound 1 in the freebase form, or a range between any two of the preceding values. In some embodiments, the composition comprises Compound 1 or a pharmaceutically acceptable salt thereof in the amount equivalent to about 40 mg, about 80 mg, or about 120 mg of Compound 1 in the freebase form.

[0205] In some embodiments, the composition comprises Compound 1 or a pharmaceutically acceptable salt thereof in the amount equivalent to between about 35 mg to 45 mg of Compound 1 in the freebase form. In some embodiments, the composition comprises Compound 1 or a pharmaceutically acceptable salt thereof in the amount equivalent to about 40 mg of Compound 1 in the freebase form. In some embodiments, the composition comprises Compound 1 or a pharmaceutically acceptable salt thereof in the amount of about 106 micromoles.

[0206] In some embodiments, the composition comprises Compound 1 or a pharmaceutically acceptable salt thereof in the amount equivalent to between about 75 mg to 85 mg of Compound 1 in the freebase form. In some embodiments, the composition comprises Compound 1 or a pharmaceutically acceptable salt thereof in the amount equivalent to about 80 mg of Compound 1 in the freebase form. In some embodiments, the composition comprises Compound 1 or a pharmaceutically acceptable salt thereof in the amount of about 212 micromoles.

[0207] In some embodiments, the composition comprises Compound 1 or a pharmaceutically acceptable salt thereof in the amount equivalent to between about 115 mg to 125 mg of Compound 1 in the freebase form. In some embodiments, the composition comprises Compound 1 or a pharmaceutically acceptable salt thereof in the amount equivalent to about 120 mg of Compound 1 in the freebase form. In some embodiments, the composition comprises Compound 1 or a pharmaceutically acceptable salt thereof in the amount of about 318 micromoles.

[0208] In some embodiments, the one or more intra-granular ingredients comprise or further comprise a filler. In some embodiments, the filler comprises microcrystalline cellulose or dicalcium phosphate, or both. In some embodiments, the composition comprises the filler in the amount of between about 40 wt.% and about 70 wt.%. In some embodiments, the composition comprises the filler in the amount of between about 50 wt.% and about 60 wt.%. In some embodiments, the composition comprises the filler in the amount of about 55 wt.%. In some embodiments, the composition comprises microcrystalline cellulose in the amount of about 20 wt.%, about 25 wt.%, about 30 wt.%, about 35 wt.%, about 40 wt.%, about 45 wt.%, about 50 wt.%, about 55 wt.%, or about 60 wt.%, or in a range between any two of the preceding values. In some embodiments, the composition comprises microcrystalline cellulose in the amount of about 40 wt.%. In some embodiments, the composition comprises dicalcium phosphate in the amount of about 5 wt.%, about 10 wt.%, about 15 wt.%, about 20 wt.%, or about 25 wt.%, or in a range between any two of the preceding values. In some embodiments, the composition comprises dicalcium phosphate in the amount of about 13 wt.%.

[0209] In some embodiments, the one or more intra-granular ingredients comprise or further comprise a binder. In some embodiments, the binder comprises Plasdone K 29 / 32 or hydroxypropyl cellulose, or both. In some embodiments, the composition comprises thebinder in the amount of about 4 wt.%, about 6 wt.%, about 8 wt.%, about 10 wt.%, about 12 wt.%, about 14 wt.%, or about 16 wt.%, or in a range between any two of the preceding values. In some embodiments, the composition comprises the binder in the amount of between about 5 wt.% and about 10 wt.%. In some embodiments, the composition comprises Plasdone K 29 / 32 in the amount of about 8 wt.%. In some embodiments, the composition comprises hydroxypropyl cellulose in the amount of about 8 wt.%.

[0210] In some embodiments, the one or more intra-granular ingredients comprise or further comprise an intra-granular lubricant. In some embodiments, the intra-granular lubricant is magnesium stearate. In some embodiments, the composition comprises the intra- granular lubricant in the amount of about 0.1 wt.%, about 0.2 wt.%, about 0.3 wt.%, about 0.4 wt.%, about 0.5 wt.%, about 0.6 wt.%, about 0.7 wt.%, about 0.8 wt.%, about 0.9 wt.%, or about 1 wt.%, or in a range between any two of the preceding values. In some embodiments, the composition comprises the intra-granular lubricant in the amount of between about 0.1 wt.% and about 1 wt.%. In some embodiments, the composition comprises the intra-granular lubricant in the amount of about 0.5 wt.%. In some embodiments, the one or more extra- granular ingredients comprise an extra-granular lubricant. In some embodiments, the extra- granular lubricant is magnesium stearate. In some embodiments, the composition comprises the extra-granular lubricant in the amount of about 0.1 wt.%, about 0.2 wt.%, about 0.3 wt.%, about 0.4 wt.%, about 0.5 wt.%, about 0.6 wt.%, about 0.7 wt.%, about 0.8 wt.%, about 0.9 wt.%, or about 1 wt.%, or in a range between any two of the preceding values. In some embodiments, the composition comprises the extra-granular lubricant in the amount of between about 0.1 wt.% and about 1 wt.%. In some embodiments, the extra-granular lubricant in the amount of about 0.5 wt.%. In some embodiments, the composition comprises magnesium stearate in the amount of about 1 wt.%.

[0211] In some embodiments, the one or more extra-granular ingredients comprise or further comprise a disintegrant. In some embodiments, the disintegrant comprises croscarmellose sodium or sodium starch glycolate, or both. In some embodiments, the composition comprises the disintegrant in the amount of about 2 wt.%, about 4 wt.%, about 6 wt.%, about 8 wt.%, about 10 wt.%, about 12 wt.%, about 14 wt.%, or about 16 wt.%, or in a range between any two of the preceding values. In some embodiments, the composition comprises the disintegrant in the amount of between about 4 wt.% and about 10 wt.%. In some embodiments, the composition comprises croscarmellose sodium in the amount ofabout 8 wt.%. In some embodiments, the composition comprises sodium starch glycolate in the amount of about 6 wt.%.

[0212] In some embodiments, the composition comprises Tosylate Form 1 as described herein; microcrystalline cellulose; dicalcium phosphate; plasdone K 29 / 32; magnesium stearate; and crocarmellose sodium. In some embodiments, the composition comprises about 30 wt.% of the crystalline form, or Compound 1 or a pharmaceutically acceptable salt thereof in the amount equivalent to about 40 mg of Compound 1 in the freebase form; about 40 wt.% of microcrystalline cellulose; about 13 wt.% of dicalcium phosphate; about 8 wt.% of plasdone K 29 / 32; about 1 wt.% of magnesium stearate; and about 8 wt.% of crocarmellose sodium. In some embodiments, the composition comprises Tosylate Form 1 as described herein; microcrystalline cellulose; dicalcium phosphate; hydroxypropyl cellulose; magnesium stearate; and sodium starch glycolate. In some embodiments, the composition comprises about 30 wt.% of the crystalline form, or Compound 1 or a pharmaceutically acceptable salt thereof in the amount equivalent to about 40 mg of Compound 1 in the freebase form; about 40 wt.% of microcrystalline cellulose; about 13 wt.% of dicalcium phosphate; about 8 wt.% of hydroxypropyl cellulose; about 1 wt.% of magnesium stearate; and about 6 wt.% of sodium starch glycolate.

[0213] In some embodiments, the composition is formulated for oral delivery. In some embodiments, the composition is a tablet.Methods of Use

[0214] In one aspect, provided herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient a crystalline form as described herein, or a pharmaceutical composition as described herein. In some embodiments, the cancer is chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or a mixed phenotype acute leukemia.

[0215] In another aspect, provided herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient (15,25)-A-(2-(4,6-bis(methoxy- t / 3)pyrimidin-5-yl)-l-methyl-lJ / -pyrrolo[2,3-c]pyridin-5-yl)-2-fluorocyclopropane-l- carboxamide (Compound 1) or a pharmaceutically acceptable salt thereof at a total daily dose of an amount equivalent to between about 5 mg and about 200 mg; between about 10 mg and about 160 mg; or between about 80 mg and about 160 mg of Compound 1 in the freebaseform. In some embodiments, the cancer is chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or a mixed phenotype acute leukemia.

[0216] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof, the crystalline form, or the pharmaceutical composition described herein is administered to the patient in a therapeutically effective amount.

[0217] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered to the patient as a once-daily oral dose. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered to the patient at a single daily oral dose of an amount equivalent to between about 10 mg to about 160 mg or between about 80 mg and about 120 mg of Compound 1 in the freebase form. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered to the patient at a single daily oral dose of an amount equivalent to about 10 mg, about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, or about 120 mg of Compound 1 in the freebase form. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered to the patient at a single daily oral dose of an amount equivalent to about 40 mg (i.e., 40 mg QD) of Compound 1 in the freebase form. . In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered to the patient at a single daily oral dose of an amount equivalent to about 60 mg (i.e., 60 mg QD) of Compound 1 in the freebase form. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered to the patient at a single daily oral dose of an amount equivalent to about 80 mg (i.e., 80 mg QD) of Compound 1 in the freebase form. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered to the patient at a single daily oral dose of an amount equivalent to about 120 mg (i.e., 100 mg QD) of Compound 1 in the freebase form. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered to the patient at a single daily oral dose of an amount equivalent to about 120 mg (i.e., 120 mg QD) of Compound 1 in the freebase form.

[0218] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered to the patient as a twice-daily oral dose. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered to the patient at a twice daily oral dose of an amount equivalent to about 60 mg each or about 80 mg each ofCompound 1 in the freebase form. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered to the patient at a twice daily oral dose of an amount equivalent to about 60 mg each (i.e., 60 mg BID) of Compound 1 in the freebase form. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered to the patient at a twice daily oral dose of an amount equivalent to about 80 mg each (i.e., 80 mg BID) of Compound 1 in the freebase form.

[0219] In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered to the patient for about 24 weeks or more.

[0220] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient in its crystalline form described herein or as a pharmaceutical composition described herein, at any of the doses provided herein.

[0221] In some embodiments, the leukemia is refractory leukemia. In some embodiments, the patient has one or more mutations in the Bcr-Abl tyrosine kinase gene resulting in M244V, L248V, G250E, G250A, Q252H, Q252R, Y253F, Y253H, E255K, E255V, D276G, F311L, T315N, T315A, F317V, F317L, M343T, M351T, E355G, F359A, F359V, V379I, F382L, L387M, H396P, H396R, S417Y, E459K, F486S, T315I, A337T, F359C, or P465S, or any combination of these amino acid substitutions in leukemia cells. In some embodiments, the patient has one or more mutations in the Bcr-Abl tyrosine kinase gene resulting in T3151 amino acid substitution in leukemia cells. In some embodiments, the patient has one or more mutations in the Bcr-Abl tyrosine kinase gene resulting in T315I, M244V, A337T, E355G, F359C, F359V, or P465S, or any combination of these amino acid substitutions in leukemia cells. In some embodiments, the patient has one or more mutations in the Bcr-Abl tyrosine kinase gene resulting in A337T amino acid substitution in leukemia cells. In some embodiments, the method further comprises detecting mutations in the Bcr-Abl tyrosine kinase gene of the patient. In some embodiments, the patient was previously treated with 1, 2, 3, 4, 5, or more tyrosine kinase inhibitors.

[0222] In some embodiments, the patient was previously treated with dasatinib, imatinib, asciminib, ponatinib, nilotinib, or bosutinib, or any combination thereof. In some embodiments, the patient was previously treated with asciminib and / or ponatinib. In some embodiments, the patient was previously treated with asciminib. In some embodiments, the method further comprises administering one or more pharmaceutical agents includingincluding anti -microtubular therapies, topoisomerase inhibitors, alkylating agents, nucleotide synthesis inhibitors, DNA synthesis inhibtiors, protein synthesis inhibitors, developmental signaling pathway inhibitors, pro-apoptotic agents, Abl myristoyl-pocket binding inhibitors, MEK1 / 2 inhibitors, AKT inhibitors, PI3K inhibitors and / or radiation.

[0223] In some embodiments, the crystalline form or pharmaceutical composition is administered to the patient without fasting. In some embodiments, the crystalline form or pharmaceutical composition is administered to the patient less than about 2 hours after the patient ate food. In some embodiments, the crystalline form or pharmaceutical composition is administered to the patient less than about 1 hour before the patient eats food. In some embodiments, the crystalline form or pharmaceutical composition is administered to the patient daily. In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof, the crystalline form, or the pharmaceutical composition is orally administered to the patient daily.

[0224] In some embodiments, the crystalline form or pharmaceutical composition is administered to the patient without fasting. In some embodiments, the crystalline form or pharmaceutical composition is administered to the patient less than about 2 hours after the patient ate food. In some embodiments, the crystalline form or pharmaceutical composition is administered to the patient less than about 12 hours, 11 hours, 10 hours, 9 hours, 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, or 30 minutes after the patient ate food. In some embodiments, the crystalline form or pharmaceutical composition is administered to the patient less than about 1 hour before the patient eats food. In some embodiments, the crystalline form or pharmaceutical composition is administered to the patient less than about 12 hours, 11 hours, 10 hours, 9 hours, 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, or 30 minutes before the patient eats food. In some embodiments, the crystalline form or pharmaceutical composition is administered to the patient daily.

[0225] In another aspect, provided herein is a method of inhibiting Bcr-Abl enzymatic activity in a cell, comprising exposing the cell with an effective amount of a crystalline form as described herein, or a pharmaceutical composition as described herein. In some embodiments, the cell has one or more mutations in the Bcr-Abl tyrosine kinase gene resulting in M244V, L248V, G250E, G250A, Q252H, Q252R, Y253F, Y253H, E255K, E255V, D276G, F311L, T315N, T315A, F317V, F317L, M343T, M351T, E355G, F359A,F359V, V379I, F382L, L387M, H396P, H396R, S417Y, E459K, F486S, T315I, A337T, F359C, or P465S, or any combination of these amino acid substitutions. In some embodiments, the cell has one or more mutations in the Bcr-Abl tyrosine kinase gene resulting in T315I amino acid substitution. In some embodiments, the cell has one or more mutations in the Bcr-Abl tyrosine kinase gene resulting in T315I, M244V, A337T, E355G, F359C, F359V, or P465S, or any combination of these amino acid substitutions in leukemia cells. In some embodiments, the cell has one or more mutations in the Bcr-Abl tyrosine kinase gene resulting in A337T amino acid substitution in leukemia cells. In some embodiments, the method further comprises detecting mutations in the Bcr-Abl tyrosine kinase gene of the cell.EXAMPLES

[0226] The presently disclosed subject matter will be better understood by reference to the following Examples, which are provided as exemplary of the invention, and not by way of limitation.

[0227] As used throughout the Examples, the term “Pattern” denotes a crystalline form for which a unique set of XRPD peaks was observed. The term “Pattern” when used to refer to a particular form is interchangeable with the term “Form” as used throughout the application. For example “HC1 Pattern 1” and “HC1 Form 1” both denote the same crystalline form, “Freebase Pattern 3” and “Freebase Form 3” both denote the same crystalline form, and “Tosylate Pattern 1” and “Tosylate Form 1” both denote the same crystalline form.Example 1: Analytical Methods

[0228] Unless otherwise stated, the following methods and procedures were used to obtain the data described in the following examples.X-Ray Powder Diffraction (XRPD)

[0229] XRPD analysis was carried out on a PANalytical X’pert pro with PIXcel detector (128 channels), scanning the samples between 3 and 35° 29. The material was gently ground to release any agglomerates and loaded onto a multi-well plate with Kapton or Mylar polymer film to support the sample. The multi-well plate was then placed into the diffractometer and analyzed using Cu K radiation (ai X = 1.54060 A; 012 = 1.54443 A; P = 1.39225 A; ai : a.2 ratio = 0.5) running in transmission mode (step size 0.0130° 29, step time 18.87s) using 40kV / 40 mA generator settings. Data were visualized and images generated using the HighScore Plus 5.2 desktop application (PANalytical, 2023).Polarized Light Microscopy (PLM)

[0230] The presence of crystallinity (birefringence) was determined using an Olympus BX53 microscope, equipped with cross-polarizing lenses and a Motic camera. Images were captured using Motic Images Plus 3.0. All images were recorded using the 20 x objective, unless otherwise stated.Thermogravimetric Analysis / Differential Scanning Calorimetry (TGA / DSC)

[0231] Approximately 5-10 mg of material was added into a pre-tared open aluminum pan and loaded into a TA Instruments Discovery SDT 650 Auto - Simultaneous DSC and held at room temperature. The sample was then heated at a rate of 10 °C / min from 30 °C to 400 °C during which time the change in sample weight was recorded along with the heat flow response (DSC). Nitrogen was used as the sample purge gas, at a flow rate of 200 cm3 / min.Differential Scanning Calorimetry (DSC)

[0232] Approximately, 1-5 mg of material was weighed into an aluminum DSC pan and sealed non-hermetically with an aluminum lid. The sample pan was then loaded into a TA Instruments Discovery DSC 2500 differential scanning calorimeter equipped with an RC90 cooler. The sample and reference were heated to the specified upper limit at a scan rate of 10 °C / min and the resulting heat flow response monitored. The sample was re-cooled to 20 °C and then reheated again to the specified upper limit all at 10 °C / min. Nitrogen was used as the purge gas, at a flow rate of 50 cm3 / min.Karl Fischer Coulometric Titration (KF)

[0233] Ca. 10-15 mg of solid material was accurately weighed into a vial. The solid was then manually introduced into the titration cell of a Mettler Toledo C30 Compact Titrator. The vial was back-weighed after the addition of the solid and the weight of the added solid entered on the instrument. Titration was initiated once the sample had fully dissolved in the cell. The water content was calculated automatically by the instrument as a percentage and the data printed.Raman

[0234] Raman analysis for the primary salt screen, the secondary salt screen, Tosylate Pattern 5, and Tosylate Pattern 6 was measured using a ThermoFisher Scientific DXR3 Raman microscope with excitation laser lines of 532 and 785 nm. The laser spot size was ~2 pm for the 532 nm laser, and ~3 pm for the 785 nm laser.

[0235] Raman analysis for the analysis of Tosylate Pattern 4 measured using ThermoFisher Scientific DXR3 Raman microscope with excitation laser lines of 532 nm (range 50-3500 cm’1, spectral resolution <5 cm’1at FWHM, laser power 0.2 mW, laser spot size was ~2 pm), and AntonPaar Cora 5500 spectrometer (not microscope) with laser excitation line of 785 nm (range 100 - 2300 cm’1spectral resolution from 6 cm’1at high frequencies to 9 cm’1at low frequency edge, laser power 300 mW, laser spot size 400 pm).Infrared Spectroscopy (IR)

[0236] Infrared spectroscopy was carried out on a Bruker ALPHA P spectrometer.Sufficient material was placed onto the centre of the plate of the spectrometer and the spectra were obtained using the following parameters:Resolution: 4 cm’Background Scan Time: 16 scansSample Scan Time: 16 scansData Collection: 4000 to 400 cm’1Result Spectrum: TransmittanceSoftware: OPUS version 6Nuclear Magnetic Resonance (NMR)

[0237] NMR experiments were performed on a Bruker AVIIIHD spectrometer equipped with a DCH cry oprobe operating at 500.12 MHz for protons. Experiments were performed in deuterated DMSO, and each sample was prepared to ca. 10 mM concentration. For the tosylate polymorph screen, a pulse sequence delay (D[l]) of 25 seconds was used so that an accurate tosylate content could be assessed.Dynamic Vapor Sorption (DVS)

[0238] Approximately, 10-20 mg of sample was placed into a mesh vapor sorption balance pan and loaded into a DVS Intrinsic or Advantage dynamic vapor sorption balance by Surface Measurement Systems. The sample was subjected to a ramping profile from 40 - 90% relative humidity (RH) at 10% increments, maintaining the sample at each step until a stable weight had been achieved (dm / dt 0.004%, minimum step length 30 minutes, maximum step length 500 minutes) at 25 °C. After completion of the sorption cycle, the sample was dried using the same procedure to 0% RH and then a second sorption cycle back to 40% RH. Two cycles were performed. The weight change during the sorption / desorption cycles were plotted, allowing for the hygroscopic nature of the sample to be determined. XRPD analysis was then carried out on any solid retained.Variable Temperature / Humidity X-ray Powder Diffraction (VT / VH-XRPD)

[0239] VT-XRPD analysis was carried out on a Philips X’Pert Pro Multipurpose diffractometer equipped with a temperature or humidity chamber. The samples were scanned between 4 and 35.99 °29 using Cu K radiation (ai L = 1.54060 A; 012 = 1.54443 A; P = 1.39225 A; ai : 012 ratio = 0.5) running in Bragg-Brentano geometry (step size 0.008 °29) using 40 kV / 40 mA generator settings. Measurements were performed at temperatures / humidities specified.High Performance Liquid Chromatogramy-Ultraviolet Detection (HPLC-UV)

[0240] The following parameters were used for HPLC-UV analysisInstrument: Dionex Ultimate 3000Column: YMC Triart C18 150x4.6mm, 3pmColumn Temperature: 30 °CAutosampler Temperature: AmbientUV wavelength: 254 nmInjection Volume: 5 pLFlow Rate: 1 mL / minMobile Phase A: 0.05% TFA in H2OMobile Phase B: 0.05% TFA in CANGradient program:Example 2: Primary Salt ScreenExperimental Methods - Compound 1 Freebase Solubility Study

[0241] A solvent solubility study was carried out using the following procedure. 20 mg of Compound 1 freebase was weighed into twelve HPLC vials. Aliquots of appropriate solvent were added at ambient temperature and the samples were checked for dissolution. If no dissolution was observed, the samples were heated and magnetically stirred at 40 °C for 1 - 2 minutes to check for solubility at elevated temperatures. This step was repeated until complete dissolution was observed or until 2 mL of solvent had been added to each vial. The resulting solutions were evaporated under ambient conditions, and the slurries were isolated via centrifugation. The recovered solids were analyzed XRPD where sample amounts allowed. PLM analysis was conducted on the solids recovered from the DCM experiment. HPLC analysis was conducted on the solids recovered from the acetic acid experiment.Experimental Methods - Salt Screen

[0242] A primary salt screen of Compound 1 was conducted employing the following procedure. 25 mg of Compound 1 freebase was weighed in clear HPLC vials. 100 pL aliquot of required solvent was added to each vial at ambient temperature and the samples were magnetically stirred and checked for dissolution (25 °C). Aliquots were added until a total of 1 mL of solvent had been added (0.8 mL for repeat experiments). 1.05 molar equivalents of counter ion were then added to the samples by stock solution or by neat addition. Solid counter ions were weighed into HPLC vials and transferred into the sample vial containing the freebase. The vial that contained the counter ion was then washed with ca. 100 pL of appropriate solvent and transferred into the vial containing the freebase. For liquid counter ions, 1 M stock solutions were prepared in the appropriate solvent. Further, the requiredvolume of IM stock solution, to give 1.05 molar equivalents of the counter ion (to the API), was added to the freebase.

[0243] The experiments were temperature cycled for 2 - 3 days using the following procedure: Heat to 40 °C at 0.1 °C / min; Hold at 40 °C for 1 hour; Cool to 5 °C at 0.1 °C / min; Hold at 5 °C for 1 hour. After 2 - 3 days the samples were removed from the stirring plate at low temperature (< 25 °C) and any slurries were isolated via centrifugation. Where clear solutions were observed, antisolvent (heptane or TBME) was added to promote precipitation. Antisolvent was added in 100 pL aliquots until precipitation was observed or the vial was full. Between each aliquot the samples were stirred at 5 °C to allow for any precipitation. After complete addition, the samples were further stirred at 5 °C for ca.18 hours. The resulting slurries were isolated via centrifugation, while remaining clear solutions were evaporated in ambient conditions.

[0244] The isolated solids were analyzed by XRPD where sample amount allowed it. The XRPD plate and the isolated solids were dried at 40 °C under vacuum for ca. 18 hours and the XRPD plate was re-analyzed. The well plate containing the dried solids was further stored at 40 °C / 75% RH for ca.18 hours and re-analyzed by XRPD. Potential salts hits that had sufficient sample amount were also analyzed by TG / DSC H NMR, PLM, and FT-IR.Results

[0245] Initial characterization was carried out on Compound 1 Freebase Form 1. XRPD and HPLC analysis showed that the freebase was highly crystalline of high purity. In addition,1H NMR and19F NMR analysis was consistent with structure of Compound 1, and TG / DSC analysis confirmed Compound 1 Freebase Form 1 was an anhydrous form.

[0246] An initial solubility study was conducted on Compound 1 Freebase Form 1. High solubility (> 300 mg / mL) in acetic acid, and high solubility (75 - 150 mg / mL) in DMSO and NMP was observed. Moderate solubility (25 - 75 mg / mL) in DMA and DMF was observed. Low solubility (10 - 25 mg / mL) in benzyl alcohol and DCM and a very low solubility (<10 mg / mL) in 2-ethy oxy ethanol, 2 -m ethyl- 1 -propanol, acetone, butyl acetate and 1,2- di chloroethane was observed.

[0247] The primary salt screen of Compound 1 was conducted using 16 counterions in 6 solvent systems. Multiple novel XRPD patterns were obtained from the primary salt screenand the characterization of these indicated the formation of multiple potential salts. A summary of the results is outlined in Tables El A-E1D.

[0248] The following abbreviations apply to the tables provided in this section. “P#” denotes observation of novel XRPD pattern for a given counterion (e.g., Pl and P2 in the “Hydrochloric acid” column denote HC1 Pattern 1 and HC1 Pattern 2, respectively, while Pl and P2 in the “Hydrobromic acid” column denote HBr Pattern 1 and HBr Pattern 2, respectively). The addition of “+” indicates that additional peaks were observed relative to other instances of a pattern. The addition of indicates that certain peaks were absent relative to other instances of a pattern. The addition ofindicates that minor differences were observed relative to other instances of a pattern. The addition of “PC” indicates that a poorly crystalline pattern was observed. “FB” denotes observation of the Compound 1 freebase pattern. “A” denotes the observation of the counterion acid pattern. EV denotes solvent evaporation.

[0249] Analysis highlighted several salts, as discussed below.

[0250] Esylate Pattern 1 was obtained in acetone, DCM and THF, with additional peaks seen in the solids isolated from DCM. Based on the gathered data, Esylate Pattern 1 was likely an anhydrous mono salt, which showed stability after drying and exposure to 40 °C / 75 %RH.

[0251] HC1 Pattern 1 was obtained in THF during the first HC1 run and remained stable through drying and exposure to 40 °C / 75 %RH. However, NMR analysis showed that there was cross-contamination from benzyl alcohol; therefore, the experiment was repeated. Upon the repetition of the THF experiment, HC1 Pattern 4 was obtained. Notably, HC1 Pattern 1 also appeared in the acetone experiment, with its occurrence observed in the first and second runs, although in the initial run, it developed from a poorly crystalline material after exposure to 40 °C / 75 %RH. Additionally, HC1 Pattern 5 from acetic acid converted to HC1 Pattern 1 after exposure to 40 °C / 75 %RH. HC1 Pattern 1 was likely a monohydrated HC1 salt.

[0252] 2-Hydroxyethanesulfonic acid Pattern 1 was obtained in acetone and THF and was stable after drying and exposure to 40 °C / 75 %RH. Based on the gathered data, the afforded pattern likely corresponded to an anhydrous mono salt.

[0253] Sulfate Pattern 3 (also referred to as Sulfuric Acid Pattern 3) was obtained through the exposure of 40 °C / 75 %RH conditions to sulfate Patterns 1, 2, 4 and 5. It was stable after subsequent drying. Sulfate Pattern 3 is likely a hydrated salt.

[0254] Mesylate Pattern 1 (also referred to as Methanesulfonic Acid Pattern 1) was obtained in acetone, DCM, ethanol: water 90: 10 % v / v and THF and showed stability upon drying and after exposure to 40 °C / 75 %RH. Mesylate Pattern 1 is likely a hydrated mono salt.

[0255] Tosylate Pattern 1 (also referred to as p-Toluenesulfonic Acid Pattern 1) was obtained in acetone, DCM, and ethanokwater 90: 10 % v / v., and remained stable upon drying and exposure to 40 °C / 75 %RH conditions. A second tosylate pattern was observed, however it converted to Pattern 1 on exposure to 40 °C / 75 %RH.

[0256] Besylate Pattern 1 and 2: Besylate Pattern 1 (also referred to as Benzenesulfonic Acid Pattern 1) was obtained in acetone and THF, showing stability after drying. Further, Besylate Pattern 1 isolated from acetone was stable under 40 °C / 75 %RH conditions, while Besylate Pattern 1 from the THF experiment converted to Besylate Pattern 2, upon exposure to the same 40 °C / 75 %RH conditions. Based on the obtained results, Besylate Pattern 1 was an anhydrous mono salt, and Besylate Pattern 2 a hydrated mono salt.

[0257] Edisylate Pattern 1+ (also referred to as Ethane- 1,2-di sulfonic Acid Pattern 1+) was obtained in acetone and was stable after drying and after exposure to 40 °C / 75 %RH conditions. Based on further characterization, Edisylate Pattern 1+ was a potential hydrated salt.

[0258] A summary of the most stable salts found throughout the primary salt screen is highlighted in Tables E2A-E2C.Table E1ATable E1BTable E1CTable EIDTable E2ATable E2BTable E2CExample 3: Secondary Salt ScreenExperimental Methods - Esylate Salt Scale-up

[0259] The selected esylate salt was scaled up using the following procedure. 500 mg of Compound 1 freebase was weighed into a 20 mL vial and suspended in ca. 8.6 mL of acetone at 25 °C. Ca. 1.4 mL of 1 molar ethanesulfonic acid stock solution (1.05 molar equivalents) prepared in acetone was added to the experiment, which was then stirred at 25 °C.Dissolution was observed, followed by a thick white slurry. A subsample of this slurry was analyzed by XRPD. After ca. 15 minutes of stirring at 25 °C, 6 mL of heptane was added to the slurry, dropwise. After antisolvent addition, the slurry was cooled from 25 °C to 5 °C at 0.1 °C / min, then held at 5 °C for ca. 13 hours. A sub sample was then analyzed by XRPD and further dried under vacuum at 40 °C. Following this, the XRPD plate was stored at 40 °C / 75 %RH for ca. 18 hours. The slurry was isolated via Buchner filtration and dried under vacuum at 40 °C for ca. 18 h.

[0260] Additional Esylate salt was prepared to fund the VT-XRPD and thermodynamic solubility experiments, due to the low yield in the scale up. 200 mg of Compound 1 freebase was weighed into a 20 mL vial and suspended in ca. 3.44 mL of acetone at 25 °C. 0.566 mL of 1 molar ethanesulfonic acid stock solution (1.05 molar equivalents) prepared in acetone was added to the experiment, which was then stirred at 25 °C. At this point dissolution was observed, followed by a thick white slurry. After ca. 15 minutes of stirring at 25 °C, 2.4 mL of heptane was added to the experiment dropwise. After antisolvent addition, the experiment was cooled from 25 °C to 5 °C at 0 1 °C / min then held at 5 °C for ca 18 hours Theexperiment was isolated via Buchner filtration and a sample was taken for XRPD analysis. The XRPD plate and bulk solids were then dried under vacuum at 40 °C for ca. 20 hours and re-analyzed.Experimental Methods - Tosylate Salt Scale-up

[0261] The selected tosylate salt was scaled up using the following procedure. 500 mg of Compound 1 freebase was weighed into a 20 mL vial and suspended in 10 mL of ethanokwater 90: 10 % v / v at 25 °C. 1.05 molar equivalents of p-toluenesulfonc acid were added to the solution. This was then stirred at 25 °C and after a few minutes a thin yellow slurry developed. After ca. 15 minutes of stirring at 25 °C, 6 mL of heptane was added to the slurry dropwise. This resulted in a thick yellow / white slurry developing. After antisolvent addition, the slurry was cooled from 25 °C to 5 °C at 0.1 °C / min and then held at 5 °C for ca. 13 hours. A sub sample was then analyzed by XRPD. The XRPD plate was further dried under vacuum at 40 °C for ca. 18 hours and then further stored at 40 °C / 75 %RH for another ca. 18 hours for XRPD analysis. The slurry was isolated via Buchner filtration and dried under vacuum at 40 °C for ca. 18 hours.Experimental Methods - One Week Stability Study

[0262] One week stability studies were performed for the two salts consisting in the following procedure. 20 mg * 6 of the salt samples were weighed into HPLC vials. The samples were then placed in 3 different environments for 1 week as follows: 40 °C / 75 %RH uncapped; 80 °C capped; or Ambient capped. After 1 week, the solids were analyzed by XRPD to evaluate the solid form, and HPLC to determine the purity.Experimental Methods - Salt Disproportionation Study

[0263] The disproportionation studies were performed as follows. 20 mg * 2 of the salt samples were weighed into HPLC vials. 100 pL aliquots of neat water were added until a mobile slurry was formed. After each addition, the samples were magnetically stirred at 25 °C for 1 - 2 minutes. The samples were held at 25 °C overnight. The samples were removed after ca. 23 hours and the pH was analyzed with a pH meter. The samples were centrifuged, and the recovered solids were analyzed by XRPD.Experimental Methods - Hydration Study

[0264] The hydration studies were performed as follows. 20 mg * 7 of the salt samples were weighed into HPLC vials. 0.4 nm molecular sieves were dried at 150 °C under vacuum overnight to activate them and then were placed in neat ethanol to dry the solvent. Four solvents were used: neat ethanol, 0.153, 0.507 and 0.745 water activity ethanol and water mixtures. The neat ethanol experiment was only conducted on tosylate salt. 100 pL aliquots of solvent were added until a mobile slurry was formed. After each addition, the samples were magnetically stirred at 25 °C for 1 - 2 minutes. The samples were stirred at 25 °C overnight. After ca. 19 hours a subsample of each sample was analyzed by XRPD. After 4 days another subsample was recovered and analyzed by XRPD.Experimental Methods - Thermodynamic Solubility Study

[0265] The thermodynamic solubility studies were performed using the following procedure. 40 mg * 6 of the salt samples were weighed into 2 ml vials. The following buffers were used: 0.1 N HC1; pH 4.5 acetate; or pH 6.8 phosphate. 100 pl aliquots of solvent were added until a mobile slurry was formed. After each addition, the samples were magnetically stirred at 37 °C for 1 - 2 minutes. The samples were left for 1 hour and then analyzed with a pH probe. The sample pH was then readjusted to the required pH with 0.2 M sodium hydroxide and 0.2 M potassium phosphate. This step was not done for the 0.1 N HC1 samples. The samples were then returned and left at 37 °C for ca.18 hours. The sample pH was then re-analyzed and then the samples were centrifuged. The mother liquors recovered were submitted for HPLC concentration analysis. The recovered solids were analyzed by XRPD.

[0266] The thermodynamic solubility study was repeated for the esylate salt following a similar experimental procedure as the one described above, with the difference of using an increased buffer capacity. This was done to limit the volume of sodium hydroxide solution 0.2 M that was needed to correct the pH.Results

[0267] Based on the results obtained in the primary salt screen these results, two salts (tosylate Pattern 1 in ethanol: water 90: 10 % v / v; and esylate Pattern 1 in acetone) were selected for scale up to produce enough material to carry out more detailed characterization and experimentation in a secondary salt screen.

[0268] The results of the secondary screen showed that the Tosylate salt was a monohydrated mono tosylate salt and the esylate salt was an anhydrous mono salt. While the esylate salt showed some favorable properties such as high solubility in buffered systems and was an anhydrous salt, the chemical degradation was observed over 7 days and disproportionation was observed. Tosylate Pattern 1 was selected for a polymorph screen due to the stability shown in the hydration, salt disproportionation and thermodynamic solubility studies, in addition to its satisfactory chemical and physical properties.

[0269] A summary of the results from the secondary screen is outlined in Tables E3 and E4.Table E3Table E4Example 4: Tosylate Salt Polymorph ScreenExperimental Methods - Primary Polymorph Screen

[0270] The primary polymorph screen of Compound 1 Tosylate was carried out using 24 different solvent systems under the following conditions: Thermal cycling; Crash cooling; Antisolvent addition at ambient temperature; Evaporation at ambient temperature; Solvent drop grinding; Vapor diffusion; or Reactive crystallization.

[0271] Temperature cycling experiments were carried out in 24 solvent systems according to the following procedure. 50 mg of amorphous Compound 1 Tosylate salt was weighed into 24 * 2 mL glass vials. 100 pL aliquots of the required solvent was added until a stable slurry was formed or until a total of 1.5 mL of solvent was added. After each addition the samples were heated to 40 °C for one hour to ensure a slurry was maintained at elevated temperatures. The sample were then temperature cycled for ca. 72 hours with the following procedure: Hold at 40 °C for 1 hour; Cool to 5 °C at 0.1 °C / min; Hold at 5 °C for 1 hour; and Heat to 40 °C at 0.1 °C / min. After ca. 72 hours, observations were recorded and where slurries were obtained samples were isolated by centrifugation at ca. 25 °C. The residual solids were isolated and analyzed by XRPD to assess the solid form. The mother liquors retained for use in further experiments. Where evaporation was observed after ca. 72 hours, additional solvent was added to re-form a slurry and the samples were temperature cycled for an additional two days (t-butanol DCM ethanol and methanol) After two days of additionaltemperature cycling the samples separated by centrifugation. The residual solids were isolated and analyzed by XRPD and the mother liquors were retained for further experiments. Samples were dried under vacuum at 40 °C for ca. 18 hours and re-analyzed by XRPD to assess any potential change in solid form. Where novel forms or forms of interest were identified, samples were further analyzed by the following techniques:JH NMR; TG / DSC; PLM; and FT-IR.

[0272] Crash cooling experiments were carried out using saturated mother liquors generated from temperature cycling according to the following procedure. Aliquots of the saturated mother liquors generated from temperature cycling were transferred to 2 mL vials. The vials were sealed and stored at 4 °C for ca. 3 - 5 days. After ca. 3 - 5 days, observations were recorded and where precipitation was observed samples were isolated. The residual solids were analyzed by XRPD to assess the solid form. If no precipitating was observed, samples were stored at -18 °C to encourage precipitation. After ca. 5 days, observations were recorded, and any solids were isolated and analyzed by XRPD. All samples were dried under vacuum at 40 °C for ca. 18 hours then re-analyzed by XRPD to assess any potential changes in solid form. Where sample amounts allowed, any novel forms were further analyzed by the followingJH NMR.

[0273] Anti-solvent addition experiments were carried out at according to the following procedure. Saturated mother liquors generated from temperature cycling were transferred to 2 mL glass vials. The appropriate anti solvent was added in 100 pL aliquots until dissolution was observed or until a total volume of 2 mL was reached. Between each addition, samples were manually agitated and allowed to stand at ambient temperature for ca. 5 minutes to allow for precipitation. Upon completion of anti-solvent addition, samples which gave clear solutions or small amounts of material were stored at 5 °C for ca. 20 hours. Samples which gave slurries were filtered by centrifugation and the residual solids were analyzed by XRPD. All samples were dried at 40 °C under vacuum for ca. 18 hours the re-analyzed by XRPD to assess any potential form changes. Any novel forms or forms of interest were further analyzed by the following techniques:JH NMR and TG / DSC.

[0274] Evaporation experiments were carried out according to the following procedure. Saturated mother liquors generated from temperature cycling were allowed to evaporate under ambient conditions. Any solids produced from the experiments were analyzed by XRPD. Samples were then dried under vacuum at 40 °C for ca. 18 hours and re-analyzed byXRPD to assess any potential changes in solid form. Any novel patterns were further characterized by 'H NMR spectroscopy.

[0275] Solvent drop grinding experiments were carried out according to the following procedure: 16 x 20 mg of amorphous Compound 1 Tosylate salt was weighed into individual 2 mL plastic vials. 5 pL of appropriate solvent system was added to each vial. Based on the solubility of amorphous Compound 1 in ethanokwater (98.5:1.5 %v / v) and ethanol: heptane (50:50 %v / v), saturated solutions generated from crash cooling experiments were used in order to prevent dissolution of material. Two stainless steel beads were added to each vial and samples were milled according to the protocol: 4500 RPM; 10 * 90 second cycles; 10 second holds between each cycle; Total mill time - One hour. Upon completion of milling, samples were analyzed by XRPD. All samples were dried under vacuum at 40 °C for ca. 19 hours and re-analyzed by XRPD to assess any potential changes in solid form. Any novel patterns were characterized by 'H NMR, TG / DSC, PLM, and FT-IR.

[0276] Vapor diffusion experiments were carried out according to the following procedure. 8 x 20 mg of amorphous Compound 1 Tosylate salt was weighed into 2 mL glass vials. The appropriate solvent system was added in 100 pL aliquots until dissolution was observed. Vials containing solutions of Compound 1 Tosylate salt were placed into individual 20 ml vials containing 2 mL of the appropriate anti-solvent. The outer vial was sealed, and samples were stored at ambient temperature for 7 days. Where solids were obtained, the solids were isolated and analyzed by XRPD. All samples were dried under vacuum at 40 °C for ca. 18 hours and were re-analyzed by XRPD to assess any potential change in solid form.

[0277] Reactive crystallization experiments were carried out according to the following procedure. 24 x 20 mg of Compound 1 freebase was weighed into HPLC vials. 300 pL of appropriate solvent system was added to each sample followed by 1.05 equivalents of p- toluenesulfonic acid. For water-miscible solvents, p-toluenesulfonic acid was added as a 1 M aqueous stock solution. The water non-miscible solvents, p-toluenesulfonic acid was added neat. Samples were temperature cycled for ca. 72 hours with the following procedure: Cool to 5 °C at 0.1 °C / min; Hold at 5 °C for 1 hour; Heat to 40 °C at 0.1 °C / min; Hold at 40 °C for 1 hour. After ca. 72 hours, samples which gave slurries were filtered by centrifugation. The residual solids were isolated and analyzed by XRPD. For samples which gave clear solutions, anti-solvent added until precipitation was observed or until a total volume of 2 mL was reached. If no precipitation was observed, samples cooled to 5 °C to aid precipitation. Anyresulting solids were analyzed by XRPD. All samples were dried under vacuum at 40 °C for ca. 19 hours and re-analyzed by XRPD to assess any potential change in solid form. Two of the mixtures of forms were characterized byJH NMR and TG / DSC.Experimental Methods - Preparation of Amorphous Compound 1 Tosylate Salt

[0278] An amorphous feasibility study was carried out to establish the feasibility of producing amorphous Compound 1 tosylate salt for use in the primary polymorph screen. Amorphous material was sought as input material in order to remove any potential for prejudice for a specific crystalline form caused by the presence of crystalline seed material. The following techniques and conditions were investigated: Lyophilization; Fast evaporation; and Bead milling.

[0279] Lyophilization trials were carried out using four solvent systems (Water; 1,4- dioxane; tert-butanol; or waterdioxane 50:50 %v / v) according to the following procedure. Ca. 10 mg of Tosylate Pattern 1 was weighed into 4 x 2 mL glass vials. 0.5 mL aliquots of the appropriate solvent was added to individual vials until full dissolution was observed or 2 mL of solvent was added. After each addition, the samples were shaken manually and if solid remained the samples were magnetically stirred for 1 - 2 minutes at 40 °C. Where dissolution was observed the samples were stored at - 40 °C. After 2 hours the samples were removed from the freeze dryer chamber, and the samples were freeze dried in the desiccator. After ca. 19 hours the samples were removed from the desiccator and analyzed by XRPD. Where amorphous material was obtained, samples were further analyzed by TG / DSC.

[0280] Fast evaporation trials were carried out in seven solvent systems (ethanol; acetone; ethyl acetate; DCM; THF; methanol; and DCM: methanol 50:50 %v / v) according to the following procedure. 100 mg of Tosylate Pattern 1 was weighed into 20 mL glass vial. The sample was transferred to 25 mL round bottom flask. 1 mL aliquots of the appropriate solvent system were added until dissolution was observed. The solvent was then removed by rotary evaporation at 40 °C and the residual solids were analyzed by XRPD to assess the solid form. Where crystalline material was obtained, the residual solids from the XRPD was re-combined with the bulk sample in the round bottom flask. The next solvent to be assessed was added to the bulk sample to create a solution and the rotary evaporation process was repeated. Where amorphous material was obtained, a fresh sample was prepared using 50 mgof Tosylate Pattern 1 to assess the repeatability of the process. Amorphous material was further analyzed by TG / DSC.

[0281] Bead milling experiments were carried out according to the following procedure. Ca. 10 mg of Tosylate Pattern 1 was weighed into 2 / 2 mL plastic bead mill vials along with two stainless steel beads. The samples were milled according to the following process: 4500 RPM; 10 x 90 second cycles; 10 second holds between each cycle; Repeat four times; Total mill time - One hour. Upon completion of milling, samples were combined and analyzed by XRPD.Experimental Methods - Preparation of Compound 1 Tosylate Salt Pattern 1

[0282] Compound 1 tosylate Pattern 1 was prepared on a 5 g scale according to the following procedure. 5 g of Compound 1 freebase was weighed into a 100 mL Duran and suspended in 20 mL of ethanol: water 90: 10 %v / v. The slurry was magnetically stirred for ca. 5 minutes at ambient temperature and 2.69 g (1.05 molar equivalents) of p-toluenesulfonic acid was added. The sample was stirred at ambient temperature for 30 minutes after which time a sub-sample was taken and filtered by centrifugation. The residual solids were isolated and analyzed by XRPD to assess the solid form of the material. The bulk sample was stirred for ca. one-hour additional time at ambient temperature after which time the sample was filtered by Buchner filtration and the solids were dried under vacuum at 40 °C for ca. 21 hours. The dry solids were analyzed by the following techniques: XRPD; TG / DSC; 'H NMR;FT-IR; HPLC and HPLC-CAD (the isolated mother liquor was analyzed by HPLC to determine sample concentration); and VH-XRPD.Experimental Methods - Preparation of Compound 1 Tosylate Salt Pattern 4

[0283] Compound 1 tosylate Pattern 4 was scaled up according to the following procedure. 500 mg of Tosylate Pattern 1 was weighed into a scintillation vial. 2 mL of ethyl lactate:water 50:50 %v / v was added. The sample was then magnetically stirred at 60 °C for ca. 5 minutes resulting in a yellow solution. 4 mL of water (antisolvent) was added dropwise while the sample was stirred at 60 °C. Resulting in a yellow / white slurry. After ca. 19 hours of stirring a sub sample was analyzed by XRPD. The off-white slurry was then isolated by Buchner filtration. The resulting mother liquor was seeded with ca. 2 mg of Tosylate Pattern 4 and cooled from 60 °C to 5 °C at 0.1 °C / min. The bulk solids were analyzed by XRPD. The solids were then dried at 40 °C under vacuum for ca. 22 hours and reanalyzed by XRPD toassess the solid form. The mother liquor developed a layer of white needle crystals after cooling to 5 °C. A sample was taken and analyzed by XRPD.

[0284] Additional Compound 1 tosylate Pattern 4 was prepared according to the following procedure. 1 g of Tosylate Pattern 1 (See Section 5.10.1 for preparation and characterization of Tosylate Pattern 1) was weighed into a 20 mL glass vial and 5 mL of ethyl lactate: water (17:83 %v / v) was added to create a slurry. The sample was magnetically stirred at 40 °C for ca. 72 hours. After ca. 72 hours a sub-sample of the slurry was taken and analyzed by XRPD to assess the solid form of the material. An additional 1 mL of ethyl lactate: water (17:83 %v / v) was added and the sample temperature was increased to 60 °C. The sample was stirred at 60 °C for ca. 24 hours after which time a sub-sample of the slurry was taken and filtered by centrifugation. The residual solids were isolated and analyzed by XRPD to assess the solid form. The bulk sample was filtered by Buchner filtration (Grade 1, 42.5 mm 0 paper) and the filter cake was washed with 2 mL of ethyl lactate:water (17:83 %v / v). The bulk sample was dried at 40 °C under vacuum and the final isolated solids were analyzed by the following techniques: XRPD; TG / DSC;JH and19F NMR; HPLC; and Variable Temperature DVS.Experimental Methods - Preparation of Compound 1 Tosylate Salt Pattern 5

[0285] The following procedure was used for the scale up of Compound 1 tosylate Pattern 5. 13.8 mL of butyl acetate was added to 460 mg of amorphous Compound 1 tosylate Pattern 1 and then sample was magnetically stirred in ambient conditions, which resulted in a yellow thin slurry. After 5 minutes of stirring a thick white slurry was observed. The sample was then temperature cycled for ca. 40 hours with the following procedure: Hold at 40 °C for 1 hour; Cool to 5 °C at 0.1 °C / min; Hold at 5 °C for 1 hour; Heat to 40 °C at 0.1 °C / min. Multiple sub samples were taken for XRPD analysis: before temperature cycling, one day of cycling and after two days of cycling. The sub sample taken after one day was analyzed by the XRPD at three different time points to see if the sample would increase in crystallinity after ambient exposure. After 40 hours of cycling the sample was held at 5 °C and isolated by Buchner filtration. A further sub sample of the damp filter cake was taken after isolation and analyzed by XRPD. The bulk solids and XRPD plate were then dried under vacuum at 40 °C for 64 hours and were re-analyzed by XRPD. Tosylate Pattern 5 was characterized by: XRPD; PLM; TG / DSC; DSC; VT-XRPD; DVS; FT-IR; Multinuclear NMR; U(H)PLC; KF.Experimental Methods - Preparation of Compound 1 Tosylate Salt Pattern 6

[0286] The following procedure was used for the scale up of Compound 1 tosylate Pattern 6. 0.9 mL of methanol was added to 450 mg of amorphous Compound 1 tosylate Pattern 1, and the sample was magnetically stirred in ambient conditions, resulting in a clear yellow solution. After five minutes of stirring a non-mobile white solid was produced. Before temperature cycling a further 3.6 mL of solvent was added based off primary screen further additions to increase the mobility of the solids before cycling, resulting in a yellow / clear solution. The sample was then temperature cycled for ca. 40 hours with the following procedure: Hold at 40 °C for 1 hour; Cool to 5 °C at 0.1 °C / min; Hold at 5 °C for 1 hour; Heat to 40 °C at 0.1 °C / min. Throughout the temperature cycling it was observed that the white solids crashed out at ~ 7 °C on a cool. Multiple sub samples were taken for XRPD analysis: before temperature cycling, one day of cycling and after two days of cycling. The sub sample taken after one day was analyzed by the XRPD at three different time points to see if the sample would increase in crystallinity after ambient exposure. After temperature cycling, the volume of solvent was reduced by approximately half using a rotary evaporator at 20 °C. The sample was subsequently cooled from 20 °C to 5 °C at 0.1 °C / min. The resulting white solids were isolated by Buchner filtration. A sub sample was taken of the isolated and residual solids that could not be isolated and analyzed by XRPD. The bulk solids and XRPD plate were then dried under vacuum at 40 °C for 64 hours and were re analyzed by XRPD.

[0287] Additional Compound 1 Tosylate Pattern 6 was prepared according to the following procedure. 115 mg of amorphous Tosylate Pattern 1 was weighed into a scintillation vial. 230 pL of methanol was added and the sample was magnetically stirred in ambient conditions. After a couple minutes white solids crashed out of the resulting clear solution. A sub sample was analyzed by XRPD. 50 pL aliquots of solvent were added in the attempt to make a mobile slurry for temperature cycling. After 200 pL, additions were stopped as the solid started to dissolve. The sample was then cooled and held at 5 °C for 1 hour, with the resulting thick solution centrifuged. The mother liquor was stored at 5 °C before HPLC analysis. The bulk solids and XRPD plate were then dried under vacuum at 40 °C for ca. 18 hours. Another sub sample was taken from the bulk solids and analyzed by XRPD in addition to the previous sub sample.Experimental Methods - Preparation of Compound 1 Tosylate Salt Pattern 7

[0288] Tosylate Pattern 7 was prepared on a 1 g scale according to the following procedure. 1 g of Tosylate Pattern 1 was weighed into a 20 mL glass vial and 5 mL of 2- propanol was added to create a slurry. The sample was magnetically stirred at 40 °C for ca. 72 hours. After ca. 72 hours a sub-sample of the slurry was taken and analyzed by XRPD to assess the solid form of the material. The bulk sample was filtered by Buchner filtration (Grade 1, 42.5 mm 0 paper) and the filter cake was washed with 2 mL of 2-propanol. The bulk sample was dried at 40 °C under vacuum and the final isolated solids were analyzed by the following techniques: XRPD; HPLC;JH and19F NMR; and TG / DSC.Experimental Methods - Polymorphic Stability Study (one-week stability)

[0289] An accelerated one-week stability study of Tosylate Pattern 5 and Pattern 6 was conducted to assess the physical and chemical stability of the two forms. 15 mg x 6 of Tosylate Pattern 5 and 6 were weighed into HPLC vials. The samples were then placed in the following 3 conditions for 1 week: 40 °C / 75 %RH uncapped; 80 °C capped; or Ambient uncapped. After 1 week, the solids were analyzed by XRPD and HPLC (purity). TG / DSC was carried out any patterns of interest to assess the weight losses attributed to water content.Experimental Methods - Thermodynamic Solubility Study

[0290] A thermodynamic solubility was conducted on Tosylate Pattern 5 and 6. Pattern 1 was assessed in biorelevant media only, as the pH solubility was assessed previously.Following this, a thermodynamic solubility study was conducted on Tosylate Pattern 1 in biorelevant buffers to investigate the particle size and morphology after exposure to these conditions. These experiments were conducted at a freebase concentration of 0.24 mg / mL. Ca. 10 mg of Tosylate Pattern 1, 5 and 6 were weighed into 2 mL vials. 100 pL aliquots of required buffer were added until a stable, mobile slurry was formed. Between each addition the samples were magnetically stirred at 37 °C for ca. 1 minute to test the slurries at an elevated temperature. The slurries were then stirred at 37 °C for 1 hour. After 1 hour, the samples pH was recorded, and the buffers pH 4.5 acetate and pH 6.8 phosphate were readjusted to the required pH by using 0.2 M NaOH. The samples were then stirred for ca. 20 hours at 37 °C. Following this the pH of each sample was recorded. The samples were then centrifuged with the mother liquors submitted for HPLC concentration analysis and the solids were analyzed by XRPD.Experimental Methods - Polymorphic Stability Study (Competitive Slurrying)

[0291] Competitive slurry experiments between Tosylate Pattern 1, 5 and 6 were performed in four solvents (ethanol: water 95:5 %v / v aw0.6; methanol: water 48:52 %v / v calculated aw0.8; 2-propanol; or THF) and at two different temperatures, 25 and 60 °C. This was conducted to experimentally determine the most stable form. The following procedure was carried out for the competitive slurry experiments. 8 x 7.5 mg of Tosylate Pattern 1, 5 and 6 was weighed into 2 mL vials. These samples were combined into 8 x 2 mL vials to make a 1: 1 : 1 ratio of the forms. Saturated solutions were prepared - 1 mL of solvent was added to the 60 °C experiments and 1.5 mL to the ambient. Tosylate Pattern 1 was then added until a stable mobile slurry was formed. The water mixtures were split in half at 60 °C due to their very high solubility. Once the slurry was formed, the solutions were then syringe filtered and added to the combined samples. The samples were wrapped in parafilm and held at ambient and 60 °C for 46 hours. The water mixtures and 2-propanol (60 °C experiments) were clear solutions with crust in the vial after ca. 18 hours. The crust was then pushed into the solutions to re-establish the slurries. This was repeated three times throughout the experiment. After 46 hours the samples were centrifuged and analyzed by XRPD. The XRPD plate and bulk samples were dried under vacuum at 40 °C for ca. 17 hours and re-analyzed. Solids were gently ground and analyzed by XRPD where necessary.Experimental Methods - Hydration Study

[0292] Following the identification of Tosylate Pattern 7 further experimentation was required to assess the hydration of Tosylate Pattern 7 and locate a route to Tosylate Pattern 4. The experiments were run at 25 and 40 °C. Ca. 20 mg of Tosylate Pattern 1 and 7 was weighed into 2 mL vials. 100 pL aliquots of solvent were added until a stable mobile slurry was formed, or 1 mL of solvent was added. The samples were magnetically stirred at the set temperature for ca 1- 2 minutes before the next aliquot was added. Tosylate Pattern 7 thinned in the 2-propanol mixture at both temperatures so additional solid was added to thicken the slurry. After a mobile slurry was formed the slurries were kept magnetically stirring for 17 - 19 hours. Following this, a sub sample was analyzed by XRPD. The experiments at 25 °C were stirred for another 24 hours and further analyzed by XRPD. Any samples that exhibited preferred orientation were ground and re-analyzed by XRPD.Experimental Methods - Drying Study

[0293] A drying study was carried out using five conditions (Table E10) to further investigate the stability of Tosylate Patterns 1 and 4 to dehydration. The drying study was carried out according to the following procedure. Ca. 20 mg of Tosylate Pattern 1 or Tosylate Pattern 4 was weighed into individual 2 mL glass vials. Samples were stored under the appropriate conditions (Table E10). Observations were recorded and samples were analyzed by XRPD to assess the solid form of the material after one, two and seven days.Results

[0294] A polymorph screen was carried out on Compound 1 tosylate salt. It was scaled up to 5 g, with amorphization trials conducted to find an amorphous form to carry out the polymorph screen with.

[0295] Employing the Compound 1 amorphous tosylate salt, a primary polymorph screen was conducted with the following experiments: crash cooling; antisolvent addition at ambient temperature; evaporation at ambient temperature; solvent drop grinding or vapor diffusion (solvent system dependent); and reactive crystallizations.

[0296] Four new forms were obtained from the primary polymorph screen including: Tosylate Pattern 3 in MIBK from solvent drop grinding both wet and dry and butyl acetate wet from the solvent solubility study and temperature cycling; Tosylate Pattern 4 in DCM from the solvent solubility study wet and dry; Tosylate Pattern 5 in butyl acetate dry from the solvent solubility study and temperature cycling; and Tosylate Pattern 6 in methanol wet and dry from temperature cycling.

[0297] Tosylate Pattern 1 was by far the most prevalent form in the polymorph screen. Multiple mixtures of patterns were obtained with mixtures of Pattern 1 and 4, and Patterns 1 and 5 observed multiple times.

[0298] A summary of the results of the primary polymorph screen are highlighted in Tables E5A-E5D. A summary of the characterization of the Compound 1 Tosylate salt forms is located in Tables E6A-E6C.

[0299] The following abbreviations apply to the tables provided in this section. “P#” denotes a particular tosylate XRPD pattern (e.g., Pl and P2 denote tosylate Pattern 1 and tosylate Pattern 2, respectively). “FB” denotes observation of Compound 1 Freebase Pattern1. “IS” denotes experiments that yielded an insufficient amount of sample for analysis. The addition of “+” indicates that additional peaks were observed relative to other instances of a pattern. The addition ofindicates loss of peaks relative to other instances of a pattern. The addition of indicates that minor differences were observed relative to other instances of a pattern. The addition of “PC” indicates that a poorly crystalline pattern was observed. The addition of “PO” indicates that a preferred orientation was observed.

[0300] A secondary polymorph screen was conducted on Tosylate Pattern 5 and 6 due to these forms exhibiting a high level of crystallinity, stability, and ease of scale up and reproducibility. Tosylate Pattern 3 was not selected as it was not stable to drying (and converted to Pattern 5). Tosylate Pattern 4 was not reproduced during attempts to prepare it for a dehydration study during the polymorph screen. Tosylate Pattern 5 was identified as a hemi-hydrated mono-salt and Tosylate Pattern 6 was a monohydrated mono-salt. A summary of the analysis and experimentation from the secondary polymorph screen on Tosylate Pattern 5 and 6 is located in Tables E7A and E7B.

[0301] Through competitive slurries with Tosylate Pattern 1, 5 and 6 it was concluded that Tosylate Pattern 1 was the stable form at 25 °C and Tosylate Pattern 4 was the stable form at 60 °C. Tosylate Pattern 4 was observed where the material had crusted at elevated temperature.

[0302] Following the competitive slurry experiments, further experimentation was conducted to experimentally acquire pure Tosylate Pattern 4, so that it could be characterized further to understand the relationship between Tosylate Pattern 1 and 4 and to mitigate any risks to converting Tosylate Pattern 1 to 4.

[0303] In the repreparation of Tosylate Pattern 4 in 2-propanol at 60 °C Tosylate Pattern 7 was observed, an anhydrous form of the Compound 1 tosylate salt. Further experimentation was conducted to produce pure Tosylate Pattern 4. Antisolvent addition of water to ethyl lactate at 60 °C with a final solvent composition of ethyl lactate:water 14:86 %v / v was selected as the solvent system to scale up Tosylate Pattern 4.

[0304] Characterization of Tosylate Pattern 4 and Tosylate Pattern 7 was conducted concluding that Tosylate Pattern 4 was a monohydrated mono-tosylate salt and Tosylate Pattern 7 was an anhydrous mono-tosylate salt.

[0305] 1 week stability study of Tosylate Pattern 4 and 7 showed both patterns to be stable, however at 80 °C Tosylate Pattern 4 converted to Tosylate Pattern 7. In the same conditions, Tosylate Pattern 1 did not convert to Tosylate Pattern 7.

[0306] Thermodynamic solubility study of Tosylate Pattern 4 showed that solubility in the buffer media was similar to Tosylate Pattern 1, 5 and 6 but in the buffers 0.1 N HC1 and FaSSGF XRPD analysis was consistent with Tosylate Pattern 4. This is in contrast to Tosylate Pattern 1, 5 and 6 that all exhibited Tosylate Pattern 1. Tosylate Pattern 7 was also experimented on, showing similar solubility results to the other patterns however, the concentration of freebase was significantly lower in FaSSIF media. In 0.1 N HC1 buffer Tosylate Pattern 7 converted to a mixture of Tosylate Pattern 1 and 4 and in FaSSGF Tosylate Pattern 7 converted to Tosylate Pattern 4. Further experimentation was conducted to investigate the stability of Tosylate Pattern 7 in the first 30 minutes of exposure to pH 1.2, 4.5 and 6.8 buffer. A mixture of Pattern 1 and 4 was observed in pH 1.2 and a mixture of pattern 1 4 and Freebase pattern 1 was observed in pH 4.5 and 6.8.

[0307] A summary of the characterization and experimentation on Tosylate Pattern 4 and 7 is located in Tables E8A and E8B.

[0308] The solvent solubility study on Tosylate Pattern 1 showed that a high quantity of solvents converted to Tosylate Pattern 7. A 2-week stability study was then conducted at 5 °C, 25 °C and 40 °C to investigate the stability of Tosylate Pattern 1. At 5 °C, Tosylate Pattern 7 was the most prevalent pattern, either in a mixture with Tosylate Pattern 1 or by itself. Tosylate Pattern 1 was observed in acetone and the Tosylate Pattern 1 crystallization solvent and a mixture of Tosylate 1 and 4 was exhibited in DCM. At 25 °C and 40 °C, all previous mixtures had either formed Tosylate Pattern 7 or 4, with Tosylate Pattern 7 being the most prevalent pattern. Tosylate Pattern 1 was only observed in the ENLV Tosylate salt crystallization solvent and Tosylate Pattern 4 was exhibited in the DCM experiment.

[0309] This further highlighted that Tosylate Pattern 7 was the stable form of Compound 1 tosylate salt in anhydrous conditions. Tosylate Pattern 4 was likely the thermodynamically stable hydrate, and Tosylate Pattern 1 likely the kinetic hydrate.

[0310] A summary of the results from the isothermal stable form screen are located inTable E9.

[0311] Based on the results of the primary and secondary polymorph screens, further developability assessments were carried out for Tosylate Pattern 1 and Pattern 4. A drying study was carried out under five conditions in order to assess the stability of each form to dehydration. A summary of the results obtained during the drying study are presented in Table E10, which showed that both Tosylate Pattern 1 and Pattern 4 were stable under all of the conditions investigated.

[0312] In addition to the drying study, an isothermal stable form screen of Tosylate Pattern 4 was conducted using 10 solvent systems at three temperatures to further investigate the stability of the form to dehydration in solution and to establish the thermodynamically favored form of the Compound 1 tosylate salt. A summary of the results for the isothermal stable form screen are presented in Table El 1 while a comparison with the isothermal stable form screen of Tosylate Pattern 1 is presented in Table E12. The isothermal stable form screen of Tosylate Pattern 4 indicated that the anhydrous form Tosylate Pattern 7 was the stable form under the majority of conditions investigated. Tosylate Pattern 4 was retained across the temperature range investigated in ethanol: water (98.5: 1.5 %v / v) and ethanol: water :lBME (45:5:50 %v / v). Tosylate Pattern 4 was also retained in DCM at 25 and 40 °C however conversion to a mixture of Tosylate Pattern 1 and Pattern 4 was observed after 15 days at 5 °C. XRPD analysis indicated conversion of Tosylate Pattern 4 to Tosylate Pattern 7 after 3 days in 2-MeTHF however a further conversion to Tosylate Pattern 1 was observed after 15 days in the same solvent system.

[0313] Based on the results of the isothermal stable form screen of Tosylate Pattern 4, a polymorphic stability study was carried out in four process relevant solvent systems at two temperatures further investigate the relative stabilities of Tosylate Pattern 1 and Pattern 4. A summary of the results obtained from the polymorph stability study are presented in Table E13. XRPD analysis indicated conversion to the anhydrous form Tosylate Pattern 7 occurred in the majority of solvent systems and conditions investigated. Tosylate Pattern 4 was retained in the ethanol: water (95:5 %v / v) solvent system at 25 °C while conversion to Pattern 7 was observed at elevated temperatures. A mixture of Tosylate Pattern 1 and Pattern 4 was obtained from ethanol: water: tB ME (45:5:50 %v / v / v) solvent system indicated that neither form was the dominant thermodynamically favored form.

[0314] In addition to the further developability assessments carried out on Tosylate Pattern 1 and Pattern 4, a hydration study of Tosylate Pattern 7 was conducted in order tomap the hydration landscape of the anhydrous form in process relevant solvent systems. A summary of the results obtained from the hydration study are presented in Table E14. The hydration study showed that Tosylate Pattern 7 was stable and did not convert to either Tosylate Pattern 1 or Pattern 4 in solvent systems which contained up to 4% water across the temperature range investigated. Conversion to Tosylate Pattern 1 was observed in solvent system with greater than 4 % water content at 5 and 25 °C. Conversion was observed after three days with no subsequent form changes observed after 15 days which indicated that Tosylate Pattern 1 was a potentially stable form. Conversion of Tosylate Pattern 1 to Tosylate Pattern 4 was observed in the ethanokwater (75:25 %v / v) solvent system after 15 days at 40 °C which was potentially indicative that Tosylate Pattern 4 was the thermodynamically favored hydrated form under the conditions investigated.Table E5ATable E5BTable E5CTable E6ATable E6BTable E7ATable E7BTable E8ATable E8BTable E9Table E10Table EllExample 5: Formulations

[0315] A series of tablet formulations comprising Compound 1 Tosylate Form 1 were prepared using the excipients and proportions shown in Tables E15-E19.Table E15* Equivalent to 40 mg of Compound 1 FreebaseTable E16* Equivalent to 40 mg of Compound 1 FreebaseTable E17* Equivalent to 40 mg of Compound 1 FreebaseTable E18* Equivalent to 40 mg of Compound 1 FreebaseTable E19* Equivalent to 40 mg of Compound 1 FreebaseExample 6: Antiproliferative activity of Compound 1 compared to approved ABL tyrosine kinase inhibitors in Ba / F3 cells harboring various BCR::ABL1 mutations

[0316] Cells were treated with compounds, and cell viability was measured as a metric of kinase inhibition. Ba / F3 cell lines were tested. The Ba / F3 cell line is an IL-3 -dependent mouse cell line. Ba / F3 cells were engineered to express various mutant human BCR-ABL proteins rendering the cells IL-3 independent.

[0317] Ba / F3 cell lines engineered to express various mutant forms of BCR-ABL (T315I, M244V, A337T, E355G, F359C, F359V and P469S) were grown in RPMI + 10% FBS. Ba / F3 cells were harvested at 50-80% confluence then counted and seeded at 600 cells per well in 384-well tissue culture plates.

[0318] Compounds were dissolved in DMSO and were added to the plated cells in each well using a TECAN liquid handler. Compounds were tested at concentrations of 5 pM to 0.16 nM, using three-fold dilutions. The final proportion of DMSO never exceeded 0.1%.

[0319] Plates were placed in a 37°C, 5% CO2 incubator for 72 hours. Plates were then removed from the incubator and equilibrated for 15 minutes at room temperature. 40 pL of CellTiter Gio 2 reagent (Promega) was added to measure the relative level of metabolically active cells by quantifying intracellular ATP concentrations. Plates were incubated for 30 minutes at room temperature, and luminescence was measured.

[0320] Percent viability was normalized to a vehicle control only employing the following formula: % viability = 100 x (Lum Sample) / (Lum HC). The high control values (“HC”) was generated from lysate from wells with cells treated with 0.25% DMSO. IC50 values were calculated in GraphPad Prism using algorithm to fit a Hill equation to doseresponse data using the following equation: Y=100 / [l+10A((LogIC5o-X)*HillSlope)].

[0321] Cell viability was measured with CellTiter Gio luminescent assay. Values are expressed as fold-shift in IC50 from BCR::ABL1WT, as summarized in Table E20 below. This data shows that Compound 1 maintains activity against T315I and other BCR:: ABL 1 mutations known to confer resistance to asciminib and other tyrosine kinase inhibitors. Most frequent mutations at baseline in patients resistant to asciminib in ASCEMBL study are F359C and F359V. See Rea D et al. A phase 3, open-label, randomized study of asciminib, aSTAMP inhibitor, v.s bosutinib in CML after 2 or more prior TKIs. Blood. 2021 ; 138:2031- 2041.Table E20. Fold-shift from native BCR::ABL1Example 7. Molecular response (MR) in patients with CML without T315I mutation by 24 weeks after daily treatment with Compound 1

[0322] The standard means of monitoring response in patients with CML is measurement in peripheral blood of BCR::ABL1 transcripts by quantitative polymerase chain reaction (qPCR) measurement. The ratio of BCR::ABL1 transcripts to ABL transcripts is normalized to control gene transcripts and converted to the International Scale (IS) which can then be used to monitor molecular response (MR). Major molecular response (MMR) is defined as < or = 0.1% BCR: ABL on the IS. Molecular response by 24 weeks was reported after daily treatment with Compound 1. A total of 18 patients were evaluable. Evaluable patients had baseline typical BCR: : ABL1 transcript without T3151 mutation and postbaseline assessment of BCR:: ABL 1 transcript at 24 weeks or achieved MMR within 24 weeks or discontinued treatment before 24 weeks without achieving MMR. For patients with MMR at baseline, onlypostbaseline assessments beyond 70 days were included in the analysis. These patients were heavily pre-treated. The 24 week cumulative MMR rate for these patients was 44% (8 / 18).

[0323] Table E21 below summarizes the change in MMR by 24 weeks. After daily treatment of Compound 1, 7 patients showed improved MR category, where two improved by one category, four improved by two categories, and one improved by three categories. Ten patients stayed in the same MR category.Table E21. 24 week MR shifta Deep response (from MR3 to MR5) was observed in this patient with lack of efficacy to prior asciminib and A337T mutation by local lab testing (below the threshold for central mutation testing). b Worsening of transcript level from 6.3% at baseline to 13% was observed after 4 weeks in this patient with E255V mutation, who previously discontinued asciminib and ponatinib due to lack of efficacy.Example 8: Compound 1 ’s pharmacokinetic (PK) profile supporting once daily dosing with flexible administration requirements

[0324] Linear PK was observed in healthy volunteers (HV) and patients. No timedependent PK was observed in either HVs or cancer patients. Both the maximumconcentration (CmaX; the highest concentration of the drug in the bloodstream after administration) and the area under the curve (AUC) increased dose-proportionally. High concordance between HV and patient PK was observed.

[0325] Fast and complete absorption with no significant food effect was observed. Mean terminal ti / 2 was ~12 hours in healthy volunteers. Similar effective ti / 2 was observed in patients (10-20 hours), suggesting a daily dose (QD) regimen.

[0326] Minimal risk of drug-drug interactions (DDIs) was found. Compound 1 is not an inhibitor (competitive or time-dependent) or inducer of major CYP enzymes, or of UGT1A1. Compound 1 is not a substrate for major CYP enzymes, BCRP, or P-gp. There is no correlation between adverse events (AEs) and PK parameters in patients.

[0327] Food effect study at 120 mg single dose in HVs showed that: (i) AUCinf under fasting conditions were similar to that under fed conditions, with a fed / fasted AUC ratio of 1.2; and (ii) Cmax under fasting conditions were similar to that under fed conditions, with a fed / fasted Cmax ratio of 0.8. See FIG. 69.Example 9. Molecular response (MR) in patients with CML without T3151 mutation by 24 weeks after daily treatment with Compound 1

[0328] This example includes an update to Example 7 above. Patients with previously treated chronic phase CML received Compound 1 orally at doses from 10-160 mg daily. Reenrollment at higher dose levels and intra-subject dose escalation was allowed if criteria were met. Molecular response was centrally assessed by RTqPCR at baseline, every 4 weeks for 6 cycles, then every 12 weeks. Efficacy was evaluated as cumulative major molecular response (MMR) rate by 24 weeks. Patients were evaluable for efficacy if assessed at 24 weeks, achieved MMR prior to 24 weeks (if not in MMR at baseline), maintained MMR for at least 70 days (if in MMR at baseline), or discontinued treatment with >one postbaseline assessment prior to 24 weeks. All patients were included for safety analyses, patients with typical BCR::ABL1 transcripts and without T315I mutation were included for the efficacy analyses provided here.

[0329] Total 74 patients were enrolled (2 re-enrolled) including 63 with typical transcript and without T3151 mutations. With a median duration of exposure of about 26 weeks (range 0.1-112 weeks), 61 (82%) patients remained on treatment, 3 (4.1%) discontinued due toadverse events, 9 (12%) discontinued due to lack of efficacy, and one (1.4%) discontinued due to a protocol deviation. Median age was 57.5 years (range 19-79 years). The majority of patients (66%) had received >3 prior tyrosine kinase inhibitors (TKIs), including ponatinib (45%) and asciminib (57%). The most common reason for discontinuing the last prior TKI was lack of efficacy (68%). The majority of adverse events regardless of study drug relationship (TEAEs) were Grade 1 / 2. Grade >3 TEAEs were reported in 11 / 72 (15%) patients, with thrombocytopenia (5.6%) and neutropenia (5.6%) most commonly reported. Two patients discontinued Compound 1 due to cytopenias and one due to Grade 2 pancreatitis. The maximum tolerated dose was not reached. Dose interruptions and reductions occurred in <10% and <5% of patients, respectively. 16 of 36 (44%) evaluable patients were in MMR by 24 weeks, with 7 / 27 (26%) achieving and 9 / 9 (100%) maintaining MMR. Of those resistant to their last TKI, 10 / 25 (40%) were in MMR by 24 weeks. Of those previously treated with asciminib or ponatinib, 9 / 25 (36%) were in MMR by 24 weeks, including one with a known asciminib resistance mutation (A337T). All patients who achieved or maintained MMR were still in MMR at the time of data cutoff.

Claims

CLAIMSWhat is claimed is:

1. A crystalline form of (15,25)-A-(2-(4,6-bis(methoxy-t / 3)pyrimidin-5-yl)-l-methyl-lJ / - pyrrolo[2,3-c]pyridin-5-yl)-2-fluorocyclopropane-l-carboxamide (Compound 1) or a pharmaceutically acceptable salt thereof.

2. The crystalline form of claim 1, wherein the crystalline form is a crystalline form of Compound 1 as freebase.

3. The crystalline form of claim 2, wherein the crystalline form is Freebase Form 1 and is characterized as having: a. an XRPD pattern substantially as shown in FIG. 65; b. an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 1; and / or c. a TGA / DSC thermogram substantially as shown in FIG. 66.

4. The crystalline form of claim 2, wherein the crystalline form is Freebase Form 3 and is characterized as having: a. an XRPD pattern substantially as shown in FIG. 67; and / or b. an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 2.

5. The crystalline form of claim 2, wherein the crystalline form is Freebase Form 4 and is characterized as having: a. an XRPD pattern substantially as shown in FIG. 68; and / or b. an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 3.

6. The crystalline form of claim 1, wherein the crystalline form is a crystalline form of a pharmaceutically acceptable salt of Compound 1.

7. The crystalline form of claim 6, wherein the crystalline form is a crystalline form of a HC1, HBr, naphthal ene-l,5-disulfonic acid, sulfuric acid, ethane-l,2-disulfonic acid, esylate, 2-hydroxyethanesulfonic acid, tosylate, methanesulfonic acid, napthalene-2- sulfonic acid, benzenesulfonic acid, maleic acid, phosphoric acid, or (+)-camphor-10- sulfonic acid salt of Compound 1.

8. The crystalline form of claim 6, wherein the crystalline form is HC1 Form 1, a crystalline form of a HC1 salt of Compound 1, and is characterized as having: a. an XRPD pattern substantially as shown in FIG. 1;b. an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 4; and / or c. a TGA / DSC thermogram substantially as shown in FIG. 2.

9. The crystalline form of claim 6, wherein the crystalline form is HC1 Form 2, a crystalline form of a HC1 salt of Compound 1, and is characterized as having: a. an XRPD pattern substantially as shown in FIG. 3; and / or b. an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 5.

10. The crystalline form of claim 6, wherein the crystalline form is HC1 Form 3, a crystalline form of a HC1 salt of Compound 1, and is characterized as having: a. an XRPD pattern substantially as shown in FIG. 4; and / or b. an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 6.

11. The crystalline form of claim 6, wherein the crystalline form is HC1 Form 4, a crystalline form of a HC1 salt of Compound 1, and is characterized as having: a. an XRPD pattern substantially as shown in FIG. 5; b. an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 7; and / or c. a TGA / DSC thermogram substantially as shown in FIG. 6.

12. The crystalline form of claim 6, wherein the crystalline form is HC1 Form 5, a crystalline form of a HC1 salt of Compound 1, and is characterized as having: a. an XRPD pattern substantially as shown in FIG. 7; and / or b. an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 8.

13. The crystalline form of claim 6, wherein the crystalline form is HC1 Form 6, a crystalline form of a HC1 salt of Compound 1, and is characterized as having: a. an XRPD pattern substantially as shown in FIG. 8; and / or b. an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 9.

14. The crystalline form of claim 6, wherein the crystalline form is HBr Form 1, a crystalline form of a HBr salt of Compound 1, and is characterized as having: a. an XRPD pattern substantially as shown in FIG. 9;b. an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 10; and / or c. a TGA / DSC thermogram substantially as shown in FIG. 10.

15. The crystalline form of claim 6, wherein the crystalline form is HBr Form 2, a crystalline form of a HBr salt of Compound 1, and is characterized as having: a. an XRPD pattern substantially as shown in FIG. 11; b. an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 11; and / or c. a TGA / DSC thermogram substantially as shown in FIG. 12.

16. The crystalline form of claim 6, wherein the crystalline form is HBr Form 3, a crystalline form of a HBr salt of Compound 1, and is characterized as having: a. an XRPD pattern substantially as shown in FIG. 13; and / or b. an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 12.

17. The crystalline form of claim 6, wherein the crystalline form is HBr Form 4, a crystalline form of a HBr salt of Compound 1, and is characterized as having: a. an XRPD pattern substantially as shown in FIG. 14; b. an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 13; and / or c. a TGA / DSC thermogram substantially as shown in FIG. 15.

18. The crystalline form of claim 6, wherein the crystalline form is Naphthalene-1,5- disulfonic Acid Form 1, a crystalline form of a naphthal ene- 1,5 -di sulfonic acid salt of Compound 1, and is characterized as having: a. an XRPD pattern substantially as shown in FIG. 16; b. an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 14; and / or c. a TGA / DSC thermogram substantially as shown in FIG. 17.

19. The crystalline form of claim 6, wherein the crystalline form is Naphthalene-1,5- disulfonic Acid Form 2, a crystalline form of a naphthal ene- 1,5 -di sulfonic acid salt of Compound 1, and is characterized as having: a. an XRPD pattern substantially as shown in FIG. 18; b. an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 15; and / orc. a TGA / DSC thermogram substantially as shown in FIG. 19.

20. The crystalline form of claim 6, wherein the crystalline form is Sulfuric Acid Form 1, a crystalline form of a sulfuric acid salt of Compound 1, and is characterized as having: a. an XRPD pattern substantially as shown in FIG. 20; b. an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 16; and / or c. a TGA / DSC thermogram substantially as shown in FIG. 21.

21. The crystalline form of claim 6, wherein the crystalline form is Sulfuric Acid Form 2, a crystalline form of a sulfuric acid salt of Compound 1, and is characterized as having: a. an XRPD pattern substantially as shown in FIG. 22; b. an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 17; and / or c. a TGA / DSC thermogram substantially as shown in FIG. 23.

22. The crystalline form of claim 6, wherein the crystalline form is Sulfuric Acid Form 3, a crystalline form of a sulfuric acid salt of Compound 1, and is characterized as having: a. an XRPD pattern substantially as shown in FIG. 24; b. an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 18; and / or c. a TGA / DSC thermogram substantially as shown in FIG. 25.

23. The crystalline form of claim 6, wherein the crystalline form is Sulfuric Acid Form 4, a crystalline form of a sulfuric acid salt of Compound 1, and is characterized as having: a. an XRPD pattern substantially as shown in FIG. 26; and / or b. an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 19.

24. The crystalline form of claim 6, wherein the crystalline form is Sulfuric Acid Form 5, a crystalline form of a sulfuric acid salt of Compound 1, and is characterized as having: a. an XRPD pattern substantially as shown in FIG. 27; and / orb. an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 20.

25. The crystalline form of claim 6, wherein the crystalline form is Ethane- 1,2-disulfonic Acid Form 1, a crystalline form of an ethane- 1,2-disulfonic acid salt of Compound 1, and is characterized as having: a. an XRPD pattern substantially as shown in FIG. 28; b. an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 21; and / or c. a TGA / DSC thermogram substantially as shown in FIG. 29.

26. The crystalline form of claim 6, wherein the crystalline form is Esylate Form 1, a crystalline form of an esylate salt of Compound 1, and is characterized as having: a. an XRPD pattern substantially as shown in FIG. 30; b. an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 22; and / or c. a TGA / DSC thermogram substantially as shown in FIG. 31.

27. The crystalline form of claim 6, wherein the crystalline form is 2- Hydroxyethanesulfonic Acid Form 1, a crystalline form of a 2-hydroxyethanesulfonic acid salt of Compound 1 and is characterized as having: a. an XRPD pattern substantially as shown in FIG. 32; b. an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 23; and / or c. a TGA / DSC thermogram substantially as shown in FIG. 33.

28. The crystalline form of claim 6, wherein the crystalline form is Methanesulfonic Acid Form 1, a crystalline form of a methanesulfonic acid salt of Compound 1, and is characterized as having: a. an XRPD pattern substantially as shown in FIG. 48; b. an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 30; and / or c. a TGA / DSC thermogram substantially as shown in FIG. 49.

29. The crystalline form of claim 6, wherein the crystalline form is Napthalene-2-sulfonic Acid Form 1, a crystalline form of a napthalene-2-sulfonic acid salt of Compound 1, and is characterized as having: a. an XRPD pattern substantially as shown in FIG. 50;b. an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 31; and / or c. a TGA / DSC thermogram substantially as shown in FIG. 51.

30. The crystalline form of claim 6, wherein the crystalline form is Napthalene-2-sulfonic Acid Form 2, a crystalline form of a napthalene-2-sulfonic acid salt of Compound 1, and is characterized as having: a. an XRPD pattern substantially as shown in FIG. 52; b. an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 32; and / or c. a TGA / DSC thermogram substantially as shown in FIG. 53.

31. The crystalline form of claim 6, wherein the crystalline form is Napthalene-2-sulfonic Acid Form 3, a crystalline form of a napthalene-2-sulfonic acid salt of Compound 1, and is characterized as having: a. an XRPD pattern substantially as shown in FIG. 54; b. an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 33; and / or c. a TGA / DSC thermogram substantially as shown in FIG. 55.

32. The crystalline form of claim 6, wherein the crystalline form is Benzenesulfonic Acid Form 1, a crystalline form of a benzenesulfonic acid salt of Compound 1, and is characterized as having: a. an XRPD pattern substantially as shown in FIG. 56; b. an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 34; and / or c. a TGA / DSC thermogram substantially as shown in FIG. 57.

33. The crystalline form of claim 6, wherein the crystalline form is Benzenesulfonic Acid Form 2, a crystalline form of a benzenesulfonic acid salt of Compound 1, and is characterized as having: a. an XRPD pattern substantially as shown in FIG. 58; b. an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 35; and / or c. a TGA / DSC thermogram substantially as shown in FIG. 59.

34. The crystalline form of claim 6, wherein the crystalline form is Maleic Acid Form 1, a crystalline form of a maleic acid salt of Compound 1, and is characterized as having:a. an XRPD pattern substantially as shown in FIG. 60; and / or b. an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 36.

35. The crystalline form of claim 6, wherein the crystalline form is Phosphoric Acid Form1, a crystalline form of a phosphoric acid salt of Compound 1, and is characterized as having: a. an XRPD pattern substantially as shown in FIG. 61; and / or b. an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 37.

36. The crystalline form of claim 6, wherein the crystalline form is Phosphoric Acid Form2, a crystalline form of a phosphoric acid salt of Compound 1, and is characterized as having: a. an XRPD pattern substantially as shown in FIG. 62; and / or b. an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 38.

37. The crystalline form of claim 6, wherein the crystalline form is (+)-Camphor-10- sulfonic acid Form 1, a crystalline form of a (+)-camphor-10-sulfonic acid salt of Compound 1, and is characterized as having: a. an XRPD pattern substantially as shown in FIG. 63; b. an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 39; and / or c. a TGA / DSC thermogram substantially as shown in FIG. 64.

38. The crystalline form of claim 6, wherein the crystalline form is a crystalline form of a tosylate salt of Compound 1.

39. The crystalline form of claim 38, wherein the tosylate salt is a mono-tosylate salt.

40. The crystalline form of claim 38 or 39, wherein the crystalline form is a hydrate.

41. The crystalline form of claim 40, wherein the crystalline form is a monohydrate.

42. The crystalline form of claim 40, wherein the crystalline form is a hemihydrate.

43. The crystalline form of claim 38 or 39, wherein the crystalline form is anhydrous.

44. The crystalline form of any one of claims 38 to 41, wherein the crystalline form is Tosylate Form 1, a crystalline form of a tosylate salt of Compound 1, and is characterized as having: a. an XRPD pattern substantially as shown in FIG. 34;b. an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 24; and / or c. a TGA / DSC thermogram substantially as shown in FIG. 35.

45. The crystalline form of any one of claims 38 to 41, wherein the crystalline form is Tosylate Form 1, a crystalline form of a tosylate salt of Compound 1, and is characterized as having an X-ray powder diffraction (XRPD) pattern comprising a peak at an angle 2-theta of about 17.65.

46. The crystalline form of claim 45, wherein the XRPD pattern further comprises a peak at an angle 2-theta of about 24.47.

47. The crystalline form of claim 46, wherein the XRPD pattern further comprises peaks at angles 2-theta of about 21.74, about 16.55, and about 14.30.

48. The crystalline form of claim 47, wherein the XRPD pattern further comprises peaks at angles 2-theta of about 23.95, about 25.29, about 15.29, about 28.77, and about 28.65.

49. The crystalline form of claim 48, wherein the XRPD pattern further comprises peaks at angles 2-theta of about 13.77, about 21.55, about 22.65, about 19.43, about 13.47, about 29.21, about 22.70, about 9.14, about 26.40, and about 23.86.

50. The crystalline form of claim 45, wherein the crystalline form is characterized as having endothermic transitions at about 71.2 °C and about 127.9 °C, as measured by DSC.

51. The crystalline form of claim 45, wherein the crystalline form is characterized as showing a weight loss of about 3.2% from about 37 °C to about 139 °C, and a weight loss of about 0.66% from about 139 °C to about 265 °C as determined by TGA.

52. The crystalline form of claim 45, wherein the crystalline form is characterized as having an XRPD pattern substantially as shown in FIG. 34.

53. The crystalline form of claim 45, wherein the crystalline form is characterized as having an TGA / DSC thermogram substantially as shown in FIG. 35.

54. The crystalline form of claim 38, wherein the crystalline form is Tosylate Form 2, a crystalline form of a tosylate salt of Compound 1, and is characterized as having: a. an XRPD pattern substantially as shown in FIG. 36; and / or b. a TGA / DSC thermogram substantially as shown in FIG. 37.

55. The crystalline form of claim 38, wherein the crystalline form is Tosylate Form 3, a crystalline form of a tosylate salt of Compound 1, and is characterized as having:a. an XRPD pattern substantially as shown in FIG. 38; b. an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 25; and / or c. a TGA / DSC thermogram substantially as shown in FIG. 39.

56. The crystalline form of any one of claims 38 to 41, wherein the crystalline form is Tosylate Form 4, a crystalline form of a tosylate salt of Compound 1, and is characterized as having: a. an XRPD pattern substantially as shown in FIG. 40; b. an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 26; and / or c. a TGA / DSC thermogram substantially as shown in FIG. 41.

57. The crystalline form of any one of claims 38 to 41, wherein the crystalline form is Tosylate Form 4, a crystalline form of a tosylate salt of Compound 1, and is characterized as having an XRPD pattern comprising a peak at an angle 2-theta of about 24.80.

58. The crystalline form of claim 57, wherein the XRPD pattern further comprises a peak at an angle 2-theta of about 17.38.

59. The crystalline form of claim 58, wherein the XRPD pattern further comprises peaks at angles 2-theta of about 17.72, about 14.45, and about 16.97.

60. The crystalline form of claim 59, wherein the XRPD pattern further comprises peaks at angles 2-theta of about 24.12, about 21.31, about 5.56, about 14.05, and about 28.84.

61. The crystalline form of claim 60, wherein the XRPD pattern further comprises peaks at angles 2-theta of about 22.34, about 29.15, about 18.63, about 19.48, about 18.81, about 22.56, about 21.71, about 10.72, about 23.79, and about 10.61.

62. The crystalline form of claim 57, wherein the crystalline form is characterized as having endothermic transitions at about 72.4 °C and about 131.5 °C, as measured by DSC.

63. The crystalline form of claim 57, wherein the crystalline form is characterized as showing a weight loss of about 3.1% from about 31 °C to about 158 °C and a weight loss of about 1.2% from about 158 °C to about 198 °C, as determined by TGA.

64. The crystalline form of claim 57, wherein the crystalline form is characterized as having an XRPD pattern substantially as shown in FIG. 40.

65. The crystalline form of claim 57, wherein the crystalline form is characterized as having an TGA / DSC thermogram substantially as shown in FIG. 41.

66. The crystalline form of claim 38, wherein the crystalline form is Tosylate Form 5, a crystalline form of a tosylate salt of Compound 1, and is characterized as having: a. an XRPD pattern substantially as shown in FIG. 42; b. an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 27; and / or c. a TGA / DSC thermogram substantially as shown in FIG. 43.

67. The crystalline form of claim 38, wherein the crystalline form is Tosylate Form 6, a crystalline form of a tosylate salt of Compound 1, and is characterized as having: a. an XRPD pattern substantially as shown in FIG. 44; b. an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 28; and / or c. a TGA / DSC thermogram substantially as shown in FIG. 45.

68. The crystalline form of claim 38, wherein the crystalline form is Tosylate Form 7, a crystalline form of a tosylate salt of Compound 1, and is characterized as having: a. an XRPD pattern substantially as shown in FIG. 46; b. an XRPD pattern comprising one or more peaks as assigned at angles 2-theta in degrees as recited in Table 29; and / or c. a TGA / DSC thermogram substantially as shown in FIG. 47.

69. The crystalline form of claim 38, wherein the crystalline form is Tosylate Form 7, a crystalline form of a tosylate salt of Compound 1, and is characterized as having an XRPD pattern comprising a peak at an angle 2-theta of about 7.48.

70. The crystalline form of claim 69, wherein the XRPD pattern further comprises a peak at an angle 2-theta of about 23.24.

71. The crystalline form of claim 70, wherein the XRPD pattern further comprises peaks at angles 2-theta of about 9.49, about 14.04, and about 18.07.

72. The crystalline form of claim 71, wherein the XRPD pattern further comprises peaks at angles 2-theta of about 25.96, about 13.88, about 27.31, about 12.51, and about 22.56.

73. The crystalline form of claim 72, wherein the XRPD pattern further comprises peaks at angles 2-theta of about 21.69, about 11.34, about 18.39, about 27.58, about 21.22, about 22.75, about 10.23, about 19.90, about 21.95, and about 13.21.

74. The crystalline form of claim 69, wherein the crystalline form is characterized as having an endothermic transition at about 216.6 °C, as measured by DSC.

75. The crystalline form of claim 69, wherein the crystalline form is characterized as having an XRPD pattern substantially as shown in FIG. 46.

76. The crystalline form of claim 69, wherein the crystalline form is characterized as having an TGA / DSC thermogram substantially as shown in FIG. 47.

77. A pharmaceutical composition comprising the crystalline form of any one of claims 1- 76 and one or more pharmaceutically acceptable excipients.

78. The pharmaceutical composition of claim 77, wherein the composition comprises one or more intra-granular ingredients and one or more extra-granular ingredients.

79. The pharmaceutical composition of claim 78, wherein the one or more intra-granular ingredients comprise the crystalline form of any one of claims 1-76.

80. The pharmaceutical composition of claim 79, wherein the crystalline form is Tosylate Form 1 or the crystalline form of any one of claims 44 to 53.

81. The pharmaceutical composition of any one of claims 77 to 80, wherein the composition comprises Compound 1 or a pharmaceutically acceptable salt thereof in the amount equivalent to about 40 mg, 80 mg, or 120 mg of Compound 1 in the freebase form.

82. The pharmaceutical composition of any one of claims 77 to 80, wherein the composition comprises Compound 1 or a pharmaceutically acceptable salt thereof in the amount equivalent to between about 35 mg to 45 mg of Compound 1 in the freebase form.

83. The pharmaceutical composition of 82, wherein the composition comprises Compound 1 or a pharmaceutically acceptable salt thereof in the amount equivalent to about 40 mg of Compound 1 in the freebase form.

84. The pharmaceutical composition of any one of claims 77 to 83, wherein the composition comprises Compound 1 or a pharmaceutically acceptable salt thereof in the amount of about 106 micromoles.

85. The pharmaceutical composition of any one of claims 78 to 84, wherein the one or more intra-granular ingredients comprise or further comprise a filler.

86. The pharmaceutical composition of claim 85, wherein the filler comprises microcrystalline cellulose or dicalcium phosphate, or both.

87. The pharmaceutical composition of claim 85 or 86, wherein the composition comprises the filler in the amount of between about 50 wt.% and about60 wt.%.

88. The pharmaceutical composition of claim 87, wherein the composition comprises the filler in the amount of about 55 wt.%.

89. The pharmaceutical composition of any one of claims 77 to 88, wherein the composition comprises microcrystalline cellulose in the amount of about 40 wt.%.

90. The pharmaceutical composition of any one of claims 77 to 89, wherein the composition comprises dicalcium phosphate in the amount of about 13 wt.%.

91. The pharmaceutical composition of any one of claims 78 to 90, wherein the one or more intra-granular ingredients comprise or further comprise a binder.

92. The pharmaceutical composition of claim 91, wherein the binder comprises Plasdone K 29 / 32 or hydroxypropyl cellulose, or both.

93. The pharmaceutical composition of claim 91 or 92, wherein the composition comprises the binder in the amount of between about 5 wt.% and about 10 wt.%.

94. The pharmaceutical composition of any one of claims 77 to 93, wherein the composition comprises Plasdone K 29 / 32 in the amount of about 8 wt.%.

95. The pharmaceutical composition of any one of claims 77 to 93, wherein the composition comprises hydroxypropyl cellulose in the amount of about 8 wt.%.

96. The pharmaceutical composition of any one of claims 78 to 95, wherein the one or more intra-granular ingredients comprise or further comprise an intra-granular lubricant.

97. The pharmaceutical composition of claim 96, wherein the intra-granular lubricant is magnesium stearate.

98. The pharmaceutical composition of claim 96 or 97, wherein the composition comprises the intra-granular lubricant in the amount of between about 0.1 wt.% and about 1 wt.%.

99. The pharmaceutical composition of claim 98, wherein the composition comprises the intra-granular lubricant in the amount of about 0.5 wt.%.

100. The pharmaceutical composition of any one of claims 78 to 99, wherein the one or more extra-granular ingredients comprise an extra-granular lubricant.

101. The pharmaceutical composition of claim 100, wherein the extra-granular lubricant is magnesium stearate.

102. The pharmaceutical composition of claim 100 or 101, wherein the composition comprises the extra-granular lubricant in the amount of between about 0.1 wt.% and about 1 wt.%.

103. The pharmaceutical composition of claim 102, wherein the composition comprises the extra-granular lubricant in the amount of about 0.5 wt.%.

104. The pharmaceutical composition of any one of claims 77 to claim 103, wherein the composition comprises magnesium stearate in the amount of about 1 wt.%.

105. The pharmaceutical composition of any one of claims 78 to 104, wherein the one or more extra-granular ingredients comprise or further comprise a disintegrant.

106. The pharmaceutical composition of claim 105, wherein the disintegrant comprises croscarmellose sodium or sodium starch glycolate, or both.

107. The pharmaceutical composition of claim 105 or 106, wherein the composition comprises the disintegrant in the amount of between about 4 wt.% and about 10 wt.%.

108. The pharmaceutical composition of any one of claims 77 to 107, wherein the composition comprises croscarmellose sodium in the amount of about 8 wt.%.

109. The pharmaceutical composition of any one of claims 77 to 107, wherein the composition comprises sodium starch glycolate in the amount of about 6 wt.%.

110. The pharmaceutical composition of claim 77, wherein the composition comprises a crystalline form of any one of claims 44 to 53; microcrystalline cellulose; dicalcium phosphate; plasdone K 29 / 32; magnesium stearate; and crocarmellose sodium.

111. The pharmaceutical composition of claim 110, wherein the composition comprises about 30 wt.% of the crystalline form, or Compound 1 or a pharmaceutically acceptable salt thereof in the amount equivalent to about 40 mg of Compound 1 in the freebase form; about 40 wt.% of microcrystalline cellulose; about 13 wt.% of dicalcium phosphate; about 8 wt.% of plasdone K 29 / 32; about 1 wt.% of magnesium stearate; and about 8 wt.% of crocarmellose sodium.

112. The pharmaceutical composition of claim 77, wherein the composition comprises a crystalline form of any one of claims 44 to 53; microcrystalline cellulose; dicalcium phosphate; hydroxypropyl cellulose; magnesium stearate; and sodium starch glycolate.

113. The pharmaceutical composition of claim 112, wherein the composition comprises about 30 wt.% of the crystalline form, or Compound 1 or a pharmaceutically acceptable salt thereof in the amount equivalent to about 40 mg of Compound 1 in the157freebase form; about 40 wt.% of microcrystalline cellulose; about 13 wt.% of dicalcium phosphate; about 8 wt.% of hydroxypropyl cellulose; about 1 wt.% of magnesium stearate; and about 6 wt.% of sodium starch glycolate.

114. The pharmaceutical compositing of any one of claims 77 to 113, wherein the composition is formulated for oral delivery.

115. The pharmaceutical composition of any one of claims 77 to 102, wherein the composition is a tablet.

116. A method of treating chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or a mixed phenotype acute leukemia, in a patient in need thereof, comprising administering to the patient the crystalline form of any one of claims 1-76, or the pharmaceutical composition of any one of claims 77-115.

117. A method of treating chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or a mixed phenotype acute leukemia in a patient in need thereof, comprising administering to the patient (lS,25)-A-(2-(4,6- bis(methoxy -fife )pyrimidin-5-yl)-l -methyl- l / 7-pyrrolo[2, 3-c]pyri din-5-yl)-2- fluorocyclopropane-1 -carboxamide (Compound 1) or a pharmaceutically acceptable salt thereof at a once daily dose of an amount equivalent to about 10 mg, about 20 mg, about 40 mg, about 60 mg, about 80 mg, or about 120 mg of Compound 1 in the freebase form; or at a twice daily dose of an amount equivalent to about 60 mg each or about 80 mg each of Compound 1 in the freebase form.

118. The method of claim 116 or 117, wherein Compound 1 or the pharmaceutically acceptable salt thereof is administered to the patient at a twice daily dose of an amount equivalent to about 60 mg each or about 80 mg each of Compound 1 in the freebase form.

119. The method of any one of 116 to 118, wherein Compound 1 or the pharmaceutically acceptable salt thereof is administered to the patient as the crystalline form of any one of claims 1-76 or the pharmaceutical composition of any one of claims 77-115.

120. The method of any one of claims 116 to 119, wherein the leukemia is refractory leukemia.

121. The method of claim 120, wherein the patient has one or more mutations in the Bcr- Abl tyrosine kinase gene resulting in M244V, L248V, G250E, G250A, Q252H, Q252R, Y253F, Y253H, E255K, E255V, D276G, F311L, T315N, T315A, F317V,158F317L, M343T, M351T, E355G, F359A, F359V, V379I, F382L, L387M, H396P, H396R, S417Y, E459K, F486S, T315I, A337T, F359C, or P465S, or any combination of these amino acid substitutions in leukemia cells.

122. The method of claim 121, wherein the patient has one or more mutations in the Bcr- Abl tyrosine kinase gene resulting in T3151 amino acid substitution in leukemia cells.

123. The method of claim 121, wherein the patient has one or more mutations in the Bcr- Abl tyrosine kinase gene resulting in T315I, M244V, A337T, E355G, F359C, F359V, or P465S, or any combination of these amino acid substitutions in leukemia cells.

124. The method of claim 121, wherein the patient has one or more mutations in the Bcr- Abl tyrosine kinase gene resulting in A337T amino acid substitution in leukemia cells.

125. The method of any one of claims 116 to 124, further comprising detecting mutations in the Bcr-Abl tyrosine kinase gene of the patient.

126. The method of any one of claims 116 to 125, wherein the patient was previously treated with 1, 2, 3, 4, 5, or more tyrosine kinase inhibitors.

127. The method of any one of claims 116 to 126, wherein the patient was previously treated with dasatinib, imatinib, asciminib, ponatinib, nilotinib, or bosutinib, or any combination thereof.

128. The method of claim 127, wherein the patient was previously treated with asciminib and / or ponatinib.

129. The method of claim 127, wherein the patient was previously treated with asciminib.

130. The method of any one of claims 116 to 129, further comprising administering one or more pharmaceutical agents including including anti-microtubular therapies, topoisomerase inhibitors, alkylating agents, nucleotide synthesis inhibitors, DNA synthesis inhibtiors, protein synthesis inhibitors, developmental signaling pathway inhibitors, pro-apoptotic agents, Abl myristoyl-pocket binding inhibitors, MEK1 / 2 inhibitors, AKT inhibitors, PI3K inhibitors and / or radiation.

131. The method of any one of claims 116 and 119 to 130, wherein the crystalline form or pharmaceutical composition is administered to the patient without fasting.

132. The method of claim 131, wherein the crystalline form or pharmaceutical composition is administered to the patient less than about 2 hours after the patient ate food.

133. The method of claim 131 or 132, wherein the crystalline form or pharmaceutical composition is administered to the patient less than about 1 hour before the patient eats food.

134. The method of any one of claims 116 to 133, wherein the crystalline form or pharmaceutical composition is orally administered to the patient daily.

135. The method of any one of claims 116 to 134, wherein the patient is human.

136. A method of inhibiting Bcr-Abl enzymatic activity in a cell, comprising exposing the cell with an effective amount of the crystalline form of any one of claims 1-76, or the pharmaceutical composition of any one of claims 77-115.

137. The method of claim 136, wherein the cell has one or more mutations in the Bcr-Abl tyrosine kinase gene resulting in M244V, L248V, G250E, G250A, Q252H, Q252R, Y253F, Y253H, E255K, E255V, D276G, F311L, T315N, T315A, F317V, F317L, M343T, M351T, E355G, F359A, F359V, V379I, F382L, L387M, H396P, H396R, S417Y, E459K, F486S, T315I, A337T, F359C, or P465S, or any combination of these amino acid substitutions.

138. The method of claim 137, wherein the cell has one or more mutations in the Bcr-Abl tyrosine kinase gene resulting in T315I amino acid substitution.

139. The method of claim 137, wherein the cell has one or more mutations in the Bcr-Abl tyrosine kinase gene resulting in T315I, M244V, A337T, E355G, F359C, F359V, or P465S, or any combination of these amino acid substitutions.

140. The method of claim 137, wherein the cell has one or more mutations in the Bcr-Abl tyrosine kinase gene resulting in A337T amino acid substitution.

141. The method of any one of claims 136 to 140, further comprising detecting mutations in the Bcr-Abl tyrosine kinase gene of the cell.

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