Salts and crystalline forms of epidermal growth factor receptor inhibitor

Abstract

Various salt forms and free base solid forms of Compound (I) represented by the following formula are disclosed. # imgabs0 also disclosed are pharmaceutical compositions comprising the same, methods of using the same to treat diseases associated with a kinase of the epidermal growth factor receptor (EGFR) family, and methods of preparing salt forms of Compound (I) and crystalline forms thereof.

Description

[0001] Related Applications

[0002] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 338,371, filed May 4, 2022, the contents of which are incorporated herein by reference. Background Art

[0003] Lung cancer is the second most common cancer and the leading cause of cancer death worldwide. In 2020, there were more than 2 million new cancer diagnoses worldwide for lung cancer and it caused more than 1 million deaths. Non-small cell lung cancer (NSCLC) accounts for approximately 80% of all lung cancers, with adenocarcinoma being the most common histological type. Although the most common causes of lung cancer are smoking and exposure to other environmental toxins, oncogenic driver mutations are often present and provide opportunities for targeted therapies.

[0004] The epidermal growth factor receptor (EGFR) is a transmembrane receptor tyrosine kinase that is activated by the epidermal growth factor ligand. In a subset of NSCLC and certain other tumors, specific mutations in the EGFR gene lead to ligand-independent receptor activation and drive uncontrolled tumor cell survival and proliferation. The incidence of EGFR mutations in NSCLC varies by region and race. According to a 2021 study, EGFR mutations are most common in adenocarcinomas, which account for approximately 40% of all lung cancers and are more common in women, Asian populations, and non-smokers. EGFR-related lung cancers are more likely to develop CNS metastases, with approximately 25% of patients having brain metastases at initial presentation and up to 50% at some time during the course of their disease.

[0005] Comprehensive genomic analysis of tumor samples from 14,483 NSCLC cases during clinical care identified 2,251 cases with EGFR mutations. EGFR exon 19 deletion (47%) and EGFR L858R (32%) are the most common EGFR mutations. Rare EGFR mutations such as G719X (4%), L861Q (2%) and S768I (1%) were identified, as well as cases with compound EGFR activating mutations (2%). Two hundred and sixty-three of the 2,251 EGFR mutation cases carried exon 20 insertions, accounting for 12% of all EGFR mutant NSCLCs and 1.8% of all NSCLCs, making it the third most common type of oncogenic EGFR mutations (Riess JW et al. J Thorac Oncol. 2018; 13: 1560-8).

[0006] Epidermal growth factor receptor exon 20 insertion mutations (Ex20ins) are characterized as in-frame mutations that result in the insertion of 1 to 7 amino acids within a span of approximately 15 amino acids. In addition to NSCLC, EGFR Ex20ins is present in a small fraction of urothelial and endometrial cancers, glioblastomas, paranasal sinus cancers, and pediatric bilateral thalamic gliomas. As with other EGFR-mutated NSCLCs, approximately one-quarter of EGFR Ex20ins patients have brain metastases at first visit.

[0007] Due to unique structural features, EGFREx20ins are generally insensitive to the first three generations of EGFR tyrosine kinase inhibitors (TKI). Therefore, the standard of care for first-line metastatic disease is still based on platinum chemotherapy. The role of immune checkpoint inhibitors is still unclear. For patients with EGFR Ex20ins and disease progression after platinum-based chemotherapy, recently with the approval of two agents of amivantamab and mobocertinib, the standard of care has changed. Both agents have obtained accelerated approval from the U.S. FDA for the treatment of NSCLC with EGFR Ex20ins that progresses during or after platinum-based chemotherapy. Although the development of targeted TKIs (such as amivantamab and mobocertinib) for NSCLC with EGFR mutations causes significantly improved patient results, especially for patients with EGFR Ex20ins, there is still a significant unmet need. More than half of the patients treated with amivantamab or mobocertinib in clinical trials did not achieve objective responses, and these two drugs have not yet been shown to have survival benefits. Furthermore, neither drug has demonstrated meaningful CNS activity, and tolerability remains problematic. Therefore, to help address this unmet need, a TKI targeting EGFR Ex20ins is needed that has high CNS penetration, exhibits potent activity against a range of EGFR Ex20ins, and spares EGFR WT, thereby resulting in an improved side effect profile.

[0008] International Patent Application No. PCT / US2021 / 057472, the entire teaching of which is incorporated herein by reference, discloses selective inhibitors of EGFR including exon 20 mutant proteins, which can be used to treat various cancers. The structure of an inhibitor disclosed in PCT Patent Application No. PCT / US2021 / 057472, referred to herein as "Compound (I)", is shown below:

[0009]

[0010] There is a need to develop new salt forms and / or solid forms of Compound (I) that are suitable for large-scale manufacturing and commercialization. Summary of the invention

[0011] The present disclosure relates to i) novel pharmaceutically acceptable mesylate salts of Compound (I) having different solid forms; and ii) novel crystalline free bases of Compound (I) having different solid forms.

[0012] It has now also been found that the 1:1 mesylate salt of compound (I) can be crystallized under well-defined conditions to afford the desired crystalline form which has good thermal behavior with a high melting point onset and is suitable for large-scale synthesis. Very little mass loss was observed during thermogravimetric analysis.

[0013] In addition, four different crystalline forms of the mesylate salt of Compound (I) have been identified (Form A, Form B, Form H and Form I). Among these crystalline forms, Form A, Form B and Form H are anhydrates, and Form I is a hydrate.

[0014] Mesylate Forms B, H, and I showed promising solid state characterization results. They were physically and chemically stable (>99.8% assay purity) for up to 2 weeks at 25°C / 60% relative humidity (RH), 40° / 75% RH, and 60°C, indicating that all three forms are physicochemically stable. See Examples 2-5.

[0015] In one aspect, the present disclosure provides a mesylate salt of compound (I) represented by the following structural formula:

[0016]

[0017] The molar ratio between compound (I) and methanesulfonic acid is 1: 1. In some embodiments, the methanesulfonate salt is a crystalline salt.

[0018] In another aspect, the present disclosure provides a crystalline mesylate salt of Compound (I), wherein the crystalline mesylate salt is in crystalline Form A.

[0019] In another aspect, the present disclosure provides a crystalline mesylate salt of Compound (I), wherein the crystalline mesylate salt is in crystalline Form B.

[0020] In another aspect, the present disclosure provides a crystalline mesylate salt of Compound (I), wherein the crystalline mesylate salt is crystalline Form H.

[0021] In another aspect, the present disclosure provides a crystalline mesylate salt of Compound (I), wherein the crystalline mesylate salt is in crystalline Form I.

[0022] In another aspect, the present disclosure provides a first crystalline polymorph of the free base of Compound (I). This first polymorph is referred to herein as "crystalline Form A".

[0023] In another aspect, the present disclosure provides a second crystalline polymorph of the free base of Compound (I). This second polymorph is referred to herein as "crystalline Form B".

[0024] In another aspect, the present disclosure provides a pharmaceutical composition comprising a mesylate salt of Compound (I) or one of the mesylate crystalline forms disclosed herein, or a crystalline form of the free base of Compound (I) as disclosed herein, and a pharmaceutically acceptable carrier.

[0025] The present disclosure also provides a method for treating a disease associated with EGFR in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a mesylate salt of Compound (I) or one of the mesylate crystalline forms disclosed herein, or administering a crystalline polymorph of a free base of Compound (I) as disclosed herein. In some embodiments, the subject's disease is characterized by an EGFR mutation.

[0026] The present disclosure also provides a method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a mesylate of compound (I) or one of the mesylate crystalline forms disclosed herein, or administering a crystalline polymorph of a free base of compound (I) as disclosed herein. In some embodiments, the cancer is bladder cancer, prostate cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, glioblastoma, head and neck cancer, lung cancer, urothelial carcinoma, sinus cancer, or non-small cell lung cancer. In some embodiments, the subject's cancer is characterized by an EGFR mutation.

[0027] The present disclosure also provides a salt or free base of a compound (I) of the present disclosure or a pharmaceutical composition comprising the substance for treating any disease listed in the previous paragraph. In one embodiment, a salt or free base of the present disclosure for use in any method of the present disclosure described herein or a pharmaceutical composition comprising the substance is provided. In another embodiment, a salt or free base of the present disclosure or a pharmaceutical composition comprising the substance is provided for the manufacture of a drug for any method of the present disclosure described. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1A The X-ray powder diffraction (XRPD) pattern of Form A of the mesylate salt of Compound (I) is shown, wherein the molar ratio between Compound (I) and methanesulfonic acid is 1:1.

[0029] Figure 1BShown are thermogravimetric analysis (TGA) and differential scanning calorimetry analysis (DSC) thermograms of Form A of the mesylate salt of Compound (I), wherein the molar ratio between Compound (I) and methanesulfonic acid is 1:1.

[0030] Figure 2A The X-ray powder diffraction (XRPD) pattern of Form B of the mesylate salt of Compound (I) is shown, wherein the molar ratio between Compound (I) and methanesulfonic acid is 1:1.

[0031] Figure 2B Shown are thermogravimetric analysis (TGA) and differential scanning calorimetry analysis (DSC) thermograms of Form B of the mesylate salt of Compound (I), wherein the molar ratio between Compound (I) and methanesulfonic acid is 1:1.

[0032] Figure 3A The X-ray powder diffraction (XRPD) pattern of Form H of the mesylate salt of Compound (I) is shown, wherein the molar ratio between Compound (I) and methanesulfonic acid is 1:1.

[0033] Figure 3B Shown are the thermogravimetric analysis (TGA) and differential scanning calorimetry analysis (DSC) thermograms of Form H of the mesylate salt of Compound (I), wherein the molar ratio between Compound (I) and methanesulfonic acid is 1:1.

[0034] Figure 4A Shown is an X-ray powder diffraction (XRPD) pattern of Form I of the mesylate salt of Compound (I), wherein the molar ratio between Compound (I) and methanesulfonic acid is 1:1.

[0035] Figure 4B Shown are thermogravimetric analysis (TGA) and differential scanning calorimetry analysis (DSC) thermograms of Form I of the mesylate salt of Compound (I), wherein the molar ratio between Compound (I) and methanesulfonic acid is 1:1.

[0036] Figure 5A Shown is the X-ray powder diffraction (XRPD) pattern of crystalline Form A of Compound (I) free base.

[0037] Figure 5B Shown are the thermogravimetric analysis (TGA) and differential scanning calorimetry analysis (DSC) thermograms of crystalline Form A of Compound (I) free base.

[0038] Fig. 6A Shown is the X-ray powder diffraction (XRPD) pattern of crystalline Form B of Compound (I) free base.

[0039] Figure 6B Shown is a differential scanning calorimetry (DSC) thermogram of crystalline Form B of Compound (I) free base.

[0040] Figure 7 Shown are mean concentrations in plasma of male beagle dogs following a single 30 mg / kg PO dose of Compound (I) free base or mesylate salt. DETAILED DESCRIPTION

[0041] The present disclosure relates to mesylate salts of Compound (I) having different solid forms and free base crystalline forms of Compound (I) having different solid forms.

[0042]

[0043] As used herein, "crystalline" refers to a solid having a crystal structure in which the individual molecules have a highly uniform, regular, three-dimensional configuration.

[0044] In some embodiments, for the crystalline form of compound (I) salt or free alkali disclosed herein, at least a specific weight percentage of compound (I) salt or free alkali is in a specific crystalline form. Specific weight percentage includes by weight 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or by weight 70%-75%, 75%-80%, 80%-85%, 85%-90%, 90%-95%, 95%-100%, 70-80%, 80-90%, 90-100% of compound (I) salt or free alkali is in a specific crystalline form. It should be understood that all values ​​and ranges between these values ​​and ranges are intended to be covered by the present disclosure.

[0045] When a crystalline Compound (I) salt or free base is defined as a specified percentage of one specific crystalline form of the Compound (I) salt or free base, the remainder consists of amorphous forms and / or crystalline forms other than the specific form or forms specified.

[0046] The crystalline Compound (I) salts disclosed herein exhibit an intense, distinctive XRPD pattern with sharp peaks corresponding to the 2θ angular peak positions and a flat baseline indicative of highly crystalline material (see, e.g., Figure 1A ).

[0047] As used herein, an X-ray powder diffraction pattern is "substantially similar to the diffraction pattern in the [specific] pattern" when at least 90%, such as at least 95%, at least 98%, or at least 99%, of the signals in both diffraction patterns are the same value ±0.2° 2θ. In determining "substantial similarity", one of ordinary skill in the art will understand that there may be variations in the intensity and / or signal positions in the XRPD diffraction patterns even for the same crystalline form. Thus, one of ordinary skill in the art will understand that a signal maximum in an XRPD diffraction pattern (in the form of 2-θ degrees (°2θ) referred to herein) is generally meant to be reported as a value ±0.2 degrees 2θ of the reported value, which is a variation recognized in the art as discussed above. In some embodiments, unless otherwise specified, when a crystalline form is characterized as having a specific value of an XRPD peak, one of ordinary skill in the art will understand that the peak may be ±0.4, ±0.3, ±0.2, or ±0.1 degrees 2θ of the reported value.

[0048] Methanesulfonate of compound (I)

[0049] In one aspect, the present disclosure provides a mesylate salt of Compound (I).

[0050]

[0051] The molar ratio between compound (I) and methanesulfonic acid is about 1:1.

[0052] In some embodiments, the mesylate salt is a crystalline mesylate salt. In some embodiments, the mesylate salt is in a single crystalline form.

[0053] In some embodiments, the mesylate salt is unsolvated. In other embodiments, the mesylate salt is solvated.

[0054] The mesylate salt of compound (I) with a molar ratio of 1:1 between compound (I) and methanesulfonic acid can be easily prepared by mixing compound (I) free base with about 1-1.1 equivalents of methanesulfonic acid in a suitable solvent (e.g., acetone, THF). The mixture can be heated to obtain the desired yield.

[0055] Form A mesylate

[0056] In some embodiments, the present disclosure provides a crystalline Form A of a mesylate salt of Compound (I), wherein the molar ratio between Compound (I) and methanesulfonic acid is 1: 1. In some embodiments, the crystalline Form A of a mesylate salt of Compound (I) is an anhydrate.

[0057] Figure 1A The XRPD pattern and peaks are shown in Figure 1BThermogravimetric analysis (TGA) and differential scanning calorimetry analysis (DSC) thermograms are shown in FIG.

[0058] Table 1 : Peak list of compound (I) mesylate form A

[0059]

[0060]

[0061] In Table 1, only those peaks are reported which have a relative intensity of five or more compared to the absolute intensity (I. in cps°) of the most intense peak.

[0062] Table 2 : Condensed peak list of Compound (I) mesylate salt form A #1

[0063]

[0064] Table 3 : Simplified Peak List #2 of Compound (I) Mesylate Form A

[0065]

[0066] Table 4 : Simplified Peak List #3 of Compound (I) Mesylate Form A

[0067]

[0068] In some embodiments, the mesylate salt in Form A is characterized by an X-ray powder diffraction pattern comprising at least three, at least four, or at least five peaks selected from 2θ of 5.9°, 7.2°, 11.9°, 12.1°, 19.3°, and 20.1° ± 0.2°.

[0069] In some embodiments, the mesylate salt in Form A is characterized by an X-ray powder diffraction pattern comprising peaks in 2-theta at 5.9°, 7.2°, 11.9°, 12.1°, 19.3°, and 20.1° ± 0.2°.

[0070] In some embodiments, the mesylate salt in Form A is characterized by an X-ray powder diffraction pattern comprising at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine peaks in 2θ at 5.9°, 7.2°, 11.9°, 12.1°, 13.4°, 19.3°, 20.1°, 21.7°, 24.1°, and 27.6° ± 0.2°.

[0071] In some embodiments, the mesylate salt in Form A is characterized by an X-ray powder diffraction pattern comprising peaks in 2θ at 5.9°, 7.2°, 11.9°, 12.1°, 13.4°, 19.3°, 20.1°, 21.7°, 24.1°, and 27.6° ± 0.2°.

[0072] In some embodiments, the mesylate salt in Form A is characterized by an X-ray powder diffraction pattern comprising at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, or at least thirteen peaks in 2θ at 5.9°, 7.2°, 11.9°, 12.1°, 13.4°, 14.6°, 15.4°, 19.3°, 20.1°, 21.7°, 22.9°, 23.8°, 24.1°, and 27.6° ± 0.2°.

[0073] In some embodiments, the mesylate salt in Form A is characterized by an X-ray powder diffraction pattern comprising peaks in 2θ at 5.9°, 7.2°, 11.9°, 12.1°, 13.4°, 14.6°, 15.4°, 19.3°, 20.1°, 21.7°, 22.9°, 23.8°, 24.1°, and 27.6° ± 0.2°.

[0074] In some embodiments, the mesylate salt of Form A is characterized by being substantially similar to Figure 1A X-ray powder diffraction pattern.

[0075] In some embodiments, the mesylate salt of Form A is characterized by a differential scanning calorimeter (DSC) thermogram comprising two endothermic and exothermic events; the endotherm starts at 202.8°C ± 2°C and the exotherm starts at 206.9°C ± 2°C. In some embodiments, the mesylate salt of Form A is characterized by being substantially similar to Figure 1B Differential scanning calorimeter (DSC) thermogram.

[0076] In some embodiments, the mesylate salt of Form A is characterized by being substantially similar to Figure 1B Thermogravimetric analysis (TGA) of

[0077] Form B mesylate

[0078] In some embodiments, the present disclosure provides a crystalline Form B of a mesylate salt of Compound (I), wherein the molar ratio between Compound (I) and methanesulfonic acid is 1: 1. In some embodiments, the crystalline Form B of a mesylate salt of Compound (I) is an anhydrate.

[0079] Figure 2A The XRPD pattern and peaks are shown in Figure 2B Thermogravimetric analysis (TGA) and differential scanning calorimetry analysis (DSC) thermograms are shown in FIG.

[0080] Table 5a : Peak list of compound (I) mesylate form B

[0081]

[0082] Table 5b : Peak list of compound (I) mesylate form B

[0083]

[0084]

[0085] In Tables 5a and 5b, only those peaks with a relative intensity of five or greater compared to the absolute intensity of the most intense peak (I. in cps°) are reported. Tables 5a and 5b are XRPD peaks obtained from two different batches of crystalline Form B of the mesylate salt of Compound (I). Tables 6a and 7a are simplified peak lists selected from the list in Table 5a and Tables 6b and 7b are simplified peak lists selected from the list in Table 5b.

[0086] Table 6a : Simplified Peak List #1 of Compound (I) Mesylate Form B

[0087]

[0088] Table 6b : Simplified Peak List #1 of Compound (I) Mesylate Form B

[0089] 2-θ (degrees) d - spacing (angle) Relative Strength 18.40 4.82 100 19.74 4.49 73 24.79 3.59 58 21.32 4.16 56 22.41 3.96 47 20.82 4.26 46 20.63 4.30 39 11.28 7.84 36 22.01 4.04 35 8.80 10.04 34

[0090] Table 7a : Simplified Peak List #2 of Compound (I) Mesylate Form B

[0091]

[0092] Table 7b: Simplified Peak List #2 for Compound (I) Mesylate Salt Form B

[0093]

[0094]

[0095] In some embodiments, the mesylate salt in Form B is characterized by an X-ray powder diffraction pattern comprising at least three or at least four peaks selected from 18.5°, 19.8°, 20.8°, 22.4°, and 24.9° 2θ. In some embodiments, the mesylate salt in Form B is characterized by an X-ray powder diffraction pattern comprising peaks at 18.5°, 19.8°, 20.8°, 22.4°, and 24.9° 2θ.

[0096] In some embodiments, the mesylate salt in Form B is characterized by an X-ray powder diffraction pattern comprising at least three or at least four peaks selected from 2θ of 18.5°, 19.8°, 20.8°, 22.4°, and 24.9° ± 0.2°.

[0097] In some embodiments, the mesylate salt in Form B is characterized by an X-ray powder diffraction pattern comprising peaks in 2-theta at 18.5°, 19.8°, 20.8°, 22.4°, and 24.9° ± 0.2°.

[0098] In some embodiments, the mesylate salt in Form B is characterized by an X-ray powder diffraction pattern comprising at least three, at least four, at least five, at least six, at least seven, or at least eight peaks in 2θ at 8.9°, 11.3°, 18.5°, 19.8°, 20.8°, 21.4°, 22.4°, 24.9°, and 25.9° ± 0.2°.

[0099] In some embodiments, the mesylate salt in Form B is characterized by an X-ray powder diffraction pattern comprising peaks in 2θ at 8.9°, 11.3°, 18.5°, 19.8°, 20.8°, 21.4°, 22.4°, 24.9°, and 25.9° ± 0.2°.

[0100] In some embodiments, the mesylate salt in Form B is characterized by an X-ray powder diffraction pattern comprising at least three or at least four peaks selected from 18.4°, 19.7°, 21.3°, 22.4°, 24.8° 2θ. In some embodiments, the mesylate salt in Form B is characterized by an X-ray powder diffraction pattern comprising peaks at 18.4°, 19.7°, 21.3°, 22.4°, 24.8° 2θ.

[0101] In some embodiments, the mesylate salt in Form B is characterized by an X-ray powder diffraction pattern comprising at least three or at least four peaks selected from 2θ of 18.4°, 19.7°, 21.3°, 22.4°, 24.8° ± 0.2°.

[0102] In some embodiments, the mesylate salt in Form B is characterized by an X-ray powder diffraction pattern comprising peaks in 2-theta at 18.4°, 19.7°, 21.3°, 22.4°, 24.8° ± 0.2°.

[0103] In some embodiments, the mesylate salt in Form B is characterized by an X-ray powder diffraction pattern comprising at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine peaks in 2θ at 8.8°, 11.3°, 18.4°, 19.7°, 20.6°, 20.8°, 21.3°, 22.0°, 22.4°, and 24.8° ± 0.2°.

[0104] In some embodiments, the mesylate salt in Form B is characterized by an X-ray powder diffraction pattern comprising peaks in 2θ at 8.8°, 11.3°, 18.4°, 19.7°, 20.6°, 20.8°, 21.3°, 22.0°, 22.4°, and 24.8° ± 0.2°.

[0105] In some embodiments, the mesylate salt in Form B is characterized by an X-ray powder diffraction pattern comprising peaks in 2θ at 6.7°, 7.7°, 8.9°, 11.3°, 11.9°, 12.4°, 13.0°, 13.7°, 15.4°, 16.8°, 17.2°, 18.5°, 19.8°, 20.9°, 21.4°, 22.4°, 24.9°, 25.9°, 26.8°, 30.0°, 31.1°, and 35.2° ± 0.2°.

[0106] In some embodiments, the mesylate salt of Form B is characterized by comprising 2θ values ​​of 5.4°, 6.6°, 7.6°, 8.8°, 11.3°, 11.8°, 12.3°, 13.6°, 15.2°, 15.4°, 16.4°, 16.7°, 17.1°, 18.0°, 18.4°, 19.5°, 19.7°, 20.6°, 20.7°, 21.9°, 22.0°, 23.1°, 24.2°, 25.3°, 26.4°, 27.5°, 28.6°, 29.9°, 30.7°, 31.9°, 32. 0, 19.4°, 20.6°, 21.7°, 22.4°, 23.7°, 24.5°, 24.8°, 25.4°, 25.7°, 25.8°, 26.5°, 27.5°, 29.8°, 30.8°, 31.2°, 35.0°, 35.3°, and 36.3° ± 0.2°. In some embodiments, the mesylate salt of Form B is characterized by peaks substantially similar to Figure 2A X-ray powder diffraction pattern.

[0107] In some embodiments, the mesylate salt of Form B is characterized by a differential scanning calorimeter (DSC) thermogram comprising an endotherm onset at 247.8°C ± 2°C. In some embodiments, the mesylate salt of Form B is characterized by being substantially similar to Figure 2B Differential scanning calorimeter (DSC) thermogram.

[0108] In some embodiments, the mesylate salt of Form B is characterized by being substantially similar to Figure 2B Thermogravimetric analysis (TGA) of

[0109] In some embodiments, the mesylate salt of Form B is characterized by a differential scanning calorimeter (DSC) thermogram comprising an endotherm with an onset at 250.1° C.±2° C. In some embodiments, the DSC thermogram further comprises an exotherm with an onset at 254.1° C.±2° C. In some embodiments, DSC is performed using a sealed aluminum pan with a pinhole.

[0110] In some embodiments, the mesylate salt of Form B is prepared by crystallization from acetone. In some embodiments, the mesylate salt of Form B is prepared by mixing Compound (I) free base and methanesulfonic acid (e.g., in an amount of 1-1.5, 1-1.4, 1-1.2, or 1-1.1 molar equivalents relative to Compound (I)) in acetone at elevated temperature (e.g., between 40°C and 70°C, between 40°C and 65°C, between 45°C and 55°C, or between 50°C and 60°C, etc.), followed by cooling the mixture to form the mesylate salt of Form B. In some embodiments, the mixture is cooled to ambient temperature or a lower temperature, e.g., between 5°C and 25°C, between 5°C and 15°C, between 15°C and 25°C, etc. In some embodiments, the mesylate salt of Form B is prepared by the following steps: (i) mixing Compound (I) free base with a small portion of methanesulfonic acid (e.g., 0.1-0.5 molar equivalents relative to Compound (I)) at elevated temperature (e.g., between 40°C and 70°C, between 40°C and 65°C, between 45°C and 55°C, or between 50°C and 60°C, etc.); (ii) adding seed crystals of the mesylate salt Form B; (iii) adding the remaining methanesulfonic acid (e.g., 0.6-1.0 molar equivalents); and (iv) cooling the mixture to form the mesylate salt of Form B. In some embodiments, the mixture is cooled to ambient temperature or a lower temperature, e.g., between 5°C and 25°C, between 5°C and 15°C, between 15°C and 25°C, etc. In some embodiments, the mesylate salt of Form B formed from the above process is washed with acetone and dried at elevated temperature (e.g., between 40°C and 70°C, between 40°C and 65°C, between 45°C and 55°C, or between 50°C and 60°C, etc.). In some embodiments, the process for preparing the mesylate salt Form B as described above can be carried out in a mixture of acetone and a small amount of water (e.g., 1-5%), rather than in acetone.

[0111] Form H mesylate

[0112] In some embodiments, the present disclosure provides a crystalline Form H of a mesylate salt of Compound (I), wherein the molar ratio between Compound (I) and methanesulfonic acid is 1: 1. In some embodiments, the crystalline Form H of a mesylate salt of Compound (I) is an anhydrate.

[0113] The XRPD pattern and peak diagram are shown in 3A, and Figure 3B Thermogravimetric analysis (TGA) and differential scanning calorimetry analysis (DSC) thermograms are shown in FIG.

[0114] Table 8a : Peak list of compound (I) mesylate salt form H

[0115]

[0116]

[0117] Table 8b : Peak list of compound (I) mesylate salt form H

[0118]

[0119]

[0120]

[0121] In Tables 8a and 8b, only those peaks with a relative intensity of five or greater compared to the absolute intensity of the most intense peak (I. in cps°) are reported. Tables 8a and 8b are XRPD peaks obtained from two different batches of crystalline Form H of the mesylate salt of Compound (I). Tables 9a and 10a are simplified peak lists selected from the list in Table 8a and Tables 9b and 10b are simplified peak lists selected from the list in Table 8b.

[0122] Table 9a : Simplified Peak List #1 of Compound (I) Mesylate Form H

[0123]

[0124] Table 9b : Simplified Peak List #1 of Compound (I) Mesylate Form H

[0125]

[0126]

[0127] Table 10a: Simplified Peak List #2 of Compound (I) Mesylate Form H

[0128]

[0129] Table 10b : Simplified Peak List #2 of Compound (I) Mesylate Form H

[0130] 2-θ (degrees) d - spacing (angle) Relative Strength 20.02 4.43 100 19.09 4.65 95 23.38 3.80 95 21.85 4.06 82 21.47 4.13 75

[0131] In some embodiments, the mesylate salt in Form H is characterized by an X-ray powder diffraction pattern comprising at least three, at least four, or at least five peaks selected from 13.7°, 19.1°, 20.0°, 21.5°, 21.9°, and 23.4° 2θ. In some embodiments, the mesylate salt in Form H is characterized by an X-ray powder diffraction pattern comprising peaks at 13.7°, 19.1°, 20.0°, 21.5°, 21.9°, and 23.4° 2θ.

[0132] In some embodiments, the mesylate salt in Form H is characterized by an X-ray powder diffraction pattern comprising at least three, at least four, or at least five peaks selected from 2θ of 13.7°, 19.1°, 20.0°, 21.5°, 21.9°, and 23.4°±0.2°.

[0133] In some embodiments, the mesylate salt in Form H is characterized by an X-ray powder diffraction pattern comprising peaks in 2-theta at 13.7°, 19.1°, 20.0°, 21.5°, 21.9°, and 23.4° ± 0.2°.

[0134] In some embodiments, the mesylate salt in Form H is characterized by an X-ray powder diffraction pattern comprising at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine peaks in 2θ at 8.1°, 10.1°, 11.7°, 13.7°, 19.1°, 20.0°, 20.8°, 21.5°, 21.9°, and 23.4° ± 0.2°.

[0135] In some embodiments, the mesylate salt in Form H is characterized by an X-ray powder diffraction pattern comprising peaks in 2θ at 8.1°, 10.1°, 11.7°, 13.7°, 19.1°, 20.0°, 20.8°, 21.5°, 21.9°, and 23.4° ± 0.2°.

[0136] In some embodiments, the mesylate salt in Form H is characterized by an X-ray powder diffraction pattern comprising at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, or at least twelve peaks in 2θ at 8.1°, 10.1°, 10.7°, 11.7°, 13.7°, 14.6°, 19.1°, 20.0°, 20.8°, 21.5°, 21.9°, 23.4°, and 24.7° ± 0.2°.

[0137] In some embodiments, the mesylate salt in Form H is characterized by an X-ray powder diffraction pattern comprising peaks in 2θ at 8.1°, 10.1°, 10.7°, 11.7°, 13.7°, 14.6°, 19.1°, 20.0°, 20.8°, 21.5°, 21.9°, 23.4°, and 24.7° ± 0.2°.

[0138] In some embodiments, the mesylate salt in Form H is characterized by an X-ray powder diffraction pattern comprising at least three or at least four peaks selected from 19.1°, 20.0°, 21.5°, 21.9°, and 23.4° 2θ. In some embodiments, the mesylate salt in Form H is characterized by an X-ray powder diffraction pattern comprising peaks at 19.1°, 20.0°, 21.5°, 21.9°, and 23.4° 2θ.

[0139] In some embodiments, the mesylate salt in Form H is characterized by an X-ray powder diffraction pattern comprising at least three or at least four peaks selected from 2θ of 19.1°, 20.0°, 21.5°, 21.9°, and 23.4°±0.2°.

[0140] In some embodiments, the mesylate salt in Form H is characterized by an X-ray powder diffraction pattern comprising peaks in 2-theta at 19.1°, 20.0°, 21.5°, 21.9°, and 23.4° ± 0.2°.

[0141] In some embodiments, the mesylate salt in Form H is characterized by an X-ray powder diffraction pattern comprising at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine peaks in 2θ at 11.7°, 13.6°, 14.6°, 19.1°, 20.0°, 20.8°, 21.5°, 21.9°, 23.4°, 24.6° ± 0.2°.

[0142] In some embodiments, the mesylate salt in Form H is characterized by an X-ray powder diffraction pattern comprising peaks in 2θ at 11.7°, 13.6°, 14.6°, 19.1°, 20.0°, 20.8°, 21.5°, 21.9°, 23.4°, 24.6° ± 0.2°.

[0143] In some embodiments, the mesylate salt of Form H is characterized by comprising 2θ values ​​of 7.0°, 8.1°, 10.1°, 10.7°, 11.7°, 12.3°, 12.7°, 13.2°, 13.7°, 13.9°, 14.6°, 14.9°, 16.2°, 16.8°, 17.1°, 17.9°, 18.1°, 18.8°, 19.1°, 19.2°, 20.0°, 20.6°, 20.8°, 20.9 , 21.0°, 21.5°, 21.9°, 22.1°, 22.7°, 22.9°, 23.2°, 23.4°, 23.5°, 24.0°, 24.7°, 24.7°, 25.6°, 26.5°, 26.8°, 27.8°, 28.2°, 29.0°, 29.7°, 30.0°, 32.1°, 32.6°, 34.0°, 37.3° and 38.8°±0.2°.

[0144] In some embodiments, the mesylate salt of Form H is characterized by comprising 2θ values ​​of 6.9°, 8.1°, 10.1°, 10.7°, 11.7°, 12.3°, 12.7°, 13.2°, 13.6°, 13.9°, 14.6°, 14.9°, 16.2°, 16.8°, 17.1°, 17.9°, 18.1°, 18.8°, 19.1°, 19.7°, 20.0°, 20.6°, 20.8°, 21.0°, 21.5°, 21.9°, 2 X-ray powder diffraction pattern of peaks at 2.1°, 22.8°, 23.2°, 23.4°, 24.1°, 24.3°, 24.6°, 25.4°, 25.6°, 26.4°, 26.8°, 27.1°, 27.8°, 28.2°, 29.0°, 29.6°, 30.0°, 31.2°, 31.8°, 32.1°, 32.6°, 33.3°, 34.0°, 34.3°, 34.8°, 35.6°, 37.3° and 38.7° ± 0.2°.

[0145] In some embodiments, the mesylate salt of Form H is characterized by being substantially similar to Figure 3A X-ray powder diffraction pattern.

[0146] In some embodiments, the mesylate salt of Form H is characterized by a differential scanning calorimeter (DSC) thermogram comprising an endotherm onset at 220.5°C ± 2°C and an exotherm onset at 239.4°C ± 2°C. In some embodiments, the mesylate salt of Form H is characterized by being substantially similar to Figure 3B Differential scanning calorimeter (DSC) thermogram.

[0147] In some embodiments, the mesylate salt of Form H is characterized by being substantially similar to Figure 3B Thermogravimetric analysis (TGA) of

[0148] In some embodiments, the mesylate salt in Form H is characterized by a differential scanning calorimeter (DSC) thermogram comprising an endotherm with an onset at 228.7° C.±2° C. In some embodiments, DSC is performed using a sealed aluminum pan with a pinhole.

[0149] Form I mesylate salt

[0150] In some embodiments, the present disclosure provides a crystalline Form I of a mesylate salt of Compound (I), wherein the molar ratio between Compound (I) and methanesulfonic acid is 1: 1. In some embodiments, the crystalline Form I of a mesylate salt of Compound (I) is a hydrate.

[0151] Figure 4A The XRPD pattern and peaks are shown in Figure 4B Thermogravimetric analysis (TGA) and differential scanning calorimetry analysis (DSC) thermograms are shown in FIG.

[0152] Table 11a : Peak list of compound (I) mesylate salt form I

[0153]

[0154]

[0155] Table 11b : Peak list of compound (I) mesylate salt form I

[0156]

[0157]

[0158] In Table 11a and Table 11b, only those peaks with a relative intensity of five or greater compared to the absolute intensity of the most intense peak (I. in cps°) are reported. Table 11a and Table 11b are XRPD peaks obtained from two different batches of crystalline Form I of the mesylate salt of Compound (I). Table 12a is a simplified peak list selected from the list in Table 11a and Table 12b and Table 12c are simplified peak lists selected from the list in Table 11b.

[0159] Table 12a : Simplified Peak List #1 of Compound (I) Mesylate Form I

[0160]

[0161] Table 12b : Simplified Peak List #1 of Compound (I) Mesylate Form I

[0162] 2-θ (degrees) d - spacing (angle) Relative Strength 18.67 4.75 100 8.49 10.40 81 20.56 4.32 73 21.51 4.13 70 24.36 3.65 67 22.13 4.01 49 24.14 3.68 45 16.68 5.31 41 19.19 4.62 41 10.91 8.10 35

[0163] Table 12c : Simplified Peak List #2 of Compound (I) Mesylate Form I

[0164] 2-θ (degrees) d - spacing (angle) Relative Strength 18.67 4.75 100 8.49 10.40 81 20.56 4.32 73 21.51 4.13 70 24.36 3.65 67

[0165] In some embodiments, the mesylate salt in Form I is characterized by an X-ray powder diffraction pattern comprising at least three or at least four peaks selected from 2θ of 11.0°, 18.7°, 20.6°, 22.2°, and 24.4° ± 0.2°.

[0166] In some embodiments, the Form I mesylate salt is characterized by an X-ray powder diffraction pattern comprising peaks in 2-theta at 11.0°, 18.7°, 20.6°, 22.2°, and 24.4° ± 0.2°.

[0167] In some embodiments, the mesylate salt in Form I is characterized by an X-ray powder diffraction pattern comprising at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine peaks in 2θ at 8.6°, 11.0°, 16.7°, 18.7°, 19.3°, 20.6°, 21.6°, 22.2°, 24.2°, and 24.4° ± 0.2°.

[0168] In some embodiments, the Form I mesylate salt is characterized by an X-ray powder diffraction pattern comprising peaks in 2θ at 8.6°, 11.0°, 16.7°, 18.7°, 19.3°, 20.6°, 21.6°, 22.2°, 24.2°, and 24.4° ± 0.2°.

[0169] In some embodiments, the mesylate salt in Form I is characterized by an X-ray powder diffraction pattern comprising at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten peaks in 2θ at 8.6°, 11.0°, 11.9°, 16.7°, 18.7°, 19.3°, 20.6°, 21.6°, 22.2°, 24.2°, and 24.4° ± 0.2°.

[0170] In some embodiments, the mesylate salt in Form I is characterized by an X-ray powder diffraction pattern comprising peaks in 2θ at 8.6°, 11.0°, 11.9°, 16.7°, 18.7°, 19.3°, 20.6°, 21.6°, 22.2°, 24.2°, and 24.4° ± 0.2°.

[0171] In some embodiments, the mesylate salt in Form I is characterized by an X-ray powder diffraction pattern comprising at least three or at least four peaks selected from 8.5°, 18.7°, 20.6°, 21.5°, and 24.4° ± 0.2° 2θ.

[0172] In some embodiments, the Form I mesylate salt is characterized by an X-ray powder diffraction pattern comprising peaks in 2-theta at 8.5°, 18.7°, 20.6°, 21.5°, and 24.4° ± 0.2°.

[0173] In some embodiments, the mesylate salt in Form I is characterized by an X-ray powder diffraction pattern comprising at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine peaks in 2θ at 8.5°, 10.9°, 16.7°, 18.7°, 19.2°, 20.6°, 21.5°, 22.1°, 24.1°, and 24.4° ± 0.2°.

[0174] In some embodiments, the mesylate salt in Form I is characterized by an X-ray powder diffraction pattern comprising peaks in 2θ at 8.5°, 10.9°, 16.7°, 18.7°, 19.2°, 20.6°, 21.5°, 22.1°, 24.1°, and 24.4° ± 0.2°.

[0175] In some embodiments, the mesylate salt of Form I is characterized by comprising 2θ values ​​of 6.8°, 8.5°, 10.9°, 11.7°, 11.9°, 13.5°, 14.6°, 15.2°, 16.7°, 17.6°, 17.9°, 18.7°, 19.2°, 19.5°, 19.6°, 20.3°, 20.6°, 21.0°, 21.5°, 2 X-ray powder diffraction pattern of peaks at 1.7°, 22.0°, 22.1°, 22.7°, 23.7°, 24.1°, 24.4°, 24.9°, 25.4°, 25.7°, 25.8°, 26.2°, 26.8°, 28.0°, 29.4°, 30.0°, 31.0°, 32.7°, 33.1°, 33.5° and 35.7°±0.2°.

[0176] In some embodiments, the mesylate salt of Form I is characterized by being substantially similar to Figure 4A X-ray powder diffraction pattern.

[0177] In some embodiments, the mesylate salt of Form I is characterized by a differential scanning calorimeter (DSC) thermogram comprising an endotherm onset at 33.2°C ± 2°C, an endotherm onset at 210.4°C ± 2°C, and an exotherm onset at 229.1°C ± 2°C. In some embodiments, the mesylate salt of Form I is characterized by being substantially similar to Figure 4B Differential scanning calorimeter (DSC) thermogram.

[0178] In some embodiments, the mesylate salt of Form I is characterized by being substantially similar to Figure 4B Thermogravimetric analysis (TGA) of

[0179] In some embodiments, the mesylate salt of Form I is characterized by a differential scanning calorimeter (DSC) thermogram comprising an endotherm with an onset at 221.3° C.±2° C. In some embodiments, the DSC thermogram further comprises an endotherm with an onset at 34.3° C.±2° C. In some embodiments, DSC is performed using a sealed aluminum pan with a pinhole.

[0180] Free base of compound (I)

[0181] In one aspect, the present disclosure provides the free base of Compound (I).

[0182]

[0183] In some embodiments, the free base of Compound (I) is in amorphous form.

[0184] In some embodiments, the free base of Compound (I) is crystalline. In some embodiments, the free base of Compound (I) is in a single crystalline form.

[0185] In some embodiments, the free base of Compound (I) is unsolvated. In other embodiments, the free base of Compound (I) is solvated.

[0186] Free base crystalline form A

[0187] In some embodiments, the present disclosure provides a free base crystalline Form A of Compound (I). In some embodiments, the free base crystalline Form A of Compound (I) is an anhydrate.

[0188] Figure 5A The XRPD pattern and peaks are shown in Figure 5B Thermogravimetric analysis (TGA) and differential scanning calorimetry analysis (DSC) thermograms are shown in FIG.

[0189] Table 13a : Peak list of compound (I) free base form A

[0190]

[0191] Table 13b: Peak list of Compound (I) free base Form A

[0192] 2-θ (degrees) d - spacing (angle) Relative Strength 5.70 15.50 100 6.04 14.63 58 6.23 14.17 39 6.52 13.55 27 9.73 9.08 5 13.02 6.79 5 15.79 5.61 5 16.89 5.25 8 17.08 5.19 7 17.30 5.12 6 18.78 4.72 6 19.45 4.56 6 19.58 4.53 17 22.44 3.96 13 22.69 3.92 6 23.70 3.75 11 24.93 3.57 10 25.23 3.53 11

[0193] In Tables 13a and 13b, only those peaks with a relative intensity of five or greater compared to the absolute intensity of the most intense peak (I. in cps°) are reported. Tables 13a and 13b are XRPD peaks obtained from two different batches of crystalline Form A of Compound (I) free base. Tables 13c and 13d are simplified peak lists selected from the list in Table 13b.

[0194] Table 13c. Simplified Peak List #1 of Compound (I) Free Base Form A

[0195] 2-θ (degrees) d - spacing (angle) Relative Strength 5.70 15.50 100 6.04 14.63 58 6.23 14.17 39 6.52 13.55 27 19.58 4.53 17 22.44 3.96 13 23.70 3.75 11 25.23 3.53 11 24.93 3.57 10 16.89 5.25 8

[0196] Table 13d. Simplified Peak List #2 for Compound (I) Free Base Form A

[0197] 2-θ (degrees) d - spacing (angle) Relative Strength 5.70 15.50 100 6.04 14.63 58 6.23 14.17 39 6.52 13.55 27 19.58 4.53 17

[0198] In some embodiments, the free base crystalline Form A is characterized by an X-ray powder diffraction pattern comprising peaks in 2-theta at 5.7°, 6.0°, and 6.2°±0.2.

[0199] In some embodiments, the free base crystalline Form A is characterized by an X-ray powder diffraction pattern comprising at least three or at least four peaks selected from 2θ of 5.7°, 6.0°, 6.2°, 6.5°, and 19.6°±0.2°.

[0200] In some embodiments, the free base crystalline Form A is characterized by an X-ray powder diffraction pattern comprising peaks in 2θ at 5.7°, 6.0°, 6.2°, 6.5°, and 19.6±0.2.

[0201] In some embodiments, the free base crystalline Form A is characterized by an X-ray powder diffraction pattern comprising at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine peaks in 2θ at 5.7°, 6.0°, 6.2°, 6.5°, 16.9°, 19.6°, 22.4°, 23.7°, 24.9°, and 25.2° ± 0.2°.

[0202] In some embodiments, the free base crystalline Form A is characterized by an X-ray powder diffraction pattern comprising peaks in 2θ at 5.7°, 6.0°, 6.2°, 6.5°, 16.9°, 19.6°, 22.4°, 23.7°, 24.9°, and 25.2° ± 0.2°.

[0203] In some embodiments, the free base crystalline Form A is characterized by an X-ray powder diffraction pattern comprising peaks in 2θ form at 5.7°, 6.0°, 6.2°, 6.5°, 9.7°, 13.0°, 15.8°, 16.9°, 17.1°, 17.3°, 18.8°, 19.5°, 19.6°, 22.4°, 22.7°, 23.7°, 24.9°, and 25.2° ± 0.2°.

[0204] In some embodiments, the free base crystalline Form A is characterized by being substantially similar to Figure 5A X-ray powder diffraction pattern.

[0205] In some embodiments, the free base crystalline Form A is characterized by a differential scanning calorimeter (DSC) thermogram comprising an endotherm starting at 263.3°C ± 2°C. In some embodiments, the free base crystalline Form A is characterized by being substantially similar to Figure 5B In some embodiments, the DSC thermogram further comprises an endotherm starting at 156.5° C.±2° C. In some embodiments, DSC is performed using a sealed aluminum pan with a pinhole.

[0206] In some embodiments, the free base crystalline Form A is characterized by being substantially similar to Figure 5B Thermogravimetric analysis (TGA) of

[0207] Free base crystalline form B

[0208] In some embodiments, the present disclosure provides a free base crystalline Form B of Compound (I). In some embodiments, the free base crystalline Form B of Compound (I) is a hydrate.

[0209] Fig. 6A The XRPD pattern and peaks are shown in .

[0210] Table 14a : Peak list of compound (I) free base form B

[0211]

[0212] *The peak at 5.7 is included due to machine error.

[0213] Table 14b : Peak list of compound (I) free base form B

[0214] 2-θ (degrees) d - spacing (angle) Relative Strength 5.16 17.1 100 5.34 16.5 64 6.13 14.4 92 8.11 10.9 6 9.12 9.7 8 13.78 6.4 5 14.22 6.2 9 15.58 5.7 12 16.56 5.3 5 17.30 5.1 5 18.46 4.8 13 18.68 4.7 12 19.53 4.5 11 21.87 4.1 6 22.53 3.9 10 23.11 3.8 6 24.41 3.6 21 24.89 3.6 10 25.37 3.5 7 26.08 3.4 11 26.18 3.4 9 26.64 3.3 6 27.10 3.3 7

[0215] In Tables 14a and 14b, only those peaks with a relative intensity of five or greater compared to the absolute intensity of the most intense peak (I. in cps°) are reported. Tables 14a and 14b are XRPD peaks obtained from two different batches of free base Form B of Compound (I). Tables 15a and 16a are simplified peak lists selected from the list in Table 14a and Tables 15b and 16b are simplified peak lists selected from the list in Table 14b.

[0216] Table 15a : Simplified Peak List of Compound (I) Free Base Form B #1

[0217]

[0218]

[0219] *The peak at 5.7 is included due to machine error.

[0220] Table 15b : Simplified Peak List of Compound (I) Free Base Form B #1

[0221] 2-θ (degrees) d - spacing (angle) Relative Strength 5.16 17.1 100 6.13 14.4 92 5.34 16.5 64 24.41 3.6 21 18.46 4.8 13 15.58 5.7 12 18.68 4.7 12 19.53 4.5 11 26.08 3.4 11 22.53 3.9 10

[0222] Table 16a : Simplified Peak List #2 of Compound (I) Free Base Form B

[0223]

[0224] *The peak at 5.7 is included due to machine error.

[0225] Table 16b : Simplified Peak List #2 of Compound (I) Free Base Form B

[0226] 2-θ (degrees) d - spacing (angle) Relative Strength 5.16 17.1 100 6.13 14.4 92 5.34 16.5 64 24.41 3.6 21 18.46 4.8 13

[0227] In some embodiments, the free base crystalline Form B is characterized by an X-ray powder diffraction pattern comprising at least three or at least four peaks selected from 2θ of 5.2°, 5.3°, 6.1°, 18.5°, and 24.4°±0.2°.

[0228] In some embodiments, the free base crystalline Form B is characterized by an X-ray powder diffraction pattern comprising peaks in 2θ at 5.2°, 5.3°, 6.1°, 18.5°, and 24.4° ± 0.2°.

[0229] In some embodiments, the free base crystalline Form B is characterized by an X-ray powder diffraction pattern comprising at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine peaks in 2θ at 5.2°, 5.3°, 6.1°, 15.6°, 18.5°, 18.7°, 19.5°, 22.5°, 24.4°, and 26.1° ± 0.2°.

[0230] In some embodiments, the free base crystalline Form B is characterized by an X-ray powder diffraction pattern comprising peaks in 2θ at 5.2°, 5.3°, 6.1°, 15.6°, 18.5°, 18.7°, 19.5°, 22.5°, 24.4°, and 26.1° ± 0.2°.

[0231] In some embodiments, the free base crystalline Form B is characterized by an X-ray powder diffraction pattern comprising peaks in 2θ at 5.4°, 6.2°, 9.2°, 10.3°, 15.1°, 18.6°, 19.1°, 20.6°, 25.0°, 26.0°, and 27.1° ± 0.2°.

[0232] In some embodiments, the free base crystalline Form B is characterized by an X-ray powder diffraction pattern comprising peaks in 2θ at 5.2°, 5.3°, 6.1°, 8.1°, 9.1°, 13.8°, 14.2°, 15.6°, 16.6°, 17.3°, 18.5°, 18.7°, 19.5°, 21.9°, 22.5°, 23.1°, 24.4°, 24.9°, 25.4°, 26.1°, 26.2°, 26.6°, and 27.1° ± 0.2°.

[0233] In some embodiments, the free base crystalline Form B is characterized by being substantially similar to Fig. 6A X-ray powder diffraction pattern.

[0234] In some embodiments, the free base crystalline Form B is characterized by a differential scanning calorimeter (DSC) thermogram comprising an endotherm starting at 262.2°C ± 2°C. In some embodiments, the free base crystalline Form A is characterized by being substantially similar to Figure 6B Differential Scanning Calorimeter (DSC) thermogram of. In some embodiments, DSC is performed using a sealed aluminum pan with a pinhole.

[0235] Pharmaceutical composition

[0236] The pharmaceutical composition of the present disclosure (also referred to herein as "the disclosed pharmaceutical composition") comprises a pharmaceutically acceptable carrier and a salt or solid form of the present disclosure.

[0237] Some embodiments of the present disclosure relate to a pharmaceutical composition comprising: a pharmaceutically acceptable carrier; and a mesylate salt of compound (I), wherein the molar ratio between compound (I) and methanesulfonic acid is about 1: 1. In some embodiments, the mesylate salt is crystalline. In some embodiments, the mesylate salt of compound (I) is crystalline Form A.

[0238] Some embodiments of the present disclosure relate to a pharmaceutical composition comprising: a pharmaceutically acceptable carrier; and a mesylate salt of compound (I), wherein the molar ratio between compound (I) and methanesulfonic acid is about 1: 1. In some embodiments, the mesylate salt is crystalline. In some embodiments, the mesylate salt of compound (I) is crystalline Form B.

[0239] Some embodiments of the present disclosure relate to a pharmaceutical composition comprising: a pharmaceutically acceptable carrier; and a mesylate salt of compound (I). In some embodiments, the mesylate salt is crystalline. In some embodiments, the mesylate salt of compound (I) is crystalline form H.

[0240] Some embodiments of the present disclosure relate to a pharmaceutical composition comprising: a pharmaceutically acceptable carrier; and a mesylate salt of compound (I). In some embodiments, the mesylate salt is crystalline. In some embodiments, the mesylate salt of compound (I) is crystalline Form I.

[0241] Some embodiments of the present disclosure relate to a pharmaceutical composition comprising: a pharmaceutically acceptable carrier; and a free base of compound (I). In some embodiments, the free base is crystalline. In some embodiments, the free base of compound (I) is crystalline form A. In some embodiments, the free base of compound (I) is crystalline form B.

[0242] The salts or solid forms of the present disclosure may be formulated for administration in any convenient manner for use in human or veterinary medicine. In some embodiments, the compound or salt included in the pharmaceutical composition may be active per se, or may be a prodrug, for example, capable of conversion into an active compound in a physiological environment.

[0243] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0244] "Pharmaceutical composition" refers to one or more active ingredients and one or more inert ingredients constituting a carrier, as well as any product produced directly or indirectly by the combination, complex or aggregation of any two or more ingredients, or the dissociation of one or more ingredients, or other types of reactions or interactions of one or more ingredients. Therefore, the pharmaceutical composition of the present disclosure encompasses any composition comprising a compound of the present disclosure and a pharmaceutically acceptable carrier.

[0245] "Carrier" refers to a diluent, adjuvant, excipient or vehicle used together with an active ingredient. In some embodiments, these pharmaceutical carriers are sterile liquids, such as water and oil, and the oil includes oils of petroleum, animal, plant or synthetic origin, including but not limited to peanut oil, soybean oil, mineral oil, sesame oil, etc. In some embodiments, when the pharmaceutical composition is orally administered, water is a carrier. In some embodiments, when the pharmaceutical composition is intravenously administered, saline and dextrose aqueous solutions are exemplary carriers. In some embodiments, saline solutions and dextrose aqueous solutions and glycerol solutions are used as liquid carriers for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene, ethylene glycol, water, ethanol, etc. In some embodiments, the pharmaceutical composition comprises a small amount of wetting agent or emulsifier or pH buffer. In some embodiments, these pharmaceutical compositions are in the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained release formulations, etc. In some embodiments, the pharmaceutical compositions are formulated as suppositories using traditional binders and carriers (such as triglycerides). In some embodiments, oral formulations include carriers such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutically acceptable carriers are described in "Remington's Pharmaceutical Sciences" by EWMartin. These pharmaceutical compositions will contain a therapeutically effective amount of active ingredients, such as active ingredients in purified form, and a suitable amount of carriers to provide a form suitable for administration to a subject. The preparation should be suitable for the mode of administration.

[0246] Treatment

[0247] Some embodiments provided herein describe different solid forms and salt forms of compound (I) that can be used as inhibitors of epidermal growth factor receptor (EGFR) family kinases. In some embodiments, the solid forms and salt forms of compound (I) can be used as inhibitors of mutant EGFR family kinases. In some embodiments,

[0248] In some embodiments, the solid form and salt form of compound (I) described herein have an improved safety profile. In some embodiments, the solid form and salt form of compound (I) described herein have an improved toxicity profile. In some embodiments, the solid form and salt form of compound (I) described herein have an improved therapeutic index. In some embodiments, the solid form and salt form of compound (I) described herein have improved anti-tumor activity against brain metastases.

[0249] In some embodiments, the presence of EGFR family kinase mutants is determined by evaluating archived tumor biopsies or blood samples. In some embodiments, commercially available test kits are used to detect EGFR family kinase mutants. In some embodiments, a method based on reverse transcription polymerase chain reaction (RT-PCR) is used to detect EGFR family kinase mutants. In some embodiments, a sequencing-based method is used to detect EGFR family kinase mutants. In some embodiments, a method based on mass spectrometry genotyping is used to detect EGFR family kinase mutants. In some embodiments, an immunohistochemistry-based method is used to detect EGFR family kinase mutants. In some embodiments, a molecular diagnostic panel is used to detect EGFR family kinase mutants. In some embodiments, EGFR family kinase mutants from tumor samples are detected. In some embodiments, EGFR family kinase mutants from circulating DNA are detected. In some embodiments, EGFR family kinase mutants from tumor cells are detected.

[0250] In one aspect, provided herein is a method of inhibiting an EGFR family kinase mutant in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a solid form or salt form of Compound (I).

[0251] In another aspect, provided herein is a method of inhibiting a drug-resistant EGFR mutant in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a solid form or salt form of compound (I). In some embodiments, the drug-resistant EGFR mutant is del19 / T790M EGFR or L858R / T790M EGFR.

[0252] In another aspect, provided herein is a method of inhibiting EGFR in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a solid form or salt form of Compound (I), wherein the compound expresses greater inhibition of EGFR mutants relative to wild-type EGFR.

[0253] In some embodiments, the EGFR mutant comprises a substitution in exon 18, a deletion in exon 19, a substitution in exon 20, an insertion in exon 20, a mutation in the extracellular domain, or a substitution in exon 21. In some embodiments, the EGFR mutant is selected from del19 / T790M EGFR, L858R / T790M EGFR, L858R EGFR, L861Q EGFR, S768I EGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGEEGFR, 770insSVDEGFR (or D770_N771insSVD EGFR), 770insNPG EGFR (or D770_N771insNPGEGFR), 770insGT EGFR, 770insGF EGFR, 770insGEGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773ins NPH EGFR (or H773insNPH EGFR), 773insH EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupASV EGFR, 773insAH EGFR, M766_A767insAI EGFR and any combination thereof. In some embodiments, the EGFR mutant is del19 / T790M EGFR or L858R / T790M EGFR. In some embodiments, the EGFR mutant is del19 / T790M EGFR. In some embodiments, the EGFR mutant is L858R / T790M EGFR. In some embodiments, the EGFR mutant is an insertion in exon 20. In some embodiments, the EGFR mutation is exon 18G719X or exon 21L861Q mutation. In some embodiments, the mutation is S768I EGFR.

[0254] In another aspect, provided herein is a method of treating a disease associated with EGFR in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a solid form or salt form of Compound (I).

[0255] In some embodiments, the subject's disease comprises an EGFR mutation (i.e., the subject's disease is characterized by an EGFR mutation). In some embodiments, the EGFR mutation comprises a substitution in exon 18, a deletion in exon 19, a substitution in exon 20, an insertion in exon 20, a mutation in the extracellular domain, or a substitution in exon 21. In some embodiments, the EGFR mutation is selected from del19 / T790M EGFR, L858R / T790ME EGFR, L858R EGFR, L861Q EGFR, S768IE EGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVD EGFR (or D770_N771insSVD EGFR), 770insNPG EGFR (or D770_N771insNPGE EGFR), 770insGT EGFR, 770insGF EGFR, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773insNPH EGFR (or H773insNPH EGFR), 773insH EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupASV EGFR, 773insAH EGFR, M766_A767insAI EGFR, and any combination thereof. In some embodiments, the EGFR mutation is del19 / T790M EGFR or L858R / T790M EGFR. In some embodiments, the EGFR mutation is del19 / T790M EGFR. In some embodiments, the EGFR mutation is L858R / T790MEGFR. In some embodiments, the EGFR mutant is an insertion in exon 20. In some embodiments, the EGFR mutant is exon 18G719X or exon 21L861Q mutation. In some embodiments, the mutation is S768I EGFR.

[0256] In another aspect, there is provided herein a method for treating cancer in a subject in need thereof, the method comprising administering to the subject a solid form or salt form of a therapeutically effective amount of compound (I). In some embodiments, cancer is an incurable recurrent cancer. In some embodiments, cancer is a locally advanced or metastatic disease. In one aspect, the subject is an adult. In one aspect, treatment is a first-line treatment. In one aspect, treatment is a second-line treatment. In one aspect, the subject has previously been treated with platinum-based chemotherapy. In one aspect, the subject's disease progresses during or after platinum-based chemotherapy. In one aspect, the subject has previously been treated with at least one systemic prior treatment. In one aspect, the subject has previously been treated with an EGFR exon 20 insertion targeting agent. In one aspect, treatment is adjuvant therapy after tumor resection. In some embodiments, cancer shows drug resistance associated with EGFR del19 / T790M activation. In some embodiments, cancer shows drug resistance associated with EGFR L858R / T790M activation. In some embodiments, cancer is characterized by EGFR mutations. In some embodiments, cancer is characterized by insertions in exon 20. In some embodiments, the cancer is characterized by an exon 18G719X or exon 21L861Q mutation.

[0257] In some embodiments, the cancer is bladder cancer, prostate cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, glioblastoma, head and neck cancer, lung cancer, urothelial cancer, sinus cancer, or non-small cell lung cancer. In some embodiments, the cancer is non-small cell lung cancer, prostate cancer, head and neck cancer, breast cancer, colorectal cancer, or glioblastoma. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is glioblastoma. In some embodiments, the glioblastoma is pediatric bilateral thalamic glioma.

[0258] In some embodiments, the subject's cancer comprises an EGFR mutation, i.e., the cancer is characterized by an EGFR mutation. In some embodiments, the EGFR mutation comprises a substitution in exon 18, a deletion in exon 19, a substitution in exon 20, an insertion in exon 20, a mutation in the extracellular domain, or a substitution in exon 21. In some embodiments, the EGFR mutation is selected from del19 / T790M EGFR, L858R / T790M EGFR, L858R EGFR, L861Q EGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVDEGFR (or D770_N771insSVD EGFR), 770insNPG EGFR (or D770_N771insNPG EGFR), 770insGT EGFR, 770insGF EGFR, 770insGEGFR, 771insH EGFR, 771insN EGFR, 772insNPEGFR, 773ins NPH EGFR (or H773insNPH EGFR), 773insH EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupASV EGFR, 773insAH EGFR, M766_A767insAI EGFR, and any combination thereof. In some embodiments, the EGFR mutation is del19 / T790M EGFR or L858R / T790M EGFR. In some embodiments, the EGFR mutation is del19 / T790M EGFR. In some embodiments, the EGFR mutation is L858R / T790M EGFR. In some embodiments, the cancer is characterized by EGFR mutation. In some embodiments, the cancer is characterized by insertion in exon 20. In some embodiments, the cancer is characterized by EGFR exon 18G719X or exon 21L861Q mutation. In some embodiments, the mutation is S768I EGFR.

[0259] The presence of CNS metastasis including brain and leptomeningeal lesions can lead to significant morbidity and is associated with poor outcomes for patients with NSCLC including EGFR mutation diseases. The control of brain metastasis depends on the extent of the disease and the need for emergency treatment. For patients who do not need immediate surgical treatment, initial treatment may consist of radiotherapy, preferably using stereotactic radiosurgery rather than whole brain radiation. Radiation may be associated with cognitive decline caused by radiation-induced necrosis, which may have a significant impact on quality of life because patients have longer survival due to improved therapy. Although chemotherapy has some activity, the results are often inferior to those achieved by radiation. For patients with common EGFR mutations, osimertinib treatment is an alternative to radiotherapy, although this method has not been formally evaluated in randomized trials. EGFR Ex20ins targeting TKI with high CNS permeability is required. In some aspects, a method for treating CNS (or brain) metastasis associated with cancer characterized by mutation EGFR in a subject in need is provided herein, the method comprising administering to the subject a solid form or salt form of a therapeutically effective amount of compound (I). In some aspects, provided herein is a method of treating asymptomatic brain metastases.

[0260] In another aspect, there is provided herein a method for treating an inflammatory disease in a subject in need thereof, the method comprising administering to the subject a solid form or salt form of a therapeutically effective amount of compound (I). Also described herein are the uses of solid forms and salt forms of compound (I) described herein for treating inflammatory diseases associated with EGFR del19 / T790M activation. Also described herein are the uses of solid forms and salt forms of compound (I) described herein for treating inflammatory diseases associated with EGFR L858R / T790M activation.

[0261] In some embodiments, the inflammatory disease is psoriasis, eczema, or atherosclerosis. In some embodiments, the inflammatory disease is psoriasis. In some embodiments, the inflammatory disease is eczema. In some embodiments, the inflammatory disease is atherosclerosis.

[0262] In some embodiments, the subject's inflammatory disease comprises an EGFR mutation. In some embodiments, the EGFR mutation comprises a substitution in exon 18, a deletion in exon 19, a substitution in exon 20, an insertion in exon 20, a mutation in the extracellular domain, or a substitution in exon 21. In some embodiments, the EGFR mutation is selected from del19 / T790ME EGFR, L858R / T790M EGFR, L858R EGFR, L861Q EGFR, S768I EGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVD EGFR (or D770_N771insSVD EGFR), 770insNPG EGFR (or D770_N771insNPG EGFR), 770insGT EGFR, 770insGF EGFR, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773insNPHE EGFR (or H773insNPH EGFR), 773insH EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupASV EGFR, 773insAH EGFR, M766_A767insAI EGFR, and any combination thereof. In some embodiments, the EGFR mutation is del19 / T790M EGFR or L858R / T790M EGFR. In some embodiments, the EGFR mutation is del19 / T790M EGFR. In some embodiments, the EGFR mutation is L858R / T790M EGFR. In some embodiments, the mutation is EGFR exon 18G719X or exon 21L861Q. In some embodiments, the mutation is S768I EGFR.

[0263] Administration and pharmaceutical compositions

[0264] In certain embodiments, the solid form or salt form of compound (I) is administered as a pure chemical. In other embodiments, the solid form or salt form of compound (I) is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier), which is selected based on the selected route of administration and standard pharmaceutical practices as described in, for example, Remington: The Science and Practice of Pharmacy (Gennaro, 21st edition Mack Pub. Co., Easton, PA (2005)).

[0265] Provided herein is a pharmaceutical composition comprising at least one solid form or salt form of Compound (I) and one or more pharmaceutically acceptable carriers. One embodiment provides a pharmaceutical composition comprising a solid form or salt form of Compound (I) and a pharmaceutically acceptable excipient.

[0266] In certain embodiments, the solid form or salt form of Compound (I) is substantially pure in that it contains less than about 5% or less than about 1% or less than about 0.1% of other small organic molecules, such as unreacted intermediates or synthesis by-products produced in one or more steps of the synthesis method.

[0267] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose, or another suitable material that dissolves easily in the digestive tract. In some embodiments, suitable nontoxic solid carriers are used, including, for example, pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, etc. (see, for example, Remington: The Science and Practice of Pharmacy (Gennaro, 21st Edition Mack Pub. Co., Easton, PA (2005)).

[0268] The dosage of the pharmaceutical composition comprising at least one solid form or salt form of Compound (I) varies depending on the patient's condition, ie, disease stage, general health status, age and other factors.

[0269] The pharmaceutical composition is administered in a manner suitable for the disease to be treated (or prevented). Suitable dosage and suitable duration and frequency of administration will be determined by factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient and the method of administration. Typically, suitable dosage and treatment regimen provide active ingredients in an amount sufficient to provide therapeutic benefit (e.g., improved clinical outcome) or alleviate symptom severity. Typically, experimental models and / or clinical trials are used to determine the optimal dose. The optimal dose depends on the patient's body mass, body weight or blood volume.

[0270] The following examples are intended to be illustrative and are not intended to limit the scope of the present disclosure in any way.

[0271] experiment

[0272] Instruments and methods

[0273] Different instruments and methods were used to test and characterize different batches of materials. For example, XRPD Method 1 was used to collect the XRPD peaks described in Table 1, Table 2, Table 3, Table 4, Table 5a, Table 6a, Table 7a, Table 8a, Table 9a, Table 10a, Table 11a, Table 12a, Table 13a, Table 14a, Table 15a, and Table 16a and XRPD Method 2 was used to collect the XRPD peaks described in Table 5b, Table 6b, Table 7b, Table 8b, Table 9b, Table 10b, Table 11b, Table 12b, Table 12c, Table 13b, Table 13c, Table 13d, Table 14b, Table 15b, and Table 16b.

[0274] X-ray powder diffraction (XRPD) method 1

[0275] Instrument: Panalytical Empyrean

[0276]

[0277] Step size: 0.01 degree

[0278]

[0279] X-ray powder diffraction (XRPD) method 2

[0280] Use the zero background sample holder designed for smaller sample loading to ensure that the mirror surface is not scratched, and the sample should be loaded into the pit in the sample holder. For sample preparation, the sample installation level must be flush with the top of the groove that the sample is to occupy. Use a lens paper with some solvent (i.e. methanol) on it to wipe the sample holder clean. Use a spatula to transfer a small amount of powder to the sample holder, and push all the surrounding powder materials on the mirror surface onto the middle pit. Make sure not to scrape the mirror surface of the sample holder with a spatula. Use a clean slide glass, gently push the powder sample down into the pit area of ​​the sample holder, and rotate the slide glass to flatten the sample. Clean the mirror surface outside the sample pit area with lens paper, and then put the sample holder into the XRPD chamber for analysis.

[0281] XRPD was performed using a Bruker D8 Advance equipped with a LYNXEYE detector in reflection mode (i.e., Bragg-Brentano geometry). Samples were prepared on Si zeroed wafers as described above. The parameters of the XRPD method used are listed below:

[0282]

[0283] Thermogravimetric analysis (TGA)

[0284] Instrument: TA Instruments Discovery TGA

[0285] Parameters: 10℃ rise per minute, 25 to 300℃, 50mL / min N2 purge

[0286] Differential Scanning Calorimetry (DSC) Method 1

[0287] Instrument: TA Instruments Discovery DSC

[0288] Parameters: Rise 10℃ every minute until 300℃

[0289] Differential Scanning Calorimetry (DSC) Method 2

[0290] DSC was performed using a TA Discovery DSC. Samples (1-5 mg) were weighed directly into a 40 μL sealed aluminum pan with a pinhole and analyzed according to the following parameters:

[0291]

[0292] Simultaneous Thermogravimetric Analysis and Differential Scanning Calorimetry (TGA and DSC):

[0293] TGA and DSC were performed simultaneously on the same sample using a Mettler Toledo TGA / DSC3+. The protective gas and purge gas were nitrogen at flow rates of 20–30 mL / min and 50–100 mL / min, respectively. The required amount of sample (5–10 mg) was weighed directly into a sealed aluminum pan with a pinhole and analyzed according to the following parameters:

[0294]

[0295] Dynamic Vapor Sorption (DVS) Method1

[0296] Dynamic vapor adsorption was performed using a TA Instruments Q5000SA DVS at 25°C under nitrogen purge. Approximately 10-15 mg of material was used. The samples were analyzed using the following method:

[0297] For anhydrous:

[0298] 0% RH to 90% RH, at 10% RH

[0299] 90% RH to 0% RH, at 10% RH

[0300] For anhydrous:

[0301] 40% RH to 90% RH, at 10% RH

[0302] 90% RH to 0% RH, at 10% RH

[0303] Dynamic Vapor Sorption (DVS) Method 2

[0304] DVS was performed using a Q5000SA. The sample (5–15 mg) was loaded into a metal quartz sample pan, suspended on a microbalance, and exposed to a humidified nitrogen flow. The weight change was relative to a matching empty reference pan suspended on a microbalance opposite the sample. At each level, the sample was kept for at least 10 min, and the next humidity level was entered only when the weight change between two measurements (interval: 5 s) was less than 0.002% or after 45 min (for 5–65% RH) or after 2 h (for 80 and 95% RH). The following program was used:

[0305] 1- Equilibrated at 50% RH

[0306] 2-50% to 5%. (50%, 35%, 20% and 5%)

[0307] 3-5% to 95% (5%, 20%, 35%, 50%, 65%, 80% and 95%)

[0308] 4-95% to 5% (95%, 80%, 65%, 50%, 35%, 20% and 5%)

[0309] 5-5% to 50% (5%, 20%, 35% and 50%)

[0310] Polarized Light Microscopy (PLM)

[0311] Instrument: Nikon Eclipse Ci POL

[0312] Camera: Nikon DS-Fi3

[0313] Software: Nikon NIS Elements

[0314] Microscopy:

[0315] Optical microscopy was performed using a Zeiss AxioScope A1 digital imaging microscope equipped with 2.5X, 10X and 40X objectives and polarizers. Images were captured via a built-in Axiocam 105 digital camera and processed using the ZEN 2 (blue version) software provided by Zeiss.

[0316] High Performance Liquid Chromatography (HPLC):

[0317] HPLC was performed using an Agilent 1220 Infinity 2LC equipped with a diode array detector (DAD). The instrument had a flow rate range of 0.2-5.0 mL / min, an operating pressure range of 0-600 bar, a temperature range of 5°C above ambient to 60°C, and a wavelength range of 190-600 nm.

[0318] The HPLC method used in this study is as follows:

[0319]

[0320] Proton NMR ( 1 H NMR) Spectrum:

[0321] Performed on Bruker Avance 300, 400 and 500 MHz spectrometers 1 H NMR. The solid was dissolved in 0.75 mL of deuterated solvent in a 4 mL vial, transferred to an NMR tube (Wilmad 5 mm thin wall 8" 200 MHz, 506-PP-8) and analyzed according to the following parameters:

[0322]

[0323]

[0324]

[0325]

[0326] Example 1: Preparation of Compound (I)

[0327] Synthesis of N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound I):

[0328]

[0329] Step 1 : Synthesis of 5-bromo-2-chloro-N-(2-fluoro-5-nitrophenyl)pyrimidin-4-amine (89):

[0330] To an ice-cold solution of 2-fluoro-5-nitroaniline (12) (1.0 equiv.) in tetrahydrofuran was added sodium hydride (60% dispersion in mineral oil, 3.0 equiv.) in portions. The resulting reaction mixture was stirred at room temperature for 30 minutes and then 2,4-dichloro-5-bromopyrimidine (88) (1.0 equiv.) was added. The resulting reaction mixture was heated at 60 ° C for 16 hours. After completion (TLC monitoring), the reaction was stopped with ice and extracted with ethyl acetate (3 times). The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by combiflash, eluted with hexane containing 40% ethyl acetate to obtain (89) (1.3 g, yield: 44.24%) as a light yellow solid. MS: [M+H] + 346.97.

[0331] Step 2 : Synthesis of 2-chloro-N-(2-fluoro-5-nitrophenyl)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-amine (91):

[0332] To a solution of the halide derivative (89) (1.0 equiv.) and the corresponding boronic acid / ester derivative (90) (1.1 equiv.) in N,N-dimethylformamide: water (4:1) was added sodium carbonate or sodium bicarbonate (2.0 equiv.). The resulting reaction mixture was degassed under an argon atmosphere for 15 minutes, followed by the addition of tetrakis(triphenylphosphine)palladium(0) (0.1 equiv.). The resulting reaction mixture was heated at 90 °C for 16 hours. After the reaction was completed (TLC monitoring), the reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate (3 times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by combiflash, eluted with hexane containing 35% ethyl acetate to obtain the desired product (91) (700 mg; yield: 50.12%) as a light yellow solid. MS: [M+H] + 413.10.

[0333] Step 3 : Synthesis of N4-(2-fluoro-5-nitrophenyl)-N2-(1-methyl-1H-pyrazol-4-yl)-5-(4-(trifluoromethyl)phenyl)pyrimidine-2,4-diamine (92):

[0334] To an ice-cold solution of the chloro compound (91) (1.0 equiv.) in isopropanol was added amine (22) (1.2 equiv.) and trifluoroacetic acid (2.0 equiv.). The reaction mixture was heated at 110 °C for 16 hours. After completion of the reaction (TLC monitoring), the reaction mixture was concentrated under reduced pressure, saturated sodium bicarbonate solution was added and extracted with dichloromethane (3 times). The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude material was purified by combiflash, eluting with dichloromethane containing 1% methanol to obtain the desired product (92) (500 mg; yield: 70.24%) as a light yellow solid. MS: [M+H] + 474.09.

[0335] Step 4 : Synthesis of N4-(5-amino-2-fluorophenyl)-N2-(1-methyl-1H-pyrazol-4-yl)-5-(4-(trifluoromethyl)phenyl)pyrimidine-2,4-diamine (93):

[0336] To an ice-cold solution of the nitro derivative (92) (1.0 eq.) in methanol:tetrahydrofuran:water (2:2:1) was added zinc or iron powder (5 eq.) and ammonium chloride (5 eq.). The resulting reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction (TLC monitoring), the reaction mixture was passed through a celite bed washed with 5% methanol in dichloromethane. The filtrate was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to obtain the desired product (93) (350 mg; yield: 74.78%) as a semi-solid. MS: [M+H] + 444.11.

[0337] Step 5 : Synthesis of N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound I):

[0338] A solution of amino compound (93) (1.0 equivalent) in dichloromethane:tetrahydrofuran (1: 1) was cooled to -40 ° C, followed by the addition of triethylamine (3-5 equivalents) and acryloyl chloride (1.0 equivalent). The mixture was stirred at the same temperature for 2 hours. After completion of the reaction (monitored by TLC), water was added and extracted with dichloromethane (3 times). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by preparative HPLC to obtain Compound I (30 mg, yield: 13.33%) as an off-white solid. 1 H NMR (400MHz, DMSO-d6): δ10.21(bs,1H),9.24(bs,1H),8.53(bs,1H),7.99(s,1H),7.71-7.81(m,5H),7. 57(s,1H),7.08-7.16(m,3H),6.37-6.44(m,1H),6.21-6.26(m,1H),5.74(d,J=8.4Hz,1H),3.54(s,3H). LCMS:[M+H] + 498.35.

[0339] Example 2: Preparation of Compound (I) Form A Methanesulfonate

[0340] About 30 mg of compound (I) free alkali is dissolved in 1.7 mL acetone (or 7.5 mL ethyl acetate) to obtain a clear solution. The methanesulfonic acid of 1:1 molar feed ratio is added to the free alkali solution and the mixture is stirred at room temperature (rt) for 2 days. Separate the precipitate by centrifugation, cool to 5 ° C, or slowly evaporate to obtain the product. As an alternative to stirring at rt, the mixture can be heated to 40 ° C and stirred overnight and seeded with Form A crystals.

[0341] XRPD analysis confirmed that the product obtained was Form A. The mesylate salt Form A was confirmed to be the anhydrate of the mono-mesylate salt.

[0342] Example 3: Preparation and Characterization of Compound (I) Form B Mesylate

[0343] General Synthesis of Mesylate Form B:

[0344] Methanesulfonate form B can be generally obtained by slurrying compound (I) in acetone (e.g., 10-30 volumes, 10-25 volumes, 15-25 volumes, etc.) or dissolving compound (I) therein at high temperature (e.g., between 40°C and 70°C, between 40°C and 65°C, between 45°C and 55°C, or between 50°C and 60°C, etc.) or under reflux. The solution is then cooled slightly, and then a small portion of methanesulfonic acid (e.g., 0.1-0.5 molar equivalents relative to compound (I)) is fed, which can cause dissolution. Then feed seed crystals (mesylate form B), and after forming a seed bed, feed the remaining methanesulfonic acid. Alternatively, seed crystals are not used and the remaining methanesulfonic acid is fed. After an optional holding period (e.g., 10 minutes to 5 hours, 10-120 minutes, 30-100 minutes, etc.), the slurry is then cooled and maintained at ambient temperature or lower (e.g., between 5°C and 25°C, between 5°C and 15°C, between 15°C and 25°C, etc.), then filtered and washed with acetone. The product is dried at elevated temperature (e.g., between 40°C and 70°C, between 40°C and 65°C, between 45°C and 55°C, or between 50°C and 60°C, etc.) to produce mesylate Form B. In some embodiments, a mixture of acetone and a small amount of water (e.g., 1-5%) may also be used instead of acetone to slurry or dissolve Compound (I).

[0345] Example 3a:

[0346] 2.595g of compound (I) free base is heated to reflux in 20 volumes of acetone. Then feed 0.3 equivalents of MSA, then cool to 42 ° C. Then feed seed (0.1% mesylate mode B) and stir for 40min. Then feed MSA (0.8 equivalent) and stir the slurry at 42 ° C for 1h. Alternatively, do not add seed and add the remaining MSA (0.8 equivalent) in three equal parts and stir the slurry at 42 ° C for 1h. After cooling to 20 ° C for 1h, then stir the slurry for 1h, then filter and wash with 3.0 volumes of acetone. The solid is dried overnight at 50 ° C in a vacuum. The yield as mesylate form B is 2.54g (86%).

[0347] Example 3b:

[0348] 500mg of compound (I) free alkali is dissolved in 20mL acetone and heated to 50 ℃ to obtain a clear solution. 75 μL (1.1M. equivalent) of methanesulfonic acid is added to the free alkali solution. Seed crystals (Form B) are added and the mixture is stirred at room temperature for 2 days. The isolated solid as mesylate Form B is weighed as 507mg (89% yield).

[0349] XRPD analysis confirmed that the isolated solid was Form B. Figure 2B ) and 1H-NMR to characterize the product. Methanesulfonate Form B was confirmed to be an anhydrate of a mono-methanesulfonate salt having an irregular plate-like morphology.

[0350] TGA analysis showed that the mass loss was negligible up to 150°C ( Figure 2B ).DSC confirmed an endotherm starting at 247.8°C.

[0351] DVS showed 2.47% weight gain at 80% RH, indicating that it might be hygroscopic, but no crystal form change was observed after DVS.

[0352] Example 4: Preparation and Characterization of Compound (I) Form H Methanesulfonate

[0353] Mesylate Form H is prepared via slow cooling crystallization in methanol: acetone (1: 1 volume). About 300mg of mesylate Form B is weighed into 4mL vial. Then at 50°C, a solvent mixture of methanol and acetone (4.5 volumes) is added incrementally until dissolved. While mixing, the solution is cooled to 5°C at 5°C per hour using a cooling block with a programmable cooler. The slurry is filtered and washed with solvent (2x 0.5 volumes), then at 50°C, dried overnight under vacuum. The yield of 0.166g (49mol%) as mesylate Form H is obtained.

[0354] Mesylate Form H was produced on an approximately 0.200 g scale via short-term slurrying of mesylate Form B in ethanol at 50°C. Seeding was performed with mesylate Form H. A yield of 0.159 g (79.5 wt / wt%) was obtained. Based on the characterization performed, mesylate Form H was determined to be anhydrous.

[0355] Slurry competition experiments between all anhydrates of the mesylate salt including Form A, Form B and Form H were performed to determine the relative stability using THF as solvent at 25° C. and isopropyl alcohol (IPA) as solvent at 25° C. and 60° C. At the end of the study, the three salt forms converted to Form H in THF at 25° C. (within 3 days), and in IPA at 25° C. (within 3 days) and at 60° C. (within 1 day). Therefore, mesylate Form H is the thermodynamically more stable form at both RT and 60° C. in both THF and IPA.

[0356] The mesylate salt Form H was identified as the anhydrate of the mono-mesylate salt having a needle-like morphology.

[0357] TGA analysis showed that the mass loss up to 150°C was 0.409 wt% ( Figure 3B DSC demonstrated two endothermic and exothermic events; a larger endotherm starting at 220.54°C, and a smaller exotherm starting at 239.42°C ( Figure 3B ).

[0358] In order to understand the hygroscopicity of mesylate form H, dynamic vapor sorption (DVS) was used to measure the mass change at 25°C as the relative humidity changed. Anhydrous mesylate type H was balanced at 0% RH to remove adsorbed moisture or residual solvent before analysis. The results showed that at 25°C / 80% RH, mesylate form H showed a water absorption of 1.76%, indicating that mesylate form H is slightly hygroscopic. After DVS evaluation, no form change of the sample was observed.

[0359] Example 5: Preparation and Characterization of Compound (I) Form I Mesylate

[0360] Mesylate Form I is prepared via slow cooling crystallization in ethanol: water (9: 1 volume). About 300mg of mesylate Form B is weighed into 4mL vial. Then at 50 ℃, solvent (9 volumes) is added incrementally until dissolved. While mixing, the solution is cooled to 5 ℃ at 5 ℃ per hour using a cooling block with a programmable cooler. The slurry is filtered and washed with solvent (2x 0.5 volume), then at 50 ℃, dried overnight under vacuum. The yield of 0.164g (48mol%) as mesylate Form I is obtained.

[0361] Solid state characterization results confirmed that mesylate salt Form I was a hydrate.

[0362] TGA analysis showed that the mass loss up to 150°C was 1.998 wt% ( Figure 4B DSC demonstrated three endothermic and exothermic events; a smaller endotherm starting at 33.16°C, a larger endotherm starting at 210.43°C, and a smaller exotherm starting at 229.09°C ( Figure 4B ).

[0363] The DVS results of mesylate salt Form I at 25°C from 30% RH to 80% RH showed a water absorption of 0.54%, indicating that mesylate salt Form I is slightly hygroscopic. No form changes of the samples were observed after the DVS evaluation.

[0364] Example 6: Preparation and Characterization of Crystalline Free Base Form A of Compound (I)

[0365] It was characterized by X-ray powder diffraction (XRPD), polarized light microscopy (PLM), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and high performance liquid chromatography (HPLC). The characterization results showed that the starting material was crystalline, defined as free base Form A, and the crystalline form was further identified as an anhydrate with a rod-like morphology.

[0366] The DVS results of the free base Form A showed a water absorption of 5.23% at 80% RH. No form changes of the samples were observed after DVS evaluation.

[0367] Example 7: Preparation and Characterization of Crystalline Free Base Form B of Compound (I)

[0368] About 30 mg of compound (I) was dissolved in 1.7 mL of acetone. The mixture was stirred at room temperature for 2 days. The free base form B of compound (I) was obtained, and the free base form B of compound (I) was confirmed by XRPD, DSC and TGA.

[0369] Example 8: Pharmacokinetics of the mesylate and free base forms of Compound (I) following oral (PO) administration to male beagle dogs.

[0370] Male beagles (3 in each treatment group) were orally administered 30 mg / kg of compound (I) free base or a mesylate salt of compound (I) equivalent to a dose of 30 mg / kg free base. The free base and mesylate salt were suspended / dissolved in a suitable volume of vehicle solution containing deionized water containing 0.5% hydroxypropylmethylcellulose (weight / volume) and 0.2% Tween 80 (volume / volume). The PO dose was administered to the stomach via a syringe and a gavage tube, followed by a 5 mL water rinse. In the morning of dose administration, the dose volume was adjusted for the weight of the animal. Blood samples were collected from accessible veins (preferentially jugular vein) at 0, 0.5, 1, 2, 4, 6, 8, 10, 12 and 24 h after administration. The blood samples were kept on ice until processing. Within 1 h of collection, all blood samples were centrifuged at 3200 RPM for 10 min at 5 ° C. Plasma samples were transferred directly to cluster tubes and stored at -20 ± 5 °C until shipment. All animals appeared normal at the time of dosing and at all blood collection time points. Animals were fasted the evening before dosing and food was resumed 4 h after dosing. Figure 7 As shown, the mesylate salt provides higher in vivo exposure compared to the free base form.

Claims

1. A methanesulfonate salt of a compound (I) represented by the following structural formula: The molar ratio of compound (I) to methanesulfonic acid is 1:

1.

2. The mesylate salt of claim 1, wherein the mesylate salt is a crystalline salt.

3. The mesylate salt of claim 2, wherein the crystalline mesylate salt is in crystalline Form A, characterized by an X-ray powder diffraction pattern comprising at least three, at least four, or at least five peaks selected from 2θ of 5.9°, 7.2°, 11.9°, 12.1°, 19.3°, and 20.1°±0.2°.

4. The mesylate salt of claim 3, wherein the crystalline mesylate salt is in crystalline Form A, characterized by an X-ray powder diffraction pattern comprising peaks in 2θ at 5.9°, 7.2°, 11.9°, 12.1°, 19.3° and 20.1°±0.2°.

5. The mesylate salt of claim 4, wherein Form A is characterized by an X-ray powder diffraction pattern comprising peaks in 2θ form at 5.9°, 7.2°, 11.9°, 12.1°, 13.4°, 19.3°, 20.1°, 21.7°, 24.1°, and 27.6°±0.2°.

6. The mesylate salt of claim 4 or 5, wherein Form A is characterized by an X-ray powder diffraction pattern comprising peaks in 2θ at 5.9°, 7.2°, 11.9°, 12.1°, 13.4°, 14.6°, 15.4°, 19.3°, 20.1°, 21.7°, 22.9°, 23.8°, 24.1°, and 27.6°±0.2°.

7. The mesylate salt of any one of claims 3-6, wherein the Form A is characterized by an X-ray powder diffraction pattern substantially similar to that of Figure 1A.

8. The mesylate salt of any one of claims 3-7, wherein the Form A is further characterized by a differential scanning calorimeter (DSC) thermogram comprising an endotherm with an onset at 202.8°C ± 2°C and an exotherm with an onset at 206.9°C ± 2°C.

9. The mesylate salt of any one of claims 3-8, wherein the Form A is further characterized by a thermogravimetric analysis (TGA) substantially similar to that of Figure IB.

10. The mesylate salt of claim 2, wherein the crystalline mesylate salt is in crystalline Form B, characterized by an X-ray powder diffraction pattern comprising at least three or at least four peaks selected from 2θ of 18.5°, 19.8°, 20.8°, 22.4°, and 24.9°±0.2°.

11. The mesylate salt of claim 2, wherein the crystalline mesylate salt is in crystalline Form B, characterized by an X-ray powder diffraction pattern comprising peaks in 2θ at 18.5°, 19.8°, 20.8°, 22.4°, and 24.9°±0.2°.

12. The mesylate salt of claim 11, wherein the Form B is characterized by an X-ray powder diffraction pattern comprising peaks in 2θ at 8.9°, 11.3°, 18.5°, 19.8°, 20.8°, 21.4°, 22.4°, 24.9°, and 25.9°±0.2°.

13. The mesylate salt of claim 2, wherein the crystalline mesylate salt is in crystalline Form B, characterized by an X-ray powder diffraction pattern comprising at least three or at least four peaks selected from 2θ of 18.4°, 19.7°, 21.3°, 22.4°, 24.8°±0.2°.

14. The mesylate salt of claim 13, wherein the crystalline mesylate salt is in crystalline Form B, characterized by an X-ray powder diffraction pattern comprising peaks in 2θ at 18.4°, 19.7°, 21.3°, 22.4°, 24.8°±0.2°.

15. The mesylate salt of claim 13, wherein the crystalline mesylate salt is in crystalline Form B, characterized by an X-ray powder diffraction pattern comprising peaks in 2θ at 8.8°, 11.3°, 18.4°, 19.7°, 20.6°, 20.8°, 21.3°, 22.0°, 22.4°, and 24.8°±0.2°.

16. The mesylate salt of claim 13, wherein the crystalline mesylate salt is in crystalline Form B, characterized in that the crystalline Form B comprises crystalline iodine in the form of 2θ at 5.4°, 6.6°, 7.6°, 8.8°, 11.3°, 11.8°, 12.3°, 13.6°, 15.2°, 15.4°, 16.4°, 16.7°, 17.1°, 18.0°, 18.4°, 19.5°, 19.6°, 19.7°, 19.8°, 19.9°, 19.1°, 19.2°, 19.3°, 19.4°, 19.6°, 19.7°, 19.8°, 19.9°, 19.9°, 19.1°, 19. .7°, 20.6°, 20.8°, 21.3°, 21.6°, 22.0°, 22.4°, 22.7°, 23.7°, 24.5°, 24.8°, 25.4°, 25.7°, 25.8°, 26.5°, 27.5°, 29.8°, 30.8°, 31.2°, 35.0°, 35.3° and 36.3°±0.2°.

17. The mesylate salt of claim 2, wherein the Form B is characterized by an X-ray powder diffraction pattern substantially similar to that of Figure 2A.

18. The mesylate salt of any one of claims 9-17, wherein the Form B is further characterized by a differential scanning calorimeter (DSC) thermogram comprising an endotherm with an onset at 247.8°C ± 2°C.

19. The mesylate salt of any one of claims 9-18, wherein the Form B is further characterized by a thermogravimetric analysis (TGA) substantially similar to that of Figure 2B.

20. The mesylate salt of claim 2, wherein the crystalline mesylate salt is crystalline Form H, characterized by an X-ray powder diffraction pattern comprising at least three, at least four, or at least five peaks selected from 2θ of 13.7°, 19.1°, 20.0°, 21.5°, 21.9°, and 23.4°±0.2°.

21. The mesylate salt of claim 20, wherein the crystalline mesylate salt is crystalline Form H, characterized by an X-ray powder diffraction pattern comprising peaks in 2θ at 13.7°, 19.1°, 20.0°, 21.5°, 21.9° and 23.4°±0.2°.

22. The mesylate salt of claim 21, wherein the Form H is characterized by an X-ray powder diffraction pattern comprising peaks in 2θ at 8.1°, 10.1°, 11.7°, 13.7°, 19.1°, 20.0°, 20.8°, 21.5°, 21.9°, and 23.4°±0.2°.

23. The mesylate salt of any one of claims 20-22, wherein the Form H is characterized by an X-ray powder diffraction pattern comprising peaks in 2θ at 8.1°, 10.1°, 10.7°, 11.7°, 13.7°, 14.6°, 19.1°, 20.0°, 20.8°, 21.5°, 21.9°, 23.4°, and 24.7°±0.2°.

24. The mesylate salt of claim 2, wherein the crystalline mesylate salt is crystalline Form H, characterized by an X-ray powder diffraction pattern comprising at least three or at least four peaks selected from 2θ of 19.1°, 20.0°, 21.5°, 21.9°, and 23.4°±0.2°.

25. The mesylate salt of claim 24, wherein the crystalline mesylate salt is in crystalline Form H, characterized by an X-ray powder diffraction pattern comprising peaks in 2θ at 19.1°, 20.0°, 21.5°, 21.9° and 23.4°±0.2°.

26. The mesylate salt of claim 24, wherein the crystalline mesylate salt is in crystalline Form H, characterized by an X-ray powder diffraction pattern comprising peaks in 2θ at 11.7°, 13.6°, 14.6°, 19.1°, 20.0°, 20.8°, 21.5°, 21.9°, 23.4°, 24.6° ± 0.2°.

27. The mesylate salt of claim 24, wherein the crystalline mesylate salt is crystalline Form H, characterized by comprising crystalline Form H having 2θ values ​​of 6.9°, 8.1°, 10.1°, 10.7°, 11.7°, 12.3°, 12.7°, 13.2°, 13.6°, 13.9°, 14.6°, 14.9°, 16.2°, 16.8°, 17.1°, 17.9°, 18.1°, 18.8°, 19.1°, 19.7°, 20.0°, 20.6°, 20.8°, 21.0°, 2 X-ray powder diffraction pattern of peaks at 1.5°, 21.9°, 22.1°, 22.8°, 23.2°, 23.4°, 24.1°, 24.3°, 24.6°, 25.4°, 25.6°, 26.4°, 26.8°, 27.1°, 27.8°, 28.2°, 29.0°, 29.6°, 30.0°, 31.2°, 31.8°, 32.1°, 32.6°, 33.3°, 34.0°, 34.3°, 34.8°, 35.6°, 37.3° and 38.7° ± 0.2°.

28. The mesylate salt of any one of claims 20-27, wherein the Form H is characterized by an X-ray powder diffraction pattern substantially similar to that of Figure 3A.

29. The mesylate salt of any one of claims 20-28, wherein the Form H is further characterized by a differential scanning calorimeter (DSC) thermogram comprising an endotherm with an onset at 220.5°C ± 2°C and an exotherm with an onset at 239.4°C ± 2°C.

30. The mesylate salt of any one of claims 20-29, wherein the Form H is further characterized by a thermogravimetric analysis (TGA) substantially similar to that of Figure 3B.

31. The mesylate salt of claim 2, wherein the crystalline mesylate salt is in crystalline Form I, characterized by an X-ray powder diffraction pattern comprising at least three or at least four peaks selected from 2θ of 11.0°, 18.7°, 20.6°, 22.2°, and 24.4°±0.2°.

32. The mesylate salt of claim 31 , wherein the crystalline mesylate salt is in crystalline Form I, characterized by an X-ray powder diffraction pattern comprising peaks in 2θ at 11.0°, 18.7°, 20.6°, 22.2° and 24.4°±0.2°.

33. The mesylate salt of claim 31 or 32, wherein the Form I is characterized by an X-ray powder diffraction pattern comprising peaks in 2θ at 8.6°, 11.0°, 16.7°, 18.7°, 19.3°, 20.6°, 21.6°, 22.2°, 24.2°, and 24.4°±0.2°.

34. The mesylate salt of claim 31, 32 or 33, wherein the Form I is characterized by an X-ray powder diffraction pattern comprising peaks in 2θ at 8.6°, 11.0°, 11.9°, 16.7°, 18.7°, 19.3°, 20.6°, 21.6°, 22.2°, 24.2° and 24.4° ± 0.2°.

35. The mesylate salt of claim 2, wherein the crystalline mesylate salt is in crystalline Form I, characterized by an X-ray powder diffraction pattern comprising at least three or at least four peaks selected from 2θ of 8.5°, 18.7°, 20.6°, 21.5°, and 24.4°±0.2°.

36. The mesylate salt of claim 35, wherein the crystalline mesylate salt is in crystalline Form I, characterized by an X-ray powder diffraction pattern comprising peaks in 2θ at 8.5°, 18.7°, 20.6°, 21.5° and 24.4°±0.2°.

37. The mesylate salt of claim 35, wherein the crystalline mesylate salt is in crystalline Form I, characterized by an X-ray powder diffraction pattern comprising peaks in 2θ at 8.5°, 10.9°, 16.7°, 18.7°, 19.2°, 20.6°, 21.5°, 22.1°, 24.1°, and 24.4° ± 0.2°.

38. The mesylate salt of claim 35, wherein the crystalline mesylate salt is in crystalline Form I, characterized by comprising crystalline crystalline Form I in the form of 6.8°, 8.5°, 10.9°, 11.7°, 11.9°, 13.5°, 14.6°, 15.2°, 16.7°, 17.6°, 17.9°, 18.7°, 19.2°, 19.5°, 19.6°, 20.3°, 20.6°, 2 X-ray powder diffraction pattern of peaks at 1.0°, 21.5°, 21.7°, 22.0°, 22.1°, 22.7°, 23.7°, 24.1°, 24.4°, 24.9°, 25.4°, 25.7°, 25.8°, 26.2°, 26.8°, 28.0°, 29.4°, 30.0°, 31.0°, 32.7°, 33.1°, 33.5° and 35.7°±0.2°.

39. The mesylate salt of any one of claims 31-38, wherein the Form I is characterized by an X-ray powder diffraction pattern substantially similar to that of Figure 4A.

40. The mesylate salt of any one of claims 31-39, wherein the Form I is further characterized by a differential scanning calorimeter (DSC) thermogram comprising an endotherm onset at 33.2°C ± 2°C, an endotherm onset at 210.4°C ± 2°C, and an exotherm onset at 229.1°C ± 2°C.

41. The mesylate salt of any one of claims 31-40, wherein the Form I is further characterized by a thermogravimetric analysis (TGA) substantially similar to that of Figure 4B.

42. Crystalline Form A of Compound (I) represented by the following structural formula: wherein Form A is characterized by an X-ray powder diffraction pattern comprising peaks at 5.7°, 6.0°, and 6.2°±0.2 in 2θ.

43. The crystalline Form A of claim 42, wherein the Form A is characterized by an X-ray powder diffraction pattern comprising at least three or at least four peaks selected from 2θ of 5.7°, 6.0°, 6.2°, 6.5°, and 19.6°±0.2°.

44. The crystalline Form A of claim 42, wherein the Form A is characterized by an X-ray powder diffraction pattern comprising peaks in 2θ at 5.7°, 6.0°, 6.2°, 6.5°, and 19.6°±0.2°.

45. The crystalline Form A of claim 42, wherein the Form A is characterized by an X-ray powder diffraction pattern comprising peaks in 2θ at 5.7°, 6.0°, 6.2°, 6.5°, 16.9°, 19.6°, 22.4°, 23.7°, 24.9°, and 25.2° ± 0.2°.

46. ​​The crystalline Form A of claim 42, wherein the Form A is characterized by an X-ray powder diffraction pattern comprising peaks in 2θ at 5.7°, 6.0°, 6.2°, 6.5°, 9.7°, 13.0°, 15.8°, 16.9°, 17.1°, 17.3°, 18.8°, 19.5°, 19.6°, 22.4°, 22.7°, 23.7°, 24.9°, and 25.2° ± 0.2°.

47. The crystalline Form A of any one of claims 42-46, wherein the Form A is characterized by an X-ray powder diffraction pattern substantially similar to that of Figure 5A.

48. The crystalline Form A of any one of claims 42-47, wherein the Form A is further characterized by a differential scanning calorimeter (DSC) thermogram comprising an endotherm with an onset at 263.3°C ± 2°C.

49. The crystalline Form A of any one of claims 42-48, wherein the Form A is further characterized by a thermogravimetric analysis (TGA) substantially similar to that of Figure 5B.

50. Crystalline Form B of Compound (I) represented by the following structural formula: wherein Form B is characterized by an X-ray powder diffraction pattern comprising at least three or at least four peaks in 2θ at 5.2°, 5.3°, 6.1°, 18.5°, and 24.4°±0.2°.

51. The crystalline Form B of claim 30, wherein the Form B is characterized by an X-ray powder diffraction pattern comprising peaks in 2θ at 5.2°, 5.3°, 6.1°, 18.5°, and 24.4° ± 0.2°.

52. The crystalline Form B of claim 50 or 51, wherein the Form B is characterized by an X-ray powder diffraction pattern comprising peaks in 2θ at 5.2°, 5.3°, 6.1°, 15.6°, 18.5°, 18.7°, 19.5°, 22.5°, 24.4° and 26.1° ± 0.2°.

53. The crystalline Form B of claim 50, 51 or 52, wherein the Form B is characterized by an X-ray powder diffraction pattern comprising peaks in 2θ at 5.2°, 5.3°, 6.1°, 8.1°, 9.1°, 13.8°, 14.2°, 15.6°, 16.6°, 17.3°, 18.5°, 18.7°, 19.5°, 21.9°, 22.5°, 23.1°, 24.4°, 24.9°, 25.4°, 26.1°, 26.2°, 26.6° and 27.1° ± 0.2°.

54. The crystalline Form B of any one of claims 50-53, wherein the Form B is characterized by an X-ray powder diffraction pattern substantially similar to that of Figure 6A.

55. The crystalline Form B of any one of claims 50-54, wherein the Form B is further characterized by a differential scanning calorimeter (DSC) thermogram comprising an endotherm with an onset at 262.2°C ± 2°C.

56. A pharmaceutical composition comprising the mesylate salt of any one of claims 1-41 or the crystalline form of any one of claims 42-55 and a pharmaceutically acceptable carrier.

57. A method of treating a disease associated with an epidermal growth factor receptor (EGFR) family kinase in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the mesylate salt of any one of claims 1-41 or the crystalline form of any one of claims 42-55.

58. The method of claim 57, wherein the disease in the subject is characterized by an EGFR mutation.

59. The method of claim 58, wherein the EGFR mutation comprises a substitution in exon 18, a deletion in exon 19, a substitution in exon 20, an insertion in exon 20, a mutation in the extracellular domain, or a substitution in exon 21.

60. The method of claim 59, wherein the EGFR mutation is selected from del19 / T790M EGFR, L858R / T790M EGFR, L858R EGFR, L861Q EGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVD EGFR, 770insNPG EGFR, 770insGT EGFR, 770insGF EGFR, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773insNPHEGFR, 773insH EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupASV EGFR, 773insAHEGFR, M766_A767insAI EGFR and any combination thereof.

61. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the mesylate salt of any one of claims 1-41 or the crystalline form of any one of claims 42-55.

62. The method of claim 61, wherein the cancer is bladder cancer, prostate cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, glioblastoma, head and neck cancer, lung cancer, urothelial carcinoma, sinus cancer, or non-small cell lung cancer.

63. The method of claim 62, wherein the cancer is non-small cell lung cancer, prostate cancer, head and neck cancer, breast cancer, colorectal cancer, or glioblastoma.

64. The method of any one of claims 61-63, wherein the cancer in the subject is characterized by an EGFR mutation.

65. The method of claim 64, wherein the EGFR mutation comprises a substitution in exon 18, a deletion in exon 19, a substitution in exon 20, an insertion in exon 20, a mutation in the extracellular domain, or a substitution in exon 21.

66. The method of claim 65, wherein the EGFR mutation is selected from del19 / T790M EGFR, L858R / T790M EGFR, L858R EGFR, L861Q EGFR, S768I EGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVD EGFR, 770insNPG EGFR, 770insGT EGFR, 770insGF EGFR, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNPEGFR, 773insNPH EGFR, 773insH EGFR, 773insPH EGFR EGFR, EGFRvii, EGFRviii, A767_dupASVEGFR, 773insAH EGFR, M766_A767insAI EGFR, and any combination thereof.

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