Salt and Crystal Forms of an Epidermal Growth Factor Receptor Inhibitor

Abstract

Disclosed are various salt forms and free base solid forms of compound (I) represented by the following formula. JPEG2025517634000052.jpg5680 Also disclosed are pharmaceutical compositions containing the same, methods for treating epithelial growth factor receptor (EGFR) family kinase-related diseases using the same, and methods for producing salt forms and crystalline forms of compound (I).

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of U.S. Provisional Application No. 63 / 338,371, filed May 4, 2022, the content of which is incorporated herein by reference.

Background Art

[0002] Lung cancer is the second most common cancer worldwide and a major cause of cancer - related death. In 2020, lung cancer accounted for over 2 million new cancer diagnoses and over 1 million deaths worldwide. Non - small cell lung cancer (NSCLC) accounts for approximately 80% of all lung cancers, and adenocarcinoma is the most common histological type. The most common causes of lung cancer are smoking and exposure to other environmental toxins, but oncogenic driver mutations are frequently present, providing opportunities for targeted therapy.

[0003] The epidermal growth factor receptor (EGFR) is a transmembrane receptor tyrosine kinase activated by epidermal growth factor ligands. In NSCLC and certain other subsets of tumors, specific mutations in the EGFR gene activate ligand - independent receptors, promoting uncontrolled survival and proliferation of tumor cells. The incidence of EGFR mutations in NSCLC varies by region and ethnicity. According to 2021 studies, EGFR mutations are most common in adenocarcinoma, which accounts for approximately 40% of all lung cancers and is more prevalent in women, Asian populations, and non - smokers. EGFR - related lung cancer is prone to CNS metastasis, with brain metastases seen in approximately 25% of patients at initial presentation and up to 50% at some point during the course of the disease.

[0004] Comprehensive genomic profiling of 14,483 tumor samples from NSCLC cases during the clinical treatment process identified 2,251 cases with EGFR mutations. EGFR exon 19 deletion (47%) and EGFR L858R (32%) were the most common EGFR mutations. Rare EGFR mutations such as G719X (4%), L861Q (2%), and S768I (1%), as well as cases with complex EGFR activating mutations (2%) were identified. Exon 20 was inserted in 263 of the 2,251 mutated EGFR cases, which corresponds to 12% of all EGFR-mutated NSCLC and 1.8% of all NSCLC, and is the third most common type of oncogenic EGFR mutation (Riess JW, et al. J Thorac Oncol. 2018;13:1560-8).

[0005] Epidermal growth factor receptor exon 20 insertion mutation (Ex20in) is characterized by an in-frame mutation that results in the insertion of 1 to 7 amino acids over a span of approximately 15 amino acids. In addition to NSCLC, EGFR Ex20in is found in a small subset of urothelial carcinoma and endometrial carcinoma, glioblastoma, paranasal sinus carcinoma, and pediatric anaplastic glioma. Similar to other EGFR-mutated NSCLC, approximately one-fourth of patients with EGFR Ex20in have brain metastases at the time of initial presentation.

[0006] Due to its unique structural features, EGFR Ex20ins is generally insensitive to the first three generations of EGFR tyrosine kinase inhibitors (TKIs). Therefore, the first-line standard treatment for metastatic disease remains platinum-based chemotherapy. The role of immune checkpoint inhibitors remains poorly defined. For patients with EGFR Ex20ins who progress after platinum-based chemotherapy, the standard treatment has recently changed with the approval of two drugs, amivantamab and mobocertinib. Both drugs received early approval from the US FDA as treatments for NSCLC with EGFR Ex20ins that progressed during or after platinum-based chemotherapy. Although the development of targeted TKIs such as amivantamab and mobocertinib for NSCLC with EGFR mutations has led to a significant improvement in patient outcomes, there are still significant unmet needs, especially for EGFR Ex20ins patients. More than half of the patients treated with either amivantamab or mobocertinib in clinical trials did not achieve an objective response, and neither drug has yet shown a survival benefit. Furthermore, neither drug has shown meaningful CNS activity, and concerns remain regarding tolerability. Therefore, there is a need for an EGFR WT-sparing, EGFR Ex20ins-targeted TKI that is highly CNS-permeable, shows potent activity against various EGFR Ex20ins, and provides an improved side effect profile to address this still-unmet need.

[0007] International Patent Application No. PCT / US2021 / 057472, the entire teachings of which are incorporated herein by reference, discloses selective inhibitors of EGFR, including exon 20 mutant proteins that can be used in the treatment of various cancers. One of the inhibitors disclosed in PCT Patent Application No. PCT / US2021 / 057472 has a structure that is referred to herein as "Compound (I)" and is shown below.

Chemical Structure

[0008] There is a need to develop novel salt forms and / or solid forms of compound (I) that are suitable for large-scale manufacturing and commercialization. SUMMARY OF THE INVENTION

[0009] The present disclosure relates to i) novel pharmaceutically acceptable mesylates of compound (I) having different solid forms, and ii) novel crystalline free bases of compound (I) having different solid forms.

[0010] It has also been found that the 1:1 mesylate of compound (I) can be crystallized under well-defined conditions to obtain a desired crystal form with good thermal behavior accompanied by a high melting point onset and suitable for large-scale synthesis. Minimal mass loss was observed during thermogravimetric analysis.

[0011] Furthermore, four different crystal forms (Form A, Form B, Form H, and Form I) of the mesylate of compound (I) have been identified. Among these crystal forms, Form A, Form B, and Form H are anhydrates, and Form I is a hydrate.

[0012] Mesylate Forms B, H, and I have shown promising solid-state property evaluation results. They are stable up to 2 weeks at 25 °C / 60% relative humidity (RH), 40 °C / 75% RH, and 60 °C (>99.8% assay purity), suggesting that all three forms are physicochemically stable. See Examples 2 - 5.

[0013] In one aspect, the present disclosure provides a mesylate of compound (I) represented by the following structural formula,

Chemical formula

[0014] In another aspect, the present disclosure provides a crystalline mesylate of compound (I), and the crystalline mesylate is Form A.

[0015] In another aspect, the present disclosure provides a crystalline mesylate of compound (I), and the crystalline mesylate is crystalline form B.

[0016] In another aspect, the present disclosure provides a crystalline mesylate of compound (I), and the crystalline mesylate is crystalline form H.

[0017] In another aspect, the present disclosure provides a crystalline mesylate of compound (I), and the crystalline mesylate is crystalline form I.

[0018] 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".

[0019] 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".

[0020] In another aspect, the present disclosure provides a pharmaceutical composition comprising a mesylate of compound (I), or one of the mesylate crystal forms disclosed herein, or a crystal form of the free base of compound (I) disclosed herein, and a pharmaceutically acceptable carrier.

[0021] The present disclosure also provides a method of treating an EGFR-related disease in a subject in need of treatment, comprising administering a therapeutically effective amount of a mesylate of compound (I), or one of the mesylate crystal forms disclosed herein, or a crystalline polymorph of the free base of compound (I) as disclosed herein. In some embodiments, the disease in the subject is characterized by an EGFR mutation.

[0022] The present disclosure also provides a method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a mesylate salt of compound (I), or one of the crystalline forms of the mesylate salts disclosed herein, or a crystalline polymorph of the 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 cancer, paranasal sinus cancer, or non-small cell lung cancer. In some embodiments, the cancer in the subject is characterized by an EGFR mutation.

[0023] The present disclosure also provides the use of a salt or free base of a compound (I) of the present disclosure or a pharmaceutical composition thereof containing the same for the treatment of any of the diseases listed in the previous paragraph. In one embodiment, there is provided a salt or free base of the present disclosure or a pharmaceutical composition thereof containing the same for use in any of the methods of the present disclosure described herein. In another embodiment, there is provided the use of a salt or free base of the present disclosure or a pharmaceutical composition thereof containing the same for the manufacture of a medicament for any of the methods of the present disclosure described herein.

Brief Description of the Drawings

[0024]

Figure 1A

Figure 1B

Figure 2A

Figure 2B

Figure 3A

Figure 3B

Figure 4A

Figure 4B

Figure 5A

Figure 5B

Figure 6A

Figure 6B

Figure 7

Mode for Carrying Out the Invention

[0025] The present disclosure relates to mesylate salts of compound (I) having different solid forms and crystalline forms of the free base of compound (I) having different solid forms. [Chemical formula]

[0026] As used herein, "crystal" refers to a solid having a crystalline structure in which individual molecules have a highly homogeneous regular three-dimensional arrangement.

[0027] In some embodiments, for the crystalline forms of the salts or free bases of compound (I) disclosed herein, at least a certain weight percentage of the salts or free bases of compound (I) are in a particular crystalline form. Particular weight percentages include 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% of the weight of the salt or free base of compound (I), or 70% - 75%, 75% - 80%, 80% - 85%, 85% - 90%, 90% - 95%, 95% - 100%, 70 - 80%, 80 - 90%, 90 - 100% being in a particular crystalline form. It should be understood that all values and ranges between these values and ranges are intended to be encompassed by the present disclosure.

[0028] When the salt or free base of crystalline compound (I) is defined as one particular crystalline form of the salt or free base of compound (I) in the specified proportion, the remainder is composed of amorphous forms and / or crystalline forms other than the one or more specified particular forms.

[0029] The salts of crystalline compound (I) disclosed herein exhibit a strong and unique XRPD pattern with sharp peaks corresponding to peak positions at an angle of 2θ and a flat baseline, indicating a highly crystalline material (see, for example, FIG. 1A).

[0030] As used herein, an X-ray powder diffractogram is "substantially similar to that of [a specific] figure" when at least 90%, such as at least 95%, at least 98%, or at least 99% of the signals in two diffractograms are the same at ±0.2° 2θ. When determining "substantial similarity", one of ordinary skill in the art will understand that even for the same crystal form, there may be variations in the intensity and / or signal position in the XRPD diffractogram. Thus, one of ordinary skill in the art will understand that the signal maximum value (°2θ as referred to herein) in the XRPD diffractogram generally means the reported value ±0.2° 2θ (the dispersion value recognized in the above technical field). In some embodiments, when the crystal form is characterized by XRPD peaks having specific values, one of ordinary skill in the art will understand that, unless otherwise specified, the peak values can be ±0.4, ±0.3, ±0.2, or ±0.1° 2θ of the reported value.

[0031] Mesylate of compound (I) In one aspect, the present disclosure provides

Chemical formula

[0032] In some embodiments, the mesylate is a crystalline mesylate. In some embodiments, the mesylate is in a single crystal form.

[0033] In some embodiments, the mesylate is not solvated. In other embodiments, the mesylate is solvated.

[0034] The mesylate of compound (I) with a molar ratio of 1:1 between compound (I) and methanesulfonic acid can be easily prepared by mixing the free base of compound (I) with about 1 to 1.1 equivalents of methanesulfonic acid in a suitable solvent (such as acetone, THF). The mixture can be heated to obtain the desired yield.

[0035] Mesylate Form A In some embodiments, the disclosure provides crystalline Form A of the mesylate salt of Compound (I), wherein the molar ratio of Compound (I) to methanesulfonic acid is 1: 1. In some embodiments, crystalline Form A of the mesylate salt of Compound (I) is anhydrous.

[0036] The XRPD pattern and peaks are shown in FIG. 1A, and the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms are shown in FIG. 1B. [Table 1]

[0037] In Table 1, only peaks with a relative intensity of 5 or greater compared to the absolute intensity (I.(cps°)) of the most intense peak are reported. [Table 2] [Table 3] [Table 4]

[0038] In some embodiments, Form A of the mesylate salt is characterized by an X-ray powder diffraction pattern comprising at least three, at least four, or at least five peaks selected from 5.9°, 7.2°, 11.9°, 12.1°, 19.3°, and 20.1°±0.2° in degrees 2θ.

[0039] In some embodiments, Form A of the mesylate salt is characterized by an X-ray powder diffraction pattern comprising peaks at 5.9°, 7.2°, 11.9°, 12.1°, 19.3°, and 20.1°±0.2° in degrees 2θ.

[0040] In some embodiments, Form A of the mesylate salt 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 at 5.9°, 7.2°, 11.9°, 12.1°, 13.4°, 19.3°, 20.1°, 21.7°, 24.1°, and 27.6°±0.2° in angle 2θ.

[0041] In some embodiments, Form A of the mesylate salt is characterized by an X-ray powder diffraction pattern comprising peaks at 5.9°, 7.2°, 11.9°, 12.1°, 13.4°, 19.3°, 20.1°, 21.7°, 24.1°, and 27.6°±0.2° in degrees 2θ.

[0042] In some embodiments, Form A of the mesylate salt is characterized by an X-ray powder diffraction pattern comprising at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, or at least 13 peaks 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° in angle 2θ.

[0043] In some embodiments, Form A of the mesylate salt is characterized by an X-ray powder diffraction pattern comprising peaks 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° in degrees 2θ.

[0044] In some embodiments, Form A of the mesylate salt is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 1A.

[0045] In some embodiments, the mesylate of Form A is characterized by a differential scanning calorimetry (DSC) thermogram that includes two endothermic and exothermic events, namely, an endotherm with an onset at 202.8 °C ± 2 °C and an exotherm with an onset at 206.9 °C ± 2 °C. In some embodiments, the mesylate of Form A is characterized by a differential scanning calorimetry (DSC) thermogram that is substantially the same as that of Figure 1B.

[0046] In some embodiments, the mesylate of Form A is characterized by a thermogravimetric analysis (TGA) that is substantially the same as that of Figure 1B.

[0047] Mesylate of Form B In some embodiments, the present disclosure provides a crystalline Form B of the mesylate of compound (I), wherein the molar ratio of compound (I) to methanesulfonic acid is 1:1. In some embodiments, the crystalline Form B of the mesylate of compound (I) is an anhydrate.

[0048] The XRPD pattern and peaks are shown in Figure 2A, and the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms are shown in Figure 2B. [Table 5] [Table 6]

[0049] In Tables 5a and 5b, only peaks with a relative intensity of 5 or more compared to the absolute intensity (I. (cps°)) of the strongest peak are reported. Tables 5a and 5b are XRPD peaks obtained from two different batches of the crystalline Form B of the mesylate of compound (I). Tables 6a and 7a are a simplified peak list selected from Table 5a, and Tables 6b and 7b are a simplified peak list selected from Table 5b. [Table 7] [Table 8]

Table 9

Table 10

[0050] In some embodiments, the mesylate salt of 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° at 2θ. In some embodiments, Form B of the mesylate salt is characterized by an X-ray powder diffraction pattern comprising peaks at 18.5°, 19.8°, 20.8°, 22.4°, and 24.9° at 2θ.

[0051] In some embodiments, the mesylate salt of 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° ± 0.2° at 2θ.

[0052] In some embodiments, Form B of the mesylate salt is characterized by an X-ray powder diffraction pattern comprising peaks at 18.5°, 19.8°, 20.8°, 22.4°, and 24.9° ± 0.2° at 2θ.

[0053] In some embodiments, Form B of the mesylate salt 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 at 2θ of 8.9°, 11.3°, 18.5°, 19.8°, 20.8°, 21.4°, 22.4°, 24.9°, and 25.9° ± 0.2°.

[0054] In some embodiments, the mesylate salt of Form B is characterized by an X-ray powder diffraction pattern comprising peaks at 2θ of 8.9°, 11.3°, 18.5°, 19.8°, 20.8°, 21.4°, 22.4°, 24.9°, and 25.9° ± 0.2°.

[0055] In some embodiments, the mesylate of 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° at 2θ. In some embodiments, Form B of the mesylate is characterized by an X-ray powder diffraction pattern comprising peaks at 18.4°, 19.7°, 21.3°, 22.4°, 24.8° at 2θ.

[0056] In some embodiments, the mesylate of 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° ± 0.2° at 2θ.

[0057] In some embodiments, Form B of the mesylate is characterized by an X-ray powder diffraction pattern comprising peaks at 18.4°, 19.7°, 21.3°, 22.4°, 24.8° ± 0.2° at 2θ.

[0058] In some embodiments, the mesylate of 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 at 2θ of 8.8°, 11.3°, 18.4°, 19.7°, 20.6°, 20.8°, 21.3°, 22.0°, 22.4°, and 24.8° ± 0.2°.

[0059] In some embodiments, Form B of the mesylate is characterized by an X-ray powder diffraction pattern comprising peaks at 2θ of 8.8°, 11.3°, 18.4°, 19.7°, 20.6°, 20.8°, 21.3°, 22.0°, 22.4°, and 24.8° ± 0.2°.

[0060] In some embodiments, Form B of the mesylate salt is characterized by an X-ray powder diffraction pattern comprising peaks at 2θ of 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°.

[0061] In some embodiments, the mesylate salt of Form B is characterized by an X-ray powder diffraction pattern comprising 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°, 19.7°, 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°. In some embodiments, the mesylate salt of Form B is characterized by an X-ray powder diffraction pattern substantially the same as that of Figure 2A.

[0062] In some embodiments, the mesylate salt of Form B is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic onset at 247.8°C ± 2°C. In some embodiments, the mesylate salt of Form B is characterized by a differential scanning calorimetry (DSC) thermogram substantially the same as that of Figure 2B.

[0063] In some embodiments, the mesylate salt of Form B is characterized by a thermogravimetric analysis (TGA) substantially the same as that of Figure 2B.

[0064] In some embodiments, the mesylate of Form B is characterized by a differential scanning calorimetry (DSC) thermogram that includes an endothermic onset at 250.1 °C ± 2 °C. In some embodiments, the DSC thermogram further includes an exothermic onset at 254.1 °C ± 2 °C. In some embodiments, DSC was performed using a sealed aluminum pan with pinholes.

[0065] In some embodiments, the mesylate of Form B is prepared by crystallization from acetone. In some embodiments, the mesylate of Form B is prepared by mixing the free base of Compound (I) and methanesulfonic acid in acetone at an elevated temperature (e.g., 40 °C to 70 °C, 40 °C to 65 °C, 45 °C to 55 °C, or 50 °C to 60 °C, etc.) (e.g., in an amount of 1 to 1.5, 1 to 1.4, 1 to 1.2, or 1 to 1.1 molar equivalents relative to Compound (I)), followed by cooling the mixture to form the mesylate of Form B. In some embodiments, the mixture is cooled to below ambient temperature, e.g., 5 °C to 25 °C, 5 °C to 15 °C, 15 °C to 25 °C, etc. In some embodiments, the mesylate of Form B is prepared by (i) mixing the free base of Compound (I) and a small amount of methanesulfonic acid at an elevated temperature (e.g., 40 °C to 70 °C, 40 °C to 65 °C, 45 °C to 55 °C, or 50 °C to 60 °C, etc.) (e.g., 0.1 to 0.5 molar equivalents relative to Compound (I)), (ii) adding seed crystals of Form B of the mesylate, (iii) adding the remainder of the methanesulfonic acid (e.g., 0.6 to 1.0 molar equivalents), and (iv) cooling the mixture to form the mesylate of Form B. In some embodiments, the mixture is cooled to below ambient temperature, e.g., 5 °C to 25 °C, 5 °C to 15 °C, 15 °C to 25 °C, etc. In some embodiments, the mesylate of Form B formed from the above method is washed with acetone and dried at an elevated temperature (e.g., 40 °C to 70 °C, 40 °C to 65 °C, 45 °C to 55 °C, or 50 °C to 60 °C, etc.). In some embodiments, the above-described method for preparing Form B of the mesylate can be performed in a mixture of acetone and a small amount of water (e.g., 1 to 5%) instead of acetone.

[0066] The mesylate of Form H In some embodiments, the present disclosure provides crystalline form H of the mesylate salt of compound (I), wherein the molar ratio of compound (I) to methanesulfonic acid is 1:1. In some embodiments, crystalline form H of the mesylate salt of compound (I) is an anhydride.

[0067] The XRPD pattern and peaks are shown in FIG. 3A, and the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms are shown in FIG. 3B.

Table 11-1

Table 11-2

Table 12-1

Table 12-2

[0068] In Tables 8a and 8b, only the peaks with a relative intensity of 5 or more compared to the absolute intensity (I.(cps°)) of the strongest peak 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 Table 8a, and Tables 9b and 10b are simplified peak lists selected from Table 8b.

Table 13

Table 14

Table 15

Table 16

[0069] In some embodiments, the mesylate salt of Form H is characterized by an X-ray powder diffraction pattern comprising at least 3, at least 4, or at least 5 peaks selected from 13.7°, 19.1°, 20.0°, 21.5°, 21.9°, and 23.4° at 2θ. In some embodiments, the mesylate salt of 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° at 2θ.

[0070] In some embodiments, the mesylate salt of Form H is characterized by an X-ray powder diffraction pattern comprising at least 3, at least 4, or at least 5 peaks selected from 13.7°, 19.1°, 20.0°, 21.5°, 21.9°, and 23.4° ± 0.2° at 2θ.

[0071] In some embodiments, the mesylate salt of 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° ± 0.2° at 2θ.

[0072] In some embodiments, the mesylate salt of Form H is characterized by an X-ray powder diffraction pattern comprising at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, or at least 9 peaks at 8.1°, 10.1°, 11.7°, 13.7°, 19.1°, 20.0°, 20.8°, 21.5°, 21.9°, and 23.4° ± 0.2° at 2θ.

[0073] In some embodiments, the mesylate salt of Form H is characterized by an X-ray powder diffraction pattern comprising peaks at 8.1°, 10.1°, 11.7°, 13.7°, 19.1°, 20.0°, 20.8°, 21.5°, 21.9°, and 23.4° ± 0.2° at 2θ.

[0074] In some embodiments, the mesylate salt of Form H is characterized by an X-ray powder diffraction pattern comprising at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, or at least 12 peaks at 2θ of 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°.

[0075] In some embodiments, the mesylate salt of Form H is characterized by an X-ray powder diffraction pattern comprising peaks at 2θ of 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°.

[0076] In some embodiments, the mesylate salt of Form H is characterized by an X-ray powder diffraction pattern comprising at least 3 or at least 4 peaks selected from 19.1°, 20.0°, 21.5°, 21.9°, and 23.4° at 2θ. In some embodiments, the mesylate salt of Form H is characterized by an X-ray powder diffraction pattern comprising peaks at 2θ of 19.1°, 20.0°, 21.5°, 21.9°, and 23.4°.

[0077] In some embodiments, the mesylate salt of Form H is characterized by an X-ray powder diffraction pattern comprising at least 3 or at least 4 peaks selected from 19.1°, 20.0°, 21.5°, 21.9°, and 23.4° ± 0.2° at 2θ.

[0078] In some embodiments, the mesylate salt of Form H is characterized by an X-ray powder diffraction pattern comprising peaks at 2θ of 19.1°, 20.0°, 21.5°, 21.9°, and 23.4° ± 0.2°.

[0079] In some embodiments, the mesylate salt of Form H is characterized by an X-ray powder diffraction pattern comprising at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, or at least 9 peaks at 2θ of 11.7°, 13.6°, 14.6°, 19.1°, 20.0°, 20.8°, 21.5°, 21.9°, 23.4°, 24.6° ± 0.2°.

[0080] In some embodiments, the mesylate salt of Form H is characterized by an X-ray powder diffraction pattern comprising peaks at 2θ of 11.7°, 13.6°, 14.6°, 19.1°, 20.0°, 20.8°, 21.5°, 21.9°, 23.4°, 24.6° ± 0.2°.

[0081] In some embodiments, the mesylate salt of Form H is characterized by an X-ray powder diffraction pattern comprising peaks at 2θ 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°.

[0082] In some embodiments, the mesylate of Form H is characterized by an X-ray powder diffraction pattern that includes peaks at 2θ 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°, 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°.

[0083] In some embodiments, the mesylate of Form H is characterized by an X-ray powder diffraction pattern that is substantially similar to that of FIG. 3A.

[0084] In some embodiments, the mesylate of Form H is characterized by a differential scanning calorimetry (DSC) thermogram that includes an endothermic onset at 220.5°C ± 2°C and an exothermic onset at 239.4°C ± 2°C. In some embodiments, the mesylate of Form H is characterized by a differential scanning calorimetry (DSC) thermogram that is substantially similar to that of FIG. 3B.

[0085] In some embodiments, the mesylate of Form H is characterized by a thermogravimetric analysis (TGA) that is substantially similar to that of FIG. 3B.

[0086] In some embodiments, the mesylate of Form H is characterized by a differential scanning calorimetry (DSC) thermogram that includes an endothermic onset at 228.7°C ± 2°C. In some embodiments, DSC was performed using a sealed aluminum pan with pinholes.

[0087] The mesylate of Form I In some embodiments, the present disclosure provides crystalline Form I of the mesylate salt of Compound (I), wherein the molar ratio of Compound (I) to methanesulfonic acid is 1:1. In some embodiments, crystalline Form I of the mesylate salt of Compound (I) is a hydrate.

[0088] The XRPD pattern and peaks are shown in Figure 4A, and the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms are shown in Figure 4B. [Table 17] [Table 18-1] [Table 18-2]

[0089] In Tables 11a and 11b, only peaks with a relative intensity of 5 or more compared to the absolute intensity (I.(cps°)) of the strongest peak are reported. Tables 11a and 11b are XRPD peaks obtained from two different batches of crystalline Form I of the mesylate salt of Compound (I). Table 12a is a reduced peak list selected from Table 11a, and Tables 12b and 12c are reduced peak lists selected from Table 11b. [Table 19] [Table 20] [Table 21]

[0090] In some embodiments, the mesylate salt of 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°.

[0091] In some embodiments, the mesylate of Form I is characterized by an X-ray powder diffraction pattern comprising peaks at 2θ of 11.0°, 18.7°, 20.6°, 22.2°, and 24.4° ± 0.2°.

[0092] In some embodiments, the mesylate of Form I is characterized by an X-ray powder diffraction pattern comprising at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, or at least 9 peaks at 2θ of 8.6°, 11.0°, 16.7°, 18.7°, 19.3°, 20.6°, 21.6°, 22.2°, 24.2°, and 24.4° ± 0.2°.

[0093] In some embodiments, the mesylate of Form I is characterized by an X-ray powder diffraction pattern comprising peaks at 2θ of 8.6°, 11.0°, 16.7°, 18.7°, 19.3°, 20.6°, 21.6°, 22.2°, 24.2°, and 24.4° ± 0.2°.

[0094] In some embodiments, the mesylate of Form I is characterized by an X-ray powder diffraction pattern comprising at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 peaks at 2θ of 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°.

[0095] In some embodiments, the mesylate of Form I is characterized by an X-ray powder diffraction pattern comprising peaks at 2θ of 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°.

[0096] In some embodiments, the mesylate of 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° at 2θ.

[0097] In some embodiments, the mesylate of Form I is characterized by an X-ray powder diffraction pattern comprising peaks at 8.5°, 18.7°, 20.6°, 21.5°, and 24.4° ± 0.2° at 2θ.

[0098] In some embodiments, the mesylate of 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 at 8.5°, 10.9°, 16.7°, 18.7°, 19.2°, 20.6°, 21.5°, 22.1°, 24.1°, and 24.4° ± 0.2° at 2θ.

[0099] In some embodiments, the mesylate of Form I is characterized by an X-ray powder diffraction pattern comprising peaks at 8.5°, 10.9°, 16.7°, 18.7°, 19.2°, 20.6°, 21.5°, 22.1°, 24.1°, and 24.4° ± 0.2° at 2θ.

[0100] In some embodiments, the mesylate of Form I is characterized by an X-ray powder diffraction pattern comprising peaks at 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°, 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° at 2θ.

[0101] In some embodiments, the mesylate salt of Form I is characterized by an X-ray powder diffraction pattern substantially similar to that of Figure 4A.

[0102] In some embodiments, the mesylate salt of Form I is characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic onset at 33.2° ± 2 °C, an endothermic onset at 210.4° ± 2 °C, and an exothermic onset at 229.1° ± 2 °C. In some embodiments, the mesylate salt of Form I is characterized by a differential scanning calorimetry (DSC) thermogram substantially similar to that of Figure 4B.

[0103] In some embodiments, the mesylate salt of Form I is characterized by a thermogravimetric analysis (TGA) substantially similar to that of Figure 4B.

[0104] In some embodiments, the mesylate salt of Form I is characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic onset at 221.3° ± 2 °C. In some embodiments, the DSC thermogram further includes an endothermic onset at 34.3° ± 2 °C. In some embodiments, DSC was performed using a sealed aluminum pan with a pinhole.

[0105] Free base of compound (I) In one aspect, the present disclosure provides the free base of compound (I).

Chemical formula

[0106] In some embodiments, the free base of compound (I) is in an amorphous form.

[0107] In some embodiments, the free base of compound (I) is crystalline. In some embodiments, the free base of compound (I) is in a single crystal form.

[0108] In some embodiments, the free base of compound (I) is not solvated. In other embodiments, the free base of compound (I) is solvated.

[0109] Free base crystalline form A In some embodiments, the present disclosure provides crystalline form A of the free base of compound (I). In some embodiments, crystalline form A of the free base of compound (I) is an anhydrate.

[0110] The XRPD pattern and peaks are shown in Figure 5A, and the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms are shown in Figure 5B. [Table 22] [Table 23]

[0111] In Tables 13a and 13b, only peaks with a relative intensity of 5 or more compared to the absolute intensity (I.(cps°)) of the strongest peak are reported. Tables 13a and 13b are XRPD peaks obtained from two different batches of crystalline form A of the free base of compound (I). Tables 13c and 13d are a reduced peak list selected from Table 13b. [Table 24] [Table 25]

[0112] In some embodiments, crystalline form A of the free base is characterized by an X-ray powder diffraction pattern that includes peaks at 2θ of 5.7°, 6.0°, and 6.2° ± 0.2.

[0113] In some embodiments, the crystalline form A of the free base is characterized by an X-ray powder diffraction pattern comprising at least three or at least four peaks selected from 5.7°, 6.0°, 6.2°, 6.5°, and 19.6° ± 0.2° in 2θ.

[0114] In some embodiments, the crystalline form A of the free base is characterized by an X-ray powder diffraction pattern comprising peaks at 5.7°, 6.0°, 6.2°, 6.5°, and 19.6° ± 0.2 in 2θ.

[0115] In some embodiments, the crystalline form A of the free base 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 at 5.7°, 6.0°, 6.2°, 6.5°, 16.9°, 19.6°, 22.4°, 23.7°, 24.9°, and 25.2° ± 0.2° in 2θ.

[0116] In some embodiments, the crystalline form A of the free base is characterized by an X-ray powder diffraction pattern comprising peaks at 5.7°, 6.0°, 6.2°, 6.5°, 16.9°, 19.6°, 22.4°, 23.7°, 24.9°, and 25.2° ± 0.2° in 2θ.

[0117] In some embodiments, the crystalline form A of the free base is characterized by an X-ray powder diffraction pattern comprising peaks 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° in 2θ.

[0118] In some embodiments, the crystalline form A of the free base is characterized by an X-ray powder diffraction pattern substantially the same as that of FIG. 5A.

[0119] In some embodiments, the crystalline form A of the free base is characterized by a differential scanning calorimetry (DSC) thermogram that includes an endothermic onset at 263.3 °C ± 2 °C. In some embodiments, the crystalline form A of the free base is characterized by a differential scanning calorimetry (DSC) thermogram substantially similar to FIG. 5B. In some embodiments, the DSC thermogram further includes an endothermic onset at 156.5 °C ± 2 °C. In some embodiments, DSC was performed using a sealed aluminum pan with a pinhole.

[0120] In some embodiments, the crystalline form A of the free base is characterized by a thermogravimetric analysis (TGA) substantially similar to FIG. 5B.

[0121] Crystalline form B of the free base In some embodiments, the present disclosure provides a crystalline form B of the free base of compound (I). In some embodiments, the crystalline form B of the free base of compound (I) is a hydrate.

[0122] The XRPD pattern and peaks are shown in FIG. 6A. [Table 26] [Table 27]

[0123] In Tables 14a and 14b, only peaks with a relative intensity of 5 or more compared to the absolute intensity (I. (cps°)) of the strongest peak are reported. Tables 14a and 14b are XRPD peaks obtained from two different batches of the free base form B of compound (I). Tables 15a and 16a are reduced peak lists selected from Table 14a, and Tables 15b and 16b are reduced peak lists selected from Table 14b. [Table 28] [Table 29]

Table 30

Table 31

[0124] In some embodiments, the crystalline form B of the free base is characterized by an X-ray powder diffraction pattern comprising at least three or at least four peaks selected from 5.2°, 5.3°, 6.1°, 18.5°, and 24.4° ± 0.2° in 2θ.

[0125] In some embodiments, the crystalline form B of the free base is characterized by an X-ray powder diffraction pattern comprising peaks at 5.2°, 5.3°, 6.1°, 18.5°, and 24.4° ± 0.2° in 2θ.

[0126] In some embodiments, the crystalline form B of the free base 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 at 5.2°, 5.3°, 6.1°, 15.6°, 18.5°, 18.7°, 19.5°, 22.5°, 24.4°, and 26.1° ± 0.2° in 2θ.

[0127] In some embodiments, the crystalline form B of the free base is characterized by an X-ray powder diffraction pattern comprising peaks at 5.2°, 5.3°, 6.1°, 15.6°, 18.5°, 18.7°, 19.5°, 22.5°, 24.4°, and 26.1° ± 0.2 in 2θ.

[0128] In some embodiments, the crystalline form B of the free base is characterized by an X-ray powder diffraction pattern comprising peaks 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° in 2θ.

[0129] In some embodiments, the crystalline form B of the free base is characterized by an X-ray powder diffraction pattern comprising peaks 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.

[0130] In some embodiments, the crystalline form B of the free base is characterized by an X-ray powder diffraction pattern substantially the same as that of FIG. 6A.

[0131] In some embodiments, the crystalline form B of the free base is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic onset at 262.2°C ± 2°C. In some embodiments, the crystalline form A of the free base is characterized by a differential scanning calorimetry (DSC) thermogram substantially the same as that of FIG. 6B. In some embodiments, DSC was performed using a sealed aluminum pan with pinholes.

[0132] Pharmaceutical composition The pharmaceutical compositions of the present disclosure (also referred to herein as "the disclosed pharmaceutical compositions") comprise a pharmaceutically acceptable carrier and a salt or solid form of the present disclosure.

[0133] Some embodiments of the present disclosure relate to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and the mesylate of compound (I), wherein the molar ratio between compound (I) and methanesulfonic acid is about 1:1. In some embodiments, the mesylate is crystalline. In some embodiments, the mesylate of compound (I) is crystalline form A.

[0134] Some embodiments of the present disclosure relate to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and the mesylate of compound (I), wherein the molar ratio between compound (I) and methanesulfonic acid is about 1:1. In some embodiments, the mesylate is crystalline. In some embodiments, the mesylate of compound (I) is crystalline form B.

[0135] Some embodiments of the present disclosure relate to pharmaceutical compositions 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.

[0136] Some embodiments of the present disclosure relate to pharmaceutical compositions 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.

[0137] Some embodiments of the present disclosure relate to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and the 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.

[0138] The salts or solid forms of the present disclosure can be formulated for administration in any convenient manner for use in human medicine or veterinary medicine. In some embodiments, the compound or salt contained in the pharmaceutical composition may itself be active or may be a prodrug, for example, that can be converted to an active compound in a physiological environment.

[0139] As used herein, the term “pharmaceutically acceptable” refers to compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0140] "Pharmaceutical composition" refers to any product that directly or indirectly results from one or more active ingredients and one or more inactive ingredients that make up the carrier, as well as combinations, complex formations, or aggregations of two or more ingredients, or dissociations of one or more ingredients, or other types of reactions or interactions of one or more ingredients. Thus, the pharmaceutical compositions of the present disclosure encompass any composition containing the compounds of the present disclosure and a pharmaceutically acceptable carrier.

[0141] "Carrier" means a diluent, adjuvant, excipient, or vehicle with which the active ingredient is administered together. In some embodiments, such a pharmaceutical carrier is a sterile liquid such as water and oils including oils derived from petroleum, animal, vegetable, or synthetic sources, including but not limited to peanut oil, soybean oil, mineral oil, sesame oil, etc. In some embodiments, water is the carrier when the pharmaceutical composition is administered orally. In some embodiments, physiological saline and aqueous dextrose are exemplary carriers when the pharmaceutical composition is administered intravenously. In some embodiments, physiological saline and aqueous dextrose and glycerol solutions are used as the liquid carrier for injection solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, corn, wheat flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, etc. In some embodiments, the pharmaceutical composition contains a small amount of wetting agent or emulsifier, or pH buffer. In some embodiments, these pharmaceutical compositions take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations, etc. In some embodiments, the pharmaceutical composition is formulated as a suppository using conventional binders and carriers such as triglycerides. In some embodiments, oral formulations contain 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 E.W. Martin. Such pharmaceutical compositions contain a therapeutically effective amount of the active ingredient (e.g., in purified form) together with a suitable amount of carrier to provide an appropriate dosage form for administration to a subject. The formulation should be compatible with the mode of administration.

[0142] Method of treatment Some embodiments provided herein describe different solid and salt forms of compound (I) that are useful as epidermal growth factor receptor (EGFR) family kinase inhibitors. In some embodiments, the solid and salt forms of compound (I) are useful as mutant EGFR family kinase inhibitors. In some embodiments,

[0143] In some embodiments, the solid and salt forms of compound (I) described herein have improved safety profiles. In some embodiments, the solid and salt forms of compound (I) described herein have improved toxicity profiles. In some embodiments, the solid and salt forms of compound (I) described herein have an improved therapeutic index. In some embodiments, the solid and salt forms of compound (I) described herein have improved antitumor activity against brain metastases.

[0144] In some embodiments, the presence of an EGFR family kinase variant is determined by evaluation of an archival tumor biopsy or a blood sample. In some embodiments, an EGFR family kinase variant is detected with a commercially available test kit. In some embodiments, an EGFR family kinase variant is detected by a reverse transcription polymerase chain reaction (RT-PCR)-based method. In some embodiments, an EGFR family kinase variant is detected by a sequencing-based method. In some embodiments, an EGFR family kinase variant is detected by a mass spectrometry genotyping-based method. In some embodiments, an EGFR family kinase variant is detected by an immunohistochemistry-based method. In some embodiments, an EGFR family kinase variant is detected using a molecular diagnostic panel. In some embodiments, an EGFR family kinase variant is detected from a tumor sample. In some embodiments, an EGFR family kinase variant is detected from circulating DNA. In some embodiments, an EGFR family kinase variant is detected from tumor cells.

[0145] In one aspect, provided herein is a method of inhibiting an EGFR family kinase variant in a subject in need of inhibition, comprising administering to the subject a solid form or a salt form of a therapeutically effective amount of compound (I).

[0146] In another aspect, provided herein is a method of inhibiting a drug-resistant EGFR variant in a subject in need of inhibition, comprising administering to the subject a solid form or a salt form of a therapeutically effective amount of compound (I). In some embodiments, the drug-resistant EGFR variant is del19 / T790M EGFR or L858R / T790M EGFR.

[0147] In another aspect, provided herein is a method of inhibiting EGFR in a subject in need of inhibition, comprising administering to the subject a solid form or a salt form of a therapeutically effective amount of compound (I), wherein the compound exhibits a greater inhibitory effect on the EGFR variant as compared to wild-type EGFR.

[0148] In some embodiments, the EGFR variant comprises a substitution within exon 18, a deletion within exon 19, a substitution within exon 20, an insertion within exon 20, a mutation within the extracellular domain, or a substitution within exon 21. In some embodiments, the EGFR variant 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 (or D770_N771insSVD EGFR), 770insNPG EGFR (or D770_N771insNPG 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 variant is del19 / T790M EGFR or L858R / T790M EGFR. In some embodiments, the EGFR variant is del19 / T790M EGFR. In some embodiments, the EGFR variant is L858R / T790M EGFR. In some embodiments, the EGFR variant is an insertion in exon 20. In some embodiments, the EGFR mutation is an exon 18 G719X or exon 21 L861Q mutation. In some embodiments, the mutation is S768I EGFR.

[0149] In another aspect, provided herein is a method of treating disease-related EGFR in a subject in need of treatment, comprising administering to the subject a therapeutically effective amount of a solid form or a salt form of compound (I).

[0150] In some embodiments, the disease of interest comprises an EGFR mutation (i.e., the disease of interest is characterized by an EGFR mutation). In some embodiments, the EGFR mutation comprises a substitution within exon 18, a deletion within exon 19, a substitution within exon 20, an insertion within exon 20, a mutation within the extracellular domain, or a substitution within exon 21. In some embodiments, 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 (or D770_N771insSVD EGFR), 770insNPG EGFR (or D770_N771insNPG 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 / T790M EGFR. In some embodiments, the EGFR variant is an insertion in exon 20. In some embodiments, the EGFR variant is an exon 18 G719X or exon 21 L861Q mutation. In some embodiments, the mutation is S768I EGFR.

[0151] In another aspect, provided herein is a method for treating cancer in a subject in need of treatment, comprising administering to the subject a solid form or a salt form of a therapeutically effective amount of compound (I). In some embodiments, the cancer is an incurable recurrent cancer. In some embodiments, the cancer is a locally advanced or metastatic disease. In one aspect, the subject is an adult. In one aspect, the treatment is a first-line treatment. In one aspect, the treatment is a second-line treatment. In one aspect, the subject has been previously treated with platinum-based chemotherapy. In one aspect, the subject's disease has progressed during or after platinum-based chemotherapy. In one aspect, the subject has been previously treated with at least one systemic pre-treatment. In one aspect, the subject has been previously treated with an EGFR exon 20 insertion targeting agent. In one aspect, the treatment is an adjuvant treatment after tumor resection. In some embodiments, the cancer exhibits drug resistance associated with the activation of EGFR del19 / T790M. In some embodiments, the cancer exhibits drug resistance associated with the activation of EGFR L858R / T790M. In some embodiments, the cancer is characterized by an EGFR mutation. In some embodiments, the cancer is characterized by an insertion in exon 20. In some embodiments, the cancer is characterized by an exon 18 G719X mutation or an exon 21 L861Q mutation.

[0152] 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, paranasal 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 glioblastoma.

[0153] In some embodiments, the cancer in the subject comprises an EGFR mutation, i.e., the cancer is characterized by an EGFR mutation. In some embodiments, the EGFR mutation includes a substitution within exon 18, a deletion within exon 19, a substitution within exon 20, an insertion within exon 20, a mutation within the extracellular domain, or a substitution within 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, 770insSVD EGFR (or D770_N771insSVD EGFR), 770insNPG EGFR (or D770_N771insNPG 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 / T790M EGFR. In some embodiments, the cancer is characterized by an EGFR mutation. In some embodiments, the cancer is characterized by an insertion in exon 20. In some embodiments, the cancer is characterized by an exon 18 G719X mutation or an exon 21 L861Q mutation of EGFR. In some embodiments, the mutation is S768I EGFR.

[0154] The presence of CNS metastases, including brain and leptomeningeal lesions, can cause significant morbidity and is associated with poor outcomes in NSCLC patients, including those with EGFR-mutated disease. The management of brain metastases varies depending on the extent of the disease and the need for urgent treatment. In patients who do not require immediate surgical treatment, initial treatment may preferably consist of radiotherapy using stereotactic radiosurgery rather than whole-brain radiotherapy. Radiation may be associated with cognitive decline due to radiation-induced necrosis and can have a significant impact on quality of life as the survival of patients is prolonged with improved treatment regimens. Chemotherapy has some activity but tends to be less effective than the effects achieved with radiation. In the case of patients with common EGFR mutations, treatment with osimertinib rather than radiotherapy is an option, but this approach has not been formally evaluated in randomized trials. There is a need for EGFR Ex20ins-targeted TKIs with high CNS penetration. In some aspects, provided herein is a method of treating CNS (or brain) metastases associated with cancer characterized by mutant EGFR in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a solid or salt form of compound (I). In some aspects, provided herein is a method of treating asymptomatic brain metastases.

[0155] In another aspect, provided herein is a method of treating an inflammatory disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a solid or salt form of compound (I). Also described herein is the use of the solid and salt forms of compound (I) described herein for the treatment of inflammatory diseases associated with EGFR del19 / T790M activation. Also described herein is the use of the solid and salt forms of compound (I) described herein for the treatment of inflammatory diseases associated with EGFR L858R / T790M activation.

[0156] 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.

[0157] In some embodiments, the inflammatory disease of interest includes an EGFR mutation. In some embodiments, the EGFR mutation includes a substitution within exon 18, a deletion within exon 19, a substitution within exon 20, an insertion within exon 20, a mutation within the extracellular domain, or a substitution within exon 21. In some embodiments, 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 (or D770_N771insSVD EGFR), 770insNPG EGFR (or D770_N771insNPG 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 / T790M EGFR. In some embodiments, the mutation is EGFR exon 18 G719X or exon 21 L861Q. In some embodiments, the mutation is S768I EGFR.

[0158] Administration and Pharmaceutical Compositions In certain embodiments, the solid or salt form of compound (I) is administered as a pure chemical substance. In other embodiments, the solid or salt form of compound (I) is combined with a pharmaceutically suitable or acceptable carrier (as used herein, a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier) selected based on the selected route of administration and standard pharmaceutical practice, as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

[0159] Provided herein are pharmaceutical compositions comprising at least one solid or salt form of compound (I) together with one or more pharmaceutically acceptable carriers. One embodiment provides a pharmaceutical composition comprising a solid or salt form of compound (I) and a pharmaceutically acceptable excipient.

[0160] In certain embodiments, the solid 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 organic small molecules, such as unreacted intermediates or synthetic by-products, that are created, for example, in one or more of the steps of the synthetic method.

[0161] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose, or another suitable material that readily dissolves in the gastrointestinal tract. In some embodiments, suitable non-toxic solid carriers are used, including, for example, pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, etc. (See, for example, Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

[0162] The dosage of the pharmaceutical composition containing at least one solid form or salt form of compound (I) varies depending on the patient's condition, namely, the stage of the disease, general health, age, and other factors.

[0163] The pharmaceutical composition is administered in a manner appropriate for the disease to be treated (or prevented). The appropriate dosage as well as the preferred administration period and frequency are 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 administration method. Generally, the appropriate dosage and treatment plan provide the active ingredient(s) in an amount sufficient to bring about a therapeutic effect (e.g., improvement in clinical outcome) or reduction in the severity of symptoms. The optimal dosage is generally determined using experimental models and / or clinical trials. The optimal dosage depends on the patient's body weight or blood volume.

[0164] The following examples are intended to be illustrative and are not intended to limit the scope of the present disclosure in any way.

Examples

[0165] Equipment and Methods Different equipment and methods were used to test and characterize different batches of materials. For example, the XRPD peaks described in Tables 1, 2, 3, 4, 5a, 6a, 7a, 8a, 9a, 10a, 11a, 12a, 13a, 14a, 15a, and 16a were collected using XRPD Method 1, and the XRPD peaks described in Tables 5b, 6b, 7b, 8b, 9b, 10b, 11b, 12b, 12c, 13b, 13c, 13d, 14b, 15b, and 16b were collected using XRPD Method 2.

[0166] X-ray Powder Diffraction (XRPD) Method 1 Equipment: Panalytical Empyrean Parameters: X-ray tube Cu(Kα radiation); tube voltage 40 kV; tube current 15 mA Scanning range: 2~40 2θ (°) Step size: 0.01° Scanning speed: 1.31°(2θ) / min

[0167] X-ray powder diffraction (XRPD) method 2 In order to fill a small amount of sample, a zero-background sample holder designed for this purpose is used to prevent the mirror surface from being damaged, and the sample needs to be filled into the recess of the sample holder. Regarding sample preparation, the sample mount level must be flush with the upper part of the recess that is intended to accommodate the sample. Use a Kimwipe coated with some solvent (i.e., methanol) to wipe the sample holder to make it clean. Use a spatula to transfer a small amount of powder to the sample holder and press all the powder materials around on the mirror surface into the central recess. Be careful not to damage the mirror surface of the sample holder with the spatula. Use a clean slide glass to gently press down the powder sample in the recess part of the sample holder and rotate the slide to flatten the sample. Before placing the sample holder in the XRPD chamber for analysis, clean the mirror surface outside the recess area of the sample with a Kimwipe.

[0168] XRPD was performed using a Bruker D8 Advance equipped with a LYNXEYE detector in reflection mode (i.e., Bragg-Brentano configuration). As described above, the sample was prepared on a Si zero-return wafer. The parameters for the XRPD method used are listed below.

Table 32

[0169] Thermogravimetric analysis (TGA) Instrument: TA Instruments Discovery TGA Parameters: Temperature gradient 10 °C per minute, 25 - 300 °C, 50 mL / min N 2 Sweep

[0170] Differential scanning calorimetry (DSC) method 1 Instrument: TA Instruments Discovery DSC Parameter: Temperature gradient 10 °C per minute, maximum 300 °C

[0171] Differential scanning calorimetry (DSC) method 2 DSC was performed using a TA Discovery DSC. Samples (1 - 5 mg) were directly weighed in a 40 μL hermetic aluminum pan equipped with a pinhole and analyzed according to the following parameters. [Table 33]

[0172] Simultaneous thermogravimetric analysis and differential scanning calorimetry (TGA and DSC): TGA and DSC were simultaneously performed on the same samples 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 desired amount of sample (5 - 10 mg) was directly weighed in a hermetic aluminum pan equipped with a pinhole and analyzed according to the following parameters. [Table 34]

[0173] Dynamic vapor sorption measurement (DVS) method 1 Dynamic vapor sorption measurements were performed at 25 °C under a nitrogen blow using a TA Instruments Q5000SA DVS. Approximately 10 - 15 mg of the material was used. The samples were analyzed using the following method.

[0174] For anhydrides: · 10% RH from 0% RH to 90% RH · 10% RH from 90% RH to 0% RH For anhydrides: · 10% RH from 40% RH to 90% RH · 10% RH from 90% RH to 0% RH

[0175] Dynamic vapor sorption measurement (DVS) method 2 DVS was performed using a Q5000SA. Samples (5 - 15 mg) were loaded into metallic quartz sample pans, suspended from a microbalance, and exposed to a humidified nitrogen gas stream. The weight change was proportional to a matching empty reference pan on the opposite side of the sample, which was suspended from the microbalance. The sample was held at each level for a minimum of 10 minutes, and progression to the next humidity level was made only if the weight change during measurement (measurement interval: 5 s) was less than 0.002%, or when 45 minutes had elapsed (for 5 - 65% RH), or when 2 hours had elapsed (for 80% RH and 95% RH). The following program was used: 1 - Equilibrate at 50% RH 2 - 50% - 5% (50%, 35%, 20%, and 5%) 3 - 5% - 95% (5%, 20%, 35%, 50%, 65%, 80%, and 95%) 4 - 95% - 5% (95%, 80%, 65%, 50%, 35%, 20%, and 5%) 5 - 5% - 50% (5%, 20%, 35%, and 50%)

[0176] Polarizing Light Microscope (PLM) Instrument: Nikon Eclipse Ci POL Camera: Nikon DS-Fi3 Software: Nikon NIS Elements

[0177] Microscopic Observation Optical microscopic observations were performed using a Zeiss AxioScope A1 digital imaging microscope equipped with 2.5x, 10x, and 40x objective lenses and a polarizer. Images were acquired using a built-in Axiocam 105 digital camera and processed using ZEN2 (blue edition) software provided by Zeiss.

[0178] High Performance Liquid Chromatography (HPLC): HPLC was performed using an Agilent 1220 Infinity 2 LC equipped with a diode array detector (DAD). The flow rate range of the instrument was 0.2-5.0 mL / min, the operating pressure range was 0-600 bar, the temperature range was 5°C above ambient to 60°C, and the wavelength range was 190-600 nm.

[0179] The HPLC method used in this study is as follows: [Table 35]

[0180] Proton nuclear magnetic resonance ( 1 H NMR) spectroscopy On Bruker Avance 300, 400, and 500 MHz spectrometers 1 H NMR was performed: 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: [Table 36] [Table 37] [Table 38]

[0181] Example 1: Preparation of Compound (I) 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): [ka] Step 1: Synthesis of 5-bromo-2-chloro-N-(2-fluoro-5-nitrophenyl)pyrimidin-4-amine (89): To an ice-cooled solution of 2-fluoro-5-nitroaniline (12) (1.0 eq) in tetrahydrofuran, sodium hydride (60% dispersion in mineral oil, 3.0 eq) was added portionwise. The resulting reaction mixture was stirred at room temperature for 30 minutes, followed by the addition of 2,4-dichloro-5-bromopyrimidine (88) (1.0 eq). The resulting reaction mixture was heated to 60 °C for 16 hours. After completion (TLC monitoring), it was quenched with ice and extracted with ethyl acetate (3 times). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash eluting with 40% ethyl acetate in hexanes to give (89) as a pale yellow solid (1.3 g, yield: 44.24%). MS: [M+H] + 346.97。

[0182] Step 2: Synthesis of 2-chloro-N-(2-fluoro-5-nitrophenyl)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-amine (91): To a solution of the halo derivative (89) (1.0 eq) and the respective boronic acid / ester derivative (90) (1.1 eq) in N,N-dimethylformamide:water (4:1), sodium carbonate or sodium bicarbonate (2.0 eq) was added. The resulting reaction mixture was degassed under an argon atmosphere for 15 minutes, followed by the addition of tetrakis(triphenylphosphine)palladium(0) (0.1 eq). The resulting reaction mixture was heated to 90 °C for 16 hours. After completion of the reaction (TLC monitoring), the reaction mixture was cooled to room temperature, water was added, and it was 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 product was purified by combiflash eluting with 35% ethyl acetate in hexanes to give the desired product (91) as a pale yellow solid (700 mg; yield: 50.12%). MS: [M+H] + 413.10。

[0183] 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): To an ice-cooled solution of the chloro compound (91) (1.0 equiv) in isopropanol, amine (22) (1.2 equiv) and trifluoroacetic acid (2.0 equiv) were added. The reaction mixture was heated at 110 °C for 16 h.

[0184] After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure, saturated sodium bicarbonate solution was added, and the mixture was 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 product was purified by combiflash eluting with 1% methanol in dichloromethane to give the desired product (92) as a pale yellow solid (500 mg; yield: 70.24%). MS: [M+H] + 474.09.

[0185] 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): To an ice-cooled solution of the nitro derivative (92) (1.0 equiv) in methanol:tetrahydrofuran:water (2:2:1), zinc dust or iron powder (5 equiv) and ammonium chloride (5 equiv) were added. The resulting reaction mixture was stirred at room temperature for 2 h. After completion of the reaction (TLC monitoring), the reaction mixture was passed through a celite bed and washed with 5% methanol in dichloromethane. The filtrate was washed with water, brine, dried over anhydrous sodium sulfate, filtered, concentrated and dried to give the desired product (93) as a semi-solid (350 mg; yield: 74.78%). MS: [M+H] + 444.11.

[0186] 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): A solution of amino compound (93) (1.0 equivalent) in dichloromethane:tetrahydrofuran (1:1) was cooled to -40 °C, and then triethylamine (3 - 5 equivalents) and acryloyl chloride (1.0 equivalent) were added. The mixture was stirred at the same temperature for 2 hours. After completion of the reaction (monitored by TLC), water was added and the mixture was extracted with dichloromethane (3 times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to obtain Compound I as an off-white solid (30 mg, yield: 13.33%). 1 H NMR (400 MHz, DMSO-d 6 ): δ 10.21 (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 = 8.4 Hz, 1H), 3.54 (s, 3H). LCMS: [M+H] + 498.35。

[0187] Example 2: Preparation of the mesylate salt of Form A of Compound (I) Approximately 30 mg of the free base of Compound (I) was dissolved in 1.7 mL of acetone (or 7.5 mL of ethyl acetate) to obtain a clear solution. Methanesulfonic acid with a molar charge ratio of 1:1 was added to the free base solution, and the mixture was stirred at room temperature (rt) for 2 days. The precipitate was isolated by centrifugation, cooled to 5 °C, or by slow evaporation to obtain the product. Instead of stirring at room temperature, the mixture can be heated to 40 °C, stirred overnight, and seeded with crystals of Form A.

[0188] By XRPD analysis, it was confirmed that the obtained product was Form A. It was confirmed that Form A of the mesylate is the anhydride of the monomesylate.

[0189] Example 3: Preparation and Characterization of Form B of the Mesylate of Compound (I) General Synthesis of Form B of the Mesylate: Form B of the mesylate can generally be obtained by slurrying or dissolving Compound (I) in acetone (e.g., 10 - 30 volumes, 10 - 25 volumes, 15 - 25 volumes, etc.) at a high temperature (e.g., 40 - 70 °C, 40 °C - 65 °C, 45 °C - 55 °C, or 50 °C - 60 °C, etc.) or by refluxing. Then, the solution is cooled slightly, and then a small amount of methanesulfonic acid (e.g., 0.1 - 0.5 molar equivalent relative to Compound (I)) is added, which can bring about dissolution. Then, a seed crystal (Form B of the mesylate) is added. After the formation of a seed bed, the remaining methanesulfonic acid is added. Alternatively, the remaining methanesulfonic acid is added without using a seed crystal. Following an optional holding period (e.g., 10 minutes - 5 hours, 10 - 120 minutes, 30 - 100 minutes, etc.), the slurry is cooled and held at ambient temperature or a lower temperature (e.g., 5 °C - 25 °C, 5 °C - 15 °C, 15 °C - 25 °C, etc.), then filtered and washed with acetone. By drying the product at a high temperature, Form B of the mesylate (e.g., 40 °C - 70 °C, 40 °C - 65 °C, 45 °C - 55 °C, or 50 °C - 60 °C) was obtained. In some embodiments, instead of acetone, a mixture of acetone and a small amount of water (e.g., 1 - 5%) can also be used to slurry or dissolve Compound (I).

[0190] Example 3a: The free base of 2.595 g of compound (I) was heated to reflux in 20 volumes of acetone. Then, 0.3 equivalent of MSA was added, and then it was cooled to 42 °C. Then, a seed crystal (0.1% mesylate form B) was added and stirred for 40 minutes. Then, MSA (0.8 equivalent) was added and the slurry was stirred at 42 °C for 1 hour. Alternatively, without adding the seed crystal, the remaining MSA (0.8 equivalent) was added in three equal portions, and the slurry was stirred at 42 °C for 1 hour. After cooling at 20 °C for 1 hour, the slurry was then stirred for 1 hour, then filtered and washed with 3.0 volumes of acetone. The solid was dried under vacuum at 50 °C overnight. The yield was 2.54 g (86%) as mesylate form B.

[0191] Example 3b: 500 mg of the free base of compound (I) was dissolved in 20 mL of acetone and heated to 50 °C to obtain a clear solution. 75 μL (1.1 M equivalent) of methanesulfonic acid was added to the free base solution. A seed crystal (form B) was added and the mixture was stirred at room temperature for 2 days. The isolated solid weighed 507 mg (yield 89%) as mesylate form B.

[0192] XRPD analysis confirmed that the isolated solid was form B. The product was characterized by HPLC, PLM, TGA / DSC (Figure 2B), and 1H-NMR. Mesylate form B was confirmed to be the anhydrous form of a monomesylate having an irregularly shaped plate-like form.

[0193] TGA analysis showed that the mass loss was very small up to 150 °C (Figure 2B). DSC showed an endothermic onset at 247.8 °C.

[0194] DVS showed a 2.47% weight gain at 80% RH, suggesting hygroscopicity, but no change in crystal form was observed after DVS.

[0195] Example 4: Preparation and Characterization of Mesylate Form H of Compound (I) Form H of the mesylate was prepared by slow cooling crystallization in methanol:acetone (1:1 volume). Approximately 300 mg of form B of the mesylate was weighed and placed in a 4 mL vial. Then, a solvent mixture of methanol and acetone (4.5 volumes) was added little by little at 50 °C until dissolved. Using a cooling block equipped with a programmable chiller, the solution was cooled to 5 °C at 5 °C per hour while mixing. The slurry was filtered, washed with the solvent (2 × 0.5 volumes), and then dried under vacuum at 50 °C overnight. A yield of 0.166 g (49 mol%) was obtained as form H of the mesylate.

[0196] Form H of the mesylate was produced on an approximately 0.200 g scale by short-term slurrying of form B of the mesylate in ethanol at 50 °C. Seeding was carried out with form H of the mesylate. A yield of 0.159 g (79.5 w / w%) was obtained. Based on the characterization performed, form H of the mesylate was determined to be anhydrous.

[0197] Slurry competition experiments were carried out among all anhydrates of the mesylate including form A, form B, and form H to determine the relative stability using THF as the solvent at 25 °C and isopropyl alcohol (IPA) as the solvent at 25 °C and 60 °C. At the end of the test, the three salt forms were converted to form H in THF at 25 °C (3 days) and in IPA at both 25 °C (3 days) and 60 °C (1 day). Therefore, in THF and IPA, form H of the mesylate is the thermodynamically more stable form at both room temperature and 60 °C.

[0198] Form H of the mesylate was confirmed to be an anhydrous monomesylate having a needle-like form.

[0199] TGA analysis showed a mass loss of 0.409 wt% up to 150 °C (Figure 3B). By DSC, two endothermic and exothermic events were shown, namely, a large endotherm starting at 220.54 °C and a small exotherm starting at 239.42 °C (Figure 3B).

[0200] To understand the hygroscopicity of form H of the mesylate salt, dynamic vapor sorption (DVS) measurements were used to measure the mass change as a function of relative humidity at 25 °C. Prior to analysis, the H-form of mesylic anhydride was equilibrated at 0% RH to remove adsorbed moisture or residual solvents. From these results, form H of the mesylate salt was shown to take up 1.76% water at 25 °C / 80% RH, suggesting that form H of the mesylate salt is slightly hygroscopic. No change in form was observed in the samples after DVS evaluation.

[0201] Example 5: Preparation and Characterization of Form I of the Mesylate Salt of Compound (I) Form I of the mesylate salt was prepared by slow cooling crystallization in ethanol:water (9:1 v / v). Approximately 300 mg of form B of the mesylate salt was weighed and placed in a 4 mL vial. Then, the solvent (9 volumes) was added little by little at 50 °C until dissolved. The solution was cooled to 5 °C at 5 °C per hour with mixing using a cooling block equipped with a programmable chiller. The slurry was filtered, washed with the solvent (2 × 0.5 volumes), and then dried under vacuum at 50 °C overnight. A yield of 0.164 g (48 mol%) was obtained as form I of the mesylate salt.

[0202] Form I of the mesylate salt was confirmed to be a hydrate from the results of solid characterization.

[0203] TGA analysis showed a mass loss of 1.998 wt% up to 150 °C (Figure 4B). DSC showed three endothermic and exothermic events, namely, a small endotherm starting at 33.16 °C, a large endotherm starting at 210.43 °C, and a small exotherm starting at 229.09 °C (Figure 4B).

[0204] The DVS results for form I of the mesylate salt showed water uptake of 0.54% at 30% RH - 80% RH at 25 °C, suggesting that form I of the mesylate salt is slightly hygroscopic. No change in form was observed in the samples after DVS evaluation.

[0205] Example 6: Preparation and Characterization of the Crystalline Free Base Form A of Compound (I) Characterization was performed by X-ray powder diffraction (XRPD), polarized light microscopy (PLM), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and high performance liquid chromatography (HPLC). As a result of the characterization, it was shown that the starting material was crystalline and was defined as form A of the free base, and this crystalline form was further identified as an anhydride having a rod-like form.

[0206] In the DVS results of the free base form A, uptake of 5.23% water was shown at 80% RH. No change in form was observed in the sample after DVS evaluation.

[0207] Example 7: Preparation and Characterization of the Crystalline Free Base Form B of Compound (I) Approximately 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 confirmed by XRPD, DSC, and TGA.

[0208] Example 8: Pharmacokinetics of the Mesylate and Free Base Forms of Compound (I) after Oral (PO) Administration to Male Beagle Dogs. Male beagle dogs (3 per treatment group) were orally administered the free base of compound (I) or the mesylate salt of compound (I) at a dose equivalent to 30 mg / kg of the free base. The free base and mesylate salt were suspended / dissolved in an appropriate amount of vehicle solution containing 0.5% hydroxypropylmethylcellulose (w / v) and 0.2% Tween 80 (v / v) in deionized water. The PO dose was administered to the stomach via syringe and a feeding tube, followed by flushing with 5 mL of water. The dosing volume was adjusted according to the body weight of the animals on the morning of dose administration. Blood samples were collected from a vein that was more accessible than the jugular vein at 0, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours after dosing. The blood samples were maintained on ice until processed. All blood samples were centrifuged at 3200 RPM for 10 minutes at 5 °C within 1 hour of collection. 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 sampling time points. The animals were fasted the evening before dosing and feeding was resumed 4 hours after dosing. As shown in Figure 7, the mesylate salt showed higher in vivo exposure compared to the free base form.

Claims

1. The mesylate salt of compound (I) represented by the following structural formula, 【Chemistry 1】 The mesylate salt wherein the molar ratio between compound (I) and methanesulfonic acid is 1:

1.

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

3. The crystalline mesylate mentioned above is as follows: (i) An X-ray powder diffraction pattern having at least three, at least four, or at least five peaks selected from 5.9°, 7.2°, 11.9°, 12.1°, 19.3°, and 20.1° ± 0.2° at 2θ, or (ii) X-ray powder diffraction pattern containing peaks at 5.9°, 7.2°, 11.9°, 12.1°, 19.3°, and 20.1°±0.2° in 2θ, or (iii) X-ray powder diffraction pattern containing peaks at 5.9°, 7.2°, 11.9°, 12.1°, 13.4°, 19.3°, 20.1°, 21.7°, 24.1°, and 27.6°±0.2° at 2θ, or (iv) 2θ: 5.9°, 7.2°, 11.9°, 12.1°, 13.4°, 14.6°, 15.4°, 19.3°, 20.1°, 21.7°, 22.9°, 23.8° X-ray powder diffraction patterns containing peaks at 24.1° and 27.6°±0.2°, or (v) X-ray powder diffraction pattern substantially similar to that of Figure 1A Crystal morphology A is characterized by, and arbitrarily The above-mentioned form A is as follows: (a) A differential scanning calorimeter (DSC) thermogram including the start of endothermic heating at 202.8°C ± 2°C and the start of exothermic heating at 206.9°C ± 2°C, or (b) Thermogravimetric analysis (TGA) substantially the same as in Figure 1B The mesylate salt according to claim 2, further characterized by...

4. The crystalline mesylate mentioned above is as follows: (i) An X-ray powder diffraction pattern having at least three or at least four peaks selected from 18.5°, 19.8°, 20.8°, 22.4°, and 24.9° ± 0.2° at 2θ, or (ii) X-ray powder diffraction pattern containing peaks at 18.5°, 19.8°, 20.8°, 22.4°, and 24.9°±0.2° in 2θ, or (iii) X-ray powder diffraction patterns containing peaks at 8.9°, 11.3°, 18.5°, 19.8°, 20.8°, 21.4°, 22.4°, 24.9°, and 25.9°±0.2° in 2θ, or (iv) An X-ray powder diffraction pattern having at least three or at least four peaks selected from 18.4°, 19.7°, 21.3°, 22.4°, and 24.8° ± 0.2° at 2θ, or (v) X-ray powder diffraction pattern containing peaks at 18.4°, 19.7°, 21.3°, 22.4°, and 24.8°±0.2° at 2θ, or (vi) X-ray powder diffraction pattern with peaks at 8.8°, 11.3°, 18.4°, 19.7°, 20.6°, 20.8°, 21.3°, 22.0°, 22.4°, and 24.8°±0.2° in 2θ, or (vii) 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°, 20.8°, 21.3°, 21.6° X-ray powder diffraction patterns containing peaks at 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°, or (viiii) X-ray powder diffraction pattern substantially similar to that of Figure 2A, Crystal morphology B is characterized by, and arbitrarily The above-mentioned form B is as follows: (a) A differential scanning calorimeter (DSC) thermogram including the start of endothermic heating at 247.8°C ± 2°C, or (b) Thermogravimetric analysis (TGA) substantially the same as in Figure 2B The mesylate salt according to claim 2, further characterized by...

5. The crystalline mesylate mentioned above is as follows: (i) An X-ray powder diffraction pattern having 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° ± 0.2° at 2θ, or (ii) X-ray powder diffraction pattern with peaks at 13.7°, 19.1°, 20.0°, 21.5°, 21.9°, and 23.4°±0.2° in 2θ, or (iii) X-ray powder diffraction pattern with peaks at 8.1°, 10.1°, 11.7°, 13.7°, 19.1°, 20.0°, 20.8°, 21.5°, 21.9°, and 23.4°±0.2° at 2θ, or (iv) X-ray powder diffraction pattern with peaks 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° at 2θ, or (v) An X-ray powder diffraction pattern having at least three or at least four peaks selected from 19.1°, 20.0°, 21.5°, 21.9°, and 23.4° ± 0.2° at 2θ, or (vi) X-ray powder diffraction pattern containing peaks at 19.1°, 20.0°, 21.5°, 21.9°, and 23.4°±0.2° in 2θ, or (vii) X-ray powder diffraction patterns containing peaks at 11.7°, 13.6°, 14.6°, 19.1°, 20.0°, 20.8°, 21.5°, 21.9°, 23.4°, and 24.6°±0.2° in 2θ, or (viiii) 2θ: 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°, 22.1°, 22.8°, 23.2 X-ray powder diffraction patterns containing peaks at 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°, or (ix) X-ray powder diffraction pattern substantially similar to Figure 3A The crystal form H is characterized by, and optionally The above-mentioned form H is as follows: (a) A differential scanning calorimeter (DSC) thermogram including the start of endothermic heating at 220.5°C ± 2°C and the start of exothermic heating at 239.4°C ± 2°C, or (b) Thermogravimetric analysis (TGA) substantially the same as in Figure 3B The mesylate salt according to claim 2, further characterized by...

6. The crystalline mesylate mentioned above is as follows: (i) An X-ray powder diffraction pattern having at least three or at least four peaks selected from 11.0°, 18.7°, 20.6°, 22.2°, and 24.4° ± 0.2° at 2θ, or (ii) X-ray powder diffraction pattern containing peaks at 11.0°, 18.7°, 20.6°, 22.2°, and 24.4°±0.2° in 2θ, or (iii) X-ray powder diffraction pattern with peaks at 8.6°, 11.0°, 16.7°, 18.7°, 19.3°, 20.6°, 21.6°, 22.2°, 24.2°, and 24.4°±0.2° at 2θ, or (iv) X-ray powder diffraction pattern with peaks 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° at 2θ, or (v) An X-ray powder diffraction pattern having at least three or at least four peaks selected from 8.5°, 18.7°, 20.6°, 21.5°, and 24.4° ± 0.2° at 2θ, or (vi) X-ray powder diffraction pattern with peaks at 8.5°, 18.7°, 20.6°, 21.5°, and 24.4°±0.2° in 2θ, or (vii) X-ray powder diffraction pattern with peaks at 8.5°, 10.9°, 16.7°, 18.7°, 19.2°, 20.6°, 21.5°, 22.1°, 24.1°, and 24.4°±0.2° in 2θ, or (viiii) 2θ: 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°, 21.7°, 22.0°, 22.1 X-ray powder diffraction patterns containing peaks at 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°, or (ix) X-ray powder diffraction pattern substantially similar to that of Figure 4A Crystal morphology I is characterized by, and arbitrarily The above-mentioned form I is as follows: (a) A differential scanning calorimeter (DSC) thermogram including the start of endothermic heating at 33.2°C ± 2°C, the start of endothermic heating at 210.4°C ± 2°C, and the start of exothermic heating at 229.1°C ± 2°C, or (b) Thermogravimetric analysis (TGA) substantially the same as in Figure 4B The mesylate salt according to claim 2, further characterized by...

7. The crystalline form A of compound (I) represented by the following structural formula, 【Chemistry 2】 The above-mentioned form A is characterized by an X-ray powder diffraction pattern that includes peaks at 5.7°, 6.0°, and 6.2°±0.2° in 2θ.

8. The above-mentioned form A is as follows: (i) An X-ray powder diffraction pattern having at least three or at least four peaks selected from 5.7°, 6.0°, 6.2°, 6.5°, and 19.6°±0.2° at 2θ, or (ii) X-ray powder diffraction pattern with peaks at 5.7°, 6.0°, 6.2°, 6.5°, and 19.6°±0.2° in 2θ, or (iii) X-ray powder diffraction patterns with peaks at 5.7°, 6.0°, 6.2°, 6.5°, 16.9°, 19.6°, 22.4°, 23.7°, 24.9°, and 25.2°±0.2° in 2θ, or (iv) An X-ray powder diffraction pattern containing peaks 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° at 2θ, or (v) X-ray powder diffraction pattern substantially similar to that of Figure 5A Crystal morphology A is characterized by, and optionally, The above-mentioned form A is as follows: (a) A differential scanning calorimeter (DSC) thermogram including the start of endothermic heating at 263.3°C ± 2°C, or (b) Thermogravimetric analysis (TGA) substantially the same as in Figure 5B The crystal morphology A according to claim 7, further characterized by...

9. The crystalline form B of compound (I) represented by the following structural formula, 【Transformation 3】 Embodiment B is characterized by an X-ray powder diffraction pattern having at least three or at least four peaks at 5.2°, 5.3°, 6.1°, 18.5°, and 24.4°±0.2° at 2θ.

10. The above-mentioned form B is as follows: (i) X-ray powder diffraction patterns containing peaks at 5.2°, 5.3°, 6.1°, 18.5°, and 24.4°±0.2° in 2θ, or (ii) X-ray powder diffraction patterns containing peaks at 5.2°, 5.3°, 6.1°, 15.6°, 18.5°, 18.7°, 19.5°, 22.5°, 24.4°, and 26.1°±0.2° in 2θ, or (iii) An X-ray powder diffraction pattern with peaks 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° at 2θ, or (iv) X-ray powder diffraction pattern substantially similar to that of Figure 6A Crystal morphology B according to claim 9, characterized by, optionally, further characterized by a differential scanning calorimeter (DSC) thermogram including an endothermic initiation at 262.2°C ± 2°C.

11. A pharmaceutical composition comprising a mesylate according to any one of claims 1 to 6 or a crystalline form according to any one of claims 7 to 10, and a pharmaceutically acceptable carrier.

12. A mesylate salt according to any one of claims 1 to 6 or a crystalline form according to any one of claims 7 to 10, for use in a method of treating cancer.

13. (i) 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, paranasal sinus cancer, or non-small cell lung cancer, or (ii) The cancer is non-small cell lung cancer, prostate cancer, head and neck cancer, breast cancer, colorectal cancer, or glioblastoma. The mesylate or crystalline form according to claim 12.

14. The cancer in the subject is characterized by an EGFR mutation, and optionally (i) The EGFR mutation includes 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, (ii) The EGFR mutation is 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, 772insNP EGFR, 773insNPH Selected from EGFR, 773insH EGFR, 773insPH EGFR, EGFRvii, EGFRviiiii, A767_dupASV EGFR, 773insAH EGFR, M766_A767insAI EGFR, and any combination thereof. The mesylate or crystalline form according to claim 12.

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