Salts and crystalline forms of epidermal growth factor receptor inhibitors

Abstract

Disclosed are various salts and polymorphic forms of Compound (I) represented by the following structural formula, and their corresponding pharmaceutical compositions. Specific crystalline forms of 1:0.5 Compound (I) half succinate, 1:0.5 Compound (I) half glutarate, and 1:1 Compound (I) fumarate, as well as amorphous free base and free base crystalline forms A and B, are characterized by various characteristics and physical measurements. Methods of preparing specific crystalline forms are also disclosed. The disclosure also provides a method of treating non-small lung cancer through EGFR inhibition, and further provides a method of inhibiting triple mutant EGFR. JPEG2024523506000050.jpg5988

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 214,089, filed June 23, 2021. The entire contents of the aforementioned application are incorporated herein by reference. [Background technology]

[0002] Epidermal growth factor receptor (EGFR) is a member of the erbB receptor family, which includes transmembrane protein tyrosine kinase receptors. When bound to a ligand, such as epidermal growth factor (EGF), EGFR can form homodimers at the cell membrane or with other members of the erbB family. The formation of these dimers often leads to tyrosine phosphorylation, which can result in the activation or alteration of various downstream cellular pathways, including cell proliferation, survival, and anti-apoptosis. Because of this cellular function, disturbances in EGFR signaling, including increased expression of EGFR or its ligands, and deletions or mutations in the EGFR gene or protein, can activate cell growth or mitigate normal apoptotic mechanisms and pathways, traditional hallmarks of tumor cell growth and proliferation. For example, EFGR mutations or deletions are commonly found in non-small cell lung cancer (NSCLC) tumors.

[0003] The two most frequent EGFR exchanges found in NSCLC tumors are 1) a short in-frame deletion (del19) in exon 19 and 2) L858R, a single missense mutation in exon 21 (Cancer Discovery 2016 6(6)601). These two alterations lead to ligand-independent EGFR activation and are referred to as primary or activating mutations in EGFR mutant NSCLC (EGFR M+). Clinical experience shows approximately 60-85% objective response rates (ORR) in EGFR M+ NSCLC patients treated in first-line (1L) with the EGFR tyrosine kinase inhibitors (TKIs) erlotinib, gefitinib, afatinib, and osimertinib (Lancet Oncol.2010 Vol.11,121, Lancet Oncol.2016 Vol.17,577, N.Engl.J.Med.2017 Nov 18 Doi:10.1056 / NEJMoa1713137, Lancet Oncol.2011 Vol.12,735). These results indicate that EGFR mutant NSCLC tumors are dependent on the oncogenic activity of mutated EGFR and that del19 and L858R are oncogenic mutations in this disease, validating them as drug targets and biomarkers in many forms of NSCLC.

[0004] However, after a mean of 10-12 months of treatment with first-generation (erlotinib and gefitinib) and second-generation (afatinib) EGFR TKIs, resistance to these small molecule inhibitors has been observed in nearly all NSCLC patients (Lancet Oncol. 2010 Feb;11(2):121-8; Lancet Oncol. 2016 May;17(5):577-89; Lancet Oncol. 2011 Aug;12(8):735-42). The most common resistance mechanism is the development of a second EGFR mutation, T790M, which occurs in 50%-70% of patients progressing on first- and second-generation EGFR inhibitors. (Blakely et al., Cancer Discov;2012,2(10);872-5; Kobayashi et al., Cancer Res 2005;65:(16)). This second mutation reduces the affinity of the drug to the target, thereby generating drug resistance, leading to tumor recurrence or disease progression.

[0005] Due to the prevalence of T790M mutation, many companies are trying to develop new small molecule EGFR inhibitors to treat patients with drug resistance mutations. For example, osimertinib (Tagrisso®), a third-generation EGFR TKI, has been developed to treat NSCLC patients when cancer cells are positive for primary EGFR mutation del19 or L858R, regardless of the presence or absence of T790M mutation in the gene encoding EGFR. Although osimertinib, a third-generation EGFR TKI, has shown efficacy for NSCLC patients, unfortunately, resistance mediated by exon 20 C797 mutation (often C797S) in EGFR usually develops within approximately 10 months (European Journal of Medicinal Chemistry 2017 Vol.142:32-47) and accounts for the majority of osiertinib resistance cases (Cancer Letters 2016 Vol.385:51-54). The EGFR del19 / L858R T790M C797S cis-mutant kinase variant typically emerges in second-line (2L) patients following treatment with osimertinib and is often referred to as "triple-mutant" EGFR, which can no longer be inhibited by first-, second-, or third-generation EGFR inhibitors.

[0006] There is no approved EGFR TKI that can inhibit triple mutant variants. Therefore, there is a need to develop novel EGFR inhibitors that can inhibit EGFR mutants with triple mutant del19 / L858R T790M C797S with high selectivity, while at the same time having no or low activity against wild-type EGFR. In addition to treating mutant forms of EGFR for which no current therapy exists, such selective EGFR inhibitors are likely to be more suitable as therapeutic agents, especially for the treatment of cancer, due to the reduced toxicology (diarrhea, skin rash) associated with wild-type EGFR inhibition.

[0007] PCT Patent Application No. PCT / US20 / 66629, the entire teachings of which are incorporated herein by reference, discloses inhibitors of "triple mutant" EGFR, which can be used to treat various cancers, such as NSCLC. The structure of one of the inhibitors disclosed in PCT Patent Application No. PCT / US20 / 66629, referred to herein as "Compound (I)," is shown below. [ka]

[0008] There is a need to develop new salt and / or solid forms of Compound (I) that are suitable for large-scale manufacture and commercialization. Summary of the Invention

[0009] The present disclosure relates to i) novel pharma- ceutically acceptable salts of Compound (I), including the corresponding solid forms (e.g., 1:0.5 Compound (I) hemi succinate, 1:0.5 Compound (I) hemi glutarate, 1:1 Compound (I) fumarate), and ii) novel solid forms of the free base of Compound (I) (collectively referred to hereinafter as "salts or solid forms of the present disclosure").

[0010] The notation "1:0.5" is the molar ratio between compound (I) and acid (succinic acid or glutaric acid), and the notation "1:1" is the molar ratio between compound (I) and acid (fumaric acid).

[0011] In one embodiment, the present disclosure provides a succinate salt of compound (I), wherein the molar ratio between compound (I) and succinic acid is 1:0.5. As mentioned above, this salt is also referred to herein as "1:0.5 compound (I) hemisuccinate".

[0012] In another embodiment, the present disclosure provides a glutarate salt of compound (I), wherein the molar ratio between compound (I) and glutarate salt is 1:0.5.As mentioned above, this salt is referred to herein as "1:0.5 compound (I) half glutarate".

[0013] In another aspect, the present disclosure provides a fumarate salt of Compound (I), wherein the molar ratio between Compound (I) and fumaric acid is 1:1. As mentioned above, this salt is also referred to herein as "1:1 Compound (I) fumarate."

[0014] In another aspect, the disclosure provides a first polymorph of the free base of Compound (I), which is also referred to herein as "Compound (I) free base Form A."

[0015] In another aspect, the disclosure provides a second polymorphic form of the free base of Compound (I), which is also referred to herein as "Compound (I) free base Form B."

[0016] In another aspect, the disclosure provides a pharmaceutical composition comprising 1:0.5 Compound (I) half succinate, 1:0.5 Compound (I) half glutarate, 1:1 Compound (I) fumarate, Compound (I) free base Form A, or Compound (I) free base Form B, and a pharma- ceutically acceptable carrier or diluent.

[0017] The present disclosure provides a method of treating or ameliorating cancer in a subject, the method comprising administering to a subject in need thereof a pharmacologic effective amount of a salt or free base form disclosed herein or a corresponding pharmaceutical composition. In some aspects, the cancer to be treated or ameliorated is non-small cell lung cancer.

[0018] The present disclosure also provides a method of inhibiting aberrant EGFR activity in a subject, the method comprising administering to a subject in need of inhibition of aberrant EGFR activity a pharma- ceutical effective amount of a salt or free base disclosed herein or a corresponding pharmaceutical composition.

[0019] The present disclosure provides methods for inhibiting various mutant forms of EGFR, including EGFR enzymes having amino acid modifications selected from the group consisting of L858R, T790M, C797S, and combinations thereof. [Brief description of the drawings]

[0020] [Figure 1] 1 shows the X-ray powder diffraction (XRPD) pattern of 1:0.5 Compound (I) hemisuccinate Form C. [Diagram 2] 1 shows thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of 1:0.5 Compound (I) hemisuccinate Form C. [Diagram 3] 1 shows a differential scanning calorimetry (DSC) thermogram of 1:0.5 Compound (I) hemisuccinate Form C. [Figure 4] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of 1:0.5 Compound (I) hemi-glutarate form D. [Diagram 5] 1 shows thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of 1:0.5 Compound (I) hemi-glutarate form D. [Figure 6] FIG. 1 shows a differential scanning calorimetry (DSC) thermogram of 1:0.5 Compound (I) hemi-glutarate form D. [Figure 7] 1 shows the X-ray powder diffraction (XRPD) pattern of 1:1 Compound (I) fumarate form E. [Figure 8] 1 shows thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of 1:1 Compound (I) fumarate form E. [Figure 9] 1 shows a differential scanning calorimetry (DSC) thermogram of 1:1 Compound (I) fumarate form E. [Figure 10] 1 shows the X-ray powder diffraction (XRPD) pattern of Compound (I) free base Form A. [Figure 11] 1 shows thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of Compound (I) free base Form A. [Figure 12] 1 shows the X-ray powder diffraction (XRPD) pattern of Compound (I) free base form B. [Figure 13] 1 shows thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of Compound (I) free base Form B. [Figure 14]1 shows a differential scanning calorimetry (DSC) thermogram of Compound (I) free base Form B. [Figure 15] 1 shows the X-ray powder diffraction (XRPD) pattern of amorphous Compound (I). [Figure 16] 1 shows thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of amorphous Compound (I). [Figure 17] 1 shows a differential scanning calorimetry (DSC) thermogram of amorphous Compound (I). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] The present disclosure relates to a succinate salt of Compound (I) (i.e., a 1:0.5 hemisuccinate salt), a glutarate salt of Compound (I) (i.e., a 1:0.5 hemiglutarate salt), a fumarate salt of Compound (I) (i.e., a 1:1 fumarate salt), a free base Form A of Compound (I), and a free base Form B of Compound (I).

[0022] As used herein, "crystalline" refers to a solid that has a crystal structure in which the individual molecules have a highly uniform, regular three-dimensional organization.

[0023] In some embodiments, for crystalline forms of Compound (I) salt or free base disclosed herein, at least a particular weight percentage of the 1:0.5 or 1:1 Compound (I) salt or free base is in a particular crystalline form, the particular weight percentage including 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or 70%-75%, 75%-80%, 80%-85%, 85%-90%, 90%-95%, 95%-100%, 70-80%, 80-90%, 90-100% weight percent of the Compound (I) salt or free base is in a particular crystalline form. It is understood that all values ​​and ranges between these values ​​and ranges are meant to be encompassed by the present disclosure.

[0024] When a crystalline Compound (I) salt or free base is defined as one specific crystalline form of a specific percentage of Compound (I) salt or free base, the remainder is composed of amorphous and / or crystalline forms other than the one or more specific forms specified. Examples of specific crystalline forms include 1:0.5 Compound (I) hemisuccinate salt Form C, 1:0.5 Compound (I) hemiglutarate Form D, 1:1 Compound (I) fumarate Form E, Compound (I) free base Form A, and Compound (I) free base Form B, each of which is characterized by one or more properties as discussed herein.

[0025] Compound (I) has four chiral centers. Compound (I) in the salt and free base polymorphs disclosed herein is at least 80%, 90%, 99%, or 99.9% pure by weight with respect to other stereoisomers, i.e., the ratio of the weight of that stereoisomer to the weight of all stereoisomers.

[0026] The crystalline Compound (I) salts disclosed herein exhibit strong, unique XRPD patterns with sharp peaks and flat baselines corresponding to the angular peak positions in 2θ indicative of highly crystalline materials (see, for example, FIG. 1).

[0027] As used herein, an X-ray powder diffractogram is "substantially similar to that in a [particular] figure" if at least 90%, such as at least 95%, at least 98%, or at least 99%, of the signals in the two diffractograms are the same ±0.2 degrees 2θ. In determining "substantial similarity," one of skill in the art will understand that there may be variations in intensity and / or signal positions in XRPD diffractograms even with the same crystalline form. Thus, one of skill in the art will understand that a signal maximum in an XRPD diffractogram (in degrees 2θ as referred to herein) generally means ±0.2 degrees 2θ of that reported value, which is an art-recognized variation as discussed above.

[0028] Succinate of Compound (I) In some embodiments, the present disclosure provides a succinate salt of Compound (I), represented by the following structural formula: [ka] The molar ratio between compound (I) and succinic acid is 1:0.5.

[0029] In some embodiments, the succinate salt is crystalline.

[0030] In some embodiments, the 1:0.5 Compound (I) hemisuccinate is a crystalline Form C and is characterized by an X-ray powder diffraction pattern comprising peaks at 4.5°, 9.3°, and 15.3°±0.2° in terms of 2θ. In some embodiments, Form C is characterized by an X-ray powder diffraction pattern comprising at least three peaks selected from 4.5°, 8.9°, 9.3°, 15.3°, and 17.8°±0.2° in terms of 2θ. In some embodiments, Form C is characterized by an X-ray powder diffraction pattern comprising peaks at 4.5°, 8.9°, 9.3°, 15.3°, and 17.8°±0.2° in terms of 2θ. In some embodiments, Form C is characterized by an X-ray powder diffraction pattern comprising peaks at 4.5°, 8.9°, 9.3°, 13.0°, 15.3°, 16.8°, 17.8°, 18.1°, 18.5°, and 22.3°±0.2 in 2θ. In some embodiments, Form C is characterized by an X-ray powder diffraction pattern comprising peaks at 4.5°, 6.7°, 8.9°, 9.3°, 11.1°, 12.3°, 13.0°, 14.4°, 15.3°, 16.3°, 16.8°, 17.8°, 18.1°, 18.5°, 20.5°, 22.3°, and 26.0°±0.2 in 2θ. In some embodiments, Form C is characterized by an X-ray powder diffraction pattern substantially similar to FIG.

[0031] In some embodiments, Form C is characterized by having an onset temperature (i.e., melting temperature) by differential scanning calorimetry of 175±2° C. In some embodiments, Form C is characterized by having an onset temperature by differential scanning calorimetry of 176±2° C. In some embodiments, Form C is characterized by having a peak temperature by differential scanning calorimetry of 182±2° C. In some embodiments, Form C is characterized by having a peak temperature by differential scanning calorimetry of 179±2° C.

[0032] In some embodiments, Form C is characterized by a thermogravimetric analysis (TGA) substantially similar to that in FIG.

[0033] In some embodiments, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% by weight of the 1:0.5 Compound (I) hemisuccinate is in crystalline form C.

[0034] Glutarate of compound (I) In some embodiments, the present disclosure provides a glutarate salt of Compound (I), represented by the following structural formula: [ka] The molar ratio between compound (I) and glutaric acid is 1:0.5.

[0035] In some embodiments, the glutarate salt is crystalline.

[0036] In some embodiments, the 1:0.5 Compound (I) hemi glutarate crystalline Form D is characterized by an X-ray powder diffraction pattern comprising peaks at 8.8°, 16.1°, and 18.3°±0.2 in 2θ. In some embodiments, Form D is characterized by an X-ray powder diffraction pattern comprising at least three peaks selected from 8.8°, 14.8°, 16.1°, 18.3°, and 18.7°±0.2 in 2θ. In some embodiments, Form D is characterized by an X-ray powder diffraction pattern comprising peaks at 8.8°, 14.8°, 16.1°, 18.3°, and 18.7°±0.2 in 2θ. In some embodiments, Form D is characterized by an X-ray powder diffraction pattern comprising peaks at 7.4°, 8.8°, 12.3°, 14.8°, 16.1°, 18.3°, and 18.7°±0.2 in 2θ. In some embodiments, Form D is characterized by an X-ray powder diffraction pattern comprising peaks at 6.6°, 7.4°, 8.8°, 12.3°, 12.9°, 14.8°, 16.1°, 18.3°, 18.7°, 19.2°, 20.0°, and 22.2°±0.2 2θ. In some embodiments, Form D is characterized by an X-ray powder diffraction pattern substantially similar to FIG.

[0037] In some embodiments, Form D is characterized by having an onset temperature by differential scanning calorimetry of 142±2° C. In some embodiments, Form D is characterized by having a peak temperature by differential scanning calorimetry of 150±2° C. In some embodiments, Form D is characterized by having a peak temperature by differential scanning calorimetry of 148±2° C.

[0038] In some embodiments, Form D is characterized by a thermogravimetric analysis (TGA) substantially similar to that in FIG.

[0039] In some embodiments, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% by weight of the 1:0.5 Compound (I) hemi glutarate is in crystalline form D.

[0040] Fumarate of compound (I) In some embodiments, the present disclosure provides a fumarate salt of Compound (I), represented by the following structural formula: [ka] The molar ratio between compound (I) and fumaric acid is 1:1.

[0041] In some embodiments, the Fumarate Salt is crystalline.

[0042] In some embodiments, the 1:1 Compound (I) Fumarate is in crystalline form E and is characterized by an X-ray powder diffraction pattern comprising peaks at 6.3°, 8.5°, and 14.5°±0.2 in 2θ. In some embodiments, form E is characterized by an X-ray powder diffraction pattern comprising at least three peaks selected from 6.3°, 8.5°, 9.0°, 14.5°, 15.7°, and 18.0°±0.2 in 2θ. In some embodiments, form E is characterized by an X-ray powder diffraction pattern comprising peaks at 6.3°, 8.5°, 9.0°, 14.5°, 15.7°, and 18.0°±0.2 in 2θ. In some embodiments, Form E is characterized by an X-ray powder diffraction pattern including peaks at 6.3°, 8.5°, 9.0°, 12.1°, 14.5°, 15.7°, 18.0°, 19.7°, 20.1°, and 21.9°±0.2 in 2θ. In some embodiments, Form E is characterized by an X-ray powder diffraction pattern including peaks at 6.3°, 8.5°, 9.0°, 12.1°, 14.5°, 15.1°, 15.2°, 15.4°, 15.7°, 18.0°, 18.2°, 18.9°, 19.3°, 19.7°, 20.1°, 20.6°, 20.7°, 21.3°, and 21.9°±0.2 in 2θ. In some embodiments, Form E is characterized by an X-ray powder diffraction pattern substantially similar to FIG.

[0043] In some embodiments, Form E is characterized by having an onset temperature by differential scanning calorimetry of 164±3° C. In some embodiments, Form E is characterized by having an onset temperature by differential scanning calorimetry of 165±2° C. In some embodiments, Form E is characterized by having an onset temperature by differential scanning calorimetry of 162±2° C. In some embodiments, Form E is characterized by having a peak temperature by differential scanning calorimetry of 171±2° C.

[0044] In some embodiments, Form E is characterized by a thermogravimetric analysis (TGA) substantially similar to that in FIG.

[0045] In some embodiments, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% by weight of the 1:1 Compound (I) fumarate is in crystalline form E.

[0046] Compound (I) Free Base Form A In some embodiments, the disclosure provides a free base of Compound (I), represented by the following structural formula: [ka] The free base of Compound (I) is in crystalline form A.

[0047] In some embodiments, the free base of Compound (I) is in crystalline Form A and is characterized by an X-ray powder diffraction pattern comprising peaks at 9.9°, 12.1°, and 14.5°±0.2 in 2θ. In some embodiments, Form A is characterized by an X-ray powder diffraction pattern comprising at least three peaks selected from 9.9°, 12.1°, 14.5°, 15.9°, and 20.1°±0.2 in 2θ. In some embodiments, Form A is characterized by an X-ray powder diffraction pattern comprising peaks at 9.9°, 12.1°, 14.5°, 15.9°, and 20.1°±0.2 in 2θ. In some embodiments, Form A is characterized by an X-ray powder diffraction pattern comprising peaks at 8.0°, 9.9°, 11.8°, 12.1°, 14.5°, 15.9°, 19.4°, 19.7°, 20.1°, and 20.7°±0.2 in 2θ. In some embodiments, Form A is characterized by an X-ray powder diffraction pattern comprising peaks at 6.7°, 8.0°, 9.9°, 11.8°, 12.1°, 14.5°, 15.9°, 18.7°, 19.4°, 19.7°, 20.1°, 20.5°, 20.7°, 22.0°, 22.8°, and 23.8°±0.2 in 2θ. In some embodiments, Form A is characterized by an X-ray powder diffraction pattern substantially similar to FIG.

[0048] In some embodiments, Form A is characterized by having an onset temperature of 198±2° C. by differential scanning calorimetry. In some embodiments, Form A is characterized by having an onset temperature of 197±2° C. by differential scanning calorimetry. In some embodiments, Form A is characterized by having a peak temperature of 202±2° C. by differential scanning calorimetry. In some embodiments, Form A is characterized by having an onset temperature of 199±2° C. by differential scanning calorimetry. In some embodiments, Form A is characterized by having a peak temperature of 203±2° C. by differential scanning calorimetry. In some embodiments, Form A is characterized by having an onset temperature of 181±2° C. by differential scanning calorimetry. In some embodiments, Form A is characterized by having a peak temperature of 188±2° C. by differential scanning calorimetry.

[0049] In some embodiments, Form A is characterized by a thermogravimetric analysis (TGA) substantially similar to that in FIG.

[0050] In some embodiments, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% by weight of Compound (I) free base is in crystalline form A.

[0051] Characterization of Compound (I) Free Base Form B In some embodiments, the disclosure provides a free base of Compound (I), represented by the following structural formula: [ka] The free base of Compound (I) is in crystalline form B.

[0052] In some embodiments, Compound (I) free base is in crystalline form B and is characterized by an X-ray powder diffraction pattern including peaks at 5.1°, 12.2°, 13.5°, 16.6°, and 20.1°±0.2° in terms of 2θ. In some embodiments, form B is characterized by an X-ray powder diffraction pattern including peaks at 5.1°, 12.2°, 13.5°, 16.3°, 16.6°, 19.5°, 20.1°, 20.4°, 21.4°, 22.7°, and 25.2°±0.2° in terms of 2θ. In some embodiments, Form B is characterized by an X-ray powder diffraction pattern comprising peaks at 5.1°, 12.2°, 13.5°, 15.2°, 16.3°, 16.6°, 17.9°, 19.5°, 20.1°, 20.4°, 20.7°, 20.9°, 21.4°, 22.7°, 25.2°, and 26.3°±0.2 2θ. In some embodiments, Form B is characterized by an X-ray powder diffraction pattern substantially similar to FIG.

[0053] In some embodiments, Form B is characterized by having an onset temperature by differential scanning calorimetry of 158±2° C. In some embodiments, Form B is characterized by having an onset temperature by differential scanning calorimetry of 159±2° C. In some embodiments, Form B is characterized by having a peak temperature by differential scanning calorimetry of 165±2° C. In some embodiments, Form B is characterized by having a peak temperature by differential scanning calorimetry of 166±2° C.

[0054] In some embodiments, Form B is characterized by a thermogravimetric analysis (TGA) substantially similar to that in FIG.

[0055] In some embodiments, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% by weight of Compound (I) free base is in crystalline form B.

[0056] Characterization of polymorphic compound (I) In some embodiments, the present disclosure provides an amorphous form of Compound (I) represented by the following structural formula: [ka]

[0057] In some embodiments, the amorphous form is characterized by an onset temperature by differential scanning calorimetry of 106±2° C. In some embodiments, the amorphous form is characterized by an onset temperature by differential scanning calorimetry of 109±2° C. In some embodiments, the amorphous form is characterized by a peak temperature by differential scanning calorimetry of 113±2° C. In some embodiments, the amorphous form is characterized by a peak temperature by differential scanning calorimetry of 114±2° C.

[0058] In some embodiments, the amorphous form is characterized by an X-ray powder diffraction pattern substantially similar to that in FIG.

[0059] In some embodiments, the amorphous form is characterized by a thermogravimetric analysis (TGA) substantially similar to that of FIG.

[0060] In some embodiments, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% by weight of Compound (I) free base is in amorphous form.

[0061] Pharmaceutical Compositions A pharmaceutical composition of the present disclosure (also referred to herein as a "pharmaceutical composition of the disclosure") comprises a pharma- ceutically acceptable carrier or diluent and a salt or solid form of the present disclosure.

[0062] Some embodiments of the present disclosure relate to a pharmaceutical composition comprising a pharma- ceutically acceptable excipient or diluent and a succinate salt of compound (I), wherein the molar ratio between compound (I) and succinic acid is 1:0.5. In some embodiments, the succinate salt is crystalline. In some embodiments, the succinate salt of compound (I) is crystalline form C.

[0063] Some embodiments of the present disclosure relate to a pharmaceutical composition comprising a pharma- ceutically acceptable excipient or diluent and a glutarate salt of compound (I), wherein the molar ratio between compound (I) and glutaric acid is 1:0.5. In some embodiments, the glutarate salt is crystalline. In some embodiments, the glutarate salt of compound (I) is crystalline form D.

[0064] Some embodiments of the present disclosure relate to a pharmaceutical composition comprising a pharma- ceutically acceptable excipient or diluent and a fumarate salt of compound (I), wherein the molar ratio between compound (I) and fumaric acid is 1:1. In some embodiments, the fumarate salt is crystalline. In some embodiments, the fumarate salt of compound (I) is crystalline form E.

[0065] Some embodiments of the present disclosure relate to a pharmaceutical composition comprising a pharma- ceutically acceptable excipient or diluent and Compound (I) free base. 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.

[0066] "Pharmaceutically acceptable carrier" or "pharmaceutically acceptable diluent" refers to a substance that aids in the formulation and / or administration of and / or absorption by an active agent to a subject and can be included in a pharmaceutical composition of the present disclosure without causing adverse toxicological effects to the subject. Non-limiting examples of pharmaceutically acceptable carriers and / or diluents include water, NaCl, normal saline, lactated Ringer's solution, normal sucrose, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavoring agents, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates such as lactose, amylose or starch, hydroxymethylcellulose, fatty acid esters, polyvinylpyrrolidine, and dyes. Such preparations can be sterilized and, if necessary, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents, and / or flavoring agents that do not adversely react with or interfere with the activity of the compounds provided herein. Those skilled in the art will recognize that other pharmaceutical excipients are suitable for use with the salts or solid forms of the present disclosure, or pharma- ceutically acceptable salts thereof.

[0067] Pharmaceutical compositions of the present disclosure optionally include one or more pharma- ceutically acceptable carriers and / or diluents therefor, such as lactose, starch, cellulose, and dextrose. Other excipients, such as flavorings, sweeteners, and preservatives, e.g., methyl, ethyl, propyl, and butyl parabens, may also be included. A more complete listing of suitable excipients can be found in the Handbook of Pharmaceutical Excipients (5 thEd., Pharmaceutical Press (2005). A person skilled in the art will know how to prepare suitable formulations for various types of administration routes. Conventional procedures and ingredients for the selection and preparation of suitable formulations can be found, for example, in Remington's Pharmaceutical Sciences (2003-20th edition) and The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999. A carrier, diluent, and / or excipient is "acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical composition and not deleterious to the recipient thereof.

[0068] Treatment method The present disclosure provides a method of inhibiting a particular mutant form of epidermal growth factor receptor (EGFR) in a subject in need thereof, the method comprising administering to the subject an effective amount of a salt or solid form of the present disclosure or a pharmaceutical composition disclosed herein. Mutant forms of EGFR include, for example, EGFR with LRTMCS mutations (exon 19 deletion (del19) or exon 21 (L858R) substitution mutations, T790M mutations, and C797S mutations). A subject "in need of inhibiting EGFR" is one who has a disease in which a beneficial therapeutic effect can be achieved by inhibiting at least one mutant EGFR, for example, slowing disease progression, alleviating one or more symptoms associated with the disease, or extending the lifespan of the subject in view of the disease.

[0069] In some embodiments, the present disclosure provides a method of treating a disease / condition / or cancer associated with or regulated by mutant EGFR, where inhibition of mutant EGFR is a therapeutic benefit, including but not limited to, treatment of cancer in a subject in need thereof. The method comprises administering to the subject an effective amount of a salt or solid form of the present disclosure herein or a pharmaceutical composition disclosed herein.

[0070] In another embodiment, the present disclosure provides a method of treating a subject having cancer, the method comprising administering to the subject an effective amount of a salt or solid form of the present disclosure or a pharmaceutical composition disclosed herein.Cancers that may be treated according to the disclosed method include lung cancer, colon cancer, urothelial cancer, breast cancer, prostate cancer, brain cancer, ovarian cancer, gastric cancer, pancreatic cancer, head and neck cancer, bladder cancer, and mesothelioma, including metastases (particularly brain metastases) of all cancers listed.Typically, the cancer is characterized by one or more EGFR mutations as described herein.In certain embodiments, the cancer has progressed during or after EGFR tyrosine kinase inhibitor (TKI) therapy.In certain embodiments, the disease has progressed during or after administration of first-line osimertinib.

[0071] In certain embodiments, the cancer to be treated is lung cancer. In more specific embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is locally advanced or metastatic NSCLC, NSCLC adenocarcinoma, squamous histology NSCLC and non-squamous histology NSCLC. In another embodiment, the lung cancer is NSCLC adenocarcinoma. In another specific embodiment, the lung cancer (or non-small cell lung cancer) metastasizes to the brain.

[0072] In another embodiment, the disease / condition / or cancer is associated with or regulated by mutant EGFR characterized by an EGFR genotype selected from genotypes 1 to 17 according to the table below ((del18=Exon 18 deletion, particularly, for example, del E709_T710 insD; del19=Exon 19 deletion, particularly, for example, delE746_A750 (most common), delE746_S752insV, del747_A750insP, delL747_P753insS, and delS752_I759; ex20ins-Exon 20 Insertions, in particular, for example, D761-E762insX, A763-Y764insX, Y764-V765insX, V765-M766insX, A767-S768insX, S768-D769insX, V769-D770insX, N771-P772insX, P772-H773insX, H773-V774insX, and V774-C775insX). [Table 1-1] [Table 1-2] [Table 1-3]

[0073] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with the salt or solid form of the disclosure, or the pharmaceutical composition disclosed herein, is characterized by EGFR, including EGFR del19.

[0074] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with the salt or solid form of the present disclosure, or the pharmaceutical composition disclosed herein, is characterized by EGFR, including EGFR del19 T790M.

[0075] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with the salt or solid form of the present disclosure, or the pharmaceutical composition disclosed herein, is characterized by EGFR, including EGFR del19 C797S.

[0076] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with the salt or solid form of the present disclosure, or the pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR del19 C797X (C797G or C797N).

[0077] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a salt or solid form of the disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR, including EGFR del19 T790M C797S.

[0078] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with the salt or solid form of the present disclosure, or the pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR del19 T790M (C797G or C797N).

[0079] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with the salt or solid form of the present disclosure, or the pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR del19 L792X (L792F, L792H, or L792Y).

[0080] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with the salt or solid form of the disclosure, or the pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR del19 T790M L792X (L792F, L792H, or L792Y).

[0081] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with the salt or solid form of the present disclosure, or the pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR del19 G796R (G796S).

[0082] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with the salt or solid form of the present disclosure, or the pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR del19 L792R (L792V or L792P).

[0083] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with the salt or solid form of the present disclosure, or the pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR del19 L718Q (L718V).

[0084] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with the salt or solid form of the disclosure, or the pharmaceutical composition disclosed herein, is characterized by EGFR, including EGFR del19 T790M G796R (G796S).

[0085] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with the salt or solid form of the disclosure, or the pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR del19 T790M L792R (L792V or L792P).

[0086] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with the salt or solid form of the present disclosure, or the pharmaceutical composition disclosed herein, is characterized by EGFR, including EGFR del19 T790M L718Q (L718V).

[0087] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with the salt or solid form of the disclosure, or the pharmaceutical composition disclosed herein, is characterized by EGFR, including EGFR L858R.

[0088] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with the salt or solid form of the disclosure, or the pharmaceutical composition disclosed herein, is characterized by EGFR, including EGFR L858R T790M.

[0089] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with the salt or solid form of the disclosure, or the pharmaceutical composition disclosed herein, is characterized by EGFR, including EGFR L858R C797S.

[0090] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with the salt or solid form of the disclosure, or the pharmaceutical composition disclosed herein, is characterized by EGFR, including EGFR L858R C797X (797G or C797N).

[0091] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a salt or solid form of the disclosure, or a pharmaceutical composition disclosed herein, is characterized by EGFR, including EGFR L858R T790M C797S.

[0092] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with the salt or solid form of the disclosure, or the pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR L858R T790M C797X (797G or C797N).

[0093] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with the salt or solid form of the disclosure, or the pharmaceutical composition disclosed herein, is characterized by EGFR, including EGFR L858R L792X (L792F, L792H, or L792Y).

[0094] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with the salt or solid form of the disclosure, or the pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR L858R L790M L792X (L792F, L792H, or L792Y).

[0095] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with the salt or solid form of the disclosure, or the pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR L858R G796R (G796S).

[0096] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with the salt or solid form of the disclosure, or the pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR L858R L792R (L792V or L792P).

[0097] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with the salt or solid form of the disclosure, or the pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR L858R L718Q (L718V).

[0098] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with the salt or solid form of the disclosure, or the pharmaceutical composition disclosed herein, is characterized by EGFR, including EGFR L858R T790M G796R (G796S).

[0099] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with the salt or solid form of the disclosure, or the pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR L858R T790M L792R (L792V or L792P).

[0100] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with the salt or solid form of the disclosure, or the pharmaceutical composition disclosed herein, is characterized by EGFR comprising EGFR L858R T790M L718Q (L718V).

[0101] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with the salt or solid form of the present disclosure, or the pharmaceutical composition disclosed herein, is characterized by EGFR, including EGFR del18.

[0102] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with the salts or solid forms of the disclosure, or the pharmaceutical compositions disclosed herein, is characterized by EGFR, including EGFR G719X (G719A, G719S, G719C, G719R, G719D, or G719V).

[0103] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with the salt or solid form of the disclosure, or the pharmaceutical composition disclosed herein, is characterized by EGFR containing EGFR E709X (E709K, E709H, or E709A).

[0104] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with the salts or solid forms of the disclosure, or the pharmaceutical compositions disclosed herein, is characterized by EGFR containing EGFR E709X (E709K, E709H, or E709A) (G719A, G719S, G719C, G719D, G719R, or G719V).

[0105] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with the salt or solid form of the disclosure, or the pharmaceutical composition disclosed herein, is characterized by EGFR, including EGFR G719X (G719A, G719S, G719C, G719D, G719R, or G719V) S768I.

[0106] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with the salt or solid form of the present disclosure, or the pharmaceutical composition disclosed herein, is characterized by EGFR containing the EGFR ex20ins.

[0107] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with the salt or solid form of the disclosure, or the pharmaceutical composition disclosed herein, is characterized by EGFR containing the EGFR ex20ins L718Q.

[0108] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with the salt or solid form of the disclosure, or the pharmaceutical composition disclosed herein, is characterized by EGFR containing the EGFR ex20ins T790M.

[0109] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with the salt or solid form of the disclosure, or the pharmaceutical composition disclosed herein, is characterized by EGFR containing the EGFR ex20ins C797S.

[0110] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with the salt or solid form of the disclosure, or the pharmaceutical composition disclosed herein, is characterized by EGFR, including EGFR S7681I.

[0111] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with the salt or solid form of the disclosure, or the pharmaceutical composition disclosed herein, is characterized by EGFR, including EGFR T790M.

[0112] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with the salt or solid form of the disclosure, or the pharmaceutical composition disclosed herein, is characterized by EGFR, including EGFR T790M C797S / G L792X (L792F, L792H, L792R, or L792Y).

[0113] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with the salt or solid form of the disclosure, or the pharmaceutical composition disclosed herein, is characterized by an EGFR genotype selected from genotypes 1-17.

[0114] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a salt or solid form of the disclosure, or a pharmaceutical composition disclosed herein, is characterized by an EGFR mutation that confers resistance to osimertinib.

[0115] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a salt or solid form of the present disclosure, or a pharmaceutical composition disclosed herein, is characterized by an EGFR mutation that confers resistance to afatinib.

[0116] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a salt or solid form of the present disclosure, or a pharmaceutical composition disclosed herein, is characterized by an EGFR mutation that confers resistance to dacomitinib.

[0117] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with the salt or solid form of the present disclosure, or the pharmaceutical composition disclosed herein, is characterized by an EGFR mutation that confers resistance to gefitinib.

[0118] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with the salt or solid form of the present disclosure, or the pharmaceutical composition disclosed herein, is characterized by an EGFR mutation that confers resistance to erlotinib.

[0119] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a salt or solid form of the present disclosure, or a pharmaceutical composition disclosed herein, is characterized by an EGFR mutation that confers resistance to osimertinib and afatinib.

[0120] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a salt or solid form of the disclosure, or a pharmaceutical composition disclosed herein, is characterized by an EGFR mutation that confers resistance to osimertinib and dacomitinib.

[0121] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with the salts or solid forms of the present disclosure, or the pharmaceutical compositions disclosed herein, is characterized by EGFR mutations that confer resistance to osimertinib and gefitinib.

[0122] In another embodiment, the disease / condition / or cancer (e.g., NSCLC) treated with a salt or solid form of the disclosure, or a pharmaceutical composition disclosed herein, is characterized by an EGFR mutation that confers resistance to osimertinib and erlotinib.

[0123] Another embodiment is the treatment of a subject with metastatic NSCLC with a tumor harboring an exon 19 deletion or an L858R EGFR mutation and an activating resistance mutation disclosed herein as detected by an approved molecular testing methodology. Another embodiment is a salt or solid form of the disclosure, or a pharmaceutical composition disclosed herein, used in combination with a first or third generation TKI indicated for the treatment of a subject with metastatic NSCLC with a tumor harboring T790M and C797S mutations detected by an approved test, and whose disease has progressed on or after at least two prior EGFR TKI therapies.

[0124] Another embodiment is the salt or solid form of the present disclosure or the pharmaceutical composition disclosed herein for the treatment of subjects with metastatic NSCLC, whose disease with target EGFR resistance progresses at or after any EGFR TKI.In certain embodiments, the salt or solid form of the present disclosure or the pharmaceutical composition disclosed herein is used in combination with a first or third generation TKI that is adapted for the treatment of subjects with metastatic NSCLC.

[0125] Another embodiment is a salt or solid form of the present disclosure, or a pharmaceutical composition disclosed herein, for the treatment of subjects with metastatic EGFR C797S mutation-positive NSCLC detected by an approved molecular test, whose disease has progressed on or after first-line omesirtinib. In certain embodiments, a salt or solid form of the present disclosure, or a pharmaceutical composition disclosed herein, is used in combination with a first or third generation TKI indicated for the treatment of subjects with metastatic NSCLC.

[0126] In certain embodiments, the deletions, mutations, and insertions disclosed herein are detected by an FDA approved test.

[0127] One of skill in the art can readily determine whether a subject has a particular EGFR alteration in their cells, cancer, gene, or gene product, e.g., whether the subject has one or more of the mutations or deletions described herein, using a detection method selected from those known in the art, such as hybridization-based methods, amplification-based methods, microarray analysis, flow cytometry analysis, DNA sequencing, next generation sequencing (NGS), primer extension, PCR, in situ hybridization, fluorescent in situ hybridization, dot blot, and Southern blot.

[0128] To detect one or more EGFR deletions and / or mutations, primary tumor samples, circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and / or circulating exosomes can be collected from a subject. Samples are processed and nucleic acids are isolated using techniques known in the art, and then the nucleic acids are sequenced using methods known in the art. Sequences are then mapped to individual exons, and a measure of transcriptional expression (e.g., RPKM, or reads per kilobase per million mapped reads) is quantified. Raw sequence and exon array data are available from sources such as TCGA, ICGC, and NCBI Gene Expression Omnibus (GEO). For a given sample, individual exon coordinates are annotated with gene identifier information, and exons that belong to the kinase domain are flagged. Exon levels are then z-score normalized across all tumor samples.

[0129] The salts and solid forms of the present disclosure, or pharmaceutical compositions disclosed herein, may be used to treat subjects who have become refractory to treatment with one or more other EGFR inhibitors. "Refractory" means that the subject's cancer previously responded to the drug, but later responded poorly or not at all. In some embodiments, the subject has become refractory to one or more first generation EGFR inhibitors, such as erlotinib, gefitinib, icotinib, or lapatinib. In some embodiments, the subject has become refractory to treatment with one or more second generation EGFR inhibitors, such as afatinib, dacomitinib, poziotinib, or neratinib. In some embodiments, the subject has become refractory to treatment with one or more first generation inhibitors and one or more second generation inhibitors. In some embodiments, the subject has become refractory to treatment with one or more third generation inhibitors, such as osimertinib, nazartinib, or avitinib. In one embodiment, the subject has become refractory to treatment with one or more first generation EGFR inhibitors and one or more third generation EGFR inhibitors. In some embodiments, the subject has become refractory to treatment with one or more second generation EGFR inhibitors and one or more third generation EGFR inhibitors. In some embodiments, the subject has become refractory to treatment with one or more first generation inhibitors and one or more third generation EGFR inhibitors.

[0130] combination The salt or solid form of the present disclosure, or the pharmaceutical composition disclosed herein, may be used in combination with one or more additional pharmacologically active substances.For example, the present disclosure includes a method of treating a condition / disease / or cancer, the method comprising administering to a subject in need thereof a salt or solid form of the present disclosure, or a pharmaceutical composition disclosed herein, such as afatinib, osimertinib, lapatinib, erlotinib, dacomitinib, poziotinib, neratinib, gefitinibJBJ-04-125-02, alfutinib (AST281 8), almonertinib (HS10296), BBT-176, BI-4020, CH7233163, gilitertinib, JND-3229, lazertinib, nazartinib (EGF816), PCC-0208027, resibertinib (BPI-7711), TQB3804, zolifertinib (AZ-3759), or DZD9008, which are EGFR (or or a bispecific EGFR and MET antibody (e.g., amivantamab ((JNJ-61186372, JNJ-372)). For the treatment of cancer, e.g., NSCLC, for example, a salt or solid form of the disclosure, or a pharmaceutical composition disclosed herein, may be used in combination with a first line therapy, e.g., a first, second, or third generation EGFR inhibitor (i.e., as an initial treatment before the cancer becomes refractory) to forestall or delay the cancer from becoming refractory. Typically, the cancer is characterized by one of the EGFR genotypes described herein.

[0131] Alternatively, the salts or solid forms of the disclosure, or the pharmaceutical compositions disclosed herein, can be used in combination with other anti-cancer agents that are not EGFR inhibitors, such as MEK, including MEK mutant MEK inhibitors (trametinib, cobimtetinib, binimetinib, selumetinib, rifametinib); c-MET, including mutant c-MET inhibitors (savolitinib, cabozantinib, foretinib, grumetinib, tepotinib) and MET antibodies (emibetuzumab, terisotuzumab vedotin (ABBV339)); mitotic kinase inhibitors (CDK4 / 6 inhibitors such as palbociclib, ribociclib, abemacicilb, GIT38); antiangiogenic agents such as bevacizumab, nintedanib; apoptosis inducers such as Bcl-2 inhibitors such as venetoclax, obatoclax, navitoclax, palsitoclax (APG-1252), and Mcl-1 inhibitors such as AZD-5991, AMG-176, S-64315; mTOR inhibitors such as rapamycin, temsirolimus, everolimus, lidforolimus; RET inhibitors such as pralsetinib and selpercatinib, and PI3K inhibitors dactolisib (BEZ235), pictilisib (GDC-0941), LY294002, idelalisib (CAL-101); JAK inhibitors (e.g., AZD4205, itacitinib), Aurora A inhibitors (e.g., alisertibi); BCR / ABL and / or Src family tyrosine kinase inhibitors (e.g., dasatinib); VEGF inhibitors (e.g., MP0250, ramucirumab); multikinase protein inhibitors (e.g., anlotinib, midostaurin); P It can be administered in combination with an ARP inhibitor (e.g., niraparib); platinum therapy (e.g., cisplatin (CDDP), carboplatin (CBDCA), or nedaplatin (CDGP); a PD-L1 inhibitor (e.g., durvalumab (MEDI4736)); a HER2 / neu receptor inhibitor (e.g., trastuzumab), an anti-HER2 or anti-HER3 antibody-drug conjugate (e.g., patritumab delquistecan (U3-1402), trastuzumab emtansine), or an immunogene therapy (e.g., Oncoplex).

[0132] A "subject" is a human in need of treatment.

[0133] Method and form of administration The exact amount of the salt or solid form of the present disclosure or pharmaceutical composition disclosed herein administered to provide an "effective amount" to a subject will depend on the mode of administration, the type and severity of the cancer, and the characteristics of the subject, such as general health, age, sex, weight, and tolerance to drugs. Those skilled in the art will be able to determine the appropriate dosage depending on these and other factors. When administered in combination with other therapeutic agents, e.g., in combination with anti-cancer drugs, the "effective amount" of any additional therapeutic agent(s) will depend on the type of drug used. Suitable dosages are known for approved therapeutic agents and can be adjusted by those skilled in the art depending on the condition of the subject, the type of condition(s) being treated, and the amount of the salt or solid form of the present disclosure used according to dosages reported in the literature and recommended in, for example, the Physician's Desk Reference (57th Ed., 2003).

[0134] "Treating" or "treatment" refers to obtaining a desired pharmacological and / or physiological effect. This effect can be therapeutic and includes partially or substantially achieving one or more of the following results: partially or substantially reducing the extent of a disease, condition, or cancer, ameliorating or improving clinical symptoms or indicators associated with a disease, condition, or cancer, delaying, inhibiting, or reducing the likelihood of progression of a disease, condition, or cancer, or reducing the likelihood of recurrence of a disease, condition, or cancer.

[0135] The term "effective amount" refers to an amount that, when administered to a subject, produces a beneficial or desired result, including a clinical result, e.g., inhibits, suppresses or reduces the symptoms of the condition being treated in the subject compared to a control. For example, a therapeutically effective amount can be provided in a unit dosage form (e.g., 0.1 mg to about 50 g per day, alternatively 1 mg to about 5 grams per day, alternatively 10 mg to 1 gram per day).

[0136] The terms "administer," "administering," "administration," and the like, as used herein, refer to methods that may be used to enable delivery of a composition to a desired site of biological action. These methods include, but are not limited to, intra-articular (into a joint), intravenous, intramuscular, intratumor, intradermal, intraperitoneal, subcutaneous, oral, topical, intrathecal, inhalation, transdermal, rectal, and the like. Administration techniques that may be used with the agents and methods described herein are found, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

[0137] In addition, the salts or solid forms of the present disclosure, or the pharmaceutical compositions disclosed herein, can be co-administered with other therapeutic agents. As used herein, "co-administration," "administered in combination," and their grammatical equivalents are meant to encompass administration of two or more therapeutic agents to a single subject, and are intended to include therapeutic regimens in which the agents are administered by the same or different routes of administration, or at the same or different times. In some embodiments, the salts or solid forms of the present disclosure, or the pharmaceutical compositions disclosed herein, are co-administered with other agents. These terms encompass administration of two or more agents to a subject, whereby both agents and / or their metabolites are present in the subject at the same time. They include simultaneous administration in separate compositions, administration at different times in separate compositions, and / or administration in a composition in which both agents are present. Thus, in some embodiments, the salts or solid forms of the present disclosure, or the pharmaceutical compositions disclosed herein, and the other agent(s) are administered in a single composition. In some embodiments, the compounds described herein and the other agent(s) are mixed in a composition.

[0138] The particular mode of administration and dosing regimen will be selected by the attending physician, taking into account the particulars of the case (e.g., subject, disease, disease state involved, particular treatment). Treatment may involve one or more daily doses, or less than once a day (such as once a week or once a month), over a period of several days to several months or even years. However, one of skill in the art will readily recognize appropriate and / or equivalent doses, consulting the dosages of compositions approved for treating diseases using the disclosed EGFR inhibitors for guidance.

[0139] As will be understood by those skilled in the art, the salt or solid form of the present disclosure, or the pharmaceutical composition disclosed herein, can be administered to a patient in various forms depending on the selected route of administration.The salt or solid form of the present disclosure, or the pharmaceutical composition disclosed herein, can be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump, or transdermal administration, and the pharmaceutical composition is formulated accordingly.Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, pulmonary, intrathecal, rectal, and topical modes of administration.Parenteral administration can be by continuous infusion over a selected period of time.

[0140] The pharmaceutical composition of the present disclosure is formulated to be compatible with its intended route of administration.In one embodiment, the composition is formulated according to routine procedures as a pharmaceutical composition that is compatible with intravenous, subcutaneous, intramuscular, oral, intranasal or topical administration to humans.In a preferred embodiment, the pharmaceutical composition is formulated for intravenous administration.

[0141] Typically, for oral therapeutic administration, the salts or solid forms of the present disclosure may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.

[0142] Typically, for parenteral administration, solutions of the salts or solid forms of the disclosure are prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO, and mixtures thereof, with or without the addition of alcohol, and in oils. These preparations contain a preservative to prevent the growth of microorganisms under ordinary conditions of storage and use.

[0143] Typically, for injectable use, sterile aqueous solutions or dispersions and sterile powders of the salts or solid forms of the disclosure are suitable for the extemporaneous preparation of sterile injectable solutions or dispersions.

[0144] The following examples are intended to illustrate, but not to limit the scope of the disclosure in any way. experiment [Table 2] [Table 3] [Table 4]

[0145] Analysis conditions Differential Scanning Calorimetry (DSC) The DSC is the Mettler Toledo DSC3. + Samples (1-5 mg) were weighed directly into 40 μL hermetically sealed aluminum pans with a pinhole and analyzed according to the following parameters: [Table 5] [Table 6]

[0146] Dynamic Vapor Sorption (DVS) DVS was performed using DVS Intrinsic1. Samples (5-25 mg) were loaded into a sample pan, suspended from a microbalance, and exposed to a humidified nitrogen gas stream. Samples were held at each level for a minimum of 5 min, progressing to the next humidity level only if there was less than 0.002% weight change between measurements (interval: 60 s) or 60 min had elapsed. The following program was used: Equilibration at 1-50% RH 2-50%~2%. (50%, 40%, 30%, 20%, 10%, and 2%) 3-2%~95% (2%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%) 4-95%~2% (95%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 2%) 5-2%~50% (2%, 10%, 20%, 30%, 40%, 50%)

[0147] High-performance liquid chromatography (HPLC) HPLC was performed using an Agilent 1220 Infinity LC. The flow rate range 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. The HPLC method is as follows: [Table 7]

[0148] Liquid Chromatography-Mass Spectrometry (LCMS) Liquid chromatography-mass spectrometry (LC-MS) data were obtained using an Agilent model-1260 LC system using an Agilent model 6120 mass spectrometer utilizing ES-API ionization equipped with an Agilent Poroshel120 (EC-C18, particle size 2.7 μm, dimensions 3.0×50 mm) reversed-phase column at 22.4° C. The mobile phase consisted of a mixture of solvents 0.1% formic acid in water and 0.1% formic acid in acetonitrile. A constant gradient of 95% aqueous / 5% organic to 5% aqueous / 95% organic mobile phase over 4 minutes was used. The flow rate was constant at 1 mL / min.

[0149] nuclear magnetic resonance (NMR) Proton NMR ( 1 H NMR was performed on a Bruker Avance 300 MHz spectrometer. Solids were dissolved in 0.75 mL of deuterated solvent in 4 mL vials, transferred to NMR tubes (Wilmad 5 mm thin wall 8 inch, 200 MHz, 506-PP-8) and analyzed according to the following parameters: [Table 8]

[0150] pH measurement pH was measured using a Mettler Toledo FP20 bench meter equipped with a Mettler Toledo InLab Micro pH electrode. The electrode had a ceramic junction and a membrane resistance of <600 MΩ. The internal reference electrolyte solution used was KCl, with an operating range of 0-14 pH units and 0-80°C.

[0151] Thermogravimetric analysis and differential scanning calorimetry (TGA and DSC) TGA and DSC: Mettler Toledo TGA / DSC 3+ The experiments were carried out simultaneously on the same samples using a 100% ethanol bromine gas (ethanol bromine) sulphate (ethanol ... [Table 9]

[0152] X-ray powder diffraction (XRPD) XRPD was performed using a Bruker D8 Advance equipped with a LYNXEYE detector in reflectance mode (i.e., Bragg-Brentano geometry). Samples were prepared on Si zero-return wafers. The parameters for the XRPD method used are listed below. [Table 10] [Table 11]

[0153] Example 1: Preparation and Characterization of the Crystalline Form of 1:0.5 Compound (I) Hemisuccinate Form C 1.1 Preparation The free base of Compound (I) (301 mg) was weighed into a 20 mL vial and 1.3 equivalents of succinic acid (83.4 mg) and a stir bar were added. 15 volumes of EtOAc (4.51 mL) were added at 45° C. and left stirring for 1 hour. The solid was light yellow and was filtered and washed with 2×2 vol. of EtOAc. The solid was dried overnight at 50° C. in a vacuum oven. The XRPD pattern showed that excess succinic acid was present. The solid was then reslurried in 5 vol. (1.36 mL) of IPA for 1 hour, then filtered and washed with 2×2 volumes of IPA. The solid was dried overnight at 50° C. in a vacuum oven. The purity by HPLC was 99.50 area %. The resulting solid was further characterized by XRPD (see FIG. 1 and Table 1) using normal scanning method, TGA-DSC (FIGS. 2 and 3), and DVS. The counterion stoichiometry (API:CI) was determined to be 1:0.5.

[0154] The combined DSC and TGA thermogram showed a total mass loss of 0.85 wt.% and an endotherm onset at 176.3° C. (FIG. 2). DSC alone showed an endotherm onset at 175.1° C. (FIG. 3). [Table 12]

[0155] 1.2 DVS of the crystalline form of 1:0.5 Compound (I) hemisuccinate The DVS was completed, showing a mass change of 7.1 wt.% at 25 °C and 2-95% relative humidity. After the standard 60 min at 95% RH the compound had not reached equilibrium and therefore this interval was kept for a total of 240 min. After this time the compound still had not reached equilibrium and the experiment was continued as described in the DVS analysis conditions above.

[0156] Example 2: Preparation and Characterization of the Crystalline Form of 1:0.5 Compound (I) Hemi-Glutarate Crystalline Form D The free base of Compound (I) (401 mg) was weighed into a 20 mL vial and 1.1 equivalents of glutaric acid (104.6 mg) and a stir bar were added. 15 volumes of EtOAc were added at 45° C. After 1 h, the temperature was reduced to RT and the pale yellow slurry was left stirring overnight. The next morning the slurry was noticeably thicker and more vibrant yellow in color. The slurry was filtered, washed with 2×2 volumes of EtOAc and dried at 50° C. for 5 h under effective vacuum (−30 in Hg). Purity by HPLC was 99.45 area % and stoichiometry was 1 Based on H NMR, it was calculated to be 1:0.53 compound (I) hemi glutarate. The resulting solid was further characterized by XRPD (see FIG. 4 and Table 2) and TGA-DSC (FIGS. 5 and 6) using normal scanning methods.

[0157] The combined DSC and TGA thermogram showed an endothermic onset at 142.5° C. with essentially no mass loss (FIG. 5). DSC alone showed an endothermic event with an onset of 142.3° C. and a small endotherm (−0.59 J / g) with an onset of 188.4° C. (FIG. 6). [Table 13]

[0158] Example 3: 1:1 Preparation and Characterization of the Crystalline Form of Compound (I) Fumarate Form E The free base of Compound (I) (409.5 mg) was weighed into a 20 mL vial and 1.1 equivalents of fumaric acid (96.6 mg) and a stir bar were added. 15 volumes of EtOAc were added at 45° C. After 1 h, the temperature was lowered to RT and the slurry remained pastel yellow and thin after stirring overnight. TFE was added (100 μL) at 45° C. to aid in dissolution of the solids. The solvent was evaporated with stirring at 45° C. and 5 mL of TFE was added to achieve complete dissolution of the solids. The solvent was again evaporated overnight with efficient stirring and the vial was placed under efficient vacuum at 50° C. for 3 h. Once dry, 15 vol. of EtOAc was added to the solids at 45° C. The light yellow slurry was stirred at 45° C. for 1 h and then at RT. The slurry was filtered, washed with 2×2 volumes of EtOAc and dried under efficient vacuum (−30 in Hg) at 50° C. for 5 h. The purity by HPLC was 99.31 area % and the stoichiometry was 1 Calculated to be 1:0.95 Compound (I) fumarate based on H NMR. The resulting solid was further characterized by XRPD (see FIG. 7 and Table 3) and TGA-DSC (FIGS. 8 and 9) using normal scanning methods.

[0159] The combined DSC and TGA thermogram showed a total mass loss of 0.3 wt.% and an endotherm onset at 162.2° C. (FIG. 8). DSC alone showed an endotherm onset at 164.8° C. (FIG. 9). [Table 14-1] [Table 14-2] [Table 14-3]

[0160] Example 4: Preparation and characterization of crystalline form A of Compound (I) free base 4.1 Synthesis of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [Compound (I)] 4.1.1 Synthesis of (2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidine: [ka] Step 1: Synthesis of (2R,3S)-1-benzhydryl-2-methylazetidin-3-yl methanesulfonate: (2R,3S)-1-Benzhydryl-2-methylazetidin-3-ol (Pharmablock, 20 g, 78.9 mmol) was dissolved in 300 mL of DCM, TEA (9.55 g, 94.6 mmol) was added and the reaction mixture was cooled in an ice bath. Mesyl chloride (9.93 g, 86.7 mmol) was added dropwise, stirred, allowed to warm slowly to room temperature and stirred overnight. The mixture was diluted with DCM, washed with water and the organic phase was dried over sodium sulfate, filtered and evaporated to give 26 g (98%) of the title compound as a viscous yellow oil. Analytical data: LC-MS: (ES, m / z) = 332 [M+1].

[0161] Step 2: Synthesis of (S)-methyl 2-((2R,3S)-1-benzhydryl-2-methylazetidin-3-yl)-2-(methylsulfonyl)acetate: (2R,3S)-1-Benzidyl-2-methylazetidin-3-yl methanesulfonate (26 g, 78.4 mmol) and methyl 2-(methylsulfonyl)acetate (15.3 g, 101 mmol) were dissolved in 260 mL of DMF, then NaH (3.75 g of a 60% dispersion in mineral oil, 6.63 mmol) was added and stirred for about 15 min until hydrogen evolution ceased. The reaction mixture was heated to 80° C. overnight. The reaction was cooled, then diluted with about 200 mL of water, extracted with EtOAc, washed with water, brine, dried over sodium sulfate, filtered, and evaporated to give the crude product. The residue was purified by chromatography (0-7% MeOH / DCM). Pure fractions were combined and evaporated to give 24 g (80%) of the title compound as a pale yellow foam.

[0162] Step 3: Synthesis of (2R,3S)-1-benzhydryl-2-methyl-3-(methylsulfonylmethyl)azetidine: (S)-Methyl-2-((2R,3S)-1-benzhydryl-2-methylazetidin-3-yl)-2-(methylsulfonyl)acetate (24 g, 61.9 mmol) was dissolved in 240 mL of DMA, lithium chloride (20.9 g, 495 mmol) was added and the flask was placed in a preheated block maintained at 150 °C. LC / MS showed the starting material was consumed after 1.5 h. Cooled to room temperature, diluted with water and extracted with EtOAc. The combined organics were washed with water, brine and dried over sodium sulfate. Filtration and evaporation gave the crude product which was further purified by chromatography (0-5% MeOH / DCM). Pure fractions were combined and evaporated to give 19 g (93%) of the title compound as a pale yellow foam. Analytical data: LC-MS: (ES, m / z) = 330 [M+1].

[0163] Step 4: Synthesis of (2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidine: To a solution of (2R,3S)-1-(diphenylmethyl)-3-(methanesulfonylmethyl)-2-methylazetidine (19 g, 57.3 mmol) in MeOH (270 mL) was added TFA (9 mL) and Pd(OH) (5.7 g) and the reaction was stirred overnight at room temperature under an atmosphere of H. The reaction mixture was filtered and evaporated to give the crude title compound (17 g) as a light brown oil. Analytical data: LC-MS: (ES, m / z) = 164 [M+1].

[0164] 4.1.2 Synthesis of 2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine [ka] Step 1: Synthesis of (3S,4R)-tert-butyl 3-fluoro-4-methoxypiperidine-1-carboxylate: Sodium hydride (218.90 mg, 9.122 mmol, 4 equiv.) was added to tert-butyl (3S,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylate (500 mg, 2.280 mmol, 1 equiv.) in THF (10 mL) at 0° C. After stirring for 20 min, methyl iodide (1294.73 mg, 9.122 mmol, 4 equiv.) was added. The resulting solution was stirred at 0° C. for an additional 1 h. The reaction was then quenched by the addition of 10 mL of water. The solids were filtered. The resulting solution was extracted with EtOAc and concentrated under vacuum. This afforded 500 mg (94.1%) of the title compound as a pale yellow oil. Analytical data: LC-MS: (ES, m / z) = 178 [M+1-56].

[0165] Step 2: Synthesis of (3S,4R)-3-fluoro-4-methoxypiperidine: A solution of tert-butyl (3S,4R)-3-fluoro-4-methoxypiperidine-1-carboxylate (500 mg, 2.143 mmol, 1 equiv) in TFA / DCM (3 / 10 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo to give 500 mg (crude) of the title compound as a solid.

[0166] Step 3: Synthesis of 2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine: A mixture of (3S,4R)-3-fluoro-4-methoxypiperidine (3 g, 22.528 mmol, 1 equiv), 2-chloropyrimidin-4-amine (2.33 g, 0.018 mmol, 0.8 equiv), and TEA (6.84 g, 0.068 mmol, 3 equiv) in IPA (3 mL) was stirred for 12 h at 100° C. The solvent was removed in vacuo and the residue was purified by FLASH (5% MeOH in DCM) to give 3.3 g (66%) of the title compound as a pale yellow solid. Analytical data: LC-MS: (ES, m / z) = 227 [M+1]. 1 H-NMR(400MHz,6d-DMSO)δ ppm 7.72(d,1H,J=5.6Hz),6.39(s,2H),5.71(d,1H,J=5.6Hz),4.83(d,1H,J=49.3Hz),4.60 - 4.49(m,1H),4.29(d,1H,J=13.3Hz),3.55 - 3.42(m,1H),3.28(d,1H,J=13.3Hz),3.20 - 3.04(m,1H),1.76 - 1.48(m,2H)

[0167] 4.1.3 Synthesis of 8-bromo-3-chloro-5-isopropylisoquinoline [ka] Step 1: Synthesis of 8-bromo-3-chloroisoquinolin-5-yl trifluoromethanesulfonate: Trifluoromethanesulfonyl trifluoromethanesulfonate (45.7 g, 162 mmol) was added dropwise to 8-bromo-3-chloroisoquinolin-5-ol (14 g, 54.1 mmol) and TEA (21.8 g, 216 mmol) in DCM (400 mL) at -60°C. The resulting mixture was allowed to warm to room temperature and stirred at room temperature for 1 h. The mixture was concentrated under vacuum. The residue was purified by silica gel column with PE:EA=5:1 to give 18 g (85%) of the title compound as a white solid. Analysis data: LC-MS: (ES,m / z)=392[M+1];1H NMR(400MHz,DMSO-d6)δ 9.46(d,1H,J=0.8Hz),8.20(d,1H,J=8.3Hz),8.02(d,1H,J=8.4Hz),7.93(d,1H,J=0.7Hz).

[0168] Step 2: Synthesis of 8-bromo-3-chloro-5-(prop-1-en-2-yl)isoquinoline: A mixture of K2CO3 (6 g, 43.5 mmol), 8-bromo-3-chloroisoquinolin-5-yl trifluoromethanesulfonate (17 g, 43.5 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (7.30 g, 43.5 mmol), and Pd(dppf)Cl2.CH2Cl2 (2.83 g, 3.48 mmol) in dioxane / H2O (200 / 20 mL) was stirred at 45 °C for 3 h. The mixture was diluted with 500 mL of EA and washed with 200 mL x 2 brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel column with PE:EtOAc = 20:1 to give 8.0 g (67%) of the title compound as an off-white solid. Analytical data: LC-MS: (ES, m / z) = 282 [M+1].

[0169] Step 3: Synthesis of 8-bromo-3-chloro-5-isopropylisoquinoline: PtO2 (1.7 g, 7.04 mmol) and 8-bromo-3-chloro-5-(prop-1-en-2-yl)isoquinoline (7.1 g, 25.1 mmol) in EA (300 mL) were stirred at room temperature under an atmosphere of H2 balloon and stirred for 1 h. The solid was filtered. The mother solvent was concentrated under vacuum. The crude product was purified by silica gel column with PE:EtOAc=10:1 to give 6.7 g (93%) of the title compound as a brown solid. Analytical data: LC-MS: (ES, m / z) = 284 [M+1].

[0170] 4.1.4 Synthesis of 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline [ka]

[0171] To a solution of 8-bromo-3-chloro-5-(propan-2-yl)isoquinoline (9 g, 31.6 mmol) in 1,4-dioxane (130 mL) was added (2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidine (5.15 g, 31.6 mmol), Cs2CO3 (20.6 g, 63.2 mmol), and Xantphos Pd G4 (1.51 g, 1.58 mmol) under nitrogen. The mixture was stirred at 100° C. under nitrogen for 3 h. The reaction mixture was cooled to room temperature and diluted with 300 mL of water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel chromatography (0-60% EtOAc in PE) to give 7.2 g (62.6%) of 3-chloro-8-[(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidin-1-yl]-5-(propan-2-yl)isoquinoline as a yellow solid.

[0172] 4.1.5 Synthesis of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka]

[0173] To a solution of 2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine (18.50 mg, 0.082 mmol, 1 equiv.), 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline (30 mg, 0.082 mmol, 1 equiv.), and Cs2CO3 (53.3 mg, 0.164 mmol, 2 equiv.) in 1,4-dioxane (0.82 ml), BrettPhos Precatalyst (Gen IV) (3.76 mg, 4.09 μmol, 0.05 equiv.) was added under N2 and the mixture was stirred at 90° C. for 16 h. The mixture was filtered and concentrated in vacuo. The crude mixture was purified by reverse phase chromatography (0-60% acetonitrile / water with 0.1% TFA). The pure fractions were combined, neutralized with saturated sodium bicarbonate solution, and then extracted with 10% MeOH / DCM (5 mL x 3). The combined organic phases were dried over sodium sulfate, filtered, and evaporated to give 17.4 mg of the title compound (38%) as a yellow solid.

[0174] An XRPD diffractogram of the resulting product demonstrated that the solid was a crystalline material designated as Form A. It was later determined that the resulting product contained XPhos-related impurities exhibiting peaks in XRPD at about 8.34 and about 9.54 2θ.

[0175] 4.2 Preparation of Compound (I) Form A Method A: Amorphous Slurry Approximately 20-25 mg of amorphous Compound (I) (see Example 6) was added to a 2 mL vial with a 5 mm stir bar. The respective solvent was added to the vial with mixing at a stirring speed of 300 rpm at RT, and the clear solution / slurry was stirred at RT. In most cases, the solids were completely dissolved into a clear solution and continued stirring was performed without the addition of additional solids. A clear solution to a thin or very thick slurry was observed in 2 minutes to 1 hour. The slurry was sampled on day 0 (as soon as a slurry was observed), day 1, day 4, and day 5. Observations were recorded and summarized in Table 4 below. [Table 15]

[0176] Method B: Amorphous Vapor Diffusion Approximately 10-20 mg of amorphous Compound (I) was weighed into a 2 mL vial and the vial was added to a 20 mL scintillation vial containing 2 mL of diffusion solvent each. The 20 mL scintillation vial was sealed with a cap and parafilm. Observations were made immediately after exposure of the amorphous solid to vapor diffusion and are summarized in Table 5. In most cases, the fluffy amorphous solid was observed to shrink into a thin layer of dark yellow color at the bottom of the vial. [Table 16-1] [Table 16-2]

[0177] Method C: Reverse addition antisolvent crystallization Approximately 25-35 mg of amorphous Compound (I) was mostly dissolved in the solvent at RT. Two volumes of anti-solvent were added to a separate vial and the solution was added in one transfer with rapid stirring. For example, if the solid dissolved in 0.5 mL of solvent, the solution was then added in one transfer to 1.0 mL of anti-solvent with vigorous stirring. Once solids formed, the slurry was filtered and the recovered solids were analyzed by XRPD. The results of anti-solvent crystallization in reverse addition are shown in Table 6.

[0178] Only in MEK / n-heptane did the solution produce a medium to thin slurry that formed 15 min after addition to the anti-solvent with vigorous stirring. The slurry was filtered and the collected solid was analyzed by XRPD. A hazy solution was produced in tetrahydrofuran (THF) / EtOH 2 h after addition of the solution to the anti-solvent with continued stirring (approximately 600 rpm). The hazy solution turned into a thin slurry that was filtered under reduced pressure and the solid was analyzed by XRPD. Also in THF / isopropyl acetate (IPAc) and THF / toluene, a hazy solution was produced 3 h after addition of the solution to the anti-solvent with continued stirring at RT. In the other solvents, the clear solution was transferred to a chiller block at -5 °C and stirring was continued for 1 week. The clear solution remained clear and the vial was transferred to a -20 °C freezer. A small amount of crystalline solid or precipitate was observed. [Table 17]

[0179] Method D: Direct addition antisolvent crystallization Approximately 22-35 mg of amorphous Compound (I) was added to either a 2 mL or 4 mL vial, depending on the solvent required to dissolve the solid. The solvent was added to the solid and the dilute / medium slurry was stirred with a stir bar (5 mm for 2 mL vials, 10 mm thin bar for 4 mL vials) at 30 °C for up to 1 h to obtain a clear solution. Twice the volume of solvent was used as anti-solvent. For example, for a solid dissolved in 0.5 mL of solvent, then 1.0 mL of anti-solvent was used for the direct addition. The anti-solvent was added dropwise in four equal portions to the vigorously stirring solution over 1 h.

[0180] In the case of MEK, 1,4-dioxane, and THF, a thin slurry was formed upon addition of the solvent to the solid, which remained even after stirring at 30° C. for 1 h. However, the thin slurry dissolved into a clear solution by heating the vial at 40° C. for less than 5 min. The vial was then transferred to RT and anti-solvent was added. In the case of 2-methyltetrahydrofuran (2-MeTHF):dimethylsulfoxide (DMSO) (9:1 vol.), the solid dissolved in 7 volumes of solvent. The hazy solution / very thin slurry was stirred continuously at RT for 2 days, and a medium to thick slurry was observed in most cases. A summary of the experiments is shown in Table 7. [Table 18]

[0181] Method E: Rapid crystallization Approximately 25-35 mg of amorphous Compound (I) was weighed into a 2 mL vial. Solvent and a 5 mm stir bar were added to the vial and stirred at 50 °C with a stirring speed of 450 rpm. The dilute slurry / hazy solution was heated to 60 °C to obtain a clear solution as required. The clear solution was transferred to an ice-water bath near 0 °C without mixing. Care was taken to ensure that no visible crust was present before cooling the sample. Generally, no slurry or solids were observed in the quench crystallization by transferring the solution to an ice-water bath. However, in some cases, hazy solutions were observed after the solution was allowed to stir on a stir plate in an ice-water bath for up to 1 h at RT, and solids were obtained after transfer to a -20 °C freezer. A summary of the quench crystallization is shown in Table 8. [Table 19]

[0182] Method F: Slow cooling crystallization Approximately 25-35 mg of amorphous Compound (I) was weighed into a 2 mL vial. Solvent and a 5 mm stir bar were added to the vial and stirred at 50 °C with a stirring speed of 450 rpm. In all cases, a thin slurry formed at approximately 50 °C depending on the concentration of solids in the solvent. Thus, the vial was heated up to 67 °C to obtain a clear solution. Care was taken to ensure that no visible crust was present before cooling the sample. The clear solution at 67 °C was then cooled to RT at a cooling rate of 5 °C / hr. This was achieved by decreasing the temperature of the hotplate by 2.5 °C every 30 min. A summary of the slow cooling crystallization is shown in Table 9. [Table 20]

[0183] Method G: Stagnant cold crystallization Approximately 25-35 mg of amorphous Compound (I) was weighed into a 2 mL vial. Solvent and a 5 mm stir bar were added to the vial and stirred at 50° C. with a stirring speed of 450 rpm. The dilute slurry / hazy solution was heated to 60° C. to obtain a clear solution as required. The clear solution was transferred to a -20° C. freezer and periodically observed for the crystallization process. Care was taken to ensure that no visible crust was present before cooling the sample. A summary of the experiment is shown in Table 10. [Table 21]

[0184] Method H: Slow Evaporation Crystallization Approximately 25-35 mg of amorphous Compound (I) was weighed into a 2 mL or 4 mL vial depending on the amount of solvent needed to completely dissolve the solid into a clear solution. The solvent was added to the vial by mixing with a 5 mm (2 mL vial) or 10 mm (4 mL vial) stir bar on a stir plate at a stirring speed of 300 rpm at RT. Once the solid was completely dissolved into a clear solution, the vial was capped or sealed and the cap was pinned with a high gauge syringe needle to allow the solvent to slowly evaporate from the vial. The solution was kept stirring during the slow evaporation. A summary of the experiment is shown in Table 11. [Table 22]

[0185] Method I: Flash Evaporative Crystallization Approximately 25-35 mg of amorphous Compound (I) was weighed into a 4 mL vial and solvent was added by mixing with a 10 mm stir bar. A microscope slide was placed on a preheated hot plate at approximately 115° C. The clear solution was added dropwise using a glass pipette onto the hot microscope slide. The solution evaporated instantly as it was dropped onto the slide, and overall the solution turned into a fluffy solid in less than 2 minutes. The solid was collected by scraping the slide with a spatula and used for analysis. A summary of the flash evaporation experiments is shown in Table 12. [Table 23]

[0186] Method J: Using crystallographic templates Slow evaporation in the presence of crystallographic templates was carried out using the clear solutions obtained in the presence of templates. Ground mixtures of various minerals (fluorite, garnet, pyrite, apophyllite, dolomite, corundum, tourmaline, topaz, celestite, staurolite, diopside, and amazonite) were used as crystallographic templates for this purpose. The solutions with added templates were allowed to evaporate using a sealed cap pinned with a high-gauge syringe needle, and the solvent was evaporated from the vial by mixing the solutions. A summary of slow evaporation using crystallographic templates is shown in Table 13. [Table 24]

[0187] 4.3 Characterization of Compound (I) Form A The obtained Compound (I) Form A was characterized by XRPD (see Figure 10 and Table 14) and TGA-DSC (Figure 11) using high resolution scanning methods.

[0188] The combined DSC and TGA thermogram showed a total mass loss of 0.7 wt.% and endothermic onsets at 170.53° C. and 196.81° C. (FIG. 11). [Table 25]

[0189] Example 5: Preparation and characterization of crystalline form B of Compound (I) free base 5.1 Preparation Form B of Compound (I) (351.2 mg) was prepared via reverse anti-solvent addition with DMAc / water as described above for Form A. The thick pale yellow slurry was filtered, washed with 1×2.0 vol. water, and left on the filter paper for 5 minutes with effective suction from an aspirator. The sample was then placed in an oven at 50° C. for 15 minutes under effective vacuum, and then left to dry on the benchtop overnight. After drying, the resulting solid was further characterized by XRPD using high resolution scanning methods (see FIG. 12 and Table 15), TGA-DSC (FIGS. 15 and 16), and DVS.

[0190] The combined DSC and TGA thermogram showed a total mass loss of 0.1 wt.% and an endotherm onset at 158.7° C. (FIG. 13). DSC alone showed an endotherm onset at 157.8° C. (FIG. 14). [Table 26]

[0191] 5.2 DVS of Compound (I) Free Base Form B DVS was completed and showed a mass change of 2.1 wt.% from 2 to 95% relative humidity at 25 °C.

[0192] Example 6: Preparation and characterization of amorphous compound (I) Approximately 263 mg of Compound (I) was weighed into a 20 mL scintillation vial and a 10 mm stir bar was added. 8 mL of ACN:water (8:2 vol.) was added to the vial by mixing at RT to form a medium to thin slurry. The slurry was stirred at about 55° C. for 10 min, at which time it turned into a thin slurry. Additional solvent (2 mL) was added and the thin slurry was continued to stir for another 10 min at about 55° C. The very thin slurry remaining after 10 min was syringe filtered using a 45 μm filter into another clean 20 mL scintillation vial. The clear yellow solution was freeze-dried by placing the vial in liquid nitrogen for 2-3 min. The vial with the completely frozen solid was lyophilized overnight. The solid recovered after overnight lyophilization was fluffy and essentially amorphous. The resulting solid was further characterized by XRPD (see Figure 15) and TGA-DSC (Figures 16 and 17) using normal scanning methods.

[0193] The combined DSC and TGA thermogram showed endothermic onsets at 30.7° C. and 108.7° C. (FIG. 16). DSC alone showed endothermic onsets at 23.1° C. and 106.5° C. (FIG. 17).

Claims

1. A salt of compound (I) represented by the following structural formula, wherein 【Chemical 1】 the salt is a succinate and the molar ratio between compound (I) and succinic acid is 1:0.5, or the salt is a glutarate and the molar ratio between compound (I) and glutaric acid is 1:0.5, or the salt is a fumarate and the molar ratio between compound (I) and fumaric acid is 1:1, said succinate.

2. The succinate according to claim 1, wherein the succinate is crystalline.

3. The succinate according to claim 2, wherein the crystalline succinate is in crystal form C: (i) Characterized by an X-ray powder diffraction pattern containing at least 3 or 4 peaks selected from 4.5°, 8.9°, 9.3°, 15.3°, and 17.8°±0.2 at 2θ; (ii) Characterized by an X-ray powder diffraction pattern containing peaks at 4.5°, 8.9°, 9.3°, 15.3°, and 17.8°±0.2 at 2θ; (iii) Characterized by an X-ray powder diffraction pattern containing at least 3, 4, 5, 6, 7, 8, 9, or 10 peaks selected from 4.5°, 8.9°, 9.3°, 13.0°, 15.3°, 16.8°, 17.8°, 18.1°, 18.5°, and 22.3°±0.2 at 2θ; (iv) Characterized by an X-ray powder diffraction pattern containing peaks at 4.5°, 6.7°, 8.9°, 9.3°, 11.1°, 12.3°, 13.0°, 14.4°, 15.3°, 16.3°, 16.8°, 17.8°, 18.1°, 18.5°, 20.5°, 22.3°, and 26.0°±0.2 at 2θ; (v) Characterized by an X-ray powder diffraction pattern substantially the same as that in Figure 1 [Chemical 2] ; and / or the crystalline succinate is in form C and is characterized by having an onset temperature of 175±2 °C by differential scanning calorimetry; and / or the crystalline succinate is in form C and is characterized by a thermogravimetric analysis (TGA) substantially the same as that in Figure 2 【Chemical Formula 3】 ; and / or at least 90% by weight of said succinate is in crystal form C, said succinate.

4. Mixing compound (I) and succinic acid in ethyl acetate, collecting the succinate of compound (I), adding 2-propanol to the succinate of compound (I), The succinate of compound (I) obtained by a process comprising re-collecting said succinate. The succinate according to any one of claims 1 to 3.

5. The glutarate according to claim 1, wherein said glutarate is crystalline.

6. The glutarate according to claim 5, wherein said crystalline glutarate is in Form D: (i) Characterized by an X-ray powder diffraction pattern including at least 3 or 4 peaks selected from 8.8°, 14.8°, 16.1°, 18.3°, and 18.7° ± 0.2 at 2θ; (ii) Characterized by an X-ray powder diffraction pattern including peaks at 8.8°, 14.8°, 16.1°, 18.3°, and 18.7° ± 0.2 at 2θ; (iii) Characterized by an X-ray powder diffraction pattern including at least 3, 4, 5, 6, or 7 peaks selected from 7.4°, 8.8°, 12.3°, 14.8°, 16.1°, 18.3°, and 18.7° ± 0.2 at 2θ; (iv) Characterized by an X-ray powder diffraction pattern including peaks at 6.6°, 7.4°, 8.8°, 12.3°, 12.9°, 14.8°, 16.1°, 18.3°, 18.7°, 20.0°, and 22.2° ± 0.2 at 2θ; or (v) Characterized by an X-ray powder diffraction pattern substantially the same as that of Figure 4 【Chemical Formula 4】 ; and / or Said crystalline glutarate is in Form D and is characterized by having an onset temperature of 142 ± 2 °C by differential scanning calorimetry; and / or Said crystalline glutarate is in Form D and is characterized by a thermogravimetric analysis (TGA) substantially the same as that of Figure 5 [Chemical Formula 5] ; and / or At least 90% by weight of said glutarate is in crystalline Form D. Said glutarate.

7. Mixing compound (I) and glutaric acid in ethyl acetate, Collecting the glutarate of compound (I). The glutarate according to any one of claims 1, 5, and 6 obtained by a process comprising the above.

8. The fumarate according to claim 1, wherein said fumarate is crystalline.

9. The fumarate according to claim 8, wherein said crystalline fumarate is in Form E: (i) Characterized by an X-ray powder diffraction pattern including at least 3, 4, or 5 peaks selected from 6.3°, 8.5°, 9.0°, 14.5°, 15.7°, and 18.0° ± 0.2 at 2θ; (ii) an X-ray powder diffraction pattern having peaks at 2θ of 6.3°, 8.5°, 9.0°, 14.5°, 15.7°, and 18.0° ± 0.2; (iii) an X-ray powder diffraction pattern having at least 3, 4, 5, 6, 7, 8, 9, or 10 peaks selected from 2θ of 6.3°, 8.5°, 9.0°, 12.1°, 14.5°, 15.7°, 18.0°, 19.7°, 20.1°, and 21.9° ± 0.2; (iv) an X-ray powder diffraction pattern having peaks at 2θ of 6.3°, 8.5°, 9.0°, 12.1°, 14.5°, 15.1°, 15.2°, 15.4°, 15.7°, 18.0°, 18.2°, 18.9°, 19.3°, 19.7°, 20.1°, 20.6°, 20.7°, 21.3°, and 21.9° ± 0.2; or (v) an X-ray powder diffraction pattern substantially the same as that of FIG. 7; 【Chemical Formula 6】 and / or the crystalline fumarate is in Form E and has an onset temperature of 164 ± 3 °C as determined by differential scanning calorimetry; and / or the crystalline fumarate is in Form E and has a thermogravimetric analysis (TGA) substantially the same as that of FIG. 8; [Chemical Formula 7] and / or at least 90% by weight of the fumarate is in crystalline Form E, the fumarate.

10. mixing compound (I) and fumaric acid in ethyl acetate, removing the ethyl acetate to obtain the fumarate of compound (I), adding trifluoroethanol to the fumarate of compound (I), removing the trifluoroethanol to obtain the fumarate of compound (I), adding ethyl acetate to the fumarate of compound (I), and the fumarate according to any one of claims 1, 8, and 9 obtained by a process comprising:

11. a free base of compound (I) in crystalline Form B represented by the following structural formula, [Chemical Formula 8] said Form B is characterized by an X-ray powder diffraction pattern having at least 3, 4, or 5 peaks selected from 2θ of 5.1°, 12.2°, 13.5°, 16.6°, and 20.1° ± 0.2; said Form B optionally: (i) further characterized by an X-ray powder diffraction pattern containing at least 3, 4, 5, 6, 7, 8, 9, 10, or 11 peaks selected from 5.1°, 12.2°, 13.5°, 16.3°, 16.6°, 19.5°, 20.1°, 20.4°, 21.4°, 22.7°, and 25.2° ± 0.2 at 2θ; (ii) further characterized by an X-ray powder diffraction pattern containing peaks at 5.1°, 12.2°, 13.5°, 15.2°, 16.3°, 16.6°, 17.9°, 19.5°, 20.1°, 20.4°, 20.7°, 20.9°, 21.4°, 22.7°, 25.2°, and 26.3° ± 0.2 at 2θ; or (iii) further characterized by an X-ray powder diffraction pattern substantially the same as that in FIG. 12 【Chemical Formula 9】 ; and / or said Form B is further characterized in that, optionally, it has an onset temperature of 158 ± 2 °C by differential scanning calorimetry; and / or said Form B is further characterized by a thermogravimetric analysis (TGA) substantially the same as that in FIG. 13 【Chemical Formula 10】 ; and / or optionally, at least 90% by weight of said free base is in crystalline Form B, said compound (I) free base.

12. adding compound (I) to dimethylacetamide to form a mixture, adding said mixture to water to obtain the compound (I) free base in crystalline Form B, the compound (I) free base according to claim 11.

13. An amorphous form of the compound (I) free base represented by the following structural formula: 【Chemical 11】 said amorphous form is characterized by having an onset temperature of 157 ± 2 °C by differential scanning calorimetry, the amorphous form of the compound (I) free base.

14. adding an acetonitrile:water mixture to compound (I) to form a solution, filtering said solution, freezing said solution, lyophilizing said frozen solution to obtain said amorphous compound (I), the amorphous form of the compound (I) free base according to claim 13.

15. A pharmaceutical composition comprising a salt according to any one of claims 1 to 3, or a free base according to any one of claims 11 to 14, and a pharmaceutically acceptable carrier or diluent.

16. A pharmaceutical composition for use in a method of treating cancer in a subject, comprising a salt according to any one of claims 1 to 3, a free base according to any one of claims 11 to 14, or a salt according to any one of claims 1 to 3 or a free base according to any one of claims 11 to 14, and a pharmaceutically acceptable carrier or diluent, Optionally: (i) the cancer in the subject is non-small cell lung cancer; (ii) the subject has at least one mutation in the EGFR gene that results in the expression of an EGFR enzyme having an amino acid modification selected from the group consisting of L858R, T790M, C797S, and combinations thereof, Optionally, the EGFR gene has amino acid modifications of L858R, T790M, and C797S; and / or (iii) the method further comprises administering to the subject an effective amount of afatinib, osimertinib, erlotinib, or gefitinib, the pharmaceutical composition.

17. A pharmaceutical composition for inhibiting epidermal growth factor receptor (EGFR), comprising a salt according to any one of claims 1 to 3, a free base according to any one of claims 11 to 14, or a salt according to any one of claims 1 to 3 or a free base according to any one of claims 11 to 14, and a pharmaceutically acceptable carrier or diluent, the pharmaceutical composition comprising the pharmaceutical composition.

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