PI3Kα inhibitor and method of preparation and use thereof

Abstract

The present disclosure relates to PI3Kα inhibitors, their crystalline forms, solvates, compositions, and methods of use. For example, the present disclosure describes solid forms of compounds including the crystalline solid form of the following compounds: N-((1S,2R,4S)-4-(((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptane-1-yl)methyl)carbamoyl)-2-hydroxycyclopentyl)pyrimidine-5-carboxamide; and (1S,3S,4R)-3-acetamido-N-((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptane-1-yl)methyl)-4-hydroxycyclopentane-1-carboxamide.

Description

Technology Field

[0001] Cross-reference regarding related applications

[0002] This application claims the benefits of U.S. Provisional Patent Application No. 63 / 599,157 filed November 15, 2023, the full text of which is incorporated herein by reference. Background Technology

[0003] Phosphatidylinositol 3-kinase (PI3K) belongs to the family of lipid kinases, which catalyzes the transfer of phosphate to the D-3' position of inositol lipids to produce phosphoinositol-3-phosphate (PIP), phosphoinositol-3,4-diphosphate (PIP2), and phosphoinositol-3,4,5-triphosphate (PIP3), and ultimately acts as a second messenger in signal transduction cascades by docking proteins containing pleckstrin-homology, FYVE, Phox, and other phospholipid-binding domains to various signal transduction complexes at the plasma membrane (Vanhaesebroeck et al., Annu. Rev. Biochem 70:535 (2001); Katso et al., Annu. Rev. Cell Dev. Biol. 17:615 (2001)). Of the two Class 1 PI3K subclasses, Class 1A PI3K is a heterodimer composed of a catalytic p110 subunit (alpha, beta, or delta isoform) constitutively associated with a regulatory subunit that may be p85 alpha, p55 alpha, p50 alpha, p85 beta, or p55 gamma. The Class 1B subclass has one family member that is a heterodimer composed of two regulatory subunits, namely a catalytic p110 gamma subunit associated with either p101 or p84 (Fruman et al., Annu Rev. Biochem. 67:481 (1998); Suire et al., Curr. Biol. 15:566 (2005)). The regulatory domain of the p85 / 55 / 50 subunit contains a Src homology (SH2) domain that binds to phosphotyrosine residues in specific sequence contexts of activated receptors and cytoplasmic tyrosine kinases, resulting in the activation and localization of class 1A PI3K. Class 1B PI3K is directly activated by G protein-coupled receptors that bind to a diverse repertoire of peptide and non-peptide ligands (Stephens et al., Cell 89:105 (1997); Katso et al., Annu. Rev. Cell Dev. Biol. 17:615-675 (2001)).

[0004] Consequently, the resulting phospholipid products of class I PI3K link upstream receptors having downstream cellular activities including proliferation, survival, chemotaxis, cell transport, motility, metabolism, inflammation and allergic responses, transcription, and translation (Cantley et al., Cell 64:281 (1991); Escobedo and Williams, Nature 335:85 (1988); Fantl et al., Cell 69:413 (1992)). In many cases, PIP2 and PIP3 replenish Aid, the human homologous product of the viral oncogene v-Akt, in the plasma membrane, which acts as a nodal point for many intracellular signaling pathways important for growth and survival (Fantl et al., Cell 69:413-423 (1992); Bader et al., Nature Rev. Cancer 5:921 (2005); Vivanco and Sawyer, Nature Rev. Cancer 2:489 (2002)).

[0005] Abnormal regulation of PI3K, which often increases survival through Aid activation, is one of the most widespread events in human cancers and has been shown to occur at multiple levels. The tumor suppressor gene PTEN, which dephosphorylates phosphoinositide at the 3' position of the inositol ring and thereby antagonizes PI3K activity, is functionally deleted in various tumors. In other tumors, genes for the p110 alpha isoform, PIK3CA, and Akt are amplified, and increased protein expression of their gene products has been demonstrated in several human cancers. Furthermore, mutations and translocations of p85 alpha, which plays a role in upregulating the p85-p110 complex, have been described in human cancers. Finally, somatic missense mutations in PIK3CA, which activates downstream signaling pathways, have been described with significant frequency in a wide variety of human cancers (Kang et al., Proc. Natl. Acad. Sci. USA 102:802 (2005); Samuels et al., Science 304:554 (2004); Samuels et al., Cancer Cell 7:561-573 (2005)). These observations indicate that the downregulation of phosphoinositol-3 kinase and its upstream and downstream components is one of the most common downregulations associated with human cancers and proliferative diseases (Parsons et al., Nature 436:792 (2005); Hennessey et al., Nature Rev. Drug Disc. 4:988-1004 (2005)).

[0006] From the above perspective, PI3Kα inhibitors would be particularly valuable for the treatment of proliferative diseases and other disorders. Although several PI3K inhibitors (e.g., taselisib, alpelisib, buparisib, and others) have been developed, these molecules inhibit multiple class 1A PI3K isoforms. Inhibitors active against multiple class 1A PI3K isoforms are known as 'pan-PI3K' inhibitors. A major obstacle to the clinical development of existing PI3K inhibitors has been the inability to achieve the required level of targeted inhibition in tumors while avoiding toxicity in cancer patients. Pan-PI3K inhibitors share specific target-related toxicities, including diarrhea, rash, fatigue, and hyperglycemia. The toxicity of PI3K inhibitors depends on their isoform selectivity profiles. Inhibition of PI3Kα is associated with hyperglycemia and rash, whereas inhibition of PI3Kδ or PI3Kγ is associated with diarrhea, bone marrow suppression, and increased liver enzyme levels (transaminitis) (Hanker et al., Cancer Discovery (2019) PMID: 30837161.

[0007] Polymorphism is the ability of a substance to crystallize into more than one crystal lattice arrangement. Crystallization or polymorphism can affect various aspects of the solid-state properties of active pharmaceutical ingredients (APIs). Crystalline forms can differ significantly from amorphous forms, and different crystal forms of a substance can differ significantly from one another in various aspects, including solubility, dissolution rate, and / or bioavailability. Generally, it is difficult to predict whether a given compound will form a crystalline solid-state form. Predicting the physical properties of such crystalline solid-state forms is even more difficult. Furthermore, for certain formulations, such as those suitable for subcutaneous use, having a crystalline form of the therapeutic agent may be advantageous.

[0008] The present disclosure generally relates to compounds I and II, solvates thereof, and solid forms thereof.

[0009] In some embodiments, the present disclosure provides a compound in solid form, wherein the compound is the following compound I or a solvate thereof:

[0010] .

[0011] In some embodiments, the present disclosure provides a compound in solid form, wherein the compound is the following compound II or a solvate thereof:

[0012] .

[0013] In another aspect, a pharmaceutical composition is provided in this specification comprising a compound as described herein, a pharmaceutically acceptable salt thereof, or a solvate thereof, or a solid form and a pharmaceutically acceptable excipient.

[0014] In another aspect, a method of using a compound or solvate thereof, or a solid form thereof, or a pharmaceutical composition thereof, as described herein, for inhibiting PI3Kα activity and treating disorders, diseases and / or pathological conditions as described herein is provided herein. Brief explanation of the drawing

[0015] Figure 1 shows the XRPD pattern of compound I form A. Figure 2 shows the XRPD pattern of compound I form B. Figure 3 shows the XRPD pattern of compound I form C. Figure 4 shows the XRPD pattern of compound II form A. Figure 5 shows the XRPD pattern of compound II form B. Figure 6 shows the DSC and TGA thermograms of compound I form A. Figure 7 shows the DSC thermogram of compound I form B. Figure 8 shows the DSC and TGA thermograms of compound I form C. Figure 9 shows the DSC and TGA thermograms of compound II form A. Figure 10 shows the DSC and TGA thermograms of compound II form B. Specific details for implementing the invention

[0016] General description of specific embodiments of the present disclosure

[0017] In some embodiments, compounds I and II are PI3Kα inhibitors and have been found to be useful for treating disorders, diseases and / or conditions, e.g., 'PI3Kα-mediated' disorders, diseases and / or conditions as described herein. In some embodiments, the present disclosure provides solid forms of compounds (e.g., as free bases or salts or solvates) that impart features such as improved water solubility, stability, and ease of formulation.

[0018] Solid form of Compound I

[0019] In some embodiments, a compound in solid form is provided herein, wherein the compound is the following compound I or a solvate thereof:

[0020] .

[0021] It is assumed that Compound I (i.e., (N-((1S,2R,4S)-4-(((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptane-1-yl)methyl)carbamoyl)-2-hydroxycyclopentyl)pyrimidine-5-carboxamide) may exist in various physical forms. For example, Compound I may be in solution, suspension, or solid form. In certain embodiments, Compound I is in solid form. When Compound I is in solid form, said compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0022] In some embodiments, Compound I is an amorphous solid. In some embodiments, the solid form of Compound I is crystalline. In some embodiments, the solid form of Compound I is a mixture of one or more crystalline forms. In some embodiments, the solid form of Compound I is a mixture of an amorphous solid and one or more crystalline forms.

[0023] In some embodiments, Compound I is an anhydrous form. In some embodiments, Compound I is in the hydrate form. In some embodiments, Compound I is in the hemihydrate form.

[0024] In some embodiments, the present invention provides a form of Compound I that is substantially free of impurities. The term "substantially free of impurities" as used herein means that the compound does not contain a significant amount of foreign matter. Such foreign matter may include different forms of Compound I, residual solvent, or any other impurities that may result from the manufacture and / or isolation of Compound I.

[0025] In some embodiments, the solid form of compound I, or a solvate thereof, is present in an amount of at least about 95, 95.5, 96, 96.5, 97, 97.5, 98.0, 98.5, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, 99.9 weight percent, and the percentages are based on the total weight of the composition. In some embodiments, the solid form of compound I, or a solvate thereof, contains any single impurity in a weight percentage of about 0.40 or less, about 0.35 or less, about 0.3 or less, about 0.25 or less, about 0.2 or less, about 0.15 or less, about 0.10 or less, or about 0.05 or less, and the percentages are based on the total weight of the composition. In some embodiments, the impurities are selected from those described in the embodiments of this specification.

[0026] In some embodiments, the solid form of compound I, or a solvate thereof, is present in an amount of at least about 95, 95.5, 96, 96.5, 97, 97.5, 98.0, 98.5, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, 99.9 area percentages relative to the total area of ​​the HPLC chromatogram. In some embodiments, the solid form of compound I, or a solvate thereof, is present in an area percentage of any single impurity of 0.4 or less, about 0.35 or less, about 0.3 or less, about 0.25 or less, about 0.2 or less, about 0.15 or less, about 0.10 or less, or about 0.05 or less relative to the total area of ​​the HPLC chromatogram. In some embodiments, the impurities are selected from those described in the embodiments of this specification. In some embodiments, the HPLC method is selected from the HPLC methods described in the embodiments of this specification.

[0027] The structure illustrated for Compound I also implies that it includes all tautomeric forms. Additionally, the structure illustrated herein also implies that it includes different compounds only in the presence of one or more isotope-rich atoms. For example, substitution of hydrogen by deuterium or tritium, or 13 C- or 14 Compounds having the structure of the present invention are within the scope of the present disclosure, except for the substitution of carbon by C-enriched carbon.

[0028] It has been discovered that Compound I can exist in various solid forms. Exemplary such forms include polymorphs as described herein. In some embodiments, the crystalline form of Compound I is Form A, Form B, or Form C as described herein.

[0029] In some embodiments, the crystalline form of compound I is form A. In some embodiments, form A of compound I has an X-ray powder diffraction pattern substantially similar to that shown in FIG. 1.

[0030] In some embodiments, the crystalline form of compound I is form B. In some embodiments, form B of compound I has an X-ray powder diffraction pattern substantially similar to that shown in FIG. 2.

[0031] In some embodiments, the crystalline form of compound I is form C. In some embodiments, form C of compound I has an X-ray powder diffraction pattern substantially similar to that shown in FIG. 3.

[0032] Form A of Compound I

[0033] In some embodiments, the solid form of compound I is form A. In some embodiments, form A of compound I may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at °2θ, each selected from the group consisting of about 17.4 2θ, about 13.3 2θ, and about 16.5 2θ. In some embodiments, form A of compound I may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at °2θ, each selected from the group consisting of about 17.4 2θ, about 13.3 2θ, about 16.5 2θ, about 24.2 2θ, about 19.8 2θ, about 14.5 2θ, and about 18.2 2θ. In some embodiments, form A of compound I may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks at °2θ, each selected from the group consisting of about 17.4 2θ, about 13.3 2θ, about 16.5 2θ, about 24.2 2θ, about 19.8 2θ, about 14.5 2θ, and about 18.2 2θ. In some embodiments, form A of compound I may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks at °2θ, each selected from the group consisting of about 17.4 2θ, about 13.3 2θ, about 16.5 2θ, about 24.2 2θ, about 19.8 2θ, about 14.5 2θ, and about 18.2 2θ. In some embodiments, form A of compound I may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks at °2θ, each selected from the group consisting of about 17.4 2θ, about 13.3 2θ, about 16.5 2θ, about 24.2 2θ, about 19.8 2θ, about 14.5 2θ, and about 18.2 2θ. In some embodiments, form A of compound I may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks at °2θ, each consisting of about 17.4 2θ, about 13.3 2θ, about 16.5 2θ, and about 24.It is selected from the group consisting of 2 2θ, about 19.8 2θ, about 14.5 2θ, and about 18.2 2θ. In some embodiments, form A of compound I may feature a powder X-ray powder diffraction pattern including characteristic peaks at about 17.4 2θ, about 13.3 2θ, about 16.5 2θ, about 24.2 2θ, about 19.8 2θ, about 14.5 2θ, and about 18.2 2θ.

[0034] In some embodiments, form A of compound I has an X-ray powder diffraction pattern substantially similar to that shown in FIG. 1. In some embodiments, form A of compound I may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at °2θ, each peak selected from the group of peaks listed in Table 1.1. In some embodiments, form A of compound I may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks at °2θ, each peak selected from the group of peaks listed in Table 1.1. In some embodiments, form A of compound I may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks at °2θ, each peak selected from the group of peaks listed in Table 1.1. In some embodiments, form A of compound I may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks at °2θ, each peak selected from the group of peaks listed in Table 1.1. In some embodiments, form A of compound I may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks at °2θ, each peak selected from the group consisting of peaks listed in Table 1.1. In some embodiments, form A of compound I may be characterized by a powder X-ray diffraction pattern having at least seven characteristic peaks at °2θ, each peak selected from the group consisting of peaks listed in Table 1.1.

[0035] [Table 1.1]

[0036]

[0037] With respect to a peak at °2θ, the term ‘about’ as used herein means that the peak may be a 2θ value ± 0.2, or a given 2θ value ± 0.1, or a given value. For example, a peak of ‘about 12.0 2θ’ means that the peak may be 11.8 2θ, 11.9 2θ, 12.0 2θ, 12.1 2θ, or 12.2 2θ.

[0038] In some embodiments, form A of compound I has a thermogravimetric analysis (TGA) pattern substantially similar to that shown in FIG. 6. In some embodiments, form A of compound III-2 may be characterized by substantial similarity to two or more figures (e.g., FIG. 1 and FIG. 6).

[0039] Form B of Compound I

[0040] In some embodiments, the solid form of compound I is form B. In some embodiments, form B of compound I may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at °2θ, each selected from the group consisting of about 18.5 2θ, about 11.4 2θ, and about 17.5 2θ. In some embodiments, form B of compound I may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at °2θ, each selected from the group consisting of about 18.5 2θ, about 11.4 2θ, about 17.5 2θ, about 5.7 2θ, about 13.6 2θ, about 17.3 2θ, and about 10.7 2θ. In some embodiments, form B of compound I may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks at °2θ, each selected from the group consisting of about 18.5 2θ, about 11.4 2θ, about 17.5 2θ, about 5.7 2θ, about 13.6 2θ, about 17.3 2θ, and about 10.7 2θ. In some embodiments, form B of compound I may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks at °2θ, each selected from the group consisting of about 18.5 2θ, about 11.4 2θ, about 17.5 2θ, about 5.7 2θ, about 13.6 2θ, about 17.3 2θ, and about 10.7 2θ. In some embodiments, form B of compound I may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks at °2θ, each selected from the group consisting of about 18.5 2θ, about 11.4 2θ, about 17.5 2θ, about 5.7 2θ, about 13.6 2θ, about 17.3 2θ, and about 10.7 2θ. In some embodiments, form B of compound I may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks at °2θ, each consisting of about 18.5 2θ, about 11.4 2θ, about 17.5 2θ, about 5.7 2θ, and about 13.It is selected from the group consisting of 6 2θ, about 17.3 2θ, and about 10.7 2θ. In some embodiments, form B of compound I may feature a powder X-ray powder diffraction pattern including characteristic peaks at about 18.5 2θ, about 11.4 2θ, about 17.5 2θ, about 5.7 2θ, about 13.6 2θ, about 17.3 2θ, and about 10.7 2θ.

[0041] In some embodiments, form B of compound I has an X-ray powder diffraction pattern substantially similar to that shown in FIG. 2. In some embodiments, form B of compound I may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at °2θ, each peak selected from the group of peaks listed in Table 1.2. In some embodiments, form B of compound I may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks at °2θ, each peak selected from the group of peaks listed in Table 1.2. In some embodiments, form B of compound I may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks at °2θ, each peak selected from the group of peaks listed in Table 1.2. In some embodiments, form B of compound I may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks at °2θ, each peak selected from the group of peaks listed in Table 1.2. In some embodiments, form B of compound I may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks at °2θ, each peak selected from the group consisting of peaks listed in Table 1.2. In some embodiments, form B of compound I may be characterized by a powder X-ray diffraction pattern having at least seven characteristic peaks at °2θ, each peak selected from the group consisting of peaks listed in Table 1.2.

[0042] [Table 1.2]

[0043]

[0044]

[0045] In some embodiments, form B of compound I has a thermogravimetric analysis (TGA) pattern substantially similar to that shown in FIG. 7. In some embodiments, form B of compound III-2 may be characterized by substantial similarity to two or more figures (e.g., FIG. 2 and FIG. 7).

[0046] Form of Compound I C

[0047] In some embodiments, the solid form of compound I is form C. In some embodiments, form C of compound I may be characterized by a powder X-ray powder diffraction pattern having at least two characteristic peaks at °2θ, each selected from the group consisting of about 19.3 2θ, about 19.9 2θ, and about 20.0 2θ. In some embodiments, form C of compound I may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at °2θ, each selected from the group consisting of about 19.3 2θ, about 19.9 2θ, about 20.0 2θ, about 10.1 2θ, about 19.6 2θ, about 15.2 2θ, and about 22.0 2θ. In some embodiments, form C of compound I may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks at °2θ, each selected from the group consisting of about 19.3 2θ, about 19.9 2θ, about 20.0 2θ, about 10.1 2θ, about 19.6 2θ, about 15.2 2θ, and about 22.0 2θ. In some embodiments, form C of compound I may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks at °2θ, each selected from the group consisting of about 19.3 2θ, about 19.9 2θ, about 20.0 2θ, about 10.1 2θ, about 19.6 2θ, about 15.2 2θ, and about 22.0 2θ. In some embodiments, form C of compound I may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks at °2θ, each selected from the group consisting of about 19.3 2θ, about 19.9 2θ, about 20.0 2θ, about 10.1 2θ, about 19.6 2θ, about 15.2 2θ, and about 22.0 2θ. In some embodiments, form C of compound I may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks at °2θ, each consisting of about 19.3 2θ, about 19.9 2θ, about 20.0 2θ, and about 10.It is selected from the group consisting of 1 2θ, about 19.6 2θ, about 15.2 2θ, and about 22.0 2θ. In some embodiments, form C of compound I may feature a powder X-ray powder diffraction pattern including characteristic peaks at about 19.3 2θ, about 19.9 2θ, about 20.0 2θ, about 10.1 2θ, about 19.6 2θ, about 15.2 2θ, and about 22.0 2θ. In some embodiments, form C of compound I has an X-ray powder diffraction pattern substantially similar to that shown in FIG. 3A.

[0048] In some embodiments, form C of compound I has an X-ray powder diffraction pattern substantially similar to that shown in FIG. 3. In some embodiments, form C of compound I may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at °2θ, each peak selected from the group of peaks listed in Table 1.3. In some embodiments, form C of compound I may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks at °2θ, each peak selected from the group of peaks listed in Table 1.3. In some embodiments, form C of compound I may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks at °2θ, each peak selected from the group of peaks listed in Table 1.3. In some embodiments, form C of compound I may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks at °2θ, each peak selected from the group of peaks listed in Table 1.3. In some embodiments, form C of compound I may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks at °2θ, each peak selected from the group consisting of peaks listed in Table 1.3. In some embodiments, form C of compound I may be characterized by a powder X-ray diffraction pattern having at least seven characteristic peaks at °2θ, each peak selected from the group consisting of peaks listed in Table 1.3.

[0049] [Table 1.3]

[0050]

[0051]

[0052] In some embodiments, form C of compound I has a thermogravimetric analysis (TGA) pattern substantially similar to that shown in FIG. 8. In some embodiments, form C of compound III-2 may be characterized by substantial similarity to two or more figures (e.g., FIG. 3 and FIG. 8).

[0053] Solid form of Compound II

[0054] In some embodiments, a compound in solid form is provided herein, wherein the compound is the following compound II or a solvate thereof:

[0055] .

[0056] It is assumed that Compound II (i.e., (1S,3S,4R)-3-acetamido-N-((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptane-1-yl)methyl)-4-hydroxycyclopentane-1-carboxamide) may exist in various physical forms. For example, Compound II may be in solution, suspension, or solid form. In certain embodiments, Compound II is in solid form. When Compound II is in solid form, said compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0057] In some embodiments, Compound II is an amorphous solid. In some embodiments, the solid form of Compound II is crystalline. In some embodiments, the solid form of Compound II is a mixture of one or more crystalline forms. In some embodiments, the solid form of Compound II is a mixture of an amorphous solid and one or more crystalline forms.

[0058] In some embodiments, the solid form of compound II is anhydrous. In some embodiments, the solid form of compound II may be a hydrate. In some embodiments, the solid form of compound II may be a hemihydrate.

[0059] In some embodiments, the present invention provides a solid form of Compound II that is substantially free of impurities. The term "substantially free of impurities" as used herein means that the compound does not contain a significant amount of foreign matter. Such foreign matter may include different forms of Compound II, residual solvent, or any other impurities that may result from the preparation and / or isolation of Compound II.

[0060] In some embodiments, the solid form of compound II, or a solvate thereof, is present in an amount of at least about 95, 95.5, 96, 96.5, 97, 97.5, 98.0, 98.5, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, 99.9 weight percent, and the percentages are based on the total weight of the composition. In some embodiments, the solid form of compound II, or a solvate thereof, contains any single impurity in a weight percentage of about 0.40 or less, about 0.35 or less, about 0.3 or less, about 0.25 or less, about 0.2 or less, about 0.15 or less, about 0.10 or less, or about 0.05 or less, and the percentages are based on the total weight of the composition. In some embodiments, the impurities are selected from those described in the embodiments of this specification.

[0061] In some embodiments, the solid form of compound II, or a solvate thereof, is present in an amount of at least about 95, 95.5, 96, 96.5, 97, 97.5, 98.0, 98.5, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, 99.9 area percentages relative to the total area of ​​the HPLC chromatogram. In some embodiments, the solid form of compound II, or a solvate thereof, is present in an area percentage of any single impurity of 0.4 or less, about 0.35 or less, about 0.3 or less, about 0.25 or less, about 0.2 or less, about 0.15 or less, about 0.10 or less, or about 0.05 or less relative to the total area of ​​the HPLC chromatogram. In some embodiments, the impurities are selected from those described in the embodiments of this specification. In some embodiments, the HPLC method is selected from the HPLC methods described in the embodiments of this specification.

[0062] The structure described for Compound II also implies that it includes all tautomeric forms. Additionally, the structure described herein also implies that it includes different compounds only in the presence of one or more isotope-rich atoms. For example, substitution of hydrogen by deuterium or tritium, or 13 C- or 14 Compounds having the structure of the present invention are within the scope of the present disclosure, except for the substitution of carbon by C-enriched carbon.

[0063] It has been discovered that Compound II may exist in various solid forms. Exemplary such forms include crystalline polymorphs as described herein. In some embodiments, the crystalline form of Compound II is Form A or Form B as described herein.

[0064] In some embodiments, the crystalline form of compound II is form A. In some embodiments, form A of compound II has an X-ray powder diffraction pattern substantially similar to that shown in FIG. 4.

[0065] In some embodiments, the crystalline form of compound II is form B. In some embodiments, form B of compound II has an X-ray powder diffraction pattern substantially similar to that shown in FIG. 5.

[0066] Form A of Compound II

[0067] In some embodiments, the solid form of compound II is form A. In some embodiments, form A of compound II may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at °2θ, each selected from the group consisting of about 15.7 2θ, about 14.7 2θ, and about 20.0 2θ. In some embodiments, form A of compound II may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at °2θ, each selected from the group consisting of about 15.7 2θ, about 14.7 2θ, about 20.0 2θ, about 21.0 2θ, about 23.2 2θ, about 16.5 2θ, about 17.5 2θ, and about 13.3 2θ. In some embodiments, form A of compound II may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks at °2θ, each selected from the group consisting of about 15.7 2θ, about 14.7 2θ, about 20.0 2θ, about 21.0 2θ, about 23.2 2θ, about 16.5 2θ, about 17.5 2θ, and about 13.3 2θ. In some embodiments, form A of compound II may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks at °2θ, each selected from the group consisting of about 15.7 2θ, about 14.7 2θ, about 20.0 2θ, about 21.0 2θ, about 23.2 2θ, about 16.5 2θ, about 17.5 2θ, and about 13.3 2θ. In some embodiments, form A of compound II may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks at °2θ, each selected from the group consisting of about 15.7 2θ, about 14.7 2θ, about 20.0 2θ, about 21.0 2θ, about 23.2 2θ, about 16.5 2θ, about 17.5 2θ, and about 13.3 2θ.In some embodiments, form A of compound II may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks at °2θ, each selected from the group consisting of about 15.7 2θ, about 14.7 2θ, about 20.0 2θ, about 21.0 2θ, about 23.2 2θ, about 16.5 2θ, about 17.5 2θ, and about 13.3 2θ. In some embodiments, form A of compound II may be characterized by a powder X-ray diffraction pattern including characteristic peaks at about 15.7 2θ, about 14.7 2θ, about 20.0 2θ, about 21.0 2θ, about 23.2 2θ, about 16.5 2θ, about 17.5 2θ, and about 13.3 2θ.

[0068] In some embodiments, form A of compound II has an X-ray powder diffraction pattern substantially similar to that shown in FIG. 4. In some embodiments, form A of compound II may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at °2θ, each peak selected from the group of peaks listed in Table 1.4. In some embodiments, form A of compound II may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks at °2θ, each peak selected from the group of peaks listed in Table 1.4. In some embodiments, form A of compound II may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks at °2θ, each peak selected from the group of peaks listed in Table 1.4. In some embodiments, form A of compound II may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks at °2θ, each peak selected from the group of peaks listed in Table 1.4. In some embodiments, form A of compound II may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks at °2θ, each peak selected from the group consisting of peaks listed in Table 1.4. In some embodiments, form A of compound II may be characterized by a powder X-ray diffraction pattern having at least seven characteristic peaks at °2θ, each peak selected from the group consisting of peaks listed in Table 1.4.

[0069] [Table 1.4]

[0070]

[0071] In some embodiments, form A of compound II has a thermogravimetric analysis (TGA) pattern substantially similar to that shown in FIG. 9. In some embodiments, form A of compound II may be characterized by substantial similarity to two or more figures (e.g., FIG. 4 and FIG. 9).

[0072] Form B of Compound II

[0073] In some embodiments, the solid form of compound II is form B. In some embodiments, form A of compound II may be characterized by a powder X-ray powder diffraction pattern having at least two characteristic peaks at °2θ, each selected from the group consisting of about 23.6 2θ, about 10.9 2θ, and about 16.9 2θ. In some embodiments, form B of compound II may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at °2θ, each selected from the group consisting of about 23.6 2θ, about 10.9 2θ, about 16.9 2θ, about 15.1 2θ, about 26.1 2θ, about 12.9 2θ, and about 19.4 2θ. In some embodiments, form B of compound II may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks at °2θ, each selected from the group consisting of about 23.6 2θ, about 10.9 2θ, about 16.9 2θ, about 15.1 2θ, about 26.1 2θ, about 12.9 2θ, and about 19.4 2θ. In some embodiments, form B of compound II may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks at °2θ, each selected from the group consisting of about 23.6 2θ, about 10.9 2θ, about 16.9 2θ, about 15.1 2θ, about 26.1 2θ, about 12.9 2θ, and about 19.4 2θ. In some embodiments, form B of compound II may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks at °2θ, each selected from the group consisting of about 23.6 2θ, about 10.9 2θ, about 16.9 2θ, about 15.1 2θ, about 26.1 2θ, about 12.9 2θ, and about 19.4 2θ. In some embodiments, form B of compound II may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks at °2θ, each consisting of about 23.6 2θ, about 10.9 2θ, about 16.9 2θ, and about 15.It is selected from the group consisting of 1 2θ, about 26.1 2θ, about 12.9 2θ, and about 19.4 2θ. In some embodiments, form B of compound II may feature a powder X-ray powder diffraction pattern including characteristic peaks at about 23.6 2θ, about 10.9 2θ, about 16.9 2θ, about 15.1 2θ, about 26.1 2θ, about 12.9 2θ, and about 19.4 2θ.

[0074] In some embodiments, form B of compound II has an X-ray powder diffraction pattern substantially similar to that shown in FIG. 5. In some embodiments, form B of compound II may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at °2θ, each peak selected from the group of peaks listed in Table 1.5. In some embodiments, form B of compound II may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks at °2θ, each peak selected from the group of peaks listed in Table 1.5. In some embodiments, form B of compound II may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks at °2θ, each peak selected from the group of peaks listed in Table 1.5. In some embodiments, form B of compound II may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks at °2θ, each peak selected from the group of peaks listed in Table 1.5. In some embodiments, form B of compound II may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks at °2θ, each peak selected from the group consisting of peaks listed in Table 1.5. In some embodiments, form B of compound II may be characterized by a powder X-ray diffraction pattern having at least seven characteristic peaks at °2θ, each peak selected from the group consisting of peaks listed in Table 1.5.

[0075] [Table 1.5]

[0076]

[0077] In some embodiments, form B of compound II has a thermogravimetric analysis (TGA) pattern substantially similar to that shown in FIG. 10. In some embodiments, form B of compound II may be characterized by substantial similarity to two or more figures (e.g., FIG. 5 and FIG. 10).

[0078] composition

[0079] Another aspect of the present disclosure provides a pharmaceutical composition comprising a compound as disclosed herein formulated with a pharmaceutically acceptable carrier. In particular, the present disclosure provides a pharmaceutical composition comprising a compound as disclosed herein formulated with one or more pharmaceutically acceptable carriers. Such formulations include those suitable for oral, topical, buccal, ocular, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or aerosol administration, but in any given case, the most suitable mode of administration will depend on the degree and severity of the condition being treated and the characteristics of the specific compound being used. For example, the disclosed composition may and / or may be formulated for oral, subcutaneous, or intravenous administration.

[0080] The exemplary pharmaceutical compositions of the present disclosure may be used in the form of pharmaceutical formulations containing one or more of the compounds of the present disclosure as active ingredients, for example, in solid, semi-solid, or liquid forms, mixed with organic or inorganic carriers or excipients suitable for topical, enteric, or parenteral application. The active ingredient may be prepared with ordinary non-toxic, pharmaceutically acceptable carriers for, for example, tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other forms suitable for use. The active ingredient compound is included in the pharmaceutical composition in an amount sufficient to produce a desired effect on the progression of the disease or pathological condition.

[0081] In some embodiments, the pharmaceutically acceptable composition may contain the disclosed compound and / or its pharmaceutically acceptable salt at a concentration ranging from about 0.01 to about 2.0 wt%, e.g., from 0.01 to about 1 wt% or from about 0.05 to about 0.5 wt%. The composition may be formulated into a solution, suspension, ointment, or capsule, etc. The pharmaceutical composition may be formulated into an aqueous solution and may contain additional components such as preservatives, buffers, tensioners, antioxidants, stabilizers, viscosity-modifying components, etc.

[0082] To prepare a solid composition such as a tablet, the main active ingredient may be mixed with a pharmaceutical carrier, e.g., a conventional tablet ingredient, e.g., corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gum, and another pharmaceutical diluent, e.g., water, to form a preformulation composition containing a homogeneous mixture of the compounds of the present disclosure or a non-toxic, pharmaceutically acceptable salt thereof. When such a preformulation composition is referred to as homogeneous, it means that the active ingredient is uniformly dispersed throughout the composition so that the composition can be easily divided into equally effective unit dosage forms, e.g., tablets, pills, and capsules.

[0083] Pharmaceutically acceptable carriers are well known to those skilled in the art and include, for example, adjuvants, diluents, excipients, fillers, lubricants, and vehicles. In some embodiments, the carrier is a diluent, adjuvant, excipient, or vehicle. In some embodiments, the carrier is a diluent, adjuvant, or excipient. In some embodiments, the carrier is a diluent or adjuvant. In some embodiments, the carrier is an excipient. Often, pharmaceutically acceptable carriers are chemically inactive to the active compound and non-toxic under conditions of use. Examples of pharmaceutically acceptable carriers may include, for example, water or saline solutions, polymers such as polyethylene glycol, carbohydrates and derivatives thereof, oils, fatty acids, or alcohols. Non-limiting examples of oils as pharmaceutical carriers include oils of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Pharmaceutical carriers may also be saline solution, acacia gum, gelatin, starch paste, talc, keratin, colloidal silica, urea, etc. Additionally, adjuvants, stabilizers, thickeners, lubricants, and coloring agents may be used. Other examples of suitable pharmaceutical carriers are, for instance, in the literature [Remington's: The Science and Practice of Pharmacy, 22nd Ed. (Allen, Loyd V., Jr ed., Pharmaceutical Press (2012)); Modern Pharmaceutics, 5 th Ed. (Alexander T. Florence, Juergen Siepmann, CRC Press (2009)); Handbook of Pharmaceutical Excipients, 7 thEd. (Rowe, Raymond C.; Sheskey, Paul J.; Cook, Walter G.; Fenton, Marian E. eds., Pharmaceutical Press (2012)) (each of which is incorporated herein by reference in its entirety)] is described.

[0084] In some embodiments, the compounds of the present disclosure are formulated into pharmaceutical compositions for administration to a subject in a biologically suitable form for in vivo administration. According to another aspect, the present disclosure provides a pharmaceutical composition comprising the disclosed compounds mixed with a pharmaceutically acceptable diluent and / or carrier. A pharmaceutically acceptable carrier is 'acceptable' in the sense that it is compatible with other components of the composition and is not harmful to the recipient thereof. Pharmaceutically acceptable carriers used herein may be selected from various organic or inorganic materials used as materials for pharmaceutical formulations and incorporated as anesthetics, buffers, binders, disintegrants, diluents, emulsifiers, excipients, volume expanders, lubricants, solubilizers, stabilizers, suspenders, thickeners, vehicles, and viscosity-increasing agents. Pharmaceutical additives, such as antioxidants, flavorings, colorings, flavor-improving agents, preservatives, and sweeteners, may also be added. Examples of acceptable pharmaceutical carriers include, in particular, carboxymethyl cellulose, crystalline cellulose, glycerin, gum arabic, lactose, magnesium stearate, methyl cellulose, powder, saline solution, sodium alginate, sucrose, starch, talc, and water. In some embodiments, the term 'pharmaceutical acceptable' means approved by a federal or state regulatory agency or listed in other generally recognized pharmacopoeias for use in animals, more specifically in humans.

[0085] Surfactants, such as detergents, are also suitable for use in formulations. Specific examples of surfactants include polyvinylpyrrolidone, polyvinyl alcohol, copolymers of vinyl acetate and vinylpyrrolidone, polyoxyethyleneated esters of polyethylene glycol, benzyl alcohol, mannitol, glycerol, sorbitol, or sorbitan; lecithin or sodium carboxymethylcellulose; or acrylic acid derivatives, such as methacrylates and others; anionic surfactants, such as alkaline stearates, in particular, sodium stearate, potassium, or ammonium; potassium stearate or triethanolamine stearate; alkyl sulfates, in particular, sodium lauryl sulfate and sodium cetyl sulfate; sodium dodecylbenzenesulfonate or sodium dioctyl sulfosuccinate; or fatty acids, in particular, those derived from coconut oil; cationic surfactants, such as those with formula N + R'R"R"'R""Y - A water-soluble quaternary ammonium salt of (wherein R radical is the same or different optionally hydroxylated hydrocarbon radical, and Y - is an anion of a strong acid, e.g., a halide, sulfate, and sulfonate anion); cetyltrimethylammonium bromide, one of the cationic surfactants that can be used, chemical formula N + The amine salt of R'R"R"' (where the R radical is the same or different optionally hydroxylated hydrocarbon radical); octadecylamine hydrochloride, which is one of the cationic surfactants that can be used; nonionic surfactants, e.g., optionally polyoxyethyleneated esters of sorbitan, particularly polysorbate 80, or polyoxyethyleneated alkyl ethers; polyethylene glycol stearate, polyoxyethylated derivatives of castor oil, polyglycerol esters, polyoxyethylated fatty alcohols, polyoxyethylated fatty acids or copolymers of ethylene oxide and propylene oxide; amphoteric surfactants, e.g., substituted lauryl compounds of betaine.

[0086] When administered to a subject, the disclosed compound and the pharmaceutically acceptable carrier may be sterile. Suitable pharmaceutical carriers may also include excipients, such as starch, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, polyethylene glycol 300, water, ethanol, polysorbate 20, etc. The composition may also, if desired, contain small amounts of a wetting agent, an emulsifier, or a pH buffer.

[0087] The pharmaceutical formulations of the present disclosure are prepared by methods well known in the pharmaceutical field. Optionally, one or more auxiliary components (e.g., buffers, flavorings, surfactants, etc.) are also added. The choice of carrier is determined by the solubility and chemical properties of the compound, the selected route of administration, and standard pharmaceutical practices.

[0088] Additionally, the compounds and / or compositions of the present disclosure are administered to human or animal subjects by known procedures including oral administration, sublingual or buccal administration. In some embodiments, the compounds and / or compositions are administered orally.

[0089] In a solid dosage form for oral administration (capsule, tablet, pill, drase, powder, granule, etc.), the target composition is mixed with one or more pharmaceutically acceptable carriers, e.g., sodium citrate or dicalcium phosphate and / or any of the following: (1) fillers or extenders, e.g., starch, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binders, e.g., carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and / or acacia; (3) wetting agents, e.g., glycerol; (4) disintegrants, e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) dissolution retardants, e.g., paraffin; (6) absorption accelerators, e.g., quaternary ammonium compounds; (7) wetting agents, e.g., acetyl alcohol and glycerol monostearate; (8) absorbents, e.g., kaolin and bentonite clay; (9) lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the composition may also include a buffer. Similar types of solid compositions may also be used as fillers in soft and hard filling gelatin using excipients such as lactose or lactose, as well as high molecular weight polyethylene glycol, etc.

[0090] For oral administration, the formulations of the compounds of the present disclosure may be provided in dosage forms such as capsules, tablets, powders, granules, or suspensions or solutions. Capsule formulations may be gelatin, soft gels, or solids. Tablet and capsule formulations may further contain one or more adjuvants, binders, diluents, disintegrants, excipients, fillers, or lubricants, each of which is known in the art. Examples of these include carbohydrates, e.g., lactose or sucrose, dibasic calcium phosphate anhydride, corn starch, mannitol, xylitol, cellulose or derivatives thereof, microcrystalline cellulose, gelatin, stearates, silicon dioxide, talc, sodium starch glycolate, acacia, flavoring agents, preservatives, buffers, disintegrants, and coloring agents. The composition for oral administration may include one or more optional agents, e.g., sweeteners, e.g., fructose, aspartame, or saccharin, to provide a pharmaceutically palatable formulation; It may contain flavoring agents, e.g., peppermint, wintergreen, or cherry oil; coloring agents; and preservatives.

[0091] Tablets may optionally be manufactured by compression or molding with one or more auxiliary components. Compression tablets may be manufactured using a binder (e.g., gelatin or hydroxypropylmethylcellulose), a lubricant, an inactive diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), a surface-active agent, or a dispersant. Molding tablets may be manufactured by molding a mixture of a wetted target composition and an inactive liquid diluent in a suitable machine. Tablets, and other solid dosage forms, e.g., drase, capsules, pills, and granules, may optionally be scored or manufactured with coatings and shells, e.g., enteric coatings and other coatings well known in the field of pharmaceutical formulation.

[0092] Compositions for inhalation or inhalation comprise solutions and suspensions in aqueous or organic solvents, or mixtures thereof, and powders. Liquid dosage forms for oral administration comprise pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the compositions to be in use, liquid dosage forms may contain inactive diluents commonly used in the art, e.g., water or other solvents, solubilizers and emulsifiers, e.g., ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), fatty acid esters of polyethylene glycol and sorbitan, cyclodextrins, and mixtures thereof.

[0093] In addition to the target composition, the suspension may contain a suspending agent, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0094] A formulation for rectal or vaginal administration may be prepared by mixing the target composition with one or more suitable non-irritating excipients or a carrier comprising, for example, cocoa butter, polyethylene glycol, suppository wax, or salicylate, and may be provided as a suppository which is solid at room temperature but liquid at body temperature, and thus melts in the body cavity and releases an active agent.

[0095] Transdermal administration forms of the target composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active ingredient may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0096] Ointments, pastes, creams, and gels may additionally contain excipients, such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silica, talc, and zinc oxide, or mixtures thereof, in addition to the target composition.

[0097] The powder and spray may additionally contain, in addition to the target composition, excipients, such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powder or mixtures of these materials. The spray may additionally contain conventional propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0098] The compositions and compounds of the present disclosure may alternatively be administered by aerosol. This is achieved by preparing aqueous aerosols, liposomal formulations, or solid particles containing the compounds. Non-aqueous (e.g., fluorocarbon propellant) suspensions may be used. Sonic nebulizers may be used because they minimize the exposure of the formulation to shear, which can lead to the degradation of the compounds contained in the target composition. Typically, aqueous aerosols are prepared by formulating an aqueous solution or suspension of the target composition with conventional pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers vary depending on the needs of the specific target composition but typically include nonionic surfactants (Tween, Pluronic, or polyethylene glycol), harmless proteins such as serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars, or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

[0099] A pharmaceutical composition of the present disclosure suitable for parenteral administration comprises one or more pharmaceutically acceptable sterile isotonic or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that may contain antioxidants, buffers, or bacteriostatic agents and may be reconstituted into sterile injectable solutions or dispersions immediately before use, in combination with a solute or suspension or thickener that provides a formulation isotonic with the blood of the intended recipient.

[0100] Examples of suitable aqueous and non-aqueous carriers that may be used in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils, e.g., olive oil, and organic esters for main use, e.g., ethyl oleate and cyclodextrin. Suitable fluidity may be maintained, for example, by the use of a coating material, e.g., lecithin, by maintaining the particle size required in the case of a dispersion, and by the use of a surfactant. For example, the crystalline form provided herein may be milled to obtain a specific particle size, and in at least some embodiments, such crystalline form may remain substantially stable upon milling.

[0101] For example, compositions suitable for subcutaneous administration comprising a suspension of the disclosed crystalline form are provided herein. Subcutaneous administration may be advantageous over intravenous administration, which typically requires a doctor's visit and can be more painful and invasive. Typical doses of the crystalline compound when administered to a patient may be about 1 mg to about 8 mg of the compound. In embodiments, pharmaceutically acceptable compositions formed from the disclosed crystalline form, for example, by mixing the crystalline form with excipients and / or a solvent, are disclosed herein.

[0102] In an embodiment, a composition comprising a disclosed crystalline form suitable for subcutaneous administration at a dosage level sufficient to deliver a subject's body weight of about 0.001 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 50 mg / kg, about 0.1 mg / kg to about 40 mg / kg, about 0.5 mg / kg to about 30 mg / kg, about 0.001 mg / kg to about 4 mg / kg, about 0.1 mg / kg to about 10 mg / kg, or about 1 mg / kg to about 25 mg / kg is provided herein. In certain embodiments, the desired dose may be delivered using multiple administrations (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 administrations). In certain embodiments, administration may occur once, twice, or three times a week.

[0103] Treatment may continue for as long or as short as desired. The composition may be administered, for example, in a regimen of 1 to 4 or more times per day. A suitable duration of treatment may be, for example, at least about 1 week, at least about 2 weeks, at least about 1 month, at least about 6 months, at least about 1 year, or indefinite. The duration of treatment may be terminated when the desired result, for example, a weight loss goal, is achieved. The treatment regimen may include a correction phase in which a dose sufficient to provide weight loss is administered, followed by a maintenance phase in which a low dose sufficient for weight gain is administered. A suitable maintenance dose may be found in the lower part of the dose range provided herein, but the correction and maintenance doses can be easily established for individual subjects by a person skilled in the art without excessive experimentation based on the disclosures of this specification. The maintenance dose may be used to maintain the weight of a subject whose weight has previously been controlled by other means, including diet and exercise, obesity treatment procedures such as bypass or banding surgery, or treatment using other pharmaceutical agents.

[0104] In certain embodiments, pharmaceutical compositions comprising a crystalline form of Compound I or II as described herein, or a solvate thereof, are provided herein. In certain embodiments, pharmaceutical compositions comprising a crystalline form of Compound I, for example, comprising Form A, Form B, or Form C, or a solvate thereof, as described herein, are provided herein. In certain embodiments, pharmaceutical compositions comprising a crystalline form of Compound II, for example, comprising Form A or Form B, or a solvate thereof, as described herein, are provided herein. In certain embodiments, pharmaceutical compositions provided herein comprise one or more pharmaceutically acceptable excipients as described herein.

[0105] Kit

[0106] In one embodiment, a kit for treating or alleviating a presumed disease or disorder is provided. For example, the disclosed kit comprises a crystalline form of the disclosed crystalline compound, e.g., Compound I, disposed in a first container. In some embodiments, the kit may further comprise a pharmaceutically acceptable excipient disposed in a second container. The kit under consideration may include written instructions describing a method for preparing a pharmaceutical composition suitable for administration to a patient from the crystalline form. For example, the written instructions may describe preparing a pharmaceutically acceptable form for patient administration by mixing the excipient with the crystalline compound disclosed herein. The disclosed kit may further include written instructions describing a method for administering the obtained composition to a patient.

[0107] process

[0108] In some embodiments, a process for producing the disclosed crystalline form of compound I is conceivable herein, comprising: (a) preparing a solution of compound I; (b) controlling the temperature so that a solid crystalline form of compound I precipitates from the solution; and (c) isolating the solid crystalline form. In some embodiments, the solution of the compound of formula (I) comprises a solvent selected from water, methanol, ethanol, acetone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, acetonitrile, t-butyl methyl ether, dichloromethane, tetrahydrofuran, 1,4-dioxane, benzyl alcohol, 2-MeTHF, IPAc, and MtBE. In some embodiments, the solution of compound I comprises a solvent selected from those described in the examples herein.

[0109] In some embodiments, a process for producing the disclosed crystalline form of Compound I is conceivable herein, comprising the steps of: (a) preparing a solution of Compound I in a solvent; (b) controlling the temperature; (c) adding heptane to the solution; and (d) isolating the solid crystalline form. In some embodiments, the solution of Compound I comprises a solvent selected from water, methanol, ethanol, acetone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, acetonitrile, t-butyl methyl ether, dichloromethane, tetrahydrofuran, 1,4-dioxane, benzyl alcohol, 2-MeTHF, IPAc, and MtBE. In some embodiments, the solution of Compound I comprises a solvent selected from those described in the examples herein.

[0110] In some embodiments, a process for preparing the crystalline form of the disclosed compound II is conceivable herein, comprising: (a) preparing a solution of compound II; (b) controlling the temperature so that a solid crystalline form of compound II precipitates from the solution; and (c) isolating the solid crystalline form. In some embodiments, the solution of compound II comprises a solvent selected from water, methanol, ethanol, acetone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, acetonitrile, t-butyl methyl ether, dichloromethane, tetrahydrofuran, 1,4-dioxane, benzyl alcohol, 2-MeTHF, IPAc, and MtBE. In some embodiments, the solution of compound II comprises a solvent selected from those described in the examples herein.

[0111] In some embodiments, a process for preparing the disclosed crystalline form of Compound II is conceivable herein, comprising the steps of: (a) preparing a solution of Compound II in a solvent; (b) controlling the temperature; (c) adding heptane to the solution; and (d) isolating the solid crystalline form. In some embodiments, the solution of Compound II comprises a solvent selected from water, methanol, ethanol, acetone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, acetonitrile, t-butyl methyl ether, dichloromethane, tetrahydrofuran, 1,4-dioxane, benzyl alcohol, 2-MeTHF, IPAc, and MtBE. In some embodiments, the solution of Compound II comprises a solvent selected from those described in the examples herein.

[0112] In some embodiments, the step of adjusting the temperature includes heating the solution. In some embodiments, heating the solution includes heating the solution to about 50°C. In some embodiments, the step of adjusting the temperature includes cooling the solution. In some embodiments, cooling the solution includes cooling the solution to about 0°C, about 5°C, or about 25°C.

[0113] In another embodiment, the disclosed process further comprises the step of coupling compound A6 and compound A7 to form compound I:

[0114] .

[0115] In another embodiment, the disclosed process further comprises the step of converting compound A5 into compound A6:

[0116] .

[0117] In another embodiment, the disclosed process further comprises the step of coupling compound A4 with compound S1 to form compound A5:

[0118] .

[0119] In another embodiment, the disclosed process further comprises the step of converting compound SM1 into compound S1:

[0120] .

[0121] In another embodiment, the disclosed process further comprises the step of converting compound 4 into compound SM1:

[0122] .

[0123] In some embodiments, the step of converting compound 4 to compound SM1 further includes the step of adding an enzyme catalyst.

[0124] In another embodiment, the disclosed process further comprises the step of converting compound S2 into compound II:

[0125] .

[0126] method

[0127] The compounds and compositions described herein are generally useful for inhibiting kinases or mutants thereof. In some embodiments, the kinase inhibited by the compounds and compositions described herein is phosphatidylinositol 3-kinase (PI3K). In some embodiments, the kinase inhibited by the compounds and compositions described herein is one or more of PI3Kα, PI3Kδ, and PI3Kγ. In some embodiments, the kinase inhibited by the compounds and compositions described herein is PI3Kα. In some embodiments, the kinase inhibited by the compounds and compositions described herein is PI3Kα containing at least one of the following mutations: E542X, E545X, Q546X, H1047X, and G1049X, where X is any amino acid other than the wild type. In some embodiments, the kinase inhibited by the compounds and compositions described herein is PI3Kα containing at least one of the following mutations: E542K, E542Q, E545A, E545G, E545K, E545Q, Q546E, Q546K, Q546L, Q546P, Q546R, H1047R, H1047L, H1047Y, G1049R, and G1049S. In some embodiments, the kinase inhibited by the compounds and compositions described herein is PI3Kα containing at least one of the following mutations: E542K, E545K, and H1047R.

[0128] The compounds or compositions of the present disclosure may be useful in applications where benefits are derived from the inhibition of PI3K enzymes. For example, the PI3K inhibitors of the present disclosure are generally useful in the treatment of proliferative cell diseases. The compounds or compositions of the present disclosure may be useful in applications where benefits are derived from the inhibition of PI3Kα enzymes. For example, the PI3Kα inhibitors of the present disclosure are generally useful in the treatment of proliferative cell diseases.

[0129] Abnormal regulation of PI3K, which often increases survival through Aid activation, is one of the most widespread events in human cancers and has been shown to occur at multiple levels. The tumor suppressor gene PTEN, which dephosphorylates phosphoinositide at the 3' position of the inositol ring and thereby antagonizes PI3K activity, is functionally deleted in various tumors. In other tumors, genes for the p110 alpha isoform, PIK3CA, and Akt are amplified, and increased protein expression of their gene products has been demonstrated in several human cancers. Furthermore, mutations and translocations of p85 alpha, which plays a role in upregulating the p85-p110 complex, have been described in human cancers. Finally, somatic missense mutations in PIK3CA, which activates downstream signaling pathways, have been described with significant frequency in a wide variety of human cancers (Kang et al., Proc. Natl. Acad. Sci. USA 102:802 (2005); Samuels et al., Science 304:554 (2004); Samuels et al., Cancer Cell 7:561-573 (2005)). These observations indicate that the downregulation of phosphoinositol-3 kinase and its upstream and downstream components is one of the most common downregulations associated with human cancers and proliferative diseases (Parsons et al., Nature 436:792 (2005); Hennessey et al., Nature Rev. Drug Disc. 4:988-1004 (2005)).

[0130] Treatment of disabilities

[0131] A compound is provided that is an inhibitor of PI3Kα and is useful for treating one or more disorders associated with the activity of PI3Kα or a mutant thereof. Accordingly, in certain embodiments, the present disclosure provides a method for treating a PI3Kα-mediated disorder in a subject, comprising the step of administering a therapeutically effective amount of the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition of one of the foregoing, to a subject requiring treatment of a PI3Kα-mediated disorder. In certain embodiments, the present disclosure provides a method for treating a PI3Kα-mediated disorder in a subject, comprising the step of administering a therapeutically effective amount of the compound of the present disclosure, or a pharmaceutically acceptable composition thereof, to a subject requiring treatment of a PI3Kα-mediated disorder. In some embodiments, the subject has a mutant PI3Kα. In some embodiments, the subject has PI3Kα containing at least one of the following mutations: H1047R, E542K, and E545K. In some embodiments, the subject has a PI3Kα containing at least one of the following mutations: E542K, E542Q, E545A, E545G, E545K, E545Q, Q546E, Q546K, Q546L, Q546P, Q546R, H1047R, H1047L, H1047Y, G1049R, and G1049S.

[0132] As used herein, the term 'PI3Kα-mediated' disorder, disease, and / or condition refers to any disease or other harmful condition known to be caused by PI3Kα or a mutant thereof. Accordingly, other embodiments of the present disclosure relate to treating or alleviating the severity of one or more diseases known to be caused by PI3Kα or a mutant thereof. Such PI3Kα-mediated disorders include, but are not limited to, proliferative disorders (e.g., cancer). In some embodiments, a PI3Kα-mediated disorder is a disorder mediated by the mutant PI3Kα. In some embodiments, a PI3Kα-mediated disorder is a disorder mediated by PI3Kα containing at least one of the following mutations: H1047R, E542K, and E545K. In some embodiments, the subject has PI3Kα containing at least one of the following mutations: E542K, E542Q, E545A, E545G, E545K, E545Q, Q546E, Q546K, Q546L, Q546P, Q546R, H1047R, H1047L, H1047Y, G1049R, and G1049S. In some embodiments, the subject has PI3Kα containing at least one of the mutations in Table A:

[0133] [Table A]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156] In some embodiments, the present disclosure provides a method for treating a proliferative cell disease, the method comprising the step of administering a therapeutically effective amount of the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition of one of the foregoing examples to a patient requiring treatment for a proliferative cell disease. In some embodiments, the present disclosure provides a method for treating a proliferative cell disease, the method comprising the step of administering a therapeutically effective amount of the compound of the present disclosure or a pharmaceutically acceptable composition thereof to a patient requiring treatment for a proliferative cell disease.

[0157] In some embodiments, the method comprises: i) identifying a subject requiring such treatment; (ii) providing the disclosed compound or a pharmaceutically acceptable salt thereof; and (iii) administering the provided compound in a therapeutically effective amount to treat, suppress, and / or prevent a diseased state or pathological condition in the subject requiring such treatment. In some embodiments, the subject has the mutant PI3Kα. In some embodiments, the subject has PI3Kα containing at least one of the following mutations: H1047R, E542K, and E545K. In some embodiments, the subject has a PI3Kα containing at least one of the following mutations: E542K, E542Q, E545A, E545G, E545K, E545Q, Q546E, Q546K, Q546L, Q546P, Q546R, H1047R, H1047L, H1047Y, G1049R, and G1049S.

[0158] In some embodiments, the method comprises: i) identifying a subject requiring such treatment; (ii) providing a composition comprising the disclosed compound or a pharmaceutically acceptable salt thereof; and (iii) administering said composition in a therapeutically effective amount to treat, suppress, and / or prevent a diseased state or pathological condition in the subject requiring such treatment. In some embodiments, the subject has the mutant PI3Kα. In some embodiments, the subject has PI3Kα containing at least one of the following mutations: H1047R, E542K, and E545K. In some embodiments, the subject has a PI3Kα containing at least one of the following mutations: E542K, E542Q, E545A, E545G, E545K, E545Q, Q546E, Q546K, Q546L, Q546P, Q546R, H1047R, H1047L, H1047Y, G1049R, and G1049S.

[0159] Another aspect of the present disclosure provides a compound according to the definition in this specification or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of one of the foregoing, for use in the treatment of the disorder described herein. Another aspect of the present disclosure provides a use of a compound according to the definition in this specification or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of one of the foregoing, for the treatment of the disorder described herein. Similarly, the present disclosure provides a use of a compound according to the definition in this specification or a pharmaceutically acceptable salt thereof for the manufacture of a medicine for the treatment of the disorder described herein.

[0160] Cell proliferative disease

[0161] In some embodiments, the disorder is a proliferative disease. In some embodiments, the proliferative disease is cancer. In some embodiments, the cancer is a tumor. In some embodiments, the cancer is a solid tumor. In some embodiments, the proliferative disease is tumor and / or cancer cell growth. In some embodiments, the proliferative disease is a tumor. In some embodiments, the proliferative disease is a solid tumor. In some embodiments, the proliferative disease is cancerous cell growth.

[0162] In some embodiments, the solid tumor has PI3Kα containing at least one of the following mutations: E542X, E545X, Q546X, H1047X, and G1049X, where X is any amino acid other than the wild type. In some embodiments, the solid tumor has PI3Kα containing at least one of the following mutations: E542K, E542Q, E545A, E545G, E545K, E545Q, Q546E, Q546K, Q546L, Q546P, Q546R, H1047R, H1047L, H1047Y, G1049R, and G1049S. In some embodiments, the solid tumor has PI3Kα containing at least one of the following mutations: H1047R, E542K, and E545K.

[0163] In some embodiments, cancer is sarcoma; lung; bronchi; prostate; breast (including sporadic breast cancer and patients with Corden's disease); pancreas; gastrointestinal; colon; rectum; carcinoma; colon carcinoma; adenocarcinoma; colorectal adenocarcinoma; thyroid; liver; intrahepatic bile duct; hepatocellular; adrenal gland; abdomen; stomach; glioma; glioblastoma; endometrium; melanoma; kidney; renal pelvis; bladder; uterine body; cervical; vagina; ovary (including clear cell ovarian cancer); multiple myeloma; esophagus; leukemia; acute myeloid leukemia; chronic myeloid leukemia; lymphocytic leukemia; myeloid leukemia; brain; carcinoma of the brain; oral cavity and pharynx; larynx; small intestine; non-Hodgkin lymphoma; choriocolon adenocarcinoma; neoplasm; neoplasm of epithelial characteristics; lymphoma; mammary carcinoma; basal cell carcinoma; squamous cell carcinoma; actinic keratosis; neck; head; It is selected from glycemic vera; essential thrombocytosis; myelofibrosis with myeloid metaplasia; and Valtenstrom macroglobulinemia.

[0164] In some embodiments, the cancer is selected from the lung; bronchi; prostate; breast (including sporadic breast cancer and Corden's disease); pancreas; gastrointestinal tract; colon; rectum; thyroid; liver; intrahepatic bile duct; hepatocellular carcinoma; adrenal gland; abdomen; stomach; endometrium; kidney; renal pelvis; bladder; uterine body; cervical tract; vagina; ovary (including clear cell ovarian cancer); esophagus; leukemia; acute myeloid leukemia; chronic myeloid leukemia; lymphocytic leukemia; myeloid leukemia; brain; oral cavity and pharynx; larynx; small intestine; neck; and head. In some embodiments, the cancer is selected from sarcoma; carcinoma; colon carcinoma; adenocarcinoma; colorectal adenocarcinoma; glioma; glioblastoma; melanoma; multiple myeloma; carcinoma of the brain; non-Hodgkin lymphoma; choriocolon adenocarcinoma; neoplasm; neoplasm of epithelial characteristics; lymphoma; mammary carcinoma; basal cell carcinoma; squamous cell carcinoma; It is selected from actinic keratosis; glycocytosis vera; essential thrombocytosis; myelofibrosis with myeloid metaplasia; and Valtenstrom macroglobulinemia.

[0165] In some embodiments, the cancer is selected from the lung; bronchi; prostate; breast (including sporadic breast cancer and Corden's disease); pancreas; gastrointestinal tract; colon; rectum; thyroid; liver; intrahepatic bile duct; hepatocellular carcinoma; adrenal gland; abdomen; stomach; endometrium; kidney; renal pelvis; bladder; uterine body; cervix; vagina; ovary (including clear cell ovarian cancer); esophagus; brain; oral cavity and pharynx; larynx; small intestine; neck; and head. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is acute myeloid leukemia; chronic myeloid leukemia; lymphocytic leukemia; or myeloid leukemia.

[0166] In some embodiments, the cancer is breast cancer (including sporadic breast cancer and Cordon's disease). In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is ER+ / HER2- breast cancer. In some embodiments, the cancer is ER+ / HER2- breast cancer, and the subject is intolerant or unsuitable for treatment with alperisib. In some embodiments, the cancer is sporadic breast cancer. In some embodiments, the cancer is Cordon's disease.

[0167] In some embodiments, the cancer is ovarian cancer. In some embodiments, the ovarian cancer is clear cell ovarian cancer.

[0168] In some embodiments, the cancer is a squamous cell carcinoma. In some embodiments, the cancer is a squamous cell carcinoma of the head and neck.

[0169] In some embodiments, the cancer is cervical cancer.

[0170] In some embodiments, a proliferative disease has the mutant PI3Kα. In some embodiments, cancer has the mutant PI3Kα. In some embodiments, breast cancer has the mutant PI3Kα. In some embodiments, ovarian cancer has the mutant PI3Kα. In some embodiments, clear cell ovarian cancer has the mutant PI3Kα.

[0171] In some embodiments, the proliferative disease has PI3Kα containing at least one of the following mutations: H1047R, E542K, and E545K. In some embodiments, the proliferative disease has PI3Kα containing at least one of the following mutations: E542K, E542Q, E545A, E545G, E545K, E545Q, Q546E, Q546K, Q546L, Q546P, Q546R, H1047R, H1047L, H1047Y, G1049R, and G1049S. In some embodiments, the cancer has PI3Kα containing at least one of the following mutations: H1047R, E542K, and E545K. In some embodiments, the cancer has PI3Kα containing at least one of the following mutations: E542K, E542Q, E545A, E545G, E545K, E545Q, Q546E, Q546K, Q546L, Q546P, Q546R, H1047R, H1047L, H1047Y, G1049R, and G1049S. In some embodiments, the breast cancer has PI3Kα containing at least one of the following mutations: H1047R, E542K, and E545K. In some embodiments, breast cancer has PI3Kα containing at least one of the following mutations: E542K, E542Q, E545A, E545G, E545K, E545Q, Q546E, Q546K, Q546L, Q546P, Q546R, H1047R, H1047L, H1047Y, G1049R, and G1049S. In some embodiments, ovarian cancer has PI3Kα containing at least one of the following mutations: H1047R, E542K, and E545K. In some embodiments, the ovarian cancer has PI3Kα containing at least one of the following mutations: E542K, E542Q, E545A, E545G, E545K, E545Q, Q546E, Q546K, Q546L, Q546P, Q546R, H1047R, H1047L, H1047Y, G1049R and G1049S.In some embodiments, the clear cell ovarian cancer has PI3Kα containing at least one of the following mutations: H1047R, E542K, and E545K. In some embodiments, the clear cell ovarian cancer has PI3Kα containing at least one of the following mutations: E542K, E542Q, E545A, E545G, E545K, E545Q, Q546E, Q546K, Q546L, Q546P, Q546R, H1047R, H1047L, H1047Y, G1049R, and G1049S.

[0172] In some embodiments, the cancer is an adenocarcinoma; a carcinoma; a sarcoma; a glioma; a glioblastoma; a melanoma; a multiple myeloma; or a lymphoma. In some embodiments, the cancer is a colorectal adenocarcinoma or a villous colon adenocarcinoma. In some embodiments, the cancer is a colon carcinoma; a carcinoma of the brain; a mammary gland carcinoma; a basal cell carcinoma; or a squamous cell carcinoma. In some embodiments, the cancer is a neoplasm or a neoplasm of epithelial tissue characteristics. In some embodiments, the cancer is a non-Hodgkin lymphoma. In some embodiments, the cancer is actinic keratosis; glycemic vera; essential thrombocytosis; myelofibrosis with myeloid metaplasia; or Valtenstrom macroglobulinemia.

[0173] In some embodiments, the proliferative disorder represents overexpression or proliferation of PI3Kα, somatic mutations of PIK3CA, germline mutations or somatic mutations of PTEN, or mutations and translocations of p85α that play a role in upregulating the p85-p110 complex. In some embodiments, the proliferative disorder represents overexpression or proliferation of PI3Kα. In some embodiments, the proliferative disorder represents somatic mutations of PIK3CA. In some embodiments, the proliferative disorder represents germline mutations or somatic mutations of PTEN. In some embodiments, the proliferative disorder represents mutations and translocations of p85α that play a role in upregulating the p85-p110 complex.

[0174] Additional failures

[0175] In some embodiments, PI3Kα-mediated disorders include glycocytosis vera, essential thrombocytosis, myelofibrosis with myeloid metaplasia, asthma, COPD, ARDS, PROS (PI3K-related overgrowth syndrome), venous vascular malformations, Loeffler syndrome, eosinophilic pneumonia, parasitic (especially metazoan) infections (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosum (including Chug-Strauss syndrome), eosinophilic granuloma, eosinophil-related disorders affecting the airway caused by drug reactions, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, herpetic dermatitis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphigus, acquired epidermal bullous disease, autoimmune hematological disorders (e.g., hemolytic anemia, asthenia Anemia, pure red blood cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), interstitial pulmonary fibrosis, psoriatic arthritis, glomerulonephritis, cardiovascular disease, atherosclerosis, hypertension, deep vein thrombosis, stroke, myocardial infarction, unstable chest tightness, thromboembolism, pulmonary embolism, thrombotic disease, acute arterial ischemia, peripheral thrombotic occlusion and coronary artery disease, reperfusion injury, retinopathy, e.g., It is selected from the group consisting of diabetic retinopathy or hyperbaric oxygen-induced retinopathy and pathological conditions characterized by elevated intraocular pressure or secretion of ocular aqueous humor, e.g., glaucoma.

[0176] In some embodiments, the PI3Kα-mediated disorder is glycocytosis vera, essential thrombocytosis, or myelofibrosis with myeloid metaplasia. In some embodiments, the PI3Kα-mediated disorder is asthma, COPD, ARDS, PROS (PI3K-related overgrowth syndrome), venous vascular malformation, Loeffler syndrome, eosinophilic pneumonia, parasitic (particularly metazoan) parasitic infection (including tropical eosinophilia), or bronchopulmonary aspergillosis. In some embodiments, the PI3Kα-mediated disorder is polyarteritis nodosum (including Chug-Strauss syndrome), eosinophilic granuloma, eosinophil-related disorders affecting the airways caused by drug-response, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, herpetic dermatitis, or scleroderma. In some embodiments, the PI3Kα-mediated disorder is vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphigus, acquired epidermal bullous disease, or an autoimmune hematological disorder (e.g., hemolytic anemia, asthenic anemia, pure red cell anemia, and idiopathic thrombocytopenia). In some embodiments, the PI3Kα-mediated disorder is systemic lupus erythematosus, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, or an autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease).

[0177] In some embodiments, the PI3Kα-mediated disorder is endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), interstitial pulmonary fibrosis, or psoriatic arthritis. In some embodiments, the PI3Kα-mediated disorder is glomerulonephritis, cardiovascular disease, atherosclerosis, hypertension, deep vein thrombosis, stroke, myocardial infarction, unstable chest tightness, thromboembolism, pulmonary embolism, thrombotic disease, acute arterial ischemia, peripheral thrombotic occlusion and coronary artery disease, or reperfusion injury. In some embodiments, the PI3Kα-mediated disorder is retinopathy, e.g., diabetic retinopathy or hyperbaric oxygen-induced retinopathy, and a condition characterized by increased intraocular pressure or secretion of ocular aqueous humor, e.g., glaucoma.

[0178] Route of administration and form of administration

[0179] Compounds and compositions according to the method of the present disclosure may be administered using any amount and any route of administration effective for treating a disorder (e.g., proliferative disorder) or alleviating its severity. The exact amount required will vary depending on the subject, depending on the subject's species, age and general condition, severity of infection, specific formulation, mode of administration, etc. The compounds of the present disclosure are preferably formulated in unit dosage forms for ease of administration and uniformity of dosage. The expression 'unit dosage form' as used herein refers to physically distinct units of the appropriate formulation for the patient under treatment. However, it will be understood that the total daily use of the compounds and compositions of the present disclosure is determined by the attending physician within the scope of sound medical judgment. The specific effective dose level for any specific patient or organism is determined by the disorder under treatment and the severity of the disorder; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health condition, sex, and diet; the time of administration, route of administration, and elimination rate of the specific compound used; the duration of treatment; It will depend on drugs used in combination with or accompanying specific compounds, and various factors including similar factors well known in the medical field.

[0180] The pharmaceutically acceptable compositions of the present disclosure may be administered to humans and other animals orally, rectally, parenterally, into a tub, vaginally, intraperitoneally, topically (by powder, ointment, or drops), buccally, or by oral or parenteral spray, etc. In certain embodiments, the compounds of the present disclosure may be administered orally or parenterally at least once a day at a dose level of about 0.01 mg / kg to about 50 mg / kg and preferably about 1 mg / kg to about 25 mg / kg per day to obtain the desired therapeutic effect.

[0181] Liquid formulations for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid formulation may contain, for example, water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (particularly cottonseed, peanut, corn, germ, olive, castor, sesame oil), fatty acid esters of glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan, and mixtures thereof, as well as inert diluents commonly used in the art. In addition to inert diluents, the oral composition may further contain adjuvants, for example, humectants, emulsifiers, suspending agents, sweeteners, flavorings, and fragrances.

[0182] Injectable formulations, e.g., sterile injectable aqueous or oily suspensions, may be formulated according to the known art using suitable dispersants or wetting agents and suspending agents. Sterile injectable formulations may also be sterile injectable solutions, suspensions, or emulsions in acceptable non-toxic parenteral diluents or solvents, e.g., solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, USP, and isotonic sodium chloride solution. Furthermore, sterile fixed oils are typically used as solvents or suspension media. For this purpose, bland fixed oils, including synthetic monoglycerides or diglycerides, may be used. Additionally, fatty acids such as oleic acid are used in injectable formulations.

[0183] Injectable formulations can be sterilized, for example, by filtration through a bacteria-maintaining filter, or by incorporating a sterile agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media before use.

[0184] To prolong the effect of the compounds of the present disclosure, it is often desirable to slow the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous material with poor water solubility. The absorption rate of said compounds depends on the subsequent dissolution rate and, consequently, may depend on crystal size and crystal form. Alternatively, delayed absorption of parenterally administered compound forms is achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are formed by forming a microencapsulation matrix of the compound in a biodegradable polymer, such as polylactide-polyglycolide. The release rate of the compound can be controlled depending on the ratio of the compound to the polymer and the characteristics of the specific polymer used. Other examples of biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by encapsulating said compounds in liposomes or microemulsions that are compatible with biological tissues.

[0185] A composition for rectal or vaginal administration is preferably a suppository, and such a suppository can be prepared by mixing the compound of the present invention with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or a suppository wax that exists as a solid at ambient temperature but as a liquid at body temperature, thereby melting in the rectal or vaginal cavity to release the active compound.

[0186] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In this solid dosage form, the active compound comprises at least one inactive, pharmaceutically acceptable excipient or carrier, e.g., sodium citrate or dicalcium phosphate and / or a) fillers or extenders, e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, e.g., carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidineone, sucrose, and acacia; c) wetting agents, e.g., glycerol; d) disintegrants, e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) dissolution retardants, e.g., paraffin; f) absorption accelerators, e.g., quaternary ammonium compounds; g) wetting agents, e.g., cetyl alcohol and glycerol monostearate; h) absorbents, e.g., kaolin and bentonite clay; and i) lubricants, For example, it is mixed with talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also include a buffer.

[0187] Similar types of solid compositions can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or lactose, as well as high molecular weight polyethylene glycol. Solid dosage forms of tablets, coated tablets, capsules, pills, and granules can be manufactured with coatings and shells, such as enteric coatings and other coatings widely known in the field of pharmaceutical formulation technology. These may optionally contain opacifying agents and may also be compositions that release only the active ingredient(s), or preferentially in a selectively delayed manner, from specific parts of the intestinal tract. Examples of filler compositions that can be used include polymeric materials and waxes. Similar types of solid compositions can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or lactose, as well as high molecular weight polyethylene glycol.

[0188] The active compound may also be in a microencapsulated form having one or more excipients as mentioned above. Solid dosage forms such as tablets, coated tablets, capsules, pills, and granules may be manufactured with coatings and shells, e.g., enteric coatings, controlled-release coatings, and other coatings widely known in the field of pharmaceutical formulation technology. In these solid dosage forms, the active compound may be mixed with at least one inert diluent, e.g., sucrose, lactose, or starch. These dosage forms may also include additional materials other than the inert diluent, e.g., tablet lubricants and other tablet preparations, e.g., magnesium stearate and microcrystalline cellulose, as in ordinary practice. In the case of capsules, tablets, and pills, the dosage forms may also include a buffer. They may optionally contain an opacifying agent and may also be compositions that release only the active ingredient(s), or preferentially in a selectively delayed manner in specific parts of the intestinal tract. Examples of embedding compositions that may be used include polymeric materials and waxes.

[0189] Dosage forms for topical or transdermal administration of the compounds of the present disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed with a pharmaceutically acceptable carrier under sterile conditions, and any necessary preservatives or buffers may be required. Ophthalmic formulations, ear drops, and ophthalmic solutions are also considered to be within the scope of the present disclosure. Additionally, the present disclosure considers the use of transdermal patches, which have the additional advantage of controlling the delivery of the compounds to the body. These dosage forms may be prepared by dissolving or dispersing the compounds in a suitable medium. Absorption enhancers may be used to increase the flux of the compounds across the skin. The rate may be controlled by providing a rate-controlling membrane or by dispersing the compounds in a polymer substrate or gel.

[0190] Dosage and Therapy

[0191] According to the method of the present disclosure, the compound of the present disclosure is administered to a subject in a therapeutically effective amount to reduce or improve, for example, the symptoms of the subject's disorder. This amount is readily determined by a person skilled in the art according to known procedures, including the analysis of titration curves established in vivo and the methods and analyses disclosed herein.

[0192] In some embodiments, the method comprises administering a therapeutically effective dose of a compound of the present disclosure. In some embodiments, a therapeutically effective dose is at least about 0.0001 mg / kg body weight, at least about 0.001 mg / kg body weight, at least about 0.01 mg / kg body weight, at least about 0.05 mg / kg body weight, at least about 0.1 mg / kg body weight, at least about 0.25 mg / kg body weight, at least about 0.3 mg / kg body weight, at least about 0.5 mg / kg body weight, at least about 0.75 mg / kg body weight, at least about 1 mg / kg body weight, at least about 2 mg / kg body weight, at least about 3 mg / kg body weight, at least about 4 mg / kg body weight, at least about 5 mg / kg body weight, at least about 6 mg / kg body weight, at least about 7 mg / kg body weight, at least about 8 mg / kg body weight, at least about 9 mg / kg body weight, at least about 10 mg / kg body weight, at least about 15 mg / kg body weight, at least about 20 mg / kg body weight, at least about 25 mg / kg body weight, at least about 30 mg / kg body weight, at least about 40 mg / kg body weight, at least about 50 mg / kg body weight, at least about 75 mg / kg body weight, at least about 100 mg / kg body weight, at least about 200 mg / kg body weight, at least about 250 mg / kg body weight, at least about 300 mg / kg body weight, at least about 350 mg / kg body weight, at least about 400 mg / kg body weight, at least about 450 mg / kg body weight, at least about 500 mg / kg body weight, at least about 550 mg / kg body weight, at least about 600 mg / kg body weight, at least about 650 mg / kg body weight, at least about 700 mg / kg body weight, at least about 750 mg / kg body weight, at least about 800 mg / kg body weight, at least about 900 mg / kg body weight or at least about It is 1000 mg / kg body weight. It will be recognized that any dosage listed in this specification may constitute an upper or lower dosage range and may be combined with any other dosage that constitutes a dosage range including the upper and lower limits.

[0193] In some embodiments, the therapeutically effective dose is in the range of about 0.1 mg to about 10 mg / kg body weight, about 0.1 mg to about 6 mg / kg body weight, about 0.1 mg to about 4 mg / kg body weight, or about 0.1 mg to about 2 mg / kg body weight.

[0194] In some embodiments, the therapeutically effective dose is in the range of about 1 to 500 mg, about 2 to 150 mg, about 2 to 120 mg, about 2 to 80 mg, about 2 to 40 mg, about 5 to 150 mg, about 5 to 120 mg, about 5 to 80 mg, about 10 to 150 mg, about 10 to 120 mg, about 10 to 80 mg, about 10 to 40 mg, about 20 to 150 mg, about 20 to 120 mg, about 20 to 80 mg, about 20 to 40 mg, about 40 to 150 mg, about 40 to 120 mg, or about 40 to 80 mg.

[0195] In some embodiments, the method comprises a single dose or administration (e.g., as a single injection or deposit). Alternatively, in some embodiments, the method comprises administration once daily, twice daily, three times daily, or four times daily to a subject requiring it for about 2 to about 28 days, or about 7 to about 10 days, or about 7 to about 15 days, or a longer period. In some embodiments, the method comprises chronic administration. In another embodiment, the method comprises administration over a course of several weeks, several months, several years, or decades. In another embodiment, the method comprises administration over a course of several weeks. In another embodiment, the method comprises administration over a course of several months. In another embodiment, the method comprises administration over a course of several years. In another embodiment, the method comprises administration over a course of several decades.

[0196] The administered dosage may vary depending on known factors such as the pharmacodynamic characteristics of the active ingredient and its mode and route of administration; the time of administration of the active ingredient; the recipient's age, sex, health status, and weight; the characteristics and severity of symptoms; the type, frequency, and intended effect of concomitant therapy; and the rate of elimination. All of these are readily determined and can be used by those skilled in the art to adjust or titrate the dosage and / or medication regimen.

[0197] Inhibition of protein kinase

[0198] According to one embodiment, the present disclosure relates to a method for inhibiting protein kinase activity in a biological sample, comprising the step of contacting the biological sample with the compound of the present disclosure or a composition comprising said compound. According to another embodiment, the present disclosure relates to a method for inhibiting the activity of PI3K or a mutant thereof in a biological sample, comprising the step of contacting the biological sample with the compound of the present disclosure or a composition comprising said compound. According to another embodiment, the present disclosure relates to a method for inhibiting the activity of PI3Kα or a mutant thereof in a biological sample, comprising the step of contacting the biological sample with the compound of the present disclosure or a composition comprising said compound. In some embodiments, PI3Kα is the mutant PI3Kα. In some embodiments, PI3Kα comprises at least one of the following mutants: H1047R, E542K, and E545K.

[0199] In another embodiment, the present disclosure provides a method for selectively inhibiting PI3Kα more than one or both of PI3Kδ and PI3Kγ. In some embodiments, the compound of the present disclosure is more than 5 times selective than PI3Kδ and PI3Kγ. In some embodiments, the compound of the present disclosure is more than 10 times selective than PI3Kδ and PI3Kγ. In some embodiments, the compound of the present disclosure is more than 50 times selective than PI3Kδ and PI3Kγ. In some embodiments, the compound of the present disclosure is more than 100 times selective than PI3Kδ and PI3Kγ. In some embodiments, the compound of the present disclosure is more than 200 times selective than PI3Kδ and PI3Kγ. In some embodiments, PI3Kα is mutant PI3Kα. In some embodiments, PI3Kα comprises at least one of the following mutations: H1047R, E542K, and E545K.

[0200] In another embodiment, the present disclosure provides a method for selectively inhibiting mutant PI3Kα over wild-type PI3Kα. In some embodiments, the compound of the present disclosure is more than 5-fold selective for mutant PI3Kα over wild-type PI3Kα. In some embodiments, the compound of the present disclosure is more than 10-fold selective for mutant PI3Kα over wild-type PI3Kα. In some embodiments, the compound of the present disclosure is more than 50-fold selective for mutant PI3Kα over wild-type PI3Kα. In some embodiments, the compound of the present disclosure is more than 100-fold selective for mutant PI3Kα over wild-type PI3Kα. In some embodiments, the compound of the present disclosure is more than 200-fold selective for mutant PI3Kα over wild-type PI3Kα. In some embodiments, the mutant PI3Kα comprises at least one of the following mutations: H1047R, E542K, and E545K.

[0201] The term 'biological sample' as used herein includes, but is not limited to, cell cultures or extracts thereof; biopsy material or extracts thereof obtained from mammals; and blood, saliva, urine, excretions, semen, tears or other body fluids or extracts thereof.

[0202] Inhibition of the activity of PI3K (e.g., PI3Kα, or mutants thereof) in biological samples is useful for various purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, biological sample storage, and biological analysis.

[0203] Another embodiment of the present disclosure relates to a method for inhibiting protein kinase activity in a patient, comprising the step of administering the compound of the present disclosure or a composition comprising said compound to the patient.

[0204] According to other embodiments, the present disclosure relates to a method for inhibiting the activity of PI3K or a mutant thereof in a patient, comprising the step of administering the compound of the present disclosure or a composition comprising said compound to said patient. In some embodiments, the present disclosure relates to a method for inhibiting the activity of PI3Kα or a mutant thereof in a patient, comprising the step of administering the compound of the present disclosure or a composition comprising said compound to said patient. In some embodiments, PI3Kα is the mutant PI3Kα. In some embodiments, PI3Kα comprises at least one of the following mutations: H1047R, E542K, and E545K.

[0205] According to other embodiments, the present disclosure provides a method for treating a disorder mediated by PI3K or a mutant thereof in a patient requiring treatment of said disorder, which comprises the step of administering a compound according to the present disclosure or a pharmaceutically acceptable composition thereof to said patient. In some embodiments, the present disclosure provides a method for treating a disorder mediated by PI3Kα or a mutant thereof in a patient requiring treatment of said disorder, which comprises the step of administering a compound according to the present disclosure or a pharmaceutically acceptable composition thereof to said patient. In some embodiments, PI3Kα is mutant PI3Kα. In some embodiments, PI3Kα comprises at least one of the following mutations: H1047R, E542K, and E545K.

[0206] According to other embodiments, the present disclosure provides a method for inhibiting the signaling activity of PI3Kα or a mutant thereof in a subject, comprising the step of administering a therapeutically effective amount of a compound according to the present disclosure or a pharmaceutically acceptable composition thereof to a subject requiring inhibition of the signaling activity of PI3Kα or a mutant thereof. In some embodiments, the present disclosure provides a method for inhibiting the signaling activity of PI3Kα in a subject, comprising the step of administering a therapeutically effective amount of a compound according to the present disclosure or a pharmaceutically acceptable composition thereof to a subject requiring inhibition of the signaling activity of PI3Kα. In some embodiments, PI3Kα is a mutant PI3Kα. In some embodiments, PI3Kα comprises at least one of the following mutations: H1047R, E542K, and E545K. In some embodiments, the subject has the mutant PI3Kα. In some embodiments, the subject has PI3Kα containing at least one of the following mutations: H1047R, E542K and E545K.

[0207] The compounds described herein may also inhibit PI3Kα function by incorporating them into agents that catalyze the degradation of PI3Kα. For example, the compounds may be incorporated into a protein degradation targeting chimera (PROTAC). PROTAC is a difunctional molecule, one portion of which may be involved in E3 ubiquitin ligase, and the other portion which has the ability to bind to a target protein, implying degradation by cellular protein quality control mechanisms. Supplementation of the target protein to a specific E3 ligase results in degradation by the proteasome (i.e., ubiquitination) and subsequent tagging of the target protein for degradation. Any E3 ligase may be used. The portion of PROTAC involved in the E3 ligase is linked to the portion of PROTAC involved in the target protein via a linker consisting of a variable chain of atoms. Thus, supplementation of PI3Kα to the E3 ligase will result in the degradation of the PI3Kα protein. The variable chain of atoms may include, for example, rings, heteroatoms, and / or repeating polymer units. It may be rigid or flexible. It may be attached to the two parts described above using standard techniques in the field of organic synthesis.

[0208] Combination therapy

[0209] Depending on the specific disorder, condition, or disease to be treated, additional therapeutic agents typically administered to treat such condition may be administered in combination with the compounds and compositions of the present disclosure. As used herein, additional agents typically administered to treat a specific disease or condition are known to be 'appropriate for the disease or condition being treated'.

[0210] Additionally, PI3K acts as a secondary messenger node integrating parallel signaling pathways, and evidence indicates that the combination of PI3K inhibitors and inhibitors of other pathways is useful for treating cancer and proliferative diseases.

[0211] Accordingly, in certain embodiments, the treatment method comprises the step of administering the compound or composition of the present disclosure in combination with one or more additional therapeutic agents. In certain other embodiments, the treatment method comprises the step of administering the compound or composition of the present disclosure as a therapeutic agent alone.

[0212] Approximately 20 to 30 percent of human breast cancers overexpress Her-2 / neu-ErbB2, which is a target for the drug trastuzumab. Although trastuzumab has demonstrated a sustained response in some patients expressing Her2 / neu-ErbB2, only some of these patients respond. Recent work has indicated that this limited response rate can be substantially improved by a combination of trastuzumab and inhibitors of the PI3K or PI13K / AKT pathways (Chan et al., Breast Can. Res. Treat. 91:187 (2005); Woods Ignatoski et al., Brit. J. Cancer 82:666 (2000); Nagata et al., Cancer Cell 6:117 (2004)). Accordingly, in certain embodiments, a treatment method comprises the step of administering a compound or composition of the present disclosure in combination with trastuzumab. In a specific embodiment, the cancer is a human breast cancer that overexpresses Her-2 / neu-ErbB2.

[0213] Various human malignancies express activating mutations or increased levels of Her1 / EGFR and numerous antibodies, and small molecule inhibitors have been developed for these receptor tyrosine kinases, including Tarceva, gefitinib, and Erbitux. However, while EGFR inhibitors demonstrate antitumor activity in certain human tumors (e.g., NSCLC), they do not increase overall patient survival in all patients with EGFR-expressing tumors. This may be justified by the fact that many downstream targets of Her1 / EGFR are frequently mutated or deregulated in various malignancies involving the PI3K / Akt pathway.

[0214] For example, gefitinib inhibits the growth of adenocarcinoma cell lines in in vitro assays. Nevertheless, subclones of these cell lines that are resistant to gefitinib and exhibit increased activation of the PI3 / Akt pathway can be selected. Downregulation or inhibition of this pathway provides gefitinib-sensitive resistant subclones (Kokubo et al., Brit. J. Cancer 92:1711 (2005)). Furthermore, in an in vitro model of breast cancer using cell lines harboring PTEN mutations and overexpressing EGFR, inhibition of both the PI3K / Akt pathway and EGFR produced a synergistic effect (She et al., Cancer Cell 8:287-297 (2005)). These results indicate that the combination of gefitinib and PI3K / Akt pathway inhibitors is an attractive therapeutic strategy in cancer.

[0215] Accordingly, in certain embodiments, the treatment method comprises the step of administering the compound or composition of the present disclosure in combination with an inhibitor of Her1 / EGFR. In certain embodiments, the treatment method comprises the step of administering the compound or composition of the present disclosure in combination with one or more of Tarceva, gefitinib, and Erbitux. In certain embodiments, the treatment method comprises the step of administering the compound or composition of the present disclosure in combination with gefitinib. In certain embodiments, the cancer expresses an activating mutation or an increased level of Her1 / EGFR.

[0216] The combination of AEE778 (an inhibitor of Her-2 / neu / ErbB2, VEGFR, and EGFR) and RAD001 (an inhibitor of mTOR, a downstream target of Akt) produced greater combined efficacy than either agent alone in a glioblastoma xenograft model (Goudar et al., Mol. Cancer. Ther. 4:101-112 (2005)).

[0217] Anti-estrogens, such as tamoxifen, inhibit breast cancer growth by inducing cell cycle inhibition that requires the action of the cell cycle inhibitor p27Kip. Recently, it has been shown that activation of the Ras-Raf-MAP kinase pathway alters the phosphorylation status of p27Kip, thereby weakening its inhibitory activity in inhibiting the cell cycle and contributing to anti-estrogen resistance (Donovan, et al, J. Biol. Chem. 276:40888, (2001)). As reported by Donovan et al., inhibition of MAPK signaling through treatment with MEK inhibitors reversed the abnormal phosphorylation status of p27 in hormone-refractory breast cancer cell lines, thereby restoring hormone sensitivity. Similarly, phosphorylation of p27Kip by Aid also eliminates its role in inhibiting the cell cycle (Viglietto et al., Nat. Med. 8:1145(2002)).

[0218] Accordingly, in certain embodiments, the treatment method comprises the step of administering the compound or composition of the present disclosure in combination with a treatment for hormone-dependent cancer. In certain embodiments, the treatment method comprises the step of administering the compound or composition of the present disclosure in combination with tamoxifen. In certain embodiments, the cancer is a hormone-dependent cancer, e.g., breast and prostate cancer. By using this, the aim is to reverse the hormone resistance commonly seen in these cancers using conventional anticancer agents.

[0219] In hematological cancers such as chronic myeloid leukemia (CML), chromosomal translocations result in constitutively activated BCR-Abl tyrosine kinase. Patients suffering from the disease respond to imatinib, a small molecule tyrosine kinase inhibitor, as a result of inhibiting Abl kinase activity. However, many patients with advanced disease initially respond to imatinib but subsequently relapse due to resistance-granting mutations in the Abl kinase domain. In vitro studies have demonstrated that BCR-Ab1 exerts its effects via the Ras-Raf kinase pathway. Furthermore, inhibiting more than one kinase in the same pathway provides additional protection against resistance-granting mutations.

[0220] Accordingly, in another aspect, the compounds and compositions of the present disclosure are used in combination with at least one additional agent selected from the group of kinase inhibitors, such as imatinib, in the treatment of blood cancers such as chronic myeloid leukemia (CML). By using this, the aim is to reverse or prevent resistance to said at least one additional agent.

[0221] Since activation of the PI3K / Akt pathway induces cell survival, inhibition of this pathway in combination with therapies that induce apoptosis in cancer cells, including radiotherapy and chemotherapy, will result in an improved response (Ghobrial et al., CA Cancer J. Clin 55:178-194 (2005)). For example, the combination of a PI3 kinase inhibitor and carboplatin demonstrated synergistic effects in in vitro proliferation and apoptosis assays as well as in vivo tumor efficacy in a xenograft model of ovarian cancer (Westfall and Skinner, Mol. Cancer Ther. 4:1764-1771 (2005)).

[0222] In some embodiments, one or more additional therapeutic agents are selected from antibodies, antibody-drug conjugates, kinase inhibitors, immunomodulators, and histone deacetylase inhibitors. Synergistic combinations of PIK3CA inhibitors and other therapeutic agents are described, for example, in the literature [Castel et al., Mol. Cell Oncol. (2014)1(3) e963447].

[0223] In some embodiments, one or more additional therapeutic agents are selected from the following agents or pharmaceutically acceptable salts thereof: BCR-ABL inhibitors (e.g., see reference [Ultimo et al. Oncotarget (2017) 8 (14) 23213-23227.]): e.g., imatinib, inilotinib, nilotinib, dasatinib, bosutinib, ponatinib, bafetinib, danusertib, saracatinib, PF03814735; ALK inhibitors (e.g., see reference [Yang et al. Tumour Biol. (2014) 35 (10) 9759-67]): e.g., crizotinib, NVP-TAE684, ceritinib, alectinib, brigatinib, entresinib, loratinib; BRAF inhibitors (e.g., see literature [Silva et al. Mol. Cancer Res. (2014) 12, 447-463]): e.g., vemurafenib, dabrafenib; FGFR inhibitors (e.g., see literature [Packer et al. Mol. Cancer Ther. (2017) 16(4) 637-648]): e.g., infigratinib, dovitinib, erdafitinib, TAS-120, pemigatinib, BLU-554, AZD4547; FLT3 inhibitors: e.g., sunitinib, midostaurin, tanutinib, sorafenib, restauritinib, quizartinib, and crenoranib; MEK inhibitors (e.g., see literature [Jokinen et al. Ther. Adv. Med. Oncol. (2015) 7(3) 170-180]): e.g., trametinib, cobimetinib, binimetinib, selumetinib; ERK inhibitors: e.g., ulixertinib, MK 8353, LY 3214996; KRAS inhibitors: e.g., AMG-510, MRTX849, ARS-3248; tyrosine kinase inhibitors (e.g., see literature [Makhov et al. Mol. Cancer. Ther.[See (2012) 11(7) 1510-1517]): e.g., erlotinib, linifanib, sunitinib, pazopanib; epidermal growth factor receptor (EGFR) inhibitors (e.g., see She et al. BMC Cancer (2016) 16, 587)): gefitinib, osimertinib, cetuximab, panitumumab; HER2 receptor inhibitors (e.g., see Lopez et al. Mol. Cancer Ther. (2015) 14(11) 2519-2526)): e.g., trastuzumab, pertuzumab, neratinib, lapatinib, lapatinib; MET inhibitors (e.g., see reference [Hervieu et al. Front. Mol. Biosci. (2018) 5, 86]): e.g., crizotinib, cabozantinib; CD20 antibodies: e.g., rituximab, tocitumomab, ofatumumab; DNA synthesis inhibitors: e.g., capecitabine, gemcitabine, nelarabine, hydroxycarbamide; antineoplastic agents (e.g., see reference [Wang et al. Cell Death & Disease (2018) 9, 739]): e.g., oxaliplatin, carboplatin, cisplatin; immunomodulators: e.g., aputuzumab, lenalidomide, thalidomide, pamalidomide; CD40 inhibitors: e.g., darsetuzumab; Pro-apoptotic receptor agonists (PARA): e.g., dulanermin; heat shock protein (HSP) inhibitors (e.g., see reference [Chen et al. Oncotarget (2014) 5 (9). 2372-2389]): e.g., tanespimycin; Hedgehog antagonists (e.g., see reference [Chaturvedi et al. Oncotarget (2018) 9 (24), 16619-16633]): e.g., bismodegib; proteasome inhibitors (e.g., see reference [Lin et al. Int. J. Oncol.[See (2014) 44 (2), 557-562]): e.g., bortezomib; PI3K inhibitors: e.g., pictilisib, dactolisib, alperisib, buparisib, taselisib, idellarisib, duvelisib, umbralisib; SHP2 inhibitors (e.g., see [Sun et al. Am. J. Cancer Res. (2019) 9 (1), 149-159]: e.g., SHP099, RMC-4550, RMC-4630); BCL-2 inhibitors (e.g., see [Bojarczuk et al. Blood (2018) 133 (1), 70-80]): e.g., venetoclax; Aromatase inhibitors (e.g., see [Mayer et al. Clin. Cancer Res. (2019) 25 (10), 2975-2987]): exemestane, letrozole, anastrozole, fulvestrant, tamoxifen; mTOR inhibitors (e.g., see [Woo et al. Oncogenesis (2017) 6, e385]): e.g., temsirolimus, lidaphorolimus, everolimus, sirolimus; CTLA-4 inhibitors (e.g., see [O'Donnell et al. (2018) 48, 91-103]): e.g., tremelimumab, ipilimumab; PD1 inhibitors (see [O'Donnell], cit.): e.g., nivolumab, pembrolizumab; immunoadhesins; Other immune checkpoint inhibitors (e.g., see reference [Zappasodi et al. Cancer Cell (2018) 33, 581-598]), where the term 'immune checkpoint' refers to a group of molecules on the cell surface of CD4 and CD8 T cells. Immune checkpoint molecules include, but are not limited to, programmed cell death 1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), B7H1, B7H4, OX-40, CD 137, CD40, and LAG3.Immunotherapeutic agents capable of acting as useful immune checkpoint inhibitors in the method of the present disclosure include: inhibitors of PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD 160, 2B4 and / or TGFR beta): e.g., pidilizumab, AMP-224; PDL1 inhibitors (e.g., see reference [O'Donnell] above): e.g., MSB0010718C; YW243.55.S70, MPDL3280A; MEDI-4736, MSB-0010718C or MDX-1105; histone deacetylase inhibitors (HDI, e.g., see reference [Rahmani et al. Clin. Cancer Res. (2014) 20(18), 4849-4860]): e.g., vorinostat; Androgen receptor inhibitors (e.g., see reference [Thomas et al. Mol. Cancer Ther. (2013) 12(11), 2342-2355]): e.g., enzalutamide, abiraterone acetate, orteronel, galetterone, seviteronel, bicalutamide, flutamide; androgens: e.g., fluoxymesterone; CDK4 / 6 inhibitors (e.g., see reference [Gul et al. Am. J. Cancer Res. (2018) 8(12), 2359-2376]): e.g., alvocidib, palbociclib, ribociclib, trilaciclib, abemaciclib.

[0224] In some embodiments, one or more additional therapeutic agents are selected from the following agents: anti-FGFR antibodies; FGFR inhibitors, cytotoxic agents; estrogen receptor-targeting or other endocrine therapies, immune checkpoint inhibitors, CDK inhibitors, receptor tyrosine kinase inhibitors, BRAF inhibitors, MEK inhibitors, other PI3K inhibitors, SHP2 inhibitors, and SRC inhibitors. (See references [Katoh, Nat. Rev. Clin. Oncol. (2019), 16:105-122; Chae, et al. Oncotarget (2017), 8:16052-16074; Formisano et al., Nat. Comm. (2019), 10:1373-1386]; and references cited therein).

[0225] In some embodiments, the estrogen receptor targeting therapy is a selective estrogen receptor degrader (SERD, e.g., fulvestrant, elacetrant, giredestrant). In some embodiments, the estrogen receptor targeting therapy is an estrogen receptor degrading PROTAC (e.g., ARV-471). In some embodiments, the endocrine therapy is an aromatase inhibitor (e.g., anastrozole, letrozole, exemestane).

[0226] In some embodiments, one or more additional therapeutic agents are inhibitors of one or more of CDK2, CDK4, and CDK6 enzymes. In some embodiments, the CDK inhibitor is a CDK2 inhibitor (e.g., PF-07104091). In some embodiments, the CDK inhibitor is a CDK4 inhibitor (e.g., PF-07220060, AU2-94). In some embodiments, the CDK inhibitor is a dual CDK4 / 6 inhibitor (e.g., palbociclib, abemaciclib, ribociclib, trilaciclib). In some embodiments, the CDK inhibitor is an inhibitor of CDK2 / 4 / 6.

[0227] In some embodiments, more than one CDK inhibitor is administered together with the compound of the present disclosure. In some embodiments, additional therapeutic agents include one or more CDK inhibitors and estrogen receptor targeting therapy. In some embodiments, additional therapeutic agents include a selective estrogen receptor degrader and one or more CDK inhibitors.

[0228] The structure of an active compound identified by a code number, generic name, or trademark name can be obtained from the actual edition of the standard summary 'The Merck Index' or from a database, for example, international patents (e.g., IMS World Publications).

[0229] The compounds of the present disclosure may also be used in combination with known therapeutic processes, e.g., hormone administration or radiation. In certain embodiments, the provided compounds are used as radiosensitizers for the treatment of tumors that exhibit poor sensitivity, particularly to radiation therapy.

[0230] The compounds of the present disclosure may be administered alone or in combination with one or more other therapeutic compounds, and possible combination therapies taking the form of a fixed combination, or the administration of the compounds of the present disclosure and one or more other therapeutic compounds may be administered at different times or independently of each other, or the fixed combination may be administered in combination with one or more other therapeutic compounds. The compounds of the present disclosure may be administered separately or additionally, particularly for tumor therapies combined with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or combinations thereof. Long-term therapy is possible in the same context as adjuvant therapy in other treatment strategies as described above. Other possible treatments include therapy to maintain the patient's condition after tumor regression, or even, for example, chemoprevention therapy in patients at risk.

[0231] These additional formulations may be administered separately from the compound-containing composition of the present invention as part of a multiple dosing regimen. Alternatively, these formulations may be part of a single-dose form mixed with the compound of the present disclosure in a single composition. When administered as part of a multiple dosing regimen, the two active agents may be introduced simultaneously, sequentially, or within a period of time, usually within 5 hours of each other.

[0232] As used herein, the terms ‘combination’, ‘combined’, and related terms refer to the simultaneous or sequential administration of a therapeutic agent according to the present disclosure. For example, the compound of the present disclosure may be administered together with another therapeutic agent, either simultaneously or sequentially, in a separate unit dosage form or in a single unit dosage form. Accordingly, the present disclosure provides a single unit dosage form comprising the compound of the present disclosure, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0233] The amounts of both the compound and the additional therapeutic agent that may be combined with a carrier material to create a single-dose form (in a corresponding composition containing the additional therapeutic agent as described above) will vary depending on the host being treated and the specific mode of administration. Preferably, the composition of the present disclosure should be formulated so that a dose of 0.01 to 100 mg / kg body weight / day of the compound can be administered.

[0234] In the composition containing an additional therapeutic agent, the additional therapeutic agent and the compound of the present disclosure may act synergistically. Therefore, in such a composition, the amount of the additional therapeutic agent will be less than that required in a monotherapy using only the therapeutic agent. In such a composition, an additional therapeutic agent may be administered in a dose of 0.01 to 1,000 µg / kg body weight / day.

[0235] The amount of additional therapeutic agent present in the composition of the present disclosure will be less than or equal to the amount normally administered in a composition containing said therapeutic agent as the sole active agent. Preferably, the amount of additional therapeutic agent in the composition disclosed in the present invention will be in the range of about 50% to 100% of the amount normally present in a composition containing said agent as the sole therapeutic active agent.

[0236] The compounds of the present disclosure, or their pharmaceutical compositions, may also be incorporated into compositions for coating implantable medical devices such as prostheses, artificial valves, vascular grafts, stents, and catheters. For example, vascular stents have been used to overcome restenosis (the narrowing of a blood vessel wall again after injury). However, patients using stents or other implantable devices are at risk of thrombosis or platelet activation. These unwanted effects can be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition containing a kinase inhibitor. An implantable device coated with a compound of the present disclosure is another embodiment of the present disclosure.

[0237] Any compound and / or composition of the present disclosure may be provided in a kit comprising the compound and / or composition. Accordingly, in some embodiments, the compound and / or composition of the present disclosure is provided in a kit.

[0238] The present disclosure is further described by the following non-limiting embodiments.

[0239] Examples

[0240] To facilitate a more complete understanding of the present disclosure, embodiments are provided herein. The following embodiments serve to illustrate exemplary ways of manufacturing and carrying out the subject matter of the present disclosure. However, the scope of the present disclosure should not be interpreted as being limited only to the specific embodiments disclosed in these exemplary embodiments.

[0241] As illustrated in the examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedure. While the general method illustrates the synthesis of specific compounds of this disclosure, it will be recognized that the following general method and other methods known to those skilled in the art may be applied to different classes, subclasses, and species of each of these compounds described herein. Additional compounds of this disclosure have been prepared in examples and methods known to those skilled in the art by methods substantially similar to those described herein.

[0242] In the description of the synthesis method described below, it will be understood that, unless otherwise noted, all reaction conditions (e.g., reaction solvent, atmosphere, temperature, duration, and work-up procedure) are selected from standard conditions for the corresponding reaction. Starting materials for the examples are commercially available or are readily prepared by standard methods from known materials.

[0243] The compounds described herein may be prepared by a number of methods based on the teachings contained herein and synthesis procedures known in the art. The following non-limiting examples are described herein.

[0244] Devices and Methodologies

[0245] X-ray powder diffraction (XRPD)

[0246] Methods. Instrument: PANalytical Empyrean. XRPD diffraction patterns were collected on a PANalytical Empyrean diffractometer using Cu Kα radiation (45 kV, 40 mA) in transmission geometry. A 0.04 rad Soller slit with a 0.5° slit, a 4 mm mask, and a focusing mirror was used for the incident beam. A PIXcel positioned on the diffracted beam. 3DThe detector was fitted with a receiving slit and a 0.04 rad Soller slit. The software used for data acquisition was X'Pert Data Collector using the X'Pert Operator Interface. The data were analyzed and presented using HighScore Plus. Samples were prepared and analyzed in transfer mode on either a metal or Millipore 96-well plate. For metal wells, X-ray transmission film was used on the metal sheet on the plate, and powder (approximately 1 to 2 mg) was used as received. For Millipore plates, a small amount of suspension was added directly to the plate to isolate the solid from the suspension; after analysis, the sample was filtered under light vacuum. The scan mode for metal plates used the gonio scan axis, while 2θ scans were used for Millipore plates. The parameters of the standard screening data acquisition method are as follows:

[0247] Angle range: 2.5 to 32.0°2θ

[0248] Step size: 0.0130°2θ

[0249] Collection time: 12.75 s / step (total collection time 2.07 min)

[0250] Differential Scanning Calorimetry (DSC)

[0251] Method 1. Instrument: TA Instruments Discovery DSC. DSC data were collected on a TA Instruments Discovery DSC equipped with a 50-position autosampler. Typically, 0.5 to 3 mg of each sample was heated in a pinhole aluminum pan at 25 to 300°C at 10°C / min. A dry nitrogen purge of 50 mL / min was maintained over the samples. The instrument control software was TRIOS, and the data were analyzed using TRIOS or Universal Analysis.

[0252] Method 2. Instrument: TA Instruments DSC2500. DSC data were collected using a TA Instruments DSC2500 equipped with a 54-position autosampler. Typically, 0.5 to 3 mg of each sample was heated in a pinhole aluminum pan at 10 °C / min at 25 °C to 300 °C. A dry nitrogen purge of 50 mL / min was maintained over the samples. Adjustable temperature DSC (MDSC) was performed using a base heating rate of 2 °C / min with a temperature control parameter of ±0.64 °C (amplitude) every 60 seconds (cycles). The instrument control software was TRIOS, and the data were analyzed using TRIOS or Universal Analysis.

[0253] Thermogravimetric Analysis (TGA)

[0254] Device Discovery 5500 or Q5000

[0255] Sample pan aluminum, open

[0256] Starting temperature ambient conditions (less than 35 ℃)

[0257] Stop the following segment if the final temperature is 300℃ or the weight is less than 80% (w / w).

[0258] (The weight loss of the compound is 20% (w / w) or less)

[0259] Heating rate 10 ℃ / min

[0260] Nitrogen flow balance 10 mL / min; sample chamber 25 mL / min

[0261] Sample mass about 2 to 10 mg

[0262] Dynamic Vapor Adsorption (DVS)

[0263] Method 1

[0264] Device uniqueness, benefits, or adventure

[0265] Total gas flow 200 sccm

[0266] Oven temperature 25 ℃

[0267] solvent water

[0268] Method Cycle: 40-0-95-0-40%RH

[0269] Stage Level: 10%

[0270] Equilibrium: 0.002 dm / dt(% / min)

[0271] Minimum dm / dt stability duration: 60 minutes

[0272] Max dm / dt stage time: 360 minutes

[0273] Method 2

[0274] Device uniqueness, benefits, or adventure

[0275] Total gas flow 200 sccm

[0276] Oven temperature 25℃

[0277] solvent water

[0278] Method Cycle: 40-95-0-95-40%RH

[0279] Stage Level: 10%

[0280] Equilibrium: 0.002 dm / dt(% / min)

[0281] Minimum dm / dt stability duration: 60 minutes

[0282] Max dm / dt stage time: 360 minutes

[0283] Nuclear Magnetic Resonance (NMR)

[0284] Instrument Bruker Avance-AV 400M (for 1H-NMR, 19F-NMR and 31P-NMR)

[0285] Bruker Avance-III 400M (for 13C-NMR)

[0286] Frequency 400 MHz

[0287] Probe 5 mm PABBO BB / 19F-1H / D Z-GRD Z108618 / 0406 (for 1H-NMR, 19F-NMR and 31P-NMR)

[0288] 5 mm PABBO BB-1H / D Z-GRD Z108618 / 0229 (for 13C NMR)

[0289] Scan count 8

[0290] Temperature 297.6K

[0291] Relaxation delay 1 second

[0292] High Performance Liquid Chromatography (HPLC)

[0293] Device Agilent 1260, SHIMADZU CBM-40,

[0294] Chiral Purity Wavelength: 220 nm

[0295] Column: Daicel OD-RH (4.6 × 150 mm × 5 µm)

[0296] Detectors: DAD, PDA

[0297] Column temperature: 40℃

[0298] Flow rate: 1 ml / min

[0299] Mobile phase A: 10 mM NH4OAc in water

[0300] Mobile Phase B: ACN

[0301] Diluent: ACN

[0302] Injection volume: 5 µL

[0303] Sample preparation: 2 mg / ml

[0304] Needle washing solvent: ACN:H2O=90:10(v / v)

[0305] Gubae: Deungyongmae Yongri

[0306] Time (min) Mobile phase A(%) Mobile phase B(%)

[0307] 0 55 45

[0308] 30 55 45

[0309] FeSSIF (feeding state simulant serous fluid)

[0310] Acetate base buffer (FeSSIF), pH 5.0: Sodium hydroxide (4.061 g), acetic acid (8.25 ml), and sodium chloride (11.88 g) were dissolved in approximately 800 ml of deionized water in a 1000 ml volumetric flask. This solution was thoroughly mixed, and then the pH was adjusted to 5.0 ± 0.05 using 1 M hydrochloric acid / sodium hydroxide. Subsequently, the volume of the solution was adjusted using deionized water, and the pH was recorded (pH 5.00).

[0311] FeSSIF medium: Phares SIF (mock serous fluid) powder (0.56 g) was dissolved in approximately 40 ml of base buffer in a 50 ml volumetric flask. This solution was thoroughly mixed and then the volume was adjusted with the same amount of base buffer. The final pH was recorded (pH 4.93).

[0312] FaSSIF (Simulated serous fluid in a fasting state)

[0313] Phosphate base buffer (FaSSIF), pH 6.5 Sodium hydroxide (0.403 g), sodium monobasic phosphate (3.95 g), and sodium chloride (6.50 g) were dissolved in approximately 800 ml of deionized water in a 1000 ml volumetric flask. This solution was thoroughly mixed, and then the pH was adjusted to 6.5 ± 0.05 using 1 M hydrochloric acid / sodium hydroxide. Subsequently, the volume of the solution was adjusted using deionized water, and the pH was recorded (pH 6.47).

[0314] FaSSIF badge : 0.112 g of Phares SIF (mock serous fluid) powder was dissolved in approximately 40 ml of base buffer in a 50 ml volumetric flask. This solution was thoroughly mixed and then the volume was adjusted with the same amount of base buffer. The final pH was recorded (pH 6.46).

[0315] FaSSGF (Fasting Simulated Gastric Acid)

[0316] base buffer ( FaSSGF), pH 1.6 Sodium chloride (1.99 g) was dissolved in approximately 800 ml of deionized water in a 1000 ml volumetric flask. This solution was thoroughly mixed, and then the pH was adjusted to 1.6 ± 0.05 using concentrated hydrochloric acid. Subsequently, the volume of the solution was adjusted using deionized water, and the pH was recorded (pH 1.60).

[0317] FaSSGF medium : 0.03 g of Phares SIF (mock serous fluid) powder was dissolved in approximately 40 ml of base buffer in a 50 ml volumetric flask. This solution was thoroughly mixed and then the volume was adjusted with the same amount of base buffer. The final pH was recorded (pH 1.63).

[0318] abbreviation Full name

[0319] MeOH methanol

[0320] EtOH ethanol

[0321] ACN Acetonitrile

[0322] TFA trifluoroacetic acid

[0323] DMSO dimethyl sulfoxide

[0324] IPAc isopropyl acetate

[0325] DCM dichloromethane

[0326] EA ethyl acetate

[0327] THF Tetrahydrofuran

[0328] MTBE methyl tert-butyl ether

[0329] DMF dimethylformamide

[0330] HATU Hexafluorophosphate, azabenzotriazole, tetramethyl uranium

[0331] HOBt Hydroxybenzotriazole

[0332] EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0333] NBS N-bromosuccinimide

[0334] DIEA (or DIPEA) diisopropylethylamine

[0335] Example 1

[0336] Preparation of synthetic intermediates

[0337] 1.1. Manufacturing of intermediate SM1

[0338]

[0339] Step 1. Preparation of methyl (1R,4S)-4-((tert-butoxycarbonyl)amino)cyclopent-2-en-1-carboxylate (1)

[0340]

[0341] A solution of methyl (1R,4S)-4-aminocyclopent-2-en-1-carboxylate hydrochloride (5000.00 g, 28.149 mol, 1 eq) in DCM (30 L) was treated with triethylamine (2.848 kg, 28.149 mol, 1.0 eq) at 0 °C. The temperature was controlled to 0 to 5 °C. Di-tert-butyl dicarbonate (6.143 kg, 28.149 mol, 1.0 eq) was added dropwise to the reaction mixture at 0 to 5 °C, and the internal temperature of the mixture was maintained below 10 °C. The mixture was heated to 22 °C and stirred for 16 hours.

[0342] The reaction mixture was diluted with water (8000 ml) and the organic layer was separated. The aqueous layer was extracted with DCM (5000.0 ml), the DCM layer was washed with brine (5.0 L), dried with anhydrous MgSO4, filtered, and concentrated. Methyl(1R,4S)-4-((tert-butoxycarbonyl)amino)cyclopent-2-en-1-carboxylate was obtained as a white solid (6.20 kg, 91.3% yield).

[0343] Step 2. Preparation of methyl(3aR,5R,6R,6aR)-6-bromo-2-oxohexahydro-2H-cyclopenta[d]oxazole-5-carboxylate (2)

[0344]

[0345] A solution of methyl(1R,4S)-4-((tert-butoxycarbonyl)amino)cyclopent-2-en-1-carboxylate (5500.00 g, 22.795 mol, 1 eq) in THF (22 L) and H2O (2.2 L) was cooled to 0 °C. Subsequently, N-bromosuccinimide (4.463 kg, 25.074 mol, 1.1 eq) was added in batches. The mixture was heated to room temperature and stirred for 16 hours. The solution was concentrated and dried. The residue was slurried in DCM (15 L), washed with 1 M HCl (5 L), saturated Na2SO3 (6 L), and base (6.0 L), dried with anhydrous MgSO4, filtered, and concentrated. The residue was slurried in n-heptane (4 L) for 30 minutes, filtered, and dried to obtain methyl (3aR,5R,6R,6aR)-6-bromo-2-oxohexahydro-2H-cyclopenta[d]oxazole-5-carboxylate as a white solid (4.033 kg, 67.0%).

[0346] Step 3. Preparation of (3R,4S)-4-((tert-butoxycarbonyl)amino)-3-hydroxycyclopent-1-en-1-carboxylic acid (3)

[0347]

[0348] A solution of methyl (3aR,5R,6R,6aR)-6-bromo-2-oxohexahydro-2H-cyclopenta[d]oxazole-5-carboxylate (2000.00 g, 7.574 mol, 1 eq) in MeOH (10 L) and H2O (10 L) was cooled to 0 °C. Subsequently, KOH (1.700 kg, 30.295 mol, 4.0 eq) was added to the batch. The mixture was heated at 80 °C for 16 hours. The mixture was cooled to 20 °C and concentrated under vacuum. Di-tert-butyl dicarbonate (1.653 kg, 7.574 mol, 1 eq) in THF (4.0 L) was added dropwise to the residue. The mixture was heated to room temperature and stirred for 16 hours. The mixture was redissolved in EA (3 L) and H2O (3 L), 1 M HCl was added dropwise to the mixture to adjust the pH to 3 to 4, and extracted with EA (5 L × 3). The organic layer was separated, washed with a base (5 L), dried with anhydrous MgSO4, filtered, and then concentrated and dried. (3R,4S)-4-((tert-butoxycarbonyl)amino)-3-hydroxycyclopent-1-en-1-carboxylic acid (1.48 kg, 80.0% yield) was obtained as a white solid.

[0349] Step 4. Preparation of methyl (3R,4S)-4-((tert-butoxycarbonyl)amino)-3-hydroxycyclopent-1-en-1-carboxylate (4)

[0350]

[0351] (3R,4S)-4-((tert-butoxycarbonyl)amino)-3-hydroxycyclopent-1-en-1-carboxylic acid (3, in DMF (14.5 L) A solution of 2900.00 g, 11.922 mol, 1 eq) was cooled to 0 ℃, and then K2CO3 (2.471 kg, 17.882 mol, 1.5 eq) was added in batches. The mixture was heated to room temperature and stirred for 1 hour. Methyl iodide (3.384 kg, 23.843 mol, 2.0 eq) was added dropwise to the resulting mixture at 0 to 5 ℃, and the mixture was heated to room temperature and stirred for 16 hours. The mixture was quenched with H2O (40.0 L) and then extracted with EA (10 L × 2). The organic layer was separated, washed with a base (5 L), dried with anhydrous MgSO4, filtered, and then concentrated and dried. The residue was slurried in (PE:EA=3:1(2 L)) for 30 minutes, filtered, and dried to obtain methyl(3R,4S)-4-((tert-butoxycarbonyl)amino)-3-hydroxycyclopent-1-en-1-carboxylate (2.200 kg, 71.7% yield) as a white solid.

[0352] Step 5. Preparation of methyl(1S,3S,4R)-3-((tert-butoxycarbonyl)amino)-4-hydroxycyclopentane-1-carboxylate (SM1)

[0353]

[0354] Glucose (1800.00 g) was dissolved in 14.4 L of 100 mM potassium phosphate buffer at pH=7. Subsequently, 800.00 g of wet whole cells of E. coli BL21 (DE3) overexpressing the enzyme Ene Reductase 10 (PE10) were added to potassium phosphate buffer and completely suspended to obtain a homogeneous suspension. Then, 8.00 g of glucose dehydrogenase powder and nicotinamide adenine dinucleotide phosphate were added to potassium phosphate buffer. To this, 800.00 g of substrate (methyl (3R,4S)-4-((tert-butoxycarbonyl)amino)-3-hydroxycyclopent-1-en-1-carboxylate) in DMSO was added as a co-solvent. The mixture was stirred at 37 °C. Due to the production of gluconic acid during the reaction process, the pH was adjusted using 3M K2CO3 to 7.0. The mixture was stirred for 16 hours.

[0355] The reaction mixture was filtered through diatomaceous earth. The filtrate was extracted with EA (3 L × 3), and the filter cake was slurried with 8 L EA. The combined organic layer was washed with a base (5 L), dried with anhydrous MgSO4, and then filtered and concentrated dried. The residue was slurried in n-heptane (1 L) for 30 minutes, filtered, and dried to obtain methyl(1S,3S,4R)-3-((tert-butoxycarbonyl)amino)-4-hydroxycyclopentane-1-carboxylate (0.685 kg, 85.0% yield) as a white solid. 1 HNMR (400MHz,CDCl3) δ 4.81 (s, 1H), 4.28 (s, 1H), 3.67 (s, 3H), 3.08 - 3.15 (m, 1H), 2.07 - 2.27 (m, 1H), 2.02 - 2.05 (m, 2H), 1.84 - 1.86 (m, 2H), 1.44 (s, 9H). HPLC purity=98.80%. ee%=100%.

[0356] 1.2. Preparation of Intermediate A1

[0357]

[0358] Step 1. Preparation of Ethyl 4-Methylenecyclohexane-1-Carboxylate

[0359] The reaction vessel was filled with Ph3MeBr (28.35 kg, 1.5 eq) in THF (72.0 L, 8.0 V) under N2. t-BuOK (8.91 kg, 1.5 eq) was added to the vessel at approximately 0 °C. Ethyl 4-oxocyclohexane-1-carboxylate (9.00 kg, 1.00 eq) in THF (18.0 L, 2.0 V) was added dropwise to the mixture, and the resulting mixture was stirred for 10 minutes at approximately 0 °C. Subsequently, 30% aq. citric acid (1 V) was added to the reaction vessel to adjust the pH to approximately 4.5. The mixture was stirred for 30 minutes at 20 to 25 °C. The aqueous phase was extracted with heptane (2 x 4 V), the organic phase was combined, concentrated to approximately 1 V, filled with heptane (2 V) in a container, and stirred for 30 minutes. The mixture was filtered, dried with MgSO4, and concentrated to provide ethyl 4-methylenecyclohexane-1-carboxylate as a bright yellow liquid (6.93 kg, 78% yield).

[0360] Step 2. Preparation of Ethyl 4-(Bromomethyl)-4-Fluorocyclohexane-1-Carboxylate

[0361] A reaction vessel was filled with DCM (93.3 L, 10 V) and ethyl 4-methylenecyclohexane-1-carboxylate (9.33 kg, 1.0 eq). Triethylamine trihydrofluoride (22.39 kg, 2.5 eq) was added to this at approximately 0 °C for 10 minutes. Subsequently, the mixture was filled with N-bromosuccinimide (14.74 kg, 1.5 eq) and stirred at 20 to 25 °C for 10 minutes. Then, distilled water (140.0 kg, 15.0 V) was added, and the mixture was stirred for 30 minutes. The mixture was washed with additional distilled water (93.0 kg, 10.0 V), the organic layer was combined, dried with MgSO4, filtered, and concentrated to provide crude ethyl 4-(bromomethyl)-4-fluorocyclohexane-1-carboxylate as a brown liquid (10.81 kg crude).

[0362] Step 3. Preparation of Ethyl 4-Fluorobicyclo[2.2.1]heptane-1-Carboxylate

[0363] A reaction vessel was filled with THF (20 L, 10 V), MTBE (6.0 L, 3 V), and crude ethyl 4-(bromomethyl)-4-fluorocyclohexane-1-carboxylate (2.0 kg, 1.0 eq). Potassium bis(trimethylsilyl)amide (13.1 L, 1.75 eq) was added to the solution at 30 to 40 °C for 60 minutes. Subsequently, 10% aq. ammonium chloride (5 V) was added dropwise to the mixture and stirred at approximately 0 °C for 30 minutes. The aqueous phase was extracted twice with MTBE (4 V), and the combined organic layer was concentrated into a crude light yellow liquid. In a separate container, N-(2-hydroxyethyl)-2-pyrrolidone (5.0 V), activated carbon (10%), and a crude light yellow concentrate were added under N2. The mixture was stirred, filtered, and concentrated to provide ethyl 4-fluorobicyclo[2.2.1]heptane-1-carboxylate as a brown liquid (2.51 kg, 58.7% yield).

[0364] Step 4. Preparation of 4-Fluoronorbonane-1-Carbaldehyde

[0365] Preparation of SDBBA reducing agent: in THF (20.0 L) t DIBAL-H (2.115 kg, 14.98 mol, 9.99 L, 1.860 eq) was added dropwise to a solution of -BuONa (1.500 kg, 15.608 mol, 1.938 eq) at -10 to 0 °C. The reaction mixture was stirred at 25 °C for 2 hours to provide the reducing agent SDBBA.

[0366] Freshly prepared SDBBA was added to a solution of ethyl 4-fluorobicyclo[2.2.1]heptane-1-carboxylate (1500.0 g, 8.055 mol, 1.0 eq) in THF (20.0 L) at -10 to 0 °C, and the mixture was stirred at -10 to 0 °C for 16 hours. Subsequently, the reaction mixture was quenched by adding 1N HCl (30.0 L) dropwise and stirred for 2 hours. The mixture was extracted with MTBE (10.0 L × 3), the combined organic layer was dried with MgSO4, filtered, and concentrated at 10 to 20 °C to provide a residue. The residue was redissolved in MTBE (1.0 L), a saturated solution of NaHSO3 (6 L) was added, and the mixture was stirred at 25 °C for 16 hours. The mixture was extracted with MTBE (5.0 L × 4), and the aqueous layer was collected. The pH of the aqueous layer was adjusted to pH = 9 to 10 by adding saturated Na2CO3 (10 L), and stirred at 25 °C for an additional 16 hours. The obtained mixture was extracted with MTBE (5.0 L × 5), the organic phases were combined, dried with MgSO4, filtered, and concentrated at 15 to 20 °C. 4-fluorobicyclo[2.2.1]heptane-1-carbaldehyde (640.6 g, 74.488% yield) was provided as a colorless oil.

[0367] Step 5. Preparation of (R,Z)-N-[(4-fluoronorbonane-1-yl)methylene]-2-methyl-propane-2-sulfinamide (A1)

[0368] (R)-2-methylpropane-2-sulfinamide (545.60 g, 4.502 mol, 1.0 eq) and tetraisopropyl titanate (TIPT, 2.561 kg, 9.003 mol, 2.0 eq) were added to a solution of 4-fluorobicyclo[2.2.1]heptane-1-carbaldehyde (640.0 g, 4.502 mol, 1.0 eq) in THF (15.0 L) at 25 °C. The reaction mixture was stirred at 70 to 75 °C for 3 hours. The reaction mixture was cooled naturally to 25 °C, diluted with EA (10.0 L), and then poured into water (10.0 L) at 10 to 20 °C. The mixture was extracted with EA (10.0 L × 3), the combined organic layer was washed with a saturated NaCl solution (4.5 L), dried with MgSO4, filtered, and concentrated at 35 to 45 ℃ to provide a residue. The residue ( n - Heptane:EA = 10:1)(1.5 L) was ground at 0 to 10 °C for 2 hours, and then filtered to provide (R,Z)-N-[(4-fluoronorbonan-1-yl)methylene]-2-methyl-propane-2-sulfinamide (521.02 g, 47.172%) as a white solid.

[0369] Example 2

[0370] Synthesis of Compound I

[0371]

[0372]

[0373] Step 1. Preparation of (1S,3S,4R)-3-((tert-butoxycarbonyl)amino)-4-hydroxycyclopentane-1-carboxylic acid (S1)

[0374] A 1M aq. LiOH solution (3.5 L, 5V) was added to a solution of methyl (1R,3R,4S)-3-((tert-butoxycarbonyl)amino)-4-hydroxycyclopentane-1-carboxylate (700 g, 1.00 eq) in THF (1.4 L, 2V) and MeOH (1.4 L, 2V) at 0 to 5 °C, and the mixture was stirred for 1 hour at 0 to 5 °C. The reaction was monitored by HPLC and LCMS. The reaction mixture was neutralized with 1N HCl to pH 6 to 7 at 0 to 5 °C. The reaction mixture was concentrated to below 40 °C to remove the organic solvent. The solution was acidified with 1N HCl to pH 2 to 3 at 20 to 25 °C and extracted with 2-MeTHF (10 V × 3). The combined organic layer was washed with a base (10V) and dried with sodium sulfate. After filtration and concentration at 40°C, the product was dried under vacuum at 50°C to provide (1S,3S,4R)-3-((tert-butoxycarbonyl)amino)-4-hydroxycyclopentane-1-carboxylic acid (S1) as a white solid (191 g, 92.9% yield).

[0375] Step 2. Preparation of (R)-N-((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptane-1-yl)methyl)-2-methylpropane-2-

[0376] n-BuLi (2.50 M, 1585 mL, 1.30 eq) was added to a solution of 1-chloro-2,4-difluorobenzene (590.5 g, 1.30 eq) in THF (5.25 L, 7 V) -65 　Added under an N2 atmosphere at °C. The mixture was stirred at -65 °C for 0.5 hours, and subsequently, a solution of (R,Z)-N-((4-fluorobicyclo[2.2.1]heptane-1-yl)methylene)-2-methylpropane-2-sulfinamide (750 g, 1.0 eq) in THF (3.75 L, 5 V) was added dropwise at -65 °C. The mixture was stirred at -65 °C for 2 hours. The reaction was monitored by HPLC and LCMS. The reaction mixture was added to a saturated NH4Cl solution (11.25 L, 15 V) at -10 to 0 °C. The aqueous phase was extracted with ethyl acetate (10 V × 2). The combined organic layer was washed with saturated brine (15 V × 2), dried with anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the crude product. The crude product was dissolved in ethanol (750 ml, 1 V). Water (3.75, 5 V) was added, and the mixture was stirred for 2 hours. The obtained solid was filtered. The solid was slurried with heptane / EA (10:1, 5 V) for 5 hours, and after filtration, the solid was dried in air at 50°C to provide pure (R)-N-((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptane-1-yl)methyl)-2-methylpropane-2-sulfinamide as a white solid (995 g, 79% yield).

[0377] Step 3. Preparation of (S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptane-1-yl)methaneamine

[0378] HCl / MeOH (3980 mL, 4 V) was added at 25 °C to a solution of (R)-N-((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptane-1-yl)methyl)-2-methylpropane-2-sulfinamide (995 g, 1.00 eq) in MeOH (2985 mL, 3 V), and the mixture was stirred at 25 °C for 1 hour. The reaction was monitored by HPLC and LCMS. The reaction mixture was concentrated under vacuum to obtain a crude product. The residue was ground with ethyl acetate / n-heptane (1:10, 5 V) at 25 °C for 2 hours, and after filtration, the filter cake was dried under vacuum at 50 °C. Compound (S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptane-1-yl)methaneamine was obtained as a white solid (738 g, 90.5% yield).

[0379] Step 4. tert-butyl ((1S,2R,4S)-4-(((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptane-1-yl)methyl)carbamoyl)-2-hydroxycyclopentyl)carbamate

[0380] After adding DIEA (4.0 eq) and HOBt (1.3 eq) to a solution of (1S,3S,4R)-3-((tert-butoxycarbonyl)amino)-4-hydroxycyclopentane-1-carboxylic acid (490 g, 1.0 eq) in DCM (7V) at 0 to 5 °C, (S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptane-1-yl)methaneamine (619 g, 0.95 eq) was added under a N2 atmosphere. EDCI (497.8 g, 1.3 eq) was added to the mixture. The resulting reaction mixture was stirred at 0 to 5 °C under N2 for 24 hours and monitored by HPLC and LCMS. The reaction mixture was washed with semi-saturated K2CO3 (15V × 2) and 1N HCl (15V × 2), followed by washing with a base (15V). The organic phase was separated and concentrated at 40 °C under reduced pressure. The crude product was crystallized using EtOAc / n-heptane (1.5V:6V). The solid was filtered, and the filter cake was dried under vacuum at 50 °C to yield tert-butyl ((1S,2R,4S)-4-(((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptane-1-yl)methyl)carbamoyl)-2-hydroxycyclopentyl)carbamate as a white solid (852 g, 83% yield).

[0381] Step 5. Preparation of (1S,3S,4R)-3-amino-N-((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptane-1-yl)methyl)-4-hydroxycyclopentane-1-carboxamide HCl

[0382] Concentrated HCl (425.5 mL, 3 eq) was added at 25 °C to a solution of tert-butyl((1S,2R,4S)-4-(((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptane-1-yl)methyl)carbamoyl)-2-hydroxycyclopentyl)carbamate (880 g, 1.00 eq) in DCM (2640 mL, 3 V), and the mixture was stirred at 25 °C for 3 hours. The reaction was monitored by HPLC and LCMS. The reaction mixture was concentrated under vacuum to provide a crude product as a semi-oil, which was used in the next step without further purification (770 g net weight of crude).

[0383] Step 6. Preparation of N-((1S,2R,4S)-4-(((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptane-1-yl)methyl)carbamoyl)-2-hydroxycyclopentyl)pyrimidine-5-carboxamide (Compound I)

[0384] After adding N-methylmorpholine (542 g, 3.0 eq) to a solution of pyrimidine-5-carboxylic acid (232.8 g, 1.05 eq) in DCM (5670 ml, 7 V) under an N2 atmosphere at 0 to 5 °C, (1S,3S,4R)-3-amino-N-((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptane-1-yl)methyl)-4-hydroxycyclopentane-1-carboxamide HCl (810 g net weight, 1.0 eq) was added to DCM (2430 ml, 3 V) at 0 to 5 °C. Subsequently, HATU (747.4 g, 1.1 eq) was finally added to the mixture under N2 at 0 to 5 °C. The resulting reaction mixture was stirred under N2 at 0 to 5 °C for 2 hours and monitored by HPLC and LCMS. N-methylmorpholine (361 g, 2.0 eq) was added to the reaction mixture at 0 to 5 °C and subsequently washed with saturated Na2CO3 (12.15 L, 15 V). The organic phase was concentrated at 40 °C under reduced pressure and dissolved in EA (1.0 L, 10 V). The resulting solution was washed with 0.5 N HCl (15 V x 3) and subsequently washed with a base (15 V). The organic phase was separated and concentrated at 40 °C under reduced pressure to yield a crude product. This was purified by silica gel column chromatography eluted with 0 to 10% MeOH in DCM, and then dried at 40°C under vacuum to provide N-((1S,2R,4S)-4-(((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptane-1-yl)methyl)carbamoyl)-2-hydroxycyclopentyl)pyrimidine-5-carboxamide (Compound I) as a grayish-white solid (733 g, 82% yield).

[0385] Example 3

[0386] Synthesis of Compound II

[0387]

[0388] Step 1. Synthesis of (1S,3S,4R)-3-acetamido-N-((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptane-1-yl)methyl)-4-hydroxycyclopentane-1-carboxamide

[0389] A round-bottom flask was filled with (1S,3S,4R)-3-amino-N-((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptane-1-yl)methyl)-4-hydroxycyclopentane-1-carboxamide (1.45 g, 3.48 mmol), acetic acid (209 mg, 3.48 mmol), NaHCO3 (1.46 g, 17.4 mmol), HATU (2.64 g, 6.96 mmol), and a stirring bar. DMF (15 mL) was added, and the solution was stirred at room temperature for 1 hour. The obtained crude material was purified by preparative HPLC (column: LuxCellulose-34.6*100 mm, 3 µm; mobile phase A: water, mobile phase B: MeOH (0.5% 2M NH3 in MeOH); flow rate: 4 ml / min; gradient: 20% B isosolvent) to provide (1S,3S,4R)-3-acetamido-N-((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptane-1-yl)methyl)-4-hydroxycyclopentane-1-carboxamide (1.34 g, 2.93 mmol) as a grayish-white amorphous solid. 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.22 (d, J = 8.2 Hz, 1H), 7.61-7.48 (m, 2H), 7.19-7.09 (m, 1H), 5.26 (d, J = 8.1 Hz, 1H), 4.78 (d, J = 3.3 Hz, 1H), 3.96-3.85 (m, 2H), 3.15-3.03 (m, 1H), 1.82 (d, J = 5.0 Hz, 2H), 1.81 (s, 3H), 1.75 (ddd, J = 21.1, 11.5, 8.1 Hz, 8H), 1.59 (d, J = 8.8 Hz, 2H), 1.45 (d, J = 9.6 Hz, 2H). [M+H] + 459.05.

[0390] Example 4

[0391] Manufacturing and characterization of crystalline forms

[0392] Compound I, Form A

[0393] A sample of Compound I (30 mg) was weighed into an HPLC vial, and 5 volumes of ethyl acetate were added. The sample was aged in an aging chamber between RT and 50°C for 24 hours (approximately 4 hours for each 1°C increase). Subsequently, 500 µL of heptane was added to the sample vial, and the sample was aged for an additional 24 hours. The suspension was filtered through an XRPD Millipore plate under vacuum for 10 minutes to obtain a crystalline solid. The crystalline form A of Compound I was attributed based on the observed pattern by XRPD analysis (see Fig. 1).

[0394] Since only trace amounts of ethyl acetate (0.09 eq) were detected in the NMR spectrum and the total weight loss observed from TGA analysis corresponded to 0.09 eq of ethyl acetate, it was found that form A was essentially the anhydrous form. Extensive endothermic (solvent loss) was observed at the beginning of the thermal analysis trace, followed by melt endothermic at 174 °C. After storage at 40 °C and 75 % RH, the sample remained in form A as monitored by X-ray powder diffraction.

[0395]

[0396] Compound I, Form B

[0397] A sample of Compound I (30 mg) was weighed into an HPLC vial, and 10 volumes of isopropyl acetate were added. The sample was aged in an aging chamber between RT and 50°C for 24 hours (approximately 4 hours for each 1°C increase). The sample was aged for an additional 24 hours. The suspension was filtered through an XRPD Millipore plate under vacuum for 10 minutes to obtain a crystalline solid. The crystalline form B of Compound I was attributed based on the observed pattern by XRPD analysis (see Fig. 2).

[0398] Characterization of Form B suggests that it may also be an anhydrous form based on the small amount of isopropyl acetate (0.26 eq) contained in the sample. The DSC trace of Form B showed a broad endothermic at the beginning of the trace (possible solvent loss), followed by another endothermic at 141 °C, and finally a melt endothermic at 172 °C. It was observed that Form B converted to Form A after accelerated storage conditions at 40 °C and 75% RH.

[0399]

[0400] Compound I, form C

[0401] A sample of Compound I (30 mg) was weighed into an HPLC vial, and 5 volumes of ethanol were added. The sample was aged in an aging chamber between RT and 50°C for 24 hours (approximately 4 hours for each increase of 1°C). Subsequently, 500 µL of heptane was added to the sample, and it was aged for an additional 24 hours. The suspension was filtered through an XRPD Millipore plate under vacuum for 10 minutes to obtain a crystalline solid. The crystalline form C of Compound I was attributed based on the observed pattern by XRPD analysis (see Fig. 3).

[0402] Analysis of form C suggests that it was an ethanol solvate. NMR analysis showed that the sample contained approximately 0.82 eq of ethanol, and weight loss from TGA analysis also indicated approximately 0.9 eq of ethanol. The sample converted to an amorphous material after storage under accelerated storage conditions.

[0403]

[0404] Compound II, Form A

[0405] A sample of Compound II (30 mg) was weighed into an HPLC vial, and 20 volumes of water were added. The sample was aged in an aging chamber between RT and 50°C for 24 hours (approximately 4 hours for each 1°C increase). The sample was further aged for 24 hours. The suspension was filtered through an XRPD Millipore plate under vacuum for 10 minutes to obtain a crystalline solid. The crystalline form A of Compound II was attributed based on the observed pattern by XRPD analysis (see Fig. 4).

[0406] TGA analysis of type A showed a weight loss of water (1.79 eq water) similar to that seen in KF (1.31 eq). The difference in the amount of water shown by TGA and KF may be surface-bound water evaporated before the KF analysis. DSC showed extensive endothermic activity starting at 46.8 °C, which may be due to water loss from the sample, followed by several endothermic events and an exothermic event at 129.6 °C, and melting may have occurred at 225.1 °C.

[0407] GVS analysis showed a reversible weight loss of 1.8% at 20 to 90% RH, followed by w (0.47 eq. water), and then a significant loss / absorption of 4.46% w / w (1.19 eq. water) at 20 to 0% RH, suggesting a monohydrate form. The sample remained in form A after GVS and static storage conditions, and there was little change in sample purity when measured by XRPD. Upon heating to 160 ℃ at 10 ℃ / min and cooling to RT, the sample converted to form B.

[0408]

[0409] Compound II, Form B

[0410] A sample of Compound II (30 mg) was weighed into an HPLC vial, and 20 volumes of ethyl acetate were added. The sample was aged in an aging chamber between RT and 50°C for 24 hours (approximately 4 hours for each 1°C increase). The sample was aged for an additional 24 hours. The suspension was filtered through an XRPD Millipore plate under vacuum for 10 minutes to obtain a crystalline solid. The crystalline form B of Compound II was attributed based on the observed pattern by XRPD analysis (see Fig. 5).

[0411] Form B was found to be anhydrous based on the small amount of residual organic solvent (ethyl acetate, 0.02 eq) observed in the NMR trace and the lack of weight loss seen in the TGA thermal trace. The only endothermic reaction observed for Form B was the melt endothermic initiated at 229 °C. Subsequently, the sample began to decompose above 250 °C. Form B remained after static storage conditions at 40 °C and 75% RH.

[0412]

[0413] Example 5

[0414] Evaluation of solubility in crystalline form in culture medium

[0415] Compound I, Form A

[0416] The solubility of form A remained high, particularly at 2.3 mg / mL in FeSSIF medium. Solubility in FaSSIF was 0.51 mg / mL (slightly less than amorphous), in FaSSGF 0.34 mg / mL, and in deionized water 0.45 mg / mL. XRPD analysis of the residue indicated that the sample remained in form A.

[0417]

[0418] Compound I, Form B

[0419] Solubility evaluation for Form B showed very high solubility in the selective medium. However, XRPD analysis of the residue following the solubility analysis confirmed that the crystal structure of Form B had collapsed, leaving mostly amorphous material. This indicates that the high solubility of the sample was due to the sample's conversion into amorphous material and is unrelated to the actual solubility of Form B.

[0420]

[0421] Compound II, Form A

[0422] Evaluation of the solubility of form A indicated that the highest solubility was 0.3 mg / mL in FeSSIF, and the solubility in all three other media was approximately 0.1 mg / mL. XRPD analysis of the residue after the solubility evaluation indicated that the sample remained as form A.

[0423]

[0424] Compound II, Form B

[0425] The solubility of Form B was slightly lower than that of Form A (but mostly similar), and the residue collected after solubility analysis indicated that the solid remained as Form B.

[0426]

[0427] Example 6

[0428] Competitive Slurry Experiment

[0429] Compound I (Form A and Form B)

[0430] Compound I, Form A (100 mg) and Compound I, Form B (100 mg) were each weighed into 4 mL vials and mixed for 2 hours. Samples were recovered and analyzed by XRPD for reference. Saturated solutions were simultaneously prepared by pipetting 500 µL of the selected solvent system into HPLC vials and stirring at 5, 25, and 50°C (see table below). Compound I was added to each sample vial until a suspension was formed. After 1 hour, all samples were observed to remain as suspensions and were allowed to be stirred for an additional 24 hours.

[0431] All samples were confirmed to remain as suspensions. Each suspension was pipetted into a syringe and filtered through a nylon filter cartridge, from which the solution was collected in a new vial. To each solution, 15 mg of the reference (1:1 Form A / Form B) was added, and the sample vials were stirred at their respective temperatures for 24 hours. Observations of the sample vials were recorded, and the first partial sample was pipetted onto a metal XRPD plate and analyzed by XRPD. After stirring the samples for an additional 5 days, a second aliquot was taken and XRPD analysis was performed.

[0432] After 24 hours, competitive slurries for Compound I indicated that all samples remained as suspensions after slurrying at 50°C and 5°C. XRPD analysis of these samples indicated that several samples were completely converted to Form A, but some were still a mixture of Forms A and B.

[0433] After an additional 5 days (a total of 6 days), all samples remained as suspensions, and XRPD analysis of these samples indicated that more samples had completely converted to pure form A. Although samples that were still mixtures were prominent in heptane, two of the three samples both formed form A, while some showed small peaks associated with form B, which is likely due to low solubility in heptane slowing down the conversion to form A. This suggests that given sufficient time, complete conversion to form A is likely to occur.

[0434]

[0435] Compound II (Form A and Form B)

[0436] Compound II, Form A (100 mg) and Compound II, Form B (100 mg) were each weighed into 4 mL vials and mixed for 2 hours. Samples were recovered and analyzed by XRPD for reference. Saturated solutions were simultaneously prepared by pipetting 500 µL of the selected solvent system into HPLC vials and stirring at 5, 25, and 50°C (see table below). Compound II was added to each sample vial until a suspension was formed. After 1 hour, all samples were observed to remain as suspensions and were allowed to be stirred for an additional 24 hours.

[0437] All samples were confirmed to remain as suspensions. Each suspension was pipetted into a syringe and filtered through a nylon filter cartridge, from which the solution was collected in a new vial. To each solution, 15 mg of the reference (1:1 Form A / Form B) was added, and the sample vials were stirred at their respective temperatures for 24 hours. Observations of the sample vials were recorded, and the first partial sample was pipetted onto a metal XRPD plate and analyzed by XRPD. After stirring the samples for an additional 5 days, a second aliquot was taken and XRPD analysis was performed.

[0438] All samples remained as suspensions, and XRPD analysis of these samples indicated a complete transition to form B after 24 hours. The samples remained as suspensions after an additional 5 days, and all of them remained in form B. This suggests that form B may be a more thermodynamically stable form compared to form A.

[0439]

[0440] Reference by reference

[0441] All publications and patents mentioned in this specification are incorporated herein by reference in their entirety for all purposes, just as each individual publication or patent application is specifically and individually referred to by reference. In the event of a conflict, the present application, including any definition in this specification, will be used as the reference.

[0442] Equality theory

[0443] Although specific embodiments of the present disclosure have been discussed, the foregoing specification is illustrative and not limiting. Many variations of the present disclosure will be apparent to those skilled in the art upon reviewing the present specification. The full scope of the present disclosure should be determined by reference to the claims and variations thereof, along with the full scope of equivalents.

[0444] Unless otherwise indicated, all numbers representing amounts of ingredients, reaction conditions, etc. used in this specification and claims should be understood as being modified by the term "about" in all cases. Accordingly, unless otherwise indicated, numerical parameters presented in this specification and appended claims are approximations that may vary depending on the desired characteristics sought to be obtained by this disclosure.

Claims

Claim 1 Compound in solid form, wherein the compound is the following compound I or a solvate thereof: . Claim 2 In claim 1, the compound is an amorphous compound. Claim 3 In paragraph 1, the compound is a crystalline compound. Claim 4 A compound according to claim 1 or 3, wherein the solid form is a crystalline form A, form B, or form C. Claim 5 A compound according to any one of claims 1, 3 and 4, wherein the solid form is form A. Claim 6 A compound according to claim 5, wherein the solid form has an X-ray powder diffraction pattern comprising at least two peaks, each peak being selected from the group consisting of about 17.4 2θ, about 13.3 2θ, and about 16.5 2θ. Claim 7 A compound according to claim 5, wherein the solid form has an X-ray powder diffraction pattern comprising at least two peaks, each peak being selected from the group consisting of about 17.4 2θ, about 13.3 2θ, about 16.5 2θ, about 24.2 2θ, about 19.8 2θ, about 14.5 2θ, and about 18.2 2θ. Claim 8 A compound according to claim 5, wherein the solid form has an X-ray powder diffraction pattern comprising at least three peaks, each peak being selected from the group consisting of about 17.4 2θ, about 13.3 2θ, about 16.5 2θ, about 24.2 2θ, about 19.8 2θ, about 14.5 2θ, and about 18.2 2θ. Claim 9 A compound according to claim 5, wherein the solid form has an X-ray powder diffraction pattern comprising at least four peaks, each peak being selected from the group consisting of about 17.4 2θ, about 13.3 2θ, about 16.5 2θ, about 24.2 2θ, about 19.8 2θ, about 14.5 2θ, and about 18.2 2θ. Claim 10 A compound according to claim 5, wherein the solid form has an X-ray powder diffraction pattern comprising at least five peaks, each peak being selected from the group consisting of about 17.4 2θ, about 13.3 2θ, about 16.5 2θ, about 24.2 2θ, about 19.8 2θ, about 14.5 2θ, and about 18.2 2θ. Claim 11 A compound according to claim 5, wherein the solid form has an X-ray powder diffraction pattern comprising at least six peaks, each peak being selected from the group consisting of about 17.4 2θ, about 13.3 2θ, about 16.5 2θ, about 24.2 2θ, about 19.8 2θ, about 14.5 2θ, and about 18.2 2θ. Claim 12 In claim 5, the compound having an X-ray powder diffraction pattern including peaks at about 17.4 2θ, about 13.3 2θ, about 16.5 2θ, about 24.2 2θ, about 19.8 2θ, about 14.5 2θ, and about 18.2 2θ, wherein the solid form is a compound. Claim 13 In claim 5, the solid form is a compound having an X-ray powder diffraction pattern comprising at least three peaks of °2θ units selected from the group of peaks listed in Table 1.

1. Claim 14 In claim 5, the compound having an X-ray powder diffraction pattern comprising at least four peaks of °2θ units selected from the group of peaks listed in Table 1.

1. Claim 15 In claim 5, the solid form is a compound having an X-ray powder diffraction pattern comprising at least five peaks of °2θ units selected from the group of peaks listed in Table 1.

1. Claim 16 In claim 5, the solid form is a compound having an X-ray powder diffraction pattern comprising at least six peaks of °2θ units selected from the group of peaks listed in Table 1.

1. Claim 17 In claim 5, the compound having an X-ray powder diffraction pattern comprising at least 7 peaks of °2θ units selected from the group of peaks listed in Table 1.

1. Claim 18 In claim 5, the compound, wherein the solid form has an X-ray powder diffraction pattern substantially similar to that shown in FIG.

1. Claim 19 A compound according to any one of claims 1, 3 and 4, wherein the solid form is form B. Claim 20 A compound according to claim 19, wherein the solid form has an X-ray powder diffraction pattern comprising at least two peaks, each peak being selected from the group consisting of about 18.5 2θ, about 11.4 2θ, and about 17.5 2θ. Claim 21 A compound according to claim 19, wherein the solid form has an X-ray powder diffraction pattern comprising at least two peaks, each peak being selected from the group consisting of about 18.5 2θ, about 11.4 2θ, about 17.5 2θ, about 5.7 2θ, about 13.6 2θ, about 17.3 2θ, and about 10.7 2θ. Claim 22 A compound according to claim 19, wherein the solid form has an X-ray powder diffraction pattern comprising at least three peaks, each peak being selected from the group consisting of about 18.5 2θ, about 11.4 2θ, about 17.5 2θ, about 5.7 2θ, about 13.6 2θ, about 17.3 2θ, and about 10.7 2θ. Claim 23 A compound according to claim 19, wherein the solid form has an X-ray powder diffraction pattern comprising at least four peaks, each peak being selected from the group consisting of about 18.5 2θ, about 11.4 2θ, about 17.5 2θ, about 5.7 2θ, about 13.6 2θ, about 17.3 2θ, and about 10.7 2θ. Claim 24 A compound according to claim 19, wherein the solid form has an X-ray powder diffraction pattern comprising at least five peaks, each peak being selected from the group consisting of about 18.5 2θ, about 11.4 2θ, about 17.5 2θ, about 5.7 2θ, about 13.6 2θ, about 17.3 2θ, and about 10.7 2θ. Claim 25 A compound according to claim 19, wherein the solid form has an X-ray powder diffraction pattern comprising at least six peaks, each peak being selected from the group consisting of about 18.5 2θ, about 11.4 2θ, about 17.5 2θ, about 5.7 2θ, about 13.6 2θ, about 17.3 2θ, and about 10.7 2θ. Claim 26 In claim 19, the compound, wherein the solid form has an X-ray powder diffraction pattern including peaks at about 18.5 2θ, about 11.4 2θ, about 17.5 2θ, about 5.7 2θ, about 13.6 2θ, about 17.3 2θ, and about 10.7 2θ. Claim 27 In claim 19, the solid form is a compound having an X-ray powder diffraction pattern comprising at least three peaks of °2θ units selected from the group of peaks listed in Table 1.

2. Claim 28 In claim 19, the solid form is a compound having an X-ray powder diffraction pattern comprising at least four peaks of °2θ units selected from the group of peaks listed in Table 1.

2. Claim 29 In claim 19, the solid form is a compound having an X-ray powder diffraction pattern comprising at least five peaks of °2θ units selected from the group of peaks listed in Table 1.

2. Claim 30 In claim 19, the solid form is a compound having an X-ray powder diffraction pattern comprising at least six peaks of °2θ units selected from the group of peaks listed in Table 1.

2. Claim 31 In claim 19, the solid form is a compound having an X-ray powder diffraction pattern comprising at least 7 peaks of °2θ units selected from the group of peaks listed in Table 1.

2. Claim 32 In claim 19, the compound, wherein the solid form has an X-ray powder diffraction pattern substantially similar to that shown in FIG.

2. Claim 33 A compound according to any one of claims 1, 3 and 4, wherein the solid form is form C. Claim 34 A compound according to claim 33, wherein the solid form has an X-ray powder diffraction pattern comprising at least two peaks, each peak being selected from the group consisting of about 19.3 2θ, about 19.9 2θ, and about 20.0 2θ. Claim 35 A compound according to claim 33, wherein the solid form has an X-ray powder diffraction pattern comprising at least two peaks, each peak being selected from the group consisting of about 19.3 2θ, about 19.9 2θ, about 20.0 2θ, about 10.1 2θ, about 19.6 2θ, about 15.2 2θ and about 22.0 2θ. Claim 36 A compound according to claim 33, wherein the solid form has an X-ray powder diffraction pattern comprising at least three peaks, each peak being selected from the group consisting of about 19.3 2θ, about 19.9 2θ, about 20.0 2θ, about 10.1 2θ, about 19.6 2θ, about 15.2 2θ and about 22.0 2θ. Claim 37 A compound according to claim 33, wherein the solid form has an X-ray powder diffraction pattern comprising at least four peaks, each peak being selected from the group consisting of about 19.3 2θ, about 19.9 2θ, about 20.0 2θ, about 10.1 2θ, about 19.6 2θ, about 15.2 2θ and about 22.0 2θ. Claim 38 A compound according to claim 33, wherein the solid form has an X-ray powder diffraction pattern comprising at least five peaks, each peak being selected from the group consisting of about 19.3 2θ, about 19.9 2θ, about 20.0 2θ, about 10.1 2θ, about 19.6 2θ, about 15.2 2θ and about 22.0 2θ. Claim 39 A compound according to claim 33, wherein the solid form has an X-ray powder diffraction pattern comprising at least six peaks, each peak being selected from the group consisting of about 19.3 2θ, about 19.9 2θ, about 20.0 2θ, about 10.1 2θ, about 19.6 2θ, about 15.2 2θ and about 22.0 2θ. Claim 40 In claim 33, the compound, wherein the solid form has an X-ray powder diffraction pattern including peaks at about 19.3 2θ, about 19.9 2θ, about 20.0 2θ, about 10.1 2θ, about 19.6 2θ, about 15.2 2θ, and about 22.0 2θ. Claim 41 In claim 33, the solid form is a compound having an X-ray powder diffraction pattern comprising at least three peaks of °2θ units selected from the group of peaks listed in Table 1.

3. Claim 42 In claim 33, the solid form is a compound having an X-ray powder diffraction pattern comprising at least four peaks of °2θ units selected from the group of peaks listed in Table 1.

3. Claim 43 In claim 33, the solid form is a compound having an X-ray powder diffraction pattern comprising at least five peaks of °2θ units selected from the group of peaks listed in Table 1.

3. Claim 44 In claim 33, the solid form is a compound having an X-ray powder diffraction pattern comprising at least six peaks of °2θ units selected from the group of peaks listed in Table 1.

3. Claim 45 In claim 33, the solid form is a compound having an X-ray powder diffraction pattern comprising at least 7 peaks of °2θ units selected from the group of peaks listed in Table 1.

3. Claim 46 In paragraph 33, the compound, wherein the solid form has an X-ray powder diffraction pattern substantially similar to that shown in FIG.

3. Claim 47 Compound in solid form, wherein the compound is the following compound II or a solvate thereof: . Claim 48 In paragraph 47, the above compound is an amorphous compound. Claim 49 In paragraph 47, the above compound is a crystalline compound. Claim 50 A compound according to paragraph 47 or 49, wherein the solid form is form A or form B. Claim 51 A compound in any one of paragraphs 47, 49 and 50, wherein the solid form is form A. Claim 52 A compound according to claim 51, wherein the solid form has an X-ray powder diffraction pattern comprising at least two peaks, each peak being selected from the group consisting of about 15.7 2θ, about 14.7 2θ, and about 20.0 2θ. Claim 53 A compound according to claim 51, wherein the solid form has an X-ray powder diffraction pattern comprising at least two peaks, each peak being selected from the group consisting of about 15.7 2θ, about 14.7 2θ, about 20.0 2θ, about 21.0 2θ, about 23.2 2θ, about 16.5 2θ, about 17.5 2θ, and about 13.3 2θ. Claim 54 A compound according to claim 51, wherein the solid form has an X-ray powder diffraction pattern comprising at least three peaks, each peak being selected from the group consisting of about 15.7 2θ, about 14.7 2θ, about 20.0 2θ, about 21.0 2θ, about 23.2 2θ, about 16.5 2θ, about 17.5 2θ, and about 13.3 2θ. Claim 55 A compound according to claim 51, wherein the solid form has an X-ray powder diffraction pattern comprising at least four peaks, each peak being selected from the group consisting of about 15.7 2θ, about 14.7 2θ, about 20.0 2θ, about 21.0 2θ, about 23.2 2θ, about 16.5 2θ, about 17.5 2θ, and about 13.3 2θ. Claim 56 A compound according to claim 51, wherein the solid form has an X-ray powder diffraction pattern comprising at least five peaks, each peak being selected from the group consisting of about 15.7 2θ, about 14.7 2θ, about 20.0 2θ, about 21.0 2θ, about 23.2 2θ, about 16.5 2θ, about 17.5 2θ, and about 13.3 2θ. Claim 57 A compound according to claim 51, wherein the solid form has an X-ray powder diffraction pattern comprising at least six peaks, each peak being selected from the group consisting of about 15.7 2θ, about 14.7 2θ, about 20.0 2θ, about 21.0 2θ, about 23.2 2θ, about 16.5 2θ, about 17.5 2θ, and about 13.3 2θ. Claim 58 In claim 51, the compound having an X-ray powder diffraction pattern including peaks at about 15.7 2θ, about 14.7 2θ, about 20.0 2θ, about 21.0 2θ, about 23.2 2θ, about 16.5 2θ, about 17.5 2θ, and about 13.3 2θ, wherein the solid form is a compound having an X-ray powder diffraction pattern including peaks at about 15.7 2θ, about 14.7 2θ, about 20.0 2θ, about 21.0 2θ, about 23.2 2θ, about 16.5 2θ, about 17.5 2θ, and about 13.3 2θ. Claim 59 In claim 51, the solid form is a compound having an X-ray powder diffraction pattern comprising at least three peaks of °2θ units selected from the group of peaks listed in Table 1.

4. Claim 60 In claim 51, the compound having an X-ray powder diffraction pattern comprising at least four peaks of °2θ units selected from the group of peaks listed in Table 1.

4. Claim 61 In claim 51, the solid form is a compound having an X-ray powder diffraction pattern comprising at least five peaks of °2θ units selected from the group of peaks listed in Table 1.

4. Claim 62 In claim 51, the compound having an X-ray powder diffraction pattern comprising at least six peaks of °2θ units selected from the group of peaks listed in Table 1.

4. Claim 63 In claim 51, the compound having an X-ray powder diffraction pattern comprising at least 7 peaks of °2θ units selected from the group of peaks listed in Table 1.

4. Claim 64 In claim 51, the compound, wherein the solid form has an X-ray powder diffraction pattern substantially similar to that shown in FIG.

4. Claim 65 A compound in any one of paragraphs 47, 49 and 50, wherein the solid form is form B. Claim 66 A compound according to claim 65, wherein the solid form has an X-ray powder diffraction pattern comprising at least two peaks, each peak being selected from the group consisting of about 23.6 2θ, about 10.9 2θ, and about 16.9 2θ. Claim 67 A compound according to claim 65, wherein the solid form has an X-ray powder diffraction pattern comprising at least two peaks, each peak being selected from the group consisting of about 23.6 2θ, about 10.9 2θ, about 16.9 2θ, about 15.1 2θ, about 26.1 2θ, about 12.9 2θ, and about 19.4 2θ. Claim 68 A compound according to claim 65, wherein the solid form has an X-ray powder diffraction pattern comprising at least three peaks, each peak being selected from the group consisting of about 23.6 2θ, about 10.9 2θ, about 16.9 2θ, about 15.1 2θ, about 26.1 2θ, about 12.9 2θ, and about 19.4 2θ. Claim 69 A compound according to claim 65, wherein the solid form has an X-ray powder diffraction pattern comprising at least four peaks, each peak being selected from the group consisting of about 23.6 2θ, about 10.9 2θ, about 16.9 2θ, about 15.1 2θ, about 26.1 2θ, about 12.9 2θ, and about 19.4 2θ. Claim 70 A compound according to claim 65, wherein the solid form has an X-ray powder diffraction pattern comprising at least five peaks, each peak being selected from the group consisting of about 23.6 2θ, about 10.9 2θ, about 16.9 2θ, about 15.1 2θ, about 26.1 2θ, about 12.9 2θ, and about 19.4 2θ. Claim 71 A compound according to claim 65, wherein the solid form has an X-ray powder diffraction pattern comprising at least six peaks, each peak being selected from the group consisting of about 23.6 2θ, about 10.9 2θ, about 16.9 2θ, about 15.1 2θ, about 26.1 2θ, about 12.9 2θ, and about 19.4 2θ. Claim 72 In paragraph 65, the compound having an X-ray powder diffraction pattern including peaks at about 23.6 2θ, about 10.9 2θ, about 16.9 2θ, about 15.1 2θ, about 26.1 2θ, about 12.9 2θ, and about 19.4 2θ. Claim 73 In claim 65, the solid form is a compound having an X-ray powder diffraction pattern comprising at least three peaks of °2θ units selected from the group of peaks listed in Table 1.

5. Claim 74 In claim 65, the solid form is a compound having an X-ray powder diffraction pattern comprising at least four peaks of °2θ units selected from the group of peaks listed in Table 1.

5. Claim 75 In claim 65, the solid form is a compound having an X-ray powder diffraction pattern comprising at least five peaks of °2θ units selected from the group of peaks listed in Table 1.

5. Claim 76 In claim 65, the solid form is a compound having an X-ray powder diffraction pattern comprising at least six peaks of °2θ units selected from the group of peaks listed in Table 1.

5. Claim 77 In claim 65, the solid form is a compound having an X-ray powder diffraction pattern comprising at least 7 peaks of °2θ units selected from the group of peaks listed in Table 1.

5. Claim 78 In paragraph 65, the compound, wherein the solid form has an X-ray powder diffraction pattern substantially similar to that shown in FIG.

5. Claim 79 A pharmaceutical composition comprising a compound of any one of claims 1 to 78 and a pharmaceutically acceptable carrier. Claim 80 A method for inhibiting the PI3Kα activity of a subject requiring inhibition of PI3Kα activity, comprising the step of administering a therapeutically effective amount of a compound of any one of claims 1 to 78 or a pharmaceutical composition of claim 79 to said subject. Claim 81 A method for treating cancer in a subject requiring cancer treatment, comprising the step of administering a therapeutically effective amount of a compound of any one of claims 1 to 78 or a pharmaceutical composition of claim 79 to the subject. Claim 82 A method according to claim 80 or 81, further comprising the step of administering a therapeutically effective amount of an antibody, an antibody-drug conjugate, a kinase inhibitor, an immunomodulator, or a histone deacetylase inhibitor. Claim 83 A kit comprising a compound of any one of claims 1 to 78. Claim 84 A kit according to paragraph 83, further comprising written instructions describing a method for preparing a pharmaceutical composition suitable for administration to a patient from the solid form or compound. Claim 85 A kit according to claim 83 or 84, further comprising written instructions describing a method of administering the obtained composition to the patient. Claim 86 A kit comprising, in any one of paragraphs 83 to 85, a pharmaceutically acceptable excipient. Claim 87 A method for preparing a crystalline form of compound I, comprising: (a) a step of preparing a solution of compound I; (b) a step of controlling the temperature so that a solid crystalline form of compound I precipitates from the solution; and (c) a step of isolating the solid crystalline form. Claim 88 A method for preparing a crystalline form of compound I, comprising: (a) preparing a solution of compound I in a solvent; (b) controlling the temperature; (c) adding heptane to the solution; and (d) isolating the solid crystalline form. Claim 89 A method for preparing a crystalline form of compound II, comprising: (a) a step of preparing a solution of compound II; (b) a step of controlling the temperature so that a solid crystalline form of compound II precipitates from the solution; and (c) a step of isolating the solid crystalline form. Claim 90 A method for preparing a crystalline form of compound II, comprising: (a) preparing a solution of compound II in a solvent; (b) controlling the temperature; (c) adding heptane to the solution; and (d) isolating the solid crystalline form.

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