PI3kα inhibitors and methods of making and using the same

Abstract

The present disclosure relates to PI3K-alpha inhibitors, the crystalline forms, the solvates thereof, and the compositions and methods of use thereof. For example, the present disclosure describes compounds in solid form, including crystalline solid forms of compounds: N-((1S,2R,4S)-4-(((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-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]heptan-1-yl)methyl)-4-hydroxycyclopentane-1-carboxamide.

Description

PI3Ka INHIBITORS AND METHODS OF MAKING AND USING THE SAMECROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 599,157, filed on November 15, 2023, the entirety of which is hereby incorporated by reference.BACKGROUND

[0002] Phosphatidylinositol 3-kinases (PI3Ks) comprise a family of lipid kinases that catalyze 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), which, in turn, act as second messengers in signaling cascades by docking proteins containing pleckstrin-homology, FYVE, Phox and other phospholipid-binding domains into a variety of signaling complexes often 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 sub-classes. Class 1A PI3Ks are heterodimers composed of a catalytic pl 10 subunit (alpha, beta, or delta isoforms) constitutively associated with a regulatory subunit that can be p85 alpha, p55 alpha, p50 alpha, p85 beta, or p55 gamma. The Class IB sub-class has one family member, aheterodimer composed of a catalytic pl 10 gamma subunit associated with one of two regulatory7subunits, plOl or p84 (Fruman et al., Annu Rev. Biochem. 67:481 (1998); Suire et al., Curr. Biol. 15:566 (2005)). The modular domains of the p85 / 55 / 50 subunits include Src Homology7(SH2) domains that bind phosphotyrosine residues in a specific sequence context on activated receptor and cytoplasmic tyrosine kinases, resulting in activation and localization of Class 1A PI3Ks. Class IB PI3K is activated directly by G protein-coupled receptors that bind 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)).

[0003] Consequently, the resultant phospholipid products of Class I PI3Ks link upstream receptors with downstream cellular activities including proliferation, survival, chemotaxis, cellular trafficking, motility7, metabolism, inflammatory7and 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 recruit Aid, the product of the human homologue of the viral oncogene v-Akt, to the plasma membrane where it actsas 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)).

[0004] Aberrant regulation of PI3K. which often increases survival through Aid activation, is one of the most prevalent events in human cancer and has been shown to occur at multiple levels. The tumor suppressor gene PTEN, which dephosphorylates phosphoinositides at the 3' position of the inositol ring, and in so doing antagonizes PI3K activity, is functionally deleted in a variety of tumors. In other tumors, the genes for the pl 10 alpha isoform, PIK.3CA, and for Akt are amplified, and increased protein expression of their gene products has been demonstrated in several human cancers. Furthermore, mutations and translocation of p85 alpha that serve to up-regulate the p85-pl 10 complex have been described in human cancers. Finally, somatic missense mutations in PIK3CA that activate downstream signaling pathways have been described at significant frequencies in a wide diversity of human cancers (Kang et el., 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 show that deregulation of phosphoinositol-3 kinase, and the upstream and downstream components of this signaling pathway, is one of the most common deregulations associated with human cancers and proliferative diseases (Parsons et al.. Nature 436:792 (2005); Hennessey at el., Nature Rev. Drug Disc. 4:988-1004 (2005)).

[0005] In view of the above, inhibitors of PI3Ka would be of particular value in the treatment of proliferative disease and other disorders. While multiple inhibitors of PI3Ks have been developed (for example, taselisib, alpelisib, buparlisib and others), these molecules inhibit multiple Class 1A PI3K isoforms. Inhibitors that are active against multiple Class 1A P13K isoforms are known as “pan-PI3K” inhibitors. A major hurdle for the clinical development of existing PI3K inhibitors has been the inability to achieve the required level of target inhibition in tumors while avoiding toxicity in cancer patients. Pan-PI3K inhibitors share certain target- related toxicities including diarrhea, rash, fatigue, and hyperglycemia. The toxicity of PI3K inhibitors is dependent on their isoform selectivity profile. Inhibition of PI3Ka is associated with hyperglycemia and rash, whereas inhibition of PI3K5 or PI3Ky is associated with diarrhea, myelosuppression, and transaminitis (Hanker et al., Cancer Discovery (2019) PMID: 30837161.

[0006] Polymorphism is the ability of a substance to crystallize in more than one cry stal lattice arrangement. Crystallization, or polymorphism, can influence many aspects of solid state properties of a drug substance. A crystalline form may differ considerably from an amorphous form, and different cry stal forms of a substance may differ considerably7from one another in many respects including solubility, dissolution rate and / or bioavailability. Generally, it is difficult to predict whether or not a given compound will form various crystalline solid state forms. It is even more difficult to predict the physical properties of these crystalline solid state forms. Further, it can be advantageous to have a crystalline form of a therapeutic agent for certain formulations, e.g., formulations suitable for subcutaneous use.SUMMARY

[0007] This disclosure is generally directed to Compounds I and II, and solvates thereof, and solid forms thereof.

[0008] In some embodiments, the present disclosure provides a compound in solid form, wherein the compound is Compound I:or a solvate thereof.

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

[0010] In another aspect, provided herein is a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a solid form, as described herein, and a pharmaceutically acceptable excipient.

[0011] In another aspect, provided herein is a method of using a compound or a solvate thereof, or a solid form, or a pharmaceutical composition thereof, as described herein, for inhibiting PI3Ka activity and for treating a disorder, disease, and / or condition as described herein.BRIEF DESCRIPTION OF THE DRAWINGS

[0012] FIG. 1 depicts an XRPD pattern of Compound I Form A.

[0013] FIG. 2 depicts an XRPD pattern of Compound I Form B.

[0014] FIG. 3 depicts an XRPD pattern of Compound I Form C.

[0015] FIG. 4 depicts an XRPD pattern of Compound II Form A.

[0016] FIG. 5 depicts an XRPD pattern of Compound II Form B.

[0017] FIG. 6 depicts a DSC and a TGA thermogram of Compound I Form A.

[0018] FIG. 7 depicts a DSC thermogram of Compound I Form B.

[0019] FIG. 8 depicts a DSC and a TGA thermogram of Compound I Form C.

[0020] FIG. 9 depicts a DSC and a TGA thermogram of Compound II Form A.

[0021] FIG. 10 depicts a DSC and a TGA thermogram of Compound II Form B.DETAILED DESCRIPTIONGeneral Description of Certain Embodiments of the Disclosure

[0022] In some embodiments, Compounds I and II are PI3Ka inhibitors and useful for treating disorders, diseases, and / or conditions, for example, theL‘PI3Ka -mediated” disorders, diseases, and / or conditions as described herein. In some embodiments, this disclosure provides solidforms of the compounds (e.g., as a freebase, or a salt, or a solvate) that imparts characteristics such as improved aqueous solubility, stability, and ease of formulation.Solid Forms of Compound I

[0023] In some embodiments, provided herein is a compound in solid form, wherein the compound is Compound I:or a solvate thereof.

[0024] It is contemplated that Compound I (i.e., (N-((lS,2R,4S)-4-(((S)-(3-chloro-2,6- difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-l-yl)methyl)carbamoyl)-2- hydroxy cyclo enh l)pyrimidine-5-carboxamide) can exist in a variety of physical forms. For example, Compound I can be in a solution, a suspension, or in a solid form. In certain embodiments, Compound I is in a solid form. When Compound I is in a solid form, said compound may be amorphous, crystalline, or a mixture thereof. Exemplary’ solid forms are described in more detail below.

[0025] In some embodiments, Compound I is an amorphous solid. In some embodiments, the solid form of Compound I is cry stalline. 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 1 is a mixture of an amorphous solid and one or more crystalline forms.

[0026] In some embodiments, Compound I is an anhydrate. In some embodiments, Compound I is in a hydrate form. In some embodiments, Compound I is in ahemi-hydrate form.

[0027] In some embodiments, the present disclosure provides a form of Compound I substantially free of impurities. As used herein, the term ‘"substantially free of impurities'’ means that the compound contains no significant amount of extraneous matter. Such extraneousmater may include different forms of Compound I, residual solvents, or any other impurities that may result from the preparation of, and / or isolation of, Compound I.

[0028] In some embodiments, a 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 where the percentages are based on the total weight of the composition. In some embodiments, a solid form of Compound I. or a solvate thereof, contains no more than about 0.40. no more than about 0.35, no more than about 0.3. no more than about 0.25, no more than about 0.2, no more than about 0. 15, no more than about 0.10, or no more than about 0.05 weight percent of any single impurity wherein the percentages are based on the total weight of the composition. In some embodiments, an impurity is selected from those as described in the Examples herein.

[0029] In some embodiments, a 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 percent by HPLC relative to the total area of the HPLC chromatogram. In some embodiments, a solid form of Compound I, or a solvate thereof, contains no more than about 0.4, no more than about 0.35. no more than about 0.3. no more than about 0.25, no more than about 0.2, no more than about 0.15, no more than about 0.10, or no more than about 0.05 area percent HPLC of any single impurity relative to the total area of the HPLC chromatogram. In some embodiments, an impurity is selected from those as described in the examples herein. In some embodiments, a HPLC method is selected from the HPLC methods as described in Examples herein.

[0030] The structure depicted for compound of Compound I is also meant to include all tautomeric forms. Additionally, structures depicted here are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of this disclosure.

[0031] It has been found that Compound I can exist in a variety of solid forms. Exemplary such forms include polymorphs such as those described herein. In some embodiments, the crystalline form of Compound I is Form A, Form B, or Form C, as described herein.

[0032] 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 depicted in FIG. 1.

[0033] 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 depicted in FIG. 2.

[0034] 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 depicted in FIG. 3.Form A of Compound I

[0035] 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 X-ray powder diffraction pattern with at least two characteristic peaks, in degrees 20, each selected from the group consisting of about17.4 20, about 13.3 20, and about 16.5 20. In some embodiments, Form A of Compound I may be characterized by a X-ray powder diffraction pattern with at least two characteristic peaks, in degrees 20, each selected from the group consisting of about 17.4 20, about 13.3 20, about16.5 20, about 24.220, about 19.8 20, about 14.5 20, and about 18.220. In some embodiments, Form A of Compound I may be characterized by a X-ray powder diffraction pattern with at least three characteristic peaks, in degrees 20, each selected from the group consisting of about17.4 20, about 13.3 20, about 16.5 20. about 24.2 20, about 19.8 20, about 14.5 20, and about 18.2 20. In some embodiments. Form A of Compound I may be characterized by a X-ray powder diffraction pattern with at least four characteristic peaks, in degrees 20, each selected from the group consisting of about 17.4 20, about 13.3 20, about 16.5 20, about 24.2 20, about 19.8 20, about 14.5 20, and about 18.220. In some embodiments, Form A of Compound I may be characterized by a X-ray powder diffraction pattern with at least five characteristic peaks, in degrees 20, each selected from the group consisting of about 17.4 20, about 13.3 20, about16.5 20, about 24.220, about 19.8 20, about 14.520, and about 18.220. In some embodiments, Form A of Compound I may be characterized by a X-ray powder diffraction pattern with at least six characteristic peaks, in degrees 20. each selected from the group consisting of about 17.4 20, about 13.3 20, about 16.5 20, about 24.2 20, about 19.8 20, about 14.5 20, and about 18.2 20. In some embodiments, Form A of Compound I may be characterized by a X-raypowder diffraction pattern comprising characteristic peaks at about 17.4 20, about 13.3 20, about 16.5 20, about 24.2 20, about 19.8 20, about 14.5 20, and about 18.2 20.

[0036] In some embodiments. Form A of Compound I has a X-Ray powder diffraction pattern substantially similar to that depicted in FIG. 1 . In some embodiments, Form A of Compound I may be characterized by a X-ray powder diffraction pattern with at least two characteristic peaks, in degrees 20. each selected from the group consisting of the peaks listed in Table 1.1. In some embodiments, Form A of Compound I may be characterized by a X-ray powder diffraction pattern with at least three characteristic peaks, in degrees 20, each selected from the group consisting of the peaks listed in Table 1.1. In some embodiments, Form A of Compound I may be characterized by a X-ray powder diffraction pattern with at least four characteristic peaks, in degrees 20. each selected from the group consisting of the peaks listed in Table 1.1. In some embodiments. Form A of Compound I may be characterized by a X-ray powder diffraction pattern with at least five characteristic peaks, in degrees 20, each selected from the group consisting of the peaks listed in Table 1.1. In some embodiments, Form A of Compound I may be characterized by a X-ray powder diffraction pattern with at least six characteristic peaks, in degrees 20. each selected from the group consisting of the peaks listed in Table 1.1. In some embodiments. Form A of Compound I may be characterized by a X-ray powder diffraction pattern with at least seven characteristic peaks, in degrees 20, each selected from the group consisting of the peaks listed in Table 1.1.Table 1.1 Compound I, Form A XRPD peak listing (each peak is within ± 0.2 degrees 20).

[0037] As used herein, the term ‘‘about” in the context of peaks at degrees 20 means that a peak can be the given 20 value ± 0.2, or the given 20 value ± 0. 1, or the given value. For example, a peak of “about 12.0 20” means a peak can be 11.8 20, 11.9 20, 12.0 20, 12. 1 20, or 12.2 20.

[0038] In some embodiments, Form A of Compound I has a thermogravimetric analysis (TGA) pattern substantially similar to that depicted in FIG. 6. In some embodiments. Form A of Compound I can be characterized by substantial similarity to two or more figures simultaneously (e.g., FIG. 1 and FIG. 6).Form B of Compound I

[0039] 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 X-ray powder diffraction pattern with at least two characteristic peaks, in degrees 20, each selected from the group consisting of about18.5 20, about 11.420, and about 17.5 20. In some embodiments, Form B of Compound I may be characterized by a X-ray powder diffraction pattern with at least two characteristic peaks, in degrees 20, each selected from the group consisting of about 18.5 20, about 11.4 20, about17.5 20, about 5.7 20, about 13.6 20, about 17.3 20, and about 10.7 20. In some embodiments, Form B of Compound I may be characterized by a X-ray powder diffraction pattern with at least three characteristic peaks, in degrees 20, each selected from the group consisting of about18.5 20, about 11.4 20, about 17.5 20, about 5.7 20, about 13.6 20, about 17.3 20, and about 10.7 20. In some embodiments, Form B of Compound I may be characterized by a X-ray powder diffraction pattern with at least four characteristic peaks, in degrees 20, each selected from the group consisting of about 18.5 29, about 11.4 20, about 17.5 20, about 5.7 20, about13.6 20, about 17.3 20, and about 10.7 29. In some embodiments, Form B of Compound I may be characterized by a X-ray powder diffraction pattern with at least five characteristic peaks, in degrees 20, each selected from the group consisting of about 18.5 20, about 11.4 20, about17.5 20, about 5.7 20, about 13.6 20, about 17.3 20, and about 10.7 20. In some embodiments, Form B of Compound I may be characterized by a X-ray powder diffraction pattern with at least six characteristic peaks, in degrees 20, each selected from the group consisting of about18.5 20, about 11.4 20, about 17.5 20, about 5.7 20, about 13.6 20, about 17.3 20, and about10.7 20. In some embodiments. Form B of Compound I may be characterized by a X-ray powder diffraction pattern comprising characteristic peaks at about 18.5 20, about 11.4 20, about 17.5 20, about 5.7 20, about 13.6 20, about 17.3 20, and about 10.7 29.

[0040] In some embodiments, Form B of Compound I has a X-Ray powder diffraction pattern substantially similar to that depicted in FIG. 2. In some embodiments, Form B of Compound 1 may be characterized by a X-ray powder diffraction pattern with at least two characteristic peaks, in degrees 20, each selected from the group consisting of the peaks listed in Table 1.2. In some embodiments, Form B of Compound I may be characterized by a X-ray powder diffraction pattern with at least three characteristic peaks, in degrees 20. each selected from the group consisting of the peaks listed in Table 1.2. In some embodiments. Form B of Compound I may be characterized by a X-ray powder diffraction pattern with at least four characteristic peaks, in degrees 20, each selected from the group consisting of the peaks listed in Table 1.2. In some embodiments, Form B of Compound I may be characterized by a X-ray powder diffraction pattern with at least five characteristic peaks, in degrees 20, each selected from the group consisting of the peaks listed in Table 1.2. In some embodiments, Form B of Compound I may be characterized by a X-ray powder diffraction pattern with at least six characteristic peaks, in degrees 20. each selected from the group consisting of the peaks listed in Table 1.2. In some embodiments, Form B of Compound I may be characterized by a X-ray powder diffraction pattern with at least seven characteristic peaks, in degrees 20, each selected from the group consisting of the peaks listed in Table 1.2.Table 1.2 Compound I, Form B XRPD peak listing (each peak is within ± 0.2 degrees 20).

[0041] In some embodiments, Form B of Compound I has athermogravimetric analysis (TGA) pattern substantially similar to that depicted in FIG. 7. In some embodiments. Form B of Compound I can be characterized by substantial similarity to two or more figures simultaneously (e.g., FIG. 2 and FIG. 7).Form C of Compound I

[0042] 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 X-ray powder diffraction pattern with at least two characteristic peaks, in degrees 20, each selected from the group consisting of about19.3 20, about 19.920, and about 20.020. In some embodiments, Form C of Compound I may be characterized by a X-ray powder diffraction pattern with at least two characteristic peaks, in degrees 20, each selected from the group consisting of about 19.3 20, about 19.9 20, about 20.020, about 10. 1 20, about 19.6 20, about 15.220, and about 22.020. In some embodiments, Form C of Compound I may be characterized by a X-ray powder diffraction pattern with at least three characteristic peaks, in degrees 20, each selected from the group consisting of about19.3 20, about 19.9 20, about 20.0 20, about 10.1 20, about 19.6 20, about 15.2 20, and about 22.0 20. In some embodiments, Form C of Compound I may be characterized by a X-ray powder diffraction pattern with at least four characteristic peaks, in degrees 20, each selected from the group consisting of about 19.3 20, about 19.9 20, about 20.0 20, about 10.1 20, about 19.6 20, about 15.2 20. and about 22.0 20. In some embodiments. Form C of Compound I may be characterized by a X-ray powder diffraction pattern with at least five characteristic peaks, in degrees 20, each selected from the group consisting of about 19.3 20, about 19.9 20, about 20.020, about 10. 1 20, about 19.6 20, about 15.220, and about 22.020. In some embodiments, Form C of Compound I may be characterized by a X-ray powder diffraction pattern with at least six characteristic peaks, in degrees 20, each selected from the group consisting of about19.3 20, about 19.9 20, about 20.0 20, about 10.1 20, about 19.6 20, about 15.2 20, and about 22.0 20. In some embodiments, Form C of Compound I may be characterized by a X-ray powder diffraction pattern comprising characteristic peaks at about 19.3 20, about 19.9 20, about 20.0 20. about 10.1 20, about 19.6 20, about 15.2 20. and about 22.0 20. In someembodiments, Form C of Compound I has a X-Ray powder diffraction pattern substantially similar to that depicted in FIG. 3A.

[0043] In some embodiments. Form C of Compound I has a X-Ray powder diffraction pattern substantially similar to that depicted in FIG. 3. In some embodiments, Form C of Compound I may be characterized by a X-ray powder diffraction pattern with at least two characteristic peaks, in degrees 20. each selected from the group consisting of the peaks listed in Table 1.3. In some embodiments, Form C of Compound I may be characterized by a X-ray powder diffraction pattern with at least three characteristic peaks, in degrees 20, each selected from the group consisting of the peaks listed in Table 1.3. In some embodiments, Form C of Compound I may be characterized by a X-ray powder diffraction pattern with at least four characteristic peaks, in degrees 20. each selected from the group consisting of the peaks listed in Table 1.3. In some embodiments. Form C of Compound I may be characterized by a X-ray powder diffraction pattern with at least five characteristic peaks, in degrees 20, each selected from the group consisting of the peaks listed in Table 1.3. In some embodiments, Form C of Compound I may be characterized by a X-ray powder diffraction pattern with at least six characteristic peaks, in degrees 20. each selected from the group consisting of the peaks listed in Table 1.3. In some embodiments. Form C of Compound I may be characterized by a X-ray powder diffraction pattern with at least seven characteristic peaks, in degrees 20, each selected from the group consisting of the peaks listed in Table 1.3.Table 1.3 Compound I, Form C XRPD peak listing (each peak is within ± 0.2 degrees 20).

[0044] In some embodiments, Form C of Compound I has a thermogravimetric analysis (TGA) patern substantially similar to that depicted in FIG. 8. In some embodiments, Form C of Compound 1 can be characterized by substantial similarity to two or more of these figures simultaneously (e g., FIG. 3 and FIG. 8).Solid Forms of Compound II

[0045] In some embodiments, provided herein is a compound in solid form, wherein the compound is Compound II:II, or a solvate thereof.

[0046] It is contemplated that Compound II (i.e., (lS,3S,4R)-3-acetamido-N-((S)-(3-chloro- 2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-l-yl)methyl)-4-hydroxycyclopentane-I- carboxamide) can exist in a variety of physical forms. For example, Compound II can be in solution, suspension, or in solid form. In certain embodiments, Compound II is in solid form. When compound II is in solid form, said compound may be amorphous, cry stalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0047] 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.

[0048] In some embodiments, the solid form of Compound II is anhydrate. 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 hemi-hydrate.

[0049] In some embodiments, the present disclosure provides a solid form of Compound II substantially free of impurities. As used herein, the term “substantially free of impurities” means that the compound contains no significant amount of extraneous matter. Such extraneous matter may include different forms of Compound II, residual solvents, or any other impurities that may result from the preparation of, and / or isolation of, Compound II.

[0050] In some embodiments, a 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 where the percentages are based on the total weight of the composition. In some embodiments, a solid form of Compound II, or a solvate thereof, contains no more than about 0.40, no more than about 0.35, no more than about 0.3, no more than about 0.25, no more than about 0.2, no more than about 0. 15, no more than about 0. 10, orno more than about 0.05 weight percent of any single impurity wherein the percentages are based on the total weight of the composition. In some embodiments, an impurity is selected from those as described in the examples herein.

[0051] In some embodiments, a 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 percent by HPLC relative to the total area of the HPLC chromatogram. In some embodiments, a solid form of Compound II, or a solvate thereof, contains no more than about 0.4, no more than about 0.35, no more than about 0.3, no more than about 0.25, no more than about 0.2, no more than about 0.15, no more than about 0.10, or no more than about 0.05 area percent HPLC of any single impurity relative to the total area of the HPLC chromatogram. In some embodiments, an impurity is selected from those as described in the examples herein. In some embodiments, a HPLC method is selected from the HPLC methods as described in Examples herein.

[0052] The structure depicted for compound of Compound II is also meant to include all tautomeric forms. Additionally, structures depicted here are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of this disclosure.

[0053] It has been found that compound II can exist in a variety of solid forms. Exemplary such forms include crystalline polymorphs such as those described herein. In some embodiments, the crystalline form of Compound II is Form A, or Form B, as described herein.

[0054] In some embodiments, the crystalline form of Compound II is Form A. In some embodiments, Form A of Compound II has a X-Ray powder diffraction pattern substantially similar to that depicted in FIG. 4.

[0055] In some embodiments, the crystalline form of Compound II is Form B. In some embodiments, Form B of Compound II has a X-Ray powder diffraction pattern substantially similar to that depicted in FIG. 5.Form A of Compound II

[0056] 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 X-ray powder diffraction pattern with at least two characteristic peaks, in degrees 20, each selected from the group consisting of about15.7 20, about 14.7 20, and about 20.0 20. In some embodiments, Form A of Compound II may be characterized by a X-ray powder diffraction pattern with at least two characteristic peaks, in degrees 20, each selected from the group consisting of about 15.7 20, about 14.7 20, about 20.0 20, about 21.0 20, about 23.2 20, about 16.5 20, about 17.5 20, and about 13.3 20. In some embodiments, Form A of Compound II may be characterized by a X-ray powder diffraction pattern with at least three characteristic peaks, in degrees 20, each selected from the group consisting of about 15.7 20. about 14.7 20, about 20.0 20, about 21.0 20. about 23.2 20, about 16.5 20, about 17.5 20, and about 13.3 20. In some embodiments, Form A of Compound II may be characterized by a X-ray powder diffraction pattern with at least four characteristic peaks, in degrees 20, each selected from the group consisting of about 15.7 20, about 14.7 20, about 20.0 20, about 21.0 20, about 23.2 20, about 16.5 20. about 17.5 20, and about 13.3 20. In some embodiments. Form A of Compound II may be characterized by a X-ray powder diffraction pattern with at least five characteristic peaks, in degrees 20, each selected from the group consisting of about 15.7 20, about 14.7 20, about 20.0 20, about 21.0 20, about 23.2 20, about 16.5 20, about 17.5 20. and about 13.3 20. In some embodiments. Form A of Compound Il may be characterized by a X-ray powder diffraction pattern with at least six characteristic peaks, in degrees 20, each selected from the group consisting of about 15.7 20, about 14.7 20, about 20.0 20, about 21.0 20, about 23.2 20, about 16.5 20, about 17.5 20, and about 13.3 20. In some embodiments, Form A of Compound II may be characterized by a X-ray powder diffraction pattern comprising characteristic peaks at about 15.7 20, about 14.7 20. about 20.0 20, about 21.0 20, about 23.2 20, about 16.5 20, about 17.5 20, and about 13.3 20.

[0057] In some embodiments, Form A of Compound II has a X-Ray powder diffraction pattern substantially similar to that depicted in FIG. 4. In some embodiments, Form A of Compound II may be characterized by a X-ray powder diffraction pattern with at least two characteristic peaks, in degrees 20, each selected from the group consisting of the peaks listed in Table 1.4. In some embodiments, Form A of Compound II may be characterized by a X-ray powder diffraction pattern with at least three characteristic peaks, in degrees 20, each selected from the group consisting of the peaks listed in Table 1.4. In some embodiments. Form A of Compound II may be characterized by a X-ray powder diffraction pattern with at least four characteristic peaks, in degrees 20, each selected from the group consisting of the peaks listed in Table 1.4. In some embodiments, Form A of Compound II may be characterized by a X-ray powder diffraction pattern with at least five characteristic peaks, in degrees 20, each selected from thegroup consisting of the peaks listed in Table 1.4. In some embodiments, Form A of Compound II may be characterized by a X-ray powder diffraction pattern with at least six characteristic peaks, in degrees 20, each selected from the group consisting of the peaks listed in Table 1.4. In some embodiments, Form A of Compound II may be characterized by a X-ray powder diffraction pattern with at least seven characteristic peaks, in degrees 20, each selected from the group consisting of the peaks listed in Table 1.4.Table 1.4 Compound II, Form A XRPD peak listing (each peak is within ± 0.2 degrees 20).

[0058] In some embodiments, Form A of Compound II has a thermogravimetric analysis (TGA) pattern substantially similar to that depicted in FIG. 9. In some embodiments, Form Aof Compound II can be characterized by substantial similarity to two or more figures simultaneously (e.g.. FIG. 4 and FIG. 9).Form B of Compound II

[0059] In some embodiments, the solid form of Compound II is Form B. In some embodiments, Form B of Compound II may be characterized by a X-ray powder diffraction pattern with at least two characteristic peaks, in degrees 20, each selected from the group consisting of about23.6 29, about 10.9 20, and about 16.9 20. In some embodiments, Form B of Compound II may be characterized by a X-ray powder diffraction pattern with at least two characteristic peaks, in degrees 20, each selected from the group consisting of about 23.6 20, about 10.9 20, about 16.9 20, about 15.1 20, about 26.1 20, about 12.9 20, and about 19.4 20. In some embodiments, Form B of Compound II may be characterized by a X-ray powder diffraction pattern with at least three characteristic peaks, in degrees 20, each selected from the group consisting of about 23.6 20, about 10.9 20, about 16.9 20, about 15.1 20, about 26.1 20, about 12.9 20, and about 19.4 20. In some embodiments, Form B of Compound II may be characterized by a X-ray powder diffraction pattern with at least four characteristic peaks, in degrees 20. each selected from the group consisting of about 23.6 20, about 10.920. about 16.9 20, about 15.1 20, about 26.1 20, about 12.9 20, and about 19.4 20. In some embodiments, Form B of Compound II may be characterized by a X-ray powder diffraction pattern with at least five characteristic peaks, in degrees 20, each selected from the group consisting of about23.6 20, about 10.9 20, about 16.9 20. about 15.1 20, about 26.1 20, about 12.9 20, and about 19.4 20. In some embodiments. Form B of Compound II may be characterized by a X-ray powder diffraction pattern with at least six characteristic peaks, in degrees 20, each selected from the group consisting of about 23.6 20, about 10.9 20, about 16.9 20, about 15.1 20, about 26. 1 20, about 12.920, and about 19.4 20. In some embodiments, Form B of Compound II may be characterized by aX-ray powder diffraction pattern comprising characteristic peaks at about23.6 20, about 10.9 20, about 16.9 20, about 15.1 20, about 26.1 20, about 12.9 20, and about 19.4 20.

[0060] In some embodiments, Form B of Compound II has a X-Ray powder diffraction pattern substantially similar to that depicted in FIG. 5. In some embodiments, Form B of Compound II may be characterized by a X-ray powder diffraction pattern with at least two characteristic peaks, in degrees 20, each selected from the group consisting of the peaks listed in Table 1.5. In some embodiments, Form B of Compound II may be characterized by a X-ray powderdiffraction pattern with at least three characteristic peaks, in degrees 20, each selected from the group consisting of the peaks listed in Table 1.5. In some embodiments, Form B of Compound II may be characterized by a X-ray powder diffraction pattern with at least four characteristic peaks, in degrees 20, each selected from the group consisting of the peaks listed in Table 1.5. In some embodiments, Form B of Compound II may be characterized by a X-ray powder diffraction pattern with at least five characteristic peaks, in degrees 20, each selected from the group consisting of the peaks listed in Table 1.5. In some embodiments. Form B of Compound II may be characterized by a X-ray powder diffraction pattern with at least six characteristic peaks, in degrees 20, each selected from the group consisting of the peaks listed in Table 1.5. In some embodiments, Form B of Compound II may be characterized by a X-ray powder diffraction pattern with at least seven characteristic peaks, in degrees 20, each selected from the group consisting of the peaks listed in Table 1.5.Table 1.5 Compound II, Form B XRPD peak listing (each peak is within ± 0.2 degrees 20).

[0061] In some embodiments, Form B of Compound II has a thermogravimetric analysis(TGA) pattern substantially similar to that depicted in FIG. 10. In some embodiments, Form B of Compound II can be characterized by substantial similarity to two or more figures simultaneously (e.g., FIG. 5 and FIG. 10).Compositions

[0062] Another aspect of the disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated together with a pharmaceutically acceptable carrier. In particular, the present disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated together with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, topical, buccal, ocular, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used. For example, disclosed compositions may be formulated as a unit dose, and / or may be formulated for oral, subcutaneous or intravenous administration.

[0063] Exemplary pharmaceutical compositions of this disclosure may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains one or more of the compound of the disclosure, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications. The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active object compound isincluded in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.

[0064] In some embodiments, pharmaceutically acceptable compositions can contain a disclosed compound and / or a pharmaceutically acceptable salt thereof at a concentration ranging from about 0.01 to about 2.0 wt%, such as 0.01 to about 1 wt% or about 0.05 to about 0.5 wt%. The composition can be formulated as a solution, suspension, ointment, or a capsule, and the like. The pharmaceutical composition can be prepared as an aqueous solution and can contain additional components, such as preservatives, buffers, tonicity agents, antioxidants, stabilizers, viscosity-modifying ingredients and the like.

[0065] For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as com starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the disclosure, or a nontoxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0066] Pharmaceutically acceptable carriers are well-known to those skilled in the art, and include, e.g., 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, the pharmaceutically acceptable carrier is chemically inert toward the active compounds and is non-toxic under the conditions of use. Examples of pharmaceutically acceptable carriers may include, e.g., water or saline solution, 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 and the like. The pharmaceutical carriers may also be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary, stabilizing, thickening, lubricating and coloring agents may be used. Other examples of suitable pharmaceutical carriers are described in e.g., Remington’s: The Science and Practiceof Pharmacy, 22nd Ed. (Allen, Loyd V., Jr ed., Pharmaceutical Press (2012)); Modem Pharmaceutics. 5thEd. (Alexander T. Florence, Juergen Siepmann, CRC Press (2009)); Handbook of Pharmaceutical Excipients, 7thEd. (Rowe, Raymond C.; Sheskey, Paul J.; Cook, Walter G.; Fenton, Marian E. eds., Pharmaceutical Press (2012)) (each of which hereby incorporated by reference in its entirety).

[0067] In some embodiments, the compounds of the disclosure are formulated into pharmaceutical compositions for administration to subjects in a biologically compatible form suitable for administration in vivo. According to another aspect, the present disclosure provides a pharmaceutical composition comprising a disclosed compound in admixture with a pharmaceutically acceptable diluent and / or carrier. The pharmaceutically -acceptable carrier is “acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof. The pharmaceutically-acceptable carriers employed herein may be selected from various organic or inorganic materials that are used as materials for pharmaceutical formulations and which are incorporated as analgesic agents, buffers, binders, disintegrants, diluents, emulsifiers, excipients, extenders, glidants, solubilizers, stabilizers, suspending agents, tonicity agents, vehicles and viscosity-increasing agents. Pharmaceutical additives, such as antioxidants, aromatics, colorants, flavor-improving agents, preservatives, and sweeteners, may also be added. Examples of acceptable pharmaceutical carriers include carboxymethyl cellulose, crystalline cellulose, glycerin, gum arabic, lactose, magnesium stearate, methyl cellulose, powders, saline, sodium alginate, sucrose, starch, talc and water, among others. In some embodiments, the term ■■pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0068] Surfactants such as, e.g., detergents, are also suitable for use in the formulations. Specific examples of surfactants include polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and of vinylpyrrolidone, polyethylene glycols, benzyl alcohol, mannitol, glycerol, sorbitol or polyoxyethylenated esters of sorbitan; lecithin or sodium carboxymethylcellulose; or acrylic derivatives, such as methacrylates and others, anionic surfactants, such as alkaline stearates, in particular sodium, potassium or ammonium stearate; calcium stearate or triethanolamine stearate; alkyd sulfates, in particular sodium lauryl sufate and sodium cetyl sulfate; sodium dodecylbenzenesulphonate or sodium dioctylsulphosuccinate; or faty acids, in particular those derived from coconut oil, cationic surfactants, such as water-soluble quaternary ammonium salts of formula N R'R"R'"R ""Y , in which the R radicals are identical or different optionally hydroxylated hydrocarbon radicals and Y" is an anion of a strong acid, such as halide, sulfate and sulfonate anions; cet l trimethyl ammonium bromide is one of the cationic surfactants which can be used, amine salts of formula N+R'R"R"', in which the R radicals are identical or different optionally hydroxylated hydrocarbon radicals; octadecylamine hydrochloride is one of the cationic surfactants which can be used, non-ionic surfactants, such as optionally polyoxyethylenated esters of sorbitan, in particular Polysorbate 80, or polyoxyethylenated alkyl ethers; polyethylene glycol stearate, polyoxyethylenated derivatives of castor oil, polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids or copolymers of ethylene oxide and of propylene oxide, amphoteric surfactants, such as substituted lauryl compounds of betaine.

[0069] When administered to a subject, the disclosed compound and pharmaceutically acceptable carriers can be sterile. Suitable pharmaceutical carriers may also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, polyethylene glycol 300, water, ethanol, polysorbate 20, and the like. The present compositions, if desired, may also contain minor amounts of weting or emulsifying agents, or pH buffering agents.

[0070] The pharmaceutical formulations of the present disclosure are prepared by methods well-known in the pharmaceutical arts. Optionally, one or more accessory ingredients (e.g. , buffers, flavoring agents, surface active agents, and the like) also are added. The choice of carrier is determined by the solubility and chemical nature of the compounds, chosen route of administration and standard pharmaceutical practice.

[0071] Additionally, the compounds and / or compositions of the present disclosure are administered to a human or animal subject by known procedures including oral administration, sublingual or buccal administration. In some embodiments, the compound and / or composition is administered orally.

[0072] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following:(1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid;(2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0073] For oral administration, a formulation of the compounds of the disclosure may be presented in dosage forms such as capsules, tablets, powders, granules, or as a suspension or solution. Capsule formulations may be gelatin, soft-gel or solid. Tablets and capsule formulations may further contain one or more adjuvants, binders, diluents, disintegrants, excipients, fillers, or lubricants, each of which are known in the art. Examples of such include carbohydrates such as lactose or sucrose, dibasic calcium phosphate anhydrous, com starch, mannitol, xylitol, cellulose or derivatives thereof, microcrystalline cellulose, gelatin, stearates, silicon dioxide, talc, sodium starch glycolate, acacia, flavoring agents, preservatives, buffering agents, disintegrants, and colorants. Orally administered compositions may contain one or more optional agents such as, e.g, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of Wintergreen, or cherry; coloring agents; and preservative agents, to provide a pharmaceutically palatable preparation.

[0074] A tablet may be made by compression or molding, optionally with one or more accessory' ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surfaceactive or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored orprepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.

[0075] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the subject composition, the liquid dosage forms may contain inert diluents commonly used in the art. such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyd alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.

[0076] Suspensions, in addition to the subject composition, may contain suspending agents, such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0077] Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository’ wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.

[0078] Dosage forms for transdermal administration of a subject composition includes powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

[0079] The ointments, pastes, creams and gels may contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0080] Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary' propellants, such aschlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0081] Compositions and compounds of the present disclosure may alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. A non-aqueous (e.g., fluorocarbon propellant) suspension could be used. Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions. Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary' with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions.

[0082] Pharmaceutical compositions of this disclosure suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0083] Examples of suitable aqueous and non-aqueous carriers which may be employed in the pharmaceutical compositions of the disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins. Proper fluidity may' be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. For example, cry stalline forms provided herein may be milled to obtain a particular particle size, and in at least some embodiments, such crystalline forms may remain substantially stable upon milling.

[0084] For example, provided herein is a composition suitable for subcutaneous administration, comprising a suspension of the disclosed crystalline form. Subcutaneousadministration can be advantageous over intravenous administration, which typically requires a doctor visit, and can be more painful and invasive. A typical dose of the crystalline compound, when administered to a patient, may be about 1 mg to about 8 mg of compound. In an embodiment, disclosed herein is a pharmaceutically acceptable composition formed from a disclosed cry stalline form, e.g. by mixing a cry stalline form with an excipient and / or a solvent.

[0085] In an embodiment, provided herein is a composition comprising a disclosed crystalline form suitable for subcutaneous administration at dosage levels sufficient to deliver from about 0.001 mg / kg to about 100 mg / kg, from about 0.01 mg / kg to about 50 mg / kg, from about 0.1 mg / kg to about 40 mg / kg, from about 0.5 mg / kg to about 30 mg / kg, from about 0.001 mg / kg to about 4 mg / kg, from about 0.1 mg / kg to about 10 mg / kg, from about 1 mg / kg to about 25 mg / kg, of subject body weight, administered daily, one or more times a day. every other day, every third or fourth day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage may be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, or ten administrations). In certain embodiments, administration may occur once, twice, or thrice weekly.

[0086] Treatment can be continued for as long or as short a period as desired. The compositions may be administered on a regimen of, for example, one to four or more times per day. A suitable treatment period can be, for example, at least about one week, at least about two weeks, at least about one month, at least about six months, at least about 1 year, or indefinitely. A treatment period can terminate when a desired result, for example a weight loss target, is achieved. A treatment regimen can include a corrective phase, during which dose sufficient to provide reduction of weight is administered, and can be followed by a maintenance phase, during which a e.g., lower dose sufficient to weight gain is administered. A suitable maintenance dose is likely to be found in the lower parts of the dose ranges provided herein, but corrective and maintenance doses can readily be established for individual subjects by those of skill in the art without undue experimentation, based on the disclosure herein. Maintenance doses can be employed to maintain body weight in subjects whose body weight has been previously controlled by other means, including diet and exercise, bariatric procedures such as bypass or banding surgeries, or treatments employing other pharmacological agents.

[0087] In certain embodiments, provided herein is a pharmaceutical composition comprising a crystalline form of Compound I, or II, or a solvate thereof, as described herein. In certain embodiments, provided herein is a pharmaceutical composition comprising a crystalline formof Compound I, including, for example, Form A, Form B, or Form C, or a solvate thereof, as described herein. In certain embodiments, provided herein is a pharmaceutical composition comprising a crystalline form of Compound II, including, for example. Form A or Form B, or a solvate thereof, as described herein. In certain embodiments, a pharmaceutical composition provided herein comprises one or more pharmaceutically acceptable excipient, as described herein.Kits

[0088] In one embodiment, a kit for treating or mitigating a contemplated disease of disorder is provided. For example, a disclosed kit comprises a disclosed crystalline compound, e.g., a crystalline form of a Compound I, disposed in a first container. In some embodiments, a kit may further include a pharmaceutically acceptable excipient, disposed in a second container. Such contemplated kits may include written instructions describing preparation of 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 an excipient and a crystalline compound disclosed herein. Disclosed kits may further comprise written instructions describing how to administer the resulting composition to the patent.Processes

[0089] In some embodiments, a process for preparing a disclosed, crystalline form of a Compound I is contemplated herein, comprising: (a) preparing a solution of a Compound I: (b) adjusting the temperature so that solid crystalline form of a Compound I precipitates out of the solution; and (c) isolating the solid crystalline form. In some embodiments, a solution of a 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, IP Ac, and MtBE. In some embodiments, a solution of a Compound I comprises a solvent selected from those as described in the examples herein.

[0090] In some embodiments, a process for preparing a disclosed, crystalline form of a Compound I is contemplated herein, comprising: (a) preparing a solution of a Compound I in a solvent; (b) adjusting the temperature; (c) adding heptane to the solution; and (d) isolating the solid crystalline form. In some embodiments, a solution of a 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, IP Ac. and MtBE. In some embodiments, a solution of Compound I comprises a solvent selected from those as described in the examples herein.

[0091] In some embodiments, a process for preparing a disclosed, crystalline form of Compound II is contemplated herein, comprising: (a) preparing a solution of Compound II; (b) adjusting the temperature so that solid crystalline form of a compound of Compound II precipitates out of the solution; and (c) isolating the solid crystalline form. In some embodiments, a solution of a 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, IP Ac, and MtBE. In some embodiments, a solution of Compound II comprises a solvent selected from those as described in the examples herein.

[0092] In some embodiments, a process for preparing a disclosed, crystalline form of a Compound II is contemplated herein, comprising: (a) preparing a solution of a Compound II in a solvent; (b) adjusting the temperature; (c) adding heptane to the solution; and (d) isolating the solid crystalline form. In some embodiments, a solution of a Compound 11 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, IP Ac, and MtBE. In some embodiments, a solution of Compound II comprises a solvent selected from those as described in the examples herein.

[0093] In some embodiments, the step of adjusting the temperature comprises heating the soludon. In some embodiments, heating the solution comprises heating the solution to about 50 °C. In some embodiments, adjusting the temperature comprises cooling the solution. In some embodiments, cooling the solution comprises cooling the solution to about 0 °C, about 5 °C, or about 25 °C.

[0094] In other embodiments, a disclosed process further comprises a step of coupling Compound A6 and Compound A7, thereby forming Compound I:

[0095] In other embodiments, a disclosed process further comprises a step convertingCompound A5 to Compound A6:

[0096] In other embodiments, a disclosed process further comprises a step of coupling compound A4 with compound SI, thereby forming Compound A5:

[0097] In other embodiments, a disclosed process further comprises a step of converting Compound SMI to Compound SI :

[0098] In other embodiments, a disclosed process further comprises a step of convertingCompound 4 to Compound SMI:4 SM1In some embodiments, the step of converting Compound 4 to Compound SMI further comprises the step of adding an enzyme catalyst.

[0099] In other embodiments, a disclosed process further comprises the step of convertingCompound S2 to Compound II:S2 Compound IIMethods

[0100] Compounds and compositions described herein are generally useful for the inhibition of a kinase or a mutant thereof. In some embodiments, the kinase inhibited by the compounds and compositions described herein is a phosphatidylinositol 3-kinase (PI3K). In some embodiments, the kinase inhibited by the compounds and compositions described herein is one or more of a PI3Ka, PI3K8, and PI3Ky. In some embodiments, the kinase inhibited by the compounds and compositions described herein is a PI3Ka. In some embodiments, the kinase inhibited by the compounds and compositions described herein is a PI3Ka containing at least one of the following mutations: E542X, E545X. Q546X, H1047X, and G1049X, wherein X is any amino acid besides its wildtype. In some embodiments, the kinase inhibited by the compounds and compositions described herein is a PI3Ka 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 a PI3Ka containing at least one of the following mutations: E542K, E545K, and H1047R.

[0101] Compounds or compositions of the disclosure can be useful in applications that benefit from inhibition of PI3K enzymes. For example, PI3K inhibitors of the present disclosure are useful for the treatment of cellular proliferative diseases generally. Compounds or compositions of the disclosure can be useful in applications that benefit from inhibition of PI3Ka enzy mes. For example, PI3Ka inhibitors of the present disclosure are useful for the treatment of cellular proliferative diseases generally.

[0102] Aberrant regulation of PI3K, which often increases survival through Aid activation, is one of the most prevalent events in human cancer and has been shown to occur at multiple levels. The tumor suppressor gene PTEN, which dephosphorylates phosphoinositides at the 3' position of the inositol ring, and in so doing antagonizes PI3K activity, is functionally deleted in a variety of tumors. In other tumors, the genes for the pl 10 alpha isoform, P1K.3CA, and for Akt are amplified, and increased protein expression of their gene products has been demonstrated in several human cancers. Furthermore, mutations and translocation of p85 alpha that serve to up-regulate the p85-pl 10 complex have been described in human cancers. Finally, somatic missense mutations in PIK3CA that activate downstream signaling pathways have been described at significant frequencies in a wide diversity of human cancers (Kang et el., 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 show that deregulation of phosphoinositol-3 kinase, and the upstream and downstream components of this signaling pathway, is one of the most common deregulations associated with human cancers and proliferative diseases (Parsons et al., Nature 436:792 (2005); Hennessey at el., Nature Rev. Drug Disc. 4:988-1004 (2005)).Treatment of Disorders

[0103] Provided compounds are inhibitors of PI3Ka and are therefore useful for treating one or more disorders associated with activity of PI3Ka or mutants thereof. Thus, in certain embodiments, the present disclosure provides a method of treating a PI3Ka-mediated disorder in a subject, comprising administering a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition of either of the foregoing, to a subject in need thereof. In certain embodiments, the present disclosure provides a method of treating a PI3Ka-mediated disorder in a subject comprising administering a therapeutically effective amount of a compound of thepresent disclosure, or a pharmaceutically acceptable composition thereof, to a subject in need thereof. In some embodiments, the subject has a mutant PI3Ka. In some embodiments, the subject has PI3Ka containing at least one of the following mutations: H1047R, E542K, and E545K. In some embodiments, the subject has PI3Ka 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.

[0104] As used herein, the term “PI3Ka-mediated’?disorders, diseases, and / or conditions means any disease or other deleterious condition in which PI3Ka or a mutant thereof is known to play a role. Accordingly, another embodiment of the present disclosure relates to treating or lessening the severity of one or more diseases in which PI3Ka, or a mutant thereof, is known to play a role. Such PI3Ka-mediated disorders include, but are not limited to, cellular proliferative disorders (e.g. cancer). In some embodiments, the PI3Kot-mediated disorder is a disorder mediated by a mutant PI3Ka. In some embodiments, the PI3Ka-mediated disorder is a disorder mediated by a PI3Ka containing at least one of the following mutations: H1047R, E542K, and E545K. In some embodiments, the subject has PI3Ka 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 PI3Ka containing at least one of the mutations in Table A:

[0105] Table A

[0106] In some embodiments, the present disclosure provides a method for treating a cellular proliferative disease, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition of either of the foregoing. In some embodiments, the present disclosure provides a method for treating a cellular proliferative disease, said method comprising administering to a patient in need thereof, a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable composition thereof.

[0107] In some embodiments, the method of treatment comprises the steps of: i) identifying a subject in need of such treatment; (ii) providing a disclosed compound, or a pharmaceutically acceptable salt thereof; and (iii) administering said provided compound in a therapeutically effective amount to treat, suppress and / or prevent the disease state or condition in a subject in need of such treatment. In some embodiments, the subject has a mutant PI3Ka. In some embodiments, the subject has PI3Ka containing at least one of the following mutations: H1047R, E542K, and E545K. In some embodiments, the subject has PI3Ka 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.

[0108] In some embodiments, the method of treatment comprises the steps of: i) identifying a subject in need of such treatment; (ii) providing a composition comprising a disclosed compound, or a pharmaceutically acceptable salt thereof; and (iii) administering said composition in a therapeutically effective amount to treat, suppress and / or prevent the disease state or condition in a subject in need of such treatment. In some embodiments, the subject has a mutant PI3Ka. In some embodiments, the subject has PI3Ka containing at least one of the following mutations: H1047R, E542K, and E545K. In some embodiments, the subject has PI3K.a 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.

[0109] Another aspect of the disclosure provides a compound according to the definitions herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of either of the foregoing, for use in the treatment of a disorder described herein. Another aspect of the disclosure provides the use of a compound according to the definitions herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of either of the foregoing, for the treatment of a disorder described herein. Similarly, the disclosure providesthe use of a compound according to the definitions herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of a disorder described herein.Cellular Proliferative Diseases

[0110] In some embodiments, the disorder is a cellular proliferative disease. In some embodiments, the cellular 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 cellular proliferative disease is a tumor and / or cancerous cell growth. In some embodiments, the cellular proliferative disease is a tumor. In some embodiments, the cellular proliferative disease is a solid tumor. In some embodiments, the cellular proliferative disease is a cancerous cell growth.

[0111] In some embodiments, the solid tumor has PI3Ka containing at least one of the following mutations: E542X, E545X, Q546X, H1047X, and G1049X, wherein X is any amino acid besides its wildtype. In some embodiments, the solid tumor has PI3Ka 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 PI3Ka containing at least one of the following mutations: H1047R. E542K, and E545K.

[0112] In some embodiments, the cancer is selected from sarcoma; lung; bronchus; prostate; breast (including sporadic breast cancers and sufferers of Cowden disease); pancreas; gastrointestinal; colon; rectum; carcinoma; colon carcinoma; adenoma; colorectal adenoma; thyroid; liver; intrahepatic bile duct; hepatocellular; adrenal gland; stomach; gastric; glioma; glioblastoma; endometrial; melanoma; kidney; renal pelvis; urinary bladder; uterine corpus; uterine cervix; vagina; ovary (including clear cell ovarian cancer); multiple myeloma; esophagus; a leukemia; acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia; brain; a carcinoma of the brain; oral cavity and pharynx; larynx; small intestine; non-Hodgkin lymphoma; villous colon adenoma; a neoplasia; a neoplasia of epithelial character; lymphoma; a mammary carcinoma; basal cell carcinoma; squamous cell carcinoma; actinic keratosis; neck; head; polycythemia vera; essential thrombocythemia; myelofibrosis with myeloid metaplasia; and Waldenstrom macroglobulinemia.

[0113] In some embodiments, the cancer is selected from lung; bronchus; prostate; breast (including sporadic breast cancers and Cowden disease); pancreas; gastrointestinal; colon;rectum; thyroid; liver; intrahepatic bile duct; hepatocellular; adrenal gland; stomach; gastric; endometrial; kidney; renal pelvis; urinary bladder; uterine corpus; uterine cervix; vagina; ovary (including clear cell ovarian cancer); esophagus; a leukemia; acute myelogenous leukemia; chronic myelogenous 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; adenoma; colorectal adenoma; glioma; glioblastoma; melanoma; multiple myeloma; a carcinoma of the brain; non-Hodgkin lymphoma; villous colon adenoma; a neoplasia; a neoplasia of epithelial character; lymphoma; a mammary carcinoma; basal cell carcinoma; squamous cell carcinoma; actinic keratosis; polycythemia vera; essential thrombocythemia; myelofibrosis with myeloid metaplasia; and Waldenstrom macroglobulinemia.

[0114] In some embodiments, the cancer is selected from lung; bronchus; prostate; breast (including sporadic breast cancers and Cowden disease); pancreas; gastrointestinal; colon; rectum; thyroid; liver; intrahepatic bile duct; hepatocellular; adrenal gland; stomach; gastric; endometrial; kidney; renal pelvis; urinary’ bladder; uterine corpus; uterine 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 a leukemia. In some embodiments, the cancer is acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; or myeloid leukemia.

[0115] In some embodiments, the cancer is breast cancer (including sporadic breast cancers and Cowden 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 to, or ineligible for, treatment with alpelisib. In some embodiments, the cancer is sporadic breast cancer. In some embodiments, the cancer is Cowden disease.

[0116] In some embodiments, the cancer is ovarian cancer. In some embodiments, the ovarian cancer is clear cell ovarian cancer.

[0117] In some embodiments, the cancer is squamous cell carcinoma. In some embodiments, the cancer is squamous cell carcinoma of the head and neck.

[0118] In some embodiments, the cancer is cervical cancer.

[0119] In some embodiments, the cellular proliferative disease has mutant PI3Ka. In some embodiments, the cancer has mutant PI3Ka. In some embodiments, the breast cancer hasmutant PI3Ka. In some embodiments, the ovarian cancer has mutant PI3Ka. In some embodiments, the clear cell ovarian cancer has mutant PI3Ka.

[0120] In some embodiments, the cellular proliferative disease has PI3Ka containing at least one of the following mutations: H1047R, E542K, and E545K. In some embodiments, the cellular proliferative disease has PI3Ka 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 PI3Ka containing at least one of the following mutations: H1047R, E542K, and E545K. In some embodiments, the cancer has PI3Kcc 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 PI3Ka containing at least one of the following mutations: H1047R, E542K, and E545K. In some embodiments, the breast cancer has PI3Ka 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 ovarian cancer has PI3Ka containing at least one of the following mutations: H1047R, E542K, and E545K. In some embodiments, the ovarian cancer has PI3Ka 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 PI3Ka containing at least one of the following mutations: H1047R, E542K, and E545K. In some embodiments, the clear cell ovarian cancer has PI3Ka containing at least one of the following mutations: E542K, E542Q, E545 A, E545G, E545K, E545Q, Q546E, Q546K, Q546L, Q546P, Q546R, H1047R, H1047L, H1047Y, G1049R, and G1049S.

[0121] In some embodiments, the cancer is adenoma; carcinoma; sarcoma; glioma; glioblastoma; melanoma; multiple myeloma; or lymphoma. In some embodiments, the cancer is a colorectal adenoma or avillous colon adenoma. In some embodiments, the cancer is colon carcinoma; a carcinoma of the brain; a mammary carcinoma; basal cell carcinoma; or a squamous cell carcinoma. In some embodiments, the cancer is a neoplasia or a neoplasia of epithelial character. In some embodiments, the cancer is non-Hodgkin lymphoma. In some embodiments, the cancer is actinic keratosis; polycythemia vera; essential thrombocythemia; myelofibrosis with myeloid metaplasia; or Waldenstrom macroglobulinemia.

[0122] In some embodiments, the cellular proliferative disease displays overexpression or amplification of PI3Ka, somatic mutation of PIK3CA. germline mutations or somatic mutation of PTEN, or mutations and translocation of p85a that serve to up-regulate the p85-pl lO complex. In some embodiments, the cellular proliferative disease displays overexpression or amplification of PI3Ka. In some embodiments, the cellular proliferative disease displays somatic mutation of PIK3CA. In some embodiments, the cellular proliferative disease displays germline mutations or somatic mutation of PTEN. In some embodiments, the cellular proliferative disease displays mutations and translocation of p85a that serve to up-regulate the p85-pl 10 complex.Additional Disorders

[0123] In some embodiments, the PI3Ka-mediated disorder is selected from the group consisting of: polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, asthma, COPD, ARDS, PROS (PI3K-related overgrowth syndrome), venous malformation, Loffler's syndrome, eosinophilic pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia), bronchopulmonary' aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma, eosinophil-related disorders affecting the airways occasioned by drug-reaction, psoriasis, contact dermatitis, atopic dermatitis, alopecia greata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity' angiitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphisus, epidermolysis bullosa acquisita, autoimmune haematogical disorders (e.g. haemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, Wegener granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), endocrine opthalmopathy. Graves’ disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), interstitial lung fibrosis, psoriatic arthritis, glomerulonephritis, cardiovascular diseases, atherosclerosis, hypertension, deep venous thrombosis, stroke, myocardial infarction, unstable angina, thromboembolism, pulmonary' embolism, thrombolytic diseases, acute arterial ischemia, peripheral thrombotic occlusions, and coronary artery disease, reperfusion injuries, retinopathy, such as diabetic retinopathy or hyperbaric oxygen-induced retinopathy, and conditions characterized by elevated intraocular pressure or secretion of ocular aqueous humor, such as glaucoma.

[0124] In some embodiments, the PI3Ka-mediated disorder is polycythemia vera, essential thrombocythemia, or myelofibrosis with myeloid metaplasia. In some embodiments, the PI3Ka-mediated disorder is asthma, COPD, ARDS, PROS (PI3K-related overgrowth syndrome), venous malformation, Loffler's syndrome, eosinophilic pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia), or bronchopulmonary aspergillosis. In some embodiments, the PI3Ka-mediated disorder is polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma, eosinophil-related disorders affecting the airways occasioned by drug-reaction, psoriasis, contact dermatitis, atopic dermatitis, alopecia greata. erythema multiforme, dermatitis herpetiformis, or scleroderma. In some embodiments, the PI3Ka-mediated disorder is vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphisus, epidermolysis bullosa acquisita, or autoimmune haematogical disorders (e.g., haemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopenia). In some embodiments, the P13Ka- mediated disorder is systemic lupus erythematosus, polychondritis, scleroderma, Wegener granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, or autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease).

[0125] In some embodiments, the PI3Ka -mediated disorder is endocrine opthalmopathy, Graves’ disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary’ biliary cirrhosis, uveitis (anterior and posterior), interstitial lung fibrosis, or psoriatic arthritis. In some embodiments, the PI3 Ka -mediated disorder is glomerulonephritis, cardiovascular diseases, atherosclerosis, hypertension, deep venous thrombosis, stroke, myocardial infarction, unstable angina, thromboembolism, pulmonary embolism, thrombolytic diseases, acute arterial ischemia, peripheral thrombotic occlusions, and coronary artery disease, or reperfusion injuries. In some embodiments, the PI3Ka-mediated disorder is retinopathy, such as diabetic retinopathy or hyperbaric oxygen-induced retinopathy, and conditions characterized by elevated intraocular pressure or secretion of ocular aqueous humor, such as glaucoma.Routes of Administration and Dosage Forms

[0126] The compounds and compositions, according to the methods of the present disclosure, may be administered using any amount and any route of administration effective for treating or lessening the severity’ of the disorder (e.g., a proliferative disorder). The exact amount required will vary from subject to subject, depending on the species, age, and general conditionof the subject, the severity of the infection, the particular agent, its mode of administration, and the like. Compounds of the disclosure are preferably formulated in unit dosage form for ease of administration and uniformity of dosage. The expression “unit dosage form’’ as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.

[0127] Pharmaceutically acceptable compositions of this disclosure can be administered to humans and other animals orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like. In certain embodiments, the compounds of the disclosure may be administered orally or parenterally at dosage levels of about 0.01 mg / kg to about 50 mg / kg and preferably from about 1 mg / kg to about 25 mg / kg, of subject body w eight per day, one or more times a day, to obtain the desired therapeutic effect.

[0128] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0129] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0130] Injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0131] In order to prolong the effect of a compound of the present disclosure, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0132] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this disclosure with suitable non-irntating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0133] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or di calcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0134] Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

[0135] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0136] Dosage forms for topical or transdermal administration of a compound of this disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceuticallyacceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this disclosure. Additionally, the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.Dosage Amounts and Regimens

[0137] In accordance with the methods of the present disclosure, the compounds of the disclosure are administered to the subject in a therapeutically effective amount, e.g., to reduce or ameliorate symptoms of the disorder in the subject. This amount is readily determined by the skilled artisan, based upon known procedures, including analysis of titration curves established in vivo and methods and assays disclosed herein.

[0138] In some embodiments, the methods comprise administration of a therapeutically effective dosage of the compounds of the disclosure. In some embodiments, the therapeutically effective dosage 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 bodyweight. 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 1000 mg / kg body weight. It will be recognized that any of the dosages listedherein may constitute an upper or lower dosage range, and may be combined with any other dosage to constitute a dosage range comprising an upper and lower limit.

[0139] In some embodiments, the therapeutically effective dosage 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.

[0140] In some embodiments the therapeutically effective dosage 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.

[0141] In some embodiments, the methods comprise a single dosage or administration (e.g., as a single injection or deposition). Alternatively, in some embodiments, the methods comprise administration once daily, twice daily, three times daily or four times daily to a subject in need thereof for a period of from about 2 to about 28 days, or from about 7 to about 10 days, or from about 7 to about 15 days, or longer. In some embodiments, the methods comprise chronic administration. In yet other embodiments, the methods comprise administration over the course of several weeks, months, years or decades. In still other embodiments, the methods comprise administration over the course of several weeks. In still other embodiments, the methods comprise administration over the course of several months. In still other embodiments, the methods comprise administration over the course of several years. In still other embodiments, the methods comprise administration over the course of several decades.

[0142] The dosage administered can vary depending upon known factors such as the pharmacodynamic characteristics of the active ingredient and its mode and route of administration; time of administration of active ingredient; age, sex, health and weight of the recipient; nature and extent of symptoms; kind of concurrent treatment, frequency of treatment and the effect desired; and rate of excretion. These are all readily determined and may be used by the skilled artisan to adjust or titrate dosages and / or dosing regimens.Inhibition of Protein Kinases

[0143] According to one embodiment, the disclosure relates to a method of inhibiting protein kinase activity in a biological sample comprising the step of contacting said biological sample with a compound of this disclosure, or a composition comprising said compound. According to another embodiment, the disclosure relates to a method of inhibiting activity of a PI3K, or a mutant thereof, in a biological sample comprising the step of contacting said biological sample with a compound of this disclosure, or a composition comprising said compound. Accordingto another embodiment, the disclosure relates to a method of inhibiting activity of PI3Ka, or a mutant thereof, in a biological sample comprising the step of contacting said biological sample with a compound of this disclosure, or a composition comprising said compound. In some embodiments, the PI3Ka is a mutant PI3Ka. In some embodiments, the PI3Ka contains at least one of the following mutations: H1047R, E542K, and E545K.

[0144] In another embodiment, the disclosure provides a method of selectively inhibiting PI3Ka over one or both of PI3K8 and PI3Ky. In some embodiments, a compound of the present disclosure is more than 5-fold selective over PI3K8 and PI3Ky. In some embodiments, a compound of the present disclosure is more than 10-fold selective over PI3K8 and PI3Ky. In some embodiments, a compound of the present disclosure is more than 50-fold selective over PI3K8 and PI3Ky. In some embodiments, a compound of the present disclosure is more than 100-fold selective over PI3K8 and PI3Ky. In some embodiments, a compound of the present disclosure is more than 200-fold selective over PI3K8 and PI3Ky. In some embodiments, the PI3Ka is a mutant PI3Koc. In some embodiments, the PI3Ka contains at least one of the following mutations: H1047R, E542K, and E545K.

[0145] In another embodiment, the disclosure provides a method of selectively inhibiting a mutant PI3Ka over a wild-type PI3Ka. In some embodiments, a compound of the present disclosure is more than 5-fold selective for mutant P13Ka over wild-type P13Kcc. In some embodiments, a compound of the present disclosure is more than 10-fold selective for mutant PI3Koc over wild-ty pe PI3Ka. In some embodiments, a compound of the present disclosure is more than 50-fold selective for mutant PI3Koc over wild-type PI3K.cc. In some embodiments, a compound of the present disclosure is more than 100-fold selective for mutant PI3Ka over wild-type PI3Koc. In some embodiments, a compound of the present disclosure is more than 200-fold selective for mutant PI3Ka over wild-type PI3Koc. In some embodiments, the mutant PI3Koc contains at least one of the following mutations: H1047R, E542K, and E545K.

[0146] The term “biological sample'’, as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

[0147] Inhibition of activity of a PI3K (for example, PI3Ka, or a mutant thereof) in a biological sample is useful for a variety of purposes that are know n to one of skill in the art. Examples of such purposes include, but are not limited to. blood transfusion, organ-transplantation, biological specimen storage, and biological assays.

[0148] Another embodiment of the present disclosure relates to a method of inhibiting protein kinase activity in a patient comprising the step of administering to said patient a compound of the present disclosure, or a composition comprising said compound.

[0149] According to another embodiment, the disclosure relates to a method of inhibiting activity of a PI3K, or a mutant thereof, in a patient comprising the step of administering to said patient a compound of the present disclosure, or a composition comprising said compound. In some embodiments, the disclosure relates to a method of inhibiting activity of PI3Ka, or a mutant thereof, in a patient comprising the step of administering to said patient a compound of the present disclosure, or a composition comprising said compound. In some embodiments, the PI3Ka is a mutant PI3Ka. In some embodiments, the PI3Ka contains at least one of the following mutations: H1047R, E542K, and E545K.

[0150] According to another embodiment, the present disclosure provides a method for treating a disorder mediated by a PI3K, or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a compound according to the present disclosure or pharmaceutically acceptable composition thereof. In some embodiments, the present disclosure provides a method for treating a disorder mediated by PI3Ka, or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a compound according to the present disclosure or pharmaceutically acceptable composition thereof. In some embodiments, the PI3Ka is a mutant PI3Ka. In some embodiments, the PI3Kcc contains at least one of the following mutations: H1047R, E542K, and E545K.

[0151] According to another embodiment, the present disclosure provides a method of inhibiting signaling activity of PI3Ka. or a mutant thereof, in a subject, comprising administering a therapeutically effective amount of a compound according to the present disclosure, or a pharmaceutically acceptable composition thereof, to a subject in need thereof. In some embodiments, the present disclosure provides a method of inhibiting PI3Ka signaling activity in a subject, comprising administering a therapeutically effective amount of a compound according to the present disclosure, or a pharmaceutically acceptable composition thereof, to a subject in need thereof. In some embodiments, the PI3Ka is a mutant PI3Ka. In some embodiments, the PI3Ka contains at least one of the following mutations: H1047R, E542K, and E545K. In some embodiments, the subject has a mutant PI3Ka. In some embodiments, the subject has PI3Ka containing at least one of the following mutations: H1047R, E542K, and E545K.

[0152] The compounds described herein can also inhibit PI3Ka function through incorporation into agents that catalyze the destruction of PI3Ka. For example, the compounds can be incorporated into proteolysis targeting chimeras (PROTACs). A PROTAC is a bifunctional molecule, with one portion capable of engaging an E3 ubiquitin ligase, and the other portion having the ability to bind to a target protein meant for degradation by the cellular protein quality control machinery. Recruitment of the target protein to the specific E3 ligase results in its tagging for destruction (i.e., ubiquitination) and subsequent degradation by the proteasome. Any E3 ligase can be used. The portion of the PROTAC that engages the E3 ligase is connected to the portion of the PROTAC that engages the target protein via a linker which consists of a variable chain of atoms. Recruitment of PI3Ka to the E3 ligase will thus result in the destruction of the PI3Ka protein. The variable chain of atoms can include, for example, rings, heteroatoms, and / or repeating polymeric units. It can be rigid or flexible. It can be attached to the two portions described above using standard techniques in the art of organic synthesis.Combination Therapies

[0153] Depending upon the particular disorder, condition, or disease, to be treated, additional therapeutic agents, that are normally administered to treat that condition, may be administered in combination with compounds and compositions of this disclosure. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated.”

[0154] Additionally, PI3K sen es as a second messenger node that integrates parallel signaling pathways, and evidence is emerging that the combination of a PI3K inhibitor with inhibitors of other pathways will be useful in treating cancer and cellular proliferative diseases.

[0155] Accordingly, in certain embodiments, the method of treatment comprises administering the compound or composition of the disclosure in combination with one or more additional therapeutic agents. In certain other embodiments, the methods of treatment comprise administering the compound or composition of the disclosure as the only therapeutic agent.

[0156] Approximately 20-30% of human breast cancers overexpress Her-2 / neu-ErbB2, the target for the drug trastuzumab. Although trastuzumab has demonstrated durable responses in some patients expressing Her2 / neu-ErbB2, only a subset of these patients respond. Recent work has indicated that this limited response rate can be substantially improved by the combination of trastuzumab with inhibitors of PI3K or the PI13K / AKT pathway (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, the method oftreatment comprises administering the compound or composition of the disclosure in combination with trastuzumab. In certain embodiments, the cancer is a human breast cancer that overexpresses Her-2 / neu-ErbB2.

[0157] A variety of human malignancies express activating mutations or increased levels of Herl / EGFR and a number of antibody and small molecule inhibitors have been developed against this receptor tyrosine kinase including tarceva, gefitinib and erbitux. However, while EGFR inhibitors demonstrate anti-tumor activity in certain human tumors (e.g.. NSCLC), they fail to increase overall patient survival in all patients with EGFR-expressing tumors. This may be rationalized by the fact that many downstream targets of Herl / EGFR are mutated or deregulated at high frequencies in a variety' of malignancies, including the PI3K / Akt pathway.

[0158] For example, gefitinib inhibits the growth of an adenocarcinoma cell line in in vitro assays. Nonetheless, sub-clones of these cell lines can be selected that are resistant to gefitinib that demonstrate increased activation of the PI3 / Akt pathway. Down-regulation or inhibition of this pathway renders the resistant sub-clones sensitive to gefitinib (Kokubo et al., Brit. J. Cancer 92: 1711 (2005)). Furthermore, in an in vitro model of breast cancer with a cell line that harbors a PTEN mutation and over-expresses EGFR inhibition of both the P13K / 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 w ould be an attractive therapeutic strategy' in cancer.

[0159] Accordingly, in certain embodiments, the method of treatment comprises administering the compound or composition of the disclosure in combination with an inhibitor of Herl / EGFR. In certain embodiments, the method of treatment comprises administering the compound or composition of the disclosure in combination with one or more of tarceva, gefitinib, and erbitux. In certain embodiments, the method of treatment comprises administering the compound or composition of the disclosure in combination with gefitinib. In certain embodiments, the cancer expresses activating mutations or increased levels of Herl / EGFR.

[0160] 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 that either agent alone in a glioblastoma xenograft model (Goudar et al., Mol. Cancer. Then 4: 101-112 (2005)).

[0161] Anti-estrogens, such as tamoxifen, inhibit breast cancer growth through induction of cell cycle arrest that requires the action of the cell cycle inhibitor p27Kip. Recently, it has been shown that activation of the Ras-Raf-MAP Kinase pathw ay alters the phosphorylation statusof p27Kip such that its inhibitor}' activity in arresting the cell cycle is attenuated, thereby 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 inhibitor reversed the aberrant phosphorylation status of p27 in hormone refractor}' breast cancer cell lines and in so doing restored hormone sensitivity. Similarly, phosphorylation of p27Kip by Aid also abrogates its role to arrest the cell cycle (Viglietto et al., Nat. Med. 8:1145 (2002)).

[0162] Accordingly, in certain embodiments, the method of treatment comprises administering the compound or composition of the disclosure in combination with a treatment for a hormonedependent cancer. In certain embodiments, the method of treatment comprises administering the compound or composition of the disclosure in combination with tamoxifen. In certain embodiments, the cancer is a hormone dependent cancer, such as breast and prostate cancers. By this use, it is aimed to reverse hormone resistance commonly seen in these cancers with conventional anticancer agents.

[0163] In hematological cancers, such as chronic myelogenous leukemia (CML), chromosomal translocation is responsible for the constitutively activated BCR-Abl tyrosine kinase. The afflicted patients are responsive to imatinib, a small molecule tyrosine kinase inhibitor, as a result of inhibition of Abl kinase activity. However, many patients with advanced stage disease respond to imatinib initially, but then relapse later due to resistance-conferring mutations in the Abl kinase domain. In vitro studies have demonstrated that BCR-Abl employs the Ras-Raf kinase pathway to elicit its effects. In addition, inhibiting more than one kinase in the same pathway provides additional protection against resistance-conferring mutations.

[0164] Accordingly, in another aspect, the compounds and compositions of the 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 hematological cancers, such as chronic myelogenous leukemia (CML). By this use, it is aimed to reverse or prevent resistance to said at least one additional agent.

[0165] Because activation of the PI3K / Akt pathway drives cell survival, inhibition of the pathway in combination with therapies that drive apoptosis in cancer cells, including radiotherapy and chemotherapy, will result in improved responses (Ghobrial et al., CA Cancer J. Clin 55: 178-194 (2005)). As an example, combination of PI3 kinase inhibitor with carboplatin demonstrated synergistic effects in both in vitro proliferation and apoptosis assays as well as in in vivo tumor efficacy in a xenograft model of ovarian cancer (Westfall and Skinner, Mol. Cancer Then 4: 1764-1771 (2005)).

[0166] In some embodiments, the one or more additional therapeutic agents is selected from antibodies, antibody-drug conjugates, kinase inhibitors, immunomodulators, and histone deacetylase inhibitors. Synergistic combinations with PIK3CA inhibitors and other therapeutic agents are described in, for example, Castel et al., Mol. Cell Oncol. (2014)1(3) e963447.

[0167] In some embodiments, the one or more additional therapeutic agent is selected from the following agents, or a pharmaceutically acceptable salt thereof: BCR-ABL inhibitors (see e.g. Ultimo et al. Oncotarget (2017) 8 (14) 23213-23227.): e.g. imatinib, inilotinib, nilotinib, dasatinib, bosutinib, ponatinib, bafetinib, danusertib, saracatinib, PF03814735; ALK inhibitors (see e.g. Yang et al. Tumour Biol. (2014) 35 (10) 9759-67): e.g. crizotinib, NVP- TAE684, ceritinib, alectinib, brigatinib, entrecinib, lorlatinib; BRAF inhibitors (see e.g. Silva et al. Mol. Cancer Res. (2014) 12, 447-463): e.g. vemurafenib, dabrafenib; FGFR inhibitors (see e.g. 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, lestaurtinib, quizartinib, and crenolanib; MEK Inhibitors (see e.g. 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 (see e.g. Makhov et al. Mol. Cancer. Ther. (2012) 11(7) 1510-1517): e.g. erlotinib, linifanib, sunitinib, pazopanib; Epidermal growth factor receptor (EGFR) inhibitors (see e.g. She et al. BMC Cancer (2016) 16, 587): gefitnib, osimertinib, cetuximab, panitumumab; HER2 receptor inhibitors (see e.g. Lopez et al. Mol. Cancer Ther. (2015) 14(1 1) 2519-2526): e.g. trastuzumab, pertuzumab, neratinib, lapatinib, lapatinib; MET inhibitors (see e.g. Hervieu et al. Front. Mol. Biosci. (2018) 5, 86): e.g. crizotinib, cabozantinib; CD20 antibodies: e.g. rituximab, tositumomab, ofatumumab; DNA Synthesis inhibitors: e.g. capecitabine, gemcitabine, nelarabine, hydroxy carbamide; Antineoplastic agents (see e.g. Wang et al. Cell Death & Disease (2018) 9, 739): e.g. oxaliplatin, carboplatin, cisplatin;; Immunomodulators: e.g. afutuzumab, lenalidomide, thalidomide, pomalidomide; CD40 inhibitors: e.g. dacetuzumab; Pro-apoptotic receptor agonists (PARAs): e.g. dulanermin; Heat Shock Protein (HSP) inhibitors (see e.g. Chen et al. Oncotarget (2014) 5 (9). 2372-2389): e.g. tanespimycin; Hedgehog antagonists (see e.g. Chaturvedi et al. Oncotarget (2018) 9 (24), 16619-16633): e g. vismodegib; Proteasome inhibitors (see e.g. Lin et al. Int. J. Oncol. (2014) 44 (2), 557-562): e.g. bortezomib; PI3K inhibitors: e.g. pictilisib, dactolisib. alpelisib, buparlisib, taselisib, idelalisib, duvelisib, umbralisib; SHP2 inhibitors (see e.g. Sun et al. Am. J. Cancer Res. (2019) 9 (1), 149-159: e.g. SHP099, RMC-4550, RMC-4630);; BCL-2 inhibitors (see e.g. Bojarczuket al. Blood (2018) 133 (1), 70-80): e.g. venetoclax; Aromatase inhibitors (see e.g. Mayer et al. Clin. Cancer Res. (2019) 25 (10), 2975-2987): exemestane, letrozole. anastrozole, fulvestrant, tamoxifen; mTOR inhibitors (see e.g. Woo et al. Oncogenesis (2017) 6, e385): e.g. temsirolimus, ridaforolimus, everolimus, sirolimus; CTLA-4 inhibitors (see e.g. O’Donnell et al. (2018) 48, 91-103): e.g. tremelimumab, ipilimumab; PD1 inhibitors (see O’Donnell, supra): e.g. nivolumab, pembrolizumab; an immunoadhesin; Other immune checkpoint inhibitors (see e.g. 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 Death 1 (PD-1), Cytotoxic T- Lymphocyte Antigen 4 (CTLA-4), B7H1, B7H4, OX-40, CD 137, CD40, and LAG3. Immunotherapeutic agents which can act as immune checkpoint inhibitors useful in the methods of the present disclosure, include, but are not limited to, 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 (see e.g. O’Donnell supra): e.g. MSB0010718C; YW243.55.S70, MPDL3280A; MEDI-4736, MSB-0010718C, or MDX-1105;; Histone deacetylase inhibitors (HD1. see e.g. Rahmani et al. Clin. Cancer Res. (2014) 20(18), 4849- 4860): e.g. vorinostat;; Androgen Receptor inhibitors (see e.g. Thomas et al. Mol. Cancer Ther. (2013) 12(11), 2342-2355): e.g. enzalutamide, abiraterone acetate, orteronel, galeterone, seviteronel, bicalutamide, flutamide; Androgens: e.g. fluoxymesterone; CDK4 / 6 inhibitors (see e.g. Gul et al. Am. J. Cancer Res. (2018) 8(12). 2359-2376): e.g. alvocidib. palbociclib, ribociclib, trilaciclib, abemaciclib.

[0168] In some embodiments, the one or more additional therapeutic agent is selected from the following agents: anti-FGFR antibodies; FGFR inhibitors, cytotoxic agents; Estrogen Receptor-targeted 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 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.).

[0169] In some embodiments, the estrogen receptor targeted therapy is a selective estrogen receptor degrader (SERD, e g. fulvestrant, elacestrant, giredestrant). In some embodiments, the estrogen receptor targeted 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).

[0170] In some embodiments, the one or more additional therapeutic agents are inhibitors of one or more of CDK2, CDK4, and CDK6 enzy mes. 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.

[0171] In some embodiments, more than one CDK inhibitor is administered together with compound of the disclosure. In some embodiments, the additional therapeutic agents comprise one or more CDK inhibitors and an estrogen receptor targeted therapy. In some embodiments, the additional therapeutic agent comprises a selective estrogen receptor degrader and one or more CDK inhibitors.

[0172] The structure of the active compounds identified by code numbers, generic or trade names may be taken from the actual edition of the standard compendium "The Merck Index" or from databases, e.g. Patents International (e.g. IMS World Publications).

[0173] A compound of the current disclosure may also be used in combination with known therapeutic processes, for example, the administration of hormones or radiation. In certain embodiments, a provided compound is used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy.

[0174] A compound of the current disclosure can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy taking the form of fixed combinations or the administration of a compound of the disclosure and one or more other therapeutic compounds being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic compounds. A compound of the current disclosure can besides or in addition be administered especially for tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination of these. Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are therapy to maintain the patient's status after tumor regression, or even chemopreventive therapy, for example in patients at risk.

[0175] Those additional agents may be administered separately from an inventive compoundcontaining composition, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a compound of this disclosure in a single composition. If administered as part of a multiple dosage regime, the two active agents maybe submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another.

[0176] As used herein, the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this disclosure. For example, a compound of the present disclosure may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present disclosure provides a single unit dosage form comprising a compound of the current disclosure, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0177] The amount of both an inventive compound and additional therapeutic agent (in those compositions which comprise an additional therapeutic agent as described above) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, compositions of this disclosure should be formulated so that a dosage of between 0.01 - 100 mg / kg body weight / day of an inventive compound can be administered.

[0178] In those compositions which comprise an additional therapeutic agent, that additional therapeutic agent and the compound of this disclosure may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions will be less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions a dosage of between 0.01 - 1,000 pg / kg body weight / day of the additional therapeutic agent can be administered.

[0179] The amount of additional therapeutic agent present in the compositions of this disclosure will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

[0180] The compounds of this disclosure, or pharmaceutical compositions thereof, may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with apharmaceutically acceptable composition comprising a kinase inhibitor. Implantable devices coated with a compound of this disclosure are another embodiment of the present disclosure.

[0181] Any of the compounds and / or compositions of the disclosure may be provided in a kit comprising the compounds and / or compositions. Thus, in some embodiments, the compound and / or composition of the disclosure is provided in a kit.

[0182] The disclosure is further described by the following non-limiting Examples.EXAMPLES

[0183] Examples are provided herein to facilitate a more complete understanding of the disclosure. The following examples serve to illustrate the exemplary modes of making and practicing the subject matter of the disclosure. However, the scope of the disclosure is not to be construed as limited to specific embodiments disclosed in these examples, which are illustrative only.

[0184] As depicted in the Examples below, in certain exemplar}' embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present disclosure, the following general methods, and other methods known to one of ordinary skill in the art. can be applied to other classes and subclasses and species of each of these compounds, as described herein. Additional compounds of the disclosure were prepared by methods substantially similar to those described herein in the Examples and methods known to one skilled in the art.

[0185] In the description of the synthetic methods described below, unless otherwise stated, it is to be understood that all reaction conditions (for example, reaction solvent, atmosphere, temperature, duration, and workup procedures) are selected from the standard conditions for that reaction, unless otherwise indicated. The starting materials for the Examples are either commercially available or are readily prepared by standard methods from know n materials.

[0186] The compounds described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art. The following nonlimiting examples illustrate the disclosures herein.Instruments and MethodologyX-ray Powder Diffraction (XRPD)

[0187] Method. Instrument: PANalytical Empyrean. XRPD diffractograms were collected on aPANalytical Empyrean diffractometer using Cu Ka radiation (45 kV, 40 mA) in transmission geometry. A 0.5° slit, 4 mm mask and 0.04 rad Soller slits with a focusing mirror were used on the incident beam. A PIXcel3Ddetector, placed on the diffracted beam, was fitted with areceiving slit and 0.04 rad Seller slits. The software used for data collection was X’Pert Data Collector using X’Pert Operator Interface. The data were analyzed and presented using HighScore Plus. Samples were prepared and analyzed in either a metal or Millipore 96 wellplate in transmission mode. X-ray transparent film was used between the metal sheets on the metal well-plate and powders (approximately 1 - 2 mg) were used as received. The Millipore plate was used to isolate and analyze solids from suspensions by adding a small amount of suspension directly to the plate before filtration under a light vacuum. The scan mode for the metal plate used the gonio scan axis, whereas a 20 scan was utilized for the Millipore plate. The parameters of the standard screening data collection method are:Angular range: 2.5 to 32.0° 20Step size: 0.0130° 20Collection time: 12.75 s / step (total collection time of 2.07 min)Differential Scanning Calorimetric (DSC)

[0188] Method 1. Instrument: TA Instruments Discovery DSC. DSC data were collected on a TA Instruments Discovery DSC equipped with a 50 position auto-sampler. Typically, 0.5 - 3 mg of each sample, in a pin-holed aluminum pan, was heated at 10 °C / min from 25 °C to 300 °C. A purge of dr ' nitrogen at 50 ml / min was maintained over the sample. The instrument control software was TRIOS and the data were analyzed using TRIOS or Universal Analysis.

[0189] Method 2. Instrument: TA Instruments DSC2500. DSC data were collected on a TA Instruments DSC2500 equipped with a 54 position auto-sampler. Typically, 0.5 - 3 mg of each sample, in a pin-holed aluminum pan, was heated at 10 °C / min from 25 °C to 300 °C. A purge of dry nitrogen at 50 ml / min was maintained over the sample. Modulated temperature DSC (MDSC) was carried out using an underlying heating rate of 2 °C / min and temperature modulation parameters of ±0.64 °C (amplitude) every 60 seconds (period). The instrument control software was TRIOS and the data were analyzed using TRIOS or Universal Analysis.Thermal Gravimetric Analysis (TGA)Instrument Discovery’ 5500 or Q5000Sample pan Aluminum, openStart temperature Ambient condition (below 35°C)Final temperature 300°C or abort next segment if weight < 80% (w / w)(The weight loss of the compound is no more than 20% (w / w))Heating rate 10°C / minNitrogen flow Balance lOmL / min; sample chamber 25mL / minSample mass About 2-10mgDynamic Vapor Sorption (DVS)Method 1Instrument Intrinsic, Advantage or AdventureTotal gas flow 200 seemOven temperature 25°CSolvent WaterMethod Cycle: 40-0-95-0-40%RHStage Step: 10%Equilibrium: 0.002 dm / dt (% / min )Minimum dm / dt stability duration: 60minMaximum dm / dt stage time: 360minMethod 2Instrument Intrinsic, Advantage or AdventureTotal gas flow 200 seemOven temperature 25 °CSolvent WaterMethod Cycle: 40-95-0-95-40%RHStage Step: 10%Equilibrium: 0.002 dm / dt (% / min )Minimum dm / dt stability duration: 60minMaximum dm / dt stage time: 360min

[0190] Nuclear Magnetic Resonance (NMR)Instrument Bruker Avance-AV 400M (for 1H-NMR, 19F-NMR and 31P-NMR)Bruker Avance-III 400M (for 13C-NMR)Frequency 400MHzProbe 5 mm PABBO BB / 19F-1H / D Z-GRD Z108618 / 0406 (for 1H-NMR, 19F-NMR and 31P-NMR)5 mm PABBO BB-1H / D Z-GRD Z 108618 / 0229 (for 13C NMR)Number of scan 8Temperature 297.6KRelaxation delay 1 second

[0191] High Performance Liquid Chromatograph (HPLC)Instrument Agilent 1260, SHIMADZU CBM-40,Chiral purity Wave length: 220nmColumn: Daicel OD-RH (4.6x 150 mm*5 pm)Detector: DAD, PDAColumn temperature: 40°CFlow rate: ImL / minMobile phase A: 1 OmM NH4OAc in waterMobile phase B: ACNDiluent: ACNInjection volume: 5 LSample Preparation: 2mg / mLNeedle Wash Solvent: ACN:H20=90: 10(v / v)Gradient: Isocratic elutionTime (min) Mobile Phase A (%) Mobile Phase B (%)0 55 4530 55 45FeSSIF (fed state simulated intestinal fluid)

[0192] 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 Ca. 800 ml of deionized water in a 1000 ml volumetric flask. This solution was mixed thoroughly and then the pH adjusted to 5.0 ± 0.05 with IM hydrochloric acid / sodium hydroxide. The solution was then made to volume with deionized water and the pH recorded (pH 5.00).

[0193] FeSSIF Media: Phares SIF (simulated intestinal fluid) powder (0.56 g) was dissolved in Ca. 40ml of base buffer in a 50 ml volumetric flask. This solution was mixed thoroughly and then made to volume with the same base buffer. The final pH was recorded (pH 4.93).FaSSIF (fasted state simulated intestinal fluid)

[0194] Phosphate Base Buffer (FaSSIF), pH 6.5: Sodium hydroxide (0.403 g), sodium phosphate monobasic (3.95 g) and sodium chloride (6.50 g) were dissolved in Ca. 800 ml of deionized water in a 1000 ml volumetric flask. This solution was mixed thoroughly and then the pH adjusted to 6.5 ± 0.05 with IM hydrochloric acid / sodium hydroxide. The solution was then made to volume with deionized water and the pH recorded (pH 6.47).

[0195] FaSSIF Media: Phares SIF (simulated intestinal fluid) powder (0.112 g) was dissolved in Ca. 40ml of base buffer in a 50 ml volumetric flask. This solution was mixed thoroughly and then made to volume with the same base buffer. The final pH was recorded (pH 6.46).FaSSGF (fasted state simulated gastric fluid)

[0196] Base Buffer (FaSSGF), pH 1.6: Sodium chloride (1.99 g) was dissolved in Ca. 800 ml of deionized water in a 1000 ml volumetric flask. This solution was mixed thoroughly and then the pH adjusted to 1.6 ± 0.05 with concentrated hydrochloric acid. The solution was then made to volume with deionized water and the pH recorded (pH 1.60).

[0197] FaSSGF Media: Phares SIF (simulated intestinal fluid) powder (0.03 g) was dissolved in Ca. 40 ml of base buffer in a 50 ml volumetric flask. This solution was mixed thoroughly and then made to volume with the same base buffer. The final pH was recorded (pH 1.63).Abbreviations Full nameMeOH MethanolEtOH EthanolACN AcetonitrileTFA Trifluoroacetic acidDMSO Dimethyl sulfoxideIP Ac Isopropyl acetateDCM DichloromethaneEA Ethyl acetateTHF TetrahydrofuranMTBE Methyl tert-butyl etherDMF DimethylformamideHATU Hexafluorophosphate azabenzotriazole tetramethyl uraniumHOBt HydroxybenzotriazoleEDCI l-Ethyl-3-(3-dimethylaminopropyl)carbodiimideNBS N-bromosuccinimideDIEA (or DIPEA) DiisopropylethylamineExample 1Preparation of Synthetic Intermediates1.1. Preparation of Intermediate SMI. . p .1 21) KOH, MeOH, H2Mel, K2CO32) (BOC)2O, THF DMFStep 3. 80.0%Step 4. 71.7%enzymeStep 5. 85 0%Step 1. Preparation of Methyl (lR,4S)-4-((tert-butoxycarbonyl)amino)cyclopent-2-ene- 1-carboxylate (1)

[0198] A solution of methyl (lR,4S)-4-aminocyclopent-2-ene-l-carboxylate hydrochloride (5000.00 g, 28.149 mol, 1 eq) in DCM (30 L) at 0 °C was treated with triethylamine (2.848 kg, 28. 149 mol, 1.0 eq). The temperature was controlled to 0-5 °C. Di-tert-butyl dicarbonate (6. 143 kg, 28. 149 mol, 1.0 eq) was added dropwise to the resulting mixture at 0-5 °C, and the internal temperature of the mixture was maintained below 10 °C. The mixture was allowed to warm to 22 °C and was stirred for 16 hrs.

[0199] The reaction was diluted with water (8000 mL) and the organic layer was separated. The aqueous layer was extracted with DCM (5000.0mL), and the DCM layer was washed with brine (5.0 L). dried over anhydrous MgSCri, filtered and concentrated. Methyl (lR,4S)-4-((tert- butoxycarbonyl)amino) cyclopent -2-ene- 1 -carboxylate was obtained as a white solid (6.20 kg, 91.3% yield).Step 2. Preparation of Methyl (3aR,5R,6R,6aR)-6-bromo-2-oxohexahydro-2H- cyclopenta[d]oxazole-5-carboxylate (2)

[0200] A solution of methyl (lR,4S)-4-((tert-butoxycarbonyl)amino)cyclopent-2-ene-l- carboxylate (5500.00 g, 22.795 mol,l eq) in THF (22 L) and H2O (2.2 L) was cooled to 0 °C. Then N-bromosuccinimide (4.463 kg, 25.074 mol, 1.1 eq) was added in batches. The mixture was allowed to warm to room temperature and stirred for 16 hrs. The solution was concentrated to dryness. The residue was slurried in DCM (15 L) and washed with IM HC1 (5 L), saturated NazSCh (6 L), brine (6.0L), dried over anhydrous MgSCH, filtered and concentrated. The residue was slurried in n-heptane (4 L) for 30 min, filtered, and dried to obtain methyl (3aR.5R,6R,6aR)-6-bromo-2-oxohexahydro-2H-cyclopenta[d]oxazole-5-carboxylate as a white solid (4.033kg, 67.0%).Step 3. Preparation of (3R,4S)-4-((tert-butoxycarbonyl)amino)-3-hydroxycydopent-l- ene-l-carboxylic acid (3)

[0201] 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. Then KOH (1.700 kg, 30.295 mol, 4.0 eq) was added in batches. The mixture was heated at 80 °C for 16 hrs. 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 allowed to warm to room temperature and stirred for 16 hrs. The mixture was redissolved in EA (3 L) and H2O (3 L), IM HC1 was added dropwise into the mixture to adjust pH=3~4 and extracted with EA (5 L x 3). The organic layer was separated, washed with brine (5 L), dried over anhydrous MgSCE. filtered and concentrated to dryness. (3R,4S)-4-((tert-butoxycarbonyl)amino)-3-hydroxycy cl opent- 1-ene-l -carboxy lie acid (1.48 kg, 80.0% yield) was obtained as a white solid.Step 4. Preparation of Methyl (3R,4S)-4-((tert-butoxycarbonyl)amino)-3- hydroxycyclopent-l-ene-l-carboxylate (4)

[0202] A solution of (3R,4S)-4-((tert-butoxycarbonyl)amino)-3-hydroxycyclopent-l-ene-l- carboxylic acid (3. 2900.00 g.11.922 mol,l eq) in DMF (14.5 L) was cooled to 0 °C. then K2CO3 (2.471 kg,17.882 mol, 1.5 eq) was added in batches. The mixture was allowed to warm to room temperature and stirred for 1 hrs. Methyl iodide (3.384 kg, 23.843 mol, 2.0 eq) was added dropwise to the resulting mixture at 0-5 °C, The mixture was allowed to warm to room temperature and was stirred for 16 hrs. The mixture was quenched with H2O (40.0 L) and then extracted with EA (10 L x 2). The organic layer was separated, washed with brine (5L), dried over anhydrous MgSO-i. filtered, and concentrated to dryness. The residue was slurried in (PE:EA=3:1 (2 L)) for 30 min, filtered, and dried to obtain methyl (3R,4S)-4-((tert- butoxycarbonyl)amino)-3-hydroxycyclopent-l-ene-l-carboxylate (2.200 kg, 71.7% yield) as a white solid.Step 5. Preparation of Methyl (lS,3S,4R)-3-((tert-butoxycarbonyl)amino)-4- hydroxycyclopentane-l-carboxylate (SMI)

[0203] Glucose (1800.00g) was dissolved in 14.4 L of 100 mM potassium phosphate buffer at pH=7. Then, 800.00g wet whole cells of E. coli BL21(DE3) overexpressing the enzyme, Ene Reductase 10 (PE10), was added to the potassium phosphate buffer and fully suspended to obtain a uniform suspension. Then, 8.00 g of glucose dehydrogenase powder and nicotinamide adenine dinucleotide phosphate were added to the potassium phosphate buffer. To this was added 800.00g of the substrate (methyl (3R,4S)-4-((tert-butoxycarbonyl)amino)-3- hydroxy cyclopent-1 -ene- 1 -carboxylate) in DMSO as a cosolvent. The mixture was stirred at 37 °C. Due to the production of gluconic acid during the reaction process, 3M K2CO3 is used to adjust the pH and control it at 7.0. The mixture was stirred for 16 hrs.

[0204] The reaction mixture was filtered over diatomaceous earth. The filtrate was extracted with EA (3L x 3), and the filter cake was slurried with 8L EA. The combined organic layerswere washed with brine (5L), dried over anhydrous MgSC>4, filtered, and concentrated to dryness. The residue was slurried in n-heptane (1 L) for 30 min. filtered, and dried to obtain methyl (lS,3S,4R)-3-((tert-butoxycarbonyl)amino)-4-hydroxycyclopentane-l-carboxylate (0.685 kg, 85.0% yield) as a white solid.1HNMR (400MHz, CDCh) 8 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 punty=98.80%. e.e%=100%.1.2. Preparation of Intermediate AlA1Step 1. Preparation of ethyl 4-methylenecyclohexane-l-carboxylate

[0205] A reaction vessel was charged with PhsMeBr (28.35 kg, 1.5 eq) in THF (72.0 L, 8.0 V) under N2. To the vessel was added t-BuOK (8.91 kg, 1.5 eq) at ~0 °C. To the mixture was added ethyl 4-oxocy cl ohexane-1 -carboxylate (9.00 kg, 1.00 eq) in THF (18.0 L, 2.0V) dropwise, and the resulting mixture was stirred at ~0 °C for 10 min. Then, 30% aq. citric acid (IV) was added to the reaction vessel to adjust the pH to ~4.5. The mixture was stirred at 20- 25 °C for 30 min. The aqueous phase was extracted with heptane (2 x 4V) and the organic phases were combined, concentrated to ~1 V, charged with heptane (2V) in a vessel, which was stirred for 30 min. The mixture was filtered, dried over MgSOv and concentrated to afford ethyl 4-methylenecyclohexane-l-carboxylate as a light yellow liquid (6.93 kg, 78% yield).Step 2. Preparation of ethyl 4-(bromoinethyl)-4-fluorocyclohexane-l-carboxylate

[0206] A reaction vessel was charged with DCM (93.3 L, 10 V) and ethyl 4- methylenecy cl ohexane-1 -carboxylate (9.33 kg, 1.0 eq). To this was added triethylamine trihydrofluoride (22.39 kg, 2.5 eq) at ~0 °C for 10 min. The mixture was then charged with N- bromosuccinimide (14.74 kg, 1.5 eq) and stirred at 20-25 °C for 10 min. Then, distilled water (140.0 kg, 15.0 V) was added, and the mixture was stirred for 30 min. The mixture was washedwith additional distilled water (93.0 kg, 10.0 V) and the organic layers were combined, dried over MgSO4, filtered and concentrated to afford crude ethyl 4-(bromomethyl)-4- fluorocyclohexane-1 -carboxylate as a brown liquid (10.81 kg crude).Step 3. Preparation of ethyl 4-fluorobicyclo[2.2.1]heptane-l-carboxylate

[0207] A reaction vessel was charged with THF (20L, 10V), MTBE (6.0L, 3V), and crude ethyl 4-(bromomethyl)-4-lluorocyclohexane-l -carboxylate (2.0 kg, 1.0 eq). To the solution potassium bis(trimethylsilyl)amide (13.1 L, 1.75 eq) was added at 30-40 °C for 60 min. Then, 10% aq. Ammonium chloride (5V) was added dropwise to the mixture, which was stirred at -0 °C for 30 min. The aqueous phase was extracted with MTBE (4V) twice, and the combined organic layer was concentrated to a crude light yellow liquid. To a separate vessel was added N-(2-hydroxyethyl)-2-pyrrolidone (5.0V). activated carbon (10%), and the crude light yellow concentrate under N2. The mixture was stirred, filtered, and concentrated to afford ethyl 4- fluorobicyclo[2.2.1]heptane-l-carboxylate as a brown liquid (2.51 kg, 58.7% yield).Step 4. Preparation of 4-fluoronorbornane-l-carbaldehyde

[0208] Preparation of SDBBA reductant: To a solution of t-BuONa (1.500 kg, 15.608 mol, 1.938 eq) in THF (20.0 L). was added D1BAL-H (2.115 kg, 14.98 mol. 9.99 L, 1.860 eq) dropwise at -10-0 °C. The reaction mixture was stirred at 25 °C for 2 hrs to give the reductant SDBBA.

[0209] To a solution of ethyl 4-fluorobicyclo[2.2. l]heptane-l-carboxylate (1500.0 g, 8.055 mol, 1.0 eq) in THF (20.0 L) was added the fresh made SDBBA at -10-0 °C and the mixture was stirred at -10—0 °C for 16 hrs. The reaction was afterwards quenched with addition of IN HC1 (30.0 L) dropwise and stirred for 2 hrs. The mixture was extracted with MTBE (10.0 L x 3), the combined organic layers were dried over MgSC , filtered and concentrated at 10-20 °C to give a residue. The residue was redissolved in MTBE (1.0 L), sat. solution of NaHSCfi (6 L) was added and stirred at 25 °C for 16 hrs. The mixture was extracted with MTBE (5.0 L x 4) and water layer was collected. pH of the water layer was adjusted by addition of sat. Na2CC>3 (10 L) to pH = 9-10 and stirred at 25 °C for furtherl6 hrs. The resulting mixture was extracted with MTBE (5.0 L x 5), the organic phases were combined and dried over MgSC>4, filtered and concentrated at 15-20 °C to give 4-fluorobicyclo[2.2.1]heptane-l- carbaldehyde (640.6 g, 74.488% yield) as colorless oil.Step 5. Preparation of (R,Z)-N-[(4-fhioronorboman-l-yl)inethylene]-2-methyl-propane- 2-sulfinamide (Al)

[0210] To a solution of 4-fluorobicyclo[2.2. l]heptane-l-carbaldehyde (640.0 g. 4.502 mol, 1.0 eq) in THF (15.0 L) was added (R)-2-methylpropane-2-sulfmamide (545.60g, 4.502 mol, 1.0eq), and tetra isopropyl titanate (TIPT, 2.561kg, 9.003 mol, 2.0 eq) at 25 °C. The reaction mixture was stirred at 70-75 °C for 3 hrs. The reaction mixture was cooled to 25 °C naturally and diluted with EA (10.0 L), then poured into water (10.0 L) at 10-20 °C. The mixture was extracted with EA (10.0 L x 3), the combined organic layers were washed with sat. NaCl solution (4.5 L), dried over MgSC>4, filtered, and concentrated at 35-45 °C to give a residue. The residue was triturated with (n -heptane: EA = 10: 1) (1.5 L) at 0-10 °C for 2 hrs then filtered to give (R,Z)-N-[(4-fluoronorboman-l-yl)methylene]-2-methyl-propane-2-sulfmamide (521.02 g, 47.172%) as white solid.Example 2Synthesis of Compound IStep 1. Preparation of (lS,3S,4R)-3-((tert-butoxycarbonyl)amino)-4- hydroxycyclopentane-l-carboxylic acid (SI)

[0211] To a solution of methyl (lR,3R,4S)-3-((tert-butoxycarbonyl)amino)-4- hydroxycyclopentane-l-carboxylate (700 g, 1.00 eq) in THF (1.4 L, 2V) and MeOH (1.4 L, 2V) was added IM aq. LiOH solution (3.5 L, 5V) at 0-5 °C, the mixture was stirred at 0-5 °C for 1 hr. The reaction was monitored by HPLC and LCMS. The reaction mixture was neutralized with IN HC1 to pH 6-7 at 0-5 °C. The reaction mixture was concentrated below 40 °C to remove organic solvent. The solution was acidified with IN HC1 to pH 2-3 at 20-25 °C and extracted with 2-MeTHF (10V x 3). The combined organic layer was washed with brine (10V) and dried over sodium sulfate. After filtration and concentration at 40 °C, the product was dried under vacuum at 50 °C to give (lS.3S,4R)-3-((tert-butoxycarbonyl)amino)-4- hydroxycyclopentane-l-carboxylic acid (SI) as a white solid (191 g, 92.9% yield).Step 2. Preparation of (R)-N-((S)-(3-chloro-2,6-difluorophenyl)(4- fluorobicyclo[2.2.1]heptan-l-yl)methyl)-2-methylpropane-2-sulfinamide

[0212] To a solution of 1 -chloro-2,4-difluorobenzene (590.5 g, 1.30 eq) in THF (5.25 L. 7 V) was added n-BuLi (2.50 M, 1585 mL, 1.30 eq) at -65 °C under a N2 atmosphere. The mixture was stirred at -65 °C for 0.5 hr, then a solution of (R,Z)-N-((4-fluorobicyclo[2.2.1]heptan-l- yl)methylene)-2-methylpropane-2-sulfinamide (750 g, 1.0 eq) in THF (3.75 L, 5V) was added dropwise at -65 °C. The mixture was stirred at -65 °C for 2 hrs. The reaction was monitored by HPLC and LCMS. The reaction mixture was added into saturated NH4CI solution (1 1.25 L,15V) at -10-0 °C. The aqueous phase was extracted with ethyl acetate (10 V x 2). The combined organic phase was washed with saturated brine (15 V x 2). dried with anhydrous Na2SO4, filtered, and concentrated in vacuum to give a crude product. The crude product was dissolved in ethanol (750 rnL, IV). Water(3.75, 5V) was added, and the mixture was stirred for 2h. The resulting solid was filtered. The solid was slurried with Heptane / EA (10: 1, 5V) for 5h, filtered, and the solid was dried in the air at 50°C to give pure (R)-N-((S)-(3-chloro-2,6- difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-l-yl)methyl)-2-methylpropane-2-sulfmamide as a white solid (995 g, 79% yield).Step 3. Preparation of (S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-l- yl)methan amine

[0213] To a solution of (R)-N-((S)-(3-chloro-2.6-difluorophenyl)(4- fluorobicyclo[2.2.1]heptan-l-yl)methyl)-2-methylpropane-2-sulfmamide (995 g, 1.00 eq) in MeOH (2985 mL, 3V) was added HCl / MeOH (3980 mL, 4V) at 25 °C, the mixture was stirred at 25 °C for 1 hr. The reaction was monitored by HPLC and LCMS. The reaction mixture was concentrated in vacuum to give a crude product. The residue was triturated with Ethyl acetate / n-heptane (1: 10, 5 V) at 25 °C for 2h. filtered, and the filter cake was dried in vacuum at 50 °C. Compound (S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2. l]heptan-l- yl)methanamine was obtained as a white solid (738 g, 90.5% yield).Step 4. Preparation of tert-butyl ((lS,2R,4S)-4-(((S)-(3-chloro-2,6-difluorophenyl)(4- fluorobicyclo[2.2.1]heptan-l-yl)methyl)carbamoyl)-2-hydroxycyclopentyl)carbamate

[0214] To a solution of (lS,3S,4R)-3-((tert-butoxycarbonyl)amino)-4-hydroxycyclopentane- 1-carboxylic acid (490 g, l.Oeq) in DCM (7V) was added DIEA (4.0eq) and HOBt (1.3eq) at 0-5 °C, followed by the addition of (S)-(3-chloro-2,6-difluorophenyl)(4- fluorobicyclo[2.2.1]heptan-l-yl)methanamine (619 g, 0.95eq) under N2 atmosphere. To the mixture was added EDCI (497.8 g, 1.3eq). The resulting reaction mixture was stirred at 0-5 °C under N2 for 24h and monitored by HPLC and LCMS. The reaction mixture was washed with half sat. K2CO3 (15V x 2), IN HC1 (15V x 2), and then brine (15V). The organic phase was separated and concentrated under reduced pressure at 40 °C. The crude product was cry stallized with EtOAc / n-heptane (1.5V:6V). Solids were filtered and the filter cake was dried in vacuum at 50 °C to give tert-butyl ((l S,2R,4S)-4-(((S)-(3-chloro-2,6-difluorophenyl)(4- fluorobicyclo[2.2. l]heptan-l-yl)methyl)carbamoyl)-2-hydroxycyclopentyl)carbamate as a white solid (852 g, 83% yield).Step 5. Preparation of (lS,3S,4R)-3-amino-N-((S)-(3-chloro-2,6-difluorophenyl)(4- fluorobicyclo[2.2.1]heptan-l-yl)methyl)-4-hydroxycyclopentane-l-carboxamide HC1

[0215] To a solution of tert-butyl ((lS,2R,4S)-4-(((S)-(3-chloro-2,6-difluorophenyl)(4- fluorobicyclo[2.2. l]heptan-l-yl)methyl)carbamoyl)-2 -hydroxy cyclopenlyl jcarbamate (880 g, 1.00 eq) in DCM (2640 mL, 3 V) was added con. HC1 (425.5 mL, 3 eq) at 25 °C, and the mixture was stirred at 25 °C for 3 hr. The reaction was monitored by HPLC and LCMS. The reaction mixture was concentrated in vacuum to give a crude product as a semi oil used in the next step without further purification (770 g crude net weight).Step 6. Preparation of N-((lS,2R,4S)-4-(((S)-(3-chloro-2,6-difluorophenyl)(4- fluorobicycIo[2.2.1]heptan-l-yl)methyl)carbamoyI)-2-hydroxycyclopentyl)pyrimidine-5- carboxamide (Compound I)

[0216] To a solution of pyrimidine-5-carboxylic acid (232.8 g, 1.05eq) in DCM (5670 mL, 7V) was added N-methylmorpholine (542 g, 3.0eq) at 0-5 °C under N2 atmosphere, followed by the addition of (1 S,3S,4R)-3-amino-N-((S)-(3-chloro-2,6-difluorophenyl)(4- fluorobicyclo[2.2.1]heptan-l-yl)methyl)-4-hydroxycyclopentane-l-carboxamide HC1 (810 g net weight, l.Oeq) in DCM (2430 mL, 3V) at 0-5 °C. Then to the mixture was finally added HATU (747.4 g, 1.1 eq) at 0-5 °C under N2. The resulting reaction mixture was stirred at 0-5 °C under N2 for 2h and monitored by HPLC and LCMS. To the reaction mixture was added N- methylmorpholine (361 g, 2.0eq) at 0-5 °C and then washed with sat. ISfeCCL (12.15 L, 15V). The organic phase was concentrated under reduced pressure at 40 °C and dissolved with EA (1.0 L, 10V). The resulting solution was washed with 0.5N HC1 (15V x 3) and then with brine (15V). The organic phase was separated and concentrated under reduced pressure at 40 °C to give the crude product. It was purified by silica gel column chromatography eluting with 0-10% MeOH in DCM and dried under vacuum at 40 °C to give N-((lS,2R,4S)-4-(((S)-(3- chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-l-yl)methyl)carbamoyl)-2- hydroxycyclopentyl)pyrimidine-5-carboxamide (Compound I) as an off-white solid (733 g, 82% yield).Example 3Synthesis of Compound IICompound IIStep 1. Synthesis of (lS,3S,4R)-3-acetamido-N-((S)-(3-chloro-2,6-difluorophenyl)(4- fhiorobicyclo[2.2.1]heptan-l-yl)methyl)-4-hydroxycyclopentane-l-carboxamide

[0217] A round bottomed flask was charged with (lS,3S,4R)-3-amino-N-((S)-(3-chloro-2,6- difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-l-yl)methyl)-4-hydroxycyclopentane-l- carboxamide (1.45 g, 3.48 mmol), acetic acid (209 mg, 3.48 mmol), NaHCCL (1.46 g, 17.4 mmol), HATU (2.64 g, 6.96 mmol) and a stir bar. DMF (15 mL) was added, and the solution was stirred for 1 hour at room temperature. The resulting crude material was purified by preparative HPLC (column: LuxCellulose-34.6*100 mm, 3 pm; mobile phase A: water, mobile phase B: MeOH (0.5% 2M NH3 in MeOH); flow rate: 4 mL / min; gradient: 20% B isocratic) to give (lS,3S,4R)-3-acetamido-N-((S)-(3-chloro-2,6-difluorophenyl)(4- fluorobicyclo[2.2.1]heptan-l-yl)methyl)-4-hydroxycyclopentane-l-carboxamide (1.34 g. 2.93 mmol) as an off-white amorphous solid.!H NMR (400 MHz, DMSO-de) 8 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.Example 4 Preparation and Characterization of Crystal Forms Compound I, Form A

[0218] A sample of Compound I (30 mg) was weighed into HPLC vials and 5 volumes of ethyl acetate was added. The sample was matured for 24 hours cycling between RT and 50 °C in a maturation chamber (~4 hours for each increase of 1 °C). Then, 500 pl of heptane was added to the sample vial, which was allowed to mature for a further 24 hours. The suspension was filtered through a XRPD Millipore plate under vacuum for 10 minutes to give a crystalline solid. The observed pattern by XRPD analysis was assigned as crystalline Form A of Compound I (see FIG. 1).

[0219] Form A appeared to be an essentially anhydrous form as only trace amounts of ethyl acetate (0.09 eq) was detected in the NMR spectra and the total weight loss observed from TGA analysis would also add up to 0.09 eq of ethyl acetate. A broad endotherm was observed at the beginning of the thermal trace (loss of solvent) then the melt endotherm at 174 °C. After storage at 40 °C 75 % RH the sample had remained Form A as monitored by X-ray powder diffraction.Table 2. Characterization of Compound I, Form ACompound I, Form B

[0220] A sample of Compound I (30 mg) was weighed into HPLC vials and 10 volumes of isopropyl acetate was added. The sample was matured for 24 hours cycling between RT and 50 °C in a maturation chamber (~4 hours for each increase of 1 °C). The sample was allowed to mature for a further 24 hours. The suspension was filtered through a XRPD Millipore plate under vacuum for 10 minutes to give a crystalline solid. The observed pattern by XRPD analysis was assigned as crystalline Form B of Compound I (see FIG. 2).

[0221] The characterization of Form B suggests that this 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 endotherm at the beginning of the trace (likely solvent loss) followed by another endotherm at 141 °C then finally the melt endotherm at 172 °C. Form B was also observed to have converted to Form A post accelerated storage conditions at 40 °C 75 % RH. Table 3. Characterization of Compound I, Form BCompound I, Form C

[0222] A sample of Compound I (30 mg) was weighed into HPLC vials and 5 volumes of ethanol was added. The sample was matured for 24 hours cycling between RT and 50 °C in a maturation chamber (~4 hours for each increase of 1 °C). Then, 500 pl of heptane was added to the sample, which was allowed to mature for a further 24 hours. The suspension was filtered through a XRPD Millipore plate under vacuum for 10 minutes to give a crystalline solid. The observed pattern by XRPD analysis was assigned as crystalline Form C of Compound I (see FIG. 3).

[0223] Analysis of Form C suggests that it was an ethanol solvate. NMR analysis showed about 0.82 eq of ethanol was contained in the sample and the weight loss from TGA analysis also showed approximately 0.9 eq of ethanol. The sample converted to amorphous material after storage at accelerated storage conditions.Table 4. Characterization of Compound I, Form CCompound II, Form A

[0224] A sample of Compound II (30 mg) was weighed into HPLC vials and 20 volumes of water was added. The sample was matured for 24 hours cycling between RT and 50 °C in a maturation chamber (~4 hours for each increase of 1 °C). The sample was allowed to mature for a further 24 hours. The suspension was filtered through a XRPD Millipore plate under vacuum for 10 minutes to give a crystalline solid. The observed pattern by XRPD analysis was assigned as crystalline Form A of Compound II (see FIG. 4).

[0225] Form A TGA analysis showed a weight loss of water (1.79 eq water) similar to that seen in the KF (1.31 eq). The difference in the quantity of water seen by TGA and KF is likely surface bound water that had evaporated before KF analysis. The DSC showed a broad endotherm at 46.8 °C onset, which is likely the loss of water from the sample, followed by several endothermic events and an exotherm at 129.6 °C with the melt likely at 225.1 °C.

[0226] The GVS analysis showed a reversable weight loss of 1.8 % w / w between 20 and 90 % RH, then w (0.47 eq water) then significant loss / absorption of 4.46 % w / w (1.19 eq water) between 20 and 0 % RH which suggests this is a monohydrated form. The sample remained Form A post GVS and static storage conditions, with little change in the purity of the samples as measured by XRPD. On heating to 160 °C at 10 °C / min and cooling to RT, the sample had converted to Form B.Table 5. Characterization of Compound II, Form ACompound II, Form B

[0227] A sample of Compound II (30 mg) was weighed into HPLC vials and 20 volumes of ethyl acetate was added. The sample was matured for 24 hours cycling between RT and 50 °C in a maturation chamber (~4 hours for each increase of 1 °C). The sample was allowed to mature for a further 24 hours. The suspension was filtered through a XRPD Millipore plate under vacuum for 10 minutes to give a crystalline solid. The observed pattern by XRPD analysis was assigned as crystalline Form B of Compound II (see FIG. 5).

[0228] Form B appeared 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 that was seen in the TGA thermal trace. The only endotherm that was observed for Form B was the melt endotherm at onset 229 °C. The sample then began to degrade above 250 °C. The sample remained Form B post static storage conditions at 40 °C 75 % RH.Table 6. Characterization of Compound II, Form BExample 5Solubility Assessment of Crystal Forms in MediaCompound I, Form A

[0229] The solubility of Form A remained high, especially in FeSSIF media at 2.3 mg / ml. Solubility in FaSSIF was 0.51 mg / ml (slightly less than amorphous) and 0.34 mg / ml in FaSSGF and 0.45 mg / ml in deionized water. XRPD analysis of the residues has shown that the samples have remained Form A.Compound I, Form B

[0230] The solubility assessment for Form B showed very high solubility in the selected media. XRPD analysis of the residues post solubility analysis however, confirmed that the crystal structure of Form B collapsed leaving mostly amorphous material. This shows that the highsolubility of the sample is due to the sample converting to amorphous material and not related to the actual solubility of Form B.Compound II, Form A

[0231] The solubility assessment of Form A showed the highest solubility was in FeSSIF at 0.3 mg / ml, with solubility' in the three other media all around 0.1 mg / ml. XRPD analysis of the residues post the solubility assessment have shown that the samples have remained Form A.Compound II, Form B

[0232] The solubility of Form B was slightly less than Form A (but mostly comparable) and residues collected post solubility analysis showed the solid had remained Form B.Example 6 Competitive Slurry ExperimentsCompound I (Form A and Form B)

[0233] Compound I, Form A (100 mg) and Compound I, Form B (100 mg) were each weighed into a 4 ml vial and mixed for 2 hours. The sample was recovered and analyzed by XRPD for use as a reference. Saturated solutions were prepared at the same time by pipetting 500 pl of selected solvent systems into a HPLC vial and stirring at 5, 25 and 50 °C (see Table below). To each of the sample vials, Compound I was added until a suspension formed. After 1 hour, all samples were observed to have remained suspensions, and were left to stir for a further 24 hours.

[0234] All samples were found to have remained suspensions. Each suspension was pipetted into a syringe and filtered through a nylon filter cartridge where the solutions were collectedinto fresh vials. To each of the solutions, 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 sample vials were recorded, and a first aliquot was pipetted into a metal XRPD plate and analyzed by XRPD. Samples were stirred for a further 5 days before a second aliquot was taken and XRPD analysis was performed.

[0235] The competitive slurries for Compound I after 24 hours has shown that all of samples had remained suspensions after slurrying at 50 and 5 °C. XRPD analysis of these samples has shown that several samples fully converted to Form A. although several are still mixtures of Form A and B.

[0236] After a further 5 days (6 days total) all of the samples had remained suspensions and XRPD analysis of these samples showed that more samples had fully converted to purely Form A. Samples that were still mixtures were notably in heptane, although all two of the three samples had mostly formed Form A with some small peaks related to Form B, and this is possibly due to lower solubility in heptane slowing the conversions to Form A. This suggests that given enough time, full conversion to Form A would likely occur.Compound II (Form A and Form B)

[0237] Compound II, Form A (100 mg) and Compound II, Form B (100 mg) were each weighed into a 4 ml vial and mixed for 2 hours. The sample was recovered and analyzed by XRPD for use as a reference. Saturated solutions were prepared at the same time by pipetting 500 pl of selected solvent systems into a HPLC vial and stirring at 5, 25 and 50 °C (see Table below). To each of the sample vials, Compound II was added until a suspension formed. After 1 hour, all samples were observed to have remained suspensions, and were left to stir for a further 24 hours.

[0238] All samples were found to have remained suspensions. Each suspension was pipetted into a syringe and filtered through a nylon filter cartridge where the solutions were collected into fresh vials. To each of the solutions, 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 sample vials were recorded, and a first aliquot was pipetted into a metal XRPD plate and analyzed by XRPD. Samples were stirred for a further 5 days before a second aliquot was taken and XRPD analysis was performed.

[0239] All of the samples had remained suspensions and XRPD analysis of these samples showed full conversion to Form B after 24 hours. The samples had remained suspensions aftera further 5 days, all of which had remained Form B. This suggests that Form B may be a more thermodynamically stable form when compared to Form A.INCORPORATION BY REFERENCE

[0240] All publications and patents mentioned herein are hereby incorporated by reference in their entirety for all purposes as if each individual publication or patent was specifically and individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.EQUIVALENTS

[0241] While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the present disclosure will become apparent to those skilled in the art upon review of this specification. The full scope ofthe disclosure should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

[0242] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term ‘'about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure.

Claims

CLAIMS1. A compound in solid form, wherein the compound is Compound I:or a solvate thereof.

2. The compound of claim 1, wherein the compound is amorphous.

3. The compound of claim 1, wherein the compound is crystalline.

4. The compound of claim 1 or 3, wherein the solid form is cry stalline Form A, Form B, or Form C.

5. The compound of any one of claims 1, 3, and 4, wherein the solid form is Form A.

6. The compound of claim 5, wherein the solid form has a X-ray pow der diffraction pattern comprising at least two peaks, each selected from the group consisting of about 17.4 20, about 13.3 20, and about 16.5 20.

7. The compound of claim 5, wherein the solid form has a X-ray pow der diffraction pattern comprising at least two peaks, each selected from the group consisting of about 17.4 20, about 13.3 20, about 16.5 20, about 24.2 20. about 19.8 20, about 14.5 20, and about 18.2 20.

8. The compound of claim 5, wherein the solid form has a X-ray powder diffraction pattern comprising at least three peaks, each selected from the group consisting of about 17.4 20, about 13.3 20, about 16.5 20, about 24.2 20. about 19.8 20, about 14.5 20, and about 18.2 20.

9. The compound of claim 5, wherein the solid form has a X-ray powder diffraction pattern comprising at least four peaks, each selected from the group consisting of about 17.4 20, about 13.3 20, about 16.5 20, about 24.2 20, about 19.8 20, about 14.5 20, and about 18.2 20.

10. The compound of claim 5. wherein the solid form has a X-ray powder diffraction pattern comprising at least five peaks, each selected from the group consisting of about 17.4 20, about 13.3 20, about 16.5 20, about 24.2 20. about 19.8 20, about 14.5 20, and about 18.2 20.

11. The compound of claim 5, wherein the solid form has a X-ray powder diffraction pattern comprising at least six peaks, each selected from the group consisting of about 17.4 20, about 13.3 20, about 16.5 20. about 24.2 20, about 19.8 20, about 14.5 20. and about 18.2 20.

12. The compound of claim 5, wherein the solid form has a X-ray powder diffraction pattern comprising peaks at about 17.4 20, about 13.3 20, about 16.5 20, about 24.2 20, about 19.8 20, about 14.5 20, and about 18.2 20.

13. The compound of claim 5, wherein the solid form has a X-ray powder diffraction pattern comprising at least three peaks, in degrees 20, selected from the group consisting of the peaks listed in Table 1.1.

14. The compound of claim 5, wherein the solid form has a X-ray powder diffraction pattern comprising at least four peaks, in degrees 20, selected from the group consisting of the peaks listed in Table 1.1.

15. The compound of claim 5, wherein the solid form has a X-ray powder diffraction pattern comprising at least five peaks, in degrees 20, selected from the group consisting of the peaks listed in Table 1.1.

16. The compound of claim 5, wherein the solid form has a X-ray powder diffraction pattern comprising at least six peaks, in degrees 20, selected from the group consisting of the peaks listed in Table 1.1.

17. The compound of claim 5, wherein the solid form has a X-ray powder diffraction pattern comprising at least seven peaks, in degrees 20, selected from the group consisting of the peaks listed in Table 1.1.

18. The compound of claim 5. wherein the solid form has a X-Ray powder diffraction pattern substantially similar to that depicted in FIG. 1.

19. The compound of any one of claims 1, 3, and 4, wherein the solid form is Form B.

20. The compound of claim 19, wherein the solid form has a X-ray powder diffraction pattern comprising at least two peaks, each selected from the group consisting of about18.5 20, about 11.4 20, and about 17.5 20.

21. The compound of claim 19, wherein the solid form has a X-ray powder diffraction pattern comprising at least two peaks, each selected from the group consisting of about18.5 20, about 11.4 20. about 17.5 20, about 5.7 20. about 13.6 20, about 17.3 20. and about10.7 20.

22. The compound of claim 19, wherein the solid form has a X-ray powder diffraction pattern comprising at least three peaks, each selected from the group consisting of about18.5 20, about 11.4 20, about 17.5 20, about 5.7 20, about 13.6 20, about 17.3 20, and about10.7 20.

23. The compound of claim 19, wherein the solid form has a X-ray powder diffraction pattern comprising at least four peaks, each selected from the group consisting of about18.5 20, about 11.4 20, about 17.5 20, about 5.7 20, about 13.6 20, about 17.3 20, and about10.7 20.

24. The compound of claim 19, wherein the solid form has a X-ray powder diffraction pattern comprising at least five peaks, each selected from the group consisting of about18.5 20, about 11.4 20, about 17.5 20, about 5.7 20, about 13.6 20, about 17.3 20, and about10.7 20.

25. The compound of claim 19, wherein the solid form has a X-ray powder diffraction pattern comprising at least six peaks, each selected from the group consisting of about18.5 20, about 11.4 20, about 17.5 20, about 5.7 20, about 13.6 20, about 17.3 20, and about 10.7 20.

26. The compound of claim 19, wherein the solid form has a X-ray powder diffraction pattern comprising peaks at about 18.5 20. about 11.4 20, about 17.5 20, about 5.7 20, about13.6 20, about 17.3 20, and about 10.7 20.

27. The compound of claim 19, wherein the solid form has a X-ray powder diffraction pattern comprising at least three peaks, in degrees 20, selected from the group consisting of the peaks listed in Table 1.2.

28. The compound of claim 19, wherein the solid form has a X-ray powder diffraction pattern comprising at least four peaks, in degrees 20, selected from the group consisting of the peaks listed in Table 1.2.

29. The compound of claim 19, wherein the solid form has a X-ray powder diffraction pattern comprising at least five peaks, in degrees 20, selected from the group consisting of the peaks listed in Table 1.2.

30. The compound of claim 19, wherein the solid form has a X-ray powder diffraction pattern comprising at least six peaks, in degrees 20, selected from the group consisting of the peaks listed in Table 1.2.

31. The compound of claim 19, wherein the solid form has a X-ray powder diffraction pattern comprising at least seven peaks, in degrees 20, selected from the group consisting of the peaks listed in Table 1.2.

32. The compound of claim 19, wherein the solid form has a X-Ray powder diffraction pattern substantially similar to that depicted in FIG. 2.

33. The compound of any one of claims 1, 3, and 4, wherein the solid form is Form C.

34. The compound of claim 33, wherein the solid form has a X-ray powder diffraction pattern comprising at least two peaks, each selected from the group consisting of about 19.3 20, about 19.9 20, and about 20.0 20.

35. The compound of claim 33, wherein the solid form has a X-ray powder diffraction pattern comprising at least two peaks, each selected from the group consisting of about19.3 20, about 19.9 20. about 20.0 20, about 10.1 20, about 19.6 20. about 15.2 20, and about 22.0 20.

36. The compound of claim 33, wherein the solid form has a X-ray powder diffraction pattern comprising at least three peaks, each selected from the group consisting of about19.3 20, about 19.9 20, about 20.0 20, about 10.1 20, about 19.6 20, about 15.2 20, and about 22.0 20.

37. The compound of claim 33, wherein the solid form has a X-ray powder diffraction pattern comprising at least four peaks, each selected from the group consisting of about19.3 20, about 19.9 20, about 20.0 20, about 10.1 20, about 19.6 20, about 15.2 20, and about 22.0 20.

38. The compound of claim 33, wherein the solid form has a X-ray powder diffraction pattern comprising at least five peaks, each selected from the group consisting of about19.3 20, about 19.9 20, about 20.0 20, about 10.1 20, about 19.6 20, about 15.2 20, and about 22.0 20.

39. The compound of claim 33, wherein the solid form has a X-ray powder diffraction pattern comprising at least six peaks, each selected from the group consisting of about19.3 20, about 19.9 20, about 20.0 20, about 10.1 20, about 19.6 20, about 15.2 20, and about 22.0 20.

40. The compound of claim 33, wherein the solid form has a X-ray powder diffraction pattern comprising peaks at about 19.3 20, about 19.9 20, about 20.0 20, about 10.1 20, about 19.6 20, about 15.2 20, and about 22.020.

41. The compound of claim 33, wherein the solid form has a X-ray powder diffraction pattern comprising at least three peaks, in degrees 29, selected from the group consisting of the peaks listed in Table 1.3.

42. The compound of claim 33, wherein the solid form has a X-ray powder diffraction pattern comprising at least four peaks, in degrees 20, selected from the group consisting of the peaks listed in Table 1.3.

43. The compound of claim 33, wherein the solid form has a X-ray powder diffraction pattern comprising at least five peaks, in degrees 20, selected from the group consisting of the peaks listed in Table 1.3.

44. The compound of claim 33, wherein the solid form has a X-ray powder diffraction pattern comprising at least six peaks, in degrees 20, selected from the group consisting of the peaks listed in Table 1.3.

45. The compound of claim 33, wherein the solid form has a X-ray powder diffraction pattern comprising at least seven peaks, in degrees 20, selected from the group consisting of the peaks listed in Table 1.3.

46. The compound of claim 33, wherein the solid form has a X-Ray powder diffraction pattern substantially similar to that depicted in FIG. 3.

47. A compound in solid form, wherein the compound is Compound II:or a solvate thereof.

48. The compound of claim 47, wherein the compound is amorphous.

49. The compound of claim 47, wherein the compound is crystalline.

50. The compound of claim 47 or claim 49, wherein the solid form is Form A or Form B.

51. The compound of any one of claims 47.

49. and 50. wherein the solid form is Form A.

52. The compound of claim 51, wherein the solid form has a X-ray powder diffraction pattern comprising at least two peaks, each selected from the group consisting of about 15.7 20, about 14.7 20, and about 20.0 20.

53. The compound of claim 51, wherein the solid form has a X-ray powder diffraction pattern comprising at least two peaks, each selected from the group consisting of about 15.7 20, about 14.7 20, about 20.0 20, about 21.0 20, about 23.2 20, about 16.5 20, about 17.5 20, and about 13.3 20.

54. The compound of claim 51, wherein the solid form has a X-ray powder diffraction pattern comprising at least three peaks, each selected from the group consisting of about 15.7 20, about 14.7 20, about 20.0 20, about 21.0 20, about 23.2 20, about 16.5 20, about 17.5 20, and about 13.3 20.

55. The compound of claim 51, wherein the solid form has a X-ray powder diffraction pattern comprising at least four peaks, each selected from the group consisting of about 15.7 20, about 14.7 20, about 20.0 20, about 21.0 20, about 23.2 20, about 16.5 20, about 17.5 20, and about 13.3 20.

56. The compound of claim 51, wherein the solid form has a X-ray powder diffraction pattern comprising at least five peaks, each selected from the group consisting of about 15.7 20, about 14.7 20, about 20.0 20, about 21.0 20, about 23.2 20, about 16.5 20, about 17.5 20, and about 13.3 20.

57. The compound of claim 51, wherein the solid form has a X-ray powder diffraction pattern comprising at least six peaks, each selected from the group consisting of about 15.720, about 14.7 20, about 20.0 20, about 21.0 20, about 23.2 20, about 16.5 20, about 17.5 20, and about 13.3 20.

58. The compound of claim 51, wherein the solid form has a X-ray powder diffraction pattern comprising peaks at about 15.7 20, about 14.7 20, about 20.0 20, about 21.0 20, about 23.2 20, about 16.5 20. about 17.5 20, and about 13.3 20.

59. The compound of claim 51, wherein the solid form has a X-ray powder diffraction pattern comprising at least three peaks, in degrees 20, selected from the group consisting of the peaks listed in Table 1.4.

60. The compound of claim 51, wherein the solid form has a X-ray powder diffraction pattern comprising at least four peaks, in degrees 20, selected from the group consisting of the peaks listed in Table 1.4.

61. The compound of claim 51, wherein the solid form has a X-ray powder diffraction pattern comprising at least five peaks, in degrees 20, selected from the group consisting of the peaks listed in Table 1.4.

62. The compound of claim 51, wherein the solid form has a X-ray powder diffraction pattern comprising at least six peaks, in degrees 20, selected from the group consisting of the peaks listed in Table 1.4.

63. The compound of claim 51, wherein the solid form has a X-ray powder diffraction pattern compnsing at least seven peaks, in degrees 20, selected from the group consisting of the peaks listed in Table 1.4.

64. The compound of claim 51, wherein the solid form has a X-Ray powder diffraction pattern substantially similar to that depicted in FIG. 4.

65. The compound of any one of claims 47, 49, and 50, wherein the solid form is Form B.

66. The compound of claim 65, wherein the solid form has a X-ray powder diffraction pattern comprising at least two peaks, each selected from the group consisting of about 23.6 20, about 10.9 20, and about 16.9 20.

67. The compound of claim 65, wherein the solid form has a X-ray powder diffraction pattern comprising at least two peaks, each selected from the group consisting of about 23.6 20, about 10.9 20, about 16.9 20, about 15.1 29. about 26.1 20, about 12.9 20, and about 19.4 20.

68. The compound of claim 65, wherein the solid form has a X-ray powder diffraction pattern comprising at least three peaks, each selected from the group consisting of about 23.6 20, about 10.9 20, about 16.9 20, about 15.1 29, about 26.1 20, about 12.9 20, and about 19.4 20.

69. The compound of claim 65, wherein the solid form has a X-ray powder diffraction pattern comprising at least four peaks, each selected from the group consisting of about 23.6 20, about 10.9 20, about 16.9 20, about 15.1 20, about 26.1 20, about 12.9 20, and about 19.4 20.

70. The compound of claim 65, wherein the solid form has a X-ray powder diffraction pattern comprising at least five peaks, each selected from the group consisting of about 23.6 20, about 10.9 20, about 16.9 20, about 15.1 20, about 26.1 20, about 12.9 20, and about 19.4 20.

71. The compound of claim 65, wherein the solid form has a X-ray powder diffraction pattern comprising at least six peaks, each selected from the group consisting of about 23.6 20, about 10.9 20, about 16.9 20, about 15.1 29, about 26.1 20, about 12.9 20, and about 19.4 29.

72. The compound of claim 65, wherein the solid form has a X-ray powder diffraction pattern comprising peaks at about 23.6 20, about 10.9 20, about 16.9 20, about 15.1 20, about 26.1 20, about 12.9 20, and about 19.420.

73. The compound of claim 65, wherein the solid form has a X-ray powder diffraction pattern comprising at least three peaks, in degrees 29, selected from the group consisting of the peaks listed in Table 1.5.

74. The compound of claim 65, wherein the solid form has a X-ray powder diffraction pattern comprising at least four peaks, in degrees 20, selected from the group consisting of the peaks listed in Table 1.5.

75. The compound of claim 65, wherein the solid form has a X-ray powder diffraction pattern comprising at least five peaks, in degrees 20, selected from the group consisting of the peaks listed in Table 1.5.

76. The compound of claim 65, wherein the solid form has a X-ray powder diffraction pattern comprising at least six peaks, in degrees 20, selected from the group consisting of the peaks listed in Table 1.5.

77. The compound of claim 65, wherein the solid form has a X-ray powder diffraction pattern comprising at least seven peaks, in degrees 20, selected from the group consisting of the peaks listed in Table 1.5.

78. The compound of claim 65, wherein the solid form has a X-Ray powder diffraction pattern substantially similar to that depicted in FIG. 5.

79. A pharmaceutical composition comprising a compound of any one of claims 1-78, and a pharmaceutically acceptable carrier.

80. A method of inhibiting PI3Ka activity' in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of any of claims 1-78. or a pharmaceutical composition of claim 79, to the subject.

81. A method of treating a cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of any one of claims 1-78, or a pharmaceutical composition of claim 79, to the subject.Ill82. The method of claim 80 or 81, further comprising administering a therapeutically effective amount of an antibody, an antibody-drug conjugate, a kinase inhibitor, an immunomodulator, or ahistone deacetylase inhibitor.

83. A kit comprising a compound of any of claims 1-78.

84. The kit of claim 83, further comprising written instructions describing preparation of a pharmaceutical composition suitable for administration to a patient from the solid form or compound.

85. The kit of claim 83 or 84, further comprising written instructions describing how to administer the resulting composition to the patient.

86. The kit of any one of claims 83-85, further comprising a pharmaceutically acceptable excipient.

87. A process for preparing a crystalline form of Compound I, comprising: (a) preparing a solution of Compound I; (b) adjusting the temperature so that solid crystalline form of Compound I precipitates out of the solution; and (c) isolating the solid crystalline form.

88. A process for preparing a crystalline form of a Compound I, comprising: (a) preparing a solution of a Compound I in a solvent; (b) adjusting the temperature; (c) adding heptane to the solution; and (d) isolating the solid crystalline form.

89. A process for preparing a crystalline form of Compound II, comprising: (a) preparing a solution of a Compound II; (b) adjusting the temperature so that solid cry stalline form of Compound II precipitates out of the solution; and (c) isolating the solid crystalline form.

90. A process for preparing a crystalline form of a Compound II, comprising: (a) preparing a solution of a Compound II in a solvent; (b) adjusting the temperature; (c) adding heptane to the solution; and (d) isolating the solid crystalline form.

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