PI3K-alpha inhibitors, methods for their preparation and use

Abstract

The present disclosure relates to PI3Ka inhibitors, their crystalline forms, salts and co-crystals, as well as compositions, methods of preparation and methods of use thereof.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 263,474, filed November 3, 2021, and International (PCT) Patent Application No. PCT / CN2021 / 128533, filed November 3, 2021, each of which is incorporated by reference herein in its entirety. [Background technology]

[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 generate phosphoinositol-3-phosphate (PIP), phosphoinositol-3,4-bisphosphate (PIP2), and phosphoinositol-3,4,5-triphosphate (PIP3), which subsequently function as second messengers in signal transduction cascades by docking pleckstrin homology, FYVE, Phox, and other phospholipid-binding domain-containing proteins into various 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 subclasses, class 1A PI3Ks are heterodimers composed of a catalytic p110 subunit (alpha, beta, or delta isoform) constitutively bound to a regulatory subunit, which can be p85alpha, p55alpha, p50alpha, p85beta, or p55gamma. The class 1B subclass has one family member, a heterodimer composed of a catalytic p110gamma subunit bound to one of two regulatory subunits, p101 or p84 (Fruman et al., Annu Rev. Biochem. 67:481 (1998); Suire et al., Curr. Biol. 15:566 (2005)). The modular domain of the p85 / 55 / 50 subunit contains an Src homology (SH2) domain that binds to phosphotyrosine residues in specific sequence context on activated receptors and cytoplasmic tyrosine kinases, resulting in the activation and localization of class 1A PI3Ks. Class 1B PI3Ks are directly activated 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] As a result, the phospholipid products of class I PI3Ks link upstream receptors to downstream cellular activities including proliferation, survival, chemotaxis, cell trafficking, motility, metabolism, inflammatory and allergic responses, transcription, and translation (Cantley et al., Cell 64:281 (1991); Escobedo and Williams, Nature 335:85 (1988); Fantl et al., Cell 69:413 (1992)). In many cases, PIP2 and PIP3 recruit Aid, the product of the human homolog of the viral oncogene v-Akt, to the plasma membrane, where it functions as a nodal point for many intracellular signaling pathways important for growth and survival (Fantl et al., Cell 69:413-423 (1992); Bader et al., Nature Rev. Cancer 5:921 (2005); Vivanco and Sawyer, Nature Rev. Cancer 2:489 (2002)).

[0004] Dysregulation of PI3K, often through activation of Aid, enhances survival, and is one of the most common events in human cancers, occurring at multiple levels. The tumor suppressor gene PTEN, which dephosphorylates phosphoinositides at the 3' position of the inositol ring, thereby antagonizing PI3K activity, is functionally deleted in a variety of tumors. In other tumors, the p110 alpha isoform, PIK3CA, and Akt genes are amplified, and increased protein expression of their gene products has been demonstrated in several human cancers. Furthermore, mutations and translocations of p85 alpha, which contribute to the upregulation of the p85-p110 complex, have been reported in human cancers. Finally, somatic missense mutations in PIK3CA that activate downstream signaling pathways have been reported with considerable frequency in various human cancers (Kang et al., Proc. Natl. Acad. Sci. USA 102:802 (2005); Samuels et al., Science 304:554 (2004); Samuels et al., Cancer Cell 7:561-573 (2005)). These observations indicate that dysregulation of phosphoinositol-3 kinase and the upstream and downstream components of this signaling pathway is one of the most common dysregulations associated with human cancer and proliferative diseases (Parsons et al., Nature 436:792 (2005); Hennessey et al., Nature Rev. Drug Disc. 4:988-1004 (2005)). Given the above, inhibitors of PI3Kα may be particularly valuable in the treatment of proliferative diseases and other disorders. While several PI3K inhibitors (e.g., taselisib, alpelisib, buparlisib, etc.) have been developed, these molecules inhibit multiple class 1A PI3K isoforms. Inhibitors that exhibit activity against multiple class 1A PI3K isoforms are known as "pan-PI3K" inhibitors. A major obstacle in the clinical development of conventional PI3K inhibitors is their 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, such as diarrhea, rash, fatigue, and hyperglycemia. The toxicity of PI3K inhibitors depends on their isoform selectivity profile. Inhibition of PI3Kα is associated with hyperglycemia and rash, while inhibition of PI3Kδ or PI3Kγ is associated with diarrhea, bone marrow suppression, and hypertransaminasemia (Hanker et al., Cancer Discovery (2019) PMID: 30837161). Therefore, selective inhibitors of PI3Kα may enable sufficient target inhibition within tumors and expand the therapeutic window while avoiding dose-limiting toxicities in cancer patients. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Vanhaesebroeck et al., Annu.Rev.Biochem 70:535(2001) [Non-patent document 2] Katso et al., Annu.Rev.Cell Dev.Biol.17:615(2001) [Non-patent document 3] Fruman et al., Annu Rev.Biochem.67:481(1998) [Non-patent document 4] Suire et al.,Curr.Biol.15:566(2005) [Non-patent document 5] Stephens et al., Cell 89:105(1997)

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Summary of the Invention

[0006] The present disclosure is generally directed to compounds of Formulas I-III and solvates thereof, as well as crystalline forms thereof.

[0007] In some embodiments, the present disclosure provides a compound of formula (I): [ka] or a solvate thereof, wherein each of X, m, and n is independently as defined and described in embodiments herein. In some embodiments, the compound of Formula (I) or the solvate thereof is in a crystalline form described herein.

[0008] In another aspect, the present specification provides a compound of formula (II): [ka] or a solvate thereof, wherein each of X, p, and q is independently as defined and described in embodiments herein. In some embodiments, the compound of Formula (II) or the solvate thereof is in a crystalline form described herein.

[0009] In another aspect, the present specification provides a compound of formula (III): [ka] or a solvate thereof, wherein each of X, r, and s is independently as defined and described in embodiments herein. In some embodiments, the compound of Formula (III) or the solvate thereof is in a crystalline form described herein.

[0010] In one aspect, the present disclosure provides a compound of formula (IV-1): [ka] or a pharmaceutically acceptable salt thereof.

[0011] In another aspect, the present specification provides a compound of formula (IV-2): [ka] or a pharmaceutically acceptable salt thereof.

[0012] In another aspect, the present disclosure provides a method comprising deuteration of compound III-1, followed by a purification step to separate the enantiomers, to form compounds IV-1 and IV-2; [ka] For example, as described in Example 3-A.

[0013] In another aspect, the present disclosure provides a method for SMB separation of compound III-1, thereby preparing compounds I-1 and II-1, [ka] For example, as described in Example 1-A.

[0014] In another aspect, the present disclosure provides a method for preparing compound III-1 by racemization of compound II-1, [ka] For example, as described in Example 2-A.

[0015] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, a solvate thereof, or a crystalline form thereof, and a pharmaceutically acceptable excipient. In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0016] In another aspect, the present specification provides methods of using the compounds described herein or solvates or crystalline forms thereof, or pharmaceutical compositions thereof, for inhibiting PI3K alpha activity and treating the disorders, diseases, and / or conditions described herein. In another aspect, the present specification provides methods of using the compounds described herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for inhibiting PI3K alpha activity and treating the disorders, diseases, and / or conditions described herein. [Brief explanation of the drawings]

[0017] [Figure 1A] 1 shows the XRPD pattern of I-1 Form A.

[0018] [Figure 1B] Figure 1 shows the DSC thermogram of I-1 Form A (heating rate: 10°C / min).

[0019] [Figure 1C] Figure 1 shows the DSC thermogram of I-1 Form A (heating rate: 2°C / min).

[0020] [Figure 1D] Figure 1 shows the DSC thermogram of I-1 Form A (heating rate: 2°C / min).

[0021] [Figure 1E] 1 shows the TGA thermogram of I-1 Form A.

[0022] [Figure 2A] 1 shows the XRPD pattern of I-1 form B.

[0023] [Figure 2B] 1 shows the DSC thermogram of I-1 Form B.

[0024] [Figure 2C] 1 shows the TGA thermogram of I-1 Form B.

[0025] [Figure 3A] 1 shows the XRPD pattern of I-1 form C.

[0026] [Figure 3B] 1 shows the DSC thermogram of I-1 Form C.

[0027] [Figure 3C] 1 shows the TGA thermogram of I-1 Form C.

[0028] [Figure 4A] 1 shows the XRPD pattern of III-1 Form A.

[0029] [Figure 4B] 1 shows the DSC thermogram of III-1 Form A.

[0030] [Figure 4C] 1 shows the TGA thermogram of III-1 Form A.

[0031] [Figure 5A] 1 shows the XRPD pattern of III-1 Form B.

[0032] [Figure 5B] 1 shows the DSC thermogram of III-1 Form B.

[0033] [Figure 6A] 1 shows the XRPD pattern of III-1 Form C.

[0034] [Figure 6B] 1 shows the DSC thermogram of III-1 Form C.

[0035] [Figure 6C] 1 shows the TGA thermogram of III-1 Form C.

[0036] [Figure 7A]1 shows the XRPD pattern of III-1 Form D.

[0037] [Figure 7B] 1 shows the DSC thermogram of III-1 Form D.

[0038] [Figure 7C] 1 shows the TGA thermogram of III-1 Form D.

[0039] [Figure 8] 1 shows the XRPD pattern of III-1 form E.

[0040] [Figure 9A] 1 shows the XRPD pattern of III-1 Form F.

[0041] [Figure 9B] 1 shows the DSC thermogram of III-1 Form F.

[0042] [Figure 10] 1 shows the XRPD pattern of II-1 Form A.

[0043] [Figure 11] 1 shows the XRPD pattern of II-1 Form B.

[0044] [Figure 12] 1 shows the XRPD pattern of II-1 Form C.

[0045] [Figure 13] 1 shows an XRPD overlay of solids obtained from a competition equilibrium experiment at 25° C. using I-1 Form A and Form C. The patterns, from top to bottom, are compound I-1 Form A in EA / heptane, compound I-1 Form A in MeOH / DCM, compound I-1 Form A in THF / MTBE, compound I-1 Form A in THF / heptane, compound I-1 Form C, and compound I-1 Form A.

[0046] [Figure 14]Figure 1 shows an XRPD overlay of the solid obtained from CE1-THF / heptane (2:3, v / v) at 25°C with I-1 Form A and Form C. The patterns are, from top to bottom, compound I-1 Form A, compound I-1 Form C, and compound I-1 Form A in THF / heptane.

[0047] [Figure 15] Figure 1 shows an XRPD overlay of the solid obtained from CE2-THF / MTBE (1:4, v / v) at 25°C with Forms A and C. The patterns, from top to bottom, are Compound I-1 Form A, Compound I-1 Form C, and Compound I-1 Form A in THF / MTBE.

[0048] [Figure 16] Figure 1 shows an XRPD overlay of the solid obtained from CE3-MeOH / DCM (1:2, v / v) at 25°C with Forms A and C. The patterns, from top to bottom, are Compound I-1 Form A, Compound I-1 Form C, and Compound I-1 Form A in MeOH / DCM.

[0049] [Figure 17] Figure 1 shows an XRPD overlay of the solid obtained from CE4-EA / heptane (1:1, v / v) at 25°C with Forms A and C. The patterns, from top to bottom, are Compound I-1 Form A, Compound I-1 Form C, and Compound I-1 Form A in EA / heptane.

[0050] [Figure 18] Figure 1 shows an XRPD overlay of the solids obtained from CE5-MeOH / DCM (1:2, v / v) at 25°C and CE3-MeOH / DCM (1:2, v / v) at 25°C.

[0051] [Figure 19]Figure 1 shows an XRPD overlay of solids obtained from a competition experiment of CE6, CE7, and CE8 at 25°C. The patterns, from top to bottom, are compound I-1 form A in THF / ACN, compound I-1 form A in THF / MTBE, compound I-1 form A in 1,4-dioxane, compound I-1 form C, and compound I-1 form A.

[0052] [Figure 20] 1 shows an XRPD overlay of solids obtained from a behavior under compression experiment. The patterns are, from top to bottom, I-1 Form A and I-1 Form A compressed at 10 MPa, 5 MPa, and 2 MPa for 5 minutes.

[0053] [Figure 21] Figure 1 shows an XRPD overlay of solids obtained from a simulated grinding experiment. The patterns are, from top to bottom, I-1 Form A and I-1 Form A manually ground using a mortar and pestle for 5, 3, and 1 minutes.

[0054] [Figure 22] 1 shows an XRPD overlay of solids obtained from a simulated granulation experiment.

[0055] [Figure 23] Figure 1 shows an XRPD overlay of Form A after heating to different temperatures at 2°C / min by DSC. The patterns are, from top to bottom, Form A heated at 300°C, 270°C, and 260°C, and I-1 Form A.

[0056] [Figure 24] Figure 1 shows a DSC overlay of Form A after heating to different temperatures at 2°C / min by DSC. From top to bottom, the patterns are Form A heated at 260°C, 270°C, and 300°C.

[0057] [Figure 25] Figure 1 shows an XRPD overlay of Form A heated by DSC at 2°C / min to 260°C. The patterns are, from top to bottom, Form A after heating, and I-1 Form A.

[0058] [Figure 26] Figure 1 shows an XRPD overlay of Form A heated by DSC at 2°C / min to 260°C and 270°C. From top to bottom, the patterns are Form A heated to 270°C and 260°C, and I-1 Form A.

[0059] [Figure 27A] 1 shows the XRPD pattern of I-2 Form A.

[0060] [Figure 27B] 1 shows the DSC thermogram of I-2 Form A.

[0061] [Figure 27C] 1 shows the TGA thermogram of I-2 Form A.

[0062] [Figure 28] 1 shows the XRPD pattern of II-2 Form A.

[0063] [Figure 29A] 1 shows the XRPD pattern of III-2 Form A.

[0064] [Figure 29B] 1 shows the DSC thermogram of III-2 Form A.

[0065] [Figure 29C] 1 shows the TGA thermogram of III-2 Form A.

[0066] [Figure 30A] 1 shows the XRPD pattern of I-3 Form A.

[0067] [Figure 30B] 1 shows the DSC thermogram of I-3 Form A.

[0068] [Figure 30C] 1 shows the TGA thermogram of I-3 Form A.

[0069] [Figure 31A] 1 shows the XRPD pattern of I-4 Form A.

[0070] [Figure 31B] 1 shows the DSC thermogram of I-4 Form A.

[0071] [Figure 31C] 1 shows the TGA thermogram of I-4 Form A.

[0072] [Figure 32A] 1 shows the XRPD pattern of I-5 Form A.

[0073] [Figure 32B] 1 shows the DSC thermogram of I-5 Form A.

[0074] [Figure 32C] 1 shows the DSC thermogram of I-5 Form A.

[0075] [Figure 32D] 1 shows the TGA thermogram of I-5 Form A.

[0076] [Figure 33] 1 shows the XRPD pattern of I-5 form B.

[0077] [Figure 34A] 1 shows the XRPD pattern of III-6 Form A.

[0078] [Figure 34B] 1 shows the DSC thermogram of III-6 Form A.

[0079] [Figure 34C] 1 shows the DSC thermogram of III-6 Form A.

[0080] [Figure 35A]1 shows an XRPD overlay of a sample from a VH-XRPD experiment of I-3 Form A.

[0081] [Figure 35B] 1 shows an XRPD overlay of samples from a VH-XRPD experiment of I-3 Form B and I-3 Form A.

[0082] [Figure 35C] 1 shows XRPD overlays of I-3 Form A after one week in different humidity chambers.

[0083] [Figure 35D] 1 shows a VH-XRPD experiment of I-3 Form A and XRPD overlays of the solid from different humidity chambers. DETAILED DESCRIPTION OF THE INVENTION

[0084] General Description of Certain Embodiments of the Invention formula [ka] are PI3K alpha inhibitors and are found to be useful in treating disorders, diseases, and / or conditions, such as the "PI3K alpha-mediated" disorders, diseases, and / or conditions described herein. It would be desirable to provide solid forms of the compounds (e.g., as free bases, salts, or solvates) that offer properties such as improved aqueous solubility, stability, and ease of formulation. It would be desirable to provide deuterated analogs of the compounds that offer properties such as improved aqueous solubility, stability, and ease of formulation.

[0085] Compounds of formula (I) In some embodiments, the present disclosure provides a compound of formula (I): [ka] or a solvate thereof, During the ceremony, m is 1, 2, 3, 4, 5, 6, 7, 8, or 9; n is 0, 0.5, 1, 1.5, 2, 2.5, or 3, and X is hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, or 2-naphthalenesulfonic acid.

[0086] Those skilled in the art will understand that the acid moiety designated as "X" and (R)-N-(3-(2-chloro-5-fluorophenyl)-6-(5-cyano-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide are ionically bonded to form the compound of formula (I). It will also be understood that when n is 0, X is absent, indicating that the compound of formula (I) exists as the "free base," i.e., in the "free form."

[0087] It is believed that the compound of formula (I) can exist in various physical forms.For example, the compound of formula (I) can be a solution, a suspension, or a solid.In certain embodiments, the compound of formula (I) is a solid.When the compound of formula (I) is a solid, the compound can be amorphous, crystalline, or a mixture thereof.Exemplary solid forms will be described in more detail below.

[0088] In some embodiments, the compound of formula (I) is anhydrous. In some embodiments, the compound of formula (I) may be in the form of a hydrate. In some embodiments, the compound of formula (I) may be in the form of a hemihydrate.

[0089] In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9.

[0090] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 0.5. In some embodiments, n is 1.5. In some embodiments, n is 2.5.

[0091] In some embodiments, X is hydrochloric acid. In some embodiments, X is p-toluenesulfonic acid. In some embodiments, X is methanesulfonic acid. In some embodiments, X is naphthalene-1,5-disulfonic acid. In some embodiments, X is 2-naphthalenesulfonic acid.

[0092] In some embodiments, the present invention provides Compound I in a form that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include different forms of Compound I, residual solvents, or other impurities that may result from the preparation and / or isolation of Compound I.

[0093] In some embodiments, the compound of Formula (I), its solvate, or crystalline form 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, or 99.9% by weight, where percentages are based on the total weight of the composition. In some embodiments, the compound of Formula (I), its solvate, or crystalline form thereof contains no more than about 0.40% by weight, no more than about 0.35% by weight, no more than about 0.3% by weight, no more than about 0.25% by weight, no more than about 0.2% by weight, no more than about 0.15% by weight, no more than about 0.10% by weight, or no more than about 0.05% by weight of any single impurity, where percentages are based on the total weight of the composition. In some embodiments, the impurities are selected from those described in the Examples herein.

[0094] In some embodiments, the compound of Formula (I), its solvate, or crystalline form 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, or 99.9 area % by HPLC based on the total area of ​​the HPLC chromatogram. In some embodiments, the compound of Formula (I), its solvate, or crystalline form thereof contains any single impurity at an HPLC area % of about 0.4 or less, about 0.35 or less, about 0.3 or less, about 0.25 or less, about 0.2 or less, about 0.15 or less, about 0.10 or less, or about 0.05 or less based on the total area of ​​the HPLC chromatogram. In some embodiments, the impurities are selected from those described in the Examples herein. In some embodiments, the HPLC method is selected from the HPLC method described in the Examples herein.

[0095] The depicted structures for the compounds of Formula (I) are also meant to include all tautomeric forms. Additionally, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacing a hydrogen with deuterium or tritium, or replacing a carbon with 13 C or 14 Compounds having the present structure except for the substitution at a C-rich carbon are within the scope of this invention.

[0096] Compound I-1 In some embodiments, the compound of formula (I) is compound I-1, which is the free base (or "free form"), [ka] or a solvate thereof.

[0097] In some embodiments, compound I-1 is an amorphous solid. In some embodiments, compound I-1 is a crystalline solid. In some embodiments, compound I-1 is a mixture of an amorphous solid and a crystalline solid.

[0098] In some embodiments, the present invention provides compound I-1 in a form that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include different forms of compound I-1, residual solvents, or other impurities that may result from the preparation and / or isolation of compound I-1.

[0099] In some embodiments, compound I-1, its solvate, or its crystalline form 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, or 99.9% by weight, where percentages are based on the total weight of the composition. In some embodiments, compound I-1, its solvate, or its crystalline form contains no more than about 0.40% by weight, no more than about 0.35% by weight, no more than about 0.3% by weight, no more than about 0.25% by weight, no more than about 0.2% by weight, no more than about 0.15% by weight, no more than about 0.10% by weight, or no more than about 0.05% by weight of any single impurity, where percentages are based on the total weight of the composition. In some embodiments, the impurities are selected from those described in the Examples herein.

[0100] In some embodiments, compound I-1, its solvates, or crystalline forms 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, or 99.9 area % by HPLC relative to the total area of ​​the HPLC chromatogram. In some embodiments, compound I-1, its solvates, or crystalline forms thereof contains any single impurity at an HPLC area % of about 0.4 or less, about 0.35 or less, about 0.3 or less, about 0.25 or less, about 0.2 or less, about 0.15 or less, about 0.10 or less, or about 0.05 or less relative to the total area of ​​the HPLC chromatogram. In some embodiments, the impurities are selected from those described in the Examples herein. In some embodiments, the HPLC method is selected from the HPLC methods described in the Examples herein.

[0101] The structure shown for compound I-1 is also meant to include all tautomeric forms of compound I-1. Additionally, the structures shown herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacing a hydrogen with deuterium or tritium, or replacing a carbon with 13 C or 14 Compounds having the present structure except for the substitution at a C-rich carbon are within the scope of this invention.

[0102] In another embodiment, compound I-1 is a crystalline solid that is substantially free of amorphous compound I-1. As used herein, the term "substantially free of amorphous compound I-1" means that the compound does not contain a significant amount of amorphous compound I-1. In certain embodiments, at least about 95% by weight of crystalline compound I-1 is present. In certain embodiments, at least about 99% by weight of crystalline compound I-1 is present.

[0103] It has been found that compound I-1 can exist in various solid forms. Exemplary such forms include the polymorphs described herein.

[0104] In some embodiments, the solid crystalline form of compound I-1 is Form A. In some embodiments, Form A of compound I-1 can be characterized by an X-ray powder diffraction pattern having at least two characteristic peaks at 2θ degrees selected from the group consisting of about 12.0 2θ, about 6.5 2θ, and about 19.5 2θ. In some embodiments, Form A of compound I-1 can be characterized by an X-ray powder diffraction pattern having at least two characteristic peaks at 2θ degrees selected from the group consisting of about 12.0 2θ, about 6.5 2θ, about 19.5 2θ, about 24.6 2θ, about 18.4 2θ, about 24.1 2θ, and about 22.1 2θ. In some embodiments, Form A of compound I-1 can be characterized by an X-ray powder diffraction pattern having at least three characteristic peaks at degrees 2θ selected from the group consisting of about 12.0 2θ, about 6.5 2θ, about 19.5 2θ, about 24.6 2θ, about 18.4 2θ, about 24.1 2θ, and about 22.1 2θ. In some embodiments, Form A of compound I-1 can be characterized by an X-ray powder diffraction pattern having at least four characteristic peaks at degrees 2θ selected from the group consisting of about 12.0 2θ, about 6.5 2θ, about 19.5 2θ, about 24.6 2θ, about 18.4 2θ, about 24.1 2θ, and about 22.1 2θ. In some embodiments, Form A of compound I-1 can be characterized by an X-ray powder diffraction pattern having at least five characteristic peaks at degrees 2θ selected from the group consisting of about 12.0 2θ, about 6.5 2θ, about 19.5 2θ, about 24.6 2θ, about 18.4 2θ, about 24.1 2θ, and about 22.1 2θ. In some embodiments, Form A of compound I-1 can be characterized by an X-ray powder diffraction pattern having at least six characteristic peaks at degrees 2θ selected from the group consisting of about 12.0 2θ, about 6.5 2θ, about 19.5 2θ, about 24.6 2θ, about 18.4 2θ, about 24.1 2θ, and about 22.1 2θ. In some embodiments, Form A of compound I-1 can be characterized by a powder X-ray diffraction pattern including characteristic peaks at about 12.0 2θ, about 6.5 2θ, about 19.5 2θ, about 24.6 2θ, about 18.4 2θ, about 24.1 2θ, and about 22.1 2θ.In some embodiments, Form A of compound I-1 has an X-ray diffraction pattern substantially similar to that shown in FIG. 1A. In some embodiments, Form A of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks, each at 2θ degrees, selected from the group consisting of the peaks listed in Table 1.1. In some embodiments, Form A of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks, each at 2θ degrees, selected from the group consisting of the peaks listed in Table 1.1. In some embodiments, Form A of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks, each at 2θ degrees, selected from the group consisting of the peaks listed in Table 1.1. In some embodiments, Form A of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks, each at 2θ degrees, selected from the group consisting of the peaks listed in Table 1.1. In some embodiments, Form A of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks, each at 2θ degrees, selected from the group consisting of the peaks listed in Table 1.1. In some embodiments, Form A of compound I-1 can be characterized by a powder X-ray diffraction pattern having at least seven characteristic peaks at degrees 2θ, each selected from the group consisting of the peaks listed in Table 1.1. [Table 1-1] [Table 1-2]

[0105] As used herein, the term "about" in the context of a peak in degrees 2θ means that the peak can be at a given 2θ value ±0.2, or at a given 2θ value ±0.1, or at the given value. For example, a peak at "about 12.0 2θ" means that the peak can be at 11.8 2θ, 11.9 2θ, 12.0 2θ, 12.1 2θ, or 12.2 2θ.

[0106] In some embodiments, Form A of compound I-1 has a differential scanning calorimetry (DSC) pattern substantially similar to that shown in Figure IB. In some embodiments, Form A of compound I-1 has a differential scanning calorimetry (DSC) pattern substantially similar to that shown in Figure 1C. In some embodiments, Form A of compound I-1 has a differential scanning calorimetry (DSC) pattern substantially similar to that shown in Figure ID. In some embodiments, Form A of compound I-1 has a thermogravimetric analysis (TGA) pattern substantially similar to that shown in Figure IE. In some embodiments, Form A of compound I-1 may be characterized by substantially similar patterns to two or more of these patterns simultaneously.

[0107] In some embodiments, the solid crystalline form of compound I-1 is Form B. In some embodiments, Form B of compound I-1 can be characterized by an X-ray powder diffraction pattern having at least two characteristic peaks at 2θ degrees selected from the group consisting of about 6.6 2θ, about 12.2 2θ, and about 15.0 2θ, respectively. In some embodiments, Form B of compound I-1 can be characterized by an X-ray powder diffraction pattern having at least two characteristic peaks at 2θ degrees selected from the group consisting of about 6.6 2θ, about 12.2 2θ, about 15.0 2θ, about 9.6 2θ, about 19.0 2θ, about 12.4 2θ, and about 24.6 2θ, respectively. In some embodiments, Form B of compound I-1 can be characterized by an X-ray powder diffraction pattern having at least three characteristic peaks at 2θ degrees selected from the group consisting of about 6.6 2θ, about 12.2 2θ, about 15.0 2θ, about 9.6 2θ, about 19.0 2θ, about 12.4 2θ, and about 24.6 2θ. In some embodiments, Form B of compound I-1 can be characterized by an X-ray powder diffraction pattern having at least four characteristic peaks at 2θ degrees selected from the group consisting of about 6.6 2θ, about 12.2 2θ, about 15.0 2θ, about 9.6 2θ, about 19.0 2θ, about 12.4 2θ, and about 24.6 2θ. In some embodiments, Form B of compound I-1 can be characterized by an X-ray powder diffraction pattern having at least five characteristic peaks at 2θ degrees selected from the group consisting of about 6.6 2θ, about 12.2 2θ, about 15.0 2θ, about 9.6 2θ, about 19.0 2θ, about 12.4 2θ, and about 24.6 2θ. In some embodiments, Form B of compound I-1 can be characterized by an X-ray powder diffraction pattern having at least six characteristic peaks at 2θ degrees selected from the group consisting of about 6.6 2θ, about 12.2 2θ, about 15.0 2θ, about 9.6 2θ, about 19.0 2θ, about 12.4 2θ, and about 24.6 2θ. In some embodiments, Form B of compound I-1 can be characterized by a powder X-ray diffraction pattern comprising characteristic peaks at about 6.6 2θ, about 12.2 2θ, about 15.0 2θ, about 9.6 2θ, about 19.0 2θ, about 12.4 2θ, and about 24.6 2θ.In some embodiments, Form B of compound I-1 has an X-ray diffraction pattern substantially similar to that shown in FIG. 2A. In some embodiments, Form B of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks, each at 2θ degrees, selected from the group consisting of the peaks listed in Table 1.2. In some embodiments, Form B of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks, each at 2θ degrees, selected from the group consisting of the peaks listed in Table 1.2. In some embodiments, Form B of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks, each at 2θ degrees, selected from the group consisting of the peaks listed in Table 1.2. In some embodiments, Form B of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks, each at 2θ degrees, selected from the group consisting of the peaks listed in Table 1.2. In some embodiments, Form B of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks, each at 2θ degrees, selected from the group consisting of the peaks listed in Table 1.2. In some embodiments, Form B of compound I-1 can be characterized by a powder X-ray diffraction pattern having at least seven characteristic peaks at degrees 2θ, each selected from the group consisting of the peaks listed in Table 1.2. [Table 2-1] [Table 2-2]

[0108] In some embodiments, Form B of compound I-1 has a differential scanning calorimetry (DSC) pattern substantially similar to that shown in Figure 2B. In some embodiments, Form B of compound I-1 has a thermogravimetric analysis (TGA) pattern substantially similar to that shown in Figure 2C. In some embodiments, Form B of compound I-1 may be characterized by substantially similar patterns to two or more of these patterns simultaneously.

[0109] In some embodiments, the solid crystalline form of compound I-1 is Form C. In some embodiments, Form C of compound I-1 can be characterized by an X-ray powder diffraction pattern having at least two characteristic peaks at 2θ degrees selected from the group consisting of about 12.1 2θ, about 6.6 2θ, and about 18.4 2θ. In some embodiments, Form C of compound I-1 can be characterized by an X-ray powder diffraction pattern having at least two characteristic peaks at 2θ degrees selected from the group consisting of about 12.1 2θ, about 6.6 2θ, about 18.4 2θ, about 19.5 2θ, about 24.7 2θ, about 14.9 2θ, and about 24.3 2θ. In some embodiments, Form C of compound I-1 can be characterized by an X-ray powder diffraction pattern having at least three characteristic peaks at 2θ degrees selected from the group consisting of about 12.1 2θ, about 6.6 2θ, about 18.4 2θ, about 19.5 2θ, about 24.7 2θ, about 14.9 2θ, and about 24.3 2θ. In some embodiments, Form C of compound I-1 can be characterized by an X-ray powder diffraction pattern having at least four characteristic peaks at 2θ degrees selected from the group consisting of about 12.1 2θ, about 6.6 2θ, about 18.4 2θ, about 19.5 2θ, about 24.7 2θ, about 14.9 2θ, and about 24.3 2θ. In some embodiments, Form C of compound I-1 can be characterized by an X-ray powder diffraction pattern having at least five characteristic peaks at 2θ degrees selected from the group consisting of about 12.1 2θ, about 6.6 2θ, about 18.4 2θ, about 19.5 2θ, about 24.7 2θ, about 14.9 2θ, and about 24.3 2θ. In some embodiments, Form C of compound I-1 can be characterized by an X-ray powder diffraction pattern having at least six characteristic peaks at 2θ degrees selected from the group consisting of about 12.1 2θ, about 6.6 2θ, about 18.4 2θ, about 19.5 2θ, about 24.7 2θ, about 14.9 2θ, and about 24.3 2θ. In some embodiments, Form C of compound I-1 can be characterized by a powder X-ray diffraction pattern comprising characteristic peaks at about 12.1 2θ, about 6.6 2θ, about 18.4 2θ, about 19.5 2θ, about 24.7 2θ, about 14.9 2θ, and about 24.3 2θ.In some embodiments, Form C of compound I-1 has an X-ray diffraction pattern substantially similar to that shown in FIG. 3A. In some embodiments, Form C of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks, each at 2θ degrees, selected from the group consisting of the peaks listed in Table 1.3. In some embodiments, Form C of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks, each at 2θ degrees, selected from the group consisting of the peaks listed in Table 1.3. In some embodiments, Form C of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks, each at 2θ degrees, selected from the group consisting of the peaks listed in Table 1.3. In some embodiments, Form C of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks, each at 2θ degrees, selected from the group consisting of the peaks listed in Table 1.3. In some embodiments, Form C of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks, each at 2θ degrees, selected from the group consisting of the peaks listed in Table 1.3. In some embodiments, Form C of compound I-1 can be characterized by a powder X-ray diffraction pattern having at least seven characteristic peaks at degrees 2θ, each selected from the group consisting of the peaks listed in Table 1.3. [Table 3-1] [Table 3-2]

[0110] In some embodiments, Form C of compound I-1 has a differential scanning calorimetry (DSC) pattern substantially similar to that shown in Figure 3B. In some embodiments, Form C of compound I-1 has a thermogravimetric analysis (TGA) pattern substantially similar to that shown in Figure 3C. In some embodiments, Form C of compound I-1 may be characterized by substantially similar patterns to two or more of these patterns simultaneously.

[0111] Compound I-2 In some embodiments, the compound of formula (I) is compound I-2, [ka] or a solvate thereof.

[0112] In some embodiments, compound I-2 is an anhydrous solid.

[0113] In some embodiments, compound I-2 is an amorphous solid. In other embodiments, compound I-2 is a crystalline solid. In some embodiments, compound I-2 is a mixture of an amorphous solid and a crystalline solid.

[0114] In some embodiments, the present invention provides compound I-2 in a form that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include different forms of compound I-2, residual solvents, or other impurities that may result from the preparation and / or isolation of compound I-2.

[0115] In some embodiments, compound I-2, its solvates, or crystalline forms 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, or 99.9% by weight, where percentages are based on the total weight of the composition. In some embodiments, compound I-2, its solvates, or crystalline forms thereof contains no more than about 0.40% by weight, no more than about 0.35% by weight, no more than about 0.3% by weight, no more than about 0.25% by weight, no more than about 0.2% by weight, no more than about 0.15% by weight, no more than about 0.10% by weight, or no more than about 0.05% by weight of any single impurity, where percentages are based on the total weight of the composition. In some embodiments, the impurities are selected from those described in the Examples herein.

[0116] In some embodiments, compound I-2, its solvates, or crystalline forms 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, or 99.9 area % by HPLC relative to the total area of ​​the HPLC chromatogram. In some embodiments, compound I-2, its solvates, or crystalline forms thereof contains any single impurity at an HPLC area % of about 0.4 or less, about 0.35 or less, about 0.3 or less, about 0.25 or less, about 0.2 or less, about 0.15 or less, about 0.10 or less, or about 0.05 or less relative to the total area of ​​the HPLC chromatogram. In some embodiments, the impurities are selected from those described in the Examples herein. In some embodiments, the HPLC method is selected from the HPLC methods described in the Examples herein.

[0117] The structure shown for compound I-2 is also meant to include all tautomeric forms of compound I-2. Additionally, the structures shown herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacing a hydrogen with deuterium or tritium, or replacing a carbon with 13 C or 14Compounds having the present structure except for the substitution at a C-rich carbon are within the scope of this invention.

[0118] In certain embodiments, compound I-2 is a crystalline solid. In another embodiment, compound I-2 is a crystalline solid that is substantially free of amorphous compound I-2. As used herein, the term "substantially free of amorphous compound I-2" means that the compound does not contain a significant amount of amorphous compound I-2. In certain embodiments, at least about 95% by weight of crystalline compound I-2 is present. In yet another embodiment of the present invention, at least about 99% by weight of crystalline compound I-2 is present.

[0119] It has been found that compound I-2 can exist in various solid forms. Exemplary such forms include the polymorphs described herein.

[0120] In some embodiments, the solid crystalline form of compound I-2 is Form A. In some embodiments, Form A of compound I-2 has an X-ray diffraction pattern substantially similar to that shown in Figure 27A.

[0121] In some embodiments, Form A of compound I-2 has a differential scanning calorimetry (DSC) pattern substantially similar to that shown in Figure 27B. In some embodiments, Form A of compound I-2 has a thermogravimetric analysis (TGA) pattern substantially similar to that shown in Figure 27C. In some embodiments, Form A of compound I-2 may be characterized by substantially similar patterns to two or more of these patterns simultaneously.

[0122] Compound I-3 In some embodiments, the compound of formula (I) is compound I-3, [ka] or a solvate thereof.

[0123] In some embodiments, compound I-3 is an anhydrous solid.

[0124] In some embodiments, compound I-3 is an amorphous solid. In other embodiments, compound I-3 is a crystalline solid. In some embodiments, compound I-3 is a mixture of an amorphous solid and a crystalline solid.

[0125] In some embodiments, the present invention provides compound I-3 in a form that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include different forms of compound I-3, residual solvents, or other impurities that may result from the preparation and / or isolation of compound I-3.

[0126] In some embodiments, compound I-3, its solvates, or crystalline forms 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, or 99.9% by weight, where percentages are based on the total weight of the composition. In some embodiments, compound I-3, its solvates, or crystalline forms thereof contains no more than about 0.40% by weight, no more than about 0.35% by weight, no more than about 0.3% by weight, no more than about 0.25% by weight, no more than about 0.2% by weight, no more than about 0.15% by weight, no more than about 0.10% by weight, or no more than about 0.05% by weight of any single impurity, where percentages are based on the total weight of the composition. In some embodiments, the impurities are selected from those described in the Examples herein.

[0127] In some embodiments, compound I-3, its solvates, or crystalline forms 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, or 99.9 area % by HPLC based on the total area of ​​the HPLC chromatogram. In some embodiments, compound I-3, its solvates, or crystalline forms thereof contains any single impurity at an HPLC area % of about 0.4 or less, about 0.35 or less, about 0.3 or less, about 0.25 or less, about 0.2 or less, about 0.15 or less, about 0.10 or less, or about 0.05 or less based on the total area of ​​the HPLC chromatogram. In some embodiments, the impurities are selected from those described in the Examples herein. In some embodiments, the HPLC method is selected from the HPLC methods described in the Examples herein.

[0128] The structure shown for compound I-3 is also meant to include all tautomeric forms of compound I-3. Additionally, the structures shown herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacing a hydrogen with deuterium or tritium, or replacing a carbon with 13 C or 14 Compounds having the present structure except for the substitution at a C-rich carbon are within the scope of this invention.

[0129] In certain embodiments, compound I-3 is a crystalline solid. In another embodiment, compound I-3 is a crystalline solid that is substantially free of amorphous compound I-3. As used herein, the term "substantially free of amorphous compound I-3" means that the compound does not contain a significant amount of amorphous compound I-3. In certain embodiments, at least about 95% by weight of crystalline compound I-3 is present. In yet another embodiment of the present invention, at least about 99% by weight of crystalline compound I-3 is present.

[0130] It has been found that compound I-3 can exist in various solid forms. Exemplary such forms include the polymorphs described herein.

[0131] In some embodiments, the solid crystalline form of compound I-3 is Form A. In some embodiments, Form A of compound I-3 has an X-ray diffraction pattern substantially similar to that shown in Figure 30A.

[0132] In some embodiments, Form A of compound I-3 has a differential scanning calorimetry (DSC) pattern substantially similar to that shown in Figure 30B. In some embodiments, Form A of compound I-3 has a thermogravimetric analysis (TGA) pattern substantially similar to that shown in Figure 30C. In some embodiments, Form A of compound I-3 may be characterized by substantially similar patterns in two or more of these figures simultaneously.

[0133] In some embodiments, the solid crystalline form of compound I-3 is Form B. In some embodiments, Form B of compound I-3 has an X-ray diffraction pattern substantially similar to that shown in Figure 35A. In some embodiments, Form B of compound I-3 has an X-ray diffraction pattern substantially similar to that shown in Figure 35B. In some embodiments, Form B of compound I-3 has an X-ray diffraction pattern substantially similar to that shown in Figure 35C. In some embodiments, Form B of compound I-3 has an X-ray diffraction pattern substantially similar to that shown in Figure 35D. In some embodiments, Form B of compound I-3 may be characterized by substantially similar patterns to two or more of these figures simultaneously.

[0134] Compound I-4 In some embodiments, the compound of formula (I) is compound I-4, [ka] or a solvate thereof.

[0135] In some embodiments, compound I-4 is an anhydrous solid.

[0136] In some embodiments, compound I-4 is an amorphous solid. In other embodiments, compound I-4 is a crystalline solid. In some embodiments, compound I-4 is a mixture of an amorphous solid and a crystalline solid.

[0137] In some embodiments, the present invention provides compound I-4 in a form that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include different forms of compound I-4, residual solvents, or other impurities that may result from the preparation and / or isolation of compound I-4.

[0138] In some embodiments, compound I-4, its solvates, or crystalline forms 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, or 99.9% by weight, where percentages are based on the total weight of the composition. In some embodiments, compound I-4, its solvates, or crystalline forms thereof contains no more than about 0.40% by weight, no more than about 0.35% by weight, no more than about 0.3% by weight, no more than about 0.25% by weight, no more than about 0.2% by weight, no more than about 0.15% by weight, no more than about 0.10% by weight, or no more than about 0.05% by weight of any single impurity, where percentages are based on the total weight of the composition. In some embodiments, the impurities are selected from those described in the Examples herein.

[0139] In some embodiments, compound I-4, its solvates, or crystalline forms 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, or 99.9 area % by HPLC relative to the total area of ​​the HPLC chromatogram. In some embodiments, compound I-4, its solvates, or crystalline forms thereof contains any single impurity at an HPLC area % of about 0.4 or less, about 0.35 or less, about 0.3 or less, about 0.25 or less, about 0.2 or less, about 0.15 or less, about 0.10 or less, or about 0.05 or less relative to the total area of ​​the HPLC chromatogram. In some embodiments, the impurities are selected from those described in the Examples herein. In some embodiments, the HPLC method is selected from the HPLC methods described in the Examples herein.

[0140] The structure shown for compound I-4 is also meant to include all tautomeric forms of compound I-4. Additionally, the structures shown herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacing a hydrogen with deuterium or tritium, or replacing a carbon with 13 C or 14 Compounds having the present structure except for the substitution at a C-rich carbon are within the scope of this invention.

[0141] In certain embodiments, compound I-4 is a crystalline solid. In another embodiment, compound I-4 is a crystalline solid that is substantially free of amorphous compound I-4. As used herein, the term "substantially free of amorphous compound I-4" means that the compound does not contain a significant amount of amorphous compound I-4. In certain embodiments, at least about 95% by weight of crystalline compound I-4 is present. In yet another embodiment of the present invention, at least about 99% by weight of crystalline compound I-4 is present.

[0142] It has been found that compound I-4 can exist in various solid forms. Exemplary such forms include the polymorphs described herein.

[0143] In some embodiments, the solid crystalline form of compound I-4 is Form A. In some embodiments, Form A of compound I-4 has an X-ray diffraction pattern substantially similar to that shown in Figure 31A.

[0144] In some embodiments, Form A of compound I-4 has a differential scanning calorimetry (DSC) pattern substantially similar to that shown in Figure 31B. In some embodiments, Form A of compound I-4 has a thermogravimetric analysis (TGA) pattern substantially similar to that shown in Figure 31C. In some embodiments, Form A of compound I-4 may be characterized by substantially similar patterns in two or more of these figures simultaneously.

[0145] Compound I-5 In some embodiments, the compound of formula (I) is compound I-5, [ka] or a solvate thereof.

[0146] In some embodiments, compound I-5 is an anhydrous solid.

[0147] In some embodiments, compound I-5 is an amorphous solid. In other embodiments, compound I-5 is a crystalline solid. In some embodiments, compound I-5 is a mixture of an amorphous solid and a crystalline solid.

[0148] In some embodiments, the present invention provides compound I-5 in a form that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include different forms of compound I-5, residual solvents, or other impurities that may result from the preparation and / or isolation of compound I-5.

[0149] In some embodiments, compound I-5, its solvates, or crystalline forms 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, or 99.9% by weight, where percentages are based on the total weight of the composition. In some embodiments, compound I-5, its solvates, or crystalline forms thereof contains no more than about 0.40% by weight, no more than about 0.35% by weight, no more than about 0.3% by weight, no more than about 0.25% by weight, no more than about 0.2% by weight, no more than about 0.15% by weight, no more than about 0.10% by weight, or no more than about 0.05% by weight of any single impurity, where percentages are based on the total weight of the composition. In some embodiments, the impurities are selected from those described in the Examples herein.

[0150] In some embodiments, compound I-5, its solvates, or crystalline forms 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, or 99.9 area % by HPLC relative to the total area of ​​the HPLC chromatogram. In some embodiments, compound I-5, its solvates, or crystalline forms thereof contains any single impurity at an HPLC area % of about 0.4 or less, about 0.35 or less, about 0.3 or less, about 0.25 or less, about 0.2 or less, about 0.15 or less, about 0.10 or less, or about 0.05 or less relative to the total area of ​​the HPLC chromatogram. In some embodiments, the impurities are selected from those described in the Examples herein. In some embodiments, the HPLC method is selected from the HPLC methods described in the Examples herein.

[0151] The structure shown for compound I-5 is also meant to include all tautomeric forms of compound I-5. Additionally, the structures shown herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacing a hydrogen with deuterium or tritium, or replacing a carbon with 13 C or 14Compounds having the present structure except for the substitution at a C-rich carbon are within the scope of this invention.

[0152] In certain embodiments, compound I-5 is a crystalline solid. In another embodiment, compound I-5 is a crystalline solid that is substantially free of amorphous compound I-5. As used herein, the term "substantially free of amorphous compound I-5" means that the compound does not contain a significant amount of amorphous compound I-5. In certain embodiments, at least about 95% by weight of crystalline compound I-5 is present. In yet another embodiment of the present invention, at least about 99% by weight of crystalline compound I-5 is present.

[0153] It has been found that compound I-5 can exist in various solid forms. Exemplary such forms include the polymorphs described herein.

[0154] In some embodiments, the solid crystalline form of compound I-5 is Form A. In some embodiments, Form A of compound I-5 has an X-ray diffraction pattern substantially similar to that shown in Figure 32A.

[0155] In some embodiments, Form A of compound I-5 has a differential scanning calorimetry (DSC) pattern substantially similar to that shown in Figure 32B. In some embodiments, Form A of compound I-5 has a differential scanning calorimetry (DSC) pattern substantially similar to that shown in Figure 32C. In some embodiments, Form A of compound I-5 has a thermogravimetric analysis (TGA) pattern substantially similar to that shown in Figure 32D. In some embodiments, Form A of compound I-5 may be characterized by substantially similar patterns to two or more of these figures simultaneously.

[0156] In some embodiments, the solid crystalline form of compound I-5 is Form B. In some embodiments, Form B of compound I-5 has an X-ray diffraction pattern substantially similar to that shown in FIG.

[0157] Compound I-6 In some embodiments, the compound of formula (I) is compound I-6, [ka] or a solvate thereof.

[0158] In some embodiments, compound I-6 is an anhydrous solid.

[0159] In some embodiments, compound I-6 is an amorphous solid. In other embodiments, compound I-6 is a crystalline solid. In some embodiments, compound I-6 is a mixture of an amorphous solid and a crystalline solid.

[0160] In some embodiments, the present invention provides compound I-6 in a form that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include different forms of compound I-6, residual solvents, or other impurities that may result from the preparation and / or isolation of compound I-6.

[0161] In some embodiments, compound I-6, its solvates, or crystalline forms 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, or 99.9% by weight, where percentages are based on the total weight of the composition. In some embodiments, compound I-6, its solvates, or crystalline forms thereof contains no more than about 0.40% by weight, no more than about 0.35% by weight, no more than about 0.3% by weight, no more than about 0.25% by weight, no more than about 0.2% by weight, no more than about 0.15% by weight, no more than about 0.10% by weight, or no more than about 0.05% by weight of any single impurity, where percentages are based on the total weight of the composition. In some embodiments, the impurities are selected from those described in the Examples herein.

[0162] In some embodiments, compound I-6, its solvates, or crystalline forms thereof are 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, or 99.9 area % by HPLC relative to the total area of ​​the HPLC chromatogram. In some embodiments, compound I-6, its solvates, or crystalline forms thereof contain any single impurity at an HPLC area % of about 0.4 or less, about 0.35 or less, about 0.3 or less, about 0.25 or less, about 0.2 or less, about 0.15 or less, about 0.10 or less, or about 0.05 or less relative to the total area of ​​the HPLC chromatogram. In some embodiments, the impurities are selected from those described in the Examples herein. In some embodiments, the HPLC method is selected from the HPLC methods described in the Examples herein.

[0163] The structure shown for compound I-6 is also meant to include all tautomeric forms of compound I-6. Additionally, the structures shown herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacing a hydrogen with deuterium or tritium, or replacing a carbon with 13 C or 14 Compounds having the present structure except for the substitution at a C-rich carbon are within the scope of this invention.

[0164] In certain embodiments, compound I-6 is a crystalline solid. In another embodiment, compound I-6 is a crystalline solid that is substantially free of amorphous compound I-6. As used herein, the term "substantially free of amorphous compound I-6" means that the compound does not contain a significant amount of amorphous compound I-6. In certain embodiments, at least about 95% by weight of crystalline compound I-6 is present. In yet another embodiment of the present invention, at least about 99% by weight of crystalline compound I-6 is present.

[0165] Compound of formula (II) In some embodiments, the present disclosure provides a compound of formula (II): [ka] or a solvate thereof, During the ceremony, p is 1, 2, 3, 4, 5, 6, 7, 8, or 9; q is 0, 0.5, 1, 1.5, 2, 2.5, or 3, and X is hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, or 2-naphthalenesulfonic acid.

[0166] Those skilled in the art will understand that the acid moiety designated "X" and (S)-N-(3-(2-chloro-5-fluorophenyl)-6-(5-cyano-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide are ionically bonded to form the compound of formula (II). It will also be understood that when q is 0, X is absent, indicating that the compound of formula (II) exists as a "free base," i.e., in the "free form."

[0167] It is believed that the compound of formula (II) can exist in various physical forms.For example, the compound of formula (II) can be a solution, a suspension, or a solid.In certain embodiments, the compound of formula (II) is a solid.When the compound of formula (II) is a solid, the compound can be amorphous, crystalline, or a mixture thereof.Exemplary solid forms will be described in more detail below.

[0168] In some embodiments, the compound of Formula (II) is anhydrous. In some embodiments, the compound of Formula (II) may be in the form of a hydrate. In some embodiments, the compound of Formula (II) may be in the form of a hemihydrate.

[0169] In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 6. In some embodiments, p is 7. In some embodiments, p is 8. In some embodiments, p is 9.

[0170] In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 0.5. In some embodiments, q is 1.5. In some embodiments, q is 2.5.

[0171] In some embodiments, X is hydrochloric acid. In some embodiments, X is p-toluenesulfonic acid. In some embodiments, X is methanesulfonic acid. In some embodiments, X is naphthalene-1,5-disulfonic acid. In some embodiments, X is 2-naphthalenesulfonic acid.

[0172] In some embodiments, the present invention provides Compound (II) in a form that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include different forms of Compound (II), residual solvents, or other impurities that may result from the preparation and / or isolation of Compound (II).

[0173] In some embodiments, the compound of Formula (II), its solvate, or crystalline form 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, or 99.9% by weight, where percentages are based on the total weight of the composition. In some embodiments, the compound of Formula (II), its solvate, or crystalline form thereof contains no more than about 0.40% by weight, no more than about 0.35% by weight, no more than about 0.3% by weight, no more than about 0.25% by weight, no more than about 0.2% by weight, no more than about 0.15% by weight, no more than about 0.10% by weight, or no more than about 0.05% by weight of any single impurity, where percentages are based on the total weight of the composition. In some embodiments, the impurities are selected from those described in the Examples herein.

[0174] In some embodiments, the compound of Formula (II), its solvate, or crystalline form 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, or 99.9 area % by HPLC based on the total area of ​​the HPLC chromatogram. In some embodiments, the compound of Formula (II), its solvate, or crystalline form thereof contains any single impurity at an HPLC area % of about 0.4 or less, about 0.35 or less, about 0.3 or less, about 0.25 or less, about 0.2 or less, about 0.15 or less, about 0.10 or less, or about 0.05 or less based on the total area of ​​the HPLC chromatogram. In some embodiments, the impurities are selected from those described in the Examples herein. In some embodiments, the HPLC method is selected from the HPLC method described in the Examples herein.

[0175] The depicted structures for compounds of formula (II) are also meant to include all tautomeric forms. Additionally, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacing a hydrogen with deuterium or tritium, or replacing a carbon with 13 C or 14Compounds having the present structure except for the substitution at a C-rich carbon are within the scope of this invention.

[0176] Compound II-1 In some embodiments, the compound of formula (II) is compound II-1 (which is the free base (or "free form")), [ka] or a solvate thereof.

[0177] In some embodiments, compound (II-1) is an amorphous solid. In some embodiments, compound (II-1) is a crystalline solid. In some embodiments, compound (II-1) is a mixture of an amorphous solid and a crystalline solid.

[0178] In some embodiments, the present invention provides compound II-1 in a form that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain a significant amount of contaminants. Such contaminants may include different forms of compound II-1, residual solvents, or other impurities that may result from the preparation and / or isolation of compound II-1.

[0179] In some embodiments, compound II-1, its solvate, or its crystalline form 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, or 99.9% by weight, where percentages are based on the total weight of the composition. In some embodiments, compound II-1, its solvate, or its crystalline form contains no more than about 0.40% by weight, no more than about 0.35% by weight, no more than about 0.3% by weight, no more than about 0.25% by weight, no more than about 0.2% by weight, no more than about 0.15% by weight, no more than about 0.10% by weight, or no more than about 0.05% by weight of any single impurity, where percentages are based on the total weight of the composition. In some embodiments, the impurities are selected from those described in the Examples herein.

[0180] In some embodiments, compound II-1, its solvates, or crystalline forms 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, or 99.9 area % by HPLC relative to the total area of ​​the HPLC chromatogram. In some embodiments, compound II-1, its solvates, or crystalline forms thereof contains any single impurity at an HPLC area % of about 0.4 or less, about 0.35 or less, about 0.3 or less, about 0.25 or less, about 0.2 or less, about 0.15 or less, about 0.10 or less, or about 0.05 or less relative to the total area of ​​the HPLC chromatogram. In some embodiments, the impurities are selected from those described in the Examples herein. In some embodiments, the HPLC method is selected from the HPLC methods described in the Examples herein.

[0181] The structure shown for compound II-1 is also meant to include all tautomeric forms of compound II-1. Additionally, the structures shown herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacing a hydrogen with deuterium or tritium, or replacing a carbon with 13 C or 14 Compounds having the present structure except for the substitution at a C-rich carbon are within the scope of this invention.

[0182] In another embodiment, compound (II-1) is a crystalline solid that is substantially free of amorphous compound (II-1). As used herein, the term "substantially free of amorphous compound (II-1)" means that the compound does not contain a significant amount of amorphous compound (II-1). In certain embodiments, at least about 95% by weight of crystalline compound (II-1) is present. In certain embodiments, at least about 99% by weight of crystalline compound (II-1) is present.

[0183] It has been found that Compound (II-1) can exist in various solid forms. Exemplary such forms include the polymorphs described herein.

[0184] In some embodiments, the solid crystalline form of compound (II-1) is Form A. In some embodiments, Form A of compound (II-1) has an X-ray diffraction pattern substantially similar to that shown in FIG.

[0185] In some embodiments, the solid crystalline form of compound (II-1) is Form B. In some embodiments, Form B of compound (II-1) has an X-ray diffraction pattern substantially similar to that shown in FIG.

[0186] In some embodiments, the solid crystalline form of compound (II-1) is Form C. In some embodiments, Form C of compound (II-1) has an X-ray diffraction pattern substantially similar to that shown in FIG.

[0187] Compound II-2 In some embodiments, the compound of formula (II) is compound II-2, [ka] or a solvate thereof.

[0188] In some embodiments, compound II-2 is an anhydrous solid.

[0189] In some embodiments, compound II-2 is an amorphous solid. In other embodiments, compound II-2 is a crystalline solid. In some embodiments, compound II-2 is a mixture of an amorphous solid and a crystalline solid.

[0190] In some embodiments, the present invention provides compound II-2 in a form that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include different forms of compound II-2, residual solvents, or other impurities that may result from the preparation and / or isolation of compound II-2.

[0191] In some embodiments, compound II-2, its solvate, or its crystalline form 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, or 99.9% by weight, where percentages are based on the total weight of the composition. In some embodiments, compound II-2, its solvate, or its crystalline form contains no more than about 0.40% by weight, no more than about 0.35% by weight, no more than about 0.3% by weight, no more than about 0.25% by weight, no more than about 0.2% by weight, no more than about 0.15% by weight, no more than about 0.10% by weight, or no more than about 0.05% by weight of any single impurity, where percentages are based on the total weight of the composition. In some embodiments, the impurities are selected from those described in the Examples herein.

[0192] In some embodiments, compound II-2, its solvates, or crystalline forms 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, or 99.9 area % by HPLC based on the total area of ​​the HPLC chromatogram. In some embodiments, compound II-2, its solvates, or crystalline forms thereof contains any single impurity at an HPLC area % of about 0.4 or less, about 0.35 or less, about 0.3 or less, about 0.25 or less, about 0.2 or less, about 0.15 or less, about 0.10 or less, or about 0.05 or less based on the total area of ​​the HPLC chromatogram. In some embodiments, the impurities are selected from those described in the Examples herein. In some embodiments, the HPLC method is selected from the HPLC methods described in the Examples herein.

[0193] The structure shown for compound II-2 is also meant to include all tautomeric forms of compound II-2. Additionally, the structures shown herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacing a hydrogen with deuterium or tritium, or replacing a carbon with 13 C or 14 Compounds having the present structure except for the substitution at a C-rich carbon are within the scope of this invention.

[0194] In certain embodiments, compound II-2 is a crystalline solid. In another embodiment, compound II-2 is a crystalline solid that is substantially free of amorphous compound II-2. As used herein, the term "substantially free of amorphous compound II-2" means that the compound does not contain a significant amount of amorphous compound II-2. In certain embodiments, at least about 95% by weight of crystalline compound II-2 is present. In yet another embodiment of the present invention, at least about 99% by weight of crystalline compound II-2 is present.

[0195] Compound II-3 In some embodiments, the compound of formula (II) is compound II-3, [ka] or a solvate thereof.

[0196] In some embodiments, compound II-3 is an anhydrous solid.

[0197] In some embodiments, compound II-3 is an amorphous solid. In other embodiments, compound II-3 is a crystalline solid. In some embodiments, compound II-3 is a mixture of an amorphous solid and a crystalline solid.

[0198] In some embodiments, the present invention provides compound II-3 in a form that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include different forms of compound II-3, residual solvents, or other impurities that may result from the preparation and / or isolation of compound II-3.

[0199] In some embodiments, compound II-3, its solvates, or crystalline forms 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, or 99.9% by weight, where percentages are based on the total weight of the composition. In some embodiments, compound II-3, its solvates, or crystalline forms thereof contains no more than about 0.40% by weight, no more than about 0.35% by weight, no more than about 0.3% by weight, no more than about 0.25% by weight, no more than about 0.2% by weight, no more than about 0.15% by weight, no more than about 0.10% by weight, or no more than about 0.05% by weight of any single impurity, where percentages are based on the total weight of the composition. In some embodiments, the impurities are selected from those described in the Examples herein.

[0200] In some embodiments, compound II-3, its solvates, or crystalline forms 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, or 99.9 area % by HPLC relative to the total area of ​​the HPLC chromatogram. In some embodiments, compound II-3, its solvates, or crystalline forms thereof contains any single impurity at an HPLC area % of about 0.4 or less, about 0.35 or less, about 0.3 or less, about 0.25 or less, about 0.2 or less, about 0.15 or less, about 0.10 or less, or about 0.05 or less relative to the total area of ​​the HPLC chromatogram. In some embodiments, the impurities are selected from those described in the Examples herein. In some embodiments, the HPLC method is selected from the HPLC methods described in the Examples herein.

[0201] The structure shown for compound II-3 is also meant to include all tautomeric forms of compound II-3. Additionally, the structures shown herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacing a hydrogen with deuterium or tritium, or replacing a carbon with 13 C or 14 Compounds having the present structure except for the substitution at a C-rich carbon are within the scope of this invention.

[0202] In certain embodiments, compound II-3 is a crystalline solid. In another embodiment, compound II-3 is a crystalline solid that is substantially free of amorphous compound II-3. As used herein, the term "substantially free of amorphous compound II-3" means that the compound does not contain a significant amount of amorphous compound II-3. In certain embodiments, at least about 95% by weight of crystalline compound II-3 is present. In yet another embodiment of the present invention, at least about 99% by weight of crystalline compound II-3 is present.

[0203] Compound II-4 In some embodiments, the compound of formula (II) is compound II-4, [ka] or a solvate thereof.

[0204] In some embodiments, compound II-4 is an anhydrous solid.

[0205] In some embodiments, compound II-4 is an amorphous solid. In other embodiments, compound II-4 is a crystalline solid. In some embodiments, compound II-4 is a mixture of an amorphous solid and a crystalline solid.

[0206] In some embodiments, the present invention provides compound II-4 in a form that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include different forms of compound II-4, residual solvents, or other impurities that may result from the preparation and / or isolation of compound II-4.

[0207] In some embodiments, compound II-4, its solvates, or crystalline forms 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, or 99.9% by weight, where percentages are based on the total weight of the composition. In some embodiments, compound II-4, its solvates, or crystalline forms thereof contains no more than about 0.40% by weight, no more than about 0.35% by weight, no more than about 0.3% by weight, no more than about 0.25% by weight, no more than about 0.2% by weight, no more than about 0.15% by weight, no more than about 0.10% by weight, or no more than about 0.05% by weight of any single impurity, where percentages are based on the total weight of the composition. In some embodiments, the impurities are selected from those described in the Examples herein.

[0208] In some embodiments, compound II-4, its solvates, or crystalline forms 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, or 99.9 area % by HPLC, based on the total area of ​​the HPLC chromatogram. In some embodiments, compound II-4, its solvates, or crystalline forms thereof contains any single impurity at an HPLC area % of about 0.4 or less, about 0.35 or less, about 0.3 or less, about 0.25 or less, about 0.2 or less, about 0.15 or less, about 0.10 or less, or about 0.05 or less, based on the total area of ​​the HPLC chromatogram. In some embodiments, the impurities are selected from those described in the Examples herein. In some embodiments, the HPLC method is selected from the HPLC methods described in the Examples herein.

[0209] The structure shown for compound II-4 is also meant to include all tautomeric forms of compound II-4. Additionally, the structures shown herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacing a hydrogen with deuterium or tritium, or replacing a carbon with 13 C or 14 Compounds having the present structure except for the substitution at a C-rich carbon are within the scope of this invention.

[0210] In certain embodiments, compound II-4 is a crystalline solid. In another embodiment, compound II-4 is a crystalline solid that is substantially free of amorphous compound II-4. As used herein, the term "substantially free of amorphous compound II-4" means that the compound does not contain a significant amount of amorphous compound II-4. In certain embodiments, at least about 95% by weight of crystalline compound II-4 is present. In yet another embodiment of the present invention, at least about 99% by weight of crystalline compound II-4 is present.

[0211] Compound II-5 In some embodiments, the compound of formula (II) is compound II-5, [ka] or a solvate thereof.

[0212] In some embodiments, compound II-5 is an anhydrous solid.

[0213] In some embodiments, compound II-5 is an amorphous solid. In other embodiments, compound II-5 is a crystalline solid. In some embodiments, compound II-5 is a mixture of an amorphous solid and a crystalline solid.

[0214] In some embodiments, the present invention provides compound II-5 in a form that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include different forms of compound II-5, residual solvents, or other impurities that may result from the preparation and / or isolation of compound II-5.

[0215] In some embodiments, compound II-5, its solvate, or its crystalline form 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, or 99.9% by weight, where percentages are based on the total weight of the composition. In some embodiments, compound II-5, its solvate, or its crystalline form contains no more than about 0.40% by weight, no more than about 0.35% by weight, no more than about 0.3% by weight, no more than about 0.25% by weight, no more than about 0.2% by weight, no more than about 0.15% by weight, no more than about 0.10% by weight, or no more than about 0.05% by weight of any single impurity, where percentages are based on the total weight of the composition. In some embodiments, the impurities are selected from those described in the Examples herein.

[0216] In some embodiments, compound II-5, its solvates, or crystalline forms thereof are 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, or 99.9 area % by HPLC relative to the total area of ​​the HPLC chromatogram. In some embodiments, compound II-5, its solvates, or crystalline forms thereof contain any single impurity at an HPLC area % of about 0.4 or less, about 0.35 or less, about 0.3 or less, about 0.25 or less, about 0.2 or less, about 0.15 or less, about 0.10 or less, or about 0.05 or less relative to the total area of ​​the HPLC chromatogram. In some embodiments, the impurities are selected from those described in the Examples herein. In some embodiments, the HPLC method is selected from the HPLC methods described in the Examples herein.

[0217] The structure shown for compound II-5 is also meant to include all tautomeric forms of compound II-5. Additionally, structures shown herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacing a hydrogen with deuterium or tritium, or replacing a carbon with 13 C or 14 Compounds having the present structure except for the substitution at a C-rich carbon are within the scope of this invention.

[0218] In certain embodiments, compound II-5 is a crystalline solid. In another embodiment, compound II-5 is a crystalline solid that is substantially free of amorphous compound II-5. As used herein, the term "substantially free of amorphous compound II-5" means that the compound does not contain a significant amount of amorphous compound II-5. In certain embodiments, at least about 95% by weight of crystalline compound II-5 is present. In yet another embodiment of the present invention, at least about 99% by weight of crystalline compound II-5 is present.

[0219] Compound II-6 In some embodiments, the compound of formula (II) is compound II-6, [ka] or a solvate thereof.

[0220] In some embodiments, compound II-6 is an anhydrous solid.

[0221] In some embodiments, compound II-6 is an amorphous solid. In other embodiments, compound II-6 is a crystalline solid. In some embodiments, compound II-6 is a mixture of an amorphous solid and a crystalline solid.

[0222] In some embodiments, the present invention provides compound II-6 in a form that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include different forms of compound II-6, residual solvents, or other impurities that may result from the preparation and / or isolation of compound II-6.

[0223] In some embodiments, compound II-6, its solvates, or crystalline forms 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, or 99.9% by weight, where percentages are based on the total weight of the composition. In some embodiments, compound II-6, its solvates, or crystalline forms thereof contains no more than about 0.40% by weight, no more than about 0.35% by weight, no more than about 0.3% by weight, no more than about 0.25% by weight, no more than about 0.2% by weight, no more than about 0.15% by weight, no more than about 0.10% by weight, or no more than about 0.05% by weight of any single impurity, where percentages are based on the total weight of the composition. In some embodiments, the impurities are selected from those described in the Examples herein.

[0224] In some embodiments, compound II-6, its solvates, or crystalline forms 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, or 99.9 area % by HPLC relative to the total area of ​​the HPLC chromatogram. In some embodiments, compound II-6, its solvates, or crystalline forms thereof contains any single impurity at an HPLC area % of about 0.4 or less, about 0.35 or less, about 0.3 or less, about 0.25 or less, about 0.2 or less, about 0.15 or less, about 0.10 or less, or about 0.05 or less relative to the total area of ​​the HPLC chromatogram. In some embodiments, the impurities are selected from those described in the Examples herein. In some embodiments, the HPLC method is selected from the HPLC methods described in the Examples herein.

[0225] The structure shown for compound II-6 is also meant to include all tautomeric forms of compound II-6. Additionally, structures shown herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacing a hydrogen with deuterium or tritium, or replacing a carbon with 13 C or 14 Compounds having the present structure except for the substitution at a C-rich carbon are within the scope of this invention.

[0226] In certain embodiments, compound II-6 is a crystalline solid. In another embodiment, compound II-6 is a crystalline solid that is substantially free of amorphous compound II-6. As used herein, the term "substantially free of amorphous compound II-6" means that the compound does not contain a significant amount of amorphous compound II-6. In certain embodiments, at least about 95% by weight of crystalline compound II-6 is present. In yet another embodiment of the present invention, at least about 99% by weight of crystalline compound II-6 is present.

[0227] Compound of formula (III) In some embodiments, the present disclosure provides a compound of formula (III): [ka] or a solvate thereof, During the ceremony, r is 1, 2, 3, 4, 5, 6, 7, 8, or 9; s is 0, 0.5, 1, 1.5, 2, 2.5, or 3, and X is hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, or 2-naphthalenesulfonic acid.

[0228] Those skilled in the art will understand that the acid moiety designated "X" and N-(3-(2-chloro-5-fluorophenyl)-6-(5-cyano-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide are ionically bonded to form the compound of formula (III). It will also be understood that when n is 0, X is absent, indicating that the compound of formula (III) exists as a "free base," i.e., in the "free form."

[0229] It is believed that the compound of formula (III) can exist in various physical forms.For example, the compound of formula (III) can be a solution, a suspension, or a solid.In certain embodiments, the compound of formula (III) is a solid.When the compound of formula (III) is a solid, the compound can be amorphous, crystalline, or a mixture thereof.Exemplary solid forms will be described in more detail below.

[0230] In some embodiments, the compound of Formula (III) is anhydrous. In some embodiments, the compound of Formula (III) may be in the form of a hydrate. In some embodiments, the compound of Formula (III) may be in the form of a hemihydrate.

[0231] In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4. In some embodiments, r is 5. In some embodiments, r is 6. In some embodiments, r is 7. In some embodiments, r is 8. In some embodiments, r is 9.

[0232] In some embodiments, s is 0. In some embodiments, s is 1. In some embodiments, s is 2. In some embodiments, s is 3. In some embodiments, s is 0.5. In some embodiments, s is 1.5. In some embodiments, s is 2.5.

[0233] In some embodiments, X is hydrochloric acid. In some embodiments, X is p-toluenesulfonic acid. In some embodiments, X is methanesulfonic acid. In some embodiments, X is naphthalene-1,5-disulfonic acid. In some embodiments, X is 2-naphthalenesulfonic acid.

[0234] In some embodiments, the present invention provides Compound (III) in a form that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include different forms of Compound (III), residual solvents, or other impurities that may result from the preparation and / or isolation of Compound (III).

[0235] In some embodiments, the compound of Formula (III), its solvate, or crystalline form 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, or 99.9% by weight, where percentages are based on the total weight of the composition. In some embodiments, the compound of Formula (III), its solvate, or crystalline form thereof contains no more than about 0.40% by weight, no more than about 0.35% by weight, no more than about 0.3% by weight, no more than about 0.25% by weight, no more than about 0.2% by weight, no more than about 0.15% by weight, no more than about 0.10% by weight, or no more than about 0.05% by weight of any single impurity, where percentages are based on the total weight of the composition. In some embodiments, the impurities are selected from those described in the Examples herein.

[0236] In some embodiments, the compound of Formula (III), its solvate, or crystalline form 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, or 99.9 area % by HPLC based on the total area of ​​the HPLC chromatogram. In some embodiments, the compound of Formula (III), its solvate, or crystalline form thereof contains any single impurity at an HPLC area % of about 0.4 or less, about 0.35 or less, about 0.3 or less, about 0.25 or less, about 0.2 or less, about 0.15 or less, about 0.10 or less, or about 0.05 or less based on the total area of ​​the HPLC chromatogram. In some embodiments, the impurities are selected from those described in the Examples herein. In some embodiments, the HPLC method is selected from the HPLC method described in the Examples herein.

[0237] The depicted structures for compounds of formula (III) are also meant to include all tautomeric forms. Additionally, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacing a hydrogen with deuterium or tritium, or replacing a carbon with 13 C or 14 Compounds having the present structure except for the substitution at a C-rich carbon are within the scope of this invention.

[0238] Compound III-1 In some embodiments, the compound of formula (III) is compound III-1 (which is the free base (or "free form")), [ka] or a solvate thereof.

[0239] In some embodiments, compound (III-1) is an amorphous solid. In some embodiments, compound (III-1) is a crystalline solid. In some embodiments, compound (III-1) is a mixture of an amorphous solid and a crystalline solid.

[0240] In some embodiments, the present invention provides compound III-1 in a form that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include different forms of compound III-1, residual solvents, or other impurities that may result from the preparation and / or isolation of compound III-1.

[0241] In some embodiments, compound III-1, its solvates, or its crystalline forms are 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, or 99.9% by weight, where percentages are based on the total weight of the composition. In some embodiments, compound III-1, its solvates, or its crystalline forms contain no more than about 0.40% by weight, no more than about 0.35% by weight, no more than about 0.3% by weight, no more than about 0.25% by weight, no more than about 0.2% by weight, no more than about 0.15% by weight, no more than about 0.10% by weight, or no more than about 0.05% by weight of any single impurity, where percentages are based on the total weight of the composition. In some embodiments, the impurities are selected from those described in the Examples herein.

[0242] In some embodiments, compound III-1, its solvates, or crystalline forms 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, or 99.9 area % by HPLC based on the total area of ​​the HPLC chromatogram. In some embodiments, compound III-1, its solvates, or crystalline forms thereof contains any single impurity at an HPLC area % of about 0.4 or less, about 0.35 or less, about 0.3 or less, about 0.25 or less, about 0.2 or less, about 0.15 or less, about 0.10 or less, or about 0.05 or less based on the total area of ​​the HPLC chromatogram. In some embodiments, the impurities are selected from those described in the Examples herein. In some embodiments, the HPLC method is selected from the HPLC methods described in the Examples herein.

[0243] The structure depicted for compound III-1 is also meant to include all tautomeric forms of compound III-1. Additionally, the structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacing a hydrogen with deuterium or tritium, or replacing a carbon with 13 C or 14 Compounds having the present structure except for the substitution at a C-rich carbon are within the scope of this invention.

[0244] In another embodiment, compound (III-1) is a crystalline solid that is substantially free of amorphous compound (III-1). As used herein, the term "substantially free of amorphous compound (III-1)" means that the compound does not contain a significant amount of amorphous compound (III-1). In certain embodiments, at least about 95% by weight of crystalline compound (III-1) is present. In certain embodiments, at least about 99% by weight of crystalline compound (III-1) is present.

[0245] It has been found that compound (III-1) can exist in various solid forms. Exemplary such forms include the polymorphs described herein.

[0246] In some embodiments, the solid crystalline form of Compound (III-1) is Form A. In some embodiments, Form A of Compound (III-1) can be characterized by an X-ray powder diffraction pattern having at least two characteristic peaks at 2θ degrees selected from the group consisting of about 18.4 2θ, about 12.0 2θ, and about 6.5 2θ. In some embodiments, Form A of Compound (III-1) can be characterized by an X-ray powder diffraction pattern having at least two characteristic peaks at 2θ degrees selected from the group consisting of about 18.4 2θ, about 12.0 2θ, about 6.5 2θ, about 22.1 2θ, about 19.9 2θ, about 13.9 2θ, and about 14.9 2θ. In some embodiments, Form A of compound (III-1) can be characterized by an X-ray powder diffraction pattern having at least three characteristic peaks at 2θ degrees selected from the group consisting of about 18.4 2θ, about 12.0 2θ, about 6.5 2θ, about 22.1 2θ, about 19.9 2θ, about 13.9 2θ, and about 14.9 2θ. In some embodiments, Form A of compound (III-1) can be characterized by an X-ray powder diffraction pattern having at least four characteristic peaks at 2θ degrees selected from the group consisting of about 18.4 2θ, about 12.0 2θ, about 6.5 2θ, about 22.1 2θ, about 19.9 2θ, about 13.9 2θ, and about 14.9 2θ. In some embodiments, Form A of compound (III-1) can be characterized by an X-ray powder diffraction pattern having at least five characteristic peaks at 2θ degrees selected from the group consisting of about 18.4 2θ, about 12.0 2θ, about 6.5 2θ, about 22.1 2θ, about 19.9 2θ, about 13.9 2θ, and about 14.9 2θ. In some embodiments, Form A of compound (III-1) can be characterized by an X-ray powder diffraction pattern having at least six characteristic peaks at 2θ degrees selected from the group consisting of about 18.4 2θ, about 12.0 2θ, about 6.5 2θ, about 22.1 2θ, about 19.9 2θ, about 13.9 2θ, and about 14.9 2θ.In some embodiments, Form A of compound (III-1) can be characterized by an X-ray powder diffraction pattern comprising characteristic peaks at about 18.4 2θ, about 12.0 2θ, about 6.5 2θ, about 22.1 2θ, about 19.9 2θ, about 13.9 2θ, and about 14.9 2θ. In some embodiments, Form A of compound (III-1) has an X-ray diffraction pattern substantially similar to that shown in FIG. 4A. In some embodiments, Form A of compound (III-1) can be characterized by an X-ray powder diffraction pattern comprising at least two characteristic peaks at 2θ degrees each selected from the group consisting of the peaks listed in Table 3.1. In some embodiments, Form A of compound (III-1) can be characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at 2θ degrees each selected from the group consisting of the peaks listed in Table 3.1. In some embodiments, Form A of compound (III-1) may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks, each at 2θ degrees, selected from the group consisting of the peaks listed in Table 3.1. In some embodiments, Form A of compound (III-1) may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks, each at 2θ degrees, selected from the group consisting of the peaks listed in Table 3.1. In some embodiments, Form A of compound (III-1) may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks, each at 2θ degrees, selected from the group consisting of the peaks listed in Table 3.1. In some embodiments, Form A of compound (III-1) may be characterized by a powder X-ray diffraction pattern having at least seven characteristic peaks, each at 2θ degrees, selected from the group consisting of the peaks listed in Table 3.1. [Table 4-1] [Table 4-2]

[0247] In some embodiments, Form A of compound (III-1) has a differential scanning calorimetry (DSC) pattern substantially similar to that shown in Figure 4B. In some embodiments, Form A of compound (III-1) has a thermogravimetric analysis (TGA) pattern substantially similar to that shown in Figure 4C. In some embodiments, Form A of compound (III-1) may be characterized by substantially similar patterns in two or more of these figures simultaneously.

[0248] In some embodiments, the solid crystalline form of Compound (III-1) is Form B. In some embodiments, Form B of Compound (III-1) can be characterized by an X-ray powder diffraction pattern having at least two characteristic peaks at 2θ degrees selected from the group consisting of about 23.6 2θ, about 10.2 2θ, and about 8.7 2θ. In some embodiments, Form B of Compound (III-1) can be characterized by an X-ray powder diffraction pattern having at least two characteristic peaks at 2θ degrees selected from the group consisting of about 23.6 2θ, about 10.2 2θ, about 8.7 2θ, about 24.4 2θ, about 25.4 2θ, about 10.9 2θ, and about 21.2 2θ. In some embodiments, Form B of compound (III-1) can be characterized by an X-ray powder diffraction pattern having at least three characteristic peaks at 2θ degrees selected from the group consisting of about 23.6 2θ, about 10.2 2θ, about 8.7 2θ, about 24.4 2θ, about 25.4 2θ, about 10.9 2θ, and about 21.2 2θ. In some embodiments, Form B of compound (III-1) can be characterized by an X-ray powder diffraction pattern having at least four characteristic peaks at 2θ degrees selected from the group consisting of about 23.6 2θ, about 10.2 2θ, about 8.7 2θ, about 24.4 2θ, about 25.4 2θ, about 10.9 2θ, and about 21.2 2θ. In some embodiments, Form B of compound (III-1) can be characterized by an X-ray powder diffraction pattern having at least five characteristic peaks at 2θ degrees selected from the group consisting of about 23.6 2θ, about 10.2 2θ, about 8.7 2θ, about 24.4 2θ, about 25.4 2θ, about 10.9 2θ, and about 21.2 2θ. In some embodiments, Form B of compound (III-1) can be characterized by an X-ray powder diffraction pattern having at least six characteristic peaks at 2θ degrees selected from the group consisting of about 23.6 2θ, about 10.2 2θ, about 8.7 2θ, about 24.4 2θ, about 25.4 2θ, about 10.9 2θ, and about 21.2 2θ.In some embodiments, Form B of compound (III-1) can be characterized by an X-ray powder diffraction pattern comprising characteristic peaks at about 23.6 2θ, about 10.2 2θ, about 8.7 2θ, about 24.4 2θ, about 25.4 2θ, about 10.9 2θ, and about 21.2 2θ. In some embodiments, Form B of compound (III-1) has an X-ray diffraction pattern substantially similar to that shown in FIG. 5A. In some embodiments, Form B of compound (III-1) can be characterized by an X-ray powder diffraction pattern comprising at least two characteristic peaks at 2θ degrees each selected from the group consisting of the peaks listed in Table 3.2. In some embodiments, Form B of compound (III-1) can be characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at 2θ degrees each selected from the group consisting of the peaks listed in Table 3.2. In some embodiments, Form B of Compound (III-1) may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks, each at 2θ degrees, selected from the group consisting of the peaks listed in Table 3.2. In some embodiments, Form B of Compound (III-1) may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks, each at 2θ degrees, selected from the group consisting of the peaks listed in Table 3.2. In some embodiments, Form B of Compound (III-1) may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks, each at 2θ degrees, selected from the group consisting of the peaks listed in Table 3.2. In some embodiments, Form B of Compound (III-1) may be characterized by a powder X-ray diffraction pattern having at least seven characteristic peaks, each at 2θ degrees, selected from the group consisting of the peaks listed in Table 3.2. [Table 5]

[0249] In some embodiments, Form B of compound (III-1) has a differential scanning calorimetry (DSC) pattern substantially similar to that shown in Figure 5B.

[0250] In some embodiments, the solid crystalline form of Compound (III-1) is Form C. In some embodiments, Form C of Compound (III-1) can be characterized by an X-ray powder diffraction pattern having at least two characteristic peaks at 2θ degrees selected from the group consisting of about 12.0 2θ, about 18.4 2θ, and about 13.9 2θ. In some embodiments, Form C of Compound (III-1) can be characterized by an X-ray powder diffraction pattern having at least two characteristic peaks at 2θ degrees selected from the group consisting of about 12.0 2θ, about 18.4 2θ, about 13.9 2θ, about 6.5 2θ, about 24.1 2θ, about 15.7 2θ, and about 21.4 2θ. In some embodiments, Form C of compound (III-1) can be characterized by an X-ray powder diffraction pattern having at least three characteristic peaks at 2θ degrees selected from the group consisting of about 12.0 2θ, about 18.4 2θ, about 13.9 2θ, about 6.5 2θ, about 24.1 2θ, about 15.7 2θ, and about 21.4 2θ. In some embodiments, Form C of compound (III-1) can be characterized by an X-ray powder diffraction pattern having at least four characteristic peaks at 2θ degrees selected from the group consisting of about 12.0 2θ, about 18.4 2θ, about 13.9 2θ, about 6.5 2θ, about 24.1 2θ, about 15.7 2θ, and about 21.4 2θ. In some embodiments, Form C of compound (III-1) can be characterized by an X-ray powder diffraction pattern having at least five characteristic peaks at 2θ degrees selected from the group consisting of about 12.0 2θ, about 18.4 2θ, about 13.9 2θ, about 6.5 2θ, about 24.1 2θ, about 15.7 2θ, and about 21.4 2θ. In some embodiments, Form C of compound (III-1) can be characterized by an X-ray powder diffraction pattern having at least six characteristic peaks at 2θ degrees selected from the group consisting of about 12.0 2θ, about 18.4 2θ, about 13.9 2θ, about 6.5 2θ, about 24.1 2θ, about 15.7 2θ, and about 21.4 2θ.In some embodiments, Form C of compound (III-1) can be characterized by an X-ray powder diffraction pattern comprising characteristic peaks at about 12.0 2θ, about 18.4 2θ, about 13.9 2θ, about 6.5 2θ, about 24.1 2θ, about 15.7 2θ, and about 21.4 2θ. In some embodiments, Form C of compound (III-1) has an X-ray diffraction pattern substantially similar to that shown in FIG. 6A. In some embodiments, Form C of compound (III-1) can be characterized by an X-ray powder diffraction pattern comprising at least two characteristic peaks at 2θ degrees each selected from the group consisting of the peaks listed in Table 3.3. In some embodiments, Form C of compound (III-1) can be characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at 2θ degrees each selected from the group consisting of the peaks listed in Table 3.3. In some embodiments, Form C of compound (III-1) may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks, each at 2θ degrees, selected from the group consisting of the peaks listed in Table 3.3. In some embodiments, Form C of compound (III-1) may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks, each at 2θ degrees, selected from the group consisting of the peaks listed in Table 3.3. In some embodiments, Form C of compound (III-1) may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks, each at 2θ degrees, selected from the group consisting of the peaks listed in Table 3.3. In some embodiments, Form C of compound (III-1) may be characterized by a powder X-ray diffraction pattern having at least seven characteristic peaks, each at 2θ degrees, selected from the group consisting of the peaks listed in Table 3.3. [Table 6-1] [Table 6-2]

[0251] In some embodiments, Form C of compound (III-1) has a differential scanning calorimetry (DSC) pattern substantially similar to that shown in Figure 6B. In some embodiments, Form C of compound (III-1) has a thermogravimetric analysis (TGA) pattern substantially similar to that shown in Figure 6C. In some embodiments, Form C of compound (III-1) may be characterized by substantially similar patterns in two or more of these figures simultaneously.

[0252] In some embodiments, the solid crystalline form of Compound (III-1) is Form D. In some embodiments, Form D of Compound (III-1) can be characterized by an X-ray powder diffraction pattern having at least two characteristic peaks at 2θ degrees selected from the group consisting of about 12.0 2θ, about 18.3 2θ, and about 6.5 2θ. In some embodiments, Form D of Compound (III-1) can be characterized by an X-ray powder diffraction pattern having at least two characteristic peaks at 2θ degrees selected from the group consisting of about 12.0 2θ, about 18.3 2θ, about 6.5 2θ, about 19.4 2θ, about 22.1 2θ, about 15.7 2θ, and about 26.6 2θ. In some embodiments, Form D of compound (III-1) can be characterized by an X-ray powder diffraction pattern having at least three characteristic peaks at 2θ degrees selected from the group consisting of about 12.0 2θ, about 18.3 2θ, about 6.5 2θ, about 19.4 2θ, about 22.1 2θ, about 15.7 2θ, and about 26.6 2θ. In some embodiments, Form D of compound (III-1) can be characterized by an X-ray powder diffraction pattern having at least four characteristic peaks at 2θ degrees selected from the group consisting of about 12.0 2θ, about 18.3 2θ, about 6.5 2θ, about 19.4 2θ, about 22.1 2θ, about 15.7 2θ, and about 26.6 2θ. In some embodiments, Form D of compound (III-1) can be characterized by an X-ray powder diffraction pattern having at least five characteristic peaks at 2θ degrees selected from the group consisting of about 12.0 2θ, about 18.3 2θ, about 6.5 2θ, about 19.4 2θ, about 22.1 2θ, about 15.7 2θ, and about 26.6 2θ. In some embodiments, Form D of compound (III-1) can be characterized by an X-ray powder diffraction pattern having at least six characteristic peaks at 2θ degrees selected from the group consisting of about 12.0 2θ, about 18.3 2θ, about 6.5 2θ, about 19.4 2θ, about 22.1 2θ, about 15.7 2θ, and about 26.6 2θ.In some embodiments, Form D of compound (III-1) can be characterized by an X-ray powder diffraction pattern comprising characteristic peaks at about 12.0 2θ, about 18.3 2θ, about 6.5 2θ, about 19.4 2θ, about 22.1 2θ, about 15.7 2θ, and about 26.6 2θ. In some embodiments, Form D of compound (III-1) has an X-ray diffraction pattern substantially similar to that shown in Figure 7A. In some embodiments, Form D of compound (III-1) can be characterized by an X-ray powder diffraction pattern comprising at least two characteristic peaks at 2θ degrees each selected from the group consisting of the peaks listed in Table 3.4. In some embodiments, Form D of compound (III-1) can be characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at 2θ degrees each selected from the group consisting of the peaks listed in Table 3.4. In some embodiments, Form D of compound (III-1) may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks, each at 2θ degrees, selected from the group consisting of the peaks listed in Table 3.4. In some embodiments, Form D of compound (III-1) may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks, each at 2θ degrees, selected from the group consisting of the peaks listed in Table 3.4. In some embodiments, Form D of compound (III-1) may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks, each at 2θ degrees, selected from the group consisting of the peaks listed in Table 3.4. In some embodiments, Form D of compound (III-1) may be characterized by a powder X-ray diffraction pattern having at least seven characteristic peaks, each at 2θ degrees, selected from the group consisting of the peaks listed in Table 3.4. [Table 7-1] [Table 7-2]

[0253] In some embodiments, Form D of compound (III-1) has a differential scanning calorimetry (DSC) pattern substantially similar to that shown in Figure 7B. In some embodiments, Form D of compound (III-1) has a thermogravimetric analysis (TGA) pattern substantially similar to that shown in Figure 7C. In some embodiments, Form D of compound (III-1) may be characterized by substantially similar patterns to two or more of these patterns simultaneously.

[0254] In some embodiments, the solid crystalline form of Compound (III-1) is Form E. In some embodiments, Form E of Compound (III-1) can be characterized by an X-ray powder diffraction pattern having at least two characteristic peaks at 2θ degrees selected from the group consisting of about 20.8 2θ, about 22.2 2θ, and about 20.0 2θ. In some embodiments, Form E of Compound (III-1) can be characterized by an X-ray powder diffraction pattern having at least two characteristic peaks at 2θ degrees selected from the group consisting of about 20.8 2θ, about 22.2 2θ, about 20.0 2θ, about 25.5 2θ, about 28.0 2θ, about 16.6 2θ, and about 25.0 2θ. In some embodiments, Form E of compound (III-1) can be characterized by an X-ray powder diffraction pattern having at least three characteristic peaks at degrees 2θ selected from the group consisting of about 20.8 2θ, about 22.2 2θ, about 20.0 2θ, about 25.5 2θ, about 28.0 2θ, about 16.6 2θ, and about 25.0 2θ. In some embodiments, Form E of compound (III-1) can be characterized by an X-ray powder diffraction pattern having at least four characteristic peaks at degrees 2θ selected from the group consisting of about 20.8 2θ, about 22.2 2θ, about 20.0 2θ, about 25.5 2θ, about 28.0 2θ, about 16.6 2θ, and about 25.0 2θ. In some embodiments, Form E of compound (III-1) can be characterized by an X-ray powder diffraction pattern having at least five characteristic peaks at degrees 2θ selected from the group consisting of about 20.8 2θ, about 22.2 2θ, about 20.0 2θ, about 25.5 2θ, about 28.0 2θ, about 16.6 2θ, and about 25.0 2θ. In some embodiments, Form E of compound (III-1) can be characterized by an X-ray powder diffraction pattern having at least six characteristic peaks at degrees 2θ selected from the group consisting of about 20.8 2θ, about 22.2 2θ, about 20.0 2θ, about 25.5 2θ, about 28.0 2θ, about 16.6 2θ, and about 25.0 2θ.In some embodiments, Form E of compound (III-1) can be characterized by an X-ray powder diffraction pattern comprising characteristic peaks at about 20.8 2θ, about 22.2 2θ, about 20.0 2θ, about 25.5 2θ, about 28.0 2θ, about 16.6 2θ, and about 25.0 2θ. In some embodiments, Form E of compound (III-1) has an X-ray diffraction pattern substantially similar to that shown in Figure 8. In some embodiments, Form E of compound (III-1) can be characterized by an X-ray powder diffraction pattern comprising at least two characteristic peaks at 2θ degrees each selected from the group consisting of the peaks listed in Table 3.5. In some embodiments, Form E of compound (III-1) can be characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at 2θ degrees each selected from the group consisting of the peaks listed in Table 3.5. In some embodiments, Form E of Compound (III-1) may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks, each at 2θ degrees, selected from the group consisting of the peaks listed in Table 3.5. In some embodiments, Form E of Compound (III-1) may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks, each at 2θ degrees, selected from the group consisting of the peaks listed in Table 3.5. In some embodiments, Form E of Compound (III-1) may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks, each at 2θ degrees, selected from the group consisting of the peaks listed in Table 3.5. In some embodiments, Form E of Compound (III-1) may be characterized by a powder X-ray diffraction pattern having at least seven characteristic peaks, each at 2θ degrees, selected from the group consisting of the peaks listed in Table 3.5. [Table 8-1] [Table 8-2]

[0255] In some embodiments, the solid crystalline form of Compound (III-1) is Form F. In some embodiments, Form F of Compound (III-1) can be characterized by an X-ray powder diffraction pattern having at least two characteristic peaks at 2θ degrees selected from the group consisting of about 21.3 2θ, about 11.0 2θ, and about 11.3 2θ. In some embodiments, Form F of Compound (III-1) can be characterized by an X-ray powder diffraction pattern having at least two characteristic peaks at 2θ degrees selected from the group consisting of about 21.3 2θ, about 11.0 2θ, about 11.3 2θ, about 18.4 2θ, about 29.6 2θ, about 24.5 2θ, and about 20.3 2θ. In some embodiments, Form F of compound (III-1) can be characterized by an X-ray powder diffraction pattern having at least three characteristic peaks at 2θ degrees selected from the group consisting of about 21.3 2θ, about 11.0 2θ, about 11.3 2θ, about 18.4 2θ, about 29.6 2θ, about 24.5 2θ, and about 20.3 2θ. In some embodiments, Form F of compound (III-1) can be characterized by an X-ray powder diffraction pattern having at least four characteristic peaks at 2θ degrees selected from the group consisting of about 21.3 2θ, about 11.0 2θ, about 11.3 2θ, about 18.4 2θ, about 29.6 2θ, about 24.5 2θ, and about 20.3 2θ. In some embodiments, Form F of compound (III-1) can be characterized by an X-ray powder diffraction pattern having at least five characteristic peaks at 2θ degrees selected from the group consisting of about 21.3 2θ, about 11.0 2θ, about 11.3 2θ, about 18.4 2θ, about 29.6 2θ, about 24.5 2θ, and about 20.3 2θ. In some embodiments, Form F of compound (III-1) can be characterized by an X-ray powder diffraction pattern having at least six characteristic peaks at 2θ degrees selected from the group consisting of about 21.3 2θ, about 11.0 2θ, about 11.3 2θ, about 18.4 2θ, about 29.6 2θ, about 24.5 2θ, and about 20.3 2θ.In some embodiments, Form F of compound (III-1) may be characterized by an X-ray powder diffraction pattern comprising characteristic peaks at about 21.3 2θ, about 11.0 2θ, about 11.3 2θ, about 18.4 2θ, about 29.6 2θ, about 24.5 2θ, and about 20.3 2θ. In some embodiments, Form F of compound (III-1) has an X-ray diffraction pattern substantially similar to that shown in Figure 9A. In some embodiments, Form F of compound (III-1) may be characterized by an X-ray powder diffraction pattern comprising at least two characteristic peaks at 2θ degrees each selected from the group consisting of the peaks listed in Table 3.6. In some embodiments, Form F of compound (III-1) may be characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at 2θ degrees each selected from the group consisting of the peaks listed in Table 3.6. In some embodiments, Form F of Compound (III-1) may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks, each at 2θ degrees, selected from the group consisting of the peaks listed in Table 3.6. In some embodiments, Form F of Compound (III-1) may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks, each at 2θ degrees, selected from the group consisting of the peaks listed in Table 3.6. In some embodiments, Form F of Compound (III-1) may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks, each at 2θ degrees, selected from the group consisting of the peaks listed in Table 3.6. In some embodiments, Form F of Compound (III-1) may be characterized by a powder X-ray diffraction pattern having at least seven characteristic peaks, each at 2θ degrees, selected from the group consisting of the peaks listed in Table 3.6. [Table 9-1] [Table 9-2]

[0256] In some embodiments, Form F of compound (III-1) has a differential scanning calorimetry (DSC) pattern substantially similar to that shown in Figure 9B.

[0257] Compound III-2 In some embodiments, the compound of formula (III) is compound III-2, [ka] or a solvate thereof.

[0258] In some embodiments, compound III-2 is an anhydrous solid.

[0259] In some embodiments, compound III-2 is an amorphous solid. In other embodiments, compound III-2 is a crystalline solid. In some embodiments, compound III-2 is a mixture of an amorphous solid and a crystalline solid.

[0260] In some embodiments, the present invention provides compound II-2 in a form that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include different forms of compound III-2, residual solvents, or other impurities that may result from the preparation and / or isolation of compound III-2.

[0261] In some embodiments, compound III-2, its solvates, or crystalline forms 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, or 99.9% by weight, where percentages are based on the total weight of the composition. In some embodiments, compound III-2, its solvates, or crystalline forms thereof contains no more than about 0.40% by weight, no more than about 0.35% by weight, no more than about 0.3% by weight, no more than about 0.25% by weight, no more than about 0.2% by weight, no more than about 0.15% by weight, no more than about 0.10% by weight, or no more than about 0.05% by weight of any single impurity, where percentages are based on the total weight of the composition. In some embodiments, the impurities are selected from those described in the Examples herein.

[0262] In some embodiments, compound III-2, its solvates, or crystalline forms 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, or 99.9 area % by HPLC based on the total area of ​​the HPLC chromatogram. In some embodiments, compound III-2, its solvates, or crystalline forms thereof contains any single impurity at an HPLC area % of about 0.4 or less, about 0.35 or less, about 0.3 or less, about 0.25 or less, about 0.2 or less, about 0.15 or less, about 0.10 or less, or about 0.05 or less based on the total area of ​​the HPLC chromatogram. In some embodiments, the impurities are selected from those described in the Examples herein. In some embodiments, the HPLC method is selected from the HPLC methods described in the Examples herein.

[0263] The structure shown for compound III-2 is also meant to include all tautomeric forms of compound III-2. Additionally, the structures shown herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacing a hydrogen with deuterium or tritium, or replacing a carbon with 13 C or 14Compounds having the present structure except for the substitution at a C-rich carbon are within the scope of this invention.

[0264] In certain embodiments, compound III-2 is a crystalline solid. In another embodiment, compound III-2 is a crystalline solid that is substantially free of amorphous compound III-2. As used herein, the term "substantially free of amorphous compound III-2" means that the compound does not contain a significant amount of amorphous compound III-2. In certain embodiments, at least about 95% by weight of crystalline compound III-2 is present. In yet another embodiment of the present invention, at least about 99% by weight of crystalline compound III-2 is present.

[0265] It has been found that compound III-2 can exist in a variety of solid forms. Exemplary such forms include the polymorphs described herein.

[0266] In some embodiments, the solid crystalline form of compound III-2 is Form A. In some embodiments, Form A of compound III-2 has an X-ray diffraction (XRPD) pattern substantially similar to that shown in Figure 29A.

[0267] In some embodiments, Form A of compound III-2 has a differential scanning calorimetry (DSC) pattern substantially similar to that shown in Figure 29B. In some embodiments, Form A of compound III-2 has a thermogravimetric analysis (TGA) pattern substantially similar to that shown in Figure 29C. In some embodiments, Form A of compound III-2 may be characterized by substantially similar patterns in two or more of these figures simultaneously.

[0268] In some embodiments, the solid crystalline form of compound III-2 is Form B. In some embodiments, Form B of compound III-2 has an X-ray diffraction pattern substantially similar to that shown in FIG.

[0269] Compound III-3 In some embodiments, the compound of formula (III) is compound III-3, [ka] or a solvate thereof.

[0270] In some embodiments, compound III-3 is an anhydrous solid.

[0271] In some embodiments, compound III-3 is an amorphous solid. In other embodiments, compound III-3 is a crystalline solid. In some embodiments, compound III-3 is a mixture of an amorphous solid and a crystalline solid.

[0272] In some embodiments, the present invention provides compound III-3 in a form that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include different forms of compound III-3, residual solvents, or other impurities that may result from the preparation and / or isolation of compound III-3.

[0273] In some embodiments, compound III-3, its solvates, or crystalline forms 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, or 99.9% by weight, where percentages are based on the total weight of the composition. In some embodiments, compound III-3, its solvates, or crystalline forms thereof contains no more than about 0.40% by weight, no more than about 0.35% by weight, no more than about 0.3% by weight, no more than about 0.25% by weight, no more than about 0.2% by weight, no more than about 0.15% by weight, no more than about 0.10% by weight, or no more than about 0.05% by weight of any single impurity, where percentages are based on the total weight of the composition. In some embodiments, the impurities are selected from those described in the Examples herein.

[0274] In some embodiments, compound III-3, its solvates, or crystalline forms 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, or 99.9 area % by HPLC based on the total area of ​​the HPLC chromatogram. In some embodiments, compound III-3, its solvates, or crystalline forms thereof contains any single impurity at an HPLC area % of about 0.4 or less, about 0.35 or less, about 0.3 or less, about 0.25 or less, about 0.2 or less, about 0.15 or less, about 0.10 or less, or about 0.05 or less based on the total area of ​​the HPLC chromatogram. In some embodiments, the impurities are selected from those described in the Examples herein. In some embodiments, the HPLC method is selected from the HPLC methods described in the Examples herein.

[0275] The structure shown for compound III-3 is also meant to include all tautomeric forms of compound III-3. Additionally, the structures shown herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacing a hydrogen with deuterium or tritium, or replacing a carbon with 13 C or 14 Compounds having the present structure except for the substitution at a C-rich carbon are within the scope of this invention.

[0276] In certain embodiments, compound III-3 is a crystalline solid. In another embodiment, compound III-3 is a crystalline solid that is substantially free of amorphous compound III-3. As used herein, the term "substantially free of amorphous compound III-3" means that the compound does not contain a significant amount of amorphous compound III-3. In certain embodiments, at least about 95% by weight of crystalline compound III-3 is present. In yet another embodiment of the present invention, at least about 99% by weight of crystalline compound III-3 is present.

[0277] Compound III-4 In some embodiments, the compound of formula (I) is compound III-4, [ka] or a solvate thereof.

[0278] In some embodiments, compound III-4 is an anhydrous solid.

[0279] In some embodiments, compound III-4 is an amorphous solid. In other embodiments, compound III-4 is a crystalline solid. In some embodiments, compound III-4 is a mixture of an amorphous solid and a crystalline solid.

[0280] In some embodiments, the present invention provides compound III-4 in a form that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include different forms of compound III-4, residual solvents, or other impurities that may result from the preparation and / or isolation of compound III-4.

[0281] In some embodiments, compound III-4, its solvates, or crystalline forms 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, or 99.9% by weight, where percentages are based on the total weight of the composition. In some embodiments, compound III-4, its solvates, or crystalline forms thereof contains no more than about 0.40% by weight, no more than about 0.35% by weight, no more than about 0.3% by weight, no more than about 0.25% by weight, no more than about 0.2% by weight, no more than about 0.15% by weight, no more than about 0.10% by weight, or no more than about 0.05% by weight of any single impurity, where percentages are based on the total weight of the composition. In some embodiments, the impurities are selected from those described in the Examples herein.

[0282] In some embodiments, compound III-4, its solvates, or crystalline forms 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, or 99.9 area % by HPLC based on the total area of ​​the HPLC chromatogram. In some embodiments, compound III-4, its solvates, or crystalline forms thereof contains any single impurity at an HPLC area % of about 0.4 or less, about 0.35 or less, about 0.3 or less, about 0.25 or less, about 0.2 or less, about 0.15 or less, about 0.10 or less, or about 0.05 or less based on the total area of ​​the HPLC chromatogram. In some embodiments, the impurities are selected from those described in the Examples herein. In some embodiments, the HPLC method is selected from the HPLC methods described in the Examples herein.

[0283] The structure shown for compound III-4 is also meant to include all tautomeric forms of compound III-4. Additionally, the structures shown herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacing a hydrogen with deuterium or tritium, or replacing a carbon with 13 C or 14 Compounds having the present structure except for the substitution at a C-rich carbon are within the scope of this invention.

[0284] In certain embodiments, compound III-4 is a crystalline solid. In another embodiment, compound III-4 is a crystalline solid that is substantially free of amorphous compound III-4. As used herein, the term "substantially free of amorphous compound III-4" means that the compound does not contain a significant amount of amorphous compound III-4. In certain embodiments, at least about 95% by weight of crystalline compound III-4 is present. In yet another embodiment of the present invention, at least about 99% by weight of crystalline compound III-4 is present.

[0285] Compound III-5 In some embodiments, the compound of formula (I) is compound III-5, [ka] or a solvate thereof.

[0286] In some embodiments, compound III-5 is an anhydrous solid.

[0287] In some embodiments, compound III-5 is an amorphous solid. In other embodiments, compound III-5 is a crystalline solid. In some embodiments, compound III-5 is a mixture of an amorphous solid and a crystalline solid.

[0288] In some embodiments, the present invention provides compound III-5 in a form that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include different forms of compound III-5, residual solvents, or other impurities that may result from the preparation and / or isolation of compound III-5.

[0289] In some embodiments, compound III-5, its solvates, or crystalline forms 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, or 99.9% by weight, where percentages are based on the total weight of the composition. In some embodiments, compound III-5, its solvates, or crystalline forms thereof contains no more than about 0.40% by weight, no more than about 0.35% by weight, no more than about 0.3% by weight, no more than about 0.25% by weight, no more than about 0.2% by weight, no more than about 0.15% by weight, no more than about 0.10% by weight, or no more than about 0.05% by weight of any single impurity, where percentages are based on the total weight of the composition. In some embodiments, the impurities are selected from those described in the Examples herein.

[0290] In some embodiments, compound III-5, its solvates, or crystalline forms 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, or 99.9 area % by HPLC based on the total area of ​​the HPLC chromatogram. In some embodiments, compound III-5, its solvates, or crystalline forms thereof contains any single impurity at an HPLC area % of about 0.4 or less, about 0.35 or less, about 0.3 or less, about 0.25 or less, about 0.2 or less, about 0.15 or less, about 0.10 or less, or about 0.05 or less based on the total area of ​​the HPLC chromatogram. In some embodiments, the impurities are selected from those described in the Examples herein. In some embodiments, the HPLC method is selected from the HPLC methods described in the Examples herein.

[0291] The structure depicted for compound III-5 is also meant to include all tautomeric forms of compound III-5. Additionally, the structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacing a hydrogen with deuterium or tritium, or replacing a carbon with 13 C or 14 Compounds having the present structure except for the substitution at a C-rich carbon are within the scope of this invention.

[0292] In certain embodiments, compound III-5 is a crystalline solid. In another embodiment, compound III-5 is a crystalline solid that is substantially free of amorphous compound III-5. As used herein, the term "substantially free of amorphous compound III-5" means that the compound does not contain a significant amount of amorphous compound III-5. In certain embodiments, at least about 95% by weight of crystalline compound III-5 is present. In yet another embodiment of the present invention, at least about 99% by weight of crystalline compound III-5 is present.

[0293] Compound III-6 In some embodiments, the compound of formula (III) is compound III-6, [ka] or a solvate thereof.

[0294] In some embodiments, compound III-6 is an anhydrous solid.

[0295] In some embodiments, compound III-6 is an amorphous solid. In other embodiments, compound III-6 is a crystalline solid. In some embodiments, compound III-6 is a mixture of an amorphous solid and a crystalline solid.

[0296] In some embodiments, the present invention provides compound III-6 in a form that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include different forms of compound III-6, residual solvents, or other impurities that may result from the preparation and / or isolation of compound III-6.

[0297] In some embodiments, compound III-6, its solvates, or crystalline forms 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, or 99.9% by weight, where percentages are based on the total weight of the composition. In some embodiments, compound III-6, its solvates, or crystalline forms thereof contains no more than about 0.40% by weight, no more than about 0.35% by weight, no more than about 0.3% by weight, no more than about 0.25% by weight, no more than about 0.2% by weight, no more than about 0.15% by weight, no more than about 0.10% by weight, or no more than about 0.05% by weight of any single impurity, where percentages are based on the total weight of the composition. In some embodiments, the impurities are selected from those described in the Examples herein.

[0298] In some embodiments, compound III-6, its solvates, or crystalline forms thereof are 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, or 99.9 area % by HPLC based on the total area of ​​the HPLC chromatogram. In some embodiments, compound III-6, its solvates, or crystalline forms thereof contain any single impurity at an HPLC area % of about 0.4 or less, about 0.35 or less, about 0.3 or less, about 0.25 or less, about 0.2 or less, about 0.15 or less, about 0.10 or less, or about 0.05 or less based on the total area of ​​the HPLC chromatogram. In some embodiments, the impurities are selected from those described in the Examples herein. In some embodiments, the HPLC method is selected from the HPLC methods described in the Examples herein.

[0299] The structure shown for compound III-6 is also meant to include all tautomeric forms of compound III-6. Additionally, structures shown herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacing a hydrogen with deuterium or tritium, or replacing a carbon with 13 C or 14 Compounds having the present structure except for the substitution at a C-rich carbon are within the scope of this invention.

[0300] In certain embodiments, compound III-6 is a crystalline solid. In another embodiment, compound III-6 is a crystalline solid that is substantially free of amorphous compound III-6. As used herein, the term "substantially free of amorphous compound III-6" means that the compound does not contain a significant amount of amorphous compound III-6. In certain embodiments, at least about 95% by weight of crystalline compound III-6 is present. In yet another embodiment of the present invention, at least about 99% by weight of crystalline compound III-6 is present.

[0301] It has been found that compound III-6 can exist in various solid forms. Exemplary such forms include the polymorphs described herein.

[0302] In some embodiments, the solid crystalline form of compound III-6 is Form A. In some embodiments, Form A of compound III-6 has an X-ray diffraction pattern substantially similar to that shown in Figure 34A.

[0303] In some embodiments, Form A of compound III-6 has a differential scanning calorimetry (DSC) pattern substantially similar to that shown in Figure 34B. In some embodiments, Form A of compound III-6 has a thermogravimetric analysis (TGA) pattern substantially similar to that shown in Figure 34C. In some embodiments, Form A of compound III-6 may be characterized by substantially similar patterns to two or more of these patterns simultaneously.

[0304] Compounds of formula (IV-1) and (IV-2) In some embodiments, the present disclosure provides a compound of formula (IV-1): [ka] or a pharmaceutically acceptable salt thereof.

[0305] In some embodiments, the present disclosure provides a compound of formula (IV-2): [ka] or a pharmaceutically acceptable salt thereof.

[0306] composition Another aspect of the present disclosure provides pharmaceutical compositions comprising the compounds disclosed herein formulated together with a pharmaceutically acceptable carrier. In particular, the present disclosure provides pharmaceutical compositions comprising the compounds 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 optimal form of administration in any given case will depend on the degree and severity of the condition being treated and the nature of the particular compound being used. For example, the disclosed compositions can be formulated as a unit dose and / or formulated for oral, subcutaneous, or intravenous administration.

[0307] Exemplary pharmaceutical compositions of the present disclosure can be used, for example, as solid, semi-solid, or liquid preparations containing one or more of the compounds of the present disclosure as an active ingredient, in admixture with organic or inorganic carriers or excipients suitable for topical, enteral, or parenteral use. The active ingredient can be combined with conventional non-toxic pharmaceutically acceptable carriers for, for example, tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the disease process or condition.

[0308] In some embodiments, the pharmaceutically acceptable composition can contain the disclosed compound and / or its pharmaceutically acceptable salt at a concentration ranging from about 0.01 to about 2.0% by weight, e.g., 0.01 to about 1% by weight, or about 0.05 to about 0.5% by weight. The composition can be formulated as a solution, suspension, ointment, capsule, or the like. The pharmaceutical composition can be prepared as an aqueous solution and can contain additional ingredients such as preservatives, buffers, tonicity agents, antioxidants, stabilizers, viscosity-adjusting ingredients, etc.

[0309] To prepare solid compositions such as tablets, the primary active ingredient can be mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn 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 present disclosure, or a non-toxic pharmaceutically acceptable salt thereof. When these preformulation compositions are referred to as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition, such that the composition can be readily subdivided into similarly effective unit dosage forms, such as tablets, pills, capsules, etc.

[0310] Pharmaceutically acceptable carriers are well known to those skilled in the art and include, for example, adjuvants, diluents, excipients, fillers, lubricants, and vehicles. In some embodiments, the carrier is a diluent, adjuvant, excipient, or vehicle. In some embodiments, the carrier is a diluent, adjuvant, or excipient. In some embodiments, the carrier is a diluent or adjuvant. In some embodiments, the carrier is an excipient. In many cases, pharmaceutically acceptable carriers are chemically inert to the active compound and non-toxic under the conditions of use. Examples of pharmaceutically acceptable carriers can include, for example, water or saline, polymers such as polyethylene glycol, carbohydrates and their derivatives, 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. Pharmaceutical carriers may also be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, etc. In addition, auxiliary substances, stabilizers, thickeners, lubricants, colorants may be used. Other examples of suitable pharmaceutical carriers are found in, for example, Remington's: The Science and Practice of Pharmacy, 22nd Ed. (Allen, Loyd V., Jr ed., Pharmaceutical Press (2012)); Modern Pharmaceutics, 5 thEd.(Alexander T.Florence,Juergen Siepmann,CRC Press(2009));Handbook of Pharmaceutical Excipients,7 th Ed. (Rowe, Raymond C.; Sheskey, Paul J.; Cook, Walter G.; Fenton, Marian E. eds., Pharmaceutical Press (2012)) (each of which is incorporated herein by reference in its entirety).

[0311] In some embodiments, the compounds of the present disclosure are formulated into pharmaceutical compositions for administration to a subject in a biologically compatible form suitable for in vivo administration. According to another aspect, the present disclosure provides pharmaceutical compositions comprising the disclosed compounds in admixture with a pharmaceutically acceptable diluent and / or carrier. A pharmaceutically acceptable carrier is "acceptable" in the sense of being compatible with the other ingredients of the composition and not harmful to the recipient thereof. As used herein, a pharmaceutically acceptable carrier can be selected from a variety of organic or inorganic materials used as ingredients in pharmaceutical formulations and incorporated as analgesics, buffers, binders, disintegrants, diluents, emulsifiers, excipients, bulking agents, glidants, solubilizers, stabilizers, suspending agents, tonicity agents, vehicles, and thickeners. Pharmaceutical additives such as antioxidants, flavoring agents, coloring agents, flavor enhancers, preservatives, and sweeteners can also be added. Examples of acceptable pharmaceutical carriers include, among others, carboxymethylcellulose, microcrystalline cellulose, glycerin, gum arabic, lactose, magnesium stearate, methylcellulose, powders, saline, sodium alginate, sucrose, starch, talc, and water. In some embodiments, the term "pharmaceutically acceptable" means approved by a federal or state regulatory agency or listed in the United States Pharmacopoeia or other generally recognized pharmacopeia for use in animals, especially humans.

[0312] Surfactants, such as detergents, are also suitable for use in the formulation. Specific examples of surfactants include polyvinylpyrrolidone, polyvinyl alcohol, copolymers of vinyl acetate and vinylpyrrolidone, polyethylene glycol, benzyl alcohol, polyoxyethylenated esters of mannitol, glycerol, sorbitol, or sorbitan, lecithin or sodium carboxymethylcellulose, or acrylic derivatives such as methacrylates, anionic surfactants such as alkali stearates, especially sodium, potassium, or ammonium stearate, calcium stearate or triethanolamine stearate, alkyl sulfates (especially sodium lauryl sulfate and sodium cetyl sulfate), sodium dodecylbenzenesulfonate, or sodium dioctyl sulfosuccinate, or fatty acids, especially those derived from coconut oil, compounds of the formula N + R'R''R'''R''''Y - cationic surfactants such as water-soluble quaternary ammonium salts of the formula: - is an anion of a strong acid, such as a halide anion, sulfate anion, and sulfonate anion), cetyltrimethylammonium bromide (one of the cationic surfactants that can be used, represented by the formula N + amine salts of R'R''R''' (where the R radicals are the same or different, optionally hydroxylated hydrocarbon radicals), octadecylamine hydrochloride (one of the cationic surfactants that can be used, as well as nonionic surfactants, such as, optionally, polyoxyethylated esters of sorbitan, especially polysorbate 80, or polyoxyethylated alkyl ethers), polyethylene glycol stearate, polyoxyethylated derivatives of castor oil, polyglycerol esters, polyoxyethylated fatty alcohols, polyoxyethylated fatty acids or copolymers of ethylene oxide and propylene oxide, and amphoteric surfactants such as substituted lauryl compounds of betaine.

[0313] When administered to a subject, the disclosed compounds and pharmaceutically acceptable carriers can be sterile.Suitable pharmaceutical carriers can also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, nonfat dry milk, glycerin, propylene glycol, polyethylene glycol 300, water, ethanol, polysorbate 20, etc.The compositions of the present invention can also contain minor amounts of wetting agents, emulsifying agents, or pH buffering agents, if desired.

[0314] The pharmaceutical preparations of the present disclosure are prepared by methods well known in the pharmaceutical field.If necessary, one or more auxiliary components (for example, buffers, flavorings, surfactants, etc.) can also be added.The choice of carrier is determined by the solubility and chemical properties of the compound, the selected administration route, and standard pharmaceutical practice.

[0315] Additionally, the compounds and / or compositions of the present disclosure are administered to a human or animal subject by known procedures, including oral, sublingual, or buccal administration, hi some embodiments, the compounds and / or compositions are administered orally.

[0316] In solid dosage forms for oral administration (e.g., capsules, tablets, pills, dragees, powders, granules, etc.), the compositions may comprise one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) sorbents, such as, for example, agar, calcium carbonate, or the like; The composition may be mixed with any of the following: (1) disintegrating agents such as potato or tapioca starch, alginic acid, certain silicates, or sodium carbonate; (2) dissolution retarders such as paraffin; (3) absorption accelerators such as quaternary ammonium compounds; (4) wetting agents such as acetyl alcohol or glycerol monostearate; (5) absorbents such as kaolin or bentonite clay; (6) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof; and (7) coloring agents. For capsules, tablets, and pills, the composition may also contain buffering agents. Solid compositions of a similar type may also be used as fillers in soft- and hard-filled gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0317] For oral administration, the compounds of the present disclosure may be provided in the form of capsules, tablets, powders, granules, or as a suspension or solution. Capsule formulations may be gelatin, soft gel, or solid. Tablet and capsule formulations may further contain one or more adjuvants, binders, diluents, disintegrants, excipients, fillers, or lubricants, each of which is well known in the art. Examples include carbohydrates such as lactose or sucrose, anhydrous dibasic calcium phosphate, corn starch, mannitol, xylitol, cellulose or its derivatives, microcrystalline cellulose, gelatin, stearates, silicon dioxide, talc, sodium starch glycolate, acacia, flavorings, preservatives, buffers, disintegrants, and coloring agents. Orally administered compositions may contain one or more optional agents to provide a pharmaceutically palatable formulation, such as sweeteners such as fructose, aspartame, or saccharin, flavorings such as peppermint, wintergreen oil, or cherry, colorings, and preservatives.

[0318] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants, or dispersants. Molded tablets can be made by molding a mixture of the subject composition moistened with an inert liquid diluent in a suitable machine. Tablets, as well as other solid dosage forms such as sugar-coated tablets, capsules, pills, and granules, can be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation field, as needed.

[0319] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the subject compositions, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, cyclodextrins, and mixtures thereof.

[0320] Suspensions may contain, in addition to the subject composition, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0321] Formulations for rectal or vaginal administration can be made by mixing the subject compositions with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, a suppository wax, or a salicylate, and can be provided as suppositories that are solid at room temperature but liquid at body temperature and therefore melt in the body cavity to release the active agent(s).

[0322] Dosage forms for transdermal administration of the subject compositions include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active ingredient may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and any preservatives, buffers, or propellants that are required.

[0323] Ointments, pastes, creams and gels may contain, in addition to the subject composition, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0324] Powders and sprays can contain, in addition to the subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0325] The compositions and compounds of the present disclosure can also be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal formulation, or solid particles containing the compound. Non-aqueous (e.g., fluorocarbon propellant) suspensions can also be used. Ultrasonic nebulizers can be used to minimize exposure of the drug to shear, which can result in degradation of the compound contained in the composition. Aqueous aerosols are typically made by formulating an aqueous solution or suspension of the composition with conventional pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers vary depending on the requirements of the particular composition, but typically include non-ionic surfactants (Tween, Pluronic®, or polyethylene glycol), non-toxic proteins such as serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars, or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

[0326] Pharmaceutical compositions of the present disclosure suitable for parenteral administration include the subject compositions in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately before use, which may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0327] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate and cyclodextrin. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. For example, the crystalline forms provided herein may be milled to obtain a particular particle size, and in at least some embodiments, such crystalline forms can remain substantially stable upon milling.

[0328] For example, provided herein are compositions suitable for subcutaneous administration comprising a suspension of the disclosed crystalline forms. Subcutaneous administration may be advantageous over intravenous administration, which typically requires medical attention and can be more painful and invasive. A typical dose of the crystalline compound can be about 1 mg to about 8 mg of compound when administered to a patient. In one embodiment, disclosed herein are pharmaceutically acceptable compositions formed from the disclosed crystalline forms, for example, by combining the crystalline form with excipients and / or solvents.

[0329] In one embodiment, the compositions provided herein comprise a disclosed crystalline form suitable for subcutaneous administration at a dosage level sufficient to deliver about 0.001 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 50 mg / kg, about 0.1 mg / kg to about 40 mg / kg, about 0.5 mg / kg to about 30 mg / kg, about 0.001 mg / kg to about 4 mg / kg, about 0.1 mg / kg to about 10 mg / kg, or about 1 mg / kg to about 25 mg / kg of a subject's body weight, administered daily, once or more daily, every other day, every 3 or 4 days, weekly, every 2 weeks, every 3 weeks, or every 4 weeks. In certain embodiments, the desired dose can be delivered using multiple administrations (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 administrations). In certain embodiments, administration can be once, twice, or three times per week.

[0330] Treatment can be continued for a long or short period of time as needed. The composition can be administered, for example, in a dosage regimen of 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 one year, or indefinitely. The treatment period can be terminated when a desired result, e.g., a weight loss goal, is achieved. The treatment regimen can include a correction phase in which a dose sufficient to cause weight loss is administered, followed by a maintenance phase in which a lower dose sufficient to cause weight gain is administered, for example. While appropriate maintenance doses are likely to be found at the lower end of the dosage ranges provided herein, correction and maintenance doses can be readily established for individual subjects by those skilled in the art based on the disclosure herein without undue experimentation. Maintenance doses can be used to maintain the weight of subjects whose weight has previously been controlled by other means, including diet and exercise, obesity treatments such as bypass surgery or banding surgery, or treatment with other pharmacological agents.

[0331] In certain embodiments, provided herein are pharmaceutical compositions comprising a crystalline form of Compound I, II, or III described herein, or a solvate thereof. In certain embodiments, provided herein are pharmaceutical compositions comprising a crystalline form of Compound I-1 described herein, including, for example, Form A, Form B, or Form C, or a solvate thereof. In certain embodiments, provided herein are pharmaceutical compositions comprising a crystalline form of Compound III-1 described herein, including, for example, Form A, Form B, Form C, Form D, Form E, or Form F, or a solvate thereof. In certain embodiments, provided herein are pharmaceutical compositions comprising a compound of Formula IV-1 or IV-2 described herein, or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical compositions provided herein comprise one or more pharmaceutically acceptable excipients described herein.

[0332] kit In one embodiment, a kit for treating or alleviating a contemplated disease or disorder is provided. For example, the disclosed kit includes a disclosed crystalline compound, e.g., a crystalline form of the compound of Formula (I), disposed in a first container. In some embodiments, the kit may further include a pharmaceutically acceptable excipient disposed in a second container. Such contemplated kits may include instructions for preparing a pharmaceutical composition suitable for administration to a patient from the crystalline form. For example, the instructions may describe preparing a pharmaceutically acceptable form for patient administration by mixing the crystalline compound disclosed herein with an excipient. The disclosed kit may further include instructions for administering the resulting composition to a patient.

[0333] In one embodiment, a kit for treating or alleviating a hypothetical disease or disorder is provided. For example, the disclosed kit includes a compound described herein disposed in a first container. In some embodiments, the kit may further include a pharmaceutically acceptable excipient disposed in a second container. Such a contemplated kit may include instructions for preparing a pharmaceutical composition suitable for administration to a patient from the disclosed compound. For example, the instructions may describe preparing a pharmaceutically acceptable form for patient administration by mixing the compound disclosed herein with an excipient. The disclosed kit may further include instructions for administering the resulting composition to a patient.

[0334] process In some embodiments, a process for preparing the disclosed crystalline form of the compound of Formula (I) is contemplated herein, the process comprising: a) preparing a solution of the compound of Formula (I); b) adjusting the temperature so that a solid crystalline form of the compound of Formula (I) precipitates from the solution; and c) isolating the solid crystalline form. In some embodiments, preparing the solution of the compound of Formula (I) comprises mixing a solution of compound I-1 with a solution of acid X, where X is as defined and described in embodiments herein. In some embodiments, the solution of the compound of Formula (I) comprises a solvent selected from methanol, ethanol, acetone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, acetonitrile, t-butyl methyl ether, dichloromethane, tetrahydrofuran, 1,4-dioxane, benzyl alcohol, 2-MeTHF, IPAc, and MtBE. In some embodiments, the solution of the compound of Formula (I) comprises a solvent selected from those described in the Examples herein.

[0335] In some embodiments, contemplated herein is a process for preparing the disclosed crystalline form of the compound of Formula (II), the process comprising: a) preparing a solution of the compound of Formula (II); b) adjusting the temperature so that a solid crystalline form of the compound of Formula (II) precipitates from the solution; and c) isolating the solid crystalline form. In some embodiments, preparing the solution of the compound of Formula (II) comprises mixing a solution of compound II-1 with a solution of acid X, where X is as defined and described in embodiments herein. In some embodiments, the solution of the compound of Formula (II) comprises a solvent selected from methanol, ethanol, acetone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, acetonitrile, t-butyl methyl ether, dichloromethane, tetrahydrofuran, 1,4-dioxane, benzyl alcohol, 2-MeTHF, IPAc, and MtBE. In some embodiments, the solution of the compound of Formula (II) comprises a solvent selected from those described in the Examples herein.

[0336] In some embodiments, contemplated herein is a process for preparing the disclosed crystalline form of the compound of Formula (III), the process comprising: a) preparing a solution of the compound of Formula (III); b) adjusting the temperature so that a solid crystalline form of the compound of Formula (III) precipitates from the solution; and c) isolating the solid crystalline form. In some embodiments, preparing the solution of the compound of Formula (III) comprises mixing a solution of compound III-1 with a solution of acid X, where X is as defined and described in embodiments herein. In some embodiments, the solution of the compound of Formula (III) comprises a solvent selected from methanol, ethanol, acetone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, acetonitrile, t-butyl methyl ether, dichloromethane, tetrahydrofuran, 1,4-dioxane, benzyl alcohol, 2-MeTHF, IPAc, and MtBE. In some embodiments, the solution of the compound of Formula (III) comprises a solvent selected from those described in the Examples herein.

[0337] In some embodiments, a solution of a compound of Formula (I), (II), or (III) comprises a solvent selected from MeOH, EtOH, acetone, IPAc, MtBE, acetonitrile, EtOAc, IPA, THF, heptane, 1,4 dioxane, DMF, and water. In some embodiments, a solution of a compound of Formula (I), (II), or (III) comprises a solvent of acetone / heptane (1:2, v / v). In some embodiments, a solution of a compound of Formula (I), (II), or (III) comprises a solvent of acetone / MTBE (1:4, v / v). In some embodiments, a solution of a compound of Formula (I), (II), or (III) comprises a solvent of THF / heptane (2:3, v / v). In some embodiments, a solution of a compound of Formula (I), (II), or (III) comprises a solvent of ethyl acetate / heptane (1:1, v / v). In some embodiments, a solution of a compound of Formula (I), (II), or (III) comprises a solvent of THF / MTBE (1:4, v / v). In some embodiments, a solution of a compound of Formula (I), (II), or (III) comprises a solvent of THF / ACN (2:1, v / v). In some embodiments, a solution of a compound of Formula (I), (II), or (III) comprises a solvent of EtOH / water (50:50, v / v). In some embodiments, a solution of a compound of Formula (I), (II), or (III) comprises a solvent of ACN / water (80:20, v / v). In some embodiments, a solution of a compound of Formula (I), (II), or (III) comprises a solvent of THF / water (85:15, v / v). In some embodiments, a solution of a compound of Formula (I), (II), or (III) comprises a solvent of acetone / water (60:40, v / v). In some embodiments, a solution of a compound of Formula (I), (II), or (III) comprises a solvent of THF / heptane (2:3, v / v). In some embodiments, a solution of a compound of Formula (I), (II), or (III) comprises a solvent of THF / MTBE (1:4, v / v). In some embodiments, a solution of a compound of Formula (I), (II), or (III) comprises a solvent of MeOH / MTBE (1:4, v / v). In some embodiments, a solution of a compound of Formula (I), (II), or (III) comprises a solvent of DMF / acetone water.

[0338] In some embodiments, heating the solution comprises heating the solution to about 50° C. In some embodiments, adjusting the temperature comprises cooling the solution to about 25° C.

[0339] In another embodiment, the disclosed process further comprises a purification step to separate the enantiomers of compound III-1, thereby forming compound I-1. [ka]

[0340] In another embodiment, the disclosed process further comprises a purification step of separating the enantiomers of compound III-1 by subjecting compound III-1 to SMB separation, for example, as described in Example 1-A, thereby forming compounds I-1 and II-1. [ka]

[0341] In another embodiment, the disclosed process further comprises racemizing II-1, thereby forming a mixture of I-1 and II-1 (or III-1). [ka]

[0342] In another embodiment, the disclosed process further comprises racemizing compound II-1, thereby forming compound III-1 (a mixture of I-1 and II-1); [ka] For example, as explained in Example 2-A.

[0343] In another embodiment, the disclosed process further comprises coupling compound 2 with compound 3, thereby forming compound III-1. [ka]

[0344] In another embodiment, the disclosed process further comprises converting compound 4 to compound 3. [ka]

[0345] In another embodiment, the disclosed process further comprises converting compound 5 to compound 4. [ka]

[0346] In another embodiment, the disclosed process further comprises coupling compound 6 with compound 7, thereby forming compound 5. [ka]

[0347] In some embodiments, the disclosed process comprises deuteration of compound III-1 followed by a purification step to separate the enantiomers, thereby forming compounds IV-1 and IV-2; [ka] For example, as described in Example 3-A.

[0348] method The compounds and compositions described herein are generally useful for inhibiting kinases or mutants thereof. In some embodiments, the kinase inhibited by the compounds and compositions described herein is phosphatidylinositol 3-kinase (PI3K). In some embodiments, the kinase inhibited by the compounds and compositions described herein is one or more of PI3Kα, PI3Kδ, and PI3Kγ. In some embodiments, the kinase inhibited by the compounds and compositions described herein is PI3Kα. In some embodiments, the kinase inhibited by the compounds and compositions described herein is PI3Kα containing at least one of the following mutations: E542X, E545X, Q546X, H1047X, and G1049X, where X is any amino acid other than the wild-type. In some embodiments, the kinase inhibited by the compounds and compositions described herein is a PI3K alpha that contains 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 PI3K alpha that contains at least one of the following mutations: E542K, E545K, and H1047R. In some embodiments, the kinase inhibited by the compounds and compositions described herein is PI3Ka containing at least one of the following mutations: E81X, R88X, R93X, G106X, R108X, K111X, G118X, A222X, V344X, N345X, G364X, E365X, C420X, E453X, P539X, E542X, E545X, Q546X, D549X, F667X, H701X, M1004X, Y1021X, T1025X, M1040X, M1043X, N1044X, H1047X, G1049X, I1058X, A1066X, and N1068X, where X is any amino acid other than the wild-type.In some embodiments, the kinases inhibited by the compounds and compositions described herein are E81K, R88Q, R93Q, R93W, G106R, G106V, R108H, K111N, K111E, G118D, A222V, V344A, N345K, G364R, E365K, C420R, E453A, E453K, P539R, E542K, E542Q, E545A, E545G, E545K, E545Q, Q and PI3Ka containing at least one of the following mutations: 546E, Q546K, Q546L, Q546P, Q546R, D549N, F667L, H701P, M1004I, Y1021C, T1025A, T1025N, M1040L, M1043I, M1043V, N1044K, H1047R, H1047L, H1047Y, G1049R, G1049S, I1058F, A1066V, and N1068fs*4.

[0349] The compound or composition of the present disclosure can be useful in the application that benefits from the inhibition of PI3K enzyme.For example, the PI3K inhibitor of the present disclosure is generally useful for treating cell proliferation disease.The compound or composition of the present disclosure can be useful in the application that benefits from the inhibition of PI3K α enzyme.For example, the PI3K α inhibitor of the present disclosure is generally useful for treating cell proliferation disease.

[0350] Dysregulation of PI3K, often through activation of Aid, enhances survival and is one of the most common events in human cancers, occurring at multiple levels. The tumor suppressor gene PTEN, which dephosphorylates phosphoinositides at the 3' position of the inositol ring, thereby antagonizing PI3K activity, is functionally deleted in a variety of tumors. In other tumors, the p110 alpha isoform, PIK3CA, and Akt genes are amplified, and increased protein expression of their gene products has been demonstrated in several human cancers. Mutations and translocations of p85 alpha, which contribute to the upregulation of the p85-p110 complex, have been reported in human cancers. Finally, somatic missense mutations in PIK3CA that activate downstream signaling pathways have been reported with considerable frequency in various human cancers (Kang et al., Proc. Natl. Acad. Sci. USA 102:802 (2005); Samuels et al., Science 304:554 (2004); Samuels et al., Cancer Cell 7:561-573 (2005)). These observations indicate that dysregulation of phosphoinositol-3 kinase and the upstream and downstream components of this signaling pathway is one of the most common dysregulations associated with human cancer and proliferative diseases (Parsons et al., Nature 436:792 (2005); Hennessey et al., Nature Rev. Drug Disc. 4:988-1004 (2005)).

[0351] Treatment of the disorder The provided compounds are inhibitors of PI3K α and are therefore useful for treating one or more disorders associated with the activity of PI3K α or its mutants. Accordingly, in certain embodiments, the present invention provides a method for treating a PI3K α-mediated disorder in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, or any of the foregoing pharmaceutically acceptable compositions. In certain embodiments, the present invention provides a method for treating a PI3K α-mediated disorder in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable composition thereof. In some embodiments, the subject has a mutant PI3K α. In some embodiments, the subject has a PI3K α containing at least one of the following mutations: H1047R, E542K, and E545K. In some embodiments, the subject has a PI3K alpha that contains 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 a PI3K alpha that contains at least one of the following mutations: E81X, R88X, R93X, G106X, R108X, K111X, G118X, A222X, V344X, N345X, G364X, E365X, C420X, E453X, P539X, E542X, E545X, Q546X, D549X, F667X, H701X, M1004X, Y1021X, T1025X, M1040X, M1043X, N1044X, H1047X, G1049X, I1058X, A1066X, and N1068X, where X is any amino acid other than wild-type.In some embodiments, the subject has one of the following markers: E81K, R88Q, R93Q, R93W, G106R, G106V, R108H, K111N, K111E, G118D, A222V, V344A, N345K, G364R, E365K, C420R, E453A, E453K, P539R, E542K, E542Q, E545A, E545G, E545K, E545Q, Q546E, Q546K, Q54 6L, Q546P, Q546R, D549N, F667L, H701P, M1004I, Y1021C, T1025A, T1025N, M1040L, M1043I, M1043V, N1044K, H1047R, H1047L, H1047Y, G1049R, G1049S, I1058F, A1066V, and N1068fs*4 mutations.

[0352] As used herein, the term "PI3K α-mediated" disorder, disease, and / or condition refers to any disease or other deleterious condition in which PI3K α or a mutant thereof is known to play a role. Accordingly, another embodiment of the present invention relates to treating or reducing the severity of one or more diseases in which PI3K α or a mutant thereof is known to play a role. Such PI3K α-mediated disorders include, but are not limited to, cell proliferative disorders (e.g., cancer). In some embodiments, the PI3K α-mediated disorder is a disorder mediated by mutant PI3K α. In some embodiments, the PI3K α-mediated disorder is a disorder mediated by PI3K α containing at least one of the following mutations: H1047R, E542K, and E545K. In some embodiments, the subject has a PI3K alpha that contains 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 a PI3K alpha that contains at least one of the following mutations: E81X, R88X, R93X, G106X, R108X, K111X, G118X, A222X, V344X, N345X, G364X, E365X, C420X, E453X, P539X, E542X, E545X, Q546X, D549X, F667X, H701X, M1004X, Y1021X, T1025X, M1040X, M1043X, N1044X, H1047X, G1049X, I1058X, A1066X, and N1068X, where X is any amino acid other than wild-type.In some embodiments, the subject has one of the following markers: E81K, R88Q, R93Q, R93W, G106R, G106V, R108H, K111N, K111E, G118D, A222V, V344A, N345K, G364R, E365K, C420R, E453A, E453K, P539R, E542K, E542Q, E545A, E545G, E545K, E545Q, Q546E, Q546K, Q54 6L, Q546P, Q546R, D549N, F667L, H701P, M1004I, Y1021C, T1025A, T1025N, M1040L, M1043I, M1043V, N1044K, H1047R, H1047L, H1047Y, G1049R, G1049S, I1058F, A1066V, and N1068fs*4 mutations.

[0353] In some embodiments, the present invention provides methods for treating a cell proliferative disorder, the methods comprising administering a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition of any of the foregoing, to a patient in need of treatment. In some embodiments, the present invention provides methods for treating a cell proliferative disorder, the methods comprising administering a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable composition thereof, to a patient in need of treatment.

[0354] In some embodiments, the method of treatment includes 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 a therapeutically effective amount of the provided compound to treat, inhibit, and / or prevent a condition or disease in the subject in need of such treatment. In some embodiments, the subject has a mutant PI3K α. In some embodiments, the subject has a PI3K α containing at least one of the following mutations: H1047R, E542K, or E545K. In some embodiments, the subject has a PI3K α 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 a PI3K alpha that contains at least one of the following mutations: E81X, R88X, R93X, G106X, R108X, K111X, G118X, A222X, V344X, N345X, G364X, E365X, C420X, E453X, P539X, E542X, E545X, Q546X, D549X, F667X, H701X, M1004X, Y1021X, T1025X, M1040X, M1043X, N1044X, H1047X, G1049X, I1058X, A1066X, and N1068X, where X is any amino acid other than wild-type.In some embodiments, the subject has one of the following markers: E81K, R88Q, R93Q, R93W, G106R, G106V, R108H, K111N, K111E, G118D, A222V, V344A, N345K, G364R, E365K, C420R, E453A, E453K, P539R, E542K, E542Q, E545A, E545G, E545K, E545Q, Q546E, Q546K, Q54 6L, Q546P, Q546R, D549N, F667L, H701P, M1004I, Y1021C, T1025A, T1025N, M1040L, M1043I, M1043V, N1044K, H1047R, H1047L, H1047Y, G1049R, G1049S, I1058F, A1066V, and N1068fs*4 mutations.

[0355] In some embodiments, the method of treatment includes 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 a therapeutically effective amount of the composition to treat, inhibit, and / or prevent a condition or disease in the subject in need of such treatment. In some embodiments, the subject has a mutant PI3K α. In some embodiments, the subject has a PI3K α containing at least one of the following mutations: H1047R, E542K, and E545K. In some embodiments, the subject has a PI3K α 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 a PI3K alpha that contains at least one of the following mutations: E81X, R88X, R93X, G106X, R108X, K111X, G118X, A222X, V344X, N345X, G364X, E365X, C420X, E453X, P539X, E542X, E545X, Q546X, D549X, F667X, H701X, M1004X, Y1021X, T1025X, M1040X, M1043X, N1044X, H1047X, G1049X, I1058X, A1066X, and N1068X, where X is any amino acid other than wild-type.In some embodiments, the subject has one of the following markers: E81K, R88Q, R93Q, R93W, G106R, G106V, R108H, K111N, K111E, G118D, A222V, V344A, N345K, G364R, E365K, C420R, E453A, E453K, P539R, E542K, E542Q, E545A, E545G, E545K, E545Q, Q546E, Q546K, Q54 6L, Q546P, Q546R, D549N, F667L, H701P, M1004I, Y1021C, T1025A, T1025N, M1040L, M1043I, M1043V, N1044K, H1047R, H1047L, H1047Y, G1049R, G1049S, I1058F, A1066V, and N1068fs*4 mutations.

[0356] Another aspect of the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or any of the aforementioned pharmaceutical compositions, for use in the treatment of a disorder as described herein. Another aspect of the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, or any of the aforementioned pharmaceutical compositions, for the treatment of a disorder as described herein. Similarly, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating a disorder as described herein.

[0357] Cell proliferative disorders In some embodiments, the disorder is a cell proliferative disorder. In some embodiments, the cell proliferative disorder is cancer. In some embodiments, the cancer is a tumor. In some embodiments, the cancer is a solid tumor. In some embodiments, the cell proliferative disorder is tumor and / or cancerous cell proliferation. In some embodiments, the cell proliferative disorder is a tumor. In some embodiments, the cell proliferative disorder is a solid tumor. In some embodiments, the cell proliferative disorder is cancerous cell proliferation.

[0358] In some embodiments, the solid tumor has a PI3K α containing at least one of the following mutations: E542X, E545X, Q546X, H1047X, and G1049X, where X is any amino acid other than wild-type. In some embodiments, the solid tumor has a PI3K α 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 a PI3K α containing at least one of the following mutations: H1047R, E542K, and E545K. In some embodiments, the solid tumor has a PI3K alpha that contains at least one of the following mutations: E81X, R88X, R93X, G106X, R108X, K111X, G118X, A222X, V344X, N345X, G364X, E365X, C420X, E453X, P539X, E542X, E545X, Q546X, D549X, F667X, H701X, M1004X, Y1021X, T1025X, M1040X, M1043X, N1044X, H1047X, G1049X, I1058X, A1066X, and N1068X, where X is any amino acid other than wild-type. In some embodiments, the solid tumor is one of the following: E81K, R88Q, R93Q, R93W, G106R, G106V, R108H, K111N, K111E, G118D, A222V, V344A, N345K, G364R, E365K, C420R, E453A, E453K, P539R, E542K, E542Q, E545A, E545G, E545K, E545Q, Q546E, Q546K, Q546R ... The patient has a PI3Kα containing at least one of the following mutations: 46L, Q546P, Q546R, D549N, F667L, H701P, M1004I, Y1021C, T1025A, T1025N, M1040L, M1043I, M1043V, N1044K, H1047R, H1047L, H1047Y, G1049R, G1049S, I1058F, A1066V, and N1068fs*4.

[0359] In some embodiments, the cancer is selected from the group consisting of sarcoma, lung, bronchial, prostate, breast (including sporadic breast cancer and Cowden's disease), pancreatic, gastrointestinal, colon, rectal, carcinoma, colon carcinoma, adenoma, colorectal adenoma, thyroid, liver, intrahepatic bile duct, hepatocellular, adrenal, abdominal, stomach, glioma, glioblastoma, endometrial, melanoma, kidney, renal pelvis, bladder, uterine corpus, cervix, vagina, ovary (including clear cell ovarian carcinoma), multiple myeloma, esophagus, leukemia, acute myeloma, and ovarian cancer. The cancer is selected from myeloid leukemia, chronic myeloid leukemia, lymphocytic leukemia, myeloid leukemia, brain, brain cancer, oral cavity and pharynx, larynx, small intestine, non-Hodgkin's lymphoma, villous colon adenoma, tumor, epithelial tumor, lymphoma, breast cancer, basal cell carcinoma, squamous cell carcinoma, actinic keratosis, neck, head, polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, and Waldenstrom's macroglobulinemia.

[0360] In some embodiments, the cancer is selected from lung, bronchus, prostate, breast (including sporadic breast cancer and Cowden's disease), pancreatic, gastrointestinal, colon, rectum, thyroid, liver, intrahepatic bile duct, hepatocellular, adrenal, abdominal, stomach, endometrium, kidney, renal pelvis, bladder, uterine corpus, cervix, vagina, ovary (including clear cell ovarian carcinoma), esophagus, leukemia, acute myeloid leukemia, chronic myeloid leukemia, lymphocytic leukemia, myeloid leukemia, brain, oral cavity and pharynx, larynx, small intestine, neck, and head. In some embodiments, the cancer is selected from sarcoma, carcinoma, colon cancer, adenoma, colorectal adenoma, glioma, glioblastoma, melanoma, multiple myeloma, brain cancer, non-Hodgkin's lymphoma, villous colon adenoma, tumor, epithelial tumor, lymphoma, breast cancer, basal cell carcinoma, squamous cell carcinoma, actinic keratosis vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, and Waldenstrom's macroglobulinemia.

[0361] In some embodiments, the cancer is selected from lung, bronchus, prostate, breast (including sporadic breast cancer and Cowden's disease), pancreas, gastrointestinal, colon, rectum, thyroid, liver, intrahepatic bile duct, hepatocellular, adrenal, abdomen, stomach, endometrium, kidney, renal pelvis, bladder, uterine corpus, 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 selected from breast, brain, cervix, endometrium, esophagus, lymph node, kidney, large intestine, liver, lung, ovary, pancreas, penis, prostate, skin, small intestine, abdomen, thyroid, head and neck, thymus, and bladder. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is acute myeloid leukemia, chronic myeloid leukemia, lymphocytic leukemia, or myeloid leukemia.

[0362] In some embodiments, the cancer is breast cancer (including sporadic breast cancer and Cowden's disease). In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is ER+ 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's disease.

[0363] In some embodiments, the cancer is ovarian cancer. In some embodiments, the ovarian cancer is clear cell ovarian cancer.

[0364] In some embodiments, the cancer is squamous cell carcinoma. In some embodiments, the cancer is squamous cell carcinoma of the head and neck.

[0365] In some embodiments, the cancer is cervical cancer.

[0366] In some embodiments, the cell proliferative disorder has mutant PI3K α. In some embodiments, the cancer has mutant PI3K α. In some embodiments, the breast cancer has mutant PI3K α. In some embodiments, the ovarian cancer has mutant PI3K α. In some embodiments, the clear cell ovarian cancer has mutant PI3K α.

[0367] In some embodiments, the cell proliferative disorder has a PI3K α that contains at least one of the following mutations: H1047R, E542K, and E545K. In some embodiments, the cell proliferative disorder has a PI3K α that contains 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 cell proliferative disorder has a PI3K alpha that contains at least one of the following mutations: E81X, R88X, R93X, G106X, R108X, K111X, G118X, A222X, V344X, N345X, G364X, E365X, C420X, E453X, P539X, E542X, E545X, Q546X, D549X, F667X, H701X, M1004X, Y1021X, T1025X, M1040X, M1043X, N1044X, H1047X, G1049X, I1058X, A1066X, and N1068X, where X is any amino acid other than the wild-type. In some embodiments, the cell proliferative disorder is one of the following: E81K, R88Q, R93Q, R93W, G106R, G106V, R108H, K111N, K111E, G118D, A222V, V344A, N345K, G364R, E365K, C420R, E453A, E453K, P539R, E542K, E542Q, E545A, E545G, E545K, E545Q, Q546E, Q546K, Q The patient has a PI3Kα that contains at least one of the following mutations: 546L, Q546P, Q546R, D549N, F667L, H701P, M1004I, Y1021C, T1025A, T1025N, M1040L, M1043I, M1043V, N1044K, H1047R, H1047L, H1047Y, G1049R, G1049S, I1058F, A1066V, and N1068fs*4.

[0368] In some embodiments, the cancer has a PI3K alpha that contains at least one of the following mutations: H1047R, E542K, and E545K. In some embodiments, the cancer has a PI3K alpha that contains 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 a PI3K alpha that contains at least one of the following mutations: E81X, R88X, R93X, G106X, R108X, K111X, G118X, A222X, V344X, N345X, G364X, E365X, C420X, E453X, P539X, E542X, E545X, Q546X, D549X, F667X, H701X, M1004X, Y1021X, T1025X, M1040X, M1043X, N1044X, H1047X, G1049X, I1058X, A1066X, and N1068X, where X is any amino acid other than wild-type. In some embodiments, the cancer is E81K, R88Q, R93Q, R93W, G106R, G106V, R108H, K111N, K111E, G118D, A222V, V344A, N345K, G364R, E365K, C420R, E453A, E453K, P539R, E542K, E542Q, E545A, E545G, E545K, E545Q, Q546E, Q546K, Q54 6L, Q546P, Q546R, D549N, F667L, H701P, M1004I, Y1021C, T1025A, T1025N, M1040L, M1043I, M1043V, N1044K, H1047R, H1047L, H1047Y, G1049R, G1049S, I1058F, A1066V, and N1068fs*4 mutations.

[0369] In some embodiments, the breast cancer has a PI3K α that contains at least one of the following mutations: H1047R, E542K, and E545K. In some embodiments, the breast cancer has a PI3K α that contains 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 a PI3K alpha that contains at least one of the following mutations: E81X, R88X, R93X, G106X, R108X, K111X, G118X, A222X, V344X, N345X, G364X, E365X, C420X, E453X, P539X, E542X, E545X, Q546X, D549X, F667X, H701X, M1004X, Y1021X, T1025X, M1040X, M1043X, N1044X, H1047X, G1049X, I1058X, A1066X, and N1068X, where X is any amino acid other than wild-type. In some embodiments, the breast cancer is E81K, R88Q, R93Q, R93W, G106R, G106V, R108H, K111N, K111E, G118D, A222V, V344A, N345K, G364R, E365K, C420R, E453A, E453K, P539R, E542K, E542Q, E545A, E545G, E545K, E545Q, Q546E, Q546K, Q54 6L, Q546P, Q546R, D549N, F667L, H701P, M1004I, Y1021C, T1025A, T1025N, M1040L, M1043I, M1043V, N1044K, H1047R, H1047L, H1047Y, G1049R, G1049S, I1058F, A1066V, and N1068fs*4 mutations.

[0370] In some embodiments, the ovarian cancer has a PI3K alpha that contains at least one of the following mutations: H1047R, E542K, and E545K. In some embodiments, the ovarian cancer has a PI3K alpha that contains 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 a PI3K alpha that contains at least one of the following mutations: E81X, R88X, R93X, G106X, R108X, K111X, G118X, A222X, V344X, N345X, G364X, E365X, C420X, E453X, P539X, E542X, E545X, Q546X, D549X, F667X, H701X, M1004X, Y1021X, T1025X, M1040X, M1043X, N1044X, H1047X, G1049X, I1058X, A1066X, and N1068X, where X is any amino acid other than wild-type. In some embodiments, the ovarian cancer is one of the following: E81K, R88Q, R93Q, R93W, G106R, G106V, R108H, K111N, K111E, G118D, A222V, V344A, N345K, G364R, E365K, C420R, E453A, E453K, P539R, E542K, E542Q, E545A, E545G, E545K, E545Q, Q546E, Q546K, Q54 6L, Q546P, Q546R, D549N, F667L, H701P, M1004I, Y1021C, T1025A, T1025N, M1040L, M1043I, M1043V, N1044K, H1047R, H1047L, H1047Y, G1049R, G1049S, I1058F, A1066V, and N1068fs*4 mutations.

[0371] In some embodiments, the clear cell ovarian cancer has a PI3K α that contains at least one of the following mutations: H1047R, E542K, and E545K. In some embodiments, the clear cell ovarian cancer has a PI3K α that contains 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 a PI3K alpha that contains at least one of the following mutations: E81X, R88X, R93X, G106X, R108X, K111X, G118X, A222X, V344X, N345X, G364X, E365X, C420X, E453X, P539X, E542X, E545X, Q546X, D549X, F667X, H701X, M1004X, Y1021X, T1025X, M1040X, M1043X, N1044X, H1047X, G1049X, I1058X, A1066X, and N1068X, where X is any amino acid other than wild-type. In some embodiments, the clear cell ovarian cancer is one of the following: E81K, R88Q, R93Q, R93W, G106R, G106V, R108H, K111N, K111E, G118D, A222V, V344A, N345K, G364R, E365K, C420R, E453A, E453K, P539R, E542K, E542Q, E545A, E545G, E545K, E545Q, Q546E, Q546K, Q The patient has a PI3Kα that contains at least one of the following mutations: 546L, Q546P, Q546R, D549N, F667L, H701P, M1004I, Y1021C, T1025A, T1025N, M1040L, M1043I, M1043V, N1044K, H1047R, H1047L, H1047Y, G1049R, G1049S, I1058F, A1066V, and N1068fs*4.

[0372] In some embodiments, the cancer is an adenoma, carcinoma, sarcoma, glioma, glioblastoma, melanoma, multiple myeloma, or lymphoma. In some embodiments, the cancer is colorectal adenoma or villous colon adenoma. In some embodiments, the cancer is colon cancer, brain cancer, breast cancer, basal cell carcinoma, or squamous cell carcinoma. In some embodiments, the cancer is a tumor or epithelial tumor. In some embodiments, the cancer is non-Hodgkin's lymphoma. In some embodiments, the cancer is actinic keratosis vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, or Waldenstrom's macroglobulinemia.

[0373] In some embodiments, the cell proliferative disorder exhibits overexpression or amplification of PI3K alpha, somatic mutations in PIK3CA, germline or somatic mutations in PTEN, or mutations and translocations in p85 alpha that play a role in upregulating the p85-p110 complex. In some embodiments, the cell proliferative disorder exhibits overexpression or amplification of PI3K alpha. In some embodiments, the cell proliferative disorder exhibits somatic mutations in PIK3CA. In some embodiments, the cell proliferative disorder exhibits germline or somatic mutations in PTEN. In some embodiments, the cell proliferative disorder exhibits mutations and translocations in p85 alpha that play a role in upregulating the p85-p110 complex.

[0374] Additional obstacles In some embodiments, the PI3Kα-mediated disorder is polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, asthma, COPD, ARDS, PROS (PI3K-associated overgrowth syndrome), venous malformations, Loeffler's syndrome, eosinophilic pneumonia, parasitic (particularly metazoan) infections (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), ), eosinophilic granuloma, eosinophil-related diseases affecting the airways caused by drug reactions, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphigus, epidermolysis bullosa acquisita, autoimmune blood disorders (e.g., hemolytic anemia, aplastic anemia, pure red blood cell anemia, idiopathic thrombocytopenia), systemic Lupus erythematosus, polychondritis, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (such as ulcerative colitis and Crohn's disease), endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), interstitial pulmonary fibrosis, psoriatic The disease is selected from the group consisting of arthritis, glomerulonephritis, cardiovascular disease, atherosclerosis, hypertension, deep vein thrombosis, stroke, myocardial infarction, unstable angina, thromboembolism, pulmonary embolism, thrombolytic disease, acute arterial ischemia, peripheral thrombotic occlusion, and diseases characterized by elevated intraocular pressure or aqueous humor secretion, such as coronary artery disease, reperfusion injury, retinopathies such as diabetic retinopathy and hyperbaric oxygen-induced retinopathy, and glaucoma.

[0375] In some embodiments, the PI3Kα-mediated disorder is polycythemia vera, essential thrombocythemia, or myelofibrosis with myeloid metaplasia. In some embodiments, the PI3Kα-mediated disorder is asthma, COPD, ARDS, PROS (PI3K-associated overgrowth syndrome), venous malformation, Loeffler's syndrome, eosinophilic pneumonia, parasitic (particularly metazoan) infection (including tropical eosinophilia), or bronchopulmonary aspergillosis. In some embodiments, the PI3Kα-mediated disorder is polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granulomatosis, eosinophil-associated diseases affecting the airways caused by drug reactions, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, or scleroderma. In some embodiments, the PI3Kα-mediated disorder is vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphigus, epidermolysis bullosa acquisita, or an autoimmune blood disorder (e.g., hemolytic anemia, aplastic anemia, pure red blood cell anemia, idiopathic thrombocytopenia, etc.). In some embodiments, the PI3Kα-mediated disorder is systemic lupus erythematosus, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, or an autoimmune inflammatory bowel disease (e.g., ulcerative colitis or Crohn's disease).

[0376] In some embodiments, the PI3Kα-mediated disorder is endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), interstitial pulmonary fibrosis, or psoriatic arthritis. In some embodiments, the PI3Kα-mediated disorder is glomerulonephritis, cardiovascular disease, atherosclerosis, hypertension, deep vein thrombosis, stroke, myocardial infarction, unstable angina, thromboembolism, pulmonary embolism, thrombolytic disease, acute arterial ischemia, peripheral thrombotic occlusion, coronary artery disease, or reperfusion injury. In some embodiments, the PI3Kα-mediated disorder is retinopathies, such as diabetic retinopathy and hyperbaric oxygen-induced retinopathy, and diseases characterized by elevated intraocular pressure and aqueous humor secretion, such as glaucoma.

[0377] Route of administration and dosage form The compounds and compositions according to the methods of the present invention may be administered using any amount and any route of administration effective for treating or reducing the severity of a disorder (e.g., a proliferative disorder). The exact amount required will vary from subject to subject, depending on the subject's species, age, general condition, severity of the infection, the particular agent, its method of administration, and the like. Preferably, the compounds of the present invention are formulated in unit dosage form for ease of administration and uniformity of dosage. As used herein, the phrase "unit dosage form" refers to a physically discrete unit of agent appropriate for the patient being treated. However, it will be understood that the total daily usage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular patient or organism will depend on a variety of factors, including the disorder and severity of the disorder being treated, the activity of the specific compound used, the specific composition used, the patient's age, weight, general health, sex, and diet, the time of administration, route of administration, and excretion rate of the specific compound used, the duration of treatment, drugs used in combination with or concurrently with the specific compound used, and similar factors well known in the medical arts.

[0378] The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (by powder, ointment, or drops), buccal tablet, oral or nasal spray, or the like. In certain embodiments, the compounds of the present invention can be administered orally or parenterally at dosage levels of about 0.01 mg / kg to about 50 mg / kg, preferably about 1 mg / kg to about 25 mg / kg of subject body weight, per day, one or more times daily to achieve the desired therapeutic effect.

[0379] 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 compound, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.In addition to inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and aromatics.

[0380] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution (USP), and isotonic sodium chloride solution. In addition, sterile fixed oils are usually used as solvents or suspending media. For this purpose, any non-irritating fixed oil, including synthetic mono- or diglycerides, may be used. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0381] Injectable preparations can be sterilized, for example, by filtration through a bacteria-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 before use.

[0382] To prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends on its rate of dissolution, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form can be accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsulated matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer used, the release rate of the compound can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0383] Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing a compound of the invention with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or a suppository wax, which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity to release the active compound.

[0384] 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 dicalcium 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, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato starch, or tapioca starch, e) solution retardants such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) humectants 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.

[0385] Solid compositions of a similar type may also be used as fillers in soft- and hard-filled gelatin capsules using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols, and the like. Solid dosage forms such as 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 used as fillers in soft- and hard-filled gelatin capsules using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols, and the like.

[0386] The active compound may also be in microencapsulated form with one or more of the excipients described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the art of pharmaceutical formulation. 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 contain, as is common practice, additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents. They may optionally contain opacifying agents and may be of a composition that releases 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 may be used include polymeric substances and waxes.

[0387] Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers, if required. Ophthalmic formulations, ear drops, and eye drops are also contemplated within the scope of the present invention. Furthermore, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the 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 providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0388] Dosage and Regimen According to the methods of the present disclosure, a compound of the present disclosure is administered to a subject in a therapeutically effective amount, e.g., to reduce or ameliorate symptoms of a disorder in the subject, which amount is readily determined by one of skill in the art based on known procedures, including analysis of titration curves established in vivo and the methods and assays disclosed herein.

[0389] In some embodiments, the method comprises administering a therapeutically effective amount of a compound of the present disclosure. In some embodiments, the therapeutically effective amount is at least about 0.0001 mg / kg body weight, at least about 0.001 mg / kg body weight, at least about 0.01 mg / kg body weight, at least about 0.05 mg / kg body weight, at least about 0.1 mg / kg body weight, at least about 0.25 mg / kg body weight, at least about 0.3 mg / kg body weight, at least about 0.5 mg / kg body weight, at least about 0.75 mg / kg body weight, at least about 1 mg / kg body weight, at least about 2 mg / kg body weight, at least about 3 mg / kg body weight, at least about 4 mg / kg body weight, at least about 5 mg / kg body weight, at least about 6 mg / kg body weight, at least about 7 mg / kg body weight, at least about 8 mg / kg body weight, at least about 9 mg / kg body weight, at least about 10 mg / kg body weight, at least about 15 mg / kg body weight, at least about 20 mg / kg body weight 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 dose recited herein may constitute an upper or lower dose range, and may be combined with any other dose to form a dose range inclusive of the upper and lower limits.

[0390] In some embodiments, the therapeutically effective amount ranges from about 0.1 mg to about 10 mg / kg body weight, from about 0.1 mg to about 6 mg / kg body weight, from about 0.1 mg to about 4 mg / kg body weight, or from about 0.1 mg to about 2 mg / kg body weight.

[0391] In some embodiments, the therapeutically effective amount is in the range of 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. In some embodiments, the therapeutically effective amount is in the range of about 1 to 2,000 mg, about 250 to 2,000 mg, about 250 to 1,500 mg, about 250 to 1,000 mg, about 250 to 750 mg, about 250 to 500 mg, about 500 to 2,000 mg, about 500 to 1,500 mg, about 500 to 1,000 mg, about 500 to 750 mg, about 750 to 2,000 mg, about 750 to 1,500 mg, about 750 to 1,000 mg, about 1,000 to 2,000 mg, about 1,000 to 1,500 mg, or about 1,500 to 2,000 mg.

[0392] In some embodiments, the method comprises a single dose or administration (e.g., as a single injection or precipitate). Alternatively, in some embodiments, the method comprises administering to a subject in need of treatment once daily, twice daily, three times daily, or four times daily for about 2 to about 28 days, or about 7 to about 10 days, or about 7 to about 15 days, or longer. In some embodiments, the method comprises chronic administration. In yet other embodiments, the method comprises administration over weeks, months, years, or decades. In yet other embodiments, the method comprises administration over weeks. In yet other embodiments, the method comprises administration over months. In yet other embodiments, the method comprises administration over years. In yet other embodiments, the method comprises administration over decades.

[0393] The dosage may vary depending on known factors such as the pharmacodynamic properties of the active ingredient and its method and route of administration, the time of administration of the active ingredient, the age, sex, health, and weight of the recipient, the nature and extent of the symptoms, type of concurrent treatment, frequency of treatment and desired effect, excretion rate, etc., all of which are readily determined and can be used by one skilled in the art to adjust or titrate the dosage and / or administration regimen.

[0394] Protein kinase inhibition According to one embodiment, the present invention relates to a method for inhibiting protein kinase activity in a biological sample, the method comprising contacting the biological sample with a compound of the present invention or a composition comprising the compound. According to another embodiment, the present invention relates to a method for inhibiting the activity of PI3K or a mutant thereof in a biological sample, the method comprising contacting the biological sample with a compound of the present invention or a composition comprising the compound. According to another embodiment, the present invention relates to a method for inhibiting the activity of PI3K α or a mutant thereof in a biological sample, the method comprising contacting the biological sample with a compound of the present invention or a composition comprising the compound. In some embodiments, the PI3K α is mutant PI3K α. In some embodiments, the PI3K α contains at least one of the following mutations: H1047R, E542K, and E545K. In some embodiments, the PI3K alpha contains at least one of the following mutations: E81X, R88X, R93X, G106X, R108X, K111X, G118X, A222X, V344X, N345X, G364X, E365X, C420X, E453X, P539X, E542X, E545X, Q546X, D549X, F667X, H701X, M1004X, Y1021X, T1025X, M1040X, M1043X, N1044X, H1047X, G1049X, I1058X, A1066X, and N1068X, where X is any amino acid other than the wild-type. In some embodiments, the PI3K alpha is selected from the group consisting of E81K, R88Q, R93Q, R93W, G106R, G106V, R108H, K111N, K111E, G118D, A222V, V344A, N345K, G364R, E365K, C420R, E453A, E453K, P539R, E542K, E542Q, E545A, E545G, E545K, E545Q, Q546E, Q54 and at least one of the following mutations: 6K, Q546L, Q546P, Q546R, D549N, F667L, H701P, M1004I, Y1021C, T1025A, T1025N, M1040L, M1043I, M1043V, N1044K, H1047R, H1047L, H1047Y, G1049R, G1049S, I1058F, A1066V, and N1068fs*4.

[0395] In another embodiment, the present invention provides a method for selectively inhibiting PI3K α over one or both of PI3K δ and PI3K γ. In some embodiments, compounds of the present invention are more than 5-fold selective for PI3K δ and PI3K γ. In some embodiments, compounds of the present invention are more than 10-fold selective for PI3K δ and PI3K γ. In some embodiments, compounds of the present invention are more than 50-fold selective for PI3K δ and PI3K γ. In some embodiments, compounds of the present invention are more than 100-fold selective for PI3K δ and PI3K γ. In some embodiments, compounds of the present invention are more than 200-fold selective for PI3K δ and PI3K γ. In some embodiments, the PI3K α is a mutant PI3K α. In some embodiments, the PI3K α contains at least one of the following mutations: H1047R, E542K, and E545K. In some embodiments, the PI3α contains at least one of the following mutations: E81X, R88X, R93X, G106X, R108X, K111X, G118X, A222X, V344X, N345X, G364X, E365X, C420X, E453X, P539X, E542X, E545X, Q546X, D549X, F667X, H701X, M1004X, Y1021X, T1025X, M1040X, M1043X, N1044X, H1047X, G1049X, I1058X, A1066X, and N1068X, where X is any amino acid other than the wild-type. In some embodiments, the PI3K alpha is selected from the group consisting of E81K, R88Q, R93Q, R93W, G106R, G106V, R108H, K111N, K111E, G118D, A222V, V344A, N345K, G364R, E365K, C420R, E453A, E453K, P539R, E542K, E542Q, E545A, E545G, E545K, E545Q, Q546E, Q54 and at least one of the following mutations: 6K, Q546L, Q546P, Q546R, D549N, F667L, H701P, M1004I, Y1021C, T1025A, T1025N, M1040L, M1043I, M1043V, N1044K, H1047R, H1047L, H1047Y, G1049R, G1049S, I1058F, A1066V, and N1068fs*4.

[0396] In another embodiment, the present invention provides a method for selectively inhibiting mutant PI3K α over wild-type PI3K α. In some embodiments, the compounds of the present invention are more than 5-fold selective for mutant PI3K α over wild-type PI3K α. In some embodiments, the compounds of the present invention are more than 10-fold selective for mutant PI3K α over wild-type PI3K α. In some embodiments, the compounds of the present invention are more than 50-fold selective for mutant PI3K α over wild-type PI3K α. In some embodiments, the compounds of the present invention are more than 100-fold selective for mutant PI3K α over wild-type PI3K α. In some embodiments, the compounds of the present invention are more than 200-fold selective for mutant PI3K α over wild-type PI3K α. In some embodiments, the mutant PI3K α contains at least one of the following mutations: H1047R, E542K, and E545K. In some embodiments, the mutant PI3K alpha contains at least one of the following mutations: E81X, R88X, R93X, G106X, R108X, K111X, G118X, A222X, V344X, N345X, G364X, E365X, C420X, E453X, P539X, E542X, E545X, Q546X, D549X, F667X, H701X, M1004X, Y1021X, T1025X, M1040X, M1043X, N1044X, H1047X, G1049X, I1058X, A1066X, and N1068X, where X is any amino acid other than the wild-type.In some embodiments, the mutant PI3K alpha is selected from the group consisting of E81K, R88Q, R93Q, R93W, G106R, G106V, R108H, K111N, K111E, G118D, A222V, V344A, N345K, G364R, E365K, C420R, E453A, E453K, P539R, E542K, E542Q, E545A, E545G, E545K, E545Q, Q546E, Q546F, Q546G, Q546H, Q546H, Q546F ... Contains at least one of the following mutations: 46K, Q546L, Q546P, Q546R, D549N, F667L, H701P, M1004I, Y1021C, T1025A, T1025N, M1040L, M1043I, M1043V, N1044K, H1047R, H1047L, H1047Y, G1049R, G1049S, I1058F, A1066V, and N1068fs*4.

[0397] As used herein, the term "biological sample" includes, but is not limited to, cell cultures or extracts thereof, biopsies or extracts thereof obtained from mammals, and blood, saliva, urine, feces, sperm, tears, or other bodily fluids or extracts thereof.

[0398] Inhibition of PI3K (e.g., PI3Kα, or a mutant thereof) activity in a biological sample is useful for a variety of purposes known to those of skill in the art, including, but not limited to, blood transfusion, organ transplantation, biological specimen storage, and bioassays.

[0399] Another embodiment of the invention relates to a method of inhibiting protein kinase activity in a patient comprising administering to the patient a compound of the invention, or a composition comprising said compound.

[0400] According to another embodiment, the present invention relates to a method for inhibiting the activity of PI3K or a mutant thereof in a patient, the method comprising administering to the patient a compound of the present invention or a composition comprising the compound. In some embodiments, the present invention relates to a method for inhibiting the activity of PI3K alpha or a mutant thereof in a patient, the method comprising administering to the patient a compound of the present invention or a composition comprising the compound. In some embodiments, the PI3K alpha is mutant PI3K alpha. In some embodiments, the PI3K alpha contains at least one of the following mutations: H1047R, E542K, and E545K. In some embodiments, the PI3K alpha contains at least one of the following mutations: E81X, R88X, R93X, G106X, R108X, K111X, G118X, A222X, V344X, N345X, G364X, E365X, C420X, E453X, P539X, E542X, E545X, Q546X, D549X, F667X, H701X, M1004X, Y1021X, T1025X, M1040X, M1043X, N1044X, H1047X, G1049X, I1058X, A1066X, and N1068X, where X is any amino acid other than the wild-type. In some embodiments, the PI3K alpha is selected from the group consisting of E81K, R88Q, R93Q, R93W, G106R, G106V, R108H, K111N, K111E, G118D, A222V, V344A, N345K, G364R, E365K, C420R, E453A, E453K, P539R, E542K, E542Q, E545A, E545G, E545K, E545Q, Q546E, Q54 and at least one of the following mutations: 6K, Q546L, Q546P, Q546R, D549N, F667L, H701P, M1004I, Y1021C, T1025A, T1025N, M1040L, M1043I, M1043V, N1044K, H1047R, H1047L, H1047Y, G1049R, G1049S, I1058F, A1066V, and N1068fs*4.

[0401] According to another embodiment, the present invention provides a method for treating a disorder mediated by PI3K or a mutant thereof in a patient in need thereof, comprising administering to the patient a compound according to the present invention or a pharmaceutically acceptable composition thereof. In some embodiments, the present invention provides a method for treating a disorder mediated by PI3K α or a mutant thereof in a patient in need thereof, comprising administering to the patient a compound according to the present invention or a pharmaceutically acceptable composition thereof. In some embodiments, the PI3K α is mutant PI3K α. In some embodiments, the PI3K α contains at least one of the following mutations: H1047R, E542K, and E545K. In some embodiments, the PI3K alpha contains at least one of the following mutations: E81X, R88X, R93X, G106X, R108X, K111X, G118X, A222X, V344X, N345X, G364X, E365X, C420X, E453X, P539X, E542X, E545X, Q546X, D549X, F667X, H701X, M1004X, Y1021X, T1025X, M1040X, M1043X, N1044X, H1047X, G1049X, I1058X, A1066X, and N1068X, where X is any amino acid other than the wild-type. In some embodiments, the PI3K alpha is selected from the group consisting of E81K, R88Q, R93Q, R93W, G106R, G106V, R108H, K111N, K111E, G118D, A222V, V344A, N345K, G364R, E365K, C420R, E453A, E453K, P539R, E542K, E542Q, E545A, E545G, E545K, E545Q, Q546E, Q54 and at least one of the following mutations: 6K, Q546L, Q546P, Q546R, D549N, F667L, H701P, M1004I, Y1021C, T1025A, T1025N, M1040L, M1043I, M1043V, N1044K, H1047R, H1047L, H1047Y, G1049R, G1049S, I1058F, A1066V, and N1068fs*4.

[0402] According to another embodiment, the present invention provides a method for inhibiting the signaling activity of PI3K α or a mutant thereof in a subject in need of treatment, comprising administering a therapeutically effective amount of a compound according to the present invention or a pharmaceutically acceptable composition thereof to a subject in need of treatment. In some embodiments, the present invention provides a method for inhibiting PI3K α signaling activity in a subject in need of treatment, comprising administering a therapeutically effective amount of a compound according to the present invention or a pharmaceutically acceptable composition thereof to a subject in need of treatment. In some embodiments, the PI3K α is mutant PI3K α. In some embodiments, the PI3K α contains at least one of the following mutations: H1047R, E542K, and E545K. In some embodiments, the subject has mutant PI3K α. In some embodiments, the subject has PI3K α containing at least one of the following mutations: H1047R, E542K, and E545K. In some embodiments, the subject has a PI3K alpha that contains at least one of the following mutations: E81X, R88X, R93X, G106X, R108X, K111X, G118X, A222X, V344X, N345X, G364X, E365X, C420X, E453X, P539X, E542X, E545X, Q546X, D549X, F667X, H701X, M1004X, Y1021X, T1025X, M1040X, M1043X, N1044X, H1047X, G1049X, I1058X, A1066X, and N1068X, where X is any amino acid other than wild-type.In some embodiments, the subject has one of the following markers: E81K, R88Q, R93Q, R93W, G106R, G106V, R108H, K111N, K111E, G118D, A222V, V344A, N345K, G364R, E365K, C420R, E453A, E453K, P539R, E542K, E542Q, E545A, E545G, E545K, E545Q, Q546E, Q546K, Q54 6L, Q546P, Q546R, D549N, F667L, H701P, M1004I, Y1021C, T1025A, T1025N, M1040L, M1043I, M1043V, N1044K, H1047R, H1047L, H1047Y, G1049R, G1049S, I1058F, A1066V, and N1068fs*4 mutations.

[0403] The compounds described herein can also inhibit PI3Kα function by incorporating them into drugs that catalyze the destruction of PI3Kα. For example, the compounds can be incorporated into proteolysis-targeting chimeras (PROTACs). PROTACs are bifunctional molecules with one portion capable of binding to an E3 ubiquitin ligase and the other portion capable of binding to a target protein for degradation by cellular protein quality control mechanisms. Once the target protein is recruited to a specific E3 ligase, it is tagged for destruction (i.e., ubiquitination) and then degraded by the proteasome. Any E3 ligase can be used. The portion of the PROTAC that binds to the E3 ligase is connected to the portion of the PROTAC that binds to the target protein via a linker consisting of a variable chain of atoms. Thus, recruitment of PI3Kα to the E3 ligase results in the destruction of the PI3Kα protein. The variable chain of atoms can include, for example, a ring, heteroatoms, and / or repeating polymer units. It can be rigid or flexible. It can be attached to the two moieties described above using standard techniques in the field of organic synthesis.

[0404] Combination therapy Depending on the particular disorder, condition, or disease to be treated, additional therapeutic agents that are normally administered to treat that condition can be administered in combination with the compounds and compositions of this invention. 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."

[0405] Furthermore, PI3K functions as a second messenger node that integrates parallel signaling pathways, and there is emerging evidence that combining PI3K inhibitors with inhibitors of other pathways may be useful in the treatment of cancer and cell proliferative disorders.

[0406] Thus, in certain embodiments, methods of treatment include administering a compound or composition of the invention in combination with one or more additional therapeutic agents, hi certain other embodiments, methods of treatment include administering a compound or composition of the invention as the only therapeutic agent.

[0407] Approximately 20-30% of human breast cancers overexpress Her-2 / neu-ErbB2, the target of the drug trastuzumab. Trastuzumab produces durable responses in some patients who express Her2 / neu-ErbB2, but only a subset of these patients respond. Recent studies have shown that this limited response rate can be significantly improved by combining trastuzumab with inhibitors of the PI3K or PI13K / AKT pathways (Chan et al., Breast Can. Res. Treat. 91:187 (2005); Woods Ignatoski et al., Brit. J. Cancer 82:666 (2000); Nagata et al., Cancer Cell 6:117 (2004)). Therefore, in certain embodiments, a method of treatment involves administering a compound or composition of the present invention in combination with trastuzumab. In certain embodiments, the cancer is a human breast cancer that overexpresses Her-2 / neu-ErbB2.

[0408] Various human malignancies express activating mutations or increased levels of Her1 / EGFR, and many antibody and small molecule inhibitors of this receptor tyrosine kinase, such as Tarceva, gefitinib, and Erbitux, have been developed. However, although EGFR inhibitors demonstrate antitumor activity in certain human tumors (e.g., NSCLC), they fail to extend the overall survival of all patients with EGFR-expressing tumors. This may be justified by the fact that many downstream targets of Her1 / EGFR, including the PI3K / Akt pathway, are frequently mutated or deregulated in various malignancies.

[0409] For example, gefitinib inhibits the growth of adenocarcinoma cell lines in in vitro assays. Nevertheless, subclones of these cell lines that are resistant to gefitinib can be selected, which show increased activation of the PI3K / Akt pathway. Downregulation or inhibition of this pathway renders the resistant subclones sensitive to gefitinib (Kokubo et al., Brit. J. Cancer 92:1711 (2005)). Furthermore, in an in vitro model of breast cancer using cell lines harboring PTEN mutations and overexpressing EGFR, inhibition of both the PI3K / Akt pathway and EGFR produced a synergistic effect (She et al., Cancer Cell 8:287-297 (2005)). These results suggest that the combination of gefitinib and PI3K / Akt pathway inhibitors is an attractive therapeutic strategy for cancer.

[0410] Thus, in certain embodiments, methods of treatment include administering a compound or composition of the present invention in combination with an inhibitor of Her1 / EGFR. In certain embodiments, methods of treatment include administering a compound or composition of the present invention in combination with one or more of Tarceva, gefitinib, and Erbitux. In certain embodiments, methods of treatment include administering a compound or composition of the present invention in combination with gefitinib. In certain embodiments, the cancer expresses an activating mutation or increased levels of Her1 / EGFR.

[0411] 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 a combined effect superior to either agent alone in a glioblastoma xenograft model (Goudar et al., Mol. Cancer. Ther. 4:101-112 (2005)).

[0412] Antiestrogens, such as tamoxifen, inhibit breast cancer growth through induction of cell cycle arrest, which requires the action of the cell cycle inhibitor p27Kip. Recently, it has been shown that activation of the Ras-Raf-MAP kinase pathway alters the phosphorylation status of p27Kip, attenuating its inhibitory activity in cell cycle arrest and thereby contributing to antiestrogen resistance (Donovan, et al., J. Biol. Chem. 276:40888, (2001)). As reported by Donovan et al., inhibition of MAPK signaling by treatment with a MEK inhibitor reversed the aberrant phosphorylation status of p27 in hormone-refractory breast cancer cell lines and restored hormone sensitivity. Similarly, phosphorylation of p27Kip by Aid also abolishes its role in cell cycle arrest (Viglietto et al., Nat. Med. 8:1145 (2002)).

[0413] Thus, in certain embodiments, the method of treatment comprises administering a compound or composition of the present invention in combination with the treatment of a hormone-dependent cancer. In certain embodiments, the method of treatment comprises administering a compound or composition of the present invention in combination with tamoxifen. In certain embodiments, the cancer is a hormone-dependent cancer, such as breast cancer or prostate cancer. This use aims to reverse the hormone resistance often seen in these cancers with conventional anticancer agents.

[0414] Hematologic cancers, such as chronic myeloid leukemia (CML), are caused by constitutively activated BCR-Abl tyrosine kinase chromosomal translocations. Affected patients respond to the small-molecule tyrosine kinase inhibitor imatinib as a result of inhibition of Abl kinase activity. However, many patients with advanced-stage disease initially respond to imatinib but subsequently relapse due to resistance-conferring mutations in the Abl kinase domain. In vitro studies have demonstrated that BCR-Abl utilizes the Ras-Raf kinase pathway to exert its effects. Furthermore, inhibiting multiple kinases within the same pathway provides additional protection against resistance-conferring mutations.

[0415] Thus, in another aspect, the compounds and compositions of the present invention 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 myeloid leukemia (CML), with the aim of reversing or preventing resistance to the at least one additional agent.

[0416] Because activation of the PI3K / Akt pathway promotes cell survival, inhibiting this pathway in combination with treatments that promote apoptosis in cancer cells, such as radiation therapy or chemotherapy, improves response (Ghobrial et al., CA Cancer J. Clin 55:178-194 (2005)). As an example, the combination of a PI3 kinase inhibitor with carboplatin demonstrated synergistic effects in both in vitro proliferation and apoptosis assays and in vivo tumor efficacy in a xenograft model of ovarian cancer (Westfall and Skinner, Mol. Cancer Ther. 4:1764-1771 (2005)).

[0417] In some embodiments, the one or more additional therapeutic agents are selected from an antibody, an antibody-drug conjugate, a kinase inhibitor, an immunomodulator, and a histone deacetylase inhibitor. Synergistic combinations of PIK3CA inhibitors with other therapeutic agents are described, for example, in Castel et al., Mol. Cell Oncol. (2014) 1(3) e963447.

[0418] In some embodiments, the one or more additional therapeutic agents are selected from the following agents or pharmaceutically acceptable salts 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. Tumor Biol. (2014) 35(10)9759-67) (e.g., crizotinib, NVP-TAE684, ceritinib, alectinib, brigatinib, entresinib, 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 ...), al. Ther. Adv. Med. Oncol. (2015) 7(3) 170-180) (e.g., trametinib, cobimetinib, binimetinib, selumetinib), ERK inhibitors (e.g., ulixertinib, MK8353, LY3214996), 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 (e.g., She et al. BMC Cancer (2016) 16, 587) (gefitinib, osimertinib, cetuximab, panitumumab), HER2 receptor inhibitors (e.g., Lopez et al. Mol.Cancer Ther. (2015) 14 (11) 2519-2526) (e.g., trastuzumab, pertuzumab, neratinib, lapatinib, lapatinib), MET inhibitors (e.g., see 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, hydroxycarbamide), antineoplastic agents (e.g., Wang et al. Cell Death & Disease (2018) 9, 739) (e.g., oxaliplatin, carboplatin, cisplatin), immunomodulatory agents (e.g., afutuzumab, lenalidomide, thalidomide, pomalidomide), CD40 inhibitors (e.g., dacetuzumab), pro-apoptotic receptor agonists (PARA) (e.g., dalnermin), 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. Oncotarget (2018) 9(24), 16619-16633) (e.g., vismodegib), 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 (e.g., see Sun et al. Am. J. Cancer Res. (2019) 9(1), 149-159, e.g., SHP099, RMC-4550, RMC-4630), BCL-2 inhibitors (e.g., see Bojarczuk et al. Blood (2018) 133(1), 70-80) (e.g., venetoclax), aromatase inhibitors (e.g., 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, ridaforimus, 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), immunoadhesins, other immune checkpoint inhibitors (see, e.g., Zappasodi et al. Cancer See Cell (2018) 33, 581-598, wherein 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, CD137, CD40, and LAG3. Immunotherapeutic agents that can act as immune checkpoint inhibitors useful in the methods of the present disclosure include PD-L1, PD-L2, CTL A4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, and / or TGFRbeta) (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 (HDIs, see, e.g., Rahmani et al. Clin. Cancer Res. (2014) 20(18), 4849-4860) (e.g., vorinostat), androgen receptor inhibitors (e.g., Thomas et al. Mol. Cancer Ther.(2013)12(11),2342-2355) (e.g., enzalutamide, abiraterone acetate, orteronel, galeterone, ceviteronel, 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).

[0419] In some embodiments, the one or more additional therapeutic agents are selected from anti-FGFR antibodies, FGFR inhibitors, cytotoxic agents, estrogen receptor-targeted therapies 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).

[0420] In some embodiments, the estrogen receptor targeted therapy is a selective estrogen receptor degrader (SERD, e.g., fulvestrant, elacestrant, giledestrant). In some embodiments, the estrogen receptor targeted therapy is a PROTAC (such as ARV-471) that degrades the estrogen receptor. In some embodiments, the endocrine therapy is an aromatase inhibitor (e.g., anastrozole, letrozole, exemestane).

[0421] In some embodiments, the one or more additional therapeutic agents are inhibitors of one or more of the CDK2, CDK4, and CDK6 enzymes. In some embodiments, the CDK inhibitor is a CDK2 inhibitor (e.g., PF-07104091). In some embodiments, the CDK inhibitor is a CDK4 inhibitor (e.g., PF-07220060, AU2-94). In some embodiments, the CDK inhibitor is a dual CDK4 / 6 inhibitor (e.g., palbociclib, abemaciclib, ribociclib, trilaciclib). In some embodiments, the CDK inhibitor is a CDK2 / 4 / 6 inhibitor.

[0422] In some embodiments, two or more CDK inhibitors are administered together with a compound of the invention. In some embodiments, the additional therapeutic agents include one or more CDK inhibitors and an estrogen receptor targeted therapy. In some embodiments, the additional therapeutic agents include a selective estrogen receptor degrader and one or more CDK inhibitors.

[0423] In some embodiments, the additional therapeutic agents comprise a CDK2 inhibitor and an estrogen receptor targeted therapy. In some embodiments, the additional therapeutic agents comprise a CDK4 inhibitor and an estrogen receptor targeted therapy. In some embodiments, the additional therapeutic agents comprise a CDK2 inhibitor, a CDK4 inhibitor, and an estrogen receptor targeted therapy. In some embodiments, the additional therapeutic agents comprise a CDK4 / 6 inhibitor and an estrogen receptor targeted therapy. In some embodiments, the additional therapeutic agents comprise a CDK2 inhibitor, a CDK4 / 6 inhibitor, and an estrogen receptor targeted therapy.

[0424] The structures of the active compounds identified by code number, generic name or trade name may be taken from the current edition of the standard compendium "The Merck Index" or from databases such as Patents International (e.g. IMS World Publications).

[0425] The compounds of the present invention may also be used in combination with known therapeutic processes, such as the administration of hormones or radiation. In certain embodiments, provided compounds are used as radiosensitizers, particularly for the treatment of tumors that exhibit insufficient sensitivity to radiation therapy.

[0426] The compound of the present invention can be administered alone or in combination with one or more other therapeutic compounds, and possible combination therapy can be in the form of a fixed combination of the compound of the present invention and one or more other therapeutic compounds, or administration that is time-delayed or administered independently, or a fixed combination and the combined administration of one or more other therapeutic compounds.Otherwise or in addition, the compound of the present invention can be administered in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination thereof, especially for tumor treatment.In the context of other therapeutic strategies such as those mentioned above, long-term therapy is equally possible, as is adjuvant therapy.Other possible treatments are therapy to maintain the patient's condition after tumor regression, or even, for example, chemoprevention therapy in patients at risk.

[0427] These additional agents can be administered separately from the compound-containing compositions of the present invention as part of a multiple dose regimen. Alternatively, these agents can be part of a single dosage form, mixed with the compound of the present invention in a single composition. When administered as part of a multiple dose regimen, the two active agents can be administered simultaneously, sequentially, or within a period of time, usually within 5 hours of each other.

[0428] As used herein, the terms "combination," "in combination," and related terms refer to simultaneous or sequential administration of therapeutic agents according to the present invention. For example, a compound of the present invention can be administered simultaneously or sequentially with another therapeutic agent, either in separate unit dosage forms or together in a single unit dosage form. Thus, the present invention provides a single unit dosage form comprising a compound of the present invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0429] The amounts of the compounds of the invention and additional therapeutic agent (for compositions containing such additional therapeutic agents) that can be combined with the carrier materials to produce a single dosage form will vary depending on the host treated and the particular mode of administration. Preferably, the compositions of the invention should be formulated so that the compound of the invention can be administered at a dosage of 0.01 to 100 mg / kg body weight / day.

[0430] In those compositions containing an additional therapeutic agent, the additional therapeutic agent and the compound of the present invention may act synergistically. Thus, the amount of the additional therapeutic agent in such compositions will be less than the amount required for monotherapy utilizing only that therapeutic agent. In such compositions, the additional therapeutic agent may be administered at a dose of 0.01 to 1,000 μg / kg body weight / day.

[0431] The amount of additional therapeutic agent present in the compositions of the invention will not exceed 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 compositions disclosed herein will range from about 50% to 100% of the amount that would normally be present in a composition comprising that agent as the only therapeutically active agent.

[0432] The compounds of the present invention or pharmaceutical compositions thereof may also be incorporated into compositions for coating implantable medical devices, such as prostheses, artificial valves, vascular grafts, stents, and catheters. For example, vascular stents are used to overcome restenosis (re-narrowing of the blood vessel wall after injury). However, patients who use stents or other implantable devices run the risk of clot formation or platelet activation. These undesirable effects can be prevented or reduced by pre-coating the device with a pharmaceutically acceptable composition containing a kinase inhibitor. An implantable device coated with the compounds of the present invention is another embodiment of the present invention.

[0433] Any of the disclosed compounds and / or compositions can be provided in a kit containing the compound and / or composition. Thus, in some embodiments, the disclosed compounds and / or compositions are provided in a kit.

[0434] The present disclosure is further illustrated by the following non-limiting examples. [Example]

[0435] To facilitate a more complete understanding of the present disclosure, examples are provided herein. The following examples serve to illustrate exemplary modes of making and practicing the subject matter of the present disclosure. However, the scope of the present disclosure should not be construed as being limited to the specific embodiments disclosed in these examples, which are for illustrative purposes only.

[0436] As illustrated in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. While these general methods are illustrated for the synthesis of certain specific compounds of the invention, it will be understood that the following general methods, and other methods known to those of skill in the art, are applicable to other classes and subclasses and species of each of these compounds as described herein. Additional compounds of the invention were prepared by methods substantially similar to those described in the Examples herein and known to those of skill in the art.

[0437] In the description of synthetic methods set forth below, it should be understood that all reaction conditions (e.g., reaction solvents, atmospheres, temperatures, times, work-up procedures) are selected from standard conditions for the reaction unless otherwise specified. Starting materials in the examples are commercially available or readily prepared by standard methods from known materials.

[0438] Examples 1 to 5 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 non-limiting examples are illustrative of the disclosure herein.

[0439] X-ray powder diffraction (XRPD) Instrument: Bruker D8 Advance Method 1 (about 10 minutes): Detector: LYNXEYE_XE_T (1D mode) Opening angle: 2.94° Radiation:Cu / K-Alpha1(λ=1.5406Å) X-ray generator: power 40kV, 40mA Primary beam path slit: Twin_Primary motorized slit 10.0 mm sample length, SollerMount axial solar 2.5° Secondary beam path slit: Detector OpticsMount Soller slit 2.5°, Twin_Secondary motorized slit 5.2mm Scanning mode: Continuous scanning Scan Type: Locked Join Step size: 0.02° Time per step: 0.3 seconds per step Scanning range: 2°~40° Sample rotation speed: 15 rpm Sample holder: Single crystal silicon, flat surface Method 2 (approximately 4 minutes, for evaluation samples: bulk stability, solubility studies, suspension stability studies): Detector: LYNXEYE_XE_T (1D mode) Opening angle: 2.94° Radiation:Cu / K-Alpha1(λ=1.5406Å) X-ray generator: power 40kV, 40mA Primary beam path slit: Twin_Primary motorized slit 10.0 mm sample length, SollerMount axial solar 2.5° Secondary beam path slit: Detector OpticsMount Soller slit 2.5°, Twin_Secondary motorized slit 5.2mm Scanning mode: Continuous scanning Scan Type: Locked Join Step size: 0.02° Time per step: 0.12 seconds per step Scanning range: 3°~40° Sample rotation speed: 15 rpm Sample holder: Single crystal silicon, flat surface Method 3: (approximately 2 min, for samples from salt screening experiments, slowly evaporate and add antisolvent experiments): Detector: LYNXEYE_XE_T (1D mode) Opening angle: 2.94° Radiation:Cu / K-Alpha1(λ=1.5406Å) X-ray generator: power 40kV, 40mA Primary beam path slit: Twin_Primary motorized slit 10.0 mm sample length, SollerMount axial solar 2.5° Secondary beam path slit: Detector OpticsMount Soller slit 2.5°, Twin_Secondary motorized slit 5.2mm Scanning mode: Continuous scanning Scan Type: Locked Join Step size: 0.02° Time per step: 0.06 seconds per step Scanning range: 3°~40° Sample rotation speed: 15 rpm Sample holder: Single crystal silicon, flat surface Variable Humidity Powder X-ray Diffractometer (VH-XRPD): Instrument: Bruker D8 Advance Detector: LynxEye Opening angle: 3° Radiation:Cu / K-Alpha1(λ=1.5406Å) X-ray generator: power 40kV, 40mA Primary beam pass slit: Primary Soller slit 2.5°, divergence slit 0.6mm Secondary beam path slits: Secondary Soller slit 2.5°, anti-scattering slit 7.100mm, detector slit 10.50mm Scanning mode: Continuous scanning Scan Type: Locked Join Step size: 0.02° Time per step: 0.6 seconds per step Scanning range: 4°~40° Non-ambient stage: CHC Plus+ Freezing and Humidity Chamber

[0440] Differential scanning calorimetry (DSC) Instrument: TA Discovery 2500 or Q2000 Sample crucibles: Tzero crucibles and Tzero airtight lids with 0.7 mm diameter pinholes Temperature range: 30 to 250°C or before decomposition Heating rate: 10°C / min or 2°C / min Nitrogen flow rate: 50 mL / min Sample mass: approx. 1 to 2 mg

[0441] Thermogravimetric analysis (TGA) Instrument: Discovery 5500 or Q5000 Sample pan: Aluminum, open Starting temperature: ambient conditions (below 35°C) Final temperature: 300°C or if weight < 80% (w / w), abort next segment (Compound weight loss is less than 20% (w / w)) Heating rate: 10℃ / min Nitrogen flow rate: Balance: 10 mL / min, Sample chamber: 25 mL / min Sample mass: approx. 2 to 10 mg

[0442] Dynamic Vapor Sorption (DVS) Method 1 (for I-1 Form A and I-3 Form A) Instrument: Intrinsic, Advantage or Adventure Total gas flow rate: 200sccm Oven temperature: 25°C Solvent: Water Method cycle: 40-0-95-0-40%RH Stage Step: 10% Equilibrium: 0.002dm / dt(% / min) Minimum dm / dt stable duration: 60 minutes Maximum dm / dt stage time: 360 minutes Method 2 (I-4 Form A) Instrument: Intrinsic, Advantage or Adventure Total gas flow rate: 200sccm Oven temperature: 25°C Solvent: Water Method cycle: 40-95-0-95-40%RH Stage Step: 10% Equilibrium: 0.002dm / dt(% / min) Minimum dm / dt stable duration: 60 minutes Maximum dm / dt stage time: 360 minutes

[0443] Karl Fischer Instrument:Mettler Toledo Coulometric KF Titrator C30 Method: coulometric analysis

[0444] Polarized Light Microscope (PLM) Instrument: Olympus BX53LED Method: Crossed polarizers, silicone oil added

[0445] 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: 400MHz Probe: 5mm PABBO BB / 19F-1H / D Z-GRD Z108618 / 0406 (for 1H-NMR, 19F-NMR, and 31P-NMR) 5mm PABBO BB-1H / D Z-GRD Z108618 / 0229(for 13C NMR) Number of scans: 8 Temperature:297.6K Wait time: 1 second

[0446] Fourier transform infrared spectrum (FT-IR) Instrument: Fourier Transform Infrared Spectroscopy (Nicolet 6700, Thermo Scientific) Number of sample scans: 32 Number of background scans: 32 Resolution: 4 Wavelength range: 4000~525cm-1 Baseline correction: Yes Speed ​​of light: 0.4747 Aperture: 150 Window: Diamond

[0447] Supercritical Fluid Chromatography (SFC) Instrument: CAS-SH-ANA-SFC-H (Watera UPCC with PDA detector) Wavelength: 220nm Column: Chiralcel OD-3 (4.6 x 150 mm x 3 μm) Detector: PDA Column temperature: 35℃ Flow rate: 2.5mL / min Mobile phase A: CO2 Mobile phase B: methanol (0.05% DEA) Diluent: ACN Injection volume: 1.00μL Sample preparation: 2mg / mL Needle washing solvent: ACN:H2O = 90:10 (v / v) Gradient: 5% to 40% B in 5 minutes, hold at 40% for 2.5 minutes, then hold at 5% B for 2.5 minutes

[0448] High-performance liquid chromatograph (HPLC) Instruments: Agilent 1260, SHIMADZU CBM-40, Chiral purity: Wavelength: 220nm Column: Daicel OD-RH (4.6 x 150 mm x 5 μm) Detector: DAD, PDA Column temperature: 40℃ Flow rate: 1mL / min Mobile phase A: 10 mM NH4OAc in water Mobile phase B: ACN Diluent: ACN Injection volume: 5μL Sample preparation: 2mg / mL Needle washing solvent: ACN:H2O = 90:10 (v / v) Gradient: Isocratic elution Time (min) Mobile phase A (%) Mobile phase B (%) 0 55 45 30 55 45

[0449] High-performance liquid chromatograph (HPLC) Instruments: Agilent 1260, SHIMADZU CBM-40, Chemical Purity and Solubility Wavelength: 220nm Column: Phenomenex Luna PFP(2), 4.6 x 150 mm, 3 μm Detector: DAD, PDA Column temperature: 40°C Flow rate: 1mL / min Mobile phase A: 0.05% TFA in water, v / v Mobile phase B: 0.05% TFA in (MeOH:ACN=1:9), v / v, e.g., mix 100 mL of MeOH and 900 mL of ACN exactly, add 0.5 mL of TFA, mix well, and degas by ultrasound. Diluent: ACN Injection volume: 5μL Sample preparation: 0.8mg / mL Needle washing solvent: ACN:H2O = 9:1 (v / v) gradient: Time (min) Mobile phase A (%) Mobile phase B (%) Initial 75 25 8.00 55 45 14.00 55 45 22.00 50 50 26.00 50 50 30.00 15 85 33.00 15 85 34.00 75 25 40.00 75 25

[0450] Ultra Performance Liquid Chromatography (UPLC) Instrument: Agilent 1290 Solubility: Wavelength: 220nm Column: Waters ACQuity UPLC BEH C18 2.1*150mm, 1.7μm Detector: DAD Column temperature: 40°C Flow rate: 0.3mL / min Mobile phase A: 0.037% TFA in water, v / v Mobile phase B: 0.018% TFA in ACN Diluent: ACN / H2O (1:1, v / v) Injection volume: 5μL Needle washing solvent: ACN:H2O = 1:1 (v / v) Gradient: Isocratic elution Time (min) Mobile phase A (%) Mobile phase B (%) Early 95 5 5.00 5 95 6.00 95 5 8.00 95 5 Abbreviation Official name MeOH Methanol EtOH ethanol ACN Acetonitrile TFA trifluoroacetic acid DMSO dimethyl sulfoxide IPAc Isopropyl acetate DCM dichloromethane EA Ethyl acetate THF tetrahydrofuran MTBE Methyl tert-butyl ether

[0451] Example 1. Synthesis of intermediates 1.1. Preparation of Compound 5 [ka] 1.1.1 Overview Through screening, a milder EDCI / HOAt / DIPEA-mediated amidation procedure was identified as an alternative to the original cryogenic system using (COCl)2 / DMF / LiHMDS, and a simplified purification process was also developed. This process was verified in a 100g-scale reaction, yielding the amide product with 97.3% HPLC purity as a 2-MeTHF solution. This solution could be used in the next step without isolating the solid. The details are summarized below.

[0452] 1.1.2 Understanding the Process The original TP conditions using (COCl)2 / DMF / LiHMDS were repeated. Compound 7 was consumed, but 7.5% of compound 6 remained as shown by HPLC. [Table 15]

[0453] 1.1.3 Screening of binding reagents Five reactions were performed to screen the coupling reagents (HATU, PyBOP, EDCI / HOAt, EDCI / HOBt, and EEDQ) and DMF as the solvent. Finally, the EDCI / HOAt system provided the best IPC results. [Table 16]

[0454] 1.1.4 Solvent System Screening When DMF was used as the solvent, a related imine impurity (RT 19.52) derived from DMF and compound 7 was detected. Therefore, DMAc was tried instead of DMF. The DMAc reaction proceeded slowly, and after stirring at 60 °C for 18 h, 71.4% of compound 5 was detected by IPC, leaving only 16.3% of compound 7. The formation of the imine impurity was completely prevented. [Table 17] [ka]

[0455] 1.1.5 Temperature Screening with DIPEA / DMAC DIPEA / DMAC conditions were evaluated at 60°C, 40°C, and 25°C. IPC results indicated that the reaction proceeded faster with increasing temperature, while the impurities RT19.52 and RT10.49 could be prevented. The reaction at 40°C gave the best results, yielding 93.0% compound 5 and 0.1% compound 7 by IPC. [Table 18]

[0456] 1.1.6 Evaluation of new procedures A scaled-up reaction using 80 g of compound 7 was carried out to verify the process using DMAc at 40 °C. IPC showed typical results. After workup, 275.2 g of a 2-MeTHF solution with an HPLC purity of 97.7% was obtained. The 2-MeTHF solution was sent directly to the next step. [Table 19]

[0457] 1.1.7 Process Validation A validation batch was carried out using 100 g of compound 7. After stirring at 40 °C for 16 hours, the reaction IPC showed 93.0% of compound 5 and only 0.1% of compound 7. After typical workup and purification, 350.6 g of a 2-MeTHF solution was obtained with an HPLC purity of 97.3%. The 2-MeTHF solution was sent directly to the next step. [Table 20] 1.1.8 Process 1. Compound 7 (100.0 g, 1.00 ± 0.01X) is added to R1 under N2. 2. Compound 6 (65.6 g, 0.66 ± 0.01X) is added to R1 under N2. 3. Add DMAc (470.0g, 4.5-5.0X) to R1. 4. HOAt (42.9 g, 0.43 ± 0.01X) is added to R1 under N2. 5. Adjust R1 to 20-30°C. 6. Add DIPEA (55.0 g, 0.55 ± 0.02X) to R1 at 20-30°C under N2. 7. Stir R1 at 20-30°C for 0.5-1 hour. 8. Add EDCI (80.6 g, 0.81 ± 0.01X) to R1 at 20-30°C under N2. 9. Adjust R1 to 35-40°C. 10. Stir R1 at 35-40°C for 16-20 hours. 11.IPC: Compound 7 / Compound 5 = Report 12. Stir R1 at 35-40°C for 4-6 hours. 13.IPC: Compound 7 / Compound 5 = Report 14. Add H2O (900g, 9.0±0.2X) to R2. 15. Add Na2CO3 (100g, 1.00±0.02X) to R2. 16. Adjust R2 to 20-30°C. 17. Stir R2 at 20-30°C for 0.5-1 hour. 18. A 10% Na2CO3 solution is placed in a drum. 19. Add H2O (900g, 9.0±0.2X) to R2. 20. Add NH4Cl (100g, 1.00±0.02X) to R2. 21. Adjust R2 to 20-30°C. 22. Stir R2 at 20-30°C for 0.5-1 hour. 23. A 10% aqueous solution of NH4Cl is placed in a drum. 24. Add H2O (450g, 4.5±0.1X) to R2. 25. Add NaCl (50g, 0.50±0.01X) to R2. 26. Adjust R2 to 20-30°C. 27. Stir R2 at 20-30°C for 0.5-1 hour. 28. A 10% NaCl solution is placed in a drum. 29. Adjust R1 to 20-30°C. 30. Add EA (900g, 9.0-10.0X) to R1. 31. Add process water (1500g, 15.0±0.3X) to R1 at 20-30°C under N2. 32. Stir R1 at 20-30°C for 0.5-1 hour. 33. Leave R1 at 20-30°C for 0.5-1 hour. 34. Separation: Pour the aqueous layer into T1 and the organic layer into T2 35. Add the aqueous layer of T1 to R1. 36. Add EA (450g, 4.5-5.0X) to R1. 37. Adjust R1 to 20-30°C. 38. Stir R1 at 20-30°C for 0.5-1 hour. 39. Place R1 at 20-30°C for 0.5-1 hour. 40. Separation: Pour the aqueous layer into T1 and the organic layer into T2. 41. IPC: Residual Compound 5 in the aqueous layer of T1: Report 42.Pour the aqueous layer of T1 into the drum. 43. Add the organic layer of T2 to R1. 44. Add 10% Na2CO3 aqueous solution (500g, 5.0±0.1X) to R1. 45. Adjust R1 to 20-30°C. 46. ​​Stir R1 at 20-30°C for 0.5-1 hour. 47. Leave R1 at 20-30°C for 0.5-1 hour. 48. Separation: Pour the aqueous layer into T3 49. Add 10% Na2CO3 aqueous solution (500g, 5.0±0.1X) to R1. 50. Adjust R1 to 20-30°C. 51. Stir R1 at 20-30°C for 0.5-1 hour. 52. Leave R1 at 20-30°C for 0.5-1 hour. 53. Separation: The aqueous layer is poured into T3, and the aqueous layer of T3 is poured into the drum. 54. Add 10% NH4Cl aqueous solution (500g, 5.0±0.1X) to R1. 55. Adjust R1 to 20-30℃ 56. Stir R1 at 20-30°C for 0.5-1 hour. 57. Leave R1 at 20-30°C for 0.5-1 hour. 58. Separation: Pour the aqueous layer into T4 59. Add 10% NH4Cl aqueous solution (500g, 5.0±0.1X) to R1. 60. Adjust R1 to 20-30°C. 61. Stir R1 at 20-30°C for 0.5-1 hour. 62. Place R1 at 20-30°C for 0.5-1 hour. 63. Separation: The aqueous layer is poured into T4, and the aqueous layer of T4 is poured into the drum. 64. Add 10% NaCl aqueous solution (500g, 5.0±0.1X) to R1. 65. Adjust R1 to 20-30℃ 66. Stir R1 at 20-30°C for 0.5-1 hour. 67. Place R1 at 20-30°C for 0.5-1 hour. 68. Separation: The aqueous layer is poured into T5, and the aqueous layer of T5 is poured into a drum. The organic layer is poured into T6. 69. Clean R1 70. Add the organic layer of T6 to R1. 71. Concentrate the organic layer of R1 to 3-4V at 45°C or less. Add 72.2-MeTHF (430.0 g, 4.3-5.0X) to R1. 73. Concentrate the organic layer of R1 to 3-4V at 45°C or less. Add 74.2-MeTHF (430.0 g, 4.3-5.0X) to R1. 75. Concentrate the organic layer of R1 to 3-4V at 45°C or less. Add 76.2-MeTHF (430.0 g, 4.3-5.0X) to R1. 77. Concentrate the organic layer of R1 to 3-4V at 45°C or less. 78. IPC: Residual EA of Compound 5 in R1: Report, KF of Compound 5 in 2-MeTHF solution ≦0.5% Add 79.2-MeTHF (430.0 g, 4.3-5.0X) to R1. 80. Concentrate the organic layer of R1 to 3-4V at 45°C or less. 81. IPC: Residual EA of Compound 5 in R1: Report, KF of Compound 5 in 2-MeTHF solution ≦0.5% Place the 82.2-MeTHF solution in a drum and rinse R1 with 2-MeTHF (86.0 g, 0.9 ± 0.4X). 83.IPC: Purity of Compound 5 in 2-MeTHF Solution

[0458] 1.2. Preparation of Compound 4 [ka] 1.2.1 Overview A process for transferring compound 7 to compound 4 was developed. The original process ran smoothly, but produced approximately 3% of an impurity (RT11.1). After temperature screening, 50°C was deemed appropriate to minimize the production of the RRT11.1 impurity. A crystallization process with MTBE / heptane was developed to isolate and purify the product. A typical process was verified in a 100g-scale reaction, and after typical workup, purification, and isolation, a product with 99.7% purity was obtained in approximately 70% yield (two steps). The details are summarized below.

[0459] 1.2.2 Understanding the Process The original TP conditions were repeated using 70 equivalents of MsOH. IPC revealed 0.1% of compound 5, 89.2% of compound 4, and approximately 3% of an impurity (RT 11.1). The workup process will be further developed. [Table 21]

[0460] 1.2.3 Temperature Screening Reaction temperatures of 80°C, 40°C, 50°C, and 55°C were evaluated. Reaction at 80°C produced 39% of the RRT11.1 impurity, the structure of which is shown below. At 40°C, the reaction was too slow. Reaction at 50°C proceeded quickly and cleanly, effectively preventing RRT11.1. [Table 22] [ka]

[0461] 1.2.4 Process Validation To verify the new process, a scale-up reaction was performed using 350 g of amide compound 5 as a solution in 2-MeTHF (1–2 V). IPC was standard. After typical workup and purification, 104 g of solid was obtained in approximately 70% yield with 99.7% HPLC purity (two steps). [Table 23] 1. Add compound 5 in 2-MeTHF solution to R1 under N2 2. Concentrate the organic layer of R1 to 1.5-2.5V at 45°C or less. 3. Adjust R1 to 15-30°C. 4. Add CH3SO3H (1414g, 14±0.2X) to R1 at 15-30°C. 5. Adjust R1 to 50-55°C. 6. Stir R1 at 50-55°C for 24-30 hours. 7. IPC: Compound 5 / Compound 4 = Report 8. Stir R1 at 50-55°C for 2-8 hours. 9. IPC: Compound 5 / Compound 4 = Report 10. Add H2O (630g, 6.3±0.2X) to R2. 11. Add NH4Cl (70g, 0.7-0.8X) to R2. 12. Adjust R2 to 20-30°C. 13. Stir R2 at 20-30°C for 0.5-1 hour. 14.Put 10% NH4Cl solution into a drum. 15. Add H2O (560g, 5.6±0.2X) to R2. 16. Add NaCl (140g, 1.4-1.6X) to R2. 17. Adjust R2 to 20-30°C. 18. Stir R2 at 20-30°C for 0.5-1 hour. 19. A 20% NaCl solution is placed in a drum. 20. Adjust R1 to 15-30°C. 21. Add 600g of 2-MeTHF (5.0-7.0X) to R1 at 15-30°C. 22. Add 420g of H2O (4.0-5.0X) to R1 at 15-30°C. 23. Adjust the pH to 10-11 with 30% NaOH (2000 g, 18-22X) at 15-30°C. 24. Adjust R1 to 15-25℃ 25. Stir R1 at 15-25°C for 0.5-1 hour. 26. Leave R1 at 15-25°C for 0.5-1 hour. 27. Separation: Pour the aqueous layer into T1 and the organic layer into T2 28. Add the aqueous layer of T1 to R1. 29. Add 600g of 2-MeTHF (5.0-7.0X) to R1. 30. Adjust R1 to 15-25℃ 31. Stir R1 at 15-25°C for 0.5-1 hour. 32. Leave R1 at 15-25°C for 0.5-1 hour. 33. Separation: Pour the aqueous layer into T1 34.IPC: Residual Compound 4 in the Aqueous Layer: Report 35.Pour the aqueous layer of T1 into the drum. 36. Add the organic layer of T2 to R1. 37. Add 10% NH4Cl aqueous solution (700g, 7.0±0.5X) to R1. 38. Adjust R1 to 15-25℃ 39. Stir R1 at 15-25°C for 0.5-1 hour. 40. Leave R1 at 15-25°C for 0.5-1 hour. 41. Separation: Pour the aqueous layer into T3 42. Add 20% NaCl aqueous solution (700g, 7.0±0.5X) to R1. 43. Adjust R1 to 15-25℃ 44. Stir R1 at 15-25°C for 0.5-1 hour. 45. Leave R1 at 15-25°C for 0.5-1 hour. 46. ​​Separation: Pour the aqueous layer into T4 and the organic layer into T5. 47. Clean R1 48. Add the organic layer of T5 to R1. 49. Concentrate the organic layer of R1 to 5-7V at 45°C or less. 50. Add MTBE (450g, 4.0-5.0X) to R1. 51. Concentrate the organic layer of R1 to 5-7V at 45°C or less. 52. Add MTBE (450g, 4.0-5.0X) to R1. 53. Concentrate the organic layer of R1 to 5-7V at 45°C or less. 54.IPC: Residual 2-MeTHF in the organic layer: Report 55. Adjust R1 to 40-45℃ 56. Stir R1 at 40-45°C for 0.5-1 hour. 57. Adjust R1 to 20-25°C for 2-4 hours. 58. Stir R1 at 20-25°C for 2-4 hours. 59. Add MTBE (180g, 1.5-2.5X) to R1. 60. Add n-heptane (550g, 5.0-7.0X) to R1 at 20-25°C. 61. Stir R1 at 20-25°C for 6-10 hours. 62. IPC: Compound 4 wet cake purity: Report, Residual Compound 4 in mother layer: Report 63. Centrifugal 64. Add MTBE / n-heptane (1 / 1, v / v, 1.0-3.0X) to R1 to rinse the cake. 65. Centrifugal 66. IPC: Compound 4 Wetcake Purity: Report 67. Dry the wet cake at 70-80°C for 16-24 hours. 68. IPC: KF of compound 4: ≦0.5%, residual MTBE, 2-MeTHF, and n-heptane of compound 4: Report 69. Dry the wet cake at 70-80°C for 8-12 hours. 70. IPC: KF of compound 4: ≦0.5%, residual MTBE, 2-MeTHF, and n-heptane of compound 4: Report 71. Product packaging 1.3. Pilot Plant Production Results [ka] [Table 24] [Table 25-1] [Table 25-2] [Table 25-3] [Table 25-4] [Table 25-5] [ka] [Table 26] [Table 27-1] [Table 27-2] [Table 27-3] [Table 27-4] [Table 27-5] [Table 27-6] Example 2. Synthesis of Compounds I-1, II-1, and III-1 Main Chain: [ka] Collection Chain: [ka] [Table 28] [Table 29]

[0462] Demo Badge 400 g (assay corrected) of compound 4 was used for the demo batch. Step 3 yielded consistent IPC results, yielding a 2-MeTHF solution containing 500 ppm NMP residuals. Step 4 had a typical IPC, but no solids precipitated as usual after cooling and adding water. After extraction and solvent switching, the product was crystallized from DMF / acetone / water = 6.25 V / 6.25 V / 4.75 V. After filtration and drying, 318 g of product was obtained with a purity of 97.8% for a crude yield of 71.3%.

[0463] Discussion: Similar residual NMP (approximately 500 ppm) was detected in the compound 3 solution. However, the product could not be directly precipitated from the reaction solution as previously, and this isolated process was not reproducible. Therefore, DMF was tested as the reaction solvent, and after the reaction, acetone and water were added to directly precipitate the product. [Table 30] [Table 31] [Table 32]

[0464] Solvent Screening The DMF process was attempted using 20 g of compound 4. Consistent IPC results were observed in step 3. In step 4, DMF was used as the solvent, but the IPC purity was only 67.7%, lower than the previous (77%). DMF could not be used as a reaction solvent, and 2-MeTHF was subsequently used. [Table 33]

[0465] Process optimization (2-MeTHF process) For workup optimization, 20 g of compound 4 was used. Consistent IPC results were observed in Step 3. In Step 4, 2-MeTHF was still used as the solvent, and the IPC was still typical, with no solids precipitating even after cooling and adding water. After extraction and water washing, 2-MeTHF was exchanged for DMF and crystallized from DMF / acetone / water = 6V:6V:6V. After crystallization, 20.0 g of product was obtained with a purity of 94.3% and an assay of 89.8%, for a yield of 80.5% (assay corrected). [Table 34] [Table 35] [Table 36] Typical Procedure Add 1.226g (5.09-6.22X) of NMP to R1. Add 2.40g (1.0X) of compound 4 to R1 3. Stir R1 at 20-25°C for 0.5-1.0 hours to form a clear solution. 4. Add 22.34 g of B2Pin2 (0.53-0.59X) to R1 under N2 protection. 5. Add 21.58 g of KOAc (0.51-0.57X) to R1 under N2 protection. 6. Add 100g (2.25-2.75X) of NMP to R1. 7. Bubble N2 through the mixture at 20-30°C for 1 hour. 8. Add 1.877g (0.045-0.057X) of Pd(dppf)Cl2 to R1. 9. Replace R1 with N2 gas three times. 10. Adjust R1 to 85-90°C. 11. Stir R1 at 85-90°C for 2-17 hours. 12.IPC: Compound 4 / Compound 3≦1.0% 13. Adjust R1 to 20-25°C. Add 14.288g (6.48-7.92X) of EtOAc to R1 Add 15.320g (7.20-8.80X) of process water to R1. 16. Stir R1 at 20-30°C for 0.5-1 hour. 17. Leave R1 for 0.5 to 1 hour. 18. Separate the upper layer into T1 and remove the lower layer into T2. 19. Add the aqueous layer from T2 to R1. Add 20.180g (4.05-4.95X) of EtOAc to R1 21. Stir R1 at 20-30°C for 0.5-1 hour. 22. Leave R1 for 0.5 to 1 hour. 23. Separate the upper layer into T1 and remove the lower layer into T2. 24. Add the aqueous layer from T2 to R1. Add 25.180g (4.05-4.95X) of EtOAc to R1 26. Stir R1 at 20-30°C for 0.5-1 hour. 27. Leave R1 for 0.5 to 1 hour. 28. Remove the lower layer to T2 29. Pour the organic layer from T1 to R1 30. Filter with 10g (0.2-0.3X) diatomaceous earth to T2 at 20-30°C. 31. Wash the cake with 36 g (0.9-1.0X) EtOAc. 32. Pour the organic layer from T2 into R1 33. Add 200 g (4.50-5.50X) of 5% NaCl solution to R1. 34. Stir R1 at 20-30°C for 0.5-1 hour. 35. Leave R1 for 0.5 to 1 hour. 36. Separate and remove the lower layer into T1. 37. Add 200 g (4.50-5.50X) of 5% NaCl solution to R1. 38. Stir R1 at 20-30°C for 0.5-1 hour. 39. Leave R1 for 0.5 to 1 hour. 40. Separate and remove the lower layer into T1. 41. Add 200 g (4.50-5.50X) of 5% NaCl solution to R1. 42. Stir R1 at 20-30°C for 0.5-1 hour. 43. Leave R1 for 0.5 to 1 hour. 44. Separate and remove the lower layer into T1. Filter through 45.40 g (0.9-1.1X) of silica gel and wash the cake with 450 g (11-14X) of EtOAc. 46. ​​Concentrate R2 to 2-3V below 40°C. Add 47.172g (6.18-7.56X) of 2-MeTHF to R2 48. Concentrate R2 to 2-3V below 40°C. Add 49.275g (6.18-7.56X) of 2-MeTHF to R2 50.Concentrate R2 to 3-4V below 40℃ Add 51.155g (3.00-5.50X) of 2-MeTHF to R2. 52. Add 18.0 g (0.40 to 0.50X) of Compound 2 to R2. Add 53.152 g (3.4-4.2X) of 20% K2CO3 solution to R2. 54. Bubble N2 for 1 hour at 20-30°C. 55. Add 2.6 g (0.062–0.078X) of Pd(Amphos)Cl2 to R2. 56. Replace R2 with N2 gas three times. 57. Adjust R2 to 60-65℃ 58.IPC: Compound 3 / Compound III-1≦1.0% 59. Adjust R2 to 20-30°C. 60. Stir R2 at 20-30°C for 1-2 hours. 61. Leave R2 for 0.5 to 1 hour. 62. The lower layer is separated and removed to T1, and the upper layer is put into T2. 63. Add the solution from T1 to R2 Add 64.108g (2.5x4.0x) of EtOAc to R2 65. Stir R2 at 20-30°C for 0.5-1 hour. 66. Leave R2 for 0.5 to 1 hour. 67. Separate and remove the lower layer into T1. 68. Add the solution from T2 to R2 69. Add 120g (2.8x-3.3x) of 10% NaCl solution to R2. 70. Stir R2 at 20-30°C for 0.5-1 hour. 71. Leave R2 for 0.5 to 1 hour. 72. Separate and remove the lower layer into T1. 73. Pull sample into analysis 74.Residual III-1 in the aqueous layer: Report 75. Filter through 1.2 g (0.25-0.35X) silica thiol and wash the cake with 320 g (5-12X) EtOAc. 76. Concentrate R2 to 2-3V at 40°C or less. 77. Add 76g (1.7-2.1X) of DMF to R2. 78. Concentrate R2 to 3-4V at 40℃ or less. 79. Add 162g (3.6-4.5X) of DMF to R2. 80. Add 198g (4.4-5.5X) of acetone to R2. 81. Add 200g (4-7X) of water dropwise to R2 at 20-30°C over 4 hours. 82. Stir R2 at 20-30°C for 2-3 hours. 83. Testing the Wet Cake Purity of Compound I-1: Report 84. Mother liquor purity test of compound I-1: Report 85. Filtration 86. Wash the wet cake with 60g (1-2X) ​​water. 87. Wash the cake with 120 g (1-2X) ​​acetone. 88. Dry under vacuum at 50-60°C for 12-18 hours. 89. Put it in the drum. Preparation and crystallization of compound I-1 [ka]

[0466] overview The demo batch was purified by SFC prep to give 102 g of standard with 98.0% purity and 99.5% chiral purity after slurrying. For the production batch, 7.65 kg of I-1 was obtained after PreHPLC, followed by 7.34 kg of product (GLP batch) with 99.2% purity and 98.3% chiral purity after slurrying.

[0467] A stability test of Compound I-1 solution showed that it was stable at pH 4-5.

[0468] PreHPLC separation 300 g of the racemic compound was separated by PreHPLC. 1) 141 g of wet cake (I-1) was obtained with a purity of 98.7% and a chiral purity of 99.5%. 2) 165.8 g of wet cake (II-1) was obtained. After PreHPLC purification, 7.65 kg of I-1 was obtained with a purity of 99.3%, a chiral purity of 98.8%, and 125 ppm of residual Pd. [Table 37]

[0469] Preparation of standard materials 141 g of the wet cake (I-1) was slurried in 10 V of EA / heptane (1:5) at 25 °C for 14 h, yielding 102.7 g of an off-white solid with a purity of 98.0% and a chiral purity of 99.5% after filtration and drying. Residual solvents: MeOH, acetone, DCM, 2-Me-THF, NMP <100 ppm, EA = 2370 ppm, n-heptane = 212 ppm, DMF = 732 ppm. [Table 38]

[0470] I-1 Slurry Process Using 20 g of I-1 after SFC preparation, a slurry process (EtOAc / heptane: 2V / 10V) was evaluated. 19.0 g of product was obtained with a purity of 99.4%, a chiral purity of 98.5%, and an assay of 100%.

[0471] For the slurrying, 7.65 kg of I-1 was used. 7.34 kg of product was obtained with a purity of 99.2% and a chiral purity of 98.3%. Solvents: ACN = 216 ppm, EtOAc = 41291 ppm, n-heptane = 669 ppm, DMF = 182 ppm, NMP = 134 ppm, MeOH, acetone, DCM, 2-Me-THF < 100 ppm [Table 39] Slurrying process: 1. Put I-1 (7.65 kg) into R1. 2. (EA 15.3L) is injected into R1. 3. (N-heptane 76.5 L) is added to R1. 4. Stir R1 at 20-30°C for 4 hours. 5. Filter the reaction mixture. 6. Dry the wet cake at 40-50°C for 17 hours. 7. Obtain I-1 (7.35 kg).

[0472] Stability of I-1 during concentration To study the chiral stability of product I-1 during concentration, three batches of I-1 from Prep-HPLC were tested under different conditions. 1) After stirring at 45-50°C and pH 6-7 for 18 hours, the ee% of the product changed from 98.20% to 78.95%. 2) After stirring at 20-25°C and pH 6-7 for 18 hours, the ee% of the product changed from 98.20% to 97.64%. 3) After stirring at 45-50°C and pH 5-6 for 18 hours, the ee% of the product changed from 98.20% to 98.15%.

[0473] For stability studies, two reactions were performed with 0.5 g of I-1 (after SFC preparation). 1) The compound is stable after stirring for 20 hours at 10-20°C and pH 4. 2) The ee% of this compound changes from 98.43% to 98.16% after stirring for 20 hours at 40-50°C and pH 4. [Table 40]

[0474] Results: 1) The compound is stable at 10-20°C for 68 hours, and 2) the purity and chiral purity show only a slight decrease even after stirring at 40-50°C for 68 hours.

[0475] Effect of light (chiral purity) Four reactions were performed to study the effect of light on chiral purity under neutral and basic conditions. In the neutral system, after 96 hours of stirring, the ee% of the product remained almost unchanged under dark conditions, but decreased to 81.68% under light irradiation. In the basic system, the ee% of the product decreased more significantly than in the neutral system. Under dark conditions, the ee% of the product decreased to 43.30%, while under light irradiation it decreased to 30.84%. [Table 41]

[0476] Two reactions were performed to study the fluorescence under neutral and basic conditions. No fluorescence was visible under a UV lamp.

[0477] Preparation of impurities 7.9 g of compound 4 (assay corrected) was used in the Miyarau and Suzuki reaction for the preparation of the homo-coupling product. An IPC purity of 92.2% was observed, with approximately 10% BHT detected. After washing with water and crystallization from DMF / acetone / water (9:6:4), 11.4 g of the homo-coupling product was obtained with a purity of 95.7%.

[0478] For the preparation of homocoupling, two reactions were carried out with 90 g of compound 4. IPC showed good results. After work-up, 127 g of homocoupling was obtained with a purity of 93.9% and QNMR of 92.2%. [Table 42] [Table 43] The impurity at 14.9 min is BHT from THF. THF was used as a co-solvent due to the low solubility of the homocoupling impurity.

[0479] spike response 20 g of the impure product was used. After spiking with 0.175 g of homocoupling and 0.173 g of II-1, a purity of 98.5% with 0.73% homocoupling and a chiral purity of 97.6% was obtained.

[0480] Another 20 g batch was run to spike impurities, and after spiking with 0.227 g of homocoupling and 0.252 g of II-1, a purity of 98.4% with 0.90% homocoupling and a chiral purity of 97.1% was obtained. [Table 44] Racemization Process [ka]

[0481] overview To recover compound I-1 from compound II-1, different bases and solvents were screened for racemization. Using KOAc in THF / ACN gave better results. Small-scale testing and validation were successful. Three batches of II-1 were run in a kilo lab for scale-up.

[0482] Optimizing conditions Six reactions were performed to screen the racemization process. Bases (KOAc / NaHCO3 / TEA) and solvents (THF+ACN / THF / THF+ACN+H2O) were screened at 20-30 °C. Better results were obtained using KOAc in THF / ACN. [Table 45]

[0483] Small-scale testing and validation 20 g of II-1 was subjected to racemization. The reaction was successful (I-1:II-1=51.4%:48.6%). After acid washing, water washing, and slurrying in EA / MeOH, 16.6 g of product was obtained with a purity of 99.0% and a chiral purity of 49.6%.

[0484] 65g of II-1 was used for verification. The reaction was still successful (I-1:II-1=51.5%:48.5%). After typical work-up, 55.8g of product was obtained with a purity of 98.5% and a chiral purity of 49.2%. [Table 46] [Table 47]

[0485] Scale up 3.12 kg of II-1 (assay corrected) was used for scale-up, and the IPC after 19 hours showed II-1 / I-1 = 52.4% / 47.6%. 2.55 kg of crude II-1 (assay corrected) was used for scale-up, and the IPC showed II-1 / I-1 = 52.0% / 48.0%. 2.24 kg of crude II-1 (assay corrected) was used for scale-up, and the IPC showed II-1 / I-1 = 50.6% / 49.4%. The products from the above three batches were combined. After work-up, 7.114 kg of crude product was obtained with a purity of 97.8%, an assay of 97.5%, and a chiral purity of 49.0%. [Table 48] [Table 49] [Table 50] Racemization Process 1. Add II-1 (3.3 kg) to R1. 2. Add (20 L of THF) to R1. 3. Add (10L of ACN) to R1. 4. Stir R1 at 25-35°C for 1 hour. 5. (KOAc 505g, 1.004 eq) is charged to R1. 6. Stir R1 at 25-35°C for 19 hours. 7. Add 3750 mL of 7% NaHCO3 solution dropwise. 8. Stir R1 at 20-30°C for 0.5 hours. 9. Filter the reaction mixture. 10. (16.5 L of EtOAc) is added to R1. 11. (2-MeTHF 16.5 L) is added to R1. 12. Stir R1 at 20-30°C for 0.5 hours. 13. Separate the top layer and remove the bottom layer. 14. (2-MeTHF 23.1 L) is added to R1. 15. Add 16.5 L of 1N HCl to R1 to adjust the pH to 2-3. 16. Stir R1 at 20-30°C for 0.5 hours. 17. Filter the reaction mixture. 18. Separate the top layer and remove the bottom layer. 19. Add (16.5L of water) to R1. 20. Stir R1 at 20-30°C for 0.5 hours. 21. Separate the top layer and remove the bottom layer. 22. Add (16.5L of water) to R1. 23. Stir R1 at 20-30°C for 20 minutes. 24. Separate the top layer and remove the bottom layer. 25. Add 16.5L of brine to R1. 26. Stir R1 at 20-30°C for 0.5 hours. 27. Separate the top layer and remove the bottom layer 28. Concentrate R1 under vacuum at 40-50°C or below. 29. Dry the wet cake at 40-50°C for 14 hours. Obtain 30.III-1 (3.1 kg). Preparation and crystallization of compound I-1 [ka]

[0486] overview 7.11 kg of III-1 was separated by pre-HPLC to obtain 3.1 kg of I-1, which was then slurried with heptane / EA to finally obtain 2.42 kg of product (about 10% EA remaining). The results are shown in the table below. [Table 51] Pilot plant production results Preparation of Compound III-1 [ka] [Table 52] [Table 53] [Table 54-1] [Table 54-2] [Table 54-3] [Table 54-4] [Table 54-5] [Table 54-6] [Table 54-7] [Table 54-8] Example 3. Synthesis of Compounds I-1, II-1, and III-1 [ka] 3.1 Preparation of Compound 5 1. Compound 7 (100.0 g, 1.00 ± 0.01X) is added to R1 under N2. 2. Compound 6 (65.6 g, 0.66 ± 0.01X) is added to R1 under N2. 3. Add DMAc (470.0g, 4.5-5.0X) to R1. 4. HOAt (42.9 g, 0.43 ± 0.01X) is added to R1 under N2. 5. Adjust R1 to 20-30°C. 6. Add DIPEA (55.0 g, 0.55 ± 0.02X) to R1 at 20-30°C under N2. 7. Stir R1 at 20-30°C for 0.5-1 hour. 8. Add EDCI (80.6 g, 0.81 ± 0.01X) to R1 at 20-30°C under N2. 9. Adjust R1 to 35-40°C. 10. Stir R1 at 35-40°C for 16-20 hours. 11.IPC: Compound 7 / Compound 5 = Report 12. Stir R1 at 35-40°C for 4-6 hours. 13.IPC: Compound 7 / Compound 5 = Report 14. Add H2O (900g, 9.0±0.2X) to R2. 15. Add Na2CO3 (100g, 1.00±0.02X) to R2. 16. Adjust R2 to 20-30°C. 17. Stir R2 at 20-30°C for 0.5-1 hour. 18. A 10% Na2CO3 solution is placed in a drum. 19. Add H2O (900g, 9.0±0.2X) to R2. 20. Add NH4Cl (100g, 1.00±0.02X) to R2. 21. Adjust R2 to 20-30°C. 22. Stir R2 at 20-30°C for 0.5-1 hour. 23. A 10% aqueous solution of NH4Cl is placed in a drum. 24. Add H2O (450g, 4.5±0.1X) to R2. 25. Add NaCl (50g, 0.50±0.01X) to R2. 26. Adjust R2 to 20-30°C. 27. Stir R2 at 20-30°C for 0.5-1 hour. 28. A 10% NaCl solution is placed in a drum. 29. Adjust R1 to 20-30°C. 30. Add EA (900g, 9.0-10.0X) to R1. 31. Add process water (1500g, 15.0±0.3X) to R1 at 20-30°C under N2. 32. Stir R1 at 20-30°C for 0.5-1 hour. 33. Leave R1 at 20-30°C for 0.5-1 hour. 34. Separation: Pour the aqueous layer into T1 and the organic layer into T2 35. Add the aqueous layer of T1 to R1. 36. Add EA (450g, 4.5-5.0X) to R1. 37. Adjust R1 to 20-30°C. 38. Stir R1 at 20-30°C for 0.5-1 hour. 39. Place R1 at 20-30°C for 0.5-1 hour. 40. Separation: Pour the aqueous layer into T1 and the organic layer into T2. 41. IPC: Residual Compound 5 in the aqueous layer of T1: Report 42.Pour the aqueous layer of T1 into the drum. 43. Add the organic layer of T2 to R1. 44. Add 10% Na2CO3 aqueous solution (500g, 5.0±0.1X) to R1. 45. Adjust R1 to 20-30°C. 46. ​​Stir R1 at 20-30°C for 0.5-1 hour. 47. Leave R1 at 20-30°C for 0.5-1 hour. 48. Separation: Pour the aqueous layer into T3 49. Add 10% Na2CO3 aqueous solution (500g, 5.0±0.1X) to R1. 50. Adjust R1 to 20-30°C. 51. Stir R1 at 20-30°C for 0.5-1 hour. 52. Leave R1 at 20-30°C for 0.5-1 hour. 53. Separation: The aqueous layer is poured into T3, and the aqueous layer of T3 is poured into the drum. 54. Add 10% NH4Cl aqueous solution (500g, 5.0±0.1X) to R1. 55. Adjust R1 to 20-30℃ 56. Stir R1 at 20-30°C for 0.5-1 hour. 57. Leave R1 at 20-30°C for 0.5-1 hour. 58. Separation: Pour the aqueous layer into T4 59. Add 10% NH4Cl aqueous solution (500g, 5.0±0.1X) to R1. 60. Adjust R1 to 20-30°C. 61. Stir R1 at 20-30°C for 0.5-1 hour. 62. Place R1 at 20-30°C for 0.5-1 hour. 63. Separation: The aqueous layer is poured into T4, and the aqueous layer of T4 is poured into the drum. 64. Add 10% NaCl aqueous solution (500g, 5.0±0.1X) to R1. 65. Adjust R1 to 20-30℃ 66. Stir R1 at 20-30°C for 0.5-1 hour. 67. Place R1 at 20-30°C for 0.5-1 hour. 68. Separation: The aqueous layer is poured into T5, and the aqueous layer of T5 is poured into a drum. The organic layer is poured into T6. 69. Clean R1 70. Add the organic layer of T6 to R1. 71. Concentrate the organic layer of R1 to 3-4V at 45°C or less. Add 72.2-MeTHF (430.0 g, 4.3-5.0X) to R1. 73. Concentrate the organic layer of R1 to 3-4V at 45°C or less. Add 74.2-MeTHF (430.0 g, 4.3-5.0X) to R1. 75. Concentrate the organic layer of R1 to 3-4V at 45°C or less. Add 76.2-MeTHF (430.0 g, 4.3-5.0X) to R1. 77. Concentrate the organic layer of R1 to 3-4V at 45°C or less. 78. IPC: Residual EA of Compound 5 in R1: Report, KF of Compound 5 in 2-MeTHF solution ≦0.5% Add 79.2-MeTHF (430.0 g, 4.3-5.0X) to R1. 80. Concentrate the organic layer of R1 to 3-4V at 45°C or less. 81. IPC: Residual EA of Compound 5 in R1: Report, KF of Compound 5 in 2-MeTHF solution ≦0.5% Place the 82.2-MeTHF solution in a drum and rinse R1 with 2-MeTHF (86.0 g, 0.9 ± 0.4X). 83.IPC: Purity of Compound 5 in 2-MeTHF Solution 3.2 Preparation of Compound 4 1. Add compound 5 in 2-MeTHF solution to R1 under N2 2. Concentrate the organic layer of R1 to 1.5-2.5V at 45°C or less. 3. Adjust R1 to 15-30°C. 4. Add CH3SO3H (1414g, 14±0.2X) to R1 at 15-30°C. 5. Adjust R1 to 50-55°C. 6. Stir R1 at 50-55°C for 24-30 hours. 7. IPC: Compound 5 / Compound 4 = Report 8. Stir R1 at 50-55°C for 2-8 hours. 9. IPC: Compound 5 / Compound 4 = Report 10. Add H2O (630g, 6.3±0.2X) to R2. 11. Add NH4Cl (70g, 0.7-0.8X) to R2. 12. Adjust R2 to 20-30°C. 13. Stir R2 at 20-30°C for 0.5-1 hour. 14.Put 10% NH4Cl solution into a drum. 15. Add H2O (560g, 5.6±0.2X) to R2. 16. Add NaCl (140g, 1.4-1.6X) to R2. 17. Adjust R2 to 20-30°C. 18. Stir R2 at 20-30°C for 0.5-1 hour. 19. A 20% NaCl solution is placed in a drum. 20. Adjust R1 to 15-30°C. 21. Add 600g of 2-MeTHF (5.0-7.0X) to R1 at 15-30°C. 22. Add 420g of H2O (4.0-5.0X) to R1 at 15-30°C. 23. Adjust the pH to 10-11 with 30% NaOH (2000 g, 18-22X) at 15-30°C. 24. Adjust R1 to 15-25℃ 25. Stir R1 at 15-25°C for 0.5-1 hour. 26. Leave R1 at 15-25°C for 0.5-1 hour. 27. Separation: Pour the aqueous layer into T1 and the organic layer into T2 28. Add the aqueous layer of T1 to R1. 29. Add 600g of 2-MeTHF (5.0-7.0X) to R1. 30. Adjust R1 to 15-25℃ 31. Stir R1 at 15-25°C for 0.5-1 hour. 32. Leave R1 at 15-25°C for 0.5-1 hour. 33. Separation: Pour the aqueous layer into T1 34.IPC: Residual Compound 4 in the Aqueous Layer: Report 35.Pour the aqueous layer of T1 into the drum. 36. Add the organic layer of T2 to R1. 37. Add 10% NH4Cl aqueous solution (700g, 7.0±0.5X) to R1. 38. Adjust R1 to 15-25℃ 39. Stir R1 at 15-25°C for 0.5-1 hour. 40. Leave R1 at 15-25°C for 0.5-1 hour. 41. Separation: Pour the aqueous layer into T3 42. Add 20% NaCl aqueous solution (700g, 7.0±0.5X) to R1. 43. Adjust R1 to 15-25℃ 44. Stir R1 at 15-25°C for 0.5-1 hour. 45. Leave R1 at 15-25°C for 0.5-1 hour. 46. ​​Separation: Pour the aqueous layer into T4 and the organic layer into T5. 47. Clean R1 48. Add the organic layer of T5 to R1. 49. Concentrate the organic layer of R1 to 5-7V at 45°C or less. 50. Add MTBE (450g, 4.0-5.0X) to R1. 51. Concentrate the organic layer of R1 to 5-7V at 45°C or less. 52. Add MTBE (450g, 4.0-5.0X) to R1. 53. Concentrate the organic layer of R1 to 5-7V at 45°C or less. 54.IPC: Residual 2-MeTHF in the organic layer: Report 55. Adjust R1 to 40-45℃ 56. Stir R1 at 40-45°C for 0.5-1 hour. 57. Adjust R1 to 20-25°C for 2-4 hours. 58. Stir R1 at 20-25°C for 2-4 hours. 59. Add MTBE (180g, 1.5-2.5X) to R1. 60. Add n-heptane (550g, 5.0-7.0X) to R1 at 20-25°C. 61. Stir R1 at 20-25°C for 6-10 hours. 62. IPC: Compound 4 wet cake purity: Report, Residual Compound 4 in mother layer: Report 63. Centrifugal 64. Add MTBE / n-heptane (1 / 1, v / v, 1.0-3.0X) to R1 to rinse the cake. 65. Centrifugal 66. IPC: Compound 4 Wetcake Purity: Report 67. Dry the wet cake at 70-80°C for 16-24 hours. 68. IPC: KF of compound 4: ≦0.5%, residual MTBE, 2-MeTHF, and n-heptane of compound 4: Report 69. Dry the wet cake at 70-80°C for 8-12 hours. 70. IPC: KF of compound 4: ≦0.5%, residual MTBE, 2-MeTHF, and n-heptane of compound 4: Report 71. Product packaging

[0487] 3.3 Preparation of Compound III-1 3.3.1 Residual Pd Purging Study Small-scale study (DMF) 6 g of crude product with a purity of 95.8% was recrystallized to improve purity and remove residual Pd. The crude product was dissolved in DMF and stirred with 0.3X silica thiol at room temperature for 17 hours. After filtration, the product was recrystallized from DMF / acetone / water = 6.25V / 6.25V / 4.75V. 4.97 g of product was obtained with a purity of 99.1% and an assay of 88.3%. Residual Pd was reduced from 2106 ppm to 76 ppm. [Table 55]

[0488] Verification (DMF) 40 g of compound 3 was used for validation and use testing. IPC showed that the reaction (two steps) was successful. The use tests for B2Pin2 and Pd(dppf)2Cl2 passed. After workup and initial crystallization from DMF / acetone / water, a wet cake with 97.7% purity and 1539 ppm Pd residue was obtained. After further purification with DMF / acetone / water, 30.58 g of product was obtained with 99.2% purity, 89.2% assay, and 61.1% yield. Residual Pd was reduced from 1539 ppm to 79 ppm. [Table 56] [Table 57] [Table 58] Estimated structure: [ka]

[0489] Accumulation To screen different conditions, 79.4 g (assay corrected) was used for accumulation. In Step 3, IPC showed 100% conversion and 95.7% purity by HPLC. In Step 4, IPC showed 78.8% purity and 5.69% homocoupling impurity. After workup and first crystallization, 66 g of crude product was obtained with a purity of 97.9%, an assay of 89.0%, and a yield of 66.3%. Residual Pd was 221 ppm. [Table 59] [Table 60]

[0490] Adsorption method screening Filtration through 0.6X silica thiol in a column: 15 g of crude III-1 was used to remove residual Pd. III-1 was dissolved in 4 V of DMF and filtered through 0.6X silica thiol in a column. After recrystallization with DMF / acetone / water = 5.45 V / 5.45 V / 4.54 V, 13.95 g of product was obtained with a purity of 99.2% and an assay of 91.5%. The residual Pd was 30 ppm.

[0491] Add 0.6X silica thiol and stir: 15 g of crude III-1 was used to remove residual Pd. III-1 was dissolved in 4 V of DMF and stirred with 0.6X silica thiol for 20 hours. After filtration and recrystallization with DMF / acetone / water = 5.45 V / 5.45 V / 4.54 V, 13.43 g of product was obtained with a purity of 99.3% and an assay of 92.3%. The residual Pd was 13 ppm.

[0492] Add 0.3X silica thiol and stir twice: 15 g of crude III-1 was used to remove residual Pd. III-1 was dissolved in 4 V of DMF and stirred with 0.3X silica thiol for 20 hours. After filtration, the organic layer was stirred with 0.3X silica thiol for 8 hours. After filtration and recrystallization with DMF / acetone / water = 5.45 V / 5.45 V / 4.54 V, 13.59 g of product was obtained with a purity of 99.1% and an assay of 90.5%. The residual Pd is 10 ppm. [Table 61] [Table 62]

[0493] Adsorbent type screening 30 g of crude plant-derived III-1 (414 ppm Pd) was dissolved in DMF and treated with 0.5X silica thiol. After filtration, the filtrate was divided into four portions. 1) Direct crystallization: After crystallization from DMF / acetone / water=6.25V / 6.25V / 4.75V, 6.36 g of product was obtained with a crude yield of 84.8% and a purity of 99.0%, and the residual Pd was 36 ppm. 2) Treatment with 0.5X silica thiol followed by crystallization: After crystallization in DMF / acetone / water = 6.25V / 6.25V / 4.75V, 6.48 g of product was obtained with a crude yield of 86.4% and a purity of 98.7%, with a residual Pd of 17 ppm. 3) Treatment with 0.2X activated carbon followed by crystallization: A crude yield of 70.9% gave 5.32 g of product with a purity of 98.8% and residual Pd of 5 ppm. 4) Treatment with 0.5X ordinary silica gel followed by crystallization: 6.02 g of product was obtained in a crude yield of 80.3% and a purity of 98.4%. Residual Pd was 29 ppm. [Table 63]

[0494] Solvent screening of crude III-1 DCM + MeOH: Because dissolving crude III-1 in DMF makes filtration difficult, 15 g of crude III-1 was dissolved in DCM / MeOH (16.7 V / 4 V) and treated twice with 0.5X silica thiol. After concentration and solvent exchange, the crude product was crystallized from DMF / acetone / water (6.25 V / 6.25 V / 4.75 V). 12.73 g of product was obtained with a purity of 98.6% and a crude yield of 84.9%. The residual Pd content was 20 ppm. After solvent exchange, approximately 10% MeOH remained in the DMF solu...

Claims

1. A solid compound, said compound being compound I-1, 【Chemistry 61】 or a solvate thereof.

2. The compound may be amorphous or crystalline, and optionally 2. The compound of claim 1, wherein the solid form is Form A, Form B, or Form C.

3. A solid compound, said compound being a compound of formula (I): 【Transformation 62】 or a solvate thereof, During the ceremony, m is 1, 2, 3, 4, 5, 6, 7, 8, or 9; n is 0, 0.5, 1, 1.5, 2, 2.5, or 3; and The solid compound wherein X is hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, or 2-naphthalenesulfonic acid.

4. The compound is (a) Compound I-2, 【Transformation 63】 or a solvate thereof, optionally The solid form is Form A. (b) Compound I-3, 【Chemistry 64】 or a solvate thereof, optionally The solid form is Form A or Form B. (c) Compound I-4, 【Transformation 65】 or a solvate thereof, optionally the solid form is Form A; or (d) Compound I-5, 【Chemical Formula 66】 or a solvate thereof, optionally 4. The compound of claim 3, wherein the solid form is Form A or Form B.

5. A solid compound, said compound being a compound of formula (II): 【Transformation 67】 or a solvate thereof, During the ceremony, p is 1, 2, 3, 4, 5, 6, 7, 8, or 9; q is 0, 0.5, 1, 1.5, 2, 2.5, or 3; and X is hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, or 2-naphthalenesulfonic acid, and optionally The solid compound, wherein the compound is amorphous or crystalline.

6. The compound is Compound II-2, Compound II-3, Compound II-4, Compound II-5, or Compound II-6, 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 6. The compound of claim 5, which is:

7. The compound is Compound II-1, 【Transformation 68】 or a solvate thereof, optionally 6. The compound of claim 5, wherein the solid form is Form A, Form B, or Form C.

8. A solid compound, said compound being a compound of formula III: 【Transformation 69】 or a solvate thereof, During the ceremony, r is 1, 2, 3, 4, 5, 6, 7, 8, or 9; s is 0, 0.5, 1, 1.5, 2, 2.5, or 3; and X is hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, or 2-naphthalenesulfonic acid, and optionally The solid compound, wherein the compound is amorphous or crystalline.

9. The compound is compound III-3, compound III-4, or compound III-5, 【Chemistry 27】 【Chemistry 28】 【Chemistry 29】 9. The compound of claim 8, which is: or a solvate thereof.

10. The compound is (a) Compound III-1, 【Transformation 70】 or a solvate thereof, optionally the solid form is Form A, Form B, Form C, Form D, Form E, or Form F; (b) Compound III-2, 【Chemistry 71】 or a solvate thereof, optionally the solid form is Form A or Form B; or (c) Compound III-6, 【Chemistry 72】 or a solvate thereof, optionally 9. The compound of claim 8, wherein the solid form is Form A. (1) A process for preparing a crystalline form of a compound of formula (I), comprising: a) preparing a solution of a compound of formula (I); b) adjusting the temperature so that a solid crystalline form of the compound of formula (I) precipitates from said solution; and c) isolating said solid crystalline form; or (2) A process for preparing a crystalline form of the compound of formula (II), comprising: a) preparing a solution of the compound of formula (II); b) adjusting the temperature so that a solid crystalline form of the compound of formula (II) precipitates from the solution; and c) isolating the solid crystalline form; or (3) A process for preparing a crystalline form of the compound of formula (III), comprising: a) preparing a solution of the compound of formula (III); b) adjusting the temperature so that a solid crystalline form of the compound of formula (III) precipitates from the solution; and c) isolating the solid crystalline form.

12. A compound of formula (IV-1) or a compound of formula (IV-2), 【Transformation 73】 【Chemistry 74】 or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising the compound according to any one of claims 1 to 10 and 12 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

14. 13. A composition for inhibiting PI3Kα activity in a subject in need thereof or for treating cancer in a subject in need thereof, comprising a compound according to any one of claims 1 to 10 and 12, or a pharmaceutically acceptable salt thereof, and optionally The composition is for administration in combination with a therapeutically effective amount of an antibody, antibody-drug conjugate, kinase inhibitor, immunomodulator, or histone deacetylase inhibitor.

15. A kit comprising a compound according to any one of claims 1 to 10 and 12 or a pharmaceutically acceptable salt thereof, optionally comprising: instructions describing the preparation of a pharmaceutical composition suitable for administration to a patient from said solid or compound; and / or instructions explaining how to administer the resulting composition to the patient; and / or pharmaceutically acceptable excipients The kit further comprises:

16. (1) A process for preparing a compound of formula IV-1 and a compound of formula IV-2, comprising deuteration of compound III-1, followed by a purification step to separate the enantiomers, to form compounds IV-1 and IV-2. 【Chemistry 75】 ,or, (2) A process for preparing a compound of formula I-1 and a compound of formula II-1, comprising subjecting compound III-1 to SMB separation, thereby forming compounds I-1 and II-1, for example, as described in Example 1-A. 【Transformation 76】 ,or, (3) A process for preparing a compound of formula III-1, comprising racemization of compound II-1. 【Chemical 77】 17. A process for preparing a compound of formula III-1, comprising the step of coupling compound 2 with compound 3, thereby forming compound III-1: 【Chemistry 37】 Optionally, the process further comprises converting compound 4 to compound 3; 【Transformation 38】 Optionally, the process further comprises converting compound 5 to compound 4, 【Chemistry 39】 Optionally, the process further comprises coupling compound 6 with compound 7, thereby forming compound 5. 【Chemistry 40】 The process.

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