Solid-state spirotricyclic APOL1 inhibitors and methods of use thereof

Abstract

The present disclosure provides novel solid forms of Compound I selected from Compound I phosphate hydrate Form A, Compound I free monohydrate, Compound I phosphate methanol solvate, and Compound I phosphate MEK solvate, compositions comprising the same, and methods of making the same, as well as methods of using the same, including in the treatment of APOL1-mediated diseases (e.g., APOL1-mediated renal diseases, etc.). Also provided herein are novel solid forms of Compound II selected from Compound II phosphate hemihydrate Form A, Compound II free hemihydrate Form A, and Compound II free Form C, compositions comprising the same, and methods of making the same, as well as methods of using the same, including in the treatment of APOL1-mediated diseases (e.g., APOL1-mediated renal diseases, etc.). TIFF2024532272000232.tif4770

Description

[Technical Field]

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 237,248, filed August 26, 2021, U.S. Provisional Application No. 63 / 306,831, filed February 4, 2022, and U.S. Provisional Application No. 63 / 315,936, filed March 2, 2022, the contents of which are incorporated by reference in their entirety. [Background technology]

[0002] The present disclosure provides solid-state compounds capable of inhibiting apolipoprotein L1 (APOL1) and methods of using the solid-state compounds to treat APOL1-mediated diseases, such as APOL1-mediated kidney diseases, including, for example, pancreatic cancer, focal segmental glomerulosclerosis (FSGS), and / or non-diabetic kidney disease (NDKD). In some embodiments, FSGS and / or NDKD are associated with common APOL1 genetic variants (G1:S342G:I384M and G2:N388del:Y389del). In some embodiments, pancreatic cancer is associated with elevated APOL1 levels (e.g., elevated APOL1 levels in pancreatic cancer tissue).

[0003] FSGS is a rare kidney disease with an estimated global incidence of 0.2–1.1 / 100,000 / year. FSGS is a disease of podocytes (glomerular visceral epithelial cells) that causes proteinuria and progressive decline in kidney function. NDKD is a kidney disease associated with damage to the podocyte or glomerular vascular bed that is not caused by diabetes. NDKD is characterized by hypertension and progressive decline in kidney function. Human genetic analysis supports the causal role of G1 and G2 APOL1 variants in inducing kidney disease. Individuals with two APOL1 alleles are at increased risk for developing end-stage kidney disease (ESKD), including primary (idiopathic) FSGS, human immunodeficiency virus (HIV)-associated FSGS, NDKD, arterionephrosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease. See P. Dummer et al., Semin Nephrol. 35(3):222-236 (2015).

[0004] FSGS and NDKD can be divided into distinct subgroups based on the underlying etiology. One homogeneous subgroup of FSGS is characterized by the presence of independent consensus sequence variants in the apolipoprotein L1 (APOL1) gene, termed "APOL1 risk alleles," designated G1 and G2. G1 encodes a correlated pair of nonsynonymous amino acid changes (S342G and I384M), G2 encodes a two-amino acid deletion (N388del:Y389del) near the C-terminus of the protein, and G0 is the ancestral (low-risk) allele. A distinct NDKD phenotype is also observed in patients with APOL1 genetic risk variants. In both APOL1-mediated FSGS and NDKD, patients with two risk alleles develop higher levels of proteinuria and more rapid loss of kidney function compared with patients with none or only one APOL1 genetic risk variant. Alternatively, AMKD can cause high levels of proteinuria and rapid loss of kidney function in patients with even one risk allele. See G. Vajgel et al., J. Rheumatol., November 2019, jrheum.190684.

[0005] APOL1 is a 44-kDa protein expressed only in humans, gorillas, and baboons. In humans, the APOL1 gene is expressed in multiple organs, including the liver and kidney. APOL1 is primarily produced by the liver and contains a signal peptide that allows it to be secreted into the bloodstream, where it circulates bound to a subset of high-density lipoproteins. APOL1 also contributes to defense against the invasive parasite Trypanosoma brucei (TbBrucei). APOL1 is endocytosed by TbBrucei and transported to lysosomes. There, it inserts into the lysosomal membrane, forming a pore that results in the parasite's swelling and death.

[0006] Although the ability to lyse Tb brucei is common to all three APOL1 variants (G0, G1, and G2), the APOL1 G1 and G2 variants confer additional protection against parasite species that have evolved serum resistance-associated proteins (SRA) that inhibit APOL1 G0. APOL1 G1 and G2 variants also confer additional protection against trypanosome species that cause sleeping sickness. The G1 and G2 variants escape SRA inhibition, and G1 confers additional protection against Tb gambiense (which causes West African sleeping sickness), while G2 confers additional protection against Tb brucei (which causes East African sleeping sickness).

[0007] In the kidney, APOL1 is expressed in podocytes, endothelial cells (including glomerular endothelial cells), and some tubular cells. In transgenic mice, podocyte-specific expression of APOL1 G1 or G2 (but not G0) induces structural and functional changes, including albuminuria, decreased renal function, podocyte abnormalities, and glomerular sclerosis. Consistent with these data, APOL1 G1 and G2 variants induce and accelerate the progression of FSGS in humans. Individuals with APOL1 risk alleles (i.e., homozygous or compound heterozygous for the APOL1 G1 or APOL1 G2 alleles) are at increased risk for developing FSGS and, if they do develop FSGS, are also at risk for rapid decline in renal function. Therefore, APOL1 inhibition may have a beneficial effect in individuals carrying APOL1 risk alleles.

[0008] Although normal plasma concentrations of APOL1 are relatively high and can vary by at least 20-fold in humans, circulating APOL1 is not causally associated with renal disease. However, renal APOL1 is thought to contribute to the development of renal diseases, including FSGS and NDKD. Under certain circumstances, APOL1 protein synthesis can be increased by approximately 200-fold by proinflammatory cytokines, such as interferon or tumor necrosis factor-α. In addition, APOL1 protein binds to the cell membrane as a pH-regulating Na+ receptor. + / K + Pore ​​formation and consequent intracellular K + Several studies have shown that this results in a net excretion of inflammatory cytokines, ultimately activating local and systemic inflammatory responses, cell swelling, and death.

[0009] The risk of end-stage kidney disease (ESKD) is significantly higher in people of modern sub-Saharan African descent compared with people of European descent. In the United States, ESKD accounts for nearly as many years of life lost in women as breast cancer and more years of life lost in men than colorectal cancer.

[0010] FSGS and NDKD are caused by damage to podocytes, which are part of the glomerular filtration barrier, resulting in proteinuria. Patients with proteinuria are at increased risk for developing ESKD and proteinuria-related complications, such as infection or thromboembolic events. There are no standardized treatment regimens or approved medications for FSGS or NDKD. Currently, FSGS and NDKD are managed with symptomatic treatment (including blood pressure control using renin-angiotensin system blockers), and patients with FSGS and severe proteinuria may be prescribed high-dose steroids. Current treatment options for NDKD are fixed on blood pressure control and renin-angiotensin system blockade.

[0011] Corticosteroids, alone or in combination with other immunosuppressants, have induced remission (e.g., remission of proteinuria in a minority of patients) in a minority of patients, but are associated with numerous side effects. However, even in patients who initially respond to corticosteroid and / or immunosuppressive treatment, remission is often short-lived. As a result, patients, particularly those of modern sub-Saharan African descent who carry two APOL1 risk alleles, experience rapid disease progression and end-stage renal disease (ESRD). Therefore, there is an unmet medical need for treatments for FSGS and NDKD. Specifically, given evidence that APOL1 plays a causative role in the induction and accelerated progression of renal disease, APOL1 inhibition should have a beneficial effect on patients with APOL1-mediated renal disease, particularly those who carry two APOL1 risk alleles (i.e., homozygous or compound heterozygous for the G1 or G2 allele). Furthermore, APOL1 is a gene that is aberrantly expressed in multiple cancers (Lin et al., Cell Death and Disease (2021), 12:760). Recently, APOL1 has been found to be abnormally elevated in human pancreatic cancer tissue compared with adjacent tissue and is associated with poor prognosis in pancreatic cancer patients. In vivo and in vitro experiments have shown that knockdown of APOL1 inhibits cancer cell proliferation and promotes apoptosis in pancreatic cancer cells. [Prior art documents] [Non-patent literature]

[0012] [Non-Patent Document 1] P.Dummer et al.,Semin Nephrol.35(3):222-236(2015) [Non-patent document 2] G.Vajgel et al.,J.Rheumatol.,November 2019,jrheum.190684 [Non-patent document 3] Lin et al.,Cell Death and Disease(2021),12:760 Summary of the Invention

[0013] Compound I, its method of preparation, and physicochemical data are described as Compound 181 in International Patent Application PCT / US2021 / 047754, filed August 26, 2021, the entirety of which is incorporated herein by reference. [ka]

[0014] Compound II, its method of preparation, and physicochemical data are described as Compound 174 in International Patent Application PCT / US2021 / 047754, filed August 26, 2021, the entirety of which is incorporated herein by reference. [ka]

[0015] One aspect of the present disclosure provides a novel solid form, phosphate salt hydrate Form A, of Compound I, which may be employed in the treatment of APOL1-mediated diseases, such as FSGS, NDKD, and pancreatic cancer, and in methods of making the compound.

[0016] One aspect of the present disclosure provides a novel solid form, the free monohydrate of Compound I, which can be employed in the treatment of APOL1-mediated diseases, such as FSGS, NDKD, and pancreatic cancer, and in methods of making the compound.

[0017] Another aspect of the present disclosure provides a novel solid form, maleate salt Form A (salt or co-crystal) of Compound I, which may be employed in the treatment of APOL1-mediated diseases such as FSGS, NDKD, and pancreatic cancer, as well as methods of making the compound.

[0018] Another aspect of the present disclosure provides a novel solid form, maleate Form B (salt or co-crystal) of Compound I, which may be employed in the treatment of APOL1-mediated diseases, such as FSGS, NDKD, and pancreatic cancer, and in methods of making the compound.

[0019] Another aspect of the present disclosure provides a novel solid form, fumaric acid Form A (salt or co-crystal) of Compound I, which may be employed in the treatment of APOL1-mediated diseases such as FSGS, NDKD, and pancreatic cancer, and in methods of making the compound.

[0020] Another aspect of the present disclosure provides a novel solid form, free Form B, of Compound I, which may be employed in the treatment of APOL1-mediated diseases, such as FSGS, NDKD, and pancreatic cancer, and in methods of making the compound.

[0021] Another aspect of the present disclosure provides a novel solid form, free Form C, of ​​Compound I, which may be employed in the treatment of APOL1-mediated diseases, such as FSGS, NDKD, and pancreatic cancer, and in methods of making the compound.

[0022] Another aspect of the present disclosure provides novel solid forms, a methanol solvate of the phosphate salt of Compound I and a MEK solvate of the phosphate salt of Compound I, which can be employed in the preparation of therapeutic solid forms of Compound I.

[0023] Another aspect of the present disclosure provides a novel solid form, phosphate hemihydrate Form A, of Compound II, which may be employed in the treatment of APOL1-mediated diseases, such as FSGS, NDKD, and pancreatic cancer, and in methods of making the same.

[0024] Another aspect of the present disclosure provides a novel solid form, free hemihydrate Form A, of Compound II, which may be employed in the treatment of APOL1-mediated diseases such as FSGS, NDKD, and pancreatic cancer, as well as methods of making the same.

[0025] Another aspect of the present disclosure provides a novel solid form, free Form C, of ​​Compound II, which may be employed in the treatment of APOL1-mediated diseases, such as FSGS, NDKD, and pancreatic cancer, and in methods of making the compounds.

[0026] One aspect of the present disclosure provides a novel solid form, Form A, of Compound II, which may be employed in the treatment of APOL1-mediated diseases such as FSGS, NDKD, and pancreatic cancer, as well as methods of making the same.

[0027] One aspect of the present disclosure provides a novel solid form, free Form B, of Compound II, which may be employed in the treatment of APOL1-mediated diseases, such as FSGS, NDKD, and pancreatic cancer, as well as methods of making the compounds.

[0028] One aspect of the present disclosure provides a novel solid form, the free quart hydrate, of Compound II, which can be employed in the treatment of APOL1-mediated diseases, such as FSGS, NDKD, and pancreatic cancer, and in methods of making the compound.

[0029] One aspect of the present disclosure provides a novel solid form, a free mixed hydrate, of Compound II, which can be employed in the treatment of APOL1-mediated diseases, such as FSGS, NDKD, and pancreatic cancer, and in methods of making the compound.

[0030] One aspect of the present disclosure provides a novel solid form, the free monohydrate of Compound II, which can be employed in the treatment of APOL1-mediated diseases, such as FSGS, NDKD, and pancreatic cancer, and in methods of making the compound.

[0031] One aspect of the present disclosure provides a novel solid form, the free dihydrate of Compound II, which can be employed in the treatment of APOL1-mediated diseases, such as FSGS, NDKD, and pancreatic cancer, and in methods of making the compound.

[0032] One aspect of the present disclosure provides a novel solid form, free EtOH solvate Form B of Compound II, which may be employed in the treatment of APOL1-mediated diseases, such as FSGS, NDKD, and pancreatic cancer, and in methods of making the same.

[0033] One aspect of the present disclosure provides a novel solid form, Form A, of the phosphate salt of Compound II, which may be employed in the treatment of APOL1-mediated diseases, such as FSGS, NDKD, and pancreatic cancer, and in methods of making the compound.

[0034] One aspect of the present disclosure provides a novel solid form, Form C, of ​​the phosphate salt of Compound II, which may be employed in the treatment of APOL1-mediated diseases, such as FSGS, NDKD, and pancreatic cancer, and in methods of making the compound.

[0035] One aspect of the present disclosure provides amorphous, free-form Compound II, which may be employed in the treatment of APOL1-mediated diseases, such as FSGS, NDKD, and pancreatic cancer, and in methods of making the compound.

[0036] Another aspect of the present disclosure provides novel solid forms of Compound II, including the free form MEK solvate of Compound II, the free form IPA solvate of Compound II, the free form MeOH solvate of Compound II, and the phosphate acetone solvate Form A of Compound II, which may be employed in the preparation of therapeutic solid forms of Compound II.

[0037] Another aspect of the present disclosure provides a method of treating an APOL1-mediated disease (e.g., pancreatic cancer, FSGS, and / or NDKD), the method comprising administering to a subject in need thereof a solid form of Compound I selected from Compound I phosphate salt hydrate Form A, Compound I free form monohydrate, Compound I maleate salt Form A (salt or co-crystal), Compound I maleate salt Form B (salt or co-crystal), Compound I fumarate salt Form A (salt or co-crystal), Compound I free form Form B, and Compound I free form Form C, or a pharmaceutical composition comprising same.

[0038] In some embodiments, the subject has one APOL1 risk allele. In some embodiments, the subject has two APOL1 risk alleles.

[0039] In some embodiments, the method of treatment comprises administering to a subject in need thereof at least one additional active agent, either in the same pharmaceutical composition as the solid form of Compound I or as a separate composition.

[0040] In some embodiments, the solid form of Compound I and at least one additional active agent are co-administered in the same pharmaceutical composition. In some embodiments, the solid form of Compound I and at least one additional active agent are co-administered in separate pharmaceutical compositions. In some embodiments, the solid form of Compound I and at least one additional active agent are co-administered simultaneously. In some embodiments, the solid form of Compound I and at least one additional active agent are co-administered sequentially.

[0041] Another aspect of the present disclosure provides a method of treating an APOL1-mediated disease (e.g., pancreatic cancer, FSGS, and / or NDKD), the method comprising administering to a subject in need thereof a solid form of Compound II selected from Compound II phosphate hemihydrate Form A, Compound II free hemihydrate Form A, Compound II free form C, Compound II free form A, Compound II free form B, Compound II free quarterhydrate, Compound II free mixed hydrate, Compound II free monohydrate, Compound II free dihydrate, Compound II free EtOH solvate Form B, Compound II phosphate Form A, and Compound II phosphate Form C, or a pharmaceutical composition comprising same.

[0042] In some embodiments, the subject has one APOL1 risk allele. In some embodiments, the subject has two APOL1 risk alleles.

[0043] In some embodiments, the method of treatment includes administering to a subject in need thereof at least one additional active agent, either in the same pharmaceutical composition as the solid form of Compound II or as a separate composition.

[0044] In some embodiments, the solid form of Compound II and at least one additional active agent are co-administered in the same pharmaceutical composition. In some embodiments, the solid form of Compound II and at least one additional active agent are co-administered in separate pharmaceutical compositions. In some embodiments, the solid form of Compound II and at least one additional active agent are co-administered simultaneously. In some embodiments, the solid form of Compound II and at least one additional active agent are co-administered sequentially.

[0045] Also provided is a method of inhibiting APOL1, the method comprising administering to a subject in need thereof a solid form of Compound I selected from Compound I phosphate salt hydrate Form A, Compound I free form monohydrate, Compound I maleate salt Form A (salt or co-crystal), Compound I maleate salt Form B (salt or co-crystal), Compound I fumarate salt Form A (salt or co-crystal), Compound I free form Form B, and Compound I free form Form C, or a pharmaceutical composition comprising same.

[0046] Also provided is a method of inhibiting APOL1, the method comprising administering to a subject in need thereof a solid form of Compound II selected from Compound II phosphate hemihydrate Form A, Compound II free hemihydrate Form A, Compound II free form C, Compound II free form A, Compound II free form B, Compound II free quartohydrate, Compound II free mixed hydrate, Compound II free monohydrate, Compound II free dihydrate, Compound II free EtOH solvate Form B, Compound II phosphate Form A, and Compound II phosphate Form C, or a pharmaceutical composition comprising same.

[0047] Also disclosed herein are solid forms of Compound I selected from Compound I phosphate salt hydrate Form A, Compound I free monohydrate, Compound I maleate salt Form A (salt or co-crystal), Compound I maleate salt Form B (salt or co-crystal), Compound I fumarate salt Form A (salt or co-crystal), Compound I free form Form B, and Compound I free form Form C for use in therapy. In some embodiments, the solid form of Compound I is combined with at least one additional active agent for simultaneous, separate, or sequential use in therapy. In some embodiments, when used simultaneously, the solid form of Compound I and the at least one additional active agent are in separate pharmaceutical compositions. In some embodiments, when used simultaneously, the solid form of Compound I and the at least one additional active agent are together in the same pharmaceutical composition.

[0048] Also disclosed herein is a solid form of Compound II selected from Compound II phosphate hemihydrate Form A, Compound II free hemihydrate Form A, Compound II free form C, Compound II free form A, Compound II free form B, Compound II free quartohydrate, Compound II free mixed hydrate, Compound II free monohydrate, Compound II free dihydrate, amorphous Compound II, Compound II free EtOH solvate Form B, Compound II phosphate Form A, and Compound II phosphate Form C for use in therapy. In some embodiments, the solid form of Compound II is combined with at least one additional active agent for simultaneous, separate, or sequential use in therapy. In some embodiments, when used simultaneously, the solid form of Compound II and the at least one additional active agent are in separate pharmaceutical compositions. In some embodiments, when used simultaneously, the solid form of Compound II and the at least one additional active agent are together in the same pharmaceutical composition.

[0049] Also disclosed herein are pharmaceutical compositions comprising a solid form of Compound I selected from Compound I phosphate salt hydrate Form A, Compound I free form monohydrate, Compound I maleate salt Form A (salt or co-crystal), Compound I maleate salt Form B (salt or co-crystal), Compound I fumarate salt Form A (salt or co-crystal), Compound I free form Form B, and Compound I free form Form C, for use in therapy.

[0050] Also disclosed herein are pharmaceutical compositions comprising a solid form of Compound II selected from Compound II phosphate hemihydrate Form A, Compound II free hemihydrate Form A, Compound II free form C, Compound II free form A, Compound II free form B, Compound II free quarter-hydrate, Compound II free mixed hydrate, Compound II free monohydrate, Compound II free dihydrate, amorphous Compound II, Compound II free EtOH solvate Form B, Compound II phosphate Form A, and Compound II phosphate Form C, for use in therapy.

[0051] It should be understood that references herein to methods of treatment and / or inhibition (e.g., methods of treating FSGS and / or NDKD, methods of inhibiting APOL1) using one or more compounds (e.g., one or more solid-state forms of Compound I or Compound II described herein) should also be interpreted as references to one or more compounds (e.g., one or more solid-state forms of Compound I or Compound II) for use in the methods of treatment and / or inhibition, and / or to the use of one or more compounds (e.g., one or more solid-state forms of Compound I or Compound II) in the manufacture of a medicament for treatment and / or inhibition. [Brief explanation of the drawings]

[0052] [Figure 1] FIG. 1 shows the XRPD diffractogram of the phosphate salt methanol solvate of Compound I.

[0053] [Figure 2] FIG. 2 shows the solid-state 13C NMR spectrum of the phosphate salt methanol solvate of Compound I.

[0054] [Figure 3] FIG. 3 shows the solid-state 19F NMR spectrum of the phosphate salt methanol solvate of Compound I.

[0055] [Figure 4] FIG. 4 shows the solid-state 31P NMR spectrum of the phosphate salt methanol solvate of Compound I.

[0056] [Figure 5] FIG. 5 shows the XRPD diffractogram of Compound I phosphate salt hydrate Form A at 25±2° C. and 40% RH.

[0057] [Figure 6] FIG. 6 shows the XRPD diffractograms of Compound I phosphate salt hydrate Form A at 25±2° C. and 5% RH (black line) or 90% RH (gray line).

[0058] [Figure 7] FIG. 7 shows the solid-state 13C NMR spectrum of Compound I phosphate salt hydrate Form A at 43% RH.

[0059] [Figure 8] FIG. 8 shows the solid-state 19F NMR spectrum of Compound I phosphate salt hydrate Form A at 43% RH.

[0060] [Figure 9] FIG. 9 shows the effect of relative humidity on the solid-state 19F NMR spectrum of Compound I phosphate hydrate Form A.

[0061] [Figure 10]FIG. 10 shows the solid-state 31P NMR spectrum of Compound I phosphate salt hydrate Form A at 43% RH.

[0062] [Figure 11] FIG. 11 shows the effect of relative humidity on the solid-state 31P NMR spectrum of Compound I phosphate hydrate Form A.

[0063] [Figure 12] FIG. 12 shows a TGA thermogram of Compound I phosphate salt hydrate Form A.

[0064] [Figure 13] FIG. 13 shows the DSC curve of Compound I phosphate hydrate Form A.

[0065] [Figure 14] FIG. 14 shows the XRPD diffractogram of Compound I free monohydrate.

[0066] [Figure 15] FIG. 15 shows the solid-state 13C NMR spectrum of the free monohydrate of Compound I.

[0067] [Figure 16] FIG. 16 shows the solid-state 13C NMR spectrum of the free monohydrate of Compound I after dehydration.

[0068] [Figure 17] FIG. 17 shows the solid-state 19F NMR spectrum of the free monohydrate of Compound I.

[0069] [Figure 18] FIG. 18 shows the solid-state 19F NMR spectrum of the free monohydrate of Compound I after dehydration.

[0070] [Figure 19] FIG. 19 shows the TGA thermogram of the free monohydrate form of Compound I.

[0071] [Figure 20] FIG. 20 shows the DSC curve of the free monohydrate of Compound I.

[0072] [Figure 21] FIG. 21 shows the XRPD diffractogram of the phosphate salt MEK solvate of Compound I.

[0073] [Figure 22] FIG. 22 shows the solid-state 13C NMR spectrum of the phosphate salt MEK solvate of Compound I.

[0074] [Figure 23] FIG. 23 shows the solid-state 19F NMR spectrum of the phosphate salt MEK solvate of Compound I.

[0075] [Figure 24] FIG. 24 shows the XRPD diffractogram of Compound II phosphate salt hemihydrate Form A.

[0076] [Figure 25] FIG. 25 shows the solid-state 13C NMR spectrum of Compound II phosphate hemihydrate Form A.

[0077] [Figure 26] FIG. 26 shows the solid-state 13C NMR spectrum of Compound II phosphate hemihydrate Form A after dehydration.

[0078] [Figure 27A] FIG. 27A shows the solid-state 31P NMR spectrum of Compound II phosphate hemihydrate Form A.

[0079] [Figure 27B] FIG. 27B shows the solid-state 31P NMR spectrum of Compound II phosphate hemihydrate Form A after dehydration.

[0080] [Figure 28] FIG. 28 shows the TGA thermogram of Compound II phosphate salt hemihydrate Form A.

[0081] [Figure 29] FIG. 29 shows the DSC curve of Compound II phosphate salt hemihydrate Form A.

[0082] [Figure 30A] FIG. 30A shows the XRPD diffractogram of the free hemihydrate Form A of Compound II measured at ambient temperature (25±2° C.).

[0083] [Figure 30B] FIG. 30B shows the XRPD diffractogram of the free hemihydrate Form A of Compound II measured at temperatures between 40°C and 50°C.

[0084] [Figure 30C] FIG. 30C shows the XRPD diffractogram of the free hemihydrate Form A of Compound II measured at temperatures between 60°C and 90°C.

[0085] [Figure 31] FIG. 31 shows the solid-state 13C NMR spectrum of the free hemihydrate Form A of Compound II.

[0086] [Figure 32] Figure 32 is an intentionally left blank.

[0087] [Figure 33] FIG. 33 shows the TGA thermogram of the free hemihydrate Form A of Compound II.

[0088] [Figure 34] FIG. 34 shows the DSC curve of the free hemihydrate Form A of Compound II.

[0089] [Figure 35] FIG. 35 shows the diffractogram of free Form C of Compound II measured at room temperature (25° C.±2° C.).

[0090] [Figure 36] FIG. 36 shows the TGA thermogram of the free form Form C of Compound II.

[0091] [Figure 37] FIG. 37 shows the DSC curve of the free form Form C of Compound II.

[0092] [Figure 38] FIG. 38 shows the solid-state 13C NMR spectrum of the free form Form C of Compound II.

[0093] [Figure 39] FIG. 39 shows the XRPD diffractogram of Compound I maleate salt Form A.

[0094] [Figure 40] FIG. 40 shows the TGA thermogram of Compound I maleate salt Form A.

[0095] [Figure 41] FIG. 41 shows the DSC curve of Compound I maleate salt Form A.

[0096] [Figure 42] FIG. 42 shows the XRPD diffractogram of Compound I maleate salt Form B.

[0097] [Figure 43] FIG. 43 shows the TGA thermogram of Compound I maleate salt Form B.

[0098] [Figure 44] FIG. 44 shows the DSC curve of Compound I maleate salt Form B.

[0099] [Figure 45] FIG. 45 shows the XRPD diffractogram of Compound I fumaric acid Form A.

[0100] [Figure 46] FIG. 46 shows the solid-state 13C CPMAS spectrum of Compound I fumaric acid Form A.

[0101] [Figure 47] FIG. 47 shows the solid-state 19F MAS spectrum of Compound I fumaric acid Form A.

[0102] [Figure 48] FIG. 48 shows the TGA thermogram of Compound I fumaric acid Form A.

[0103] [Figure 49] FIG. 49 shows the DSC curve of Compound I fumaric acid Form A.

[0104] [Figure 50] FIG. 50 shows the XRPD diffractogram of Compound I free form Form B.

[0105] [Figure 51] FIG. 51 shows the solid-state 13C CPMAS spectrum of free Form B of Compound I.

[0106] [Figure 52] FIG. 52 shows the solid-state 19F MAS spectrum of free Form B of Compound I.

[0107] [Figure 53] FIG. 53 shows the TGA thermogram of Compound I free form Form B.

[0108] [Figure 54] FIG. 54 shows the DSC curve of the free form Form B of Compound I.

[0109] [Figure 55] FIG. 55 shows the XRPD diffractogram of the free form Form C of Compound I.

[0110] [Figure 56] FIG. 56 shows the solid-state 13C CPMAS spectrum of free Form C of Compound I.

[0111] [Figure 57] FIG. 57 shows the solid-state 19F MAS spectrum of free Form C of Compound I.

[0112] [Figure 58] FIG. 58 shows the TGA thermogram of the free form Form C of Compound I.

[0113] [Figure 59] FIG. 59 shows the DSC curve of the free form Form C of Compound I.

[0114] [Figure 60] FIG. 60 shows the XRPD diffractogram of the free form Form A of Compound II.

[0115] [Figure 61] FIG. 61 shows the solid-state 13C CPMAS spectrum of free Form A of Compound II.

[0116] [Figure 62] FIG. 62 shows the TGA thermogram of the free form Form A of Compound II.

[0117] [Figure 63] FIG. 63 shows the DSC curve of the free form Form A of Compound II.

[0118] [Figure 64] FIG. 64 shows the solid-state 13C CPMAS spectrum of free Form B of Compound II.

[0119] [Figure 65] FIG. 65 shows the solid-state 13C CPMAS spectrum of a physical mixture of approximately 19% of the free hemihydrate of Compound II, Form A, and the free quarter-hydrate of Compound II.

[0120] [Figure 66] FIG. 66 shows the solid-state 13C CPMAS spectrum of the free quartohydrate of Compound II, with the spectrum of the free hemihydrate Form A of Compound II subtracted.

[0121] [Figure 67] FIG. 67 shows the XRPD diffractogram of the free mixed hydrate of Compound II.

[0122] [Figure 68] Figure 68 shows the solid-state 13C CPMAS spectrum of the free monohydrate of Compound II.

[0123] [Figure 69] FIG. 69 shows the solid-state 13C CPMAS spectrum of Compound II free dihydrate mixed with about 29% Compound II free hemihydrate Form A and about 18% Compound II free Form A.

[0124] [Figure 70] FIG. 70 shows the solid-state 13C CPMAS spectrum of the free dihydrate of Compound II (subtracting approximately 29% of the free hemihydrate Form A of Compound II and approximately 18% of the free Form A of Compound II).

[0125] [Figure 71] FIG. 71 shows the XRPD diffractogram of the free EtOH solvate Form B of Compound II.

[0126] [Figure 72]FIG. 72 shows the TGA thermogram of the free EtOH solvate Form B of Compound II.

[0127] [Figure 73] FIG. 73 shows the DSC curve of the free EtOH solvate Form B of Compound II.

[0128] [Figure 74] FIG. 74 shows the XRPD diffractogram of the free IPA solvate Form B of Compound II.

[0129] [Figure 75] FIG. 75 shows the solid-state 13C CPMAS spectrum of the free IPA solvate of Compound II.

[0130] [Figure 76] FIG. 76 shows the solid-state 13C CPMAS spectrum of the free MEK solvate of Compound II.

[0131] [Figure 77] FIG. 77 shows the XRPD diffractogram of the free MeOH solvate Form B of Compound II.

[0132] [Figure 78] Figure 78 shows the solid-state 13C CPMAS spectrum of the free MeOH solvate of compound II.

[0133] [Figure 79] FIG. 79 shows the TGA thermogram of the free MeOH solvate of Compound II.

[0134] [Figure 80] FIG. 80 shows the DSC curve of the free MeOH solvate Form B of Compound II.

[0135] [Figure 81] FIG. 81 shows the XRPD diffractogram of the amorphous free form of Compound II.

[0136] [Figure 82] Figure 82 shows the solid-state 13C CPMAS spectrum of amorphous free form of Compound II.

[0137] [Figure 83] Figure 83 shows the TGA thermogram of the amorphous free form of Compound II.

[0138] [Figure 84] FIG. 84 shows the DSC curve of the amorphous free form of Compound II.

[0139] [Figure 85] Figure 85 shows the XRPD diffractogram of the phosphate acetone solvate Form A of Compound II.

[0140] [Figure 86] Figure 86 shows the solid-state 13C CPMAS spectrum of the phosphate acetone solvate Form A of Compound II.

[0141] [Figure 87] Figure 87 shows the TGA thermogram of Compound II phosphate salt acetone solvate Form A.

[0142] [Figure 88] Figure 88 shows the DSC curve of phosphate acetone solvate Form A of Compound II.

[0143] [Figure 89] Figure 89 shows the XRPD diffractogram of the phosphate salt Form A of Compound II.

[0144] [Figure 90] FIG. 90 shows the solid-state 13C CPMAS spectrum of the phosphate salt Form A of Compound II.

[0145] [Figure 91] FIG. 91 shows the solid-state 31P CPMAS spectrum of the phosphate salt Form A of Compound II.

[0146] [Figure 92] Figure 92 shows the TGA thermogram of the phosphate salt Form A of Compound II.

[0147] [Figure 93] FIG. 93 shows the DSC curve of the phosphate salt Form A of Compound II.

[0148] [Figure 94] FIG. 94 shows the XRPD diffractogram of the phosphate salt Form C of Compound II.

[0149] [Figure 95] Figure 95 shows the solid-state 13C CPMAS spectrum of the phosphate salt Form C of Compound II.

[0150] [Figure 96] Figure 96 shows the TGA thermogram of the phosphate salt Form C of Compound II.

[0151] [Figure 97] FIG. 97 shows the DSC curve of the phosphate salt Form C of Compound II.

[0152] [Figure 98] FIG. 98 shows the XRPD diffractogram of Compound I phosphate salt Form B.

[0153] [Figure 99] Figure 99 shows the TGA thermogram of Compound I phosphate salt Form B.

[0154] [Figure 100] FIG. 100 shows the DSC curve of Compound I phosphate salt Form B.

[0155] [Figure 101] FIG. 101 shows the solid-state 13C NMR spectrum of Compound I phosphate salt Form B.

[0156] [Figure 102] FIG. 102 shows the solid-state 19F NMR spectrum of Compound I phosphate salt Form B.

[0157] [Figure 103] FIG. 103 shows the solid-state 31P NMR spectrum of Compound I phosphate salt Form B.

[0158] [Figure 104] FIG. 104 shows the XRPD diffractogram of Compound I phosphate salt Form C.

[0159] [Figure 105] FIG. 105 shows the TGA thermogram of Compound I phosphate salt Form C.

[0160] [Figure 106] FIG. 106 shows the DSC curve of the phosphate salt Form C of Compound I.

[0161] [Figure 107] FIG. 107 shows the solid-state 13C NMR spectrum of Compound I phosphate salt Form C.

[0162] [Figure 108] FIG. 108 shows the solid-state 19F NMR spectrum of the phosphate salt Form C of Compound I.

[0163] [Figure 109] FIG. 109 shows the solid-state 31P NMR spectrum of Compound I phosphate salt Form C.

[0164] [Figure 110]FIG. 110 shows an XRPD diffractogram of a mixture of crystalline forms of the phosphate salt of Compound I.

[0165] [Figure 111] FIG. 111 shows a TGA thermogram of a crystalline form mixture of the phosphate salt of Compound I.

[0166] [Figure 112] FIG. 112 shows the DSC curve of a mixture of crystalline forms of the phosphate salt of Compound I.

[0167] [Figure 113] FIG. 113 shows the solid-state 13C NMR spectrum of a crystalline form mixture of Compound I phosphate salt.

[0168] [Figure 114] FIG. 114 shows the solid-state 19F NMR spectrum of a crystalline form mixture of Compound I phosphate salt.

[0169] [Figure 115] FIG. 115 shows the solid-state 31P NMR spectrum of a mixture of Compound I phosphate crystalline forms. DETAILED DESCRIPTION OF THE INVENTION

[0170] definition The term "APOL1" as used herein means apolipoprotein L1 protein and the term "APOL1" means apolipoprotein L1 gene.

[0171] The term "APOL1-mediated disease" refers to a disease or condition associated with abnormal APOL1 (e.g., a particular APOL1 genetic variant, elevated APOL1 levels). In some embodiments, the APOL1-mediated disease is an APOL1-mediated kidney disease. In some embodiments, the APOL1-mediated disease is associated with patients with two APOL1 risk alleles, e.g., homozygous or compound heterozygous for the G1 allele or the G2 allele. In some embodiments, the APOL1-mediated disease is associated with patients with one APOL1 risk allele.

[0172] The term "APOL1-mediated renal disease" refers to a disease or condition that impairs kidney function and can be caused by APOL1. In some embodiments, the APOL1-mediated renal disease is associated with a patient who has two APOL1 risk alleles, for example, who is homozygous or compound heterozygous for the G1 allele or the G2 allele. In some embodiments, the APOL1-mediated renal disease is selected from ESKD, NDKD, FSGS, HIV-associated nephropathy, arteriosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease. In some embodiments, the APOL1-mediated renal disease is chronic kidney disease or proteinuria.

[0173] As used herein, the term "FSGS" refers to focal segmental glomerulosclerosis, a disease of the podocytes (glomerular visceral epithelial cells) that causes proteinuria and a progressive decline in kidney function. In some embodiments, FSGS is associated with two APOL1 risk alleles.

[0174] As used herein, the term "NDKD" refers to a non-diabetic kidney disease characterized by severe hypertension and progressive decline in kidney function. In some embodiments, NDKD is associated with two APOL1 risk alleles.

[0175] The terms "ESKD" and "ESRD" are used interchangeably herein and refer to end-stage renal disease or end-stage renal disease. ESKD / ESRD refers to end-stage renal disease, i.e., kidney failure, where the kidneys do not function well enough to prevent the patient from surviving without dialysis or a kidney transplant. In some embodiments, ESKD / ESRD is associated with two APOL1 risk alleles.

[0176] The term "compound," when referring to a compound of the present disclosure, refers to a collection of molecules having identical chemical structures, unless otherwise indicated as a collection of stereoisomers (e.g., a collection of racemates, a collection of cis / trans stereoisomers, or a collection of (E) and (Z) stereoisomers), except that isotopic variations may exist among the constituent atoms of the molecule. Thus, it will be apparent to one of skill in the art that a compound represented by a particular chemical structure containing a deuterium atom shown also includes lesser amounts of isotopic substitutions having a hydrogen atom at one or more of the designated deuterium positions in the structure. The relative amounts of such isotopic substitutions in the compounds of the present disclosure will depend on several factors, including the isotopic purity of the reagents used to make the compound and the efficiency of isotope incorporation in the various synthetic steps used to prepare the compound. However, as noted above, the relative amount of such isotopic substitutions will be less than 49.9% of the compound as a whole. In other embodiments, the overall relative amount of such isotopic substitution will be less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the compound.

[0177] As used herein, the term "stable" refers to compounds or solid forms that do not substantially change when subjected to conditions that allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein.

[0178] As used herein, the term "chemically stable" means that a solid-state form of Compound I or Compound II does not decompose into one or more different compounds when subjected to specified conditions, such as, for example, 40°C / 75% relative humidity, for a specified period of time, e.g., 1 day, 2 days, 3 days, 1 week, 2 weeks, or more. In some embodiments, less than 25% of the solid-state form of Compound I or Compound II is decomposed. In some embodiments, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 3%, less than about 1%, or less than about 0.5% of the form of Compound I or Compound II is decomposed under the specified conditions. In some embodiments, no detectable amount of the solid-state form of Compound I or Compound II is decomposed.

[0179] As used herein, the term "physically stable" means that the solid state form of Compound I or Compound II does not change into one or more different physical forms (e.g., different solid state forms as measured by XRPD, DSC, etc.) when subjected to specified conditions, such as, for example, 40°C / 75% relative humidity, for a specified period of time, e.g., 1 day, 2 days, 3 days, 1 week, 2 weeks, or more. In some embodiments, less than 25% of the solid state form of Compound I or Compound II changes into one or more different physical forms when subjected to the specified conditions. In some embodiments, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 3%, less than about 1%, or less than about 0.5% of the solid state form of Compound I or Compound II changes into one or more different physical forms when subjected to the specified conditions. In some embodiments, no detectable amount of the solid state form of Compound I or Compound II changes into one or more physically different solid state forms of Compound I or Compound II.

[0180] As used herein, the term "hydrate" refers to any crystalline Compound I or crystalline Compound II that contains water in its crystal lattice. The stoichiometry of a Compound I hydrate or a Compound II hydrate can vary. For example, a Compound I or Compound II hydrate can be a quarter-hydrate, hemihydrate, monohydrate, dihydrate, or partially dehydrated.

[0181] The "free base" form of a compound does not include ionic salts.Please note that the disclosed amount of compounds or their pharmaceutically acceptable salts herein is based on their free base form.For example, "10 mg of at least one compound selected from Compound I and its pharmaceutically acceptable salts" includes 10 mg of Compound I and the mass of the pharmaceutically acceptable salt of Compound I that is equivalent to 10 mg of Compound I.

[0182] "Selected" and "chosen" are used interchangeably herein.

[0183] As used herein, the term "solvent" refers to any liquid in which the product is at least partially soluble (solubility of product >1 g / L).

[0184] Non-limiting examples of suitable solvents that can be used in the methods of the present disclosure include water, methanol (MeOH), ethanol (EtOH), dichloromethane or "methylene chloride" (CHCl), toluene, acetonitrile (MeCN), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), heptane, isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropyl alcohol (IPA), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (EtO), methyl tert-butyl ether (MTBE), 1,4-dioxane, and N-methylpyrrolidone (NMP).

[0185] Non-limiting examples of amine bases that can be used in the present disclosure include, for example, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), N-methylmorpholine (NMM), triethylamine (EtN; TEA), diisopropylethylamine (i-PrEtN; DIPEA), pyridine, 2,2,6,6-tetramethylpiperidine, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), t-Bu-tetramethylguanidine, pyridine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), and potassium bis(trimethylsilyl)amide (KHMDS).

[0186] Non-limiting examples of carbonate bases that can be used in the present disclosure include, for example, sodium carbonate (Na2CO3), potassium carbonate (K2CO3), cesium carbonate (Cs2CO3), lithium carbonate (Li2CO3), sodium bicarbonate (NaHCO3), and potassium bicarbonate (KHCO3).

[0187] Non-limiting examples of alkoxide bases that can be used in the present disclosure include, for example, t-AmOLi (lithium t-amylate), t-AmONa (sodium t-amylate), t-AmOK (potassium t-amylate), sodium tert-butoxide (NaOtBu), potassium tert-butoxide (KOtBu), and sodium methoxide (NaOMe; NaOCH).

[0188] Non-limiting examples of hydroxide bases that can be used in the present disclosure include, for example, lithium hydroxide (LiOH), sodium hydroxide (NaOH), and potassium hydroxide (KOH).

[0189] Non-limiting examples of phosphate groups that can be used in the present disclosure include, for example, tribasic sodium phosphate (NaPO), tribasic potassium phosphate (KPO), dibasic potassium phosphate (KHPO), and monobasic potassium phosphate (KHPO).

[0190] Non-limiting examples of acids that can be used in the present disclosure include, for example, trifluoroacetic acid (TFA), hydrochloric acid (HCl), methanesulfonic acid (MsOH), phosphoric acid (H3PO4), and sulfuric acid (H2SO4).

[0191] Non-limiting examples of organic acids that may be used in the present disclosure include, for example, acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, and malonic acid.

[0192] Non-limiting examples of mineral acids that may be used in the present disclosure include, for example, hydrochloric acid (HCl), nitric acid (HNO3), phosphoric acid (H3PO4), hydrofluoric acid (HF), and sulfuric acid (H2SO4).

[0193] A non-limiting example of a carboxylic acid that can be used in the present disclosure is trichloroacetic acid.

[0194] A non-limiting example of a phosphonic acid that can be used in the present disclosure is phenylphosphonic acid.

[0195] Non-limiting examples of sulfonic acids that can be used in the present disclosure include, for example, p-toluenesulfonic acid, benzenesulfonic acid, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), and methanesulfonic acid.

[0196] Non-limiting examples of metal hydroxides that can be used in the present disclosure include, for example, lithium hydroxide (LiOH), sodium hydroxide (NaOH), cesium hydroxide (CsOH), and potassium hydroxide (KOH).

[0197] Non-limiting examples of activating agents that can be used in the present disclosure include, for example, carbonyldiimidazole, hydroxybenzotriazole (HOBt), and N,N-dimethylaminopyridine (DMAP).

[0198] Non-limiting examples of brominating agents that can be used in the present disclosure include, for example, bromine (Br2), N-bromosuccinimide (NBS), and 1,3-dibromo-5,5-dimethylhydantoin (DBDMH).

[0199] Non-limiting examples of phosphonium reagents that can be used in the present disclosure include, for example, benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP), benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP), 7-azabenzotriazol-1-yloxy)trispyrrolidinophosphonium hexafluorophosphate (PyAOP).

[0200] Non-limiting examples of peptide coupling reagents that can be used in the present disclosure include, for example, N,N'-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (EDCl), and 1-propanephosphonic anhydride (T3P).

[0201] Non-limiting examples of acetylating reagents that can be used in the present disclosure include, for example, acetyl chloride, acetyl bromide, and acetic anhydride.

[0202] Non-limiting examples of iodinating reagents that can be used in the present disclosure include, for example, iodine (I2), N-iodosuccinimide (NIS), and 1,3-diiodo-5,5-dimethylhydantoin (DIH).

[0203] Non-limiting examples of uronium reagents that can be used in the present disclosure include, for example, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uranium hexafluorophosphate (HBTU).

[0204] Non-limiting examples of trifluoromethylating reagents that can be used in the present disclosure include, for example, (1,10-phenanthroline)(trifluoromethyl)copper(I).

[0205] Non-limiting examples of nucleophiles that can be used in the present disclosure include, for example, MeLi and MeMgBr.

[0206] As used herein, the terms "about" and "approximately," when used in connection with amounts, volumes, reaction times, reaction temperatures, and the like, refer to an acceptable error for a particular value as determined by one of ordinary skill in the art and depend, in part, on how the value is measured or determined. In some embodiments, the terms "about" and "approximately" mean within 1, 2, 3, or 4 standard deviations. In certain embodiments, the terms "about" and "approximately" mean within 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, or 0.05% of a given value or range. As used herein, the symbol "~" appearing immediately before a numerical value has the same meaning as the terms "about" and "approximately."

[0207] The terms "patient" and "subject" are used interchangeably herein and refer to animals, including humans. In some embodiments, the subject is a human.

[0208] The terms "effective dose" and "effective amount" are used interchangeably herein and refer to the amount of the compound for which it is administered that produces the desired effect (e.g., amelioration of one or more symptoms of FSGS and / or NDKD, reduction in the severity of FSGS and / or NDKD, or alleviation of symptoms of FSGS and / or NDKD, and / or reduction in the progression of FSGS and / or NDKD, or reduction in the progression of symptoms of FSGS and / or NDKD). The exact amount of an effective dose will depend on the purpose of treatment and will be ascertainable by one of ordinary skill in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0209] As used herein, the term "treatment" and its cognates refer to slowing or halting disease progression. As used herein, "treatment" and its cognates include, but are not limited to, elimination or reduction in the severity of any symptoms, complete or partial remission, reduced risk of renal failure (e.g., ESRD), and disease-related complications (e.g., edema, susceptibility to infection, or thromboembolic events). Improvement or reduction in the severity of any symptom of an APOL1-mediated disease (e.g., an APOL1-mediated renal disease) can be readily assessed according to methods and techniques known in the art or subsequently developed. In some embodiments, the terms "treat," "treating," and "treatment" refer to the reduction in the severity of one or more symptoms of FSGS and / or NDKD.

[0210] The solid forms of Compound I disclosed herein can be administered once daily, twice daily, or three times daily, for example, for the treatment of APOL1-mediated diseases (e.g., FSGS). In some embodiments, a solid form of Compound I selected from Compound I phosphate hydrate Form A, Compound I free monohydrate, Compound I maleate Form A (salt or co-crystal), Compound I maleate Form B (salt or co-crystal), Compound I fumarate Form A (salt or co-crystal), Compound I free form B, and Compound I free form C is administered once daily. In some embodiments, a solid form of Compound I selected from Compound I phosphate hydrate Form A, Compound I free monohydrate, Compound I maleate Form A (salt or co-crystal), Compound I maleate Form B (salt or co-crystal), Compound I fumarate Form A (salt or co-crystal), Compound I free form B, and Compound I free form C is administered twice daily. In some embodiments, a solid form of Compound I selected from Compound I phosphate salt hydrate Form A, Compound I free form monohydrate, Compound I maleate salt Form A (salt or co-crystal), Compound I maleate salt Form B (salt or co-crystal), Compound I fumarate salt Form A (salt or co-crystal), Compound I free form Form B, and Compound I free form Form C is administered three times daily.

[0211] In some embodiments, 2 mg to 1500 mg of a solid form of Compound I selected from Compound I phosphate salt hydrate Form A, Compound I free form monohydrate, Compound I maleate salt Form A (salt or co-crystal), Compound I maleate salt Form B (salt or co-crystal), Compound I fumarate salt Form A (salt or co-crystal), Compound I free form Form B, and Compound I free form Form C is administered once daily, twice daily, or three times daily.

[0212] The solid forms of Compound II disclosed herein can be administered once daily, twice daily, or three times daily, for example, for the treatment of an APOL1-mediated disease (e.g., FSGS). In some embodiments, a solid form of Compound II selected from Compound II phosphate hemihydrate Form A, Compound II free hemihydrate Form A, Compound II free form C, Compound II free form A, Compound II free form B, Compound II free quarterhydrate, Compound II free mixed hydrate, Compound II free monohydrate, Compound II free dihydrate, Compound II free EtOH solvate Form B, amorphous free Compound II, Compound II phosphate Form A, and Compound II phosphate Form C is administered once daily. In some embodiments, a solid form of Compound II selected from Compound II phosphate hemihydrate Form A, Compound II free hemihydrate Form A, Compound II free form C, Compound II free form A, Compound II free form B, Compound II free quartohydrate, Compound II free mixed hydrate, Compound II free monohydrate, Compound II free dihydrate, Compound II free EtOH solvate Form B, amorphous free Compound II, Compound II phosphate Form A, and Compound II phosphate Form C is administered twice daily. In some embodiments, a solid form of Compound II selected from Compound II phosphate hemihydrate Form A, Compound II free hemihydrate Form A, Compound II free form C, Compound II free form A, Compound II free form B, Compound II free quartohydrate, Compound II free mixed hydrate, Compound II free monohydrate, Compound II free dihydrate, Compound II free EtOH solvate Form B, amorphous free Compound II, Compound II phosphate Form A, and Compound II phosphate Form C is administered three times daily.

[0213] In some embodiments, 2 mg to 1500 mg of a solid form of Compound II selected from Compound II phosphate hemihydrate Form A, Compound II free hemihydrate Form A, Compound II free form C, Compound II free form A, Compound II free form B, Compound II free quartohydrate, Compound II free mixed hydrate, Compound II free monohydrate, Compound II free dihydrate, Compound II free EtOH solvate Form B, Compound II free IPA solvate, Compound II free MEK solvate, Compound II free MeOH solvate, amorphous free Compound II, Compound II phosphate acetone solvate Form A, Compound II phosphate Form A, and Compound II phosphate Form C is administered once a day, twice a day, or three times a day.

[0214] As used herein, the term "ambient conditions" refers to room temperature, open air, and uncontrolled humidity. The terms "room temperature" and "ambient temperature" refer to temperatures between 15°C and 30°C.

[0215] As used herein, the terms "crystalline form" and "form" refer interchangeably to a crystalline structure (or polymorph) having a particular molecular packing arrangement within a crystal lattice. Crystalline forms can be identified and distinguished from one another by one or more characterization techniques, including, for example, X-ray powder diffraction (XRPD), single crystal X-ray diffraction, solid-state nuclear magnetic resonance (SSNMR), differential scanning calorimetry (DSC), infrared radiation (IR), and / or thermogravimetric analysis (TGA). Thus, as used herein, "crystalline Form [X] of compound [Y]" refers to a unique crystalline form that can be identified and distinguished from other crystalline forms of compound [Y] by one or more characterization techniques, including, for example, X-ray powder diffraction (XRPD), single crystal X-ray diffraction, SSNMR, differential scanning calorimetry (DSC), infrared radiation (IR), and / or thermogravimetric analysis (TGA). In some embodiments, the novel crystalline Form [X] of compound [Y] is characterized by an X-ray powder diffractogram having one or more signals at one or more specific two-theta values ​​(°2θ).

[0216] As used herein, the term "SSNMR" refers to solid-state nuclear magnetic resonance analytical characterization. SSNMR spectra can be recorded at ambient or non-ambient conditions (e.g., 275 K) for any magnetically active isotopes present in the sample. Common examples of active isotopes for small molecule active pharmaceutical ingredients include: 1 H, 2 H, 13 C. 19 F, 31 P, 15 N, 14 N, 35 Cl, 11 B. 7 Li, 17 O. 23 Na, 79 Br, and 195 Examples include Pt.

[0217] As used herein, the term "XRPD" refers to the analytical characterization method of X-ray powder diffraction. XRPD patterns can be recorded under ambient conditions in transmission or reflection geometry using a diffractometer.

[0218] As used herein, the terms "X-ray powder diffractogram," "X-ray powder diffraction pattern," and "XRPD pattern" refer interchangeably to an experimentally obtained pattern that plots signal position (on the abscissa) against signal intensity on the ordinate. For amorphous materials, the X-ray powder diffractogram may include one or more broad signals; for crystalline materials, the X-ray powder diffractogram may include one or more signals, each identified by its angular value, measured in degrees 2θ (°2θ), depicted on the abscissa of the X-ray powder diffractogram, which may be expressed as "signal at ... °2θ," "signal at 2θ value of ...," and / or "signal at at least ... 2θ value selected from ...."

[0219] As used herein, a "signal" or "peak" refers to a point in an XRPD pattern where the intensity, as measured in counts, is at a local maximum. Those skilled in the art will recognize that one or more signals (or peaks) in an XRPD pattern may overlap and may not be apparent to the naked eye, for example. Indeed, those skilled in the art will recognize that several art-recognized methods are capable and suitable for determining whether a signal is present in a pattern, such as, for example, Rietveld refinement.

[0220] As used herein, "signal at ...° 2θ," "signal at 2θ value of ..." and / or "signal at at least ... 2θ value selected from ..." refer to the X-ray reflection position measured and observed in an X-ray powder diffraction experiment (° 2θ).

[0221] The reproducibility of the angle values ​​is within ±0.2°2θ, i.e., the angle value can be the recited angle value +0.2°2θ, the angle value −0.2°2θ, or any value between those two endpoints (angle value +0.2°2θ and angle value −0.2°2θ).

[0222] As used herein, the terms "signal intensity" and "peak intensity" refer interchangeably to relative signal intensities within a given X-ray powder diffractogram. Factors that can affect relative signal intensity or peak intensity include sample thickness and preferred orientation (e.g., crystalline particles are not randomly distributed).

[0223] The terms "X-ray powder diffractogram having signals at 2 theta values..." and "X-ray powder diffractogram including signals at 2 theta values..." are used interchangeably herein and refer to an XRPD pattern including X-ray reflection positions (°2θ) measured and observed in an X-ray powder diffraction experiment.

[0224] As used herein, an X-ray powder diffractogram is "substantially similar to that of a [particular] figure" if at least 90%, such as at least 95%, at least 98%, or at least 99%, of the signals in the two diffractograms overlap. In determining "substantial similarity," one skilled in the art will understand that even for the same crystalline form, there may be variations in intensity and / or signal positions in XRPD diffractograms. Thus, one skilled in the art will understand that signal positions (in degrees two-theta (°2θ) as referred to herein) in an XRPD diffractogram generally mean that the reported values ​​are ±0.2 degrees 2θ, an art-recognized variance of the reported value.

[0225] As used herein, an SSNMR spectrum is "substantially similar to that of a particular figure" if at least 90%, such as at least 95%, at least 98%, or at least 99%, of the signals in the two spectra overlap. In determining "substantial similarity," those skilled in the art will understand that even for the same crystalline form, there may be variations in the intensity and / or signal positions of SSNMR spectra. Thus, those skilled in the art will understand that signal positions in SSNMR spectra (ppm) referred to herein generally mean that the reported values ​​are within ±0.2 ppm of the reported value, which is an art-recognized variance.

[0226] As used herein, a DSC curve is "substantially similar to that of a [particular] figure" if at least 90%, such as at least 95%, at least 98%, or at least 99%, of the features in the two curves overlap. In determining "substantial similarity," one skilled in the art will understand that there may be variations in the intensity and / or peak (e.g., endothermic or exothermic) locations of DSC curves even for the same solid form.

[0227] As used herein, a TGA thermogram is "substantially similar to that of a [particular] figure" if at least 90%, such as at least 95%, at least 98%, or at least 99%, of the features in the two thermograms overlap. In determining "substantial similarity," one skilled in the art will understand that there may be variations in the intensities and / or peak (e.g., decomposition peak) positions of TGA thermograms even for the same solid form.

[0228] As used herein, a crystalline form is "substantially pure" when it accounts for 90% or more by weight of the sum of all solid forms in a sample, as determined by art-known methods such as, for example, quantitative XRPD. In some embodiments, a solid form is "substantially pure" when it accounts for 95% or more by weight of the sum of all solid forms in a sample. In some embodiments, a solid form is "substantially pure" when it accounts for 99% or more by weight of the sum of all solid forms in a sample.

[0229] As used herein, the term "DSC" refers to the analytical method of differential scanning calorimetry.

[0230] As used herein, the term "TGA" refers to the analytical method of Thermo Gravimetric (or thermogravimetric) analysis.

[0231] As used herein, a "crystalline hydrate" is a crystalline form containing either stoichiometric or non-stoichiometric water in the crystal lattice. In the case of non-stoichiometric hydrates, the amount of water present in the crystalline hydrate may vary at least as a function of relative humidity (RH). The presence (or absence) of water or different amounts of water may cause a shift in the peak position of the X-ray diffractogram, or the appearance or disappearance of peaks. The presence (or absence) of water or different amounts of water may cause a peak shift or the appearance of new peaks in the solid-state NMR spectrum of proton, carbon, fluorine, phosphorus, nitrogen, chlorine (or other NMR-active nuclei).

[0232] Compound I is disclosed as Compound 181 in International Patent Application PCT / US2021 / 047754, filed August 26, 2021, the entirety of which is incorporated herein by reference.

[0233] Compound I is depicted as follows: [ka]

[0234] Compound II is disclosed as Compound 174 in International Patent Application PCT / US2021 / 047754, filed August 26, 2021, the entirety of which is incorporated herein by reference.

[0235] Compound II is depicted as follows: [ka]

[0236] Compound I phosphate hydrate Form A Some embodiments of the present disclosure provide a phosphate salt hydrate of Compound I (phosphate salt hydrate Form A of Compound I). In some embodiments, the phosphate salt hydrate of Compound I, Form A, is substantially pure.

[0237] In some embodiments, Compound I phosphate salt hydrate Form A is characterized by an X-ray powder diffractogram comprising signals at 2-theta of 8.6, 19.9, and / or 28.3±0.2. In some embodiments, Compound I phosphate salt hydrate Form A is characterized by an X-ray powder diffractogram comprising signals at the following 2-theta values: 8.6±0.2, 19.9±0.2, and 28.3±0.2.

[0238] In some embodiments, Compound I phosphate salt hydrate Form A is characterized by an X-ray powder diffractogram comprising signals at one or more (e.g., two or more) 2-theta values ​​selected from 8.6±0.2, 19.9±0.2, and 28.3±0.2. In some embodiments, Compound I phosphate salt hydrate Form A is characterized by an X-ray powder diffractogram comprising signals at two or more 2-theta values ​​selected from 8.6±0.2, 19.9±0.2, and 28.3±0.2.

[0239] In some embodiments, Compound I phosphate salt hydrate Form A is characterized by an X-ray powder diffractogram, measured at 25±2°C and 5% relative humidity (RH), comprising: (a) signals at the following 2-theta values: 8.6±0.2, 19.9±0.2, and 28.3±0.2, and (b) signals at one or more (e.g., two or more) 2-theta values ​​selected from 17.2±0.2, 20.4±0.2, and 22.8±0.2. In some embodiments, Compound I phosphate salt hydrate Form A is characterized by an X-ray powder diffractogram comprising signals at one or more 2-theta values ​​(e.g., two or more, three or more, four or more, five or more) selected from 8.6±0.2, 17.2±0.2, 19.9±0.2, 20.4±0.2, 22.8±0.2, and 28.3±0.2, measured at 25±2° C. and 5% relative humidity (RH). In some embodiments, Compound I phosphate salt hydrate Form A is characterized by an X-ray powder diffractogram comprising signals at the following 2-theta values: 8.6±0.2, 17.2±0.2, 19.9±0.2, 20.4±0.2, 22.8±0.2, and 28.3±0.2, measured at 25±2° C. and 5% relative humidity (RH).

[0240] In some embodiments, Compound I phosphate salt hydrate Form A is characterized by an X-ray powder diffractogram, measured at 25±2°C and 5% relative humidity (RH), comprising: (a) signals at the following 2-theta values: 8.6±0.2, 19.9±0.2, and 28.3±0.2, and (b) signals at one or more (e.g., two or more, three or more, four or more) 2-theta values ​​selected from 17.2±0.2, 20.4±0.2, 21.1±0.2, 21.9±0.2, and 22.8±0.2. In some embodiments, Compound I phosphate salt hydrate Form A is characterized by an X-ray powder diffractogram comprising signals at one or more 2-theta values ​​(e.g., two or more, three or more, four or more, five or more, six or more, seven or more) selected from 8.6±0.2, 17.2±0.2, 19.9±0.2, 20.4±0.2, 21.1±0.2, 21.9±0.2, 22.8±0.2, and 28.3±0.2, measured at 25±2°C and 5% relative humidity (RH). In some embodiments, Compound I phosphate salt hydrate Form A is characterized by an X-ray powder diffractogram comprising signals at the following 2-theta values: 8.6±0.2, 17.2±0.2, 19.9±0.2, 20.4±0.2, 21.1±0.2, 21.9±0.2, 22.8±0.2, and 28.3±0.2, measured at 25±2°C and 5% relative humidity (RH).

[0241] In some embodiments, Compound I phosphate salt hydrate Form A is characterized by an X-ray powder diffractogram, measured at 25±2°C and 5% relative humidity (RH), comprising: (a) signals at the following 2-theta values: 8.6±0.2, 19.9±0.2, and 28.3±0.2, and (b) signals at one or more (e.g., two or more, three or more, four or more, five or more, six or more) 2-theta values ​​selected from 15.7±0.2, 17.2±0.2, 20.4±0.2, 21.1±0.2, 21.9±0.2, 22.8±0.2, and 27.0±0.2. In some embodiments, Compound I phosphate salt hydrate Form A is characterized by an X-ray powder diffractogram comprising signals at one or more 2-theta values ​​(e.g., two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more) selected from 8.6±0.2, 15.7±0.2, 17.2±0.2, 19.9±0.2, 20.4±0.2, 21.1±0.2, 21.9±0.2, 22.8±0.2, 27.0±0.2, and 28.3±0.2, measured at 25±2°C and 5% relative humidity (RH). In some embodiments, Compound I phosphate salt hydrate Form A is characterized by an X-ray powder diffractogram comprising signals at the following 2-theta values: 8.6±0.2, 15.7±0.2, 17.2±0.2, 19.9±0.2, 20.4±0.2, 21.1±0.2, 21.9±0.2, 22.8±0.2, 27.0±0.2, and 28.3±0.2, measured at 25±2°C and 5% relative humidity (RH).

[0242] In some embodiments, Compound I phosphate salt hydrate Form A is characterized by an X-ray powder diffractogram substantially similar to that in FIG. 6, measured at 25° C.±2° C. and 5% relative humidity (RH).

[0243] In some embodiments, Compound I phosphate salt hydrate Form A is characterized by an X-ray powder diffractogram, measured at 25±2°C and 40% relative humidity (RH), comprising: (a) signals at the following 2-theta values: 8.6±0.2, 19.9±0.2, and 28.3±0.2, and (b) signals at one or more (e.g., two or more) 2-theta values ​​selected from 20.4±0.2, 21.0±0.2, and 22.8±0.2. In some embodiments, Compound I phosphate salt hydrate Form A is characterized by an X-ray powder diffractogram comprising signals at one or more 2-theta values ​​(e.g., two or more, three or more, four or more, five or more) selected from 8.6±0.2, 19.9±0.2, 20.4±0.2, 21.0±0.2, 22.8±0.2, and 28.3±0.2, measured at 25±2°C and 40% relative humidity (RH). In some embodiments, Compound I phosphate salt hydrate Form A is characterized by an X-ray powder diffractogram comprising signals at the following 2-theta values: 8.6±0.2, 19.9±0.2, 20.4±0.2, 21.0±0.2, 22.8±0.2, and 28.3±0.2, measured at 25±2°C and 40% relative humidity (RH).

[0244] In some embodiments, Compound I phosphate salt hydrate Form A is characterized by an X-ray powder diffractogram, measured at 25±2°C and 40% relative humidity (RH), comprising: (a) signals at the following 2-theta values: 8.6±0.2, 19.9±0.2, and 28.3±0.2, and (b) signals at one or more (e.g., two or more, three or more, four or more) 2-theta values ​​selected from 17.2±0.2, 20.4±0.2, 21.0±0.2, 22.8±0.2, and 27.8±0.2. In some embodiments, Compound I phosphate salt hydrate Form A is characterized by an X-ray powder diffractogram comprising signals at one or more 2-theta values ​​(e.g., two or more, three or more, four or more, five or more, six or more, seven or more) selected from 8.6±0.2, 17.2±0.2, 19.9±0.2, 20.4±0.2, 21.0±0.2, 22.8±0.2, 27.8±0.2, and 28.3±0.2, measured at 25±2°C and 40% relative humidity (RH). In some embodiments, Compound I phosphate salt hydrate Form A is characterized by an X-ray powder diffractogram comprising signals at the following 2-theta values: 8.6±0.2, 17.2±0.2, 19.9±0.2, 20.4±0.2, 21.0±0.2, 22.8±0.2, 27.8±0.2, and 28.3±0.2, measured at 25±2°C and 40% relative humidity (RH).

[0245] In some embodiments, Compound I phosphate salt hydrate Form A is characterized by an X-ray powder diffractogram, measured at 25±2°C and 40% relative humidity (RH), comprising: (a) signals at the following 2-theta values: 8.6±0.2, 19.9±0.2, and 28.3±0.2, and (b) signals at one or more (e.g., two or more, three or more, four or more, five or more, six or more) 2-theta values ​​selected from 17.2±0.2, 17.8±0.2, 20.4±0.2, 21.0±0.2, 22.8±0.2, 26.4±0.2, and 27.8±0.2. In some embodiments, Compound I phosphate salt hydrate Form A is characterized by an X-ray powder diffractogram comprising signals at one or more 2-theta values ​​(e.g., two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more) selected from 8.6±0.2, 17.2±0.2, 17.8±0.2, 19.9±0.2, 20.4±0.2, 21.0±0.2, 22.8±0.2, 26.4±0.2, 27.8±0.2, and 28.3±0.2, measured at 25±2°C and 40% relative humidity (RH). In some embodiments, Compound I phosphate salt hydrate Form A is characterized by an X-ray powder diffractogram comprising signals at the following 2-theta values: 8.6±0.2, 17.2±0.2, 17.8±0.2, 19.9±0.2, 20.4±0.2, 21.0±0.2, 22.8±0.2, 26.4±0.2, 27.8±0.2, and 28.3±0.2, measured at 25±2°C and 40% relative humidity (RH).

[0246] In some embodiments, Compound I phosphate salt hydrate Form A is characterized by an X-ray powder diffractogram substantially similar to that in FIG. 5, measured at 25° C.±2° C. and 40% relative humidity (RH).

[0247] In some embodiments, Compound I phosphate salt hydrate Form A is characterized by an X-ray powder diffractogram, measured at 25±2°C and 90% relative humidity (RH), comprising: (a) signals at the following 2-theta values: 8.6±0.2, 19.9±0.2, and 28.3±0.2, and (b) signals at one or more (e.g., two or more) 2-theta values ​​selected from 20.4±0.2, 21.0±0.2, and 27.8±0.2. In some embodiments, Compound I phosphate salt hydrate Form A is characterized by an X-ray powder diffractogram comprising signals at one or more 2-theta values ​​(e.g., two or more, three or more, four or more, five or more) selected from 8.6±0.2, 19.9±0.2, 20.4±0.2, 21.0±0.2, 27.8±0.2, and 28.3±0.2, measured at 25±2°C and 90% relative humidity (RH). In some embodiments, Compound I phosphate salt hydrate Form A is characterized by an X-ray powder diffractogram comprising signals at the following 2-theta values: 8.6±0.2, 19.9±0.2, 20.4±0.2, 21.0±0.2, 27.8±0.2, and 28.3±0.2, measured at 25±2°C and 90% relative humidity (RH).

[0248] In some embodiments, Compound I phosphate salt hydrate Form A is characterized by an X-ray powder diffractogram, measured at 25±2°C and 90% relative humidity (RH), comprising: (a) signals at the following 2-theta values: 8.6±0.2, 19.9±0.2, and 28.3±0.2, and (b) signals at one or more (e.g., two or more, three or more, four or more) 2-theta values ​​selected from 17.2±0.2, 20.4±0.2, 21.0±0.2, 22.8±0.2, and 27.8±0.2. In some embodiments, Compound I phosphate salt hydrate Form A is characterized by an X-ray powder diffractogram comprising signals at one or more 2-theta values ​​(e.g., two or more, three or more, four or more, five or more, six or more, seven or more) selected from 8.6±0.2, 17.2±0.2, 19.9±0.2, 20.4±0.2, 21.0±0.2, 22.8±0.2, 27.8±0.2, and 28.3±0.2, measured at 25±2°C and 90% relative humidity (RH). In some embodiments, Compound I phosphate salt hydrate Form A is characterized by an X-ray powder diffractogram comprising signals at the following 2-theta values: 8.6±0.2, 17.2±0.2, 19.9±0.2, 20.4±0.2, 21.0±0.2, 22.8±0.2, 27.8±0.2, and 28.3±0.2, measured at 25±2°C and 90% relative humidity (RH).

[0249] In some embodiments, Compound I phosphate salt hydrate Form A is characterized by an X-ray powder diffractogram, measured at 25±2°C and 90% relative humidity (RH), comprising: (a) signals at the following 2-theta values: 8.6±0.2, 19.9±0.2, and 28.3±0.2, and (b) signals at one or more (e.g., two or more, three or more, four or more, five or more, six or more) 2-theta values ​​selected from 17.2±0.2, 19.5±0.2, 20.4±0.2, 21.0±0.2, 22.8±0.2, 25.5±0.2, and 27.8±0.2. In some embodiments, Compound I phosphate salt hydrate Form A is characterized by an X-ray powder diffractogram comprising signals at one or more 2-theta values ​​(e.g., two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more) selected from 8.6±0.2, 17.2±0.2, 19.5±0.2, 19.9±0.2, 20.4±0.2, 21.0±0.2, 22.8±0.2, 25.5±0.2, 27.8±0.2, and 28.3±0.2, measured at 25±2°C and 90% relative humidity (RH). In some embodiments, Compound I phosphate salt hydrate Form A is characterized by an X-ray powder diffractogram comprising signals at the following 2-theta values: 8.6±0.2, 17.2±0.2, 19.5±0.2, 19.9±0.2, 20.4±0.2, 21.0±0.2, 22.8±0.2, 25.5±0.2, 27.8±0.2, and 28.3±0.2, measured at 25±2°C and 90% relative humidity (RH).

[0250] In some embodiments, Compound I phosphate salt hydrate Form A is characterized by an X-ray powder diffractogram substantially similar to that in FIG. 6, measured at 25° C.±2° C. and 90% relative humidity (RH).

[0251] In some embodiments, Compound I phosphate salt hydrate Form A comprises one or more signals selected from 62.1±0.2 ppm, 62.7±0.2 ppm, 128.6±0.2 ppm, 139.3±0.2 ppm, and 141.7±0.2 ppm, measured at 43% relative humidity (RH).13 Characterized by C NMR spectrum.

[0252] In some embodiments, Compound I phosphate salt hydrate Form A comprises one or more (e.g., two or more, three or more, four or more) signals selected from 16.0±0.2 ppm, 38.4±0.2 ppm, 128.6±0.2 ppm, 139.3±0.2 ppm, and 141.7±0.2 ppm, measured at 43% relative humidity (RH). 13 Characterized by C NMR spectrum.

[0253] In some embodiments, the phosphate salt hydrate of Compound I, Form A, comprises one or more signals selected from 16.0±0.2 ppm, 38.4±0.2 ppm, 47.3±0.2 ppm, 62.1±0.2 ppm, 62.7±0.2 ppm, 73.2±0.2 ppm, 73.6±0.2 ppm, 128.6±0.2 ppm, 139.3±0.2 ppm, and 141.7±0.2 ppm, measured at 43% relative humidity (RH). 13 Characterized by C NMR spectrum.

[0254] In some embodiments, Compound I phosphate salt hydrate Form A comprises one or more (e.g., two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more) signals selected from 16.0±0.2 ppm, 36.7±0.2 ppm, 38.4±0.2 ppm, 126.6±0.2 ppm, 128.6±0.2 ppm, 129.4±0.2 ppm, 139.3±0.2 ppm, 141.7±0.2 ppm, 144.0±0.2 ppm, and 145.8±0.2 ppm, measured at 43% relative humidity (RH). 13 Characterized by C NMR spectrum.

[0255] In some embodiments, the phosphate salt hydrate Form A of Compound I comprises signals at 62.1±0.2 ppm, 62.7±0.2 ppm, 128.6±0.2 ppm, 139.3±0.2 ppm, and 141.7±0.2 ppm measured at 43% relative humidity (RH).13 Characterized by C NMR spectrum.

[0256] In some embodiments, the phosphate salt hydrate Form A of Compound I comprises signals at 16.0±0.2 ppm, 38.4±0.2 ppm, 128.6±0.2 ppm, 139.3±0.2 ppm, and 141.7±0.2 ppm measured at 43% relative humidity (RH). 13 Characterized by C NMR spectrum.

[0257] In some embodiments, Compound I phosphate salt hydrate Form A comprises signals measured at 43% relative humidity (RH) of 16.0±0.2 ppm, 38.4±0.2 ppm, 47.3±0.2 ppm, 62.1±0.2 ppm, 62.7±0.2 ppm, 73.2±0.2 ppm, 73.6±0.2 ppm, 128.6±0.2 ppm, 139.3±0.2 ppm, and 141.7±0.2 ppm. 13 Characterized by C NMR spectrum.

[0258] In some embodiments, the phosphate salt hydrate Form A of Compound I comprises signals at 16.0±0.2 ppm, 36.7±0.2 ppm, 38.4±0.2 ppm, 126.6±0.2 ppm, 128.6±0.2 ppm, 129.4±0.2 ppm, 139.3±0.2 ppm, 141.7±0.2 ppm, 144.0±0.2 ppm, and 145.8±0.2 ppm measured at 43% relative humidity (RH). 13 Characterized by C NMR spectrum.

[0259] In some embodiments, the phosphate salt hydrate of Compound I, Form A, has a pH substantially similar to that of FIG. 7, measured at 43% relative humidity (RH). 13 Characterized by C NMR spectrum.

[0260] In some embodiments, Compound I phosphate salt hydrate Form A comprises a signal at one or more ppm values ​​selected from −57.4±0.2 ppm and −53.8±0.2 ppm, measured at 43% relative humidity (RH). 19 Characterized by F NMR spectrum.

[0261] In some embodiments, the phosphate salt hydrate Form A of Compound I comprises signals at −57.4±0.2 ppm and −53.8±0.2 ppm measured at 43% relative humidity (RH). 19 Characterized by F NMR spectrum.

[0262] In some embodiments, the phosphate salt hydrate of Compound I, Form A, has a pH substantially similar to that of FIG. 8, measured at 43% relative humidity (RH). 19 Characterized by F NMR spectrum.

[0263] In some embodiments, Compound I phosphate salt hydrate Form A has a pH substantially similar to that of FIG. 9 measured at 0% relative humidity (RH), 6% RH, 22%, 33% RH, 43% RH, 53% RH, 75% RH, or 100% RH. 19 Characterized by F NMR spectrum.

[0264] In some embodiments, Compound I phosphate salt hydrate Form A comprises a signal at one or more ppm values ​​selected from 2.6±0.2 ppm and 4.2±0.2 ppm, measured at 43% relative humidity (RH). 31 Characterized by P NMR spectrum.

[0265] In some embodiments, Compound I phosphate salt hydrate Form A comprises signals at 2.6±0.2 ppm and 4.2±0.2 ppm measured at 43% relative humidity (RH). 31 Characterized by P NMR spectrum.

[0266] In some embodiments, the phosphate salt hydrate of Compound I, Form A, has a pH substantially similar to that of FIG. 10, measured at 43% relative humidity (RH). 31 Characterized by P NMR spectrum.

[0267] In some embodiments, Compound I phosphate salt hydrate Form A has a pH substantially similar to that of FIG. 11 measured at 0% relative humidity (RH), 6% RH, 22%, 33% RH, 43% RH, 53% RH, 75% RH, or 100% RH. 31 Characterized by P NMR spectrum.

[0268] In some embodiments, Compound I phosphate salt hydrate Form A is characterized by a TGA thermogram exhibiting a weight loss of 0.5% from ambient temperature to 150°C.

[0269] In some embodiments, Compound I phosphate salt hydrate Form A is characterized by a TGA thermogram substantially similar to FIG.

[0270] In some embodiments, Compound I phosphate salt hydrate Form A is characterized by a DSC curve comprising two endothermic peaks at about 226°C and about 251°C.

[0271] In some embodiments, Compound I phosphate salt hydrate Form A is characterized by a DSC curve substantially similar to that in FIG.

[0272] In some embodiments, Compound I phosphate salt hydrate Form A is characterized by an orthorhombic crystal system, a P212121 space group, and the following unit cell dimensions, measured at 100 K on a Bruker diffractometer with Cu Kα radiation (λ=1.54178 Å): [Table 92]

[0273] In some embodiments, Compound I phosphate salt hydrate Form A is characterized by an orthorhombic crystalline system, a P212121 space group, and the following unit cell dimensions, measured at 100 K on a Bruker diffractometer with Cu Kα radiation (λ=1.54178 Å) after drying at 300 K under dry nitrogen for 1 hour: [Table 93]

[0274] Some embodiments of the present disclosure provide a method of making Compound I phosphate salt hydrate Form A, comprising drying Compound I phosphate salt methanol solvate at about 50°C.

[0275] In some embodiments, the method comprises drying the phosphate salt methanol solvate of Compound I at about 50° C. for 21 hours with a nitrogen purge.

[0276] Some embodiments of the present disclosure provide a method of making Compound I phosphate salt hydrate Form A, the method comprising: charging the free monohydrate of Compound I and MEK into a reactor; agitating the reactor (e.g., at about 20°C); adding water to the reactor and further stirring; seeding the reactor with Compound I phosphate salt hydrate Form A; Slowly adding a 0.5 M phosphoric acid MEK / water solution to the reactor; and The reactor is stirred at about 20°C.

[0277] In some embodiments, the method further comprises isolating the wet cake, washing the wet cake with MEK, and drying the wet cake under vacuum.

[0278] Some embodiments of the present disclosure provide a method of making Compound I phosphate salt hydrate Form A, the method comprising: charging Compound I monohydrate and MEK into a reactor; agitating the reactor; adding water to the reactor and further stirring; Slowly adding a 0.5 M phosphoric acid MEK / water solution to the reactor; and The reactor is stirred at about 20°C.

[0279] In some embodiments, the method further comprises isolating the wet cake, washing the wet cake with MEK, and drying the wet cake under vacuum.

[0280] Free monohydrate of Compound I Some embodiments of the present disclosure provide a monohydrate form of Compound I (the free monohydrate of Compound I). In some embodiments, the free monohydrate of Compound I is substantially pure.

[0281] In some embodiments, the free monohydrate of Compound I is characterized by an X-ray powder diffractogram comprising signals at 2-theta of 8.7, 12.8, 16.7 and / or 21.7±0.2.

[0282] In some embodiments, the free monohydrate of Compound I is characterized by an X-ray powder diffractogram comprising signals at one or more (e.g., two or more, three or more) 2-theta values ​​selected from 8.7±0.2, 12.8±0.2, 16.7±0.2, and 21.7±0.2. In some embodiments, the free monohydrate of Compound I is characterized by an X-ray powder diffractogram comprising signals at two or more 2-theta values ​​selected from 8.7±0.2, 12.8±0.2, 16.7±0.2, and 21.7±0.2. In some embodiments, the free monohydrate of Compound I is characterized by an X-ray powder diffractogram comprising signals at three or more 2-theta values ​​selected from 8.7±0.2, 12.8±0.2, 16.7±0.2, and 21.7±0.2.

[0283] In some embodiments, the free monohydrate of Compound I is characterized by an X-ray powder diffractogram comprising signals at the following 2-theta values: 8.7±0.2, 12.8±0.2, 16.7±0.2, and 21.7±0.2. In some embodiments, the free monohydrate of Compound I is characterized by an X-ray powder diffractogram comprising signals at the following 2-theta values: 8.7±0.2, 12.8±0.2, 16.7±0.2, and 21.7±0.2, and (b) signals at one or more (e.g., two or more) 2-theta values ​​selected from 13.8±0.2, 19.8±0.2, and 25.8±0.2. In some embodiments, the free monohydrate of Compound I is characterized by an X-ray powder diffractogram comprising signals at one or more (e.g., two or more, three or more, four or more, five or more, six or more) 2-theta values ​​selected from 8.7±0.2, 12.8±0.2, 13.8±0.2, 16.7±0.2, 19.8±0.2, 21.7±0.2, and 25.8±0.2. In some embodiments, the free monohydrate of Compound I is characterized by an X-ray powder diffractogram comprising signals at the following 2-theta values: 8.7±0.2, 12.8±0.2, 13.8±0.2, 16.7±0.2, 19.8±0.2, 21.7±0.2, and 25.8±0.2.

[0284] In some embodiments, the free monohydrate of Compound I is characterized by an X-ray powder diffractogram comprising: (a) signals at the following 2-theta values: 8.7±0.2, 12.8±0.2, 16.7±0.2, and 21.7±0.2, and (b) signals at one or more (e.g., two or more, three or more, four or more) 2-theta values ​​selected from 13.8±0.2, 15.5±0.2, 19.8±0.2, 24.3±0.2, and 25.8±0.2. In some embodiments, the free monohydrate of Compound I is characterized by an X-ray powder diffractogram comprising signals at one or more (e.g., two or more, three or more, four or more, five or more, six or more, seven or more, eight or more) 2-theta values ​​selected from 8.7±0.2, 12.8±0.2, 13.8±0.2, 15.5±0.2, 16.7±0.2, 19.8±0.2, 21.7±0.2, 24.3±0.2, and 25.8±0.2. In some embodiments, the free monohydrate of Compound I is characterized by an X-ray powder diffractogram comprising signals at the following 2-theta values: 8.7±0.2, 12.8±0.2, 13.8±0.2, 15.5±0.2, 16.7±0.2, 19.8±0.2, 21.7±0.2, 24.3±0.2, and 25.8±0.2.

[0285] In some embodiments, the free monohydrate of Compound I is characterized by an X-ray powder diffractogram substantially similar to FIG.

[0286] In some embodiments, the free monohydrate of Compound I comprises one or more (e.g., two or more, three or more, four or more) signals selected from 24.9±0.2 ppm, 49.8±0.2 ppm, 74.4±0.2 ppm, 135.3±0.2 ppm, and 149.6±0.2 ppm, measured at 43% relative humidity (RH). 13 Characterized by C NMR spectrum.

[0287] In some embodiments, the free monohydrate of Compound I comprises one or more (e.g., two or more, three or more, four or more) signals selected from 24.9±0.2 ppm, 35.1±0.2 ppm, 39.3±0.2 ppm, 135.3±0.2 ppm, and 149.6±0.2 ppm, measured at 43% relative humidity (RH). 13 Characterized by C NMR spectrum.

[0288] In some embodiments, the free monohydrate of Compound I comprises one or more (e.g., two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more) signals selected from 24.9±0.2 ppm, 35.1±0.2 ppm, 39.3±0.2 ppm, 47.0±0.2 ppm, 49.8±0.2 ppm, 61.6±0.2 ppm, 68.1±0.2 ppm, 74.4±0.2 ppm, 135.3±0.2 ppm, and 149.6±0.2 ppm, measured at 43% relative humidity (RH). 13 Characterized by C NMR spectrum.

[0289] In some embodiments, the free monohydrate of Compound I comprises one or more (e.g., two or more, three or more, four or more, five or more, six or more, seven or more, eight or more) signals selected from 24.9±0.2 ppm, 35.1±0.2 ppm, 39.3±0.2 ppm, 126.2±0.2 ppm, 127.7±0.2 ppm, 129.6±0.2 ppm, 135.3±0.2 ppm, 149.4±0.2 ppm, and 149.6±0.2 ppm, measured at 43% relative humidity (RH). 13 Characterized by C NMR spectrum.

[0290] In some embodiments, the free monohydrate of Compound I comprises signals at 24.9±0.2 ppm, 49.8±0.2 ppm, 74.4±0.2 ppm, 135.3±0.2 ppm, and 149.6±0.2 ppm measured at 43% relative humidity (RH). 13 Characterized by C NMR spectrum.

[0291] In some embodiments, the free monohydrate of Compound I comprises signals at 24.9±0.2 ppm, 35.1±0.2 ppm, 39.3±0.2 ppm, 135.3±0.2 ppm, and 149.6±0.2 ppm measured at 43% relative humidity (RH). 13 Characterized by C NMR spectrum.

[0292] In some embodiments, the free monohydrate of Compound I comprises signals at 24.9±0.2 ppm, 35.1±0.2 ppm, 39.3±0.2 ppm, 47.0±0.2 ppm, 49.8±0.2 ppm, 61.6±0.2 ppm, 68.1±0.2 ppm, 74.4±0.2 ppm, 135.3±0.2 ppm, and 149.6±0.2 ppm measured at 43% relative humidity (RH). 13 Characterized by C NMR spectrum.

[0293] In some embodiments, the free monohydrate of Compound I comprises signals measured at 43% relative humidity (RH) of 24.9±0.2 ppm, 35.1±0.2 ppm, 39.3±0.2 ppm, 126.2±0.2 ppm, 127.7±0.2 ppm, 129.6±0.2 ppm, 135.3±0.2 ppm, 149.4±0.2 ppm, and 149.6±0.2 ppm. 13 Characterized by C NMR spectrum.

[0294] In some embodiments, the free monohydrate of Compound I has a pH substantially similar to that of FIG. 15 measured at 43% relative humidity (RH). 13 Characterized by C NMR spectrum.

[0295] In some embodiments, the free monohydrate of Compound I comprises one or more (e.g., two or more, three or more, four or more) signals selected from 25.6±0.2 ppm, 50.7±0.2 ppm, 74.7±0.2 ppm, 135.3±0.2 ppm, and 150±0.2 ppm, measured after dehydration (in a rotor at 80° C. overnight (2x), incubation with P2O5 at 80° C. over the weekend).13 Characterized by C NMR spectrum.

[0296] In some embodiments, the free monohydrate of Compound I comprises one or more (e.g., two or more, three or more, four or more) signals selected from 25.6±0.2 ppm, 35.8±0.2 ppm, 36.8±0.2 ppm, 135.3±0.2 ppm, and 150±0.2 ppm, measured after dehydration (in a rotor at 80° C. overnight (2x), incubation with P2O5 at 80° C. over the weekend). 13 Characterized by C NMR spectrum.

[0297] In some embodiments, the free monohydrate of Compound I comprises one or more (e.g., two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more) signals selected from 25.6±0.2 ppm, 35.8±0.2 ppm, 36.8±0.2 ppm, 47.2±0.2 ppm, 48.3±0.2 ppm, 50.7±0.2 ppm, 61.5±0.2 ppm, 74.7±0.2 ppm, 135.3±0.2 ppm, and 150±0.2 ppm, measured after dehydration (in a rotor at 80° C. overnight (2x), incubation with PO at 80° C. over the weekend), 13 Characterized by C NMR spectrum.

[0298] In some embodiments, the free monohydrate of Compound I comprises one or more (e.g., two or more, three or more, four or more, five or more, six or more, seven or more, eight or more) signals selected from 25.6±0.2 ppm, 35.8±0.2 ppm, 36.8±0.2 ppm, 126.6±0.2 ppm, 127.2±0.2 ppm, 129.6±0.2 ppm, 135.3±0.2 ppm, 150±0.2 ppm, and 150.9±0.2 ppm, measured after dehydration (in a rotor at 80° C. overnight (2x), incubation with PO at 80° C. over the weekend), 13 Characterized by C NMR spectrum.

[0299] In some embodiments, the free monohydrate of Compound I comprises signals at 25.6±0.2 ppm, 50.7±0.2 ppm, 74.7±0.2 ppm, 135.3±0.2 ppm, and 150±0.2 ppm measured after dehydration (rotator overnight (2x) at 80° C., weekend incubation at 80° C. with P2O5). 13 Characterized by C NMR spectrum.

[0300] In some embodiments, the free monohydrate of Compound I comprises signals at 25.6±0.2 ppm, 35.8±0.2 ppm, 36.8±0.2 ppm, 135.3±0.2 ppm, and 150±0.2 ppm measured after dehydration (rotator overnight (2x) at 80° C., weekend incubation with P2O5 at 80° C.). 13 Characterized by C NMR spectrum.

[0301] In some embodiments, the free monohydrate of Compound I comprises signals at 25.6±0.2 ppm, 35.8±0.2 ppm, 36.8±0.2 ppm, 47.2±0.2 ppm, 48.3±0.2 ppm, 50.7±0.2 ppm, 61.5±0.2 ppm, 74.7±0.2 ppm, 135.3±0.2 ppm, and 150±0.2 ppm measured after dehydration (rotator overnight (2x) at 80° C., weekend incubation with P2O5 at 80° C.). 13 Characterized by C NMR spectrum.

[0302] In some embodiments, the free monohydrate of Compound I comprises signals at 25.6±0.2 ppm, 35.8±0.2 ppm, 36.8±0.2 ppm, 126.6±0.2 ppm, 127.2±0.2 ppm, 129.6±0.2 ppm, 135.3±0.2 ppm, 150±0.2 ppm, and 150.9±0.2 ppm measured after dehydration (rotator overnight (2x) at 80° C., weekend incubation at 80° C. with P2O5). 13 Characterized by C NMR spectrum.

[0303] In some embodiments, the free monohydrate of Compound I is measured after dehydration (rotator overnight at 80° C. (2×), weekend incubation with P2O5 at 80° C.) in a manner substantially similar to that shown in FIG. 16. 13 Characterized by C NMR spectrum.

[0304] In some embodiments, the free monohydrate of Compound I comprises a signal of −55.8±0.2 ppm measured at 43% relative humidity (RH). 19 Characterized by F NMR spectrum.

[0305] In some embodiments, the free monohydrate of Compound I has a pH substantially similar to that of FIG. 17, measured at 43% relative humidity (RH). 19 Characterized by F NMR spectrum.

[0306] In some embodiments, the free monohydrate of Compound I contains a signal at -55.5±0.2 ppm measured after dehydration (rotator overnight (2x) at 80° C., weekend incubation with P2O5 at 80° C.). 19 Characterized by F NMR spectrum.

[0307] In some embodiments, the free monohydrate of Compound I is measured after dehydration (rotator overnight at 80° C. (2×), incubation with P2O5 over the weekend at 80° C.), as shown in Figure 18. 19 Characterized by F NMR spectrum.

[0308] In some embodiments, the free monohydrate of Compound I is characterized by a TGA thermogram that exhibits a weight loss of about 3% to about 4% from ambient temperature to 100°C.

[0309] In some embodiments, the free monohydrate of Compound I is characterized by a TGA thermogram substantially similar to FIG.

[0310] In some embodiments, the free monohydrate of Compound I is characterized by a DSC curve comprising endothermic peaks at about 61°C, about 94°C, and about 111°C.

[0311] In some embodiments, the free monohydrate of Compound I is characterized by a DSC curve substantially similar to that in FIG.

[0312] In some embodiments, the free monohydrate of Compound I is characterized by a tetragonal crystal system, a P43 space group, and the following unit cell dimensions, measured at 100 K on a Bruker diffractometer with Cu Kα radiation (λ=1.54178 Å): [Table 94]

[0313] In some embodiments, the free monohydrate of Compound I is characterized by a tetragonal crystal system, a P43 space group, and the following unit cell dimensions, measured at 100 K on a Bruker diffractometer with Cu Kα radiation (λ=1.54178 Å) after drying at 325 K for 1 hour under dry nitrogen: [Table 95]

[0314] Some embodiments of the present disclosure provide a method of making the free form monohydrate of Compound I, the method comprising: adding amorphous Compound I to saline to form a solution; Incubating the solution at ambient temperature; filtering the solution to obtain a solid material; and and drying the solid material.

[0315] In some embodiments, incubating the solution at ambient temperature comprises incubating the solution at ambient temperature overnight.

[0316] In some embodiments, drying the solid material comprises drying the solid material in a vacuum oven at about 45° C. overnight.

[0317] Phosphate salt methanol solvate of Compound I Some embodiments of the present disclosure provide a phosphate salt methanol solvate of Compound I (Compound I phosphate salt methanol solvate). In some embodiments, the phosphate salt methanol solvate of Compound I is substantially pure.

[0318] In some embodiments, the phosphate salt methanol solvate of Compound I is characterized by an X-ray powder diffractogram comprising signals at 2-theta of 12.7, 14.8, and / or 20.7±0.2.

[0319] In some embodiments, the phosphate salt methanol solvate of Compound I is characterized by an X-ray powder diffractogram comprising signals at one or more 2-theta values ​​selected from 12.7±0.2, 14.8±0.2, and 20.7±0.2. In some embodiments, the phosphate salt methanol solvate of Compound I is characterized by an X-ray powder diffractogram comprising signals at two or more 2-theta values ​​selected from 12.7±0.2, 14.8±0.2, and 20.7±0.2.

[0320] In some embodiments, the phosphate salt methanol solvate of Compound I is characterized by an X-ray powder diffractogram comprising signals at the following 2-theta values: 12.7±0.2, 14.8±0.2, and 20.7±0.2. In some embodiments, the phosphate salt methanol solvate of Compound I is characterized by an X-ray powder diffractogram comprising signals at the following 2-theta values: 12.7±0.2, 14.8±0.2, and 20.7±0.2, and (b) one or more (e.g., two or more) 2-theta values ​​selected from 8.5±0.2, 15.8±0.2, and 19.5±0.2. In some embodiments, the phosphate salt methanol solvate of Compound I is characterized by an X-ray powder diffractogram comprising signals at one or more 2-theta values ​​(e.g., two or more, three or more, four or more, five or more) selected from 8.5±0.2, 12.7±0.2, 14.8±0.2, 15.8±0.2, 19.5±0.2, and 20.7±0.2. In some embodiments, the phosphate salt methanol solvate of Compound I is characterized by an X-ray powder diffractogram comprising signals at the following 2-theta values: 8.5±0.2, 12.7±0.2, 14.8±0.2, 15.8±0.2, 19.5±0.2, and 20.7±0.2.

[0321] In some embodiments, the phosphate salt methanol solvate of Compound I is characterized by an X-ray powder diffractogram comprising: (a) signals at the following 2-theta values: 12.7±0.2, 14.8±0.2, and 20.7±0.2, and (b) signals at one or more (e.g., two or more, three or more, four or more) 2-theta values ​​selected from 8.5±0.2, 13.9±0.2, 15.8±0.2, 18.7±0.2, and 19.5±0.2. In some embodiments, the phosphate salt methanol solvate of Compound I is characterized by an X-ray powder diffractogram comprising signals at one or more 2-theta values ​​(e.g., two or more, three or more, four or more, five or more, six or more, seven or more) selected from 8.5±0.2, 12.7±0.2, 13.9±0.2, 14.8±0.2, 15.8±0.2, 18.7±0.2, 19.5±0.2, and 20.7±0.2. In some embodiments, the phosphate salt methanol solvate of Compound I is characterized by an X-ray powder diffractogram comprising signals at the following 2-theta values: 8.5±0.2, 12.7±0.2, 13.9±0.2, 14.8±0.2, 15.8±0.2, 18.7±0.2, 19.5±0.2, and 20.7±0.2.

[0322] In some embodiments, the phosphate salt methanol solvate of Compound I is characterized by an X-ray powder diffractogram comprising: (a) signals at the following 2-theta values: 12.7±0.2, 14.8±0.2, and 20.7±0.2, and (b) signals at one or more (e.g., two or more, three or more, four or more, five or more, six or more) 2-theta values ​​selected from 8.5±0.2, 10.2±0.2, 13.9±0.2, 15.8±0.2, 18.7±0.2, 19.5±0.2, and 22.5±0.2. In some embodiments, the phosphate salt methanol solvate of Compound I is characterized by an X-ray powder diffractogram comprising signals at one or more 2-theta values ​​(e.g., two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more) selected from 8.5±0.2, 10.2±0.2, 12.7±0.2, 13.9±0.2, 14.8±0.2, 15.8±0.2, 18.7±0.2, 19.5±0.2, 20.7±0.2, and 22.5±0.2. In some embodiments, the phosphate salt methanol solvate of Compound I is characterized by an X-ray powder diffractogram having signals at the following 2-theta values: 8.5±0.2, 10.2±0.2, 12.7±0.2, 13.9±0.2, 14.8±0.2, 15.8±0.2, 18.7±0.2, 19.5±0.2, 20.7±0.2, and 22.5±0.2.

[0323] In some embodiments, the phosphate salt methanol solvate of Compound I is characterized by an X-ray powder diffractogram substantially similar to that shown in FIG.

[0324] In some embodiments, the phosphate salt methanol solvate of Compound I comprises one or more (e.g., two or more, three or more, four or more) signals selected from 15.7±0.2 ppm, 17.7±0.2 ppm, 40.5±0.2 ppm, 61.6±0.2 ppm, and 129.4±0.2 ppm. 13 Characterized by C NMR spectrum.

[0325] In some embodiments, the phosphate salt methanol solvate of Compound I comprises one or more (e.g., two or more, three or more, four or more) signals selected from 15.7±0.2 ppm, 17.7±0.2 ppm, 38.9±0.2 ppm, 129.4±0.2 ppm, and 140.6±0.2 ppm. 13 Characterized by C NMR spectrum.

[0326] In some embodiments, the phosphate salt methanol solvate of Compound I comprises one or more (e.g., two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more) signals selected from 15.7±0.2 ppm, 17.7±0.2 ppm, 40.5±0.2 ppm, 47.1±0.2 ppm, 48.5±0.2 ppm, 61.6±0.2 ppm, 72.2±0.2 ppm, 73.8±0.2 ppm, 129.4±0.2 ppm, and 140.6±0.2 ppm. 13 Characterized by C NMR spectrum.

[0327] In some embodiments, the phosphate salt methanol solvate of Compound I comprises one or more (e.g., two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more) signals selected from 15.7±0.2 ppm, 17.7±0.2 ppm, 36.8±0.2 ppm, 37.7±0.2 ppm, 38.9±0.2 ppm, 127.9±0.2 ppm, 128.5±0.2 ppm, 129.4±0.2 ppm, 139.5±0.2 ppm, and 140.6±0.2 ppm. 13 Characterized by C NMR spectrum.

[0328] In some embodiments, the phosphate salt methanol solvate of Compound I comprises signals at 15.7±0.2 ppm, 17.7±0.2 ppm, 40.5±0.2 ppm, 61.6±0.2 ppm, and 129.4±0.2 ppm. 13 Characterized by C NMR spectrum.

[0329] In some embodiments, the phosphate salt methanol solvate of Compound I comprises signals at 15.7±0.2 ppm, 17.7±0.2 ppm, 38.9±0.2 ppm, 129.4±0.2 ppm, and 140.6±0.2 ppm. 13 Characterized by C NMR spectrum.

[0330] In some embodiments, the phosphate salt methanol solvate of Compound I comprises signals at 15.7±0.2 ppm, 17.7±0.2 ppm, 40.5±0.2 ppm, 47.1±0.2 ppm, 48.5±0.2 ppm, 61.6±0.2 ppm, 72.2±0.2 ppm, 73.8±0.2 ppm, 129.4±0.2 ppm, and 140.6±0.2 ppm. 13 Characterized by C NMR spectrum.

[0331] In some embodiments, the phosphate salt methanol solvate of Compound I comprises signals at 15.7±0.2 ppm, 17.7±0.2 ppm, 36.8±0.2 ppm, 37.7±0.2 ppm, 38.9±0.2 ppm, 127.9±0.2 ppm, 128.5±0.2 ppm, 129.4±0.2 ppm, 139.5±0.2 ppm, and 140.6±0.2 ppm. 13 Characterized by C NMR spectrum.

[0332] In some embodiments, the phosphate salt methanol solvate of Compound I has a structure substantially similar to that shown in FIG. 13 Characterized by C NMR spectrum.

[0333] In some embodiments, the methanol solvate of the phosphate salt of Compound I comprises a signal at one or more ppm values ​​selected from −57.7±0.2 ppm and −54.7±0.2 ppm. 19 Characterized by F NMR spectrum.

[0334] In some embodiments, the phosphate salt methanol solvate of Compound I comprises signals at −57.7±0.2 ppm and −54.7±0.2 ppm. 19Characterized by F NMR spectrum.

[0335] In some embodiments, the phosphate salt methanol solvate of Compound I has a structure substantially similar to that shown in FIG. 19 Characterized by F NMR spectrum.

[0336] In some embodiments, the phosphate salt methanol solvate of Compound I comprises a signal at one or more ppm values ​​selected from 1.8±0.2 ppm and 2.5±0.2 ppm. 31 Characterized by P NMR spectrum.

[0337] In some embodiments, the phosphate salt methanol solvate of Compound I comprises signals at 1.8±0.2 ppm and 2.5±0.2 ppm. 31 Characterized by P NMR spectrum.

[0338] In some embodiments, the phosphate salt methanol solvate of Compound I has a structure substantially similar to that shown in FIG. 31 Characterized by P NMR spectrum.

[0339] In some embodiments, the phosphate salt methanol solvate of Compound I is characterized by an orthorhombic crystal system, a P212121 space group, and the following unit cell dimensions, measured at 100 K on a Bruker diffractometer with Cu Kα radiation (λ=1.54178 Å): [Table 96]

[0340] Some embodiments of the present disclosure provide a method of making a phosphate salt methanol solvate of Compound I, the method comprising: adding amorphous Compound I to MEK to form a solution; adding 0.5M H3PO4 in MeOH / water to the solution; Incubating the solution at ambient temperature; filtering the solution to isolate the solid material; and washing the solid material.

[0341] Compound I phosphate MEK solvate Some embodiments of the present disclosure provide a phosphate MEK solvate of Compound I (Compound I phosphate MEK solvate). In some embodiments, the phosphate MEK solvate of Compound I is substantially pure.

[0342] In some embodiments, the phosphate salt MEK solvate of Compound I is characterized by an X-ray powder diffractogram comprising signals at 8.6, 15.4, and / or 20.1±0.2 2-theta.

[0343] In some embodiments, the phosphate salt MEK solvate of Compound I is characterized by an X-ray powder diffractogram comprising signals at one or more 2-theta values ​​selected from 8.6±0.2, 15.4±0.2, and 20.1±0.2. In some embodiments, the phosphate salt MEK solvate of Compound I is characterized by an X-ray powder diffractogram comprising signals at two or more 2-theta values ​​selected from 8.6±0.2, 15.4±0.2, and 20.1±0.2.

[0344] In some embodiments, the phosphate salt MEK solvate of Compound I is characterized by an X-ray powder diffractogram comprising signals at the following 2-theta values: 8.6±0.2, 15.4±0.2, and 20.1±0.2. In some embodiments, the phosphate salt MEK solvate of Compound I is characterized by an X-ray powder diffractogram comprising signals at the following 2-theta values: 8.6±0.2, 15.4±0.2, and 20.1±0.2, and (b) one or more (e.g., two or more) 2-theta values ​​selected from 15.7±0.2, 18.2±0.2, and 19.4±0.2. In some embodiments, the phosphate salt MEK solvate of Compound I is characterized by an X-ray powder diffractogram comprising signals at one or more 2-theta values ​​(e.g., two or more, three or more, four or more, five or more) selected from 8.6±0.2, 15.4±0.2, 15.7±0.2, 18.2±0.2, 19.4±0.2, and 20.1±0.2. In some embodiments, the phosphate salt MEK solvate of Compound I is characterized by an X-ray powder diffractogram comprising signals at the following 2-theta values: 8.6±0.2, 15.4±0.2, 15.7±0.2, 18.2±0.2, 19.4±0.2, and 20.1±0.2.

[0345] In some embodiments, the phosphate salt MEK solvate of Compound I is characterized by an X-ray powder diffractogram comprising: (a) signals at the following 2-theta values: 8.6±0.2, 15.4±0.2, and 20.1±0.2, and (b) signals at one or more (e.g., two or more, three or more, four or more) 2-theta values ​​selected from 15.7±0.2, 18.2±0.2, 19.4±0.2, 21.7±0.2, and 21.9±0.2. In some embodiments, the phosphate salt MEK solvate of Compound I is characterized by an X-ray powder diffractogram comprising signals at one or more 2-theta values ​​(e.g., two or more, three or more, four or more, five or more, six or more, seven or more) selected from 8.6±0.2, 15.4±0.2, 15.7±0.2, 18.2±0.2, 19.4±0.2, 20.1±0.2, 21.7±0.2, and 21.9±0.2. In some embodiments, the phosphate salt MEK solvate of Compound I is characterized by an X-ray powder diffractogram comprising signals at the following 2-theta values: 8.6±0.2, 15.4±0.2, 15.7±0.2, 18.2±0.2, 19.4±0.2, 20.1±0.2, 21.7±0.2, and 21.9±0.2.

[0346] In some embodiments, the phosphate salt MEK solvate of Compound I is characterized by an X-ray powder diffractogram comprising: (a) signals at the following 2-theta values: 8.6±0.2, 15.4±0.2, and 20.1±0.2, and (b) signals at one or more (e.g., two or more, three or more, four or more, five or more, six or more) 2-theta values ​​selected from 13.2±0.2, 15.7±0.2, 18.2±0.2, 19.4±0.2, 21.7±0.2, 21.9±0.2, and 23.8±0.2. In some embodiments, the phosphate salt MEK solvate of Compound I is characterized by an X-ray powder diffractogram comprising signals at one or more 2-theta values ​​(e.g., two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more) selected from 8.6±0.2, 13.2±0.2, 15.4±0.2, 15.7±0.2, 18.2±0.2, 19.4±0.2, 20.1±0.2, 21.7±0.2, 21.9±0.2, and 23.8±0.2. In some embodiments, the phosphate salt MEK solvate of Compound I is characterized by an X-ray powder diffractogram comprising signals at the following 2-theta values: 8.6±0.2, 13.2±0.2, 15.4±0.2, 15.7±0.2, 18.2±0.2, 19.4±0.2, 20.1±0.2, 21.7±0.2, 21.9±0.2, and 23.8±0.2.

[0347] In some embodiments, the phosphate salt MEK solvate of Compound I is characterized by an X-ray powder diffractogram substantially similar to that in FIG.

[0348] In some embodiments, the phosphate salt MEK solvate of Compound I comprises one or more (e.g., two or more, three or more, four or more) signals selected from 16.0±0.2 ppm, 38.4±0.2 ppm, 62.3±0.2 ppm, 73.2±0.2 ppm, and 73.7±0.2 ppm. 13 Characterized by C NMR spectrum.

[0349] In some embodiments, the phosphate salt MEK solvate of Compound I comprises one or more (e.g., two or more, three or more, four or more) signals selected from 16.0±0.2 ppm, 37.5±0.2 ppm, 38.4±0.2 ppm, 126.5±0.2 ppm, and 142.0±0.2 ppm. 13 Characterized by C NMR spectrum.

[0350] In some embodiments, the phosphate salt MEK solvate of Compound I comprises one or more (e.g., two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more) signals selected from 16.0±0.2 ppm, 37.5±0.2 ppm, 38.4±0.2 ppm, 47.4±0.2 ppm, 62.3±0.2 ppm, 66.3±0.2 ppm, 73.2±0.2 ppm, 73.7±0.2 ppm, 126.5±0.2 ppm, and 142.0±0.2 ppm. 13 Characterized by C NMR spectrum.

[0351] In some embodiments, the phosphate salt MEK solvate of Compound I comprises one or more (e.g., two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more) signals selected from 7.4±0.2 ppm, 16.0±0.2 ppm, 36.8±0.2 ppm, 37.5±0.2 ppm, 38.4±0.2 ppm, 126.5±0.2 ppm, 128.7±0.2 ppm, 129.6±0.2 ppm, 139.4±0.2 ppm, and 142.0±0.2 ppm. 13 Characterized by C NMR spectrum.

[0352] In some embodiments, the phosphate MEK solvate of Compound I comprises signals at 16.0±0.2 ppm, 38.4±0.2 ppm, 62.3±0.2 ppm, 73.2±0.2 ppm, and 73.7±0.2 ppm. 13 Characterized by C NMR spectrum.

[0353] In some embodiments, the phosphate MEK solvate of Compound I comprises signals at 16.0±0.2 ppm, 37.5±0.2 ppm, 38.4±0.2 ppm, 126.5±0.2 ppm, and 142.0±0.2 ppm. 13 Characterized by C NMR spectrum.

[0354] In some embodiments, the phosphate MEK solvate of Compound I comprises signals at 16.0±0.2 ppm, 37.5±0.2 ppm, 38.4±0.2 ppm, 47.4±0.2 ppm, 62.3±0.2 ppm, 66.3±0.2 ppm, 73.2±0.2 ppm, 73.7±0.2 ppm, 126.5±0.2 ppm, and 142.0±0.2 ppm. 13 Characterized by C NMR spectrum.

[0355] In some embodiments, the phosphate MEK solvate of Compound I comprises signals at 7.4±0.2 ppm, 16.0±0.2 ppm, 36.8±0.2 ppm, 37.5±0.2 ppm, 38.4±0.2 ppm, 126.5±0.2 ppm, 128.7±0.2 ppm, 129.6±0.2 ppm, 139.4±0.2 ppm, and 142.0±0.2 ppm. 13 Characterized by C NMR spectrum.

[0356] In some embodiments, the phosphate salt MEK solvate of Compound I has a structure substantially similar to that shown in FIG. 13 Characterized by C NMR spectrum.

[0357] In some embodiments, the phosphate salt MEK solvate of Compound I comprises signals at one or more (e.g., two or more) ppm values ​​selected from −53.6±0.2 ppm, −55.2±0.2 ppm, and −57.2±0.2 ppm. 19 Characterized by F NMR spectrum.

[0358] In some embodiments, the phosphate MEK solvate of Compound I comprises signals at −53.6±0.2 ppm, −55.2±0.2 ppm, and −57.2±0.2 ppm. 19 Characterized by F NMR spectrum.

[0359] In some embodiments, the phosphate salt MEK solvate of Compound I has a structure substantially similar to that shown in FIG. 19 Characterized by F MAS spectra.

[0360] In some embodiments, the phosphate salt MEK solvate of Compound I comprises signals at one or more (e.g., two or more) ppm values ​​selected from 0.1±0.2 ppm, 2.7±0.2 ppm, and 4.8±0.2 ppm. 31 P characterized by CPMAS spectrum.

[0361] In some embodiments, the phosphate MEK solvate of Compound I comprises signals at 0.1±0.2 ppm, 2.7±0.2 ppm, and 4.8±0.2 ppm. 31 P characterized by CPMAS spectrum.

[0362] Some embodiments of the present disclosure provide a method of making a phosphate salt MEK solvate of Compound I, the method comprising: adding Compound I phosphate salt hydrate Form A to MEK and mixing to form a slurry; incubating the slurry at a low temperature to obtain a solid material; and and centrifuging the solid material.

[0363] In some embodiments, the low temperature is about 5°C.

[0364] In some embodiments, incubating the slurry at a low temperature to obtain a solid material comprises incubating the slurry at about 5° C. for about 11 days to obtain a solid material.

[0365] Maleate Form A of Compound I (salt or cocrystal) Some embodiments of the present disclosure provide a maleate / co-crystal form (Compound I maleate Form A) of Compound I. In some embodiments, Compound I maleate Form A is substantially pure.

[0366] In some embodiments, Compound I maleate salt Form A is characterized by an X-ray powder diffractogram comprising signals at 27.6±0.2 2-theta. In some embodiments, Compound I maleate salt Form A is characterized by an X-ray powder diffractogram comprising signals at 27.6±0.2 2-theta and 20.0±0.2 2-theta.

[0367] In some embodiments, Compound I maleate salt Form A is characterized by an X-ray powder diffractogram comprising a signal at a 2-theta value of 27.6±0.2 and signals at one or more 2-theta values ​​selected from 13.7±0.2, 14.5±0.2, 15.5±0.2, 18.3±0.2, and 20.0±0.2. In some embodiments, Compound I maleate salt Form A is characterized by an X-ray powder diffractogram comprising a signal at a 2-theta value of 27.6±0.2 and signals at two or more 2-theta values ​​selected from 13.7±0.2, 14.5±0.2, 15.5±0.2, 18.3±0.2, and 20.0±0.2. In some embodiments, Compound I maleate salt Form A is characterized by an X-ray powder diffractogram comprising a signal at a 2-theta value of 27.6±0.2 and signals at three or more 2-theta values ​​selected from 13.7±0.2, 14.5±0.2, 15.5±0.2, 18.3±0.2, and 20.0±0.2. In some embodiments, Compound I maleate salt Form A is characterized by an X-ray powder diffractogram comprising a signal at a 2-theta value of 27.6±0.2 and signals at four or more 2-theta values ​​selected from 13.7±0.2, 14.5±0.2, 15.5±0.2, 18.3±0.2, and 20.0±0.2.

[0368] In some embodiments, Compound I maleate salt Form A is characterized by an X-ray powder diffractogram comprising signals at 2-theta values ​​of 27.6±0.2, 13.7±0.2, 14.5±0.2, 15.5±0.2, 18.3±0.2, and 20.0±0.2.

[0369] In some embodiments, the maleate salt Form A of Compound I (salt or co-crystal) is characterized by an X-ray powder diffractogram substantially similar to that in FIG.

[0370] In some embodiments, the maleate salt of Compound I, Form A (salt or co-crystal), is characterized by a TGA thermogram that exhibits minimal weight loss prior to decomposition.

[0371] In some embodiments, the maleate salt Form A of Compound I (salt or co-crystal) is characterized by a TGA thermogram substantially similar to FIG.

[0372] In some embodiments, the maleate salt of Compound I, Form A (salt or co-crystal), is characterized by a DSC curve having an endothermic peak at about 201°C.

[0373] In some embodiments, the maleate salt Form A of Compound I (salt or co-crystal) is characterized by a DSC curve substantially similar to that in FIG.

[0374] Some embodiments of the present disclosure provide a method of making the maleate salt Form A (salt or co-crystal) of Compound I, the method comprising: Dissolving the monohydrate of Compound I in acetonitrile; adding maleic acid to form a suspension and stirring at ambient temperature for 3 days; centrifuging the suspension and air-drying the resulting wet cake; and heating to 165°C and isolating the solid.

[0375] Maleate Form B of Compound I (salt or cocrystal) Some embodiments of the present disclosure provide a second maleate / co-crystal form (Compound I maleate Form B) of Compound I. In some embodiments, Compound I maleate Form B is substantially pure.

[0376] In some embodiments, Compound I maleate salt Form B is characterized by an X-ray powder diffractogram comprising a signal at 4.9±0.2 2-theta. In some embodiments, Compound I maleate salt Form B is characterized by an X-ray powder diffractogram comprising a signal at 26.0±0.2 2-theta. In some embodiments, Compound I maleate salt Form B is characterized by an X-ray powder diffractogram comprising signals at 4.9±0.2 2-theta and 26.0±0.2 2-theta.

[0377] In some embodiments, Compound I maleate salt Form B is characterized by an X-ray powder diffractogram comprising (a) a signal at 4.9±0.2 2-theta and / or 26.0±0.2 2-theta, and (b) a signal at one or more 2-theta values ​​selected from 13.8±0.2, 14.7±0.2, 15.4±0.2, 18.3±0.2, and 19.6±0.2. In some embodiments, Compound I maleate salt Form B is characterized by an X-ray powder diffractogram comprising (a) a signal at 4.9±0.2 2-theta and / or 26.0±0.2 2-theta, and (b) a signal at two or more 2-theta values ​​selected from 13.8±0.2, 14.7±0.2, 15.4±0.2, 18.3±0.2, and 19.6±0.2. In some embodiments, Compound I maleate salt Form B is characterized by an X-ray powder diffractogram comprising (a) signals at 4.9±0.2 2-theta and / or 26.0±0.2 2-theta, and (b) signals at three or more 2-theta values ​​selected from 13.8±0.2, 14.7±0.2, 15.4±0.2, 18.3±0.2, and 19.6±0.2. In some embodiments, Compound I maleate salt Form B is characterized by an X-ray powder diffractogram comprising (a) signals at 4.9±0.2 2-theta and / or 26.0±0.2 2-theta, and (b) signals at four or more 2-theta values ​​selected from 13.8±0.2, 14.7±0.2, 15.4±0.2, 18.3±0.2, and 19.6±0.2.

[0378] In some embodiments, Compound I maleate salt Form B is characterized by an X-ray powder diffractogram comprising signals at 4.9±0.2 2-theta, 13.8±0.2 2-theta, 14.7±0.2 2-theta, 15.4±0.2 2-theta, 18.3±0.2 2-theta, 19.6±0.2 2-theta, and 26.0±0.2 2-theta.

[0379] In some embodiments, the maleate salt Form B of Compound I (salt or co-crystal) is characterized by an X-ray powder diffractogram substantially similar to that in FIG.

[0380] In some embodiments, the maleate salt Form B of Compound I (salt or co-crystal) is characterized by a TGA thermogram that exhibits minimal weight loss prior to decomposition.

[0381] In some embodiments, the maleate salt Form B of Compound I (salt or co-crystal) is characterized by a TGA thermogram substantially similar to that in FIG.

[0382] In some embodiments, the maleate salt Form B of Compound I (salt or co-crystal) is characterized by a DSC curve having an endothermic peak at about 206°C.

[0383] In some embodiments, the maleate salt Form B of Compound I (salt or co-crystal) is characterized by a DSC curve substantially similar to that in FIG.

[0384] Some embodiments of the present disclosure provide a method of making the maleate salt Form B (salt or co-crystal) of Compound I, the method comprising: Dissolving the monohydrate of Compound I in ethanol; adding maleic acid and stirring at ambient temperature for 3 days; Rapid evaporation for 5 days, and heating to 150°C and isolating the solid.

[0385] Fumaric Acid Form A of Compound I (Salt or Cocrystal) Some embodiments of the present disclosure provide a fumarate salt / co-crystal form (Compound I fumarate Form A) of Compound I. In some embodiments, Compound I fumarate Form A is substantially pure.

[0386] In some embodiments, Compound I fumaric acid Form A is characterized by an X-ray powder diffractogram comprising a signal at 21.5±0.2 2-theta. In some embodiments, Compound I fumaric acid Form A is characterized by an X-ray powder diffractogram comprising a signal at 14.4±0.2 2-theta. In some embodiments, Compound I fumaric acid Form A is characterized by an X-ray powder diffractogram comprising a signal at 14.6±0.2 2-theta. In some embodiments, Compound I fumaric acid Form A is characterized by an X-ray powder diffractogram comprising a signal at 16.9±0.2 2-theta. In some embodiments, Compound I fumaric acid Form A is characterized by an X-ray powder diffractogram comprising a signal at 20.7±0.2 2-theta. In some embodiments, Compound I fumaric acid Form A is characterized by an X-ray powder diffractogram comprising a signal at 20.9±0.2 2-theta.

[0387] In some embodiments, Compound I fumaric acid Form A is characterized by an X-ray powder diffractogram comprising signals at two or more 2-theta values ​​selected from 14.4±0.2, 14.6±0.2, 16.9±0.2, 20.7±0.2, 20.9±0.2, and 21.5±0.2. In some embodiments, Compound I fumaric acid Form A is characterized by an X-ray powder diffractogram comprising signals at three or more 2-theta values ​​selected from 14.4±0.2, 14.6±0.2, 16.9±0.2, 20.7±0.2, 20.9±0.2, and 21.5±0.2. In some embodiments, Compound I fumaric acid Form A is characterized by an X-ray powder diffractogram comprising signals at four or more 2-theta values ​​selected from 14.4±0.2, 14.6±0.2, 16.9±0.2, 20.7±0.2, 20.9±0.2, and 21.5±0.2. In some embodiments, Compound I fumaric acid Form A is characterized by an X-ray powder diffractogram comprising signals at five or more 2-theta values ​​selected from 14.4±0.2, 14.6±0.2, 16.9±0.2, 20.7±0.2, 20.9±0.2, and 21.5±0.2. In some embodiments, Compound I fumaric acid Form A is characterized by an X-ray powder diffractogram comprising signals at 14.4±0.2 2-theta, 14.6±0.2 2-theta, 16.9±0.2 2-theta, 20.7±0.2 2-theta, 20.9±0.2 2-theta, and 21.5±0.2 2-theta.

[0388] In some embodiments, Compound I fumaric acid Form A exhibits (a) a signal at 2-theta of 21.5±0.2 and / or a signal at 2-theta of 16.9±0.2, and (b) a signal at 2-theta of 9.5±0.2, 14.4±0.2, 14.6±0.2, 15.6±0.2, 16.9±0.2, 17.3±0.2, 17.5±0.2, 19.1±0.2, 19.5±0.2 , 19.7±0.2, 20.7±0.2, 20.9±0.2, 21.0±0.2, 22.5±0.2, 23.2±0.2, 25.7±0.2, 28.3±0.2, and 29.4±0.2, and characterized by an X-ray powder diffractogram including signals at one, two, three, four, five, six, seven, eight, nine, ten, or more 2-theta values ​​selected from: 19.7±0.2, 20.7±0.2, 20.9±0.2, 21.0±0.2, 22.5±0.2, 23.2±0.2, 25.7±0.2, 28.3±0.2, and 29.4±0.2.

[0389] In some embodiments, the fumaric acid Form A of Compound I (salt or co-crystal) is characterized by an X-ray powder diffractogram substantially similar to that in FIG.

[0390] In some embodiments, Compound I fumaric acid Form A (salt or co-crystal) is characterized by a TGA thermogram that exhibits minimal weight loss from ambient temperature to 100°C.

[0391] In some embodiments, Compound I fumaric acid Form A (salt or co-crystal) is characterized by a TGA thermogram substantially similar to FIG.

[0392] In some embodiments, Compound I fumaric acid Form A (salt or co-crystal) is characterized by a DSC curve with two endothermic peaks at about 137°C and 165°C. In some embodiments, the fumaric acid Form A of Compound I (salt or co-crystal) is characterized by a DSC curve substantially similar to that in FIG.

[0393] In some embodiments, Compound I fumaric acid Form A comprises one or more signals selected from 172.4±0.2 ppm, 128.1±0.2 ppm, 72.9±0.2 ppm, and 17.2±0.2 ppm. 13In some embodiments, Compound I fumaric acid Form A is characterized by a C NMR spectrum comprising two or more signals selected from 172.4±0.2 ppm, 128.1±0.2 ppm, 72.9±0.2 ppm, and 17.2±0.2 ppm. 13 In some embodiments, Compound I fumaric acid Form A is characterized by a C NMR spectrum comprising three or more signals selected from 172.4±0.2 ppm, 128.1±0.2 ppm, 72.9±0.2 ppm, and 17.2±0.2 ppm. 13 In some embodiments, Compound I fumaric acid Form A is characterized by a C NMR spectrum, comprising signals at 172.4±0.2 ppm, 128.1±0.2 ppm, 72.9±0.2 ppm, and 17.2±0.2 ppm. 13 Characterized by C NMR spectrum.

[0394] In some embodiments, Compound I fumaric acid Form A has a saturation of 172.4±0.2 ppm, 171.4±0.2 ppm, 148.4±0.2 ppm, 143.8±0.2 ppm, 142.1±0.2 ppm, 135.5±0.2 ppm, 130.7±0.2 ppm, 128.1±0.2 ppm, 127.3±0.2 ppm, 124.3±0.2 ppm, 121.5±0.2 ppm pm, 72.9±0.2 ppm, 65.7±0.2 ppm, 61.8±0.2 ppm, 50.8±0.2 ppm, 48.3±0.2 ppm, 47.3±0.2 ppm, 42.0±0.2 ppm, 38.3±0.2 ppm, 34.6±0.2 ppm, and 17.2±0.2 ppm (e.g., two or more, three or more, four or more, etc.). 13 Characterized by C NMR spectrum.

[0395] In some embodiments, the fumaric acid Form A of Compound I is prepared in a manner substantially similar to that shown in FIG. 13 Characterized by C NMR spectrum.

[0396] In some embodiments, Compound I fumaric acid Form A (salt or co-crystal) contains a single signal at -55.8±0.2 ppm. 19 Characterized by F MAS spectra.

[0397] In some embodiments, the fumaric acid Form A (salt or co-crystal) of Compound I is prepared in a manner substantially similar to that shown in FIG. 19 Characterized by F MAS spectra.

[0398] Some embodiments of the present disclosure provide a method of making fumaric acid Form A (salt or co-crystal) of Compound I, the method comprising: adding a vial containing ceramic beads and water to a high-throughput ball mill containing Compound I monohydrate and fumaric acid in a 3:4 ratio; Running the ball mill for three 60-second cycles with a 10-second pause between cycles; Place in a vacuum oven at 45°C overnight, and and isolating the solid material.

[0399] Free Form B of Compound I Some embodiments of the present disclosure provide the free form of Compound I (Form B of Compound I). In some embodiments, the free form of Compound I, Form B, is substantially pure.

[0400] In some embodiments, the free form of Compound I, Form B, is characterized by an X-ray powder diffractogram comprising a signal at 21.6±0.2 2-theta. In some embodiments, the free form of Compound I, Form B, is characterized by an X-ray powder diffractogram comprising a signal at 13.9±0.2 2-theta. In some embodiments, the free form of Compound I, Form B, is characterized by an X-ray powder diffractogram comprising a signal at 19.1±0.2 2-theta. In some embodiments, the free form of Compound I, Form B, is characterized by an X-ray powder diffractogram comprising a signal at 11.7±0.2 2-theta. In some embodiments, the free form of Compound I, Form B, is characterized by an X-ray powder diffractogram comprising a signal at 14.2±0.2 2-theta. In some embodiments, the free form of Compound I, Form B, is characterized by an X-ray powder diffractogram comprising a signal at 24.6±0.2 2-theta.

[0401] In some embodiments, the free form Form B of Compound I is characterized by an X-ray powder diffractogram comprising signals at two or more 2-theta values ​​selected from 11.7±0.2, 13.9±0.2, 14.2±0.2, 19.1±0.2, 21.6±0.2, and 24.6±0.2. In some embodiments, the free form Form B of Compound I is characterized by an X-ray powder diffractogram comprising signals at three or more 2-theta values ​​selected from 11.7±0.2, 13.9±0.2, 14.2±0.2, 19.1±0.2, 21.6±0.2, and 24.6±0.2. In some embodiments, the free form Form B of Compound I is characterized by an X-ray powder diffractogram comprising signals at four or more 2-theta values ​​selected from 11.7±0.2, 13.9±0.2, 14.2±0.2, 19.1±0.2, 21.6±0.2, and 24.6±0.2. In some embodiments, the free form Form B of Compound I is characterized by an X-ray powder diffractogram comprising signals at five or more 2-theta values ​​selected from 11.7±0.2, 13.9±0.2, 14.2±0.2, 19.1±0.2, 21.6±0.2, and 24.6±0.2. In some embodiments, the free form Form B of Compound I is characterized by an X-ray powder diffractogram comprising signals at 11.7±0.2 2-theta, 13.9±0.2 2-theta, 14.2±0.2 2-theta, 19.1±0.2 2-theta, 21.6±0.2 2-theta, and 24.6±0.2 2-theta.

[0402] In some embodiments, the free form Form B of Compound I is characterized by an X-ray powder diffractogram comprising: (a) signals at one or more 2-theta values ​​selected from 11.7±0.2, 13.9±0.2, 14.2±0.2, 19.1±0.2, 21.6±0.2, and 24.6±0.2; and (b) signals at one or more 2-theta values ​​selected from 13.1±0.2, 20.6±0.2, 17.5±0.2, 15.8±0.2, and 18.9±0.2. In some embodiments, the free form Form B of Compound I is characterized by an X-ray powder diffractogram comprising: (a) signals at one or more 2-theta values ​​selected from 11.7±0.2, 13.9±0.2, 14.2±0.2, 19.1±0.2, 21.6±0.2, and 24.6±0.2; and (b) signals at 13.1±0.2 2-theta and 20.6±0.2 2-theta. In some embodiments, the free form Form B of Compound I is characterized by an X-ray powder diffractogram comprising: (a) signals at one or more 2-theta values ​​selected from 11.7±0.2, 13.9±0.2, 14.2±0.2, 19.1±0.2, 21.6±0.2, and 24.6±0.2; and (b) signals at 2-theta of 13.1±0.2, 20.6±0.2, and 17.5±0.2. In some embodiments, the free form Form B of Compound I is characterized by an X-ray powder diffractogram comprising: (a) signals at one or more 2-theta values ​​selected from 11.7±0.2, 13.9±0.2, 14.2±0.2, 19.1±0.2, 21.6±0.2, and 24.6±0.2; and (b) signals at 13.1±0.2 2-theta, 20.6±0.2, 17.5±0.2 2-theta, and 15.8±0.2 2-theta.In some embodiments, the free form Form B of Compound I is characterized by an X-ray powder diffractogram comprising: (a) signals at one or more 2-theta values ​​selected from 11.7±0.2, 13.9±0.2, 14.2±0.2, 19.1±0.2, 21.6±0.2, and 24.6±0.2; and (b) signals at 13.1±0.2 2-theta, 20.6±0.2, 17.5±0.2 2-theta, 15.8±0.2 2-theta, and 18.9±0.2 2-theta.

[0403] In some embodiments, the free form Form B of Compound I is characterized by an X-ray powder diffractogram substantially similar to FIG.

[0404] In some embodiments, the free form of Compound I, Form B, is characterized by a TGA thermogram that exhibits minimal weight loss from ambient temperature to 180°C.

[0405] In some embodiments, the free form Form B of Compound I is characterized by a TGA thermogram substantially similar to FIG.

[0406] In some embodiments, the free form of Compound I, Form B, is characterized by a DSC curve having a broad endothermic peak at about 132°C.

[0407] In some embodiments, the free form Form B of Compound I is characterized by a DSC curve substantially similar to that in FIG.

[0408] In some embodiments, the free form Form B of Compound I comprises one or more signals selected from 152.2±0.2 ppm, 148.1±0.2 ppm, and 140.0±0.2 ppm. 13 In some embodiments, the free form of Compound I, Form B, is characterized by a C NMR spectrum comprising one or more signals selected from 73.7±0.2 ppm, 47.9±0.2 ppm, and 23.5±0.2 ppm. 13In some embodiments, the free form of Compound I, Form B, is characterized by a C NMR spectrum comprising: (a) one or more signals selected from 152.2±0.2 ppm, 148.1±0.2 ppm, and 140.0±0.2 ppm; and (b) one or more signals selected from 73.7±0.2 ppm, 47.9±0.2 ppm, and 23.5±0.2 ppm. 13 Characterized by C NMR spectrum.

[0409] In some embodiments, the free form Form B of Compound I comprises signals at 152.2±0.2 ppm, 148.1±0.2 ppm, and 140.0±0.2 ppm. 13 In some embodiments, the free form of Compound I, Form B, is characterized by a C NMR spectrum, comprising signals at 73.7±0.2 ppm, 47.9±0.2 ppm, and 23.5±0.2 ppm. 13 In some embodiments, the free form of Compound I, Form B, is characterized by a C NMR spectrum, comprising signals at 152.2±0.2 ppm, 148.1±0.2 ppm, 140.0±0.2 ppm, 73.7±0.2 ppm, 47.9±0.2 ppm, and 23.5±0.2 ppm. 13 Characterized by C NMR spectrum.

[0410] In some embodiments, the free form of Compound I, Form B, has a structure substantially similar to that shown in FIG. 13 Characterized by C NMR spectrum.

[0411] In some embodiments, the free form Form B of Compound I comprises a signal at −54.8±0.2 ppm. 19 Characterized by F MAS spectra.

[0412] In some embodiments, the free form Form B of Compound I is substantially similar to that shown in FIG. 19 Characterized by F MAS spectra.

[0413] In some embodiments, the free form Form B of Compound I is characterized by an orthorhombic crystalline system, a P212121 space group, and the following unit cell dimensions, measured at 100 K on a Bruker diffractometer with Cu Kα radiation (λ=1.54178 Å): [Table 97]

[0414] In some embodiments, the free form Form B of Compound I is characterized by an orthorhombic crystalline system, a P212121 space group, and the following unit cell dimensions, measured at 298 K on a Bruker diffractometer with Cu Kα radiation (λ=1.54178 Å): [Table 98]

[0415] Some embodiments of the present disclosure provide a method A (Method A) for making the free form Form B of Compound I, the method comprising: heating the free monohydrate of Compound I to 120°C for two hours; Cooling to 90°C and maintaining at 90°C for 5 days; and isolating the free form Form B of solid Compound I.

[0416] Some embodiments of the present disclosure provide another method (Method B) of making the free form Form B of Compound I, which method comprises: placing amorphous free Compound I in heptane vapor for 5 days; and isolating the free form Form B of solid Compound I.

[0417] Free Form C of Compound I Some embodiments of the present disclosure provide the free form of Compound I (free Form C of Compound I). In some embodiments, the free form of Compound I, Form C, is substantially pure.

[0418] In some embodiments, the free form Form C of Compound I is characterized by an X-ray powder diffractogram comprising a signal at 11.1±0.2 2-theta. In some embodiments, the free form Form C of Compound I is characterized by an X-ray powder diffractogram comprising a signal at 25.7±0.2 2-theta. In some embodiments, the free form Form C of Compound I is characterized by an X-ray powder diffractogram comprising a signal at 14.7±0.2 2-theta. In some embodiments, the free form Form C of Compound I is characterized by an X-ray powder diffractogram comprising a signal at 21.0±0.2 2-theta.

[0419] In some embodiments, the free form of Compound I, Form C, is characterized by an X-ray powder diffractogram comprising signals at two or more 2-theta values ​​selected from 11.1±0.2, 14.7±0.2, 21.0±0.2, and 25.7±0.2. In some embodiments, the free form of Compound I, Form C, is characterized by an X-ray powder diffractogram comprising signals at three or more 2-theta values ​​selected from 11.1±0.2, 14.7±0.2, 21.0±0.2, and 25.7±0.2. In some embodiments, the free form of Compound I, Form C, is characterized by an X-ray powder diffractogram comprising signals at 11.1±0.2 2-theta, 14.7±0.2 2-theta, 21.0±0.2, and 25.7±0.2 2-theta.

[0420] In some embodiments, the free form Form C of Compound I is characterized by an X-ray powder diffractogram comprising: (a) signals at one or more 2-theta values ​​selected from 11.1±0.2, 14.7±0.2, 21.0±0.2, and 25.7±0.2; and (b) signals at one or more 2-theta values ​​selected from 9.5±0.2, 17.7±0.2, 12.9±0.2, 15.4±0.2, 18.6±0.2, and 25.9±0.2. In some embodiments, the free form Form C of Compound I is characterized by an X-ray powder diffractogram comprising: (a) signals at one or more 2-theta values ​​selected from 11.1±0.2, 14.7±0.2, 21.0±0.2, and 25.7±0.2; and (b) signals at two or more 2-theta values ​​selected from 9.5±0.2, 17.7±0.2, 12.9±0.2, 15.4±0.2, 18.6±0.2, and 25.9±0.2. In some embodiments, the free form Form C of Compound I is characterized by an X-ray powder diffractogram comprising: (a) signals at one or more 2-theta values ​​selected from 11.1±0.2, 14.7±0.2, 21.0±0.2, and 25.7±0.2; and (b) signals at three or more 2-theta values ​​selected from 9.5±0.2, 17.7±0.2, 12.9±0.2, 15.4±0.2, 18.6±0.2, and 25.9±0.2. In some embodiments, the free form Form C of Compound I is characterized by an X-ray powder diffractogram comprising: (a) signals at one or more 2-theta values ​​selected from 11.1±0.2, 14.7±0.2, 21.0±0.2, and 25.7±0.2; and (b) signals at four or more 2-theta values ​​selected from 9.5±0.2, 17.7±0.2, 12.9±0.2, 15.4±0.2, 18.6±0.2, and 25.9±0.2.In some embodiments, the free form Form C of Compound I is characterized by an X-ray powder diffractogram comprising: (a) signals at one or more 2-theta values ​​selected from 11.1±0.2, 14.7±0.2, 21.0±0.2, and 25.7±0.2; and (b) signals at 17.7±0.2 2-theta, 12.9±0.2 2-theta, 15.4±0.2 2-theta, and 18.6±0.2 2-theta.

[0421] In some embodiments, the free form Form C of Compound I is characterized by an X-ray powder diffractogram substantially similar to that in FIG.

[0422] In some embodiments, the free form of Compound I, Form C, is characterized by a TGA thermogram that exhibits minimal weight loss from ambient temperature to 190°C.

[0423] In some embodiments, the free form Form C of Compound I is characterized by a TGA thermogram substantially similar to that in FIG.

[0424] In some embodiments, the free form of Compound I, Form C, is characterized by a DSC curve having an endothermic peak at about 134°C.

[0425] In some embodiments, the free form Form C of Compound I is characterized by a DSC curve substantially similar to that in FIG.

[0426] In some embodiments, the free form Form C of Compound I comprises one or more signals selected from 149.6±0.2 ppm, 149.2±0.2 ppm, and 137.1±0.2 ppm. 13 In some embodiments, the free form of Compound I, Form C, is characterized by a C NMR spectrum comprising one or more signals selected from 74.5±0.2 ppm, 62.4±0.2 ppm, 48.3±0.2 ppm, and 24.6±0.2 ppm. 13In some embodiments, the free form of Compound I, Form C, is characterized by a C NMR spectrum. In some embodiments, the free form of Compound I, Form C, comprises one or more signals selected from (a) 149.6±0.2 ppm, 149.2±0.2 ppm, and 137.1±0.2 ppm, and (b) 74.5±0.2 ppm, 62.4±0.2 ppm, 48.3±0.2 ppm, and 24.6±0.2 ppm. 13 Characterized by C NMR spectrum.

[0427] In some embodiments, the free form Form C of Compound I comprises signals at 149.6±0.2 ppm, 149.2±0.2 ppm, and 137.1±0.2 ppm. 13 In some embodiments, the free form of Compound I, Form C, is characterized by a C NMR spectrum, comprising signals at 74.5±0.2 ppm, 62.4±0.2 ppm, 48.3±0.2 ppm, and 24.6±0.2 ppm. 13 In some embodiments, the free form of Compound I, Form C, is characterized by a C NMR spectrum, comprising signals at 149.6±0.2 ppm, 149.2±0.2 ppm, 137.1±0.2 ppm, 74.5±0.2 ppm, 62.4±0.2 ppm, 48.3±0.2 ppm, and 24.6±0.2 ppm. 13 Characterized by C NMR spectrum.

[0428] In some embodiments, the free form Form C of Compound I is substantially similar to that shown in FIG. 13 Characterized by C NMR spectrum.

[0429] In some embodiments, the free form Form C of Compound I comprises a signal at −54.0±0.2 ppm. 19 Characterized by F MAS spectra.

[0430] In some embodiments, the free form Form C of Compound I is substantially similar to that shown in FIG. 19 Characterized by F MAS spectra.

[0431] In some embodiments, the free form Form C of Compound I is characterized by an orthorhombic crystalline system, a P212121 space group, and the following unit cell dimensions, measured at 100 K on a Bruker diffractometer with Cu Kα radiation (λ=1.54178 Å): [Table 99]

[0432] Some embodiments of the present disclosure provide a method (Method A) of making the free form Form C of Compound I, the method comprising: obtaining a species of Compound I in free form C by subjecting a physical mixture of Compound I free form monohydrate and Compound II free form C to heat treatment in a TGA pan; Heat treatment with a TGA ramp of 10°C / min to 120°C, isothermal at 120°C for 60 minutes, followed by cooling at 2°C / min to 25°C; adding the seeds generated by this heat treatment to a slurry of the free monohydrate of Compound I in heptane and maintaining the mixture at 50°C for 7 days; and isolating the free form Form C of solid Compound I.

[0433] Some embodiments of the present disclosure provide another method (Method B) of making the free form Form C of Compound I, which method comprises: placing the free monohydrate of Compound I, heptane, and ethyl acetate in a reactor; Stirring and heating the slurry to 65°C; seeding with the free form C of Compound I; Stirring at 65°C for 3 days and isolating; and Isolating the solid and drying it under vacuum at 50°C under a nitrogen blanket.

[0434] Compound II Phosphate Hemihydrate Form A Some embodiments of the present disclosure provide Compound II phosphate hemihydrate (Compound II phosphate hemihydrate Form A). In some embodiments, Compound II phosphate hemihydrate Form A is substantially pure.

[0435] In some embodiments, Compound II phosphate salt hemihydrate Form A is characterized by an X-ray powder diffractogram comprising signals at 9.1 2-theta, 16.7 2-theta, and / or 18.7±0.2 2-theta.

[0436] In some embodiments, Compound II phosphate salt hemihydrate Form A is characterized by an X-ray powder diffractogram comprising signals at one or more 2-theta values ​​selected from 9.1±0.2, 16.7±0.2, and 18.7±0.2. In some embodiments, Compound II phosphate salt hemihydrate Form A is characterized by an X-ray powder diffractogram comprising signals at two or more 2-theta values ​​selected from 9.1±0.2, 16.7±0.2, and 18.7±0.2.

[0437] In some embodiments, Compound II phosphate salt hemihydrate Form A is characterized by an X-ray powder diffractogram comprising signals at the following 2-theta values: 9.1±0.2, 16.7±0.2, and 18.7±0.2. In some embodiments, Compound II phosphate salt hemihydrate Form A is characterized by an X-ray powder diffractogram comprising signals at the following 2-theta values: 9.1±0.2, 16.7±0.2, and 18.7±0.2, and (b) one or more (e.g., two or more) 2-theta values ​​selected from: 14.9±0.2, 15.7±0.2, and 20.0±0.2. In some embodiments, Compound II phosphate salt hemihydrate Form A is characterized by an X-ray powder diffractogram comprising signals at one or more 2-theta values ​​(e.g., two or more, three or more, four or more, five or more) selected from 9.1±0.2, 14.9±0.2, 15.7±0.2, 16.7±0.2, 18.7±0.2, and 20.0±0.2. In some embodiments, Compound II phosphate salt hemihydrate Form A is characterized by an X-ray powder diffractogram comprising signals at the following 2-theta values: 9.1±0.2, 14.9±0.2, 15.7±0.2, 16.7±0.2, 18.7±0.2, and 20.0±0.2.

[0438] In some embodiments, Compound II phosphate salt hemihydrate Form A is characterized by an X-ray powder diffractogram comprising: (a) signals at the following 2-theta values: 9.1±0.2, 16.7±0.2, and 18.7±0.2, and (b) signals at one or more (e.g., two or more, three or more, four or more) 2-theta values ​​selected from 10.1±0.2, 14.9±0.2, 15.7±0.2, 18.4±0.2, and 20.0±0.2. In some embodiments, Compound II phosphate salt hemihydrate Form A is characterized by an X-ray powder diffractogram comprising signals at one or more 2-theta values ​​(e.g., two or more, three or more, four or more, five or more, six or more, seven or more) selected from 9.1±0.2, 10.1±0.2, 14.9±0.2, 15.7±0.2, 16.7±0.2, 18.4±0.2, 18.7±0.2, and 20.0±0.2. In some embodiments, Compound II phosphate salt hemihydrate Form A is characterized by an X-ray powder diffractogram comprising signals at the following 2-theta values: 9.1±0.2, 10.1±0.2, 14.9±0.2, 15.7±0.2, 16.7±0.2, 18.4±0.2, 18.7±0.2, and 20.0±0.2.

[0439] In some embodiments, Compound II phosphate salt hemihydrate Form A is characterized by an X-ray powder diffractogram comprising: (a) signals at the following 2-theta values: 9.1±0.2, 16.7±0.2, and 18.7±0.2, and (b) signals at one or more (e.g., two or more, three or more, four or more, five or more, six or more) 2-theta values ​​selected from 10.1±0.2, 14.9±0.2, 15.2±0.2, 15.7±0.2, 18.4±0.2, 20.0±0.2, and 20.2±0.2. In some embodiments, Compound II phosphate salt hemihydrate Form A is characterized by an X-ray powder diffractogram comprising signals at one or more 2-theta values ​​(e.g., two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more) selected from 9.1±0.2, 10.1±0.2, 14.9±0.2, 15.7±0.2, 16.7±0.2, 18.4±0.2, 18.7±0.2, and 20.0±0.2. In some embodiments, Compound II phosphate salt hemihydrate Form A is characterized by an X-ray powder diffractogram comprising signals at the following 2-theta values: 9.1±0.2, 10.1±0.2, 14.9±0.2, 15.2±0.2, 15.7±0.2, 16.7±0.2, 18.4±0.2, 18.7±0.2, 20.0±0.2, and 20.2±0.2.

[0440] In some embodiments, Compound II phosphate salt hemihydrate Form A is characterized by an X-ray powder diffractogram substantially similar to FIG.

[0441] In some embodiments, Compound II phosphate hemihydrate Form A comprises one or more (e.g., two or more, three or more, four or more) signals selected from 47.7±0.2 ppm, 50.5±0.2 ppm, 72.5±0.2 ppm, 73±0.2 ppm, and 141.3±0.2 ppm. 13 Characterized by C NMR spectrum.

[0442] In some embodiments, Compound II phosphate hemihydrate Form A comprises one or more (e.g., two or more, three or more, four or more) signals selected from 15.3±0.2 ppm, 15.8±0.2 ppm, 16.6±0.2 ppm, 39.9±0.2 ppm, and 141.3±0.2 ppm. 13 Characterized by C NMR spectrum.

[0443] In some embodiments, Compound II phosphate salt hemihydrate Form A comprises one or more (e.g., two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more) signals selected from 15.3±0.2 ppm, 16.6±0.2 ppm, 46.9±0.2 ppm, 47.7±0.2 ppm, 50.5±0.2 ppm, 63.4±0.2 ppm, 65.4±0.2 ppm, 72.5±0.2 ppm, 73±0.2 ppm, and 141.3±0.2 ppm. 13 Characterized by C NMR spectrum.

[0444] In some embodiments, Compound II phosphate salt hemihydrate Form A comprises one or more (e.g., two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more) signals selected from 15.3±0.2 ppm, 15.8±0.2 ppm, 16.6±0.2 ppm, 18.4±0.2 ppm, 38.6±0.2 ppm, 39.9±0.2 ppm, 126.6±0.2 ppm, 127.1±0.2 ppm, 136.8±0.2 ppm, and 141.3±0.2 ppm. 13 Characterized by C NMR spectrum.

[0445] In some embodiments, Compound II phosphate salt hemihydrate Form A comprises signals at 47.7±0.2 ppm, 50.5±0.2 ppm, 72.5±0.2 ppm, 73±0.2 ppm, and 141.3±0.2 ppm. 13 Characterized by C NMR spectrum.

[0446] In some embodiments, Compound II phosphate hemihydrate Form A comprises signals at 15.3±0.2 ppm, 15.8±0.2 ppm, 16.6±0.2 ppm, 39.9±0.2 ppm, and 141.3±0.2 ppm. 13 Characterized by C NMR spectrum.

[0447] In some embodiments, Compound II phosphate salt hemihydrate Form A comprises signals at 15.3±0.2 ppm, 16.6±0.2 ppm, 46.9±0.2 ppm, 47.7±0.2 ppm, 50.5±0.2 ppm, 63.4±0.2 ppm, 65.4±0.2 ppm, 72.5±0.2 ppm, 73±0.2 ppm, and 141.3±0.2 ppm. 13 Characterized by C NMR spectrum.

[0448] In some embodiments, Compound II phosphate salt hemihydrate Form A comprises signals at 15.3±0.2 ppm, 15.8±0.2 ppm, 16.6±0.2 ppm, 18.4±0.2 ppm, 38.6±0.2 ppm, 39.9±0.2 ppm, 126.6±0.2 ppm, 127.1±0.2 ppm, 136.8±0.2 ppm, and 141.3±0.2 ppm. 13 Characterized by C NMR spectrum.

[0449] In some embodiments, Compound II phosphate salt hemihydrate Form A may be prepared in a manner substantially similar to that shown in FIG. 13 Characterized by C NMR spectrum.

[0450] In some embodiments, Compound II phosphate salt hemihydrate Form A comprises one or more (e.g., two or more, three or more, four or more) signals selected from 16.5±0.2 ppm, 48.5±0.2 ppm, 66.5±0.2 ppm, 72.2±0.2 ppm, and 73.3±0.2 ppm, measured after dehydration. 13 Characterized by C NMR spectrum.

[0451] In some embodiments, Compound II phosphate salt hemihydrate Form A comprises one or more (e.g., two or more, three or more, four or more) signals selected from 16.5±0.2 ppm, 38.5±0.2 ppm, 39.3±0.2 ppm, 125.6±0.2 ppm, and 127.5±0.2 ppm, measured after dehydration. 13 Characterized by C NMR spectrum.

[0452] In some embodiments, Compound II phosphate salt hemihydrate Form A comprises one or more (e.g., two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more) signals selected from 16.5±0.2 ppm, 38.5±0.2 ppm, 39.3±0.2 ppm, 48.5±0.2 ppm, 64.1±0.2 ppm, 66.5±0.2 ppm, 72.2±0.2 ppm, 73±0.2 ppm, 73.3±0.2 ppm, and 127.5±0.2 ppm, measured after dehydration. 13 Characterized by C NMR spectrum.

[0453] In some embodiments, Compound II phosphate salt hemihydrate Form A comprises one or more (e.g., two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more) signals selected from 16.5±0.2 ppm, 36.6±0.2 ppm, 37±0.2 ppm, 38.5±0.2 ppm, 39.3±0.2 ppm, 125.6±0.2 ppm, 127.5±0.2 ppm, 136.8±0.2 ppm, 141.3±0.2 ppm, and 143±0.2 ppm, measured after dehydration. 13 Characterized by C NMR spectrum.

[0454] In some embodiments, Compound II phosphate salt hemihydrate Form A comprises signals at 16.5±0.2 ppm, 48.5±0.2 ppm, 66.5±0.2 ppm, 72.2±0.2 ppm, and 73.3±0.2 ppm, measured after dehydration. 13 Characterized by C NMR spectrum.

[0455] In some embodiments, Compound II phosphate salt hemihydrate Form A comprises signals at 16.5±0.2 ppm, 38.5±0.2 ppm, 39.3±0.2 ppm, 125.6±0.2 ppm, and 127.5±0.2 ppm, measured after dehydration. 13 Characterized by C NMR spectrum.

[0456] In some embodiments, Compound II phosphate salt hemihydrate Form A comprises signals at 16.5±0.2 ppm, 38.5±0.2 ppm, 39.3±0.2 ppm, 48.5±0.2 ppm, 64.1±0.2 ppm, 66.5±0.2 ppm, 72.2±0.2 ppm, 73±0.2 ppm, 73.3±0.2 ppm, and 127.5±0.2 ppm, measured after dehydration. 13 Characterized by C NMR spectrum.

[0457] In some embodiments, Compound II phosphate salt hemihydrate Form A comprises signals at 16.5±0.2 ppm, 36.6±0.2 ppm, 37±0.2 ppm, 38.5±0.2 ppm, 39.3±0.2 ppm, 125.6±0.2 ppm, 127.5±0.2 ppm, 136.8±0.2 ppm, 141.3±0.2 ppm, and 143±0.2 ppm, measured after dehydration. 13 Characterized by C NMR spectrum.

[0458] In some embodiments, the phosphate salt hemihydrate Form A of Compound II may be measured after dehydration, and may have a pH substantially similar to that shown in FIG. 13 Characterized by C NMR spectrum.

[0459] In some embodiments, Compound II phosphate salt hemihydrate Form A comprises signals at one or more (e.g., two or more) ppm values ​​selected from -1.8±0.2 ppm, -1.1±0.2 ppm, and 3.1±0.2 ppm. 31 Characterized by P NMR spectrum.

[0460] In some embodiments, Compound II phosphate salt hemihydrate Form A comprises signals at -1.8±0.2 ppm, -1.1±0.2 ppm, and 3.1±0.2 ppm. 31 Characterized by P NMR spectrum.

[0461] In some embodiments, Compound II phosphate salt hemihydrate Form A may be prepared in a manner substantially similar to that shown in FIG. 27A. 31 Characterized by P NMR spectrum.

[0462] In some embodiments, Compound II phosphate salt hemihydrate Form A comprises signals at one or more (e.g., two or more, three or more) ppm values ​​selected from 3.0±0.2 ppm, 3.2±0.2 ppm, 4.4±0.2 ppm, and 5.6±0.2 ppm, measured after dehydration. 31 Characterized by P NMR spectrum.

[0463] In some embodiments, Compound II phosphate salt hemihydrate Form A comprises signals at 3.0±0.2 ppm, 3.2±0.2 ppm, 4.4±0.2 ppm, and 5.6±0.2 ppm, measured after dehydration. 31 Characterized by P NMR spectrum.

[0464] In some embodiments, Compound II phosphate salt hemihydrate Form A exhibits a pH substantially similar to that shown in FIG. 27B, measured after dehydration. 31 Characterized by P NMR spectrum.

[0465] In some embodiments, Compound II phosphate salt hemihydrate Form A is characterized by a TGA thermogram exhibiting a weight loss of 2.4% from ambient temperature to 150°C.

[0466] In some embodiments, Compound II phosphate salt hemihydrate Form A is characterized by a TGA thermogram substantially similar to FIG.

[0467] In some embodiments, Compound II phosphate salt hemihydrate Form A is characterized by a DSC curve having endothermic peaks at about 123°C and about 224°C.

[0468] In some embodiments, Compound II phosphate salt hemihydrate Form A is characterized by a DSC curve substantially similar to that in FIG.

[0469] In some embodiments, Compound II phosphate salt hemihydrate Form A is characterized by an orthorhombic crystal system, a P212121 space group, and the following unit cell dimensions, measured at 100 K on a Bruker diffractometer with Cu Kα radiation (λ=1.54178 Å): [Table 100]

[0470] Some embodiments of the present disclosure provide a method of making Compound II phosphate salt hemihydrate Form A, the method comprising: adding the free form hemihydrate Form A of Compound II to 2-MeTHF to form a solution; adding H3PO4 dropwise to the solution; stirring the solution at ambient temperature; collecting the solid material by centrifugation; and and drying the solid material.

[0471] In some embodiments, stirring the solution at ambient temperature comprises stirring the solution at ambient temperature for about 2 days.

[0472] In some embodiments, drying the solid material comprises drying the solid material in a vacuum oven at about 40° C. overnight.

[0473] Some embodiments of the present disclosure provide a method of making Compound II phosphate salt hemihydrate Form A, the method comprising: charging the free hemihydrate of Compound II and 2-MeTHF into a reactor; stirring the reactor at about 40°C; seeding the reactor with Compound II phosphate hemihydrate Form A; slowly adding a phosphoric acid solution to the reactor to form a slurry; cooling the slurry; and agitating the cooled slurry and filtering under vacuum to obtain a wet cake; and and drying the wet cake.

[0474] In some embodiments, cooling the slurry comprises cooling the slurry to about 20°C.

[0475] In some embodiments, cooling the slurry comprises cooling the slurry to about 20° C. over a period of about 5 hours.

[0476] In some embodiments, stirring the cooled slurry comprises stirring the cooled slurry at about 20° C. for at least about 2 hours.

[0477] Free hemihydrate Form A of Compound II Some embodiments of the present disclosure provide a hemihydrate of Compound II (Compound II free hemihydrate Form A). In some embodiments, the Compound II free hemihydrate Form A is substantially pure.

[0478] In some embodiments, the free hemihydrate of Compound II, Form A, is characterized by an X-ray powder diffractogram containing signals at 2-theta of 17.1, 19.1, and / or 20.4±0.2, measured at ambient temperature.

[0479] In some embodiments, the free form hemihydrate Form A of Compound II is characterized by an X-ray powder diffractogram comprising signals at one or more 2-theta values ​​selected from 17.1±0.2, 19.1±0.2, and 20.4±0.2, measured at ambient temperature. In some embodiments, the free form hemihydrate Form A of Compound II is characterized by an X-ray powder diffractogram comprising signals at two or more 2-theta values ​​selected from 17.1±0.2, 19.1±0.2, and 20.4±0.2, measured at ambient temperature.

[0480] In some embodiments, the free form hemihydrate Form A of Compound II is characterized by an X-ray powder diffractogram measured at ambient temperature comprising signals at the following 2-theta values: 17.1±0.2, 19.1±0.2, and 20.4±0.2. In some embodiments, the free form hemihydrate Form A of Compound II is characterized by an X-ray powder diffractogram measured at ambient temperature comprising: (a) signals at the following 2-theta values: 17.1±0.2, 19.1±0.2, and 20.4±0.2, and (b) signals at one or more 2-theta values ​​selected from 5.7±0.2, 6.5±0.2, and 14.4±0.2. In some embodiments, the free form hemihydrate Form A of Compound II is characterized by an X-ray powder diffractogram, measured at ambient temperature, comprising signals at one or more 2-theta values ​​(e.g., two or more, three or more, four or more, five or more) selected from 5.7±0.2, 6.5±0.2, 14.4±0.2, 17.1±0.2, 19.1±0.2, and 20.4±0.2. In some embodiments, the free form hemihydrate Form A of Compound II is characterized by an X-ray powder diffractogram, measured at ambient temperature, comprising signals at the following 2-theta values: 5.7±0.2, 6.5±0.2, 14.4±0.2, 17.1±0.2, 19.1±0.2, and 20.4±0.2.

[0481] In some embodiments, the free hemihydrate of Compound II, Form A, is characterized by an X-ray powder diffractogram, measured at ambient temperature, comprising: (a) signals at the following 2-theta values: 17.1±0.2, 19.1±0.2, and 20.4±0.2, and (b) signals at one or more 2-theta values ​​selected from 5.7±0.2, 6.5±0.2, 11.4±0.2, 12.1±0.2, and 14.4±0.2. In some embodiments, the free hemihydrate Form A of Compound II is characterized by an X-ray powder diffractogram, measured at ambient temperature, comprising signals at one or more 2-theta values ​​(e.g., two or more, three or more, four or more, five or more, six or more, seven or more) selected from 5.7±0.2, 6.5±0.2, 11.4±0.2, 12.1±0.2, 14.4±0.2, 17.1±0.2, 19.1±0.2, and 20.4±0.2. In some embodiments, the free hemihydrate Form A of Compound II is characterized by an X-ray powder diffractogram comprising signals at the following 2-theta values, measured at ambient temperature: 5.7±0.2, 6.5±0.2, 11.4±0.2, 12.1±0.2, 14.4±0.2, 17.1±0.2, 19.1±0.2, and 20.4±0.2.

[0482] In some embodiments, the free hemihydrate Form A of Compound II is characterized by an X-ray powder diffractogram, measured at ambient temperature, comprising: (a) signals at the following 2-theta values: 17.1±0.2, 19.1±0.2, and 20.4±0.2, and (b) signals at one or more 2-theta values ​​selected from 5.7±0.2, 6.5±0.2, 11.4±0.2, 12.1±0.2, 12.3±0.2, 14.4±0.2, and 25.5±0.2. In some embodiments, the free hemihydrate of Compound II, Form A, is characterized by an X-ray powder diffractogram, measured at ambient temperature, comprising signals at one or more 2-theta values ​​(e.g., two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more) selected from 5.7±0.2, 6.5±0.2, 11.4±0.2, 12.1±0.2, 12.3±0.2, 14.4±0.2, 17.1±0.2, 19.1±0.2, 20.4±0.2, and 25.5±0.2. In some embodiments, the free hemihydrate of Compound II, Form A, is characterized by an X-ray powder diffractogram comprising signals at the following 2-theta values, measured at ambient temperature: 5.7±0.2, 6.5±0.2, 11.4±0.2, 12.1±0.2, 12.3±0.2, 14.4±0.2, 17.1±0.2, 19.1±0.2, 20.4±0.2, and 25.5±0.2.

[0483] In some embodiments, the free hemihydrate of Compound II, Form A, is characterized by an X-ray powder diffractogram substantially similar to that of Figure 30A, measured at ambient temperature.

[0484] In some embodiments, the free hemihydrate of Compound II, Form A, is characterized by an X-ray powder diffractogram comprising signals at 2-theta of 11.3, 19.0, and / or 20.1±0.2, measured at a temperature ranging from 40° C. to 50° C.

[0485] In some embodiments, the free form hemihydrate of Compound II, Form A, is characterized by an X-ray powder diffractogram comprising signals at one or more 2-theta values ​​selected from 11.3±0.2, 19.0±0.2, and 20.1±0.2, measured at a temperature ranging from 40° C. to 50° C. In some embodiments, the free form hemihydrate of Compound II, Form A, is characterized by an X-ray powder diffractogram comprising signals at two or more 2-theta values ​​selected from 11.3±0.2, 19.0±0.2, and 20.1±0.2, measured at a temperature ranging from 40° C. to 50° C.

[0486] In some embodiments, the free form hemihydrate Form A of Compound II is characterized by an X-ray powder diffractogram comprising signals at the following 2-theta values: 11.3±0.2, 19.0±0.2, and 20.1±0.2, measured at a temperature ranging from 40° C. to 50° C. In some embodiments, the free form hemihydrate Form A of Compound II is characterized by an X-ray powder diffractogram comprising (a) signals at the following 2-theta values: 11.3±0.2, 19.0±0.2, and 20.1±0.2, and (b) signals at one or more 2-theta values ​​selected from 5.6±0.2, 22.3±0.2, and 25.1±0.2, measured at a temperature ranging from 40° C. to 50° C. In some embodiments, the free form hemihydrate Form A of Compound II is characterized by an X-ray powder diffractogram comprising signals at one or more 2-theta values ​​(e.g., two or more, three or more, four or more, five or more) selected from 5.6±0.2, 11.3±0.2, 19.0±0.2, 20.1±0.2, 22.3±0.2, and 25.1±0.2, measured at a temperature ranging from 40° C. to 50° C. In some embodiments, the free form hemihydrate Form A of Compound II is characterized by an X-ray powder diffractogram comprising signals at the following 2-theta values: 5.6±0.2, 11.3±0.2, 19.0±0.2, 20.1±0.2, 22.3±0.2, and 25.1±0.2, measured at a temperature ranging from 40° C. to 50° C.

[0487] In some embodiments, the free hemihydrate Form A of Compound II is characterized by an X-ray powder diffractogram measured at a temperature ranging from 40°C to 50°C, comprising: (a) signals at the following 2-theta values: 11.3±0.2, 19.0±0.2, and 20.1±0.2, and (b) signals at one or more (e.g., two or more, three or more, four or more) 2-theta values ​​selected from 5.6±0.2, 22.3±0.2, 24.8±0.2, 25.1±0.2, and 27.8±0.2. In some embodiments, the free hemihydrate of Compound II, Form A, is characterized by an X-ray powder diffractogram comprising signals at one or more 2-theta values ​​(e.g., two or more, three or more, four or more, five or more, six or more, seven or more) selected from 5.6±0.2, 11.3±0.2, 19.0±0.2, 20.1±0.2, 22.3±0.2, 24.8±0.2, 25.1±0.2, and 27.8±0.2, measured at a temperature ranging from 40°C to 50°C. In some embodiments, the free hemihydrate of Compound II, Form A, is characterized by an X-ray powder diffractogram comprising signals at the following 2-theta values: 5.6±0.2, 11.3±0.2, 19.0±0.2, 20.1±0.2, 22.3±0.2, 24.8±0.2, 25.1±0.2, and 27.8±0.2, measured at a temperature ranging from 40°C to 50°C.

[0488] In some embodiments, the free hemihydrate of Compound II, Form A, is characterized by an X-ray powder diffractogram, measured at a temperature ranging from 40°C to 50°C, comprising: (a) signals at the following 2-theta values: 11.3±0.2, 19.0±0.2, and 20.1±0.2, and (b) signals at one or more (e.g., two or more, three or more, four or more, five or more, six or more) 2-theta values ​​selected from 5.6±0.2, 17.2±0.2, 22.1±0.2, 22.3±0.2, 24.8±0.2, 25.1±0.2, and 27.8±0.2. In some embodiments, the free hemihydrate of Compound II, Form A, is characterized by an X-ray powder diffractogram comprising signals at one or more 2-theta values ​​(e.g., two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more) selected from 5.6±0.2, 11.3±0.2, 17.2±0.2, 19.0±0.2, 20.1±0.2, 22.1±0.2, 22.3±0.2, 24.8±0.2, 25.1±0.2, and 27.8±0.2, measured at a temperature ranging from 40°C to 50°C. In some embodiments, the free hemihydrate of Compound II, Form A, is characterized by an X-ray powder diffractogram comprising signals at the following 2-theta values: 5.6±0.2, 11.3±0.2, 17.2±0.2, 19.0±0.2, 20.1±0.2, 22.1±0.2, 22.3±0.2, 24.8±0.2, 25.1±0.2, and 27.8±0.2, measured at a temperature ranging from 40°C to 50°C.

[0489] In some embodiments, the free hemihydrate of Compound II, Form A, is characterized by an X-ray powder diffractogram substantially similar to Figure 30B, measured at a temperature ranging from 40°C to 50°C.

[0490] In some embodiments, the free hemihydrate of Compound II, Form A, is characterized by an X-ray powder diffractogram containing signals at 2-theta of 5.5, 19.2, and / or 19.8±0.2, measured at a temperature ranging from 60°C to 90°C.

[0491] In some embodiments, the free form hemihydrate of Compound II, Form A, is characterized by an X-ray powder diffractogram comprising signals at one or more 2-theta values ​​selected from 5.5±0.2, 19.2±0.2, and 19.8±0.2, measured at a temperature ranging from 60° C. to 90° C. In some embodiments, the free form hemihydrate of Compound II, Form A, is characterized by an X-ray powder diffractogram comprising signals at two or more 2-theta values ​​selected from 5.5±0.2, 19.2±0.2, and 19.8±0.2, measured at a temperature ranging from 60° C. to 90° C.

[0492] In some embodiments, the free form hemihydrate Form A of Compound II is characterized by an X-ray powder diffractogram comprising signals at the following 2-theta values: 5.5±0.2, 19.2±0.2, and 19.8±0.2, measured at a temperature ranging from 60° C. to 90° C. In some embodiments, the free form hemihydrate Form A of Compound II is characterized by an X-ray powder diffractogram comprising: (a) signals at the following 2-theta values: 5.5±0.2, 19.2±0.2, and 19.8±0.2, and (b) signals at one or more (e.g., two or more) 2-theta values ​​selected from 11.0±0.2, 21.8±0.2, and 27.2±0.2, measured at a temperature ranging from 60° C. to 90° C. In some embodiments, the free form hemihydrate Form A of Compound II is characterized by an X-ray powder diffractogram comprising signals at one or more 2-theta values ​​(e.g., two or more, three or more, four or more, five or more) selected from 5.5±0.2, 11.0±0.2, 19.2±0.2, 19.8±0.2, 21.8±0.2, and 27.2±0.2, measured at a temperature ranging from 60° C. to 90° C. In some embodiments, the free form hemihydrate Form A of Compound II is characterized by an X-ray powder diffractogram comprising signals at the following 2-theta values: 5.5±0.2, 11.0±0.2, 19.2±0.2, 19.8±0.2, 21.8±0.2, and 27.2±0.2, measured at a temperature ranging from 60° C. to 90° C.

[0493] In some embodiments, the free hemihydrate of Compound II, Form A, is characterized by an X-ray powder diffractogram, measured at a temperature ranging from 60°C to 90°C, comprising: (a) signals at the following 2-theta values: 5.5±0.2, 19.2±0.2, and 19.8±0.2, and (b) signals at one or more (e.g., two or more, three or more, four or more) 2-theta values ​​selected from 11.0±0.2, 19.0±0.2, 21.8±0.2, 24.7±0.2, and 27.2±0.2. In some embodiments, the free hemihydrate of Compound II, Form A, is characterized by an X-ray powder diffractogram comprising signals at one or more 2-theta values ​​(e.g., two or more, three or more, four or more, five or more, six or more, seven or more) selected from 5.5±0.2, 11.0±0.2, 19.0±0.2, 19.2±0.2, 19.8±0.2, 21.8±0.2, 24.7±0.2, and 27.2±0.2, measured at a temperature ranging from 60°C to 90°C. In some embodiments, the free hemihydrate of Compound II, Form A, is characterized by an X-ray powder diffractogram comprising signals at the following 2-theta values: 5.5±0.2, 11.0±0.2, 19.0±0.2, 19.2±0.2, 19.8±0.2, 21.8±0.2, 24.7±0.2, and 27.2±0.2, measured at a temperature ranging from 60°C to 90°C.

[0494] In some embodiments, the free hemihydrate of Compound II, Form A, is characterized by an X-ray powder diffractogram, measured at a temperature ranging from 60°C to 90°C, comprising: (a) signals at the following 2-theta values: 5.5±0.2, 19.2±0.2, and 19.8±0.2, and (b) signals at one or more (e.g., two or more, three or more, four or more, five or more, six or more) 2-theta values ​​selected from 11.0±0.2, 19.0±0.2, 21.8±0.2, 22.0±0.2, 24.3±0.2, 24.7±0.2, and 27.2±0.2. In some embodiments, the free hemihydrate of Compound II, Form A, is characterized by an X-ray powder diffractogram comprising signals at one or more 2-theta values ​​(e.g., two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more) selected from 5.5±0.2, 11.0±0.2, 19.0±0.2, 19.2±0.2, 19.8±0.2, 21.8±0.2, 22.0±0.2, 24.3±0.2, 24.7±0.2, and 27.2±0.2, measured at a temperature ranging from 60°C to 90°C. In some embodiments, the free hemihydrate of Compound II, Form A, is characterized by an X-ray powder diffractogram comprising signals at the following 2-theta values: 5.5±0.2, 11.0±0.2, 19.0±0.2, 19.2±0.2, 19.8±0.2, 21.8±0.2, 22.0±0.2, 24.3±0.2, 24.7±0.2, and 27.2±0.2, measured at a temperature ranging from 60°C to 90°C.

[0495] In some embodiments, the free hemihydrate Form A of Compound II is characterized by an X-ray powder diffractogram substantially similar to Figure 30C, measured at temperatures ranging from 60°C to 90°C.

[0496] In some embodiments, the free hemihydrate Form A of Compound II comprises one or more (e.g., two or more, three or more, four or more) signals selected from 21.9±0.2 ppm, 22.6±0.2 ppm, 67.9±0.2 ppm, 74.6±0.2 ppm, and 139.8±0.2 ppm. 13Characterized by C NMR spectrum.

[0497] In some embodiments, the free hemihydrate Form A of Compound II comprises one or more (e.g., two or more, three or more, four or more) signals selected from 21.9±0.2 ppm, 22.6±0.2 ppm, 133.2±0.2 ppm, 139.8±0.2 ppm, and 140.9±0.2 ppm. 13 Characterized by C NMR spectrum.

[0498] In some embodiments, the free hemihydrate Form A of Compound II comprises one or more (e.g., two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more) signals selected from 21.9±0.2 ppm, 22.6±0.2 ppm, 49.7±0.2 ppm, 65±0.2 ppm, 67.9±0.2 ppm, 74.6±0.2 ppm, 133.2±0.2 ppm, 139.8±0.2 ppm, 140.9±0.2 ppm, and 142.7±0.2 ppm. 13 Characterized by C NMR spectrum.

[0499] In some embodiments, the free hemihydrate Form A of Compound II comprises one or more (e.g., two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more) signals selected from 21.9±0.2 ppm, 22.6±0.2 ppm, 38.4±0.2 ppm, 124.2±0.2 ppm, 124.7±0.2 ppm, 133.2±0.2 ppm, 139.8±0.2 ppm, 140.9±0.2 ppm, 142.7±0.2 ppm, and 147.6±0.2 ppm. 13 Characterized by C NMR spectrum.

[0500] In some embodiments, the free hemihydrate Form A of Compound II comprises signals at 21.9±0.2 ppm, 22.6±0.2 ppm, 67.9±0.2 ppm, 74.6±0.2 ppm, and 139.8±0.2 ppm. 13 Characterized by C NMR spectrum.

[0501] In some embodiments, the free hemihydrate Form A of Compound II comprises signals at 21.9±0.2 ppm, 22.6±0.2 ppm, 133.2±0.2 ppm, 139.8±0.2 ppm, and 140.9±0.2 ppm. 13 Characterized by C NMR spectrum.

[0502] In some embodiments, the free hemihydrate Form A of Compound II comprises signals at 21.9±0.2 ppm, 22.6±0.2 ppm, 49.7±0.2 ppm, 65±0.2 ppm, 67.9±0.2 ppm, 74.6±0.2 ppm, 133.2±0.2 ppm, 139.8±0.2 ppm, 140.9±0.2 ppm, and 142.7±0.2 ppm. 13 Characterized by C NMR spectrum.

[0503] In some embodiments, the free hemihydrate Form A of Compound II comprises signals at 21.9±0.2 ppm, 22.6±0.2 ppm, 38.4±0.2 ppm, 124.2±0.2 ppm, 124.7±0.2 ppm, 133.2±0.2 ppm, 139.8±0.2 ppm, 140.9±0.2 ppm, 142.7±0.2 ppm, and 147.6±0.2 ppm. 13 Characterized by C NMR spectrum.

[0504] In some embodiments, the free hemihydrate Form A of Compound II is prepared in a manner substantially similar to that shown in FIG. 13 Characterized by C NMR spectrum.

[0505] In some embodiments, the free hemihydrate of Compound II, Form A, is characterized by a TGA thermogram exhibiting a weight loss of about 2.4% from ambient temperature to 150°C.

[0506] In some embodiments, the free hemihydrate of Compound II, Form A, is characterized by a TGA thermogram substantially similar to that shown in FIG.

[0507] In some embodiments, the free hemihydrate of Compound II, Form A, is characterized by a DSC curve having endothermic peaks at about 77°C, about 107°C, and about 125°C.

[0508] In some embodiments, the free hemihydrate of Compound II, Form A, is characterized by a DSC curve substantially similar to that in FIG.

[0509] In some embodiments, the free hemihydrate Form A of Compound II is characterized by a monoclinic crystal system, a P21 space group, and the following unit cell dimensions, measured at 100 K on a Bruker diffractometer with Cu Kα radiation (λ=1.54178 Å): [Table 101]

[0510] Some embodiments of the present disclosure provide a method of making the free form hemihydrate Form A of Compound II, the method comprising: adding amorphous free-form Compound II to MEK to form a solution; adding water and n-heptane to the solution; stirring the solution at ambient temperature; filtering the solution to obtain a solid material; and and drying the solid material.

[0511] In some embodiments, stirring the solution at ambient temperature comprises stirring the solution at ambient temperature for about 18 hours, hi some embodiments, drying the solid material comprises drying the solid material in a vacuum oven at about 60°C overnight.

[0512] Free Form C of Compound II Some embodiments of the present disclosure provide the free form of Compound II (Compound II free Form C). In some embodiments, Compound II free Form C is substantially pure.

[0513] In some embodiments, the free form of Compound II, Form C, is characterized by an X-ray powder diffractogram comprising a signal at 11.1±0.2 2-theta. In some embodiments, the free form of Compound II, Form C, is characterized by an X-ray powder diffractogram comprising a signal at 13.0±0.2 2-theta. In some embodiments, the free form of Compound II, Form C, is characterized by an X-ray powder diffractogram comprising a signal at 19.8±0.2 2-theta. In some embodiments, the free form of Compound II, Form C, is characterized by an X-ray powder diffractogram comprising a signal at 21.6±0.2 2-theta.

[0514] In some embodiments, the free form of Compound II, Form C, is characterized by an X-ray powder diffractogram comprising signals at two or more 2-theta values ​​selected from 11.1±0.2, 13.0±0.2, 19.8±0.2, and 21.6±0.2. In some embodiments, the free form of Compound II, Form C, is characterized by an X-ray powder diffractogram comprising signals at three or more 2-theta values ​​selected from 11.1±0.2, 13.0±0.2, 19.8±0.2, and 21.6±0.2. In some embodiments, the free form of Compound II, Form C, is characterized by an X-ray powder diffractogram comprising signals at 11.1±0.2 2-theta, 13.0±0.2 2-theta, 19.8±0.2 2-theta, and 21.6±0.2 2-theta.

[0515] In some embodiments, the free form Form C of Compound II is characterized by an X-ray powder diffractogram comprising: (a) signals at one or more 2-theta values ​​selected from 11.1±0.2, 13.0±0.2, 19.8±0.2, and 21.6±0.2; and (b) signals at one or more 2-theta values ​​selected from 15.7±0.2, 17.7±0.2, 18.5±0.2, and 23.6±0.2. In some embodiments, the free form Form C of Compound II is characterized by an X-ray powder diffractogram comprising: (a) signals at one or more 2-theta values ​​selected from 11.1±0.2, 13.0±0.2, 19.8±0.2, and 21.6±0.2; and (b) signals at two or more 2-theta values ​​selected from 15.7±0.2, 17.7±0.2, 18.5±0.2, and 23.6±0.2. In some embodiments, the free form Form C of Compound II is characterized by an X-ray powder diffractogram comprising: (a) signals at one or more 2-theta values ​​selected from 11.1±0.2, 13.0±0.2, 19.8±0.2, and 21.6±0.2; and (b) signals at three or more 2-theta values ​​selected from 15.7±0.2, 17.7±0.2, 18.5±0.2, and 23.6±0.2. In some embodiments, the free form Form C of Compound II is characterized by an X-ray powder diffractogram comprising: (a) signals at one or more 2-theta values ​​selected from 11.1±0.2, 13.0±0.2, 19.8±0.2, and 21.6±0.2; and (b) signals at 15.7±0.2 2-theta, 17.7±0.2 2-theta, 18.5±0.2 2-theta, and 23.6±0.2 2-theta.

[0516] In some embodiments, the free form Form C of Compound II is characterized by an X-ray powder diffractogram comprising: (a) signals at two or more 2-theta values ​​selected from 11.1±0.2, 13.0±0.2, 19.8±0.2, and 21.6±0.2; and (b) signals at 15.7±0.2 2-theta, 17.7±0.2 2-theta, 18.5±0.2 2-theta, and 23.6±0.2 2-theta. In some embodiments, the free form Form C of Compound II is characterized by an X-ray powder diffractogram comprising: (a) signals at three or more 2-theta values ​​selected from 11.1±0.2, 13.0±0.2, 19.8±0.2, and 21.6±0.2; and (b) signals at 15.7±0.2 2-theta, 17.7±0.2 2-theta, 18.5±0.2 2-theta, and 23.6±0.2 2-theta. In some embodiments, the free form Form C of Compound II is characterized by an X-ray powder diffractogram comprising signals at 11.1±0.2 2-theta, 13.0±0.2 2-theta, 19.8±0.2 2-theta, 21.6±0.2 2-theta, 15.7±0.2 2-theta, 17.7±0.2 2-theta, 18.5±0.2 2-theta, and 23.6±0.2 2-theta.

[0517] In some embodiments, the free form Form C of Compound II exhibits (a) signals at two or more of the following 2-theta values: 11.1±0.2, 13.0±0.2, 19.8±0.2, and 21.6±0.2; and (b) signals at two or more of the following 2-theta values: 11.1±0.2, 15.5±0.2, and 15.7±0.2, 16.5±0.2, 17.1±0.2, 17.7±0.2, 17.9±0.2. and an X-ray powder diffractogram comprising signals at one or more (e.g., two or more, three or more, four or more, five or more) 2-theta values ​​selected from: 0.2, 18.5±0.2, 22.0±0.2, 23.3±0.2, 23.6±0.2, 24.0±0.2, 26.3±0.2, 26.7±0.2, 26.8±0.2, 30.6±0.2. In some embodiments, the free form Form C of Compound II exhibits (a) signals at three or more of the following 2-theta values: 11.1±0.2, 13.0±0.2, 19.8±0.2, and 21.6±0.2; and (b) signals at three or more of the following 2-theta values: 11.1±0.2, 15.5±0.2, and 15.7±0.2, 16.5±0.2, 17.1±0.2, 17.7±0.2, 17.9±0.2. and an X-ray powder diffractogram comprising signals at one or more (e.g., two or more, three or more, four or more, five or more) 2-theta values ​​selected from: 0.2, 18.5±0.2, 22.0±0.2, 23.3±0.2, 23.6±0.2, 24.0±0.2, 26.3±0.2, 26.7±0.2, 26.8±0.2, 30.6±0.2. In some embodiments, the free form Form C of Compound II is characterized by an X-ray powder diffractogram comprising: (a) signals at each of theta values ​​11.1±0.2, 13.0±0.2, 19.8±0.2, and 21.6±0.2, and (b) signals at one or more (e.g., two or more, three or more, four or more, five or more) two-theta values ​​selected from 15.5±0.2, 15.7±0.2, 16.5±0.2, 17.1±0.2, 17.7±0.2, 17.9±0.2, 18.5±0.2, 22.0±0.2, 23.3±0.2, 23.6±0.2, 24.0±0.2, 26.3±0.2, 26.7±0.2, 26.8±0.2, 30.6±0.2.

[0518] In some embodiments, the free form Form C of Compound II is characterized by an X-ray powder diffractogram substantially similar to that in FIG.

[0519] In some embodiments, the free form of Compound II, Form C, is characterized by a TGA thermogram that exhibits negligible weight loss from ambient temperature to 200°C.

[0520] In some embodiments, the free form Form C of Compound II is characterized by a TGA thermogram substantially similar to FIG.

[0521] In some embodiments, the free form of Compound II, Form C, is characterized by a DSC curve having an endothermic peak at about 218°C.

[0522] In some embodiments, the free form Form C of Compound II is characterized by a DSC curve substantially similar to that in FIG.

[0523] In some embodiments, the free form Form C of Compound II comprises one or more (e.g., two or more, three or more, four or more) signals selected from 149.3±0.2 ppm, 144.3±0.2 ppm, 135.0±0.2 ppm, 127.2±0.2 ppm, and 124.5±0.2 ppm. 13 In some embodiments, the free form of Compound II, Form C, is characterized by a C NMR spectrum, comprising signals at 149.3±0.2 ppm, 144.3±0.2 ppm, 135.0±0.2 ppm, 127.2±0.2 ppm, and 124.5±0.2 ppm. 13 Characterized by C NMR spectrum.

[0524] In some embodiments, the free form Form C of Compound II comprises one or more signals selected from 66.9±0.2 ppm, 49.4±0.2 ppm, 37.7±0.2 ppm, 36.8±0.2 ppm, and 25.9±0.2 ppm. 13In some embodiments, the free form of Compound II, Form C, is characterized by a C NMR spectrum comprising two or more signals selected from 66.9±0.2 ppm, 49.4±0.2 ppm, 37.7±0.2 ppm, 36.8±0.2 ppm, and 25.9±0.2 ppm. 13 In some embodiments, the free form of Compound II, Form C, is characterized by a C NMR spectrum comprising three or more signals selected from 66.9±0.2 ppm, 49.4±0.2 ppm, 37.7±0.2 ppm, 36.8±0.2 ppm, and 25.9±0.2 ppm. 13 In some embodiments, the free form of Compound II, Form C, is characterized by a C NMR spectrum. In some embodiments, the free form of Compound II, Form C, comprises four or more signals selected from 74.0±0.2 ppm, 66.9±0.2 ppm, 62.0±0.2 ppm, 49.4±0.2 ppm, 47.8±0.2 ppm, 37.7±0.2 ppm, 36.8±0.2 ppm, and 25.9±0.2 ppm. 13 In some embodiments, the free form of Compound II, Form C, is characterized by a C NMR spectrum comprising five or more signals selected from 74.0±0.2 ppm, 66.9±0.2 ppm, 62.0±0.2 ppm, 49.4±0.2 ppm, 47.8±0.2 ppm, 37.7±0.2 ppm, 36.8±0.2 ppm, and 25.9±0.2 ppm. 13 In some embodiments, the free form of Compound II, Form C, is characterized by a C NMR spectrum comprising six or more signals selected from 74.0±0.2 ppm, 66.9±0.2 ppm, 62.0±0.2 ppm, 49.4±0.2 ppm, 47.8±0.2 ppm, 37.7±0.2 ppm, 36.8±0.2 ppm, and 25.9±0.2 ppm. 13 In some embodiments, the free form of Compound II, Form C, is characterized by a C NMR spectrum comprising seven or more signals selected from 74.0±0.2 ppm, 66.9±0.2 ppm, 62.0±0.2 ppm, 49.4±0.2 ppm, 47.8±0.2 ppm, 37.7±0.2 ppm, 36.8±0.2 ppm, and 25.9±0.2 ppm. 13In some embodiments, the free form of Compound II, Form C, is characterized by a C NMR spectrum, comprising signals at 74.0±0.2 ppm, 66.9±0.2 ppm, 62.0±0.2 ppm, 49.4±0.2 ppm, 47.8±0.2 ppm, 37.7±0.2 ppm, 36.8±0.2 ppm, and 25.9±0.2 ppm. 13 Characterized by C NMR spectrum.

[0525] In some embodiments, the free form Form C of Compound II comprises (a) one or more (e.g., two or more, three or more, four or more) signals selected from 149.3±0.2 ppm, 144.3±0.2 ppm, 135.0±0.2 ppm, 127.2±0.2 ppm, and 124.5±0.2 ppm, and (b) one or more (e.g., two or more, three or more, four or more) signals selected from 74.0±0.2 ppm, 66.9±0.2 ppm, 62.0±0.2 ppm, 49.4±0.2 ppm, 47.8±0.2 ppm, 37.7±0.2 ppm, 36.8±0.2 ppm, and 25.9±0.2 ppm. 13 Characterized by C NMR spectrum.

[0526] In some embodiments, the free form of Compound II, Form C, is substantially similar to that shown in FIG. 13 Characterized by C NMR spectrum.

[0527] In some embodiments, the free form Form C of Compound II is characterized by a single crystalline unit cell characterized by an orthorhombic crystal system, a P212121 space group, and the following unit cell dimensions, measured at 298 K on a Bruker diffractometer with Cu Kα radiation (λ=1.54178 Å): [Table 102]

[0528] In some embodiments, the free form Form C of Compound II is characterized by an orthorhombic crystalline system, a P212121 space group, and the following unit cell dimensions, measured at 100 K on a Bruker diffractometer with Cu Kα radiation (λ=1.54178 Å): [Table 103]

[0529] Some embodiments of the present disclosure provide a method of making the free form Form C of Compound II, the method comprising: Adding 0.5 ml of MEK to Compound II free hemihydrate Form A; Stirring overnight at 20°C, and and isolating the solid material.

[0530] Free Form A of Compound II Some embodiments of the present disclosure provide the free form of Compound II (Compound II free form Form A). In some embodiments, Compound II free form Form A is substantially pure.

[0531] In some embodiments, the free form of Compound II, Form A, is characterized by an X-ray powder diffractogram comprising a signal at 9.1±0.2 2-theta. In some embodiments, the free form of Compound II, Form A, is characterized by an X-ray powder diffractogram comprising a signal at 11.7±0.2 2-theta. In some embodiments, the free form of Compound II, Form A, is characterized by an X-ray powder diffractogram comprising a signal at 13.9±0.2 2-theta. In some embodiments, the free form of Compound II, Form A, is characterized by an X-ray powder diffractogram comprising a signal at 14.1±0.2 2-theta. In some embodiments, the free form of Compound II, Form A, is characterized by an X-ray powder diffractogram comprising a signal at 20.5±0.2 2-theta.

[0532] In some embodiments, the free form of Compound II, Form A, is characterized by an X-ray powder diffractogram comprising signals at two or more 2-theta values ​​selected from 9.1±0.2, 11.7±0.2, 13.9±0.2, 14.1±0.2, and 20.5±0.2. In some embodiments, the free form of Compound II, Form A, is characterized by an X-ray powder diffractogram comprising signals at three or more 2-theta values ​​selected from 9.1±0.2, 11.7±0.2, 13.9±0.2, 14.1±0.2, and 20.5±0.2. In some embodiments, the free form of Compound II, Form A, is characterized by an X-ray powder diffractogram comprising signals at four or more 2-theta values ​​selected from 9.1±0.2, 11.7±0.2, 13.9±0.2, 14.1±0.2, and 20.5±0.2. In some embodiments, the free form Form A of Compound II is characterized by an X-ray powder diffractogram comprising signals at 9.1±0.2 2-theta, 11.7±0.2 2-theta, 13.9±0.2 2-theta, 14.1±0.2 2-theta, and 20.5±0.2 2-theta.

[0533] In some embodiments, the free form Form A of Compound II is characterized by an X-ray powder diffractogram comprising: (a) signals at one or more 2-theta values ​​selected from 9.1±0.2, 11.7±0.2, 13.9±0.2, 14.1±0.2, and 20.5±0.2; and (b) signals at one or more (e.g., two, three, four, or five) 2-theta values ​​selected from 16.6±0.2, 17.3±0.2, 18.3±0.2, 22.1±0.2, and 24.4±0.2. In some embodiments, the free form Form A of Compound II is characterized by an X-ray powder diffractogram comprising: (a) signals at two or more 2-theta values ​​selected from 9.1±0.2, 11.7±0.2, 13.9±0.2, 14.1±0.2, and 20.5±0.2; and (b) signals at one or more (e.g., two, three, four, or five) 2-theta values ​​selected from 16.6±0.2, 17.3±0.2, 18.3±0.2, 22.1±0.2, and 24.4±0.2. In some embodiments, the free form Form A of Compound II is characterized by an X-ray powder diffractogram comprising: (a) signals at three or more 2-theta values ​​selected from 9.1±0.2, 11.7±0.2, 13.9±0.2, 14.1±0.2, and 20.5±0.2; and (b) signals at one or more (e.g., two, three, four, or five) 2-theta values ​​selected from 16.6±0.2, 17.3±0.2, 18.3±0.2, 22.1±0.2, and 24.4±0.2. In some embodiments, the free form Form A of Compound II is characterized by an X-ray powder diffractogram comprising: (a) signals at 9.1±0.2 2-theta, 11.7±0.2 2-theta, 13.9±0.2 2-theta, 14.1±0.2 2-theta, and 20.5±0.2 2-theta, and (b) signals at one or more (e.g., two, three, four, or five) 2-theta values ​​selected from 16.6±0.2, 17.3±0.2, 18.3±0.2, 22.1±0.2, and 24.4±0.2.

[0534] In some embodiments, the free form Form A of Compound II is characterized by an X-ray powder diffractogram substantially similar to that in FIG.

[0535] In some embodiments, the free form of Compound II, Form A, is characterized by a TGA thermogram that exhibits negligible weight loss from ambient temperature to 200°C.

[0536] In some embodiments, the free form of Compound II, Form A, is characterized by a TGA thermogram substantially similar to that in FIG.

[0537] In some embodiments, the free form of Compound II, Form A, is characterized by a DSC curve having an endothermic peak at about 130°C.

[0538] In some embodiments, the free form of Compound II, Form A, is characterized by a DSC curve substantially similar to that in FIG.

[0539] In some embodiments, the free form of Compound II, Form A, comprises one or more (e.g., two or more, three or more, four) signals selected from 143.6±0.2 ppm, 134.1±0.2 ppm, 128.8±0.2 ppm, and 123.4±0.2 ppm. 13 In some embodiments, the free form of Compound II, Form A, is characterized by a C NMR spectrum, comprising signals at 143.6±0.2 ppm, 134.1±0.2 ppm, 128.8±0.2 ppm, and 123.4±0.2 ppm. 13 Characterized by C NMR spectrum.

[0540] In some embodiments, the free form of Compound II, Form A, comprises one or more (e.g., two or more, three or more, four or more, five) signals selected from 68.3±0.2 ppm, 48.9±0.2 ppm, 39.1±0.2 ppm, and 21.6±0.2 ppm. 13In some embodiments, the free form of Compound II, Form A, is characterized by a C NMR spectrum, comprising signals at 68.3±0.2 ppm, 48.9±0.2 ppm, 39.6±0.2 ppm, 39.1±0.2 ppm, and 21.6±0.2 ppm. 13 Characterized by C NMR spectrum.

[0541] In some embodiments, the free form of Compound II, Form A, is substantially similar to that shown in FIG. 13 Characterized by C NMR spectrum.

[0542] In some embodiments, the free form Form A of compound II is characterized by a single crystalline unit cell characterized by the monoclinic system, the I2 space group, and the following unit cell dimensions, measured at 298 K on a Bruker diffractometer with Cu Kα radiation (λ=1.54178 Å): [Table 104]

[0543] Some embodiments of the present disclosure provide a method of making Compound II Form A, the method comprising: Desolvating the free MeOH solvate of Compound II in a vacuum oven at 40°C; and and isolating the solid material.

[0544] Free Form B of Compound II Some embodiments of the present disclosure provide the free form of Compound II (Compound II free form Form B). In some embodiments, Compound II free form Form B is substantially pure.

[0545] In some embodiments, the free form of Compound II, Form B, comprises one or more (e.g., two or more, three or more, four or more, five) signals selected from 22.4±0.2 ppm, 22.6±0.2 ppm, 47.7±0.2 ppm, 64.1±0.2 ppm, and 74.6±0.2 ppm. 13Characterized by C NMR spectrum.

[0546] In some embodiments, the free form of Compound II, Form B, comprises one or more (e.g., two or more, three or more, four or more, five) signals selected from 22.4±0.2 ppm, 22.6±0.2 ppm, 38.5±0.2 ppm, 132.9±0.2 ppm, and 139.4±0.2 ppm. 13 Characterized by C NMR spectrum.

[0547] In some embodiments, the free form Form B of Compound II comprises one or more (e.g., two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more) signals selected from 22.4±0.2 ppm, 22.6±0.2 ppm, 44.3±0.2 ppm, 47.3±0.2 ppm, 47.7±0.2 ppm, 61.8±0.2 ppm, 64.1±0.2 ppm, 67.6±0.2 ppm, 74.6±0.2 ppm, and 139.4±0.2 ppm. 13 Characterized by C NMR spectrum.

[0548] In some embodiments, the free form Form B of Compound II comprises one or more (e.g., two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten) signals selected from 22.4±0.2 ppm, 22.6±0.2 ppm, 35.3±0.2 ppm, 38.5±0.2 ppm, 39.8±0.2 ppm, 124.4±0.2 ppm, 132.9±0.2 ppm, 139.4±0.2 ppm, 141.5±0.2 ppm, and 142.2±0.2 ppm. 13 Characterized by C NMR spectrum.

[0549] In some embodiments, the free form of Compound II, Form B, comprises signals at 22.4±0.2 ppm, 22.6±0.2 ppm, 47.7±0.2 ppm, 64.1±0.2 ppm, and 74.6±0.2 ppm. 13 Characterized by C NMR spectrum.

[0550] In some embodiments, the free form of Compound II, Form B, comprises signals at 22.4±0.2 ppm, 22.6±0.2 ppm, 38.5±0.2 ppm, 132.9±0.2 ppm, and 139.4±0.2 ppm. 13 Characterized by C NMR spectrum.

[0551] In some embodiments, the free form Form B of Compound II comprises signals at 22.4±0.2 ppm, 22.6±0.2 ppm, 44.3±0.2 ppm, 47.3±0.2 ppm, 47.7±0.2 ppm, 61.8±0.2 ppm, 64.1±0.2 ppm, 67.6±0.2 ppm, 74.6±0.2 ppm, and 139.4±0.2 ppm. 13 Characterized by C NMR spectrum.

[0552] In some embodiments, the free form Form B of Compound II comprises signals at 22.4±0.2 ppm, 22.6±0.2 ppm, 35.3±0.2 ppm, 38.5±0.2 ppm, 39.8±0.2 ppm, 124.4±0.2 ppm, 132.9±0.2 ppm, 139.4±0.2 ppm, 141.5±0.2 ppm, and 142.2±0.2 ppm. 13 Characterized by C NMR spectrum.

[0553] In some embodiments, the free form Form B of Compound II comprises one or more (e.g., two or more, three or more, four or more, five) signals selected from 22.4±0.2 ppm, 22.6±0.2 ppm, 44.3±0.2 ppm, 47.3±0.2 ppm, 64.1±0.2 ppm, 67.6±0.2 ppm, 74.6±0.2 ppm, 132.9±0.2 ppm, 139.4±0.2 ppm, 13 Characterized by C NMR spectrum.

[0554] In some embodiments, the free form of Compound III, Form B, is substantially similar to that shown in FIG. 13 Characterized by C NMR spectrum.

[0555] In some embodiments, the free form Form B of Compound II is characterized by a single crystalline unit cell characterized by a monoclinic crystal system, a P21 space group, and the following unit cell dimensions, as measured at 100 K on a Bruker diffractometer with Cu Kα radiation (λ=1.54178 Å): [Table 105]

[0556] Some embodiments of the present disclosure provide a method of making Compound II Form B, the method comprising: Loading the free hemihydrate Form A of Compound II into an ssNMR rotor; Dry overnight in an oven at 80°C, and and sealing the rotor cap and removing the solids from the oven for analysis.

[0557] Free quarter hydrate of Compound II Some embodiments of the present disclosure provide the free form of Compound II (the free form quarter hydrate of Compound II). In some embodiments, the free form quarter hydrate of Compound II is substantially pure.

[0558] In some embodiments, the free quart-hydrate of Compound II comprises a signal at 64.5±0.2 ppm. 13 In some embodiments, the free tetrahydrate of Compound II is characterized by a C NMR spectrum comprising one or more (e.g., two, three, or four) signals selected from 151.8±0.2 ppm, 151.5±0.2 ppm, 121.1±0.2 ppm, and 35.3±0.2 ppm. 13 In some embodiments, the free tetrahydrate of Compound II is characterized by a C NMR spectrum, comprising signals at 151.8±0.2 ppm, 151.5±0.2 ppm, 121.1±0.2 ppm, 64.5±0.2 ppm, and 35.3±0.2 ppm. 13Characterized by C NMR spectrum.

[0559] In some embodiments, the free quart hydrate of Compound II comprises (a) one or more (e.g., two, three, or even four) signals selected from 151.8±0.2 ppm, 151.5±0.2 ppm, ppm, 121.1±0.2 ppm, and 35.3±0.2 ppm, and (b) one or more (e.g., two or more, three or more, four or more, five or more, six or more, seven or more, eight) signals at 74.4±0.2 ppm, 67.6±0.2 ppm, 64.5±0.2 ppm, 61.8±0.2 ppm, 47.5±0.2 ppm, 47.2±0.2 ppm, 44.1±0.2 ppm, and 22.1±0.2 ppm. 13 In some embodiments, the free tetrahydrate of Compound II is characterized by a C NMR spectrum. In some embodiments, the free tetrahydrate of Compound II comprises (a) a signal at 64.5±0.2 ppm, and (b) one or more (e.g., two or more, three or more, four or more, five or more, six or more, seven) signals at 74.4±0.2 ppm, 67.6±0.2 ppm, 61.8±0.2 ppm, 47.5±0.2 ppm, 47.2±0.2 ppm, 44.1±0.2 ppm, and 22.1±0.2 ppm. 13 Characterized by C NMR spectrum.

[0560] In some embodiments, the free quart hydrate of Compound II may be a compound substantially similar to that shown in FIG. 65 or FIG. 66. 13 Characterized by C NMR spectrum.

[0561] In some embodiments, the free quart hydrate of Compound II is characterized by a monoclinic crystal system, a P21 space group, and a single crystalline unit cell characterized by the following unit cell dimensions, measured at 100 K on a Bruker diffractometer with Cu Kα radiation (λ=1.54178 Å): [Table 106]

[0562] Some embodiments of the present disclosure provide a method for making the free form quaternary hydrate of Compound II, the method comprising: Dehydrating the free hemihydrate Form A of Compound II in a TGA at a constant temperature of 80°C for 1 hour; removing the solids and packing them into the rotor as quickly as possible; and and sealing the rotor cap once the solid object is loaded for analysis.

[0563] Free mixed hydrate of compound II In some embodiments, the free mixed hydrate of Compound II is characterized by an X-ray powder diffractogram comprising a signal at 8.6±0.2 2-theta. In some embodiments, the free mixed hydrate of Compound II is characterized by an X-ray powder diffractogram comprising a signal at 24.1±0.2 2-theta. In some embodiments, the free mixed hydrate of Compound II is characterized by an X-ray powder diffractogram comprising a signal at 24.5±0.2 2-theta. In some embodiments, the free mixed hydrate of Compound II is characterized by an X-ray powder diffractogram comprising a signal at 13.7±0.2 2-theta. In some embodiments, the free mixed hydrate of Compound II is characterized by an X-ray powder diffractogram comprising a signal at 3.6±0.2 2-theta. In some embodiments, the free mixed hydrate of Compound II is characterized by an X-ray powder diffractogram comprising a signal at 19.9±0.2 2-theta.

[0564] In some embodiments, the free mixed hydrate of Compound II is characterized by an X-ray powder diffractogram comprising signals at one or more (e.g., two or more, three or more, four or more, five or more, six) 2-theta values ​​selected from 3.6±0.2, 8.6±0.2, 13.7±0.2, 19.9±0.2, 24.1±0.2, and 24.5±0.2. In some embodiments, the free mixed hydrate of Compound II is characterized by an X-ray powder diffractogram comprising signals at 3.6±0.2 2-theta, 8.6±0.2 2-theta, 13.7±0.2 2-theta, 19.9±0.2 2-theta, 24.1±0.2 2-theta, and 24.5±0.2 2-theta.

[0565] In some embodiments, the free mixed hydrate of Compound II is characterized by an X-ray powder diffractogram comprising: (a) signals at one or more (e.g., two or more, three or more, four or more, five or more, six) 2-theta values ​​selected from 3.6±0.2, 8.6±0.2, 13.7±0.2, 19.9±0.2, 24.1±0.2, and 24.5±0.2; and (b) signals at one or more (e.g., two or more, three or more, four) 2-theta values ​​selected from 22.2±0.2, 21.6±0.2, 17.0±0.2, and 14.6±0.2. In some embodiments, the free mixed hydrate of Compound II is characterized by an X-ray powder diffractogram comprising: (a) signals at one or more (e.g., two or more, three or more, four or more, five or more, six) 2-theta values ​​selected from 3.6±0.2, 8.6±0.2, 13.7±0.2, 19.9±0.2, 24.1±0.2, and 24.5±0.2; and (b) signals at 22.2±0.2 2-theta, 21.6±0.2 2-theta, 17.0±0.2 2-theta, and 14.6±0.2 2-theta.

[0566] In some embodiments, the free mixed hydrate of Compound II is characterized by an X-ray powder diffractogram substantially similar to that in FIG.

[0567] Some embodiments of the present disclosure provide a method for making a free mixed hydrate of Compound II, the method comprising: Equilibrating neat Form A of Compound II in a humidified chamber set at 95% RH for 3 days; and and isolating the solid material.

[0568] Free monohydrate of Compound II In some embodiments, the free monohydrate of Compound II comprises a signal at 134.1±0.2 ppm. 13 In some embodiments, the free monohydrate of Compound II is characterized by a C NMR spectrum, comprising a signal at 21.1±0.2 ppm. 13 In some embodiments, the free monohydrate of Compound II is characterized by a C NMR spectrum, comprising a signal at 134.1±0.2 ppm and a signal at 21.1±0.2 ppm. 13 Characterized by C NMR spectrum.

[0569] In some embodiments, the free monohydrate of Compound II comprises (a) a signal at 134.1±0.2 ppm and / or a signal at 21.1±0.2 ppm, and (b) one or more (e.g., two, three, four, or five) signals selected from 74.5±0.2 ppm, 62.4±0.2 ppm, 49.0±0.2 ppm, 39.1±0.2 ppm, and 21.7±0.2 ppm. 13 In some embodiments, the free monohydrate of Compound II is characterized by a C NMR spectrum, comprising: (a) a signal at 134.1±0.2 ppm and / or a signal at 21.1±0.2 ppm; and (b) signals at 74.5±0.2 ppm, 62.4±0.2 ppm, 49.0±0.2 ppm, 39.1±0.2 ppm, and 21.7±0.2 ppm. 13 Characterized by C NMR spectrum.

[0570] In some embodiments, the free monohydrate of Compound II has a structure substantially similar to that shown in FIG. 13Characterized by C NMR spectrum.

[0571] Some embodiments of the present disclosure provide a method of making the free form monohydrate of Compound II, the method comprising: Neat Form A of Compound II was equilibrated in saturated potassium iodide in a humidified 69% RH chamber under static conditions for 1-2 months; and and isolating the solids.

[0572] Free dihydrate of Compound II In some embodiments, the free dihydrate of Compound II comprises a signal at 143.8±0.2 ppm and a signal at 38.2±0.2 ppm. 13 In some embodiments, the free dihydrate of Compound II is characterized by a C NMR spectrum. In some embodiments, the free dihydrate of Compound II comprises (a) one or more (e.g., two, three, four, five, or six) signals selected from 143.8±0.2 ppm, 128.9±0.2 ppm, 126.6±0.2 ppm, 68.6±0.2 ppm, 62.7±0.2 ppm, and 37.8±0.2 ppm, and (b) one or more (e.g., two, three, four, or five) signals selected from 131.8±0.2 ppm, 124.5±0.2 ppm, 124.1±0.2 ppm, 38.2±0.2 ppm, and 22.5±0.2 ppm. 13 Characterized by C NMR spectrum.

[0573] In some embodiments, the free dihydrate of Compound II has a structure substantially similar to that shown in FIG. 69 or FIG. 70. 13 Characterized by C NMR spectrum.

[0574] Some embodiments of the present disclosure provide a method for making a 94% RH hydrate of Compound II, the method comprising: Neat Form A of Compound II was equilibrated in saturated potassium nitrate for 12 days under static conditions in a humidified 94% RH chamber; and and isolating the solids.

[0575] Free EtOH solvate Form B of Compound II Some embodiments of the present disclosure provide an EtOH solvate form of Compound II (Compound II free EtOH solvate Form B). In some embodiments, Compound II free EtOH solvate Form B is substantially pure.

[0576] In some embodiments, the free EtOH solvate of Compound II, Form B, is characterized by an X-ray powder diffractogram comprising a signal at 11.6±0.2 2-theta. In some embodiments, the free EtOH solvate of Compound II, Form B, is characterized by an X-ray powder diffractogram comprising a signal at 17.1±0.2 2-theta. In some embodiments, the free EtOH solvate of Compound II, Form B, is characterized by an X-ray powder diffractogram comprising a signal at 23.8±0.2 2-theta.

[0577] In some embodiments, the free EtOH solvate of Compound II, Form B, is characterized by an X-ray powder diffractogram comprising a signal at 11.6±0.2 2-theta and a signal at 17.1±0.2 2-theta. In some embodiments, the free EtOH solvate of Compound II, Form B, is characterized by an X-ray powder diffractogram comprising a signal at 11.6±0.2 2-theta and a signal at 23.8±0.2 2-theta. In some embodiments, the free EtOH solvate of Compound II, Form B, is characterized by an X-ray powder diffractogram comprising a signal at 17.1±0.2 2-theta and a signal at 23.8±0.2 2-theta. In some embodiments, the free EtOH solvate Form B of Compound II is characterized by an X-ray powder diffractogram comprising a signal at 11.6±0.2 2-theta, a signal at 17.1±0.2 2-theta, and a signal at 23.8±0.2 2-theta.

[0578] In some embodiments, Compound II free EtOH solvate Form B is characterized by an X-ray powder diffractogram comprising: (a) signals at one or more 2-theta values ​​selected from 11.6±0.2, 17.1±0.2, and 23.8±0.2, and (b) signals at one or more (e.g., two, three, or four) 2-theta values ​​selected from 7.6±0.2, 16.6±0.2, 23.3±0.2, and 23.7±0.2. In some embodiments, the free EtOH solvate Form B of Compound II is characterized by an X-ray powder diffractogram comprising: (a) signals at two or more 2-theta values ​​selected from 11.6±0.2, 17.1±0.2, and 23.8±0.2, and (b) signals at one or more (e.g., two, three, or four) 2-theta values ​​selected from 7.6±0.2, 16.6±0.2, 23.3±0.2, and 23.7±0.2. In some embodiments, Compound II free EtOH solvate Form B is characterized by an X-ray powder diffractogram comprising: (a) signals at 11.6±0.2 2-theta, 17.1±0.2 2-theta, and 23.8±0.2 2-theta, and (b) signals at one or more (e.g., two, three, or four) 2-theta values ​​selected from 7.6±0.2, 16.6±0.2, 23.3±0.2, and 23.7±0.2.

[0579] In some embodiments, Compound II free EtOH solvate Form B is characterized by an X-ray powder diffractogram comprising signals at 7.6±0.2 2-theta, 11.6±0.2 2-theta, 16.6±0.2 2-theta, 17.1±0.2 2-theta, 23.3±0.2 2-theta, 23.7±0.2 2-theta, and 23.8±0.2 2-theta.

[0580] In some embodiments, the free EtOH solvate Form B of Compound II is characterized by an X-ray powder diffractogram substantially similar to that shown in FIG.

[0581] In some embodiments, the free EtOH solvate of Compound II, Form A, is characterized by a TGA thermogram showing a weight loss of about 9% from ambient temperature to 200°C.

[0582] In some embodiments, the free EtOH solvate Form B of Compound II is characterized by a TGA thermogram substantially similar to that in FIG.

[0583] In some embodiments, the free EtOH solvate of Compound II, Form B, is characterized by a DSC curve having endothermic peaks at about 67°C and 105°C.

[0584] In some embodiments, the free EtOH solvate Form B of Compound II is characterized by a DSC curve substantially similar to that in FIG.

[0585] Some embodiments of the present disclosure provide a method of making the free EtOH solvate Form B of Compound II, comprising: Slow evaporation of Compound II in EtOH at 4°C, and and isolating the solid material.

[0586] Free IPA solvate of Compound II Some embodiments of the present disclosure provide an IPA solvate form of Compound II (Compound II free form IPA solvate). In some embodiments, the Compound II free form IPA solvate is substantially pure.

[0587] In some embodiments, the free IPA solvate of Compound II is characterized by an X-ray powder diffractogram comprising a signal at 8.4±0.2 2-theta. In some embodiments, the free IPA solvate of Compound II is characterized by an X-ray powder diffractogram comprising a signal at 11.7±0.2 2-theta. In some embodiments, the free IPA solvate of Compound II is characterized by an X-ray powder diffractogram comprising a signal at 21.6±0.2 2-theta. In some embodiments, the free IPA solvate of Compound II is characterized by an X-ray powder diffractogram comprising a signal at 23.3±0.2 2-theta.

[0588] In some embodiments, the free IPA solvate of Compound II is characterized by an X-ray powder diffractogram comprising signals at two or more 2-theta values ​​selected from 8.4±0.2, 11.7±0.2, 21.6±0.2, and 23.3±0.2. In some embodiments, the free IPA solvate of Compound II is characterized by an X-ray powder diffractogram comprising signals at three or more 2-theta values ​​selected from 8.4±0.2, 11.7±0.2, 21.6±0.2, and 23.3±0.2. In some embodiments, the free IPA solvate of Compound II is characterized by an X-ray powder diffractogram comprising signals at 8.4±0.2 2-theta, 11.7±0.2 2-theta, 21.6±0.2 2-theta, and 23.3±0.2 2-theta.

[0589] In some embodiments, the free IPA solvate of Compound II is characterized by an X-ray powder diffractogram comprising: (a) signals at two or more 2-theta values ​​selected from 8.4±0.2, 11.7±0.2, 21.6±0.2, and 23.3±0.2; and (b) signals at one or more (e.g., two, three, or four) 2-theta values ​​selected from 17.0±0.2, 19.9±0.2, 21.9±0.2, and 22.1±0.2. In some embodiments, the free IPA solvate of Compound II is characterized by an X-ray powder diffractogram comprising: (a) signals at three or more 2-theta values ​​selected from 8.4±0.2, 11.7±0.2, 21.6±0.2, and 23.3±0.2; and (b) signals at one or more (e.g., two, three, or four) 2-theta values ​​selected from 17.0±0.2, 19.9±0.2, 21.9±0.2, and 22.1±0.2. In some embodiments, the free IPA solvate of Compound II is characterized by an X-ray powder diffractogram comprising: (a) signals at 8.4±0.2 2-theta, 11.7±0.2 2-theta, 21.6±0.2 2-theta, and 23.3±0.2 2-theta, and (b) signals at one or more (e.g., two, three, or four) 2-theta values ​​selected from 17.0±0.2, 19.9±0.2, 21.9±0.2, and 22.1±0.2.

[0590] In some embodiments, the free IPA solvate of Compound II is characterized by an X-ray powder diffractogram comprising signals at 8.4±0.2 2-theta, 11.7±0.2 2-theta, 17.0±0.2 2-theta, 19.9±0.2 2-theta, 21.6±0.2 2-theta, 21.9±0.2 2-theta, 22.1±0.2 2-theta, and 23.3±0.2 2-theta.

[0591] In some embodiments, the free IPA solvate of Compound II is characterized by an X-ray powder diffractogram substantially similar to that in FIG.

[0592] In some embodiments, the free IPA solvate of Compound II comprises one or more signals selected from 147.5±0.2 ppm, 74.5±0.2 ppm, and 49.5±0.2 ppm. 13 In some embodiments, the free IPA solvate of Compound II is characterized by a C NMR spectrum comprising two or more signals selected from 147.5±0.2 ppm, 74.5±0.2 ppm, and 49.5±0.2 ppm. 13 In some embodiments, the free IPA solvate of Compound II is characterized by a C NMR spectrum, comprising signals at 147.5±0.2 ppm, 74.5±0.2 ppm, and 49.5±0.2 ppm. 13 Characterized by C NMR spectrum.

[0593] In some embodiments, the free IPA solvate of Compound II comprises one or more (e.g., two, three, four, five, six, seven, eight, nine or more) signals selected from 147.5±0.2 ppm, 143.0±0.2 ppm, 74.9±0.2 ppm, 74.5±0.2 ppm, 61.7±0.2 ppm, 49.5±0.2 ppm, 48.9±0.2 ppm, 22.4±0.2 ppm, 22.0±0.2 ppm, 21.7±0.2 ppm. 13 In some embodiments, the free IPA solvate of Compound II is characterized by C NMR spectrum. In some embodiments, the free IPA solvate of Compound II comprises signals at 147.5±0.2 ppm, 143.0±0.2 ppm, 74.9±0.2 ppm, 74.5±0.2 ppm, 61.7±0.2 ppm, 49.5±0.2 ppm, 48.9±0.2 ppm, 22.4±0.2 ppm, 22.0±0.2 ppm, and 21.7±0.2 ppm. 13 Characterized by C NMR spectrum.

[0594] In some embodiments, the free IPA solvate of Compound II has a structure substantially similar to that shown in FIG. 13 Characterized by C NMR spectrum.

[0595] Some embodiments of the present disclosure provide a method of making the free form IPA solvate of Compound II, the method comprising: making a slurry of Compound II free hemihydrate Form A in 50 / 50 IPA / heptane (vol / vol); Shaking overnight in a shaking block at 20°C and 1000 rpm, and and isolating the solid material.

[0596] Free MEK solvate of Compound II Some embodiments of the present disclosure provide a MEK solvate form of Compound II (Compound II free MEK solvate). In some embodiments, the free MEK solvate of Compound II is substantially pure.

[0597] In some embodiments, the free MEK solvate of Compound II comprises one or more (e.g., two, three, four, five, six, or more) signals selected from 8.2±0.2 ppm, 23.2±0.2 ppm, 30.0±0.2 ppm, 35.0±0.2 ppm, 35.7±0.2 ppm, 39.3±0.2 ppm, and 63.3±0.2 ppm. 13 In some embodiments, the free MEK solvate of Compound II is characterized by a C NMR spectrum, comprising signals at 8.2±0.2 ppm, 23.2±0.2 ppm, 30.0±0.2 ppm, 35.0±0.2 ppm, 35.7±0.2 ppm, 39.3±0.2 ppm, and 63.3±0.2 ppm. 13 Characterized by C NMR spectrum.

[0598] In some embodiments, the free MEK solvate of Compound II has a structure substantially similar to that shown in FIG. 13 Characterized by C NMR spectrum.

[0599] Some embodiments of the present disclosure provide a method of making a free MEK solvate of Compound II, the method comprising: charging the free hemihydrate of Compound II Form A into a jacketed reactor and adding methyl ethyl ketone; stirring the reactor at 45°C and 300 rpm; Seeding with the free hemihydrate of Compound II, Form A, and maintaining at 45°C for 30 minutes; Cool to 20°C for 1 hour, and and isolating the solid material.

[0600] Free MeOH solvate of Compound II Some embodiments of the present disclosure provide a MeOH solvate form of Compound II (Compound II free MeOH solvate). In some embodiments, the free MeOH solvate of Compound II is substantially pure.

[0601] In some embodiments, the free MeOH solvate of compound II is characterized by an X-ray powder diffractogram comprising a signal at 13.4±0.2 2-theta. In some embodiments, the free MeOH solvate of compound II is characterized by an X-ray powder diffractogram comprising a signal at 16.6±0.2 2-theta. In some embodiments, the free MeOH solvate of compound II is characterized by an X-ray powder diffractogram comprising a signal at 24.3±0.2 2-theta. In some embodiments, the free MeOH solvate of compound II is characterized by an X-ray powder diffractogram comprising a signal at 24.4±0.2 2-theta. In some embodiments, the free MeOH solvate of compound II is characterized by an X-ray powder diffractogram comprising a signal at 26.3±0.2 2-theta.

[0602] In some embodiments, the free MeOH solvate of compound II is characterized by an X-ray powder diffractogram comprising signals at two or more 2-theta values ​​selected from 13.4±0.2, 16.6±0.2, 24.3±0.2, 24.4±0.2, and 26.3±0.2. In some embodiments, the free MeOH solvate of compound II is characterized by an X-ray powder diffractogram comprising signals at three or more 2-theta values ​​selected from 13.4±0.2, 16.6±0.2, 24.3±0.2, 24.4±0.2, and 26.3±0.2. In some embodiments, the free MeOH solvate of compound II is characterized by an X-ray powder diffractogram comprising signals at four or more 2-theta values ​​selected from 13.4±0.2, 16.6±0.2, 24.3±0.2, 24.4±0.2, and 26.3±0.2. In some embodiments, the free MeOH solvate of compound II is characterized by an X-ray powder diffractogram comprising signals at 13.4±0.2 2-theta, 16.6±0.2 2-theta, 24.3±0.2 2-theta, 24.4±0.2 2-theta, and 26.3±0.2 2-theta.

[0603] In some embodiments, the free MeOH solvate of Compound II is characterized by an X-ray powder diffractogram comprising: (a) signals at two or more 2-theta values ​​selected from 13.4±0.2, 16.6±0.2, 24.3±0.2, 24.4±0.2, and 26.3±0.2; and (b) signals at one or more (e.g., two, three, or four) 2-theta values ​​selected from 12.0±0.2, 21.2±0.2, 24.1±0.2, and 24.2±0.2. In some embodiments, the free MeOH solvate of Compound II is characterized by an X-ray powder diffractogram comprising: (a) signals at three or more 2-theta values ​​selected from 13.4±0.2, 16.6±0.2, 24.3±0.2, 24.4±0.2, and 26.3±0.2; and (b) signals at one or more (e.g., two, three, or four) 2-theta values ​​selected from 12.0±0.2, 21.2±0.2, 24.1±0.2, and 24.2±0.2. In some embodiments, the free MeOH solvate of Compound II is characterized by an X-ray powder diffractogram comprising: (a) signals at 13.4±0.2 2-theta, 16.6±0.2 2-theta, 24.3±0.2 2-theta, 24.4±0.2 2-theta, and 26.3±0.2 2-theta; and (b) signals at one or more (e.g., two, three, or four) 2-theta values ​​selected from 12.0±0.2, 21.2±0.2, 24.1±0.2, and 24.2±0.2.

[0604] In some embodiments, the free MeOH solvate of compound II is characterized by an X-ray powder diffractogram comprising signals at 12.0±0.2 2-theta, 13.4±0.2 2-theta, 16.6±0.2 2-theta, 21.2±0.2 2-theta, 24.1±0.2 2-theta, and 24.2±0.2, 24.3±0.2 2-theta, and 24.4±0.2 2-theta.

[0605] In some embodiments, the free MeOH solvate of Compound II is characterized by an X-ray powder diffractogram substantially similar to that in FIG.

[0606] In some embodiments, the free MeOH solvate of compound II is characterized by a TGA thermogram that exhibits a weight loss of about 0.87% from ambient temperature to 150°C.

[0607] In some embodiments, the free MeOH solvate of compound II is characterized by a TGA thermogram substantially similar to that in FIG.

[0608] In some embodiments, the free MeOH solvate of compound II is characterized by a DSC curve with endothermic peaks at about 79°C, 112°C, and 266°C.

[0609] In some embodiments, the free MeOH solvate of compound II is characterized by a DSC curve substantially similar to that in FIG.

[0610] In some embodiments, the free MeOH solvate of Compound II comprises one or more (e.g., two, three, four, five, or six) signals selected from 133.6±0.2 ppm, 74.8±0.2 ppm, 67.7±0.2 ppm, 62.6±0.2 ppm, 49.8±0.2 ppm, and 21.2±0.2 ppm. 13 In some embodiments, the free MeOH solvate of compound II is characterized by a C NMR spectrum, comprising signals at 133.6±0.2 ppm, 74.8±0.2 ppm, 67.7±0.2 ppm, 62.6±0.2 ppm, 49.8±0.2 ppm, and 21.2±0.2 ppm. 13 Characterized by C NMR spectrum.

[0611] In some embodiments, the free MeOH solvate of compound II has a structure substantially similar to that shown in FIG. 13 Characterized by C NMR spectrum.

[0612] In some embodiments, the free MeOH solvate of compound II is characterized by a single crystalline unit cell characterized by the monoclinic system, C2 space group, and the following unit cell dimensions, measured at 100 K on a Bruker diffractometer with Cu Kα radiation (λ=1.54178 Å): [Table 107]

[0613] Some embodiments of the present disclosure provide a method of making the free MeOH solvate of compound II, the method comprising: mixing amorphous free-form Compound II with MeOH followed by rotary evaporation; and and isolating the solid material.

[0614] Amorphous free compound II Some embodiments of the present disclosure provide an amorphous form of Compound II (amorphous free Compound II). In some embodiments, the amorphous free Compound II is substantially pure. In some embodiments, the amorphous free Compound II is characterized by an X-ray powder diffractogram substantially similar to Figure 81.

[0615] In some embodiments, amorphous free Compound II is characterized by a TGA thermogram that exhibits a weight loss of about 0.7% from ambient temperature to 150°C.

[0616] In some embodiments, amorphous free Compound II is characterized by a TGA thermogram substantially similar to FIG.

[0617] In some embodiments, amorphous free Compound II is characterized by a DSC curve exhibiting a glass transition at about 78-88°C.

[0618] In some embodiments, amorphous free Compound II is characterized by a DSC curve substantially similar to that in FIG.

[0619] In some embodiments, amorphous free Compound II comprises one or more (e.g., two, three, or four) signals selected from 74.3±0.2 ppm, 63.0±0.2 ppm, 48.2±0.2 ppm, and 37.2±0.2 ppm. 13 In some embodiments, amorphous free Compound II is characterized by a C NMR spectrum, comprising signals at 74.3±0.2 ppm, 63.0±0.2 ppm, 48.2±0.2 ppm, and 37.2±0.2 ppm. 13 Characterized by C NMR spectrum.

[0620] In some embodiments, the free MeOH solvate of compound II has a structure substantially similar to that shown in FIG. 13 Characterized by C NMR spectrum.

[0621] Compound II phosphate acetone solvate Form A Some embodiments of the present disclosure provide a phosphate acetone solvate form of Compound II (Compound II phosphate acetone solvate Form A). In some embodiments, Compound II phosphate acetone solvate Form A is substantially pure.

[0622] In some embodiments, Compound II phosphate acetone solvate Form A is characterized by an X-ray powder diffractogram comprising a signal at 8.7±0.2 2-theta. In some embodiments, Compound II phosphate acetone solvate Form A is characterized by an X-ray powder diffractogram comprising a signal at 9.4±0.2 2-theta. In some embodiments, Compound II phosphate acetone solvate Form A is characterized by an X-ray powder diffractogram comprising a signal at 15.0±0.2 2-theta. In some embodiments, Compound II phosphate acetone solvate Form A is characterized by an X-ray powder diffractogram comprising a signal at 18.4±0.2 2-theta.

[0623] In some embodiments, Compound II phosphate acetone solvate Form A is characterized by an X-ray powder diffractogram comprising signals at two or more 2-theta values ​​selected from 8.7±0.2, 9.4±0.2, 15.0±0.2, and 18.4±0.2. In some embodiments, Compound II phosphate acetone solvate Form A is characterized by an X-ray powder diffractogram comprising signals at three or more 2-theta values ​​selected from 8.7±0.2, 9.4±0.2, 15.0±0.2, and 18.4±0.2. In some embodiments, Compound II phosphate acetone solvate Form A is characterized by an X-ray powder diffractogram comprising signals at 8.7±0.2 2-theta, 9.4±0.2 2-theta, 15.0±0.2 2-theta, and 18.4±0.2 2-theta.

[0624] In some embodiments, Compound II phosphate acetone solvate Form A is characterized by an X-ray powder diffractogram comprising: (a) signals at 8.7±0.2 2-theta, 9.4±0.2 2-theta, 15.0±0.2 2-theta, and 18.4±0.2 2-theta, and (b) signals at one or more 2-theta values ​​selected from 10.4±0.2, 18.8±0.2, 20.8±0.2, and 22.6±0.2. In some embodiments, Compound II phosphate acetone solvate Form A is characterized by an X-ray powder diffractogram comprising: (a) signals at 8.7±0.2 2-theta, 9.4±0.2 2-theta, 15.0±0.2 2-theta, and 18.4±0.2 2-theta, and (b) signals at two or more 2-theta values ​​selected from 10.4±0.2, 18.8±0.2, 20.8±0.2, and 22.6±0.2. In some embodiments, Compound II phosphate acetone solvate Form A is characterized by an X-ray powder diffractogram comprising: (a) signals at 8.7±0.2 2-theta, 9.4±0.2 2-theta, 15.0±0.2 2-theta, and 18.4±0.2 2-theta, and (b) signals at three or more (e.g., two, three, or four) 2-theta values ​​selected from 10.4±0.2, 18.8±0.2, 20.8±0.2, and 22.6±0.2.

[0625] In some embodiments, Compound II phosphate acetone solvate Form A is characterized by an X-ray powder diffractogram comprising signals at 8.7±0.2 2-theta, 9.4±0.2 2-theta, 10.4±0.2 2-theta, 15.0±0.2 2-theta, 18.4±0.2 2-theta, 18.8±0.2 2-theta, 20.8±0.2 2-theta, and 22.6±0.2 2-theta.

[0626] In some embodiments, Compound II phosphate acetone solvate Form A is characterized by an X-ray powder diffractogram substantially similar to that in FIG.

[0627] In some embodiments, the phosphate salt acetone solvate of Compound II is characterized by a TGA thermogram that exhibits a weight loss of about 0.9% from ambient temperature to 200°C.

[0628] In some embodiments, the phosphate salt acetone solvate of Compound II is characterized by a TGA thermogram substantially similar to that in FIG.

[0629] In some embodiments, the phosphate salt acetone solvate of Compound II is characterized by a DSC curve having an endothermic peak at about 242°C.

[0630] In some embodiments, the phosphate acetone solvate of Compound II is characterized by a DSC curve substantially similar to that in FIG.

[0631] In some embodiments, the phosphate acetone solvate of Compound II comprises one or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) signals selected from 142.3±0.2 ppm, 126.3±0.2 ppm, 73.0±0.2 ppm, 72.3±0.2 ppm, 64.8±0.2 ppm, 62.0±0.2 ppm, 49.4±0.2 ppm, 47.9±0.2 ppm, and 38.2±0.2 ppm. 13 In some embodiments, the phosphate acetone solvate of Compound II is characterized by a C NMR spectrum, comprising signals at 142.3±0.2 ppm, 126.3±0.2 ppm, 73.0±0.2 ppm, 72.3±0.2 ppm, 64.8±0.2 ppm, 62.0±0.2 ppm, 49.4±0.2 ppm, 47.9±0.2 ppm, and 38.2±0.2 ppm. 13 Characterized by C NMR spectrum.

[0632] In some embodiments, the phosphate acetone solvate of Compound II has a structure substantially similar to that shown in FIG. 13 Characterized by C NMR spectrum.

[0633] Some embodiments of the present disclosure provide a method of making a phosphate acetone solvate of Compound II, the method comprising: (a) mixing Compound II phosphate hemihydrate Form A with a mixture of acetone and water; Stirring at ambient temperature for three days; and isolating the solids, or (b) adding Compound II phosphate hemihydrate Form A to a mixture of acetone and water at room temperature to form a suspension; Stir overnight and filter to obtain a clear saturated solution. adding equal amounts of Compound II phosphate hemihydrate Form A and Compound II phosphate Form C to the saturated solution; Stirring at ambient temperature for 4 days, and and isolating the solid material.

[0634] Compound II Phosphate Form A Some embodiments of the present disclosure provide a phosphate salt form of Compound II (Compound II phosphate Form A). In some embodiments, Compound II phosphate acetone solvate Form A is substantially pure.

[0635] In some embodiments, Compound II phosphate salt Form A is characterized by an X-ray powder diffractogram comprising a signal at 7.0±0.2 2-theta. In some embodiments, Compound II phosphate salt Form A is characterized by an X-ray powder diffractogram comprising a signal at 9.9±0.2 2-theta. In some embodiments, Compound II phosphate salt Form A is characterized by an X-ray powder diffractogram comprising a signal at 14.1±0.2 2-theta. In some embodiments, Compound II phosphate salt Form A is characterized by an X-ray powder diffractogram comprising a signal at 17.5±0.2 2-theta. In some embodiments, Compound II phosphate salt Form A is characterized by an X-ray powder diffractogram comprising a signal at 19.9±0.2 2-theta.

[0636] In some embodiments, Compound II phosphate salt Form A is characterized by an X-ray powder diffractogram comprising signals at two or more 2-theta values ​​selected from 7.0±0.2, 9.9±0.2, 14.1±0.2, 17.5±0.2, and 19.9±0.2. In some embodiments, Compound II phosphate salt Form A is characterized by an X-ray powder diffractogram comprising signals at three or more 2-theta values ​​selected from 7.0±0.2, 9.9±0.2, 14.1±0.2, 17.5±0.2, and 19.9±0.2. In some embodiments, Compound II phosphate salt Form A is characterized by an X-ray powder diffractogram comprising signals at four or more 2-theta values ​​selected from 7.0±0.2±0.2, 9.9±0.2, 14.1±0.2, 17.5±0.2, and 19.9±0.2. In some embodiments, Compound II phosphate salt Form A is characterized by an X-ray powder diffractogram comprising signals at 7.0±0.2 2-theta, 9.9±0.2 2-theta, 14.1±0.2 2-theta, 17.5±0.2 2-theta, and 19.9±0.2 2-theta.

[0637] In some embodiments, Compound II phosphate salt Form A is characterized by an X-ray powder diffractogram comprising: (a) signals at one or more (e.g., two, three, four, or five) 2-theta values ​​selected from 7.0±0.2, 9.9±0.2, 14.1±0.2, 17.5±0.2, and 19.9±0.2, and (b) signals at one or more 2-theta values ​​selected from 8.9±0.2, 16.9±0.2, 18.5±0.2, and 21.6±0.2. In some embodiments, Compound II phosphate salt Form A is characterized by an X-ray powder diffractogram comprising: (a) signals at one or more (e.g., two, three, four, or five) 2-theta values ​​selected from 7.0±0.2, 9.9±0.2, 14.1±0.2, 17.5±0.2, and 19.9±0.2, and (b) signals at two or more 2-theta values ​​selected from 8.9±0.2, 16.9±0.2, 18.5±0.2, and 21.6±0.2. In some embodiments, Compound II phosphate salt Form A is characterized by an X-ray powder diffractogram comprising: (a) signals at 7.0±0.2, 9.9±0.2, 14.1±0.2, 17.5±0.2, and 19.9±0.2, and (b) signals at three or more (e.g., two, three, or four) 2-theta values ​​selected from 8.9±0.2, 16.9±0.2, 18.5±0.2, and 21.6±0.2.

[0638] In some embodiments, Compound II phosphate salt Form A is characterized by an X-ray powder diffractogram comprising signals at 7.0±0.2 2-theta, 8.9±0.2, 9.9±0.2 2-theta, 14.1±0.2 2-theta, 16.9±0.2, 17.5±0.2 2-theta, 18.5±0.2, 19.9±0.2 2-theta, and 21.6±0.2 2-theta.

[0639] In some embodiments, the phosphate salt of Compound II, Form A, is characterized by an X-ray powder diffractogram substantially similar to that in FIG.

[0640] In some embodiments, the phosphate salt of Compound II, Form A, is characterized by a TGA thermogram that exhibits negligible weight loss from ambient temperature to 200°C.

[0641] In some embodiments, the phosphate salt of Compound II, Form A, is characterized by a TGA thermogram substantially similar to that in FIG.

[0642] In some embodiments, the phosphate salt of Compound II, Form A, is characterized by a DSC curve having endothermic peaks at about 228°C and about 237°C.

[0643] In some embodiments, the phosphate salt of Compound II, Form A, is characterized by a DSC curve substantially similar to that in FIG.

[0644] In some embodiments, the phosphate salt of Compound II, Form A, comprises one or more signals selected from 72.1±0.2 ppm, 62.0±0.2 ppm, 49.4±0.2 ppm, and 17.5±0.2 ppm. 13 In some embodiments, Compound II phosphate Form A is characterized by a C NMR spectrum comprising two or more signals selected from 72.1±0.2 ppm, 62.0±0.2 ppm, 49.4±0.2 ppm, and 17.5±0.2 ppm. 13 In some embodiments, Compound II phosphate Form A is characterized by a C NMR spectrum comprising three or more signals selected from 72.1±0.2 ppm, 62.0±0.2 ppm, 49.4±0.2 ppm, and 17.5±0.2 ppm. 13 In some embodiments, Compound II phosphate Form A is characterized by a C NMR spectrum, comprising signals at 72.1±0.2 ppm, 62.0±0.2 ppm, 49.4±0.2 ppm, and 17.5±0.2 ppm. 13 Characterized by C NMR spectrum.

[0645] In some embodiments, the phosphate salt of Compound II, Form A, comprises one or more signals selected from (a) 72.1±0.2 ppm, 62.0±0.2 ppm, 49.4±0.2 ppm, and 17.5±0.2 ppm, and (b) one or more signals selected from 72.9±0.2 ppm, 64.4±0.2 ppm, and 64.1±0.2 ppm. 13 In some embodiments, Compound II phosphate Form A is characterized by a C NMR spectrum comprising one or more signals selected from (a) 72.1±0.2 ppm, 62.0±0.2 ppm, 49.4±0.2 ppm, and 17.5±0.2 ppm, and (b) signals at 72.9±0.2 ppm, 64.4±0.2 ppm, and 64.1±0.2 ppm. 13 In some embodiments, Compound II phosphate Form A is characterized by a C NMR spectrum, comprising signals at 72.9±0.2 ppm, 72.1±0.2 ppm, 64.4±0.2 ppm, 64.1±0.2 ppm, 62.0±0.2 ppm, 49.4±0.2 ppm, and 17.5±0.2 ppm. 13 Characterized by C NMR spectrum.

[0646] In some embodiments, the phosphate salt of Compound II, Form A, is prepared in a manner substantially similar to that shown in FIG. 13 Characterized by C NMR spectrum.

[0647] In some embodiments, the phosphate salt of Compound II, Form A, comprises one or more signals selected from 3.3±0.2 ppm, 2.2±0.2 ppm, and −0.4±0.2 ppm. 31 In some embodiments, Compound II phosphate Form A is characterized by a P CPMAS spectrum, including signals at 3.3±0.2 ppm, 2.2±0.2 ppm, and −0.4±0.2 ppm. 31 In some embodiments, the phosphate salt of Compound II, Form A, is characterized by a P CPMAS spectrum substantially similar to that shown in Figure 91. 31 P characterized by CPMAS spectrum.

[0648] Some embodiments of the present disclosure provide a method of making the phosphate salt of Compound II, Form A, comprising: adding MEK followed by phosphoric acid to amorphous free-form Compound II; Stirring at ambient temperature for 48 hours. filtering and washing the solid with 4:1 n-heptane / MEK (v / v); Drying in a vacuum oven at 60°C for 18 hours; and and isolating the solid material.

[0649] Compound II phosphate Form C Some embodiments of the present disclosure provide a phosphate salt form of Compound II (Compound II phosphate Form C). In some embodiments, Compound II phosphate acetone solvate Form C is substantially pure.

[0650] In some embodiments, Compound II phosphate salt Form C is characterized by an X-ray powder diffractogram comprising a signal at 13.5±0.2 2-theta. In some embodiments, Compound II phosphate salt Form C is characterized by an X-ray powder diffractogram comprising a signal at 13.7±0.2 2-theta. In some embodiments, Compound II phosphate salt Form C is characterized by an X-ray powder diffractogram comprising a signal at 15.0±0.2 2-theta.

[0651] In some embodiments, Compound II phosphate salt Form C is characterized by an X-ray powder diffractogram comprising signals at two or more 2-theta values ​​selected from 13.5±0.2, 13.7±0.2, and 15.0±0.2. In some embodiments, Compound II phosphate salt Form C is characterized by an X-ray powder diffractogram comprising signals at 13.5±0.2±0.2 2-theta, 13.7±0.2 2-theta, and 15.0±0.2 2-theta.

[0652] In some embodiments, Compound II phosphate salt Form C is characterized by an X-ray powder diffractogram comprising: (a) signals at 13.5±0.2±0.2 2-theta, 13.7±0.2 2-theta, and 15.0±0.2 2-theta, and (b) signals at one or more 2-theta values ​​selected from 9.1±0.2, 9.4±0.2, 10.4±0.2, 11.0±0.2, and 18.6±0.2. In some embodiments, Compound II phosphate salt Form C is characterized by an X-ray powder diffractogram comprising: (a) signals at 13.5±0.2 2-theta, 13.7±0.2 2-theta, and 15.0±0.2 2-theta, and (b) signals at two or more 2-theta values ​​selected from 9.1±0.2, 9.4±0.2, 10.4±0.2, 11.0±0.2, and 18.6±0.2. In some embodiments, Compound II phosphate salt Form C is characterized by an X-ray powder diffractogram comprising: (a) signals at 13.5±0.2 2-theta, 13.7±0.2 2-theta, and 15.0±0.2 2-theta, and (b) signals at three or more 2-theta values ​​selected from 9.1±0.2, 9.4±0.2, 10.4±0.2, 11.0±0.2, and 18.6±0.2. In some embodiments, Compound II phosphate salt Form C is characterized by an X-ray powder diffractogram comprising signals at 9.1±0.2 2-theta, 9.4±0.2 2-theta, 10.4±0.2 2-theta, 11.0±0.2 2-theta, 13.5±0.2±0.2 2-theta, 13.7±0.2 2-theta, 15.0±0.2 2-theta, and 18.6±0.2 2-theta.

[0653] In some embodiments, the phosphate salt of Compound II, Form C, is characterized by an X-ray powder diffractogram substantially similar to that in FIG.

[0654] In some embodiments, the phosphate salt of Compound II, Form C, is characterized by a TGA thermogram that exhibits a weight loss of about 1.6% from ambient temperature to 150°C.

[0655] In some embodiments, the phosphate salt of Compound II, Form C, is characterized by a TGA thermogram substantially similar to that in FIG.

[0656] In some embodiments, the phosphate salt of Compound II, Form C, is characterized by a DSC curve having an endothermic peak at about 244°C.

[0657] In some embodiments, the phosphate salt of Compound II, Form C, is characterized by a DSC curve substantially similar to that in FIG.

[0658] In some embodiments, the phosphate salt of Compound II, Form C, comprises one or more signals selected from 139.0±0.2 ppm, 127.8±0.2 ppm, 66.5±0.2 ppm, 62.5±0.2 ppm, and 16.8±0.2 ppm. 13 In some embodiments, Compound II phosphate Form C is characterized by a C NMR spectrum comprising two or more signals selected from 139.0±0.2 ppm, 127.8±0.2 ppm, 66.5±0.2 ppm, 62.5±0.2 ppm, and 16.8±0.2 ppm. 13 In some embodiments, Compound II phosphate Form C is characterized by a C NMR spectrum comprising three or more signals selected from 139.0±0.2 ppm, 127.8±0.2 ppm, 66.5±0.2 ppm, 62.5±0.2 ppm, and 16.8±0.2 ppm. 13 In some embodiments, Compound II phosphate salt Form C is characterized by C NMR spectroscopy, including signals at 139.0±0.2 ppm, 127.8±0.2 ppm, 66.5±0.2 ppm, 62.5±0.2 ppm, and 16.8±0.2 ppm. 13 Characterized by C NMR spectrum.

[0659] In some embodiments, the phosphate salt of Compound II, Form C, comprises (a) one or more signals selected from 139.0±0.2 ppm, 127.8±0.2 ppm, 66.5±0.2 ppm, 62.5±0.2 ppm, and 16.8±0.2 ppm, and (b) one or more (e.g., two, three, four, or five) signals selected from 143.0±0.2 ppm, 140.3±0.2 ppm, 139.6±0.2 ppm, 72.7±0.2 ppm, 64.1±0.2 ppm, and 47.7±0.2 ppm. 13 In some embodiments, Compound II phosphate salt Form C is characterized by a C NMR spectrum. In some embodiments, Compound II phosphate salt Form C includes (a) two or more signals selected from 139.0±0.2 ppm, 127.8±0.2 ppm, 66.5±0.2 ppm, 62.5±0.2 ppm, and 16.8±0.2 ppm, and (b) one or more (e.g., two, three, four, or five) signals selected from 143.0±0.2 ppm, 140.3±0.2 ppm, 139.6±0.2 ppm, 72.7±0.2 ppm, 64.1±0.2 ppm, and 47.7±0.2 ppm. 13 In some embodiments, Compound II phosphate Form C is characterized by a C NMR spectrum. In some embodiments, Compound II phosphate Form C includes (a) signals at 139.0±0.2 ppm, 127.8±0.2 ppm, 66.5±0.2 ppm, 62.5±0.2 ppm, and 16.8±0.2 ppm, and (b) one or more (e.g., two, three, four, or five) signals selected from 143.0±0.2 ppm, 140.3±0.2 ppm, 139.6±0.2 ppm, 72.7±0.2 ppm, 64.1±0.2 ppm, and 47.7±0.2 ppm. 13 Characterized by C NMR spectrum.

[0660] In some embodiments, the phosphate salt of Compound II, Form C, is prepared in a manner substantially similar to that shown in FIG. 13 Characterized by C NMR spectrum.

[0661] Some embodiments of the present disclosure provide a method of making the phosphate salt of Compound II, Form C, comprising: preparing a slurry of Compound II phosphate hemihydrate Form A in 1-butanol at 80°C; and and centrifuging the slurry to isolate the solids.

[0662] Another aspect of the present disclosure provides pharmaceutical compositions comprising a solid form of Compound I selected from Compound I phosphate salt hydrate Form A, Compound I free monohydrate, Compound I maleate salt Form A (salt or co-crystal), Compound I maleate salt Form B (salt or co-crystal), Compound I fumarate salt Form A (salt or co-crystal), Compound I free form Form B, and Compound I free form Form C. In some embodiments, a pharmaceutical composition comprising Compound I in a solid form selected from Compound I phosphate salt hydrate Form A, Compound I free monohydrate, Compound I maleate salt Form A (salt or co-crystal), Compound I maleate salt Form B (salt or co-crystal), Compound I fumarate salt Form A (salt or co-crystal), Compound I free form Form B, and Compound I free form Form C is administered to a patient in need thereof.

[0663] Another aspect of the present disclosure provides a pharmaceutical composition comprising a solid form of Compound II selected from Compound II phosphate hemihydrate Form A, Compound II free hemihydrate Form A, Compound II free form C, Compound II free form A, Compound II free form B, Compound II free quartohydrate, Compound II free mixed hydrate, Compound II free monohydrate, Compound II free dihydrate, Compound II free EtOH solvate Form B, amorphous free Compound II, Compound II phosphate Form A, and Compound II phosphate Form C. In some embodiments, a pharmaceutical composition comprising a solid form of Compound II selected from Compound II phosphate hemihydrate Form A, Compound II free hemihydrate Form A, Compound II free form C, Compound II free form A, Compound II free form B, Compound II free quartohydrate, Compound II free mixed hydrate, Compound II free monohydrate, Compound II free dihydrate, Compound II free EtOH solvate Form B, amorphous free Compound II, Compound II phosphate Form A, and Compound II phosphate Form C is administered to a patient in need thereof.

[0664] The pharmaceutical composition may further comprise at least one pharmaceutically acceptable carrier. In some embodiments, the at least one pharmaceutically acceptable carrier is selected from a pharmaceutically acceptable vehicle and a pharmaceutically acceptable adjuvant. In some embodiments, the at least one pharmaceutically acceptable carrier is selected from a pharmaceutically acceptable filler, disintegrant, surfactant, binder, and lubricant.

[0665] It will also be understood that the pharmaceutical compositions of the present disclosure may be employed in combination therapy, i.e., the pharmaceutical compositions described herein may further comprise at least one additional active therapeutic agent. Alternatively, the pharmaceutical compositions may comprise a solid form of Compound I selected from Compound I phosphate salt hydrate Form A, Compound I free monohydrate, Compound I maleate salt Form A (salt or co-crystal), Compound I maleate salt Form B (salt or co-crystal), Compound I fumarate salt Form A (salt or co-crystal), Compound I Form B, and Compound I free form C; or Compound II phosphate salt hemihydrate Form A, Compound II free hemihydrate Form A, Compound II free form C, Compound II free form A, Compound II A pharmaceutical composition comprising a solid form of Compound II selected from Compound II free form Form B, Compound II free form quartohydrate, Compound II free form mixed hydrate, Compound II free form monohydrate, Compound II free form dihydrate, Compound II free form EtOH solvate Form B, amorphous Compound II, Compound II phosphate Form A, and Compound II phosphate Form C may be administered as a separate composition, simultaneously with, prior to, or subsequent to a composition comprising at least one other active therapeutic agent. In some embodiments, a solid form of Compound I is selected from phosphate salt hydrate Form A of Compound I, free monohydrate of Compound I, maleate salt Form A (salt or co-crystal) of Compound I, maleate salt Form B (salt or co-crystal) of Compound I, fumarate salt Form A (salt or co-crystal) of Compound I, free form Form B of Compound I, and free form Form C of Compound I; or phosphate salt hemihydrate Form A of Compound II, free form hemihydrate Form A of Compound II, free form Form C of Compound II, free form For A pharmaceutical composition comprising a solid form of Compound II selected from mA, Compound II free form Form B, Compound II free form quarter-hydrate, Compound II free form mixed hydrate, Compound II free form monohydrate, Compound II free form dihydrate, Compound II free form EtOH solvate Form B, amorphous Compound II, Compound II phosphate Form A, and Compound II phosphate Form C may be administered as a separate composition, simultaneously with, prior to, or subsequent to a composition comprising at least one other active therapeutic agent.

[0666] As described above, the pharmaceutical compositions disclosed herein may optionally further comprise at least one pharmaceutically acceptable carrier. The at least one pharmaceutically acceptable carrier may be selected from adjuvants and vehicles. As used herein, the at least one pharmaceutically acceptable carrier includes any solvent, diluent, other liquid vehicle, dispersion aid, suspension aid, surfactant, isotonicity agent, thickener, emulsifier, preservative, solid binder, and lubricant suitable for the desired specific dosage form. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York, disclose various carriers used in formulating pharmaceutical compositions and known techniques for their preparation. Except insofar as any conventional carrier is incompatible with the solid forms of the present disclosure, for example, by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component of the pharmaceutical composition, its use is contemplated within the scope of the present disclosure.Non-limiting examples of suitable pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates, glycine, sorbic acid, and potassium sorbate), saturated vegetable fatty acids, partial glyceride mixtures of water, salts, and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars (such as lactose, glucose, and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (such as carboxymethylcellulose), and the like. Examples of suitable carriers include cellulose, ethylcellulose, and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (e.g., cocoa butter and suppository wax), oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (e.g., propylene glycol and polyethylene glycol), esters (e.g., ethyl oleate and ethyl laurate), agar, buffers (e.g., magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer, non-toxic compatible lubricants (e.g., sodium lauryl sulfate and magnesium stearate), colorants, release agents, coating agents, sweeteners, flavors, fragrances, preservatives, and antioxidants. In some embodiments, the pharmaceutically acceptable carrier is citrate buffer.

[0667] In some embodiments, the solid form of Compound I is a crystalline solid consisting of 1 to 99% of Form A phosphate hydrate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 2 to 99% of Form A phosphate hydrate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 5 to 99% of Form A phosphate hydrate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 10 to 99% of Form A phosphate hydrate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 15 to 99% of Form A phosphate hydrate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 20 to 99% of Form A phosphate hydrate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid comprises 25 to 99% of Form A phosphate hydrate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid comprises 30 to 99% of Form A phosphate hydrate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid comprises 35 to 99% of Form A phosphate hydrate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid comprises 45 to 99% of Form A phosphate hydrate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid comprises 50 to 99% of Form A phosphate hydrate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid comprises 55 to 99% of Form A phosphate hydrate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 60 to 99% of Form A phosphate hydrate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 65 to 99% of Form A phosphate hydrate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 70 to 99% of Form A phosphate hydrate of Compound I, based on the total weight of the crystalline solid Compound I.In some embodiments, the crystalline solid consists of 75 to 99% of Form A phosphate hydrate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 80 to 99% of Form A phosphate hydrate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 85 to 99% of Form A phosphate hydrate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 90 to 99% of Form A phosphate hydrate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 95 to 99% of Form A phosphate hydrate of Compound I, based on the total weight of the crystalline solid Compound I.

[0668] In some embodiments, the solid form of Compound I is a crystalline solid consisting of 1 to 99% of the free monohydrate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 2 to 99% of the free monohydrate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 5 to 99% of the free monohydrate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 10 to 99% of the free monohydrate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 15 to 99% of the free monohydrate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 20 to 99% of the free monohydrate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid comprises 25-99% of the free monohydrate of Compound I based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid comprises 30-99% of the free monohydrate of Compound I based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid comprises 35-99% of the free monohydrate of Compound I based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid comprises 45-99% of the free monohydrate of Compound I based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid comprises 50-99% of the free monohydrate of Compound I based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid comprises 55-99% of the free monohydrate of Compound I based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid comprises 60-99% of the free monohydrate of Compound I based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 65-99% of the free monohydrate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 70-99% of the free monohydrate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 75-99% of the free monohydrate of Compound I, based on the total weight of the crystalline solid Compound I.In some embodiments, the crystalline solid consists of 80-99% of the free monohydrate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 85-99% of the free monohydrate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 90-99% of the free monohydrate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 95-99% of the free monohydrate of Compound I, based on the total weight of the crystalline solid Compound I.

[0669] In some embodiments, the solid form of Compound I is a crystalline solid consisting of 1 to 99% of the phosphate salt methanol solvate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 2 to 99% of the phosphate salt methanol solvate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 5 to 99% of the phosphate salt methanol solvate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 10 to 99% of the phosphate salt methanol solvate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 15 to 99% of the phosphate salt methanol solvate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 20 to 99% of the phosphate salt methanol solvate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid comprises 25-99% of the phosphate salt methanol solvate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid comprises 30-99% of the phosphate salt methanol solvate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid comprises 35-99% of the phosphate salt methanol solvate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid comprises 45-99% of the phosphate salt methanol solvate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid comprises 50-99% of the phosphate salt methanol solvate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid comprises 55-99% of the phosphate salt methanol solvate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid comprises 60-99% of the phosphate salt methanol solvate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 65 to 99% of the phosphate salt methanol solvate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 70 to 99% of the phosphate salt methanol solvate of Compound I, based on the total weight of the crystalline solid Compound I.In some embodiments, the crystalline solid consists of 75-99% of the phosphate salt methanol solvate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 80-99% of the phosphate salt methanol solvate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 85-99% of the phosphate salt methanol solvate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 90-99% of the phosphate salt methanol solvate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 95-99% of the phosphate salt methanol solvate of Compound I, based on the total weight of the crystalline solid Compound I.

[0670] In some embodiments, the solid form of Compound I is a crystalline solid consisting of 1 to 99% of the phosphate MEK solvate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 2 to 99% of the phosphate MEK solvate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 5 to 99% of the phosphate MEK solvate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 10 to 99% of the phosphate MEK solvate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 15 to 99% of the phosphate MEK solvate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 20 to 99% of the phosphate MEK solvate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 25-99% of the phosphate MEK solvate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 30-99% of the phosphate MEK solvate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 35-99% of the phosphate MEK solvate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 45-99% of the phosphate MEK solvate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 50-99% of the phosphate MEK solvate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 55-99% of the phosphate MEK solvate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 60-99% of the phosphate salt MEK solvate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 65-99% of the phosphate salt MEK solvate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 70-99% of the phosphate salt MEK solvate of Compound I, based on the total weight of the crystalline solid Compound I.In some embodiments, the crystalline solid consists of 75-99% of the phosphate MEK solvate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 80-99% of the phosphate MEK solvate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 85-99% of the phosphate MEK solvate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 90-99% of the phosphate MEK solvate of Compound I, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 95-99% of the phosphate MEK solvate of Compound I, based on the total weight of the crystalline solid Compound I.

[0671] In some embodiments of the present disclosure, a solid form of Compound I selected from Compound I phosphate salt hydrate Form A, Compound I free monohydrate, Compound I maleate salt Form A (salt or co-crystal), Compound I maleate salt Form B (salt or co-crystal), Compound I fumarate salt Form A (salt or co-crystal), Compound I free form Form B, and Compound I free form Form C is used to treat an APOL1-mediated disease (such as an APOL1-mediated kidney disease). In some embodiments, the APOL1-mediated disease is selected from ESKD, FSGS, HIV-associated nephropathy, NDKD, arteriosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease. In some embodiments, the APOL1-mediated disease treated with a solid form of Compound I selected from Compound I phosphate salt hydrate Form A, Compound I free monohydrate, Compound I maleate salt Form A (salt or co-crystal), Compound I maleate salt Form B (salt or co-crystal), Compound I fumarate salt Form A (salt or co-crystal), Compound I free form Form B, and Compound I free form C is FSGS. In some embodiments, the APOL1-mediated disease treated with a solid form of Compound I selected from Compound I phosphate salt hydrate Form A, Compound I free monohydrate, Compound I maleate salt Form A (salt or co-crystal), Compound I maleate salt Form B (salt or co-crystal), Compound I fumarate salt Form A (salt or co-crystal), Compound I free form Form B, and Compound I free form C is NDKD. In some embodiments, the APOL1-mediated disease treated with a solid form of Compound I selected from Compound I phosphate salt hydrate Form A, Compound I free monohydrate, Compound I maleate salt Form A (salt or co-crystal), Compound I maleate salt Form B (salt or co-crystal), Compound I fumarate salt Form A (salt or co-crystal), Compound I Form B, and Compound I free form Form C is ESKD.In some embodiments, the APOL1-mediated disease treated with a solid form of Compound I selected from Compound I phosphate salt hydrate Form A, Compound I free monohydrate, Compound I maleate salt Form A (salt or co-crystal), Compound I maleate salt Form B (salt or co-crystal), Compound I fumarate salt Form A (salt or co-crystal), Compound I free form Form B, and Compound I free form Form C is cancer. In some embodiments, the APOL1-mediated disease treated with a solid form of Compound I selected from Compound I phosphate salt hydrate Form A, Compound I free monohydrate, Compound I maleate salt Form A (salt or co-crystal), Compound I maleate salt Form B (salt or co-crystal), Compound I fumarate salt Form A (salt or co-crystal), Compound I free form Form B, and Compound I free form Form C is pancreatic cancer. In some embodiments, a patient with an APOL1-mediated disease (e.g., APOL1-mediated renal disease) being treated with a solid form of Compound I selected from Compound I phosphate salt hydrate Form A, Compound I free monohydrate, Compound I maleate salt Form A (salt or co-crystal), Compound I maleate salt Form B (salt or co-crystal), Compound I fumarate salt Form A (salt or co-crystal), Compound I free form Form B, and Compound I free form Form C has two APOL1 risk alleles. In some embodiments, a patient with an APOL1-mediated disease (e.g., APOL1-mediated renal disease) is homozygous for the APOL1 genetic risk allele G1:S342G:I384M. In some embodiments, a patient with an APOL1-mediated disease (e.g., APOL1-mediated renal disease) is homozygous for the APOL1 genetic risk allele G2:N388del:Y389del. In some embodiments, the patient with an APOL1-mediated disease (eg, APOL1-mediated kidney disease) is heterozygous for the APOL1 genetic risk alleles G1:S342G:I384M, and G2:N388del:Y389del.

[0672] In some embodiments, the solid form of Compound II is a crystalline solid consisting of 1% to 99% of Compound II phosphate hemihydrate Form A, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 2% to 99% of Compound II phosphate hemihydrate Form A, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 5% to 99% of Compound II phosphate hemihydrate Form A, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 10% to 99% of Compound II phosphate hemihydrate Form A, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 15% to 99% of Compound II phosphate hemihydrate Form A, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 20% to 99% of Compound II phosphate hemihydrate Form A, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 25% to 99% Compound II phosphate hemihydrate Form A, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 30% to 99% Compound II phosphate hemihydrate Form A, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 35% to 99% Compound II phosphate hemihydrate Form A, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 45% to 99% Compound II phosphate hemihydrate Form A, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 50% to 99% Compound II phosphate hemihydrate Form A, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 55% to 99% Compound II phosphate hemihydrate Form A, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 60% to 99% Compound II phosphate hemihydrate Form A, based on the total weight of the crystalline solid Compound II.In some embodiments, the crystalline solid consists of 65% to 99% Compound II phosphate hemihydrate Form A, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 70% to 99% Compound II phosphate hemihydrate Form A, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 75% to 99% Compound II phosphate hemihydrate Form A, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 80% to 99% Compound II phosphate hemihydrate Form A, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 85% to 99% Compound II phosphate hemihydrate Form A, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 90% to 99% Compound II phosphate hemihydrate Form A, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 95% to 99% Compound II phosphate hemihydrate Form A, based on the total weight of the crystalline solid Compound II.

[0673] In some embodiments, the solid form of Compound II is a crystalline solid consisting of 1% to 99% of the free form hemihydrate Form A of Compound II, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 2% to 99% of the free form hemihydrate Form A of Compound II, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 5% to 99% of the free form hemihydrate Form A of Compound II, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 10% to 99% of the free form hemihydrate Form A of Compound II, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 15% to 99% of the free form hemihydrate Form A of Compound II, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 20% to 99% of the free form hemihydrate Form A of Compound II, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 25% to 99% of the free form hemihydrate Form A of Compound II, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 30% to 99% of the free form hemihydrate Form A of Compound II, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 35% to 99% of the free form hemihydrate Form A of Compound II, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 45% to 99% of the free form hemihydrate Form A of Compound II, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 50% to 99% of the free form hemihydrate Form A of Compound II, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 55% to 99% of the free form hemihydrate Form A of Compound II, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 60% to 99% of the free hemihydrate Form A of Compound II, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 65% to 99% of the free hemihydrate Form A of Compound II, based on the total weight of the crystalline solid Compound II.In some embodiments, the crystalline solid consists of 70% to 99% of the free form hemihydrate Form A of Compound II, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 75% to 99% of the free form hemihydrate Form A of Compound II, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 80% to 99% of the free form hemihydrate Form A of Compound II, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 85% to 99% of the free form hemihydrate Form A of Compound II, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 90% to 99% of the free form hemihydrate Form A of Compound II, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 95% to 99% of the free form hemihydrate Form A of Compound II, based on the total weight of the crystalline solid Compound II.

[0674] In some embodiments, the solid form of Compound II is a crystalline solid consisting of 1% to 99% of the free form Form C of Compound II, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 2% to 99% of the free form Form C of Compound II, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 5% to 99% of the free form Form C of Compound II, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 10% to 99% of the free form Form C of Compound II, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 15% to 99% of the free form Form C of Compound II, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 20% to 99% of the free form Form C of Compound II, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 25% to 99% of the free form Form C of Compound II, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid comprises 30% to 99% of the free form C of Compound II, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid comprises 35% to 99% of the free form C of Compound II, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid comprises 45% to 99% of the free form C of Compound II, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid comprises 50% to 99% of the free form C of Compound II, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid comprises 55% to 99% of the free form C of Compound II, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid comprises 60% to 99% of the free form C of Compound II, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid comprises 65% to 99% of the free form C of Compound II, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 70% to 99% of the free form Form C of Compound II, based on the total weight of the crystalline solid Compound II.In some embodiments, the crystalline solid consists of 75% to 99% of the free form Form C of Compound II, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 80% to 99% of the free form Form C of Compound II, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 85% to 99% of the free form Form C of Compound II, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 90% to 99% of the free form Form C of Compound II, based on the total weight of the crystalline solid Compound II. In some embodiments, the crystalline solid consists of 95% to 99% of the free form Form C of Compound II, based on the total weight of the crystalline solid Compound II.

[0675] In some embodiments of the present disclosure, a solid form of Compound II selected from Compound II phosphate hemihydrate Form A, Compound II free hemihydrate Form A, Compound II free form C, Compound II free form A, Compound II free form B, Compound II free quartohydrate, Compound II free mixed hydrate, Compound II free monohydrate, Compound II free dihydrate, Compound II free EtOH solvate Form B, amorphous free Compound II, Compound II phosphate Form A, and Compound II phosphate Form C is used to treat an APOL1-mediated disease (e.g., an APOL1-mediated kidney disease). In some embodiments, the APOL1-mediated disease is selected from ESKD, FSGS, HIV-associated nephropathy, NDKD, arteriosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease. In some embodiments, the APOL1-mediated disease treated with a solid form of Compound II selected from Compound II phosphate hemihydrate Form A, Compound II free hemihydrate Form A, Compound II free form C, Compound II free form A, Compound II free form B, Compound II free quarterhydrate, Compound II free mixed hydrate, Compound II free monohydrate, Compound II free dihydrate, Compound II free EtOH solvate Form B, amorphous free Compound II, Compound II phosphate Form A, and Compound II phosphate Form C is FSGS. In some embodiments, the APOL1-mediated disease treated with a solid form of Compound II selected from Compound II phosphate hemihydrate Form A, Compound II free hemihydrate Form A, Compound II free form C, Compound II free form A, Compound II free form B, Compound II free quarterhydrate, Compound II free mixed hydrate, Compound II free monohydrate, Compound II free dihydrate, Compound II free EtOH solvate Form B, amorphous free Compound II, Compound II phosphate Form A, and Compound II phosphate Form C is NDKD.In some embodiments, the APOL1-mediated disease treated with a solid form of Compound II selected from Compound II phosphate hemihydrate Form A, Compound II free hemihydrate Form A, Compound II free form C, Compound II free form A, Compound II free form B, Compound II free quartohydrate, Compound II free mixed hydrate, Compound II free monohydrate, Compound II free dihydrate, Compound II free EtOH solvate Form B, Compound II free IPA solvate, Compound II free MEK solvate, Compound II free MeOH solvate, amorphous free Compound II, Compound II phosphate acetone solvate Form A, Compound II phosphate Form A, and Compound II phosphate Form C is ESKD. In some embodiments, the APOL1-mediated disease treated with a solid form of Compound II selected from Compound II phosphate hemihydrate Form A, Compound II free hemihydrate Form A, Compound II free form C, Compound II free form A, Compound II free form B, Compound II free quarterhydrate, Compound II free mixed hydrate, Compound II free monohydrate, Compound II free dihydrate, Compound II free EtOH solvate Form B, amorphous free Compound II, Compound II phosphate Form A, and Compound II phosphate Form C is cancer. In some embodiments, the APOL1-mediated disease treated with a solid form of Compound II selected from Compound II phosphate hemihydrate Form A, Compound II free hemihydrate Form A, Compound II free form C, Compound II free form A, Compound II free form B, Compound II free quarterhydrate, Compound II free mixed hydrate, Compound II free monohydrate, Compound II free dihydrate, Compound II free EtOH solvate Form B, amorphous free Compound II, Compound II phosphate Form A, and Compound II phosphate Form C is pancreatic cancer.In some embodiments, a patient with an APOL1-mediated disease (e.g., an APOL1-mediated renal disease) treated with a solid form of Compound II selected from Compound II phosphate hemihydrate Form A, Compound II free hemihydrate Form A, Compound II free form C, Compound II free form A, Compound II free form B, Compound II free quartohydrate, Compound II free mixed hydrate, Compound II free monohydrate, Compound II free dihydrate, Compound II free EtOH solvate Form B, amorphous free Compound II, Compound II phosphate Form A, and Compound II phosphate Form C has two APOL1 risk alleles. In some embodiments, a patient with an APOL1-mediated disease (e.g., an APOL1-mediated renal disease) is homozygous for the APOL1 genetic risk allele G1:S342G:I384M. In some embodiments, patients with an APOL1-mediated disease (e.g., APOL1-mediated renal disease) are homozygous for the APOL1 genetic risk allele G2:N388del:Y389del. In some embodiments, patients with an APOL1-mediated disease (e.g., APOL1-mediated renal disease) are heterozygous for the APOL1 genetic risk alleles G1:S342G:I384M and G2:N388del:Y389del.

[0676] In some embodiments, the methods of the disclosure comprise administering to a patient in need thereof a solid form of Compound I selected from Compound I phosphate salt hydrate Form A, Compound I free monohydrate, Compound I maleate salt Form A (salt or co-crystal), Compound I maleate salt Form B (salt or co-crystal), Compound I fumarate salt Form A (salt or co-crystal), Compound I Form B, and Compound I free form Form C. In some embodiments, the patient in need thereof carries the APOL1 gene variants G1;S342G:I384M, and G2:N388del:Y389del.

[0677] In some embodiments, the methods of the disclosure comprise administering to a patient in need thereof a solid form of Compound II selected from Compound II phosphate hemihydrate Form A, Compound II free hemihydrate Form A, Compound II free form C, Compound II free form A, Compound II free form B, Compound II free quartohydrate, Compound II free mixed hydrate, Compound II free monohydrate, Compound II free dihydrate, Compound II free EtOH solvate Form B, amorphous free Compound II, Compound II phosphate Form A, and Compound II phosphate Form C. In some embodiments, the patient in need thereof carries the APOL1 gene variants G1;S342G:I384M, and G2:N388del:Y389del.

[0678] Another aspect of the present disclosure provides a method for inhibiting the activity of APOL1, comprising contacting said APOL1 with a solid form of Compound I selected from Compound I phosphate salt hydrate Form A, Compound I free monohydrate, Compound I maleate salt Form A (salt or co-crystal), Compound I maleate salt Form B (salt or co-crystal), Compound I fumarate salt Form A (salt or co-crystal), Compound I Form B, and Compound I free form Form C.

[0679] Another aspect of the present disclosure provides a method for inhibiting the activity of APOL1, comprising contacting said APOL1 with a solid form of Compound II selected from Compound II phosphate hemihydrate Form A, Compound II free hemihydrate Form A, Compound II free form C, Compound II free form A, Compound II free form B, Compound II free quarterhydrate, Compound II free mixed hydrate, Compound II free monohydrate, Compound II free dihydrate, Compound II free EtOH solvate Form B, amorphous free Compound II, Compound II phosphate Form A, and Compound II phosphate Form C.

[0680] Synthesis of Compound I and Compound II The present disclosure features Compound I, Compound II, solid state forms of Compound I, and methods for making solid state forms of Compound II.

[0681] In some embodiments, compound I is made according to Scheme 1.

[0682] [ka]

[0683] In some embodiments, compound I is isolated in the form of compound I.H2O.

[0684] In some embodiments, compound I is isolated in the form of compound I.H3PO4.

[0685] In some embodiments, the compound I.H3PO4 is made by converting the compound I.H2O to the compound I.H3PO4.

[0686] In some embodiments, the conversion of compound I.H2O to compound I.H3PO4 is carried out in the presence of methyl ethyl ketone (MEK), water (H2O), and phosphoric acid (H3PO4).

[0687] In some embodiments, compound I.H3PO4 is triturated from a 1:1 mixture of MEK / MeOH.

[0688] In some embodiments, compound I.H2O is selected from compounds C153 / K13: [ka] to the compound I.H2O.

[0689] In some embodiments, the conversion of compound C153 / K13 to compound I.H2O is carried out in the presence of a hydroxide base and a protic solvent.

[0690] In some embodiments, the conversion of compound C153 / K13 to compound I.H2O is carried out in the presence of a hydroxide base selected from lithium hydroxide, sodium hydroxide, and potassium hydroxide.

[0691] In some embodiments, the conversion of compound C153 / K13 to compound I.H2O is carried out in the presence of a protic solvent selected from methanol, ethanol, and 2-propanol.

[0692] In some embodiments, the conversion of compound C153 / K13 to compound I.H2O is carried out in the presence of a hydroxide base and methanol.

[0693] In some embodiments, the conversion of compound C153 / K13 to compound I.H2O is carried out in the presence of sodium hydroxide and a protic solvent.

[0694] In some embodiments, the conversion of compound C153 / K13 to compound I.H2O is carried out in the presence of sodium hydroxide (NaOH) and methanol (MeOH).

[0695] In some embodiments, compound C153 / K13 is selected from the group consisting of compound S32 / K12: [ka] to compounds C153 / K13.

[0696] In one embodiment, the conversion of compounds C154 / K15 to compounds S33 / K17 is carried out in the presence of cobalt diacetate tetrahydrate (Co(OAc) 2 ·4H 2 O), N-hydroxyphthalimide, and oxygen (O 2 ).

[0697] In some embodiments, the conversion of compound S32 / K12 to compound C153 / K13 is carried out in the presence of pentamethylcyclopentadienyl rhodium chloride dimer (RhClCp*), (R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine ((R,R)-TsDPEN), formic acid (HCOH), and triethylamine (EtN).

[0698] In some embodiments, the conversion of compounds S32 / K12 to compounds C153 / K13 is carried out in the presence of 0.2 mol % of pentamethylcyclopentadienyl rhodium chloride dimer (RhCl2Cp*)2.

[0699] In some embodiments, the conversion of compounds S32 / K12 to compounds C153 / K13 is carried out in the presence of 0.05 mol % of pentamethylcyclopentadienyl rhodium chloride dimer (RhCl2Cp*)2.

[0700] In some embodiments, purification of compound C153 / K13 comprises rhodium remediation using a resin.

[0701] In some embodiments, purification of compound C153 / K13 comprises rhodium remediation using DMT resin.

[0702] In some embodiments, purification of compound C153 / K13 includes rhodium remediation using SiliaMetS® DMT resin.

[0703] In some embodiments, purification of compound C153 / K13 includes rhodium remediation using Florisil®.

[0704] In some embodiments, compound C32 / K12 is selected from the group consisting of compound C62 / K10: [ka] to compounds S32 / K12.

[0705] In some embodiments, the conversion of compounds C62 / K10 to compounds S32 / K12 includes: (i) Compound C62 / K10 to compound K11: [ka] and (i) Conversion of compound K11 to compound S32 / K12.

[0706] In some embodiments, the conversion of compound C62 / K10 to compound K11 is carried out in the presence of 1,3-dibromo-5,5-dimethylhydantoin and a radical initiator.

[0707] In some embodiments, the conversion of compound C62 / K10 to compound K11 is carried out in the presence of 1,3-dibromo-5,5-dimethylhydantoin and 2,2′-azo-bis-isobutyronitrile (AIBN).

[0708] Bromination may be carried out in dichloromethane and other solvents using catalytic ZrCl4 or ZrBr4 instead of AIBN, which allows for a potential temperature reduction to 0°C and removal of AIBN. AIBN is thermally unstable due to its low thermal onset temperature.

[0709] In some embodiments, the conversion of compound C62 / K10 to compound K11 is carried out at 75°C.

[0710] In some embodiments, the conversion of compound C62 / K10 to compound K11 is carried out at 50°C.

[0711] In some embodiments, the conversion of compound K11 to compound S32 / K12 is carried out in the presence of an amine base.

[0712] In some embodiments, the conversion of compound K11 to compound S32 / K12 is carried out in the presence of triethylamine (Et3N).

[0713] In some embodiments, compound C62 / K10 is selected from the group consisting of compound L2 / K9: [ka] to compound C62 / K10.

[0714] In some embodiments, the conversion of compound L2 / K9 to compound C62 / K10 is carried out in the presence of trifluoroacetic anhydride (TFAA) and an amine base.

[0715] In some embodiments, the conversion of compound L2 / K9 to compound C62 / K10 is carried out in the presence of trifluoroacetic anhydride (TFAA) and N,N-diisopropylethylamine (DIPEA).

[0716] In some embodiments, the conversion of compound L2 / K9 to compound C62 / K10 is carried out in the presence of trifluoroacetic anhydride (TFAA) and triethylamine (Et3N).

[0717] In some embodiments, compound L2 / K9 is selected from the group consisting of compounds S26 / K7: [ka] and compounds S3 / J6 / K8: [ka] to produce compound L2 / K9.

[0718] In some embodiments, the reaction of compound S26 / K7 with compound S3 / J6 / K8 is carried out in the presence of an acid.

[0719] In some embodiments, the reaction of compounds S26 / K7 with compounds S3 / J6 / K8 is carried out in the presence of a sulfonic acid.

[0720] In some embodiments, the reaction of compounds S26 / K7 with compounds S3 / J6 / K8 is carried out in the presence of methanesulfonic acid (MsOH).

[0721] In some embodiments, the reaction of compounds S26 / K7 with compounds S3 / J6 / K8 is carried out at 39°C.

[0722] In some embodiments, the reaction of compounds S26 / K7 with compounds S3 / J6 / K8 is carried out at 45°C.

[0723] In some embodiments, compound L2 / K9 is crystallized using MTBE / n-heptane.

[0724] In some embodiments, compound L2 / K9 is crystallized using 9:10 MTBE / n-heptane.

[0725] In some embodiments, Compound I is made using a compound of the present disclosure.

[0726] In some embodiments, Compound I is made using a compound selected from the following: [ka]

[0727] In some embodiments, the compound of the present disclosure is selected from the following: [ka]

[0728] Forming compound I according to Scheme 1 and the embodiments described above has several non-limiting advantages. These advantages are even more apparent when producing compound I on an industrial scale. The parameters for steps 3 and 4 (Scheme 1) have also been improved, resulting in a significant reduction in reaction temperature and an improved safety profile for the process. The parameters for step 5 (Scheme 1) have also been optimized, allowing for a significant reduction in the amount of rhodium catalyst used, providing a method for rhodium remediation via Florosil®. Finally, step 6 (Scheme 1) has been improved by adding an optional retrituration step used to reduce residual solvent in the product.

[0729] In some embodiments, compound II is made according to Scheme 2.

[0730] [ka]

[0731] In some embodiments, compound II is isolated in the form of compound II free form Form C.

[0732] In some embodiments, compound II is compound C63 / K18: [ka] to compound II.

[0733] In some embodiments, the conversion of compound C63 / K18 to compound II is carried out in the presence of a hydroxide base and a protic solvent.

[0734] In some embodiments, the conversion of compound C63 / K18 to compound II is carried out in the presence of a hydroxide base selected from lithium hydroxide, sodium hydroxide, and potassium hydroxide.

[0735] In some embodiments, the conversion of compound C63 / K18 to compound II is carried out in the presence of a protic solvent selected from methanol, ethanol, and 2-propanol.

[0736] In some embodiments, the conversion of compound C63 / K18 to compound II is carried out in the presence of a hydroxide base and methanol.

[0737] In some embodiments, the conversion of compound C63 / K18 to compound II is carried out in the presence of a hydroxide base and 2-propanol.

[0738] In some embodiments, the conversion of compound C63 / K18 to compound II is carried out in the presence of sodium hydroxide and a protic solvent.

[0739] In some embodiments, the conversion of compound C63 / K18 to compound II is carried out in the presence of sodium hydroxide (NaOH) and methanol (MeOH).

[0740] In some embodiments, the free hemihydrate of Compound II, Form A, is produced by crystallizing Compound II in the presence of MEK / water.

[0741] In some embodiments, the conversion of compound C63 / K18 to compound II is carried out in the presence of sodium hydroxide (NaOH) and 2-propanol.

[0742] In some embodiments, the free form Form C of compound II is produced by crystallizing compound II in the presence of MEK.

[0743] In some embodiments, compound C63 / K18 is selected from the group consisting of compound S33 / K17: [ka] to the compound C63 / K18.

[0744] In some embodiments, the conversion of compound S33 / K17 to compound C63 / K18 is carried out in the presence of pentamethylcyclopentadienyl rhodium chloride dimer (RhClCp*), (R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine ((R,R)-TsDPEN), formic acid (HCOH), and triethylamine (EtN).

[0745] In some embodiments, the conversion of compounds S33 / K17 to compounds C63 / K18 is carried out in the presence of 0.5 mol % of pentamethylcyclopentadienyl rhodium chloride dimer (RhCl2Cp*)2.

[0746] In some embodiments, the conversion of compounds S33 / K17 to compounds C63 / K18 is carried out in the presence of 0.05 mol % of pentamethylcyclopentadienyl rhodium chloride dimer (RhCl2Cp*)2.

[0747] In some embodiments, compound S33 / K17 is selected from the group consisting of compounds C154 / K15: [ka] to compound S33 / K17.

[0748] In some embodiments, the conversion of compounds C154 / K15 to compounds S33 / K17 can be achieved by the addition of cobalt diacetate tetrahydrate (Co(OAc)2·4H2O), It is carried out in the presence of N-hydroxyphthalimide and oxygen (O2).

[0749] In some embodiments, the conversion of compounds C154 / K15 to compounds S33 / K17 includes: (i) Compound C154 / K15 to compound K16: [ka] and (i) Conversion of compound K16 to compound S33 / K17.

[0750] In some embodiments, the conversion of compounds C154 / K15 to compound K16 is carried out in the presence of 1,3-dibromo-5,5-dimethylhydantoin and a radical initiator.

[0751] In some embodiments, the conversion of compounds C154 / K15 to compound K16 is carried out in the presence of 1,3-dibromo-5,5-dimethylhydantoin and 2,2'-azo-bis-isobutyronitrile (AIBN).

[0752] In some embodiments, the conversion of compound C154 / K15 to compound K16 is carried out in chlorobenzene at 75°C.

[0753] In some embodiments, the conversion of compounds C154 / K15 to compound K16 is carried out at 50° C. in a chlorobenzene / 1,4-dioxane mixture.

[0754] In some embodiments, the conversion of compound K16 to compound S33 / K17 is carried out in the presence of triethylamine (Et3N) and DMSO at 75°C.

[0755] In some embodiments, the conversion of compound K16 to compound S33 / K17 is carried out in the presence of triethylamine (Et3N) and DMSO at 65°C.

[0756] In some embodiments, compound C154 / K15 is selected from the group consisting of compound L1 / K14: [ka] to compounds C154 / K15.

[0757] In some embodiments, the conversion of compound L1 / K14 to compound C154 / K15 is carried out in the presence of trifluoroacetic anhydride (TFAA) and N,N-diisopropylethylamine (DIPEA).

[0758] In some embodiments, the conversion of compound L1 / K14 to compound C154 / K15 is carried out in the presence of trifluoroacetic anhydride (TFAA) and triethylamine (Et3N).

[0759] In some embodiments, compound L1 / K14 is selected from compounds S26 / K7: [ka] and compound S2: [ka] to produce compound L1 / K14.

[0760] In some embodiments, the reaction of compound S26 / K7 with compound S2 is carried out in the presence of an acid.

[0761] In some embodiments, the reaction of compound S26 / K7 with compound S2 is carried out in the presence of a sulfonic acid.

[0762] In some embodiments, the reaction of compound S26 / K7 with compound S2 is carried out in the presence of methanesulfonic acid (MsOH).

[0763] In some embodiments, compound L1 / K14 is purified by silica gel chromatography.

[0764] In some embodiments, compound L1 / K14 is purified by crystallization from MTBE.

[0765] In some embodiments, compound L1 / K14 is purified by crystallization from MTBE / n-heptane.

[0766] In some embodiments, compound II is made using a compound of the present disclosure.

[0767] In some embodiments, compound II is made using a compound selected from the following: [ka]

[0768] In some embodiments, the compound of the present disclosure is selected from the following: [ka]

[0769] Forming Compound II according to Scheme 2 and the above-described embodiments has several non-limiting advantages. These advantages are even more apparent when producing Compound II on an industrial scale. For example, the crystallization / isolation of Step 1 (Scheme 2) has been improved, resulting in improved slurry performance and improved scalability, processability, and throughput of Step 1. The parameters of Steps 3 and 4 (Scheme 2) have also been improved in several ways, including by changing the amount and addition profile of AIBN, resulting in a significant reduction in reaction temperature and an improved safety profile of the process. The parameters of Step 5 (Scheme 2) have also been optimized, allowing for a significant reduction in the amount of rhodium catalyst used. Finally, the process of Step 6 (Scheme 2) has been developed to enable the isolation of Form C.

[0770] In some embodiments, compound I is made according to Scheme 3.

[0771] [ka]

[0772] In some embodiments, compound I is compound 20a: [ka] to compound I.

[0773] In some embodiments, the conversion of compound 20a to compound I is carried out in the presence of pentamethylcyclopentadienyl rhodium chloride dimer (RhClCp*), (R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine ((R,R)-TsDPEN), formic acid (HCOH), and triethylamine (EtN).

[0774] In some embodiments, the conversion of compound 20a to compound I is carried out at -15 to 0°C.

[0775] In some embodiments, compound 20a is compound L2 / K9: [ka] to compound 20a.

[0776] In some embodiments, the conversion of compound L2 / K9 to compound 20a is carried out in the presence of 2,4,6-triphenylpyrylium tetrafluoroborate, acid, a 460 nm LED, and air / N 2 .

[0777] In some embodiments, the conversion of compound L2 / K9 to compound 20a is carried out in the presence of 2,4,6-triphenylpyrylium tetrafluoroborate, methanesulfonic acid (MsOH), a 460 nm LED, and air / N 2 .

[0778] In some embodiments, the conversion of compound L2 / K9 to compound 20a is carried out in the presence of copper(II) acetate, ammonium persulfate, and water.

[0779] In some embodiments, compound L2 / K9 is selected from the group consisting of compounds S26 / K7: [ka] and compounds S3 / J6 / K8: [ka] to produce compound L2 / K9.

[0780] In some embodiments, the reaction of compounds S26 / K7 with compounds S3 / J6 / K8 is carried out in the presence of methanesulfonic acid (MsOH).

[0781] In some embodiments, the reaction of compounds S26 / K7 with compounds S3 / J6 / K8 is carried out at 39°C.

[0782] In some embodiments, Compound I is made using a compound selected from the following: [ka]

[0783] In some embodiments, the compound of the present disclosure is selected from the following: [ka]

[0784] The preparation of compound I according to Scheme 3 uses a sufficiently short route (three steps overall) to provide high yield / throughput.

[0785] In some embodiments, compound II is made according to Scheme 4.

[0786] [ka]

[0787] In some embodiments, compound II is compound 20b: [ka] to compound II.

[0788] In some embodiments, the conversion of compound 20b to compound II is carried out in the presence of pentamethylcyclopentadienyl rhodium chloride dimer (RhClCp*), (R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine ((R,R)-TsDPEN), formic acid (HCOH), and triethylamine (EtN).

[0789] In some embodiments, the conversion of compound 20b to compound II is carried out at -15 to 0°C.

[0790] In some embodiments, compound 20b is compound L1 / K14: [ka] to compound 20b.

[0791] In some embodiments, the conversion of compound L1 / K14 to compound 20b is carried out in the presence of 2,4,6-triphenylpyrylium tetrafluoroborate, acid, a 460 nm LED, and air / N 2 .

[0792] In some embodiments, the conversion of compound L1 / K14 to compound 20b is carried out in the presence of 2,4,6-triphenylpyrylium tetrafluoroborate, methanesulfonic acid (MsOH), a 460 nm LED, and air / N 2 .

[0793] In some embodiments, the conversion of compound L1 / K14 to compound 20b is carried out in the presence of copper(II) acetate, ammonium persulfate, and water.

[0794] In some embodiments, compound L1 / K14 is selected from compounds S26 / K7: [ka] and compound S2: [ka] to produce compound L1 / K14.

[0795] In some embodiments, the reaction of compound S26 / K7 with compound S2 is carried out in the presence of methanesulfonic acid (MsOH).

[0796] In some embodiments, the reaction of compound S26 / K7 with compound S2 is carried out at 39°C.

[0797] In some embodiments, compound II is made using a compound selected from the following: [ka]

[0798] In some embodiments, the compound of the present disclosure is selected from the following: [ka]

[0799] The preparation of compound II according to Scheme 4 uses a sufficiently short route (three steps overall) to result in high yield / throughput.

[0800] Non-limiting exemplary embodiments Some embodiments of the present disclosure include, but are not limited to: 1. Phosphate hydrate Form A of Compound I. 2. The phosphate salt hydrate Form A of Compound I according to embodiment 1, characterized by an X-ray powder diffractogram comprising signals at 2-theta of 28.6±0.2, 19.9±0.2, and / or 28.3±0.2. 2. The phosphate salt hydrate Form A of Compound I according to embodiment 1, characterized by an X-ray powder diffractogram comprising signals at two or more 2-theta values ​​selected from 3.8.6±0.2, 19.9±0.2, and 28.3±0.2. 2. The phosphate salt hydrate Form A of Compound I according to embodiment 1, characterized by an X-ray powder diffractogram comprising signals at 2-theta of 4.8.6±0.2, 19.9±0.2, and 28.3±0.2. 2. The phosphate salt hydrate Form A of compound I according to embodiment 1, characterized by an X-ray powder diffractogram comprising: (a) signals at the following 2-theta values: 8.6±0.2, 19.9±0.2, and 28.3±0.2, and (b) signals at one or more 2-theta values ​​selected from 17.2±0.2, 20.4±0.2, and 22.8±0.2, measured at 5.25±2°C and 5% relative humidity (RH). 2. The phosphate salt hydrate Form A of compound I according to embodiment 1, characterized by an X-ray powder diffractogram comprising signals at 8.6±0.2, 17.2±0.2, 19.9±0.2, 20.4±0.2, 22.8±0.2, and 28.3±0.2, measured at 6.25±2°C and 5% relative humidity (RH). 2. The phosphate salt hydrate Form A of compound I according to embodiment 1, characterized by an X-ray powder diffractogram comprising: (a) signals at the following 2-theta values: 8.6±0.2, 19.9±0.2, and 28.3±0.2, and (b) signals at one or more 2-theta values ​​selected from 17.2±0.2, 20.4±0.2, 21.1±0.2, 21.9±0.2, and 22.8±0.2, measured at 7.25±2°C and 5% relative humidity (RH). 2. The phosphate salt hydrate Form A of compound I according to embodiment 1, characterized by an X-ray powder diffractogram comprising signals at 2-theta of 8.6±0.2, 17.2±0.2, 19.9±0.2, 20.4±0.2, 21.1±0.2, 21.9±0.2, 22.8±0.2, and 28.3±0.2, measured at 8.25±2°C and 5% relative humidity (RH). 9. Phosphate salt hydrate Form A of Compound I as described in embodiment 1, characterized by an X-ray powder diffractogram substantially similar to that in FIG. 6, measured at 25° C.±2° C. and 5% relative humidity (RH). 10. The phosphate salt hydrate Form A of Compound I according to any one of embodiments 1 to 9, characterized by an X-ray powder diffractogram comprising: (a) signals at the following 2-theta values: 8.6±0.2, 19.9±0.2, and 28.3±0.2, and (b) signals at one or more 2-theta values ​​selected from 20.4±0.2, 21.0±0.2, and 22.8±0.2, measured at 10.25±2°C and 40% relative humidity (RH). 10. The phosphate salt hydrate Form A of Compound I according to any one of embodiments 1 to 9, characterized by an X-ray powder d...

Claims

1. Compound I in solid form: 【Chemistry 101】 wherein the solid form is (a) an X-ray powder diffractogram comprising signals at 8.6±0.2, 19.9±0.2, and / or 28.3±0.2 2-theta; and / or (b) a 13 C NMR spectrum measured at 43% relative humidity (RH) comprising one or more signals selected from 16.0±0.2 ppm, 38.4±0.2 ppm, 128.6±0.2 ppm, 139.3±0.2 ppm, and 141.7±0.2 ppm; and / or (c) a 19 F NMR spectrum measured at 43% relative humidity (RH) comprising one or more signals selected from −57.4±0.2 ppm and −53.8±0.2 ppm; and / or (d) a 31 P NMR spectrum measured at 43% relative humidity (RH) comprising one or more signals selected from 2.6±0.2 ppm and 4.2±0.2 ppm; and / or (e) Orthorhombic, P2 1 2 1 2 1 space group, and the following unit cell dimensions, measured at 100 K on a diffractometer with Cu Kα radiation (λ=1.54178 Å): Table 125 A solid form of Compound I, which is a phosphate hydrate Form A of Compound I, characterized by:

2. Compound I in solid form: 【Chemistry 102】 wherein the solid form is (a) an X-ray powder diffractogram comprising signals at 2-theta of 8.7±0.2, 12.8±0.2, 16.7±0.2, and / or 21.7±0.2; and / or (b) a 13 C NMR spectrum measured at 43% relative humidity (RH) comprising one or more signals selected from 24.9±0.2 ppm, 35.1±0.2 ppm, 39.3±0.2 ppm, 135.3±0.2 ppm, and 149.6±0.2 ppm; and / or (c) a 19 F NMR spectrum measured at 43% relative humidity (RH) containing a signal at −55.8±0.2 ppm; and / or (d) Tetragonal crystal system, P4 3 space group, and the following unit cell dimensions, measured at 100 K on a diffractometer with Cu Kα radiation (λ=1.54178 Å): Table 126 A solid form of Compound I, which is the free monohydrate of Compound I, characterized by:

3. Compound I in solid form: 【Chemistry 103】 wherein the solid form is (a) an X-ray powder diffractogram comprising signals at 2-theta of 12.7±0.2, 14.8±0.2, and / or 20.7±0.2; and / or (b) an X-ray powder diffractogram comprising (a) signals at the following 2-theta values: 12.7±0.2, 14.8±0.2, and 20.7±0.2, and (b) signals at one or more 2-theta values selected from 8.5±0.2, 15.8±0.2, and 19.5±0.2; and / or (c) a 13 C NMR spectrum comprising one or more signals selected from 15.7±0.2 ppm, 17.7±0.2 ppm, 38.9±0.2 ppm, 129.4±0.2 ppm, and 140.6±0.2 ppm; and / or (d) a 19 F NMR spectrum comprising one or more signals selected from −57.7±0.2 ppm and −54.7±0.2 ppm; and / or (e) a 31 P NMR spectrum comprising one or more signals selected from 1.8±0.2 ppm and 2.5±0.2 ppm; and / or (f) Orthorhombic, P2 1 2 1 2 1 space group, and the following unit cell dimensions, measured at 100 K on a diffractometer with Cu Kα radiation (λ=1.54178 Å): Table 127 A solid form of Compound I, which is a phosphate salt methanol solvate of Compound I, characterized by:

4. Compound I in solid form: 【Chemistry 104】 wherein the solid form is (a) an X-ray powder diffractogram comprising signals at 8.6±0.2, 15.4±0.2, and / or 20.1±0.2 2-theta; and / or (b) a 13 C NMR spectrum comprising one or more signals selected from 16.0±0.2 ppm, 37.5±0.2 ppm, 38.4±0.2 ppm, 126.5±0.2 ppm, and 142.0±0.2 ppm; and / or (c) a 19 F NMR spectrum comprising one or more signals selected from −53.6±0.2 ppm, −55.2±0.2 ppm, and −57.2±0.2 ppm; and / or (d) a 31 P NMR spectrum comprising one or more signals selected from 0.1±0.2 ppm, 2.7±0.2 ppm, and 4.8±0.2 ppm. A solid form of Compound I, which is a phosphate MEK solvate of Compound I, characterized by:

5. Compound I in solid form: 【Chemistry 105】 1. A solid form of Compound I, which is the maleate salt / co-crystalline Form A of Compound I, characterized by an X-ray powder diffractogram comprising signals at 27.6±0.2 2-theta and 20.0±0.2 2-theta.

6. Compound I in solid form: 【Chemistry 106】 1. A solid form of Compound I, which is maleate salt / co-crystalline Form B of Compound I, characterized by an X-ray powder diffractogram containing signals at 4.9±0.2 2-theta and 26.0±0.2 2-theta.

7. Compound I in solid form: 【Chemistry 107】 1. A solid form of Compound I which is a fumarate salt / co-crystalline Form A of Compound I, wherein the solid form is characterized by an X-ray powder diffractogram comprising signals at two or more 2-theta values selected from 14.4±0.2, 14.6±0.2, 16.9±0.2, 20.7±0.2, 20.9±0.2, and 21.5±0.

2.

8. Compound I in solid form: 【Chemistry 108】 1. A solid form of Compound I, wherein the solid form is the free form, Form B, of Compound I, characterized by an X-ray powder diffractogram comprising signals at two or more 2-theta values selected from 11.7±0.2, 13.9±0.2, 14.2±0.2, 19.1±0.2, 21.6±0.2, and 24.6±0.

2.

9. Compound I in solid form: 【Chemistry 109】 1. A solid form of Compound I, wherein the solid form is the free form, Form C, of Compound I, characterized by an X-ray powder diffractogram comprising signals at two or more 2-theta values selected from 11.1±0.2, 14.7±0.2, 21.0±0.2, and 25.7±0.

2.

10. A solid form of Compound II: 【Chemistry 110】 wherein the solid form is (a) an X-ray powder diffractogram comprising signals at 9.1±0.2, 16.7±0.2, and / or 18.7±0.2 2-theta; and / or (b) a 13 C NMR spectrum comprising one or more signals selected from 15.3±0.2 ppm, 15.8±0.2 ppm, 16.6±0.2 ppm, 39.9±0.2 ppm, and 141.3±0.2 ppm; and / or (c) a 31 P NMR spectrum comprising one or more signals selected from −1.8±0.2 ppm, −1.1±0.2 ppm, and 3.1±0.2 ppm; and / or (d) Orthorhombic, P2 1 2 1 2 1 space group, and the following unit cell dimensions, measured at 100 K on a diffractometer with Cu Kα radiation (λ = 1.54178 Å): Table 128 A solid form of Compound II, which is Compound II phosphate hemihydrate Form A, characterized by:

11. A solid form of Compound II: 【Chemistry 111】 wherein the solid form is (a) an X-ray powder diffractogram measured at ambient temperature containing signals at 2-theta of 17.1±0.2, 19.1±0.2, and / or 20.4±0.2; and / or (b) a 13 C NMR spectrum comprising one or more signals selected from 21.9±0.2 ppm, 22.6±0.2 ppm, 133.2±0.2 ppm, 139.8±0.2 ppm, and 140.9±0.2 ppm; and / or (c) Monoclinic crystal system, P2 1 space group, and the following unit cell dimensions, measured at 100 K on a diffractometer with Cu Kα radiation (λ=1.54178 Å): Table 129 A solid form of Compound II, which is the free hemihydrate Form A of Compound II, characterized by:

12. A compound II in solid form: 【Chemistry 112】 wherein the solid form is (a) an X-ray powder diffractogram measured at ambient temperature containing a signal at 2-theta of 13.0±0.2; and / or (b) a 13 C NMR spectrum comprising one or more signals selected from 149.3±0.2 ppm, 144.3±0.2 ppm, 135.0±0.2 ppm, 127.2±0.2 ppm, and 124.5±0.2 ppm; and / or (c) orthorhombic, P2 1 2 1 2 1 space group, and the following unit cell dimensions, measured at 298 K on a diffractometer with Cu Kα radiation (λ=1.54178 Å); and / or Table 130 (d) Orthorhombic, P2 1 2 1 2 1 space group, and the following unit cell dimensions, measured at 100 K on a diffractometer with Cu Kα radiation (λ = 1.54178 Å): Table 131 A solid form of Compound II, which is the free form Form C of Compound II, characterized by:

13. A solid form of Compound II: 【Chemistry 113】 1. A solid form of Compound II, wherein the solid form is the free form Form A of Compound II, characterized by an X-ray powder diffractogram comprising signals at two or more 2-theta values selected from 9.1±0.2, 11.7±0.2, 13.9±0.2, 14.1±0.2, and 20.5±0.

2.

14. A solid form of Compound II: 【Chemistry 114】 wherein the solid form is the free form Form B of Compound II, characterized by a single crystalline unit cell characterized by a monoclinic crystal system, a P2 1 space group, and the following unit cell dimensions, measured at 100K on a diffractometer with Cu Kα radiation (λ=1.54178 Å): Table 201 15. A solid form of Compound II: 【Chemistry 115】 A solid form of Compound II, which is a free quart-hydrate of Compound II, characterized by a single crystalline unit cell characterized by a monoclinic crystal system, a P2 1 space group, and the following unit cell dimensions, measured at 100K on a diffractometer with Cu Kα radiation (λ=1.54178 Å): Table 202 16. A solid form of Compound II: 【Chemistry 116】 1. A solid form of Compound II which is a free mixed hydrate of Compound II, wherein the solid form is characterized by an X-ray powder diffractogram comprising signals at two or more 2-theta values selected from 3.6±0.2, 8.6±0.2, 13.7±0.2, 19.9±0.2, 24.1±0.2, and 24.5±0.

2.

17. A solid form of Compound II: 【Chemistry 117】 A solid form of Compound II, which is a free monohydrate of Compound II, characterized by a C NMR spectrum comprising: (a) a signal at 134.1±0.2 ppm and / or a signal at 21.1±0.2 ppm; and (b) one or more signals selected from 74.5±0.2 ppm, 62.4±0.2 ppm, 49.0±0.2 ppm, 39.1±0.2 ppm, and 21.7±0.2 ppm.

18. A solid form of Compound II: 【Chemistry 118】 1. A solid form of Compound II, the solid form being the free dihydrate of Compound II, characterized by a C NMR spectrum comprising: (a) one or more signals selected from 143.8±0.2 ppm, 128.9±0.2 ppm, 126.6±0.2 ppm, 68.6±0.2 ppm, 62.7±0.2 ppm, and 37.8±0.2 ppm; and (b) one or more signals selected from 131.8±0.2 ppm, 124.5±0.2 ppm, 124.1±0.2 ppm, 38.2±0.2 ppm, and 22.5±0.2 ppm.

19. A solid form of Compound II: 【Chemistry 119】 1. A solid form of Compound II, which is EtOH solvate Form B of Compound II, characterized by an X-ray powder diffractogram comprising a signal at 11.6±0.2 2-theta, a signal at 17.1±0.2 2-theta, and a signal at 23.8±0.2 2-theta.

20. A solid form of Compound II: 【Chemistry 120】 1. A solid form of Compound II which is a free IPA solvate of Compound II, wherein the solid form is characterized by an X-ray powder diffractogram comprising signals at two or more 2-theta values selected from 8.4±0.2, 11.7±0.2, 21.6±0.2, and 23.3±0.

2.

21. A solid form of Compound II: 【Chemistry 121】 1. A solid form of Compound II, which is a free MEK solvate of Compound II, characterized by a C NMR spectrum comprising two or more signals selected from 8.2±0.2 ppm, 23.2±0.2 ppm, 30.0±0.2 ppm, 35.0±0.2 ppm, 35.7±0.2 ppm, 39.3±0.2 ppm, and 63.3±0.2 ppm.

22. A solid form of Compound II: 【Chemistry 122】 1. A solid form of Compound II which is a free MeOH solvate of Compound II, wherein the solid form is characterized by an X-ray powder diffractogram comprising signals at two or more 2-theta values selected from 13.4±0.2, 16.6±0.2, 24.3±0.2, 24.4±0.2, and 26.3±0.

2.

23. A solid form of Compound II: 【Chemical 123】 1. A solid form of Compound II which is a phosphate acetone solvate of Compound II, wherein the solid form is characterized by an X-ray powder diffractogram comprising signals at two or more 2-theta values selected from 8.7±0.2, 9.4±0.2, 15.0±0.2, and 18.4±0.

2.

24. A solid form of Compound II: 【Chemical 124】 1. A solid form of Compound II, which is Compound II phosphate salt Form A, wherein the solid form is characterized by an X-ray powder diffractogram comprising signals at two or more 2-theta values selected from 7.0±0.2, 9.9±0.2, 14.1±0.2, 17.5±0.2, and 19.9±0.

2.

25. A solid form of Compound II: 【Chemistry 125】 1. A solid form of Compound II, wherein the solid form is Compound II phosphate Form C, characterized by an X-ray powder diffractogram comprising signals at two or more 2-theta values selected from 13.5±0.2, 13.7±0.2, and 15.0±0.

2.

26. A pharmaceutical composition comprising at least one solid form according to any one of claims 1 to 25 and a pharmaceutically acceptable carrier.

27. A composition for use in the treatment of an APOL1-mediated disease, comprising at least one solid form according to any one of claims 1 to 25.

28. The composition of claim 27, wherein the APOL1-mediated disease is an APOL1-mediated kidney disease.

29. 29. The composition of claim 28, wherein the APOL1-mediated kidney disease is selected from end-stage kidney disease (ESKD), non-diabetic kidney disease (NDKD), focal segmental glomerulosclerosis (FSGS), HIV-associated nephropathy, arteriosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease.

30. Use of a solid form according to any one of claims 1 to 25 in the manufacture of a medicament for treating an APOL1-mediated disease.

31. The use described in claim 30, wherein the APOL1-mediated disease is an APOL1-mediated renal disease.

32. The use of claim 31, wherein the APOL1-mediated renal disease is selected from end-stage kidney disease (ESKD), non-diabetic kidney disease (NDKD), focal segmental glomerulosclerosis (FSGS), HIV-associated nephropathy, arteriosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease.

33. Compound I: 【126】 A method of making 【Chemistry 70】 to compound I.

34. 【Catalog 71】 A compound selected from:

35. Compound II: 【Chemistry 127】 A method of making 【Chemistry 80】 to compound II.

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