Salts of PD-1 / PD-L1 inhibitors

Abstract

The present invention relates to salt forms of the PD-1 / PD-L1 inhibitor (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid, including methods for its preparation, and the compounds are useful in the treatment of various diseases, including infectious diseases and cancer.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 884,996, filed August 9, 2019, which is incorporated by reference in its entirety.

[0002] The present application relates to a salt form of the PD-1 / PD-L1 inhibitor (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid, including methods for its preparation, which compounds are useful in the treatment of a variety of diseases, including infectious diseases and cancer. [Background technology]

[0003] The immune system plays a key role in controlling and eradicating diseases such as cancer. However, cancer cells often develop strategies to evade or suppress the immune system to favor their growth. One such mechanism is to alter the expression of costimulatory and co-inhibitory molecules expressed in immune cells (Postow et al, J. Clinical Oncology 2015,1-9). Blocking the signaling of inhibitory immune checkpoints such as PD-1 has proven to be a promising and effective treatment.

[0004] Programmed cell death-1 (PD-1), also known as CD279, is a cell surface receptor expressed on activated T cells, natural killer T cells, B cells, and macrophages (Greenwald et al, Annu. Rev. Immunol 2005,23:515-548; Okazaki and Honjo, Trends Immunol 2006,(4):195-201). It functions as an intrinsic negative feedback mechanism to prevent T cell activation, which in turn reduces autoimmunity and promotes self-tolerance. In addition, PD-1 is also known to play an important role in suppressing antigen-specific T cell responses in diseases such as cancer and viral infections (Sharpe et al, Nat Immunol 2007 8,239-245; Postow et al, J. Clinical Oncol 2015,1-9).

[0005] The structure of PD-1 consists of an extracellular immunoglobulin variable-like domain followed by a transmembrane region and an intracellular domain (Parry et al, Mol Cell Biol 2005, 9543-9553). The intracellular domain contains two phosphorylation sites located at an immunoreceptor tyrosine-based inhibitory motif and an immunoreceptor tyrosine-based switch motif, suggesting that PD-1 negatively regulates T cell receptor-mediated signals. PD-1 has two ligands, PD-L1 and PD-L2 (Parry et al, Mol Cell Biol 2005, 9543-9553; Latchman et al, Nat Immunol 2001, 2, 261-268), which differ in their expression patterns. PD-L1 protein is upregulated in macrophages and dendritic cells in response to lipopolysaccharide and GM-CSF treatment, and in T cells and B cells by T cell receptor and B cell receptor signaling. PD-L1 is also highly expressed by almost all tumor cells, and expression is further increased after IFN-γ treatment (Iwai et al, PNAS 2002, 99(19):12293-7; Blank et al, Cancer Res 2004, 64(3):1140-5). Indeed, tumor PD-L1 expression status has been shown to be prognostic in multiple tumor types (Wang et al, Eur J Surg Oncol 2015; Huang et al, Oncol Rep 2015; Sabatier et al, Oncotarget 2015, 6(7): 5449-5464). In contrast, PD-L2 expression is more restricted and is mainly expressed by dendritic cells (Nakae et al, J Immunol 2006, 177:566-73). Ligation of PD-1 and its ligands PD-L1 and PD-L2 on T cells results in signals that inhibit the production of IL-2 and IFN-γ, as well as cell proliferation induced by T cell receptor activation (Carter et al, Eur J Immunol 2002, 32(3):634-43; Freeman et al, J Exp Med 2000, 192(7):1027-34).This mechanism involves recruitment of SHP-2 or SHP-1 phosphatases that inhibit T cell receptor signaling, such as phosphorylation of Syk and Lck (Sharpe et al, Nat Immunol 2007, 8, 239-245). Activation of the PD-1 signaling axis also attenuates activation of the NF-κB and AP1 pathways, as well as phosphorylation of the PKC-θ activation loop, which is required for cytokine production, such as IL-2, IFN-γ, and TNF (Sharpe et al, Nat Immunol 2007, 8, 239-245; Carter et al, Eur J Immunol 2002, 32(3):634-43; Freeman et al, J Exp Med 2000, 192(7):1027-34).

[0006] Several lines of evidence from preclinical animal studies indicate that PD-1 and its ligands negatively regulate immune responses. PD-1-deficient mice have been shown to develop lupus-like glomerulonephritis and dilated cardiomyopathy (Nishimura et al, Immunity 1999, 11:141-151; Nishimura et al, Science 2001, 291:319-322). Using the LCMV model of chronic infection, PD-1 / PD-L1 interaction has been shown to inhibit the activation, expansion, and acquisition of effector function of virus-specific CD8 T cells (Barber et al, Nature 2006, 439, 682-7). Taken together, these data support the development of therapeutic approaches that block PD-1-mediated inhibitory signaling cascades to augment or "rescue" T cell responses. Thus, new compounds and salts that block PD-1 / PD-L1 protein / protein interactions are needed. Summary of the Invention

[0007] The present disclosure relates to salts of (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid.

[0008] The present disclosure further relates to the monohydrobromide, monooxalate, monohydrochloride, mono-L-tartrate, dihydrobromide, dioxalate, L-tartrate (1:1.5), hydrochloride (1:1.7), monomalonate, phosphate (about 1:3), and phosphate (about 1:2) salts of (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid.

[0009] The present disclosure further relates to crystalline forms of the salts described herein.

[0010] The present disclosure further relates to a pharmaceutical composition comprising a salt or crystalline form described herein and at least one pharma- ceutically acceptable carrier or excipient. The present disclosure further relates to a solid dosage form comprising the pharmaceutical composition.

[0011] The disclosure further relates to methods of inhibiting PD-1 / PD-L1 interaction comprising administering to a patient the salts and crystalline forms described herein.The disclosure also provides for the use of the salts and crystalline forms described herein in the manufacture of a medicament for use in inhibiting PD-1 / PD-L1 interaction.The disclosure also provides for the salts and crystalline forms described herein for use in inhibiting PD-1 / PD-L1 interaction.

[0012] The disclosure further relates to treating a disease or disorder associated with inhibition of PD-1 / PD-L1 interaction comprising administering to a patient the salts and crystalline forms described herein. The disclosure also provides the use of the salts and crystalline forms described herein in the manufacture of a medicament for use in treating a disease or disorder associated with inhibition of PD-1 / PD-L1 interaction. The disclosure also provides the salts and crystalline forms described herein for use in treating a disease or disorder associated with inhibition of PD-1 / PD-L1 interaction.

[0013] The present disclosure further relates to enhancing, stimulating, and / or increasing an immune response in a patient, comprising administering to the patient the salts and crystalline forms described herein. The present disclosure also provides the use of the salts and crystalline forms described herein in the manufacture of a medicament for use in enhancing, stimulating, and / or increasing an immune response in a patient. The present disclosure also provides the salts and crystalline forms described herein for use in enhancing, stimulating, and / or increasing an immune response in a patient.

[0014] The present invention further relates to processes for preparing the salts and crystalline forms described herein. [Brief description of the drawings]

[0015] [Figure 1] 1 shows the XRPD pattern of the monohydrobromide salt of compound 1. [Diagram 2] 1 shows the XRPD pattern of the monohydrobromide salt of compound 1 prepared by an alternative method. [Diagram 3] 1 shows the XRPD pattern of the monooxalate salt of compound 1. [Figure 4] 1 shows a TGA thermogram of the monooxalate salt of Compound 1. [Diagram 5] 1 shows the XRPD pattern of the monohydrochloride salt of compound 1. [Figure 6] 1 shows the XRPD pattern of the L-tartrate salt of compound 1 (1:1.5). [Figure 7]1H NMR of the L-tartrate salt of compound 1 (1:1.5) is shown. [Figure 8] 1 shows the XRPD patterns of two samples of the dihydrobromide salt of compound 1. [Figure 9] 1 shows the XRPD pattern of the dihydrobromide salt of compound 1 prepared by an alternative method. [Figure 10] 1 shows the XRPD pattern of the disoxalate salt of compound 1. [Figure 11] 1 shows a DSC thermogram of the disoxalate salt of Compound 1. [Figure 12] 1 shows a TGA thermogram of the dioxalate salt of Compound 1. [Figure 13] 1 shows the XRPD pattern of the L-tartrate salt of compound 1 (1:1.7). [Figure 14] 1H NMR of the L-tartrate salt of compound 1 (1:1.7) is shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] The present disclosure relates inter alia to a salt of (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid (Compound 1), wherein the salt is selected from the following: (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid hydrobromide (the hydrobromide salt of compound 1); (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid oxalate (the oxalate salt of compound 1); (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid hydrochloride (the hydrochloride salt of compound 1); (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid L-tartrate (the L-tartrate salt of compound 1); (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid malonate (the malonate salt of Compound 1); and (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid phosphate (phosphate salt of compound 1).

[0017] [ka]

[0018] Compound 1 is described in U.S. Patent Application Publication No. 2018 / 0179197A1, the entirety of which is incorporated herein by reference.

[0019] Hydrobromide In some embodiments, the salt of compound 1 is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid hydrobromide (the hydrobromide salt of compound 1). In some embodiments, the hydrobromide salt of compound 1 is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid monohydrobromide (the monohydrobromide salt of compound 1). In some embodiments, the hydrobromide salt of compound 1 is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid dihydrobromide (the dihydrobromide salt of compound 1).

[0020] The monohydrobromide salt of compound 1 can be prepared by any method suitable for preparing hydrobromic acid addition salts. For example, compound 1 can be combined with hydrobromic acid (e.g., about 1.0 molar equivalent or more) in a solvent, and the resulting salt can be isolated by filtering the salt from the solution. In certain embodiments, compound 1 is combined with about 1 to about 2 molar equivalents of hydrobromic acid. In certain embodiments, compound 1 is combined with about 1.0 to about 1.5 molar equivalents of hydrobromic acid. In certain embodiments, compound 1 is combined with about 1.05 molar equivalents of hydrobromic acid.

[0021] The solvent can include any solvent or mixture of solvents capable of at least partially dissolving compound 1. In some embodiments, the solvent includes an alcohol. Suitable alcohols include methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, isopropanol (isopropyl alcohol, 2-propanol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-pentanol, 2-pentanol, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol. In some embodiments, the solvent includes acetone, tetrahydrofuran, dichloromethane, methanol, ethanol, 1-propanol, or isopropanol. In some embodiments, the solvent includes dichloromethane. In some embodiments, the solvent includes tetrahydrofuran.

[0022] In some embodiments, the solvent is a mixture of isopropyl alcohol, methanol, water, and dichloromethane, hi some embodiments, the solvent is a mixture of isopropyl alcohol, water, and tetrahydrofuran.

[0023] In some embodiments, the solvent is at about room temperature. In some embodiments, the solvent is heated to a temperature of about 50° C. In some embodiments, the temperature is about 50° C. to about 80° C. In some embodiments, the temperature is about 40° C. to about 60° C. In some embodiments, the temperature is about 45° C. to about 55° C. In some embodiments, the temperature is about 45° C., about 50° C., about 55° C., about 60° C., about 65° C., about 70° C., about 75° C., or about 80° C.

[0024] In some embodiments, the solvent is heated to a temperature capable of inducing precipitation at a practical rate. In some embodiments, precipitation is complete within about 12 to about 24 hours, although longer and shorter periods are possible depending on the selection of the precipitation solvent and temperature. In some embodiments, precipitation is complete within about 12 hours. In some embodiments, precipitation is complete within about 2 hours.

[0025] In some embodiments, precipitation of the monohydrobromide salt of Compound 1 is carried out by filtering the salt from solution.

[0026] In some embodiments, the monohydrobromide salt of Compound 1 may be characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 1. In some embodiments, the monohydrobromide salt of Compound 1 may be characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 2.

[0027] In some embodiments, the monohydrobromide salt of Compound 1 is amorphous.

[0028] The dihydrobromide salt of compound 1 can be prepared by any method suitable for preparing hydrobromic acid addition salts. For example, compound 1 can be combined with hydrobromic acid (e.g., about 2.0 molar equivalents or more) in a solvent, and the resulting salt can be isolated by filtering the salt from the solution. In certain embodiments, compound 1 is combined with about 2 to about 3 molar equivalents of hydrobromic acid. In certain embodiments, compound 1 is combined with about 2.0 to about 2.5 molar equivalents of hydrobromic acid. In certain embodiments, compound 1 is combined with about 2.3 molar equivalents of hydrobromic acid. In certain embodiments, compound 1 is combined with about 2.05 molar equivalents of hydrobromic acid.

[0029] The solvent can include any solvent or mixture of solvents capable of at least partially dissolving compound 1. In some embodiments, the solvent includes an alcohol. Suitable alcohols include methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, isopropanol (isopropyl alcohol, 2-propanol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-pentanol, 2-pentanol, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol. In some embodiments, the solvent includes acetone, tetrahydrofuran, dichloromethane, methanol, ethanol, 1-propanol, or isopropanol. In some embodiments, the solvent includes methanol. In some embodiments, the solvent includes tetrahydrofuran.

[0030] In some embodiments, the solvent is a mixture of isopropyl alcohol, water, and methanol. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is a mixture of isopropyl alcohol, water, and tetrahydrofuran.

[0031] In some embodiments, the solvent is at about room temperature. In some embodiments, the solvent is heated to a temperature of about 50° C. In some embodiments, the temperature is about 50° C. to about 80° C. In some embodiments, the temperature is about 40° C. to about 60° C. In some embodiments, the temperature is about 45° C. to about 55° C. In some embodiments, the temperature is about 45° C., about 50° C., about 55° C., about 60° C., about 65° C., about 70° C., about 75° C., or about 80° C.

[0032] In some embodiments, the solvent is heated to a temperature capable of inducing precipitation at a practical rate. In some embodiments, precipitation is complete within about 12 to about 24 hours, although longer and shorter periods are possible depending on the selection of the precipitation solvent and temperature. In some embodiments, precipitation is complete within about 16 hours. In some embodiments, precipitation is complete within about 12 hours. In some embodiments, precipitation is complete within about 2.5 hours.

[0033] In some embodiments, precipitation of the dihydrobromide salt is carried out by filtering the salt from solution.

[0034] In some embodiments, the dihydrobromide salt of Compound 1 may be characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 8. In some embodiments, the dihydrobromide salt of Compound 1 may be characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 9.

[0035] In some embodiments, the dihydrobromide salt of Compound 1 is amorphous.

[0036] Oxalates In some embodiments, the salt of compound 1 is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid oxalate (the oxalate salt of compound 1). In some embodiments, the oxalate salt of compound 1 is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid monooxalate (the monooxalate salt of compound 1). In some embodiments, the oxalate salt of compound 1 is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid disoxalate (the disoxalate salt of compound 1).

[0037] The monooxalate salt of compound 1 can be prepared by any suitable method for preparing an oxalic acid addition salt. For example, compound 1 can be combined with oxalic acid (e.g., about 1.0 molar equivalent or more) in a solvent, and the resulting salt can be isolated by filtering the salt from the solution. In certain embodiments, compound 1 is combined with about 1 to about 2 molar equivalents of oxalic acid. In certain embodiments, compound 1 is combined with about 1.0 to about 1.5 molar equivalents of oxalic acid. In certain embodiments, compound 1 is combined with about 1.05 molar equivalents of oxalic acid. In certain embodiments, compound 1 is combined with about 1.1 molar equivalents of oxalic acid.

[0038] The solvent can include any solvent or mixture of solvents that can at least partially dissolve compound 1. In some embodiments, the solvent includes an alcohol. Suitable alcohols include methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, isopropanol (isopropyl alcohol, 2-propanol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-pentanol, 2-pentanol, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol. In some embodiments, the solvent includes acetone, tetrahydrofuran, dichloromethane, methanol, ethanol, 1-propanol, or isopropanol. In some embodiments, the solvent includes acetone.

[0039] In some embodiments, the solvent is tetrahydrofuran, hi some embodiments, the solvent is a mixture of acetone, methanol, and dichloromethane.

[0040] In some embodiments, the solvent is at about room temperature. In some embodiments, the solvent is heated to a temperature of about 50° C. In some embodiments, the temperature is about 50° C. to about 80° C. In some embodiments, the temperature is about 40° C. to about 60° C. In some embodiments, the temperature is about 45° C. to about 55° C. In some embodiments, the temperature is about 45° C., about 50° C., about 55° C., about 60° C., about 65° C., about 70° C., about 75° C., or about 80° C.

[0041] In some embodiments, the solvent is heated to a temperature capable of inducing precipitation at a practical rate. In some embodiments, precipitation is complete within about 12 to about 24 hours, although longer and shorter periods are possible depending on the selection of the precipitation solvent and temperature. In some embodiments, precipitation is complete within about 2 hours. In some embodiments, precipitation is complete within about 90 minutes.

[0042] In some embodiments, precipitation of the monooxalate salt is carried out by filtering the salt from solution.

[0043] In some embodiments, the monooxalate salt of Compound 1 may be characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 3. In some embodiments, the monooxalate salt of Compound 1 may be characterized by a thermogravimetric analysis (TGA) spectrum substantially as shown in Figure 4.

[0044] In some embodiments, the monooxalate salt of Compound 1 is amorphous.

[0045] The dioxalate salt of compound 1 can be prepared by any suitable method for preparing an oxalic acid addition salt. For example, compound 1 can be combined with oxalic acid (e.g., about 2.0 molar equivalents or more) in a solvent, and the resulting salt can be isolated by filtering the salt from the solution. In certain embodiments, compound 1 is combined with about 2 to about 3 molar equivalents of oxalic acid. In certain embodiments, compound 1 is combined with about 2.0 to about 2.5 molar equivalents of oxalic acid. In certain embodiments, compound 1 is combined with about 2.05 molar equivalents of oxalic acid.

[0046] The solvent can include any solvent or mixture of solvents that can at least partially dissolve compound 1. In some embodiments, the solvent includes an alcohol. Suitable alcohols include methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, isopropanol (isopropyl alcohol, 2-propanol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-pentanol, 2-pentanol, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol. In some embodiments, the solvent includes acetone, tetrahydrofuran, dichloromethane, methanol, ethanol, 1-propanol, or isopropanol. In some embodiments, the solvent includes dichloromethane.

[0047] In some embodiments, the solvent is tetrahydrofuran.

[0048] In some embodiments, the solvent is at about room temperature. In some embodiments, the solvent is heated to a temperature of about 50° C. In some embodiments, the temperature is about 50° C. to about 80° C. In some embodiments, the temperature is about 40° C. to about 60° C. In some embodiments, the temperature is about 45° C. to about 55° C. In some embodiments, the temperature is about 45° C., about 50° C., about 55° C., about 60° C., about 65° C., about 70° C., about 75° C., or about 80° C.

[0049] In some embodiments, the solvent is heated to a temperature capable of inducing precipitation and / or crystallization at a practical rate. In some embodiments, precipitation and / or crystallization is complete within about 12 to about 24 hours, although longer and shorter periods are possible depending on the selection of the precipitation and / or crystallization solvent and temperature. In some embodiments, precipitation and / or crystallization is complete within about 2 hours.

[0050] In some embodiments, precipitation and / or crystallization of the dioxalate salt is carried out by filtering the salt from solution.

[0051] In some embodiments, the disoxalate salt of Compound 1 may be characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG.

[0052] In some embodiments, the dioxalate salt of Compound 1 has a characteristic X-ray powder diffraction (XRPD) peak at 7.0±0.2 degrees 2-theta. In some embodiments, the dioxalate salt of Compound 1 has a characteristic X-ray powder diffraction (XRPD) peak at 11.4±0.2 degrees 2-theta. In some embodiments, the dioxalate salt of Compound 1 has a characteristic X-ray powder diffraction (XRPD) peak at 13.2±0.2 degrees 2-theta. In some embodiments, the dioxalate salt of Compound 1 has a characteristic X-ray powder diffraction (XRPD) peak at 14.9±0.2 degrees 2-theta. In some embodiments, the dioxalate salt of Compound 1 has a characteristic X-ray powder diffraction (XRPD) peak at 17.0±0.2 degrees 2-theta.

[0053] In some embodiments, the dioxalate salt of Compound 1 has characteristic X-ray powder diffraction (XRPD) peaks at 7.0±0.2 degrees, 11.4±0.2 degrees, and 14.9±0.2 degrees 2-theta. In some embodiments, the dioxalate salt of Compound 1 has characteristic X-ray powder diffraction (XRPD) peaks at 7.0±0.2 degrees, 11.4±0.2 degrees, 14.9±0.2 degrees, and 17.0±0.2 degrees 2-theta. In some embodiments, the dioxalate salt of Compound 1 has characteristic X-ray powder diffraction (XRPD) peaks at 7.0±0.2 degrees, 11.4±0.2 degrees, 13.2±0.2 degrees, 14.9±0.2 degrees, and 17.0±0.2 degrees 2-theta.

[0054] In some embodiments, the dioxalate salt of Compound 1 has at least one X-ray powder diffraction (XRPD) peak selected from 7.0±0.2 degrees, 11.4±0.2 degrees, 13.2±0.2 degrees, 14.9±0.2 degrees, and 17.0±0.2 degrees 2-theta. In some embodiments, the dioxalate salt of Compound 1 has at least two X-ray powder diffraction (XRPD) peaks selected from 7.0±0.2 degrees, 11.4±0.2 degrees, 13.2±0.2 degrees, 14.9±0.2 degrees, and 17.0±0.2 degrees 2-theta. In some embodiments, the dioxalate salt of Compound 1 has at least three X-ray powder diffraction (XRPD) peaks selected from 7.0±0.2 degrees, 11.4±0.2 degrees, 13.2±0.2 degrees, 14.9±0.2 degrees, and 17.0±0.2 degrees 2-theta. In some embodiments, the dioxalate salt of Compound 1 has at least four X-ray powder diffraction (XRPD) peaks selected from 7.0±0.2 degrees, 11.4±0.2 degrees, 13.2±0.2 degrees, 14.9±0.2 degrees, and 17.0±0.2 degrees 2-theta.

[0055] In some embodiments, the dioxalate salt of Compound 1 exhibits a DSC thermogram with an endothermic peak at a temperature of 235±3° C. In some embodiments, the dioxalate salt of Compound 1 has a DSC thermogram substantially as shown in FIG. 11. In some embodiments, the dioxalate salt of Compound 1 has a TGA thermogram substantially as shown in FIG.

[0056] In some embodiments, the dioxalate salt of Compound 1 has at least one characteristic XRPD peak selected from 7.0±0.2 degrees, 11.4±0.2 degrees, 13.2±0.2 degrees, 14.9±0.2 degrees, and 17.0±0.2 degrees 2-theta, and the dioxalate salt of Compound 1 exhibits a DSC thermogram with an endothermic peak at a temperature of 235±3° C.

[0057] In some embodiments, the dioxalate salt of Compound 1 is amorphous. In some embodiments, the dioxalate salt of Compound 1 is crystalline. In some embodiments, the dioxalate salt of Compound 1 is a mixture comprising a crystalline form and an amorphous form.

[0058] Hydrochloride In some embodiments, the salt of compound 1 is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid hydrochloride (the hydrochloride salt of compound 1). In some embodiments, the hydrochloride salt of compound 1 is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid monohydrochloride (the monohydrochloride salt of compound 1). In some embodiments, the hydrochloride salt of compound 1 is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid trihydrochloride (the trihydrochloride salt of compound 1).

[0059] The monohydrochloride salt of compound 1 can be prepared by any suitable method for preparing monohydrochloride acid addition salts. For example, compound 1 can be combined with hydrochloric acid (e.g., about 1.0 molar equivalent or more) in a solvent, and the resulting salt can be isolated by filtering the salt from the solution. In certain embodiments, compound 1 is combined with about 1 to about 2 molar equivalents of hydrochloric acid. In certain embodiments, compound 1 is combined with about 1 to about 1.5 molar equivalents of hydrochloric acid. In certain embodiments, compound 1 is combined with about 1.05 molar equivalents of hydrochloric acid.

[0060] The solvent can include any solvent or mixture of solvents capable of at least partially dissolving compound 1. In some embodiments, the solvent includes an alcohol. Suitable alcohols include methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, isopropanol (isopropyl alcohol, 2-propanol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-pentanol, 2-pentanol, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol. In some embodiments, the solvent includes acetone, tetrahydrofuran, dichloromethane, methanol, ethanol, 1-propanol, or isopropanol. In some embodiments, the solvent includes dichloromethane. In some embodiments, the solvent includes methanol.

[0061] In some embodiments, the solvent is a mixture of isopropanol, water, methanol, and dichloromethane.In some embodiments, the solvent is a mixture of isopropanol, water, and methanol.

[0062] In some embodiments, the solvent is at about room temperature. In some embodiments, the solvent is heated to a temperature of about 50° C. In some embodiments, the temperature is about 50° C. to about 80° C. In some embodiments, the temperature is about 40° C. to about 60° C. In some embodiments, the temperature is about 45° C. to about 55° C. In some embodiments, the temperature is about 45° C., about 50° C., about 55° C., about 60° C., about 65° C., about 70° C., about 75° C., or about 80° C.

[0063] In some embodiments, the solvent is heated to a temperature capable of inducing precipitation at a practical rate. In some embodiments, precipitation is complete within about 12 to about 24 hours, although longer and shorter periods are possible depending on the selection of the precipitation solvent and temperature. In some embodiments, precipitation is complete within about 12 hours.

[0064] In some embodiments, precipitation of the monohydrochloride salt is carried out by filtering the salt from solution.

[0065] In some embodiments, the monohydrochloride salt of Compound 1 may be characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG.

[0066] In some embodiments, the monohydrochloride salt of Compound 1 is amorphous.

[0067] The trihydrochloride salt of compound 1 can be prepared by any suitable method for preparing a trihydrochloride acid addition salt. For example, compound 1 can be combined with hydrochloric acid (e.g., about 3.0 molar equivalents or more) in a solvent, and the resulting salt can be isolated by filtering the salt from the solution. In certain embodiments, compound 1 is combined with about 3 to about 5 molar equivalents of hydrochloric acid. In certain embodiments, compound 1 is combined with about 3 to about 4 molar equivalents of hydrochloric acid. In certain embodiments, compound 1 is combined with about 4 molar equivalents of hydrochloric acid.

[0068] The solvent can include any solvent or mixture of solvents that can at least partially dissolve compound 1. In some embodiments, the solvent includes an alcohol. Suitable alcohols include methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, isopropanol (isopropyl alcohol, 2-propanol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-pentanol, 2-pentanol, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol. In some embodiments, the solvent includes dioxane, dimethyl sulfoxide, acetone, tetrahydrofuran, dichloromethane, methanol, ethanol, 1-propanol, or isopropanol. In some embodiments, the solvent includes tetrahydrofuran.

[0069] In some embodiments, the solvent is a mixture of dimethylsulfoxide, tetrahydrofuran, and dioxane.

[0070] In some embodiments, the solvent is at about room temperature. In some embodiments, the solvent is heated to a temperature of about 50° C. In some embodiments, the temperature is about 50° C. to about 80° C. In some embodiments, the temperature is about 40° C. to about 60° C. In some embodiments, the temperature is about 45° C. to about 55° C. In some embodiments, the temperature is about 45° C., about 50° C., about 55° C., about 60° C., about 65° C., about 70° C., about 75° C., or about 80° C.

[0071] In some embodiments, the solvent is heated to a temperature capable of inducing precipitation at a practical rate. In some embodiments, precipitation is complete within about 12 to about 24 hours, although longer and shorter periods are possible depending on the selection of the precipitation solvent and temperature. In some embodiments, precipitation is complete within about 12 hours.

[0072] In some embodiments, precipitation of the trihydrochloride salt is carried out by filtering the salt from solution.

[0073] In some embodiments, the trihydrochloride salt of Compound 1 is amorphous.

[0074] L-tartrate In some embodiments, the salt of compound 1 is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid L-tartrate (the L-tartrate salt of compound 1). In some embodiments, the L-tartrate salt of compound 1 is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid L-tartrate salt (1:1.5) (the L-tartrate salt of compound 1 (1:1.5)), and the ratio of compound 1 to L-tartaric acid is about 1:1.5. In some embodiments, the L-tartrate salt of compound 1 is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid L-tartrate salt (1:1.7) (the L-tartrate salt of compound 1 (1:1.7)), and the ratio of compound 1 to L-tartaric acid is about 1:1.7.

[0075] The L-tartrate salt of compound 1 (1:1.5) can be prepared by any suitable method for preparing an L-tartaric acid addition salt. For example, compound 1 can be combined with L-tartaric acid in a solvent, and the resulting salt can be isolated by filtering the salt from the solution. In certain embodiments, compound 1 is combined with about 0.8 to about 2.5 molar equivalents of L-tartaric acid. In certain embodiments, compound 1 is combined with about 1.5 to about 2.5 molar equivalents of L-tartaric acid. In certain embodiments, compound 1 is combined with about 1.9 to about 2.1 molar equivalents of L-tartaric acid. In certain embodiments, compound 1 is combined with about 1.8 to about 2.2 molar equivalents of L-tartaric acid. In certain embodiments, compound 1 is combined with about 0.9 to about 1.1 molar equivalents of L-tartaric acid. In certain embodiments, compound 1 is combined with about 0.8 to about 1.2 molar equivalents of L-tartaric acid. In certain embodiments, compound 1 is combined with about 0.5 to about 1.5 molar equivalents of L-tartaric acid. In certain embodiments, compound 1 is combined with about 1.5 to about 2.0 molar equivalents of L-tartaric acid. In certain embodiments, compound 1 is combined with about 1.5 molar equivalents of L-tartaric acid. In certain embodiments, compound 1 is combined with about 1.05 molar equivalents of L-tartaric acid. In certain embodiments, compound 1 is combined with about 2.05 molar equivalents of L-tartaric acid.

[0076] The solvent can include any solvent or mixture of solvents that can at least partially dissolve compound 1. In some embodiments, the solvent includes an alcohol. Suitable alcohols include methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, isopropanol (isopropyl alcohol, 2-propanol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-pentanol, 2-pentanol, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol. In some embodiments, the solvent includes acetone, tetrahydrofuran, dichloromethane, methanol, ethanol, 1-propanol, or isopropanol. In some embodiments, the solvent includes dichloromethane.

[0077] In some embodiments, the solvent is tetrahydrofuran.

[0078] In some embodiments, the solvent is at about room temperature. In some embodiments, the solvent is heated to a temperature of at least about 50° C. In some embodiments, the temperature is from about 50° C. to about 80° C. In some embodiments, the temperature is from about 40° C. to about 60° C. In some embodiments, the temperature is from about 45° C. to about 55° C. In some embodiments, the temperature is about 45° C., about 50° C., about 55° C., about 60° C., about 65° C., about 70° C., about 75° C., or about 80° C.

[0079] In some embodiments, the solvent is heated to a temperature capable of inducing precipitation at a practical rate. In some embodiments, precipitation is complete within about 12 to about 24 hours, although longer and shorter periods are possible depending on the choice of precipitation solvent and temperature. In some embodiments, precipitation is complete within about 2 hours.

[0080] In some embodiments, precipitation of the L-tartrate salt (1:1.5) is carried out by filtering the salt from the solution.

[0081] In some embodiments, the L-tartrate salt of Compound 1 (1:1.5) may be characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 6. In some embodiments, the L-tartrate salt of Compound 1 (1:1.5) may be characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 7. 1 It can be characterized by H NMR spectroscopy.

[0082] In some embodiments, the L-tartrate salt of Compound 1 (1:1.5) is amorphous.

[0083] The L-tartrate salt of compound 1 (1:1.7) can be prepared by any suitable method for preparing an L-tartaric acid addition salt. For example, compound 1 can be combined with L-tartaric acid (e.g., about 1.7 molar equivalents or more) in a solvent, and the resulting salt can be isolated by filtering the salt from the solution. In certain embodiments, compound 1 is combined with about 1.7 to about 3 molar equivalents of L-tartaric acid. In certain embodiments, compound 1 is combined with about 1.7 to about 2.5 molar equivalents of L-tartaric acid. In certain embodiments, compound 1 is combined with about 2.05 molar equivalents of L-tartaric acid. In certain embodiments, compound 1 is combined with about 1.7 molar equivalents of L-tartaric acid.

[0084] The solvent can include any solvent or mixture of solvents that can at least partially dissolve compound 1. In some embodiments, the solvent includes an alcohol. Suitable alcohols include methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, isopropanol (isopropyl alcohol, 2-propanol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-pentanol, 2-pentanol, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol. In some embodiments, the solvent includes acetone, tetrahydrofuran, dichloromethane, methanol, ethanol, 1-propanol, or isopropanol. In some embodiments, the solvent includes dichloromethane.

[0085] In some embodiments, the solvent is tetrahydrofuran.

[0086] In some embodiments, the solvent is at about room temperature. In some embodiments, the solvent is heated to a temperature of at least about 50° C. In some embodiments, the temperature is from about 50° C. to about 80° C. In some embodiments, the temperature is from about 40° C. to about 60° C. In some embodiments, the temperature is from about 45° C. to about 55° C. In some embodiments, the temperature is about 45° C., about 50° C., about 55° C., about 60° C., about 65° C., about 70° C., about 75° C., or about 80° C.

[0087] In some embodiments, the solvent is heated to a temperature capable of inducing precipitation at a practical rate. In some embodiments, precipitation is complete within about 12 to about 24 hours, although longer and shorter periods are possible depending on the choice of precipitation solvent and temperature. In some embodiments, precipitation is complete within about 2 hours.

[0088] In some embodiments, precipitation of the L-tartrate salt (1:1.7) is carried out by filtering the salt from solution.

[0089] In some embodiments, the L-tartrate salt of Compound 1 (1:1.7) may be characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 13. In some embodiments, the L-tartrate salt of Compound 1 (1:1.7) may be characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 14. 1 It can be characterized by H NMR spectroscopy.

[0090] In some embodiments, the L-tartrate salt of Compound 1 (1:1.7) is amorphous.

[0091] Malonate In some embodiments, the salt of compound 1 is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid malonate (the malonate salt of compound 1). In some embodiments, the malonate salt of compound 1 is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid monomalonate (the monomalonate salt of compound 1).

[0092] The mono-malonate salt of compound 1 can be prepared by any suitable method for preparing mono-malonic acid addition salts. For example, compound 1 can be combined with malonic acid (e.g., about 1.0 molar equivalent or more) in a solvent, and the resulting salt can be isolated by filtering the salt from the solution. In certain embodiments, compound 1 is combined with about 1 to about 2 molar equivalents of malonic acid. In certain embodiments, compound 1 is combined with about 1 to about 1.5 molar equivalents of malonic acid. In certain embodiments, compound 1 is combined with about 1.1 molar equivalents of malonic acid.

[0093] The solvent can include any solvent or mixture of solvents that can at least partially dissolve compound 1. In some embodiments, the solvent includes an alcohol. Suitable alcohols include methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, isopropanol (isopropyl alcohol, 2-propanol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-pentanol, 2-pentanol, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol. In some embodiments, the solvent includes acetone, tetrahydrofuran, dichloromethane, methanol, ethanol, 1-propanol, or isopropanol. In some embodiments, the solvent includes dichloromethane.

[0094] In some embodiments, the solvent is a mixture of acetone, methanol, and dichloromethane.

[0095] In some embodiments, the solvent is at about room temperature. In some embodiments, the solvent is heated to a temperature of about 50° C. In some embodiments, the temperature is about 50° C. to about 80° C. In some embodiments, the temperature is about 40° C. to about 60° C. In some embodiments, the temperature is about 45° C. to about 55° C. In some embodiments, the temperature is about 45° C., about 50° C., about 55° C., about 60° C., about 65° C., about 70° C., about 75° C., or about 80° C.

[0096] In some embodiments, the solvent is heated to a temperature capable of inducing precipitation at a practical rate. In some embodiments, precipitation is complete within about 12 to about 24 hours, although longer and shorter periods are possible depending on the selection of the precipitation solvent and temperature. In some embodiments, precipitation is complete within about 1 to about 2 hours. In some embodiments, precipitation is complete within about 90 minutes.

[0097] In some embodiments, precipitation of the monomalonate salt is carried out by filtering the salt from solution.

[0098] In some embodiments, the monomalonate salt of Compound 1 is amorphous.

[0099] Phosphate In some embodiments, the salt of compound 1 is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid phosphate (the phosphate salt of compound 1). In some embodiments, the phosphate salt of compound 1 is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid phosphate (about 1:2) (the phosphate salt of compound 1 (about 1:2)), and the ratio of compound 1 to phosphate is about 1 to 2. In some embodiments, the phosphate salt of compound 1 is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid phosphate (about 1:3) (the phosphate salt of compound 1 (about 1:3)), and the ratio of compound 1 to phosphate is about 1:3.

[0100] The phosphate salt (about 1:2) of compound 1 can be prepared by any suitable method for preparing a phosphoric acid (about 1:2) addition salt. For example, compound 1 can be combined with phosphoric acid (e.g., about 2.0 molar equivalents or more) in a solvent, and the resulting salt can be isolated by filtering the salt from the solution. In certain embodiments, compound 1 is combined with about 2 to about 3 molar equivalents of phosphoric acid. In certain embodiments, compound 1 is combined with about 2 to about 2.5 molar equivalents of phosphoric acid. In certain embodiments, compound 1 is combined with about 2 molar equivalents of phosphoric acid.

[0101] The solvent can include any solvent or mixture of solvents capable of at least partially dissolving compound 1. In some embodiments, the solvent includes an alcohol. Suitable alcohols include methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, isopropanol (isopropyl alcohol, 2-propanol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-pentanol, 2-pentanol, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol. In some embodiments, the solvent includes acetone, tetrahydrofuran, dichloromethane, methanol, ethanol, 1-propanol, or isopropanol. In some embodiments, the solvent includes dichloromethane. In some embodiments, the solvent includes acetone.

[0102] In some embodiments, the solvent is a mixture of acetone, methanol, and dichloromethane.

[0103] In some embodiments, the solvent is at about room temperature. In some embodiments, the solvent is heated to a temperature of about 50° C. In some embodiments, the temperature is about 50° C. to about 80° C. In some embodiments, the temperature is about 40° C. to about 60° C. In some embodiments, the temperature is about 45° C. to about 55° C. In some embodiments, the temperature is about 45° C., about 50° C., about 55° C., about 60° C., about 65° C., about 70° C., about 75° C., or about 80° C.

[0104] In some embodiments, the solvent is heated to a temperature capable of inducing precipitation at a practical rate. In some embodiments, precipitation is complete within about 12 to about 24 hours, although longer and shorter periods are possible depending on the choice of precipitation solvent and temperature. In some embodiments, precipitation is complete within about 90 minutes.

[0105] In some embodiments, precipitation of the phosphate salt (about 1:2) is carried out by filtering the salt from the solution.

[0106] In some embodiments, the phosphate salt of Compound 1 (about 1:2) is amorphous.

[0107] The phosphate salt (about 1:3) of compound 1 can be prepared by any suitable method for preparing a phosphoric acid (about 1:3) addition salt. For example, compound 1 can be combined with phosphoric acid (e.g., about 3.0 molar equivalents or more) in a solvent, and the resulting salt can be isolated by filtering the salt from the solution. In certain embodiments, compound 1 is combined with about 3 to about 5 molar equivalents of phosphoric acid. In certain embodiments, compound 1 is combined with about 3 to about 4 molar equivalents of phosphoric acid. In certain embodiments, compound 1 is combined with about 3 molar equivalents of phosphoric acid.

[0108] The solvent can include any solvent or mixture of solvents that can at least partially dissolve compound 1. In some embodiments, the solvent includes an alcohol. Suitable alcohols include methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, isopropanol (isopropyl alcohol, 2-propanol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-pentanol, 2-pentanol, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol. In some embodiments, the solvent includes acetone, tetrahydrofuran, dichloromethane, methanol, ethanol, 1-propanol, or isopropanol. In some embodiments, the solvent includes acetone.

[0109] In some embodiments, the solvent is a mixture of acetone, methanol, and dichloromethane.

[0110] In some embodiments, the solvent is at about room temperature. In some embodiments, the solvent is heated to a temperature of about 50° C. In some embodiments, the temperature is about 50° C. to about 80° C. In some embodiments, the temperature is about 40° C. to about 60° C. In some embodiments, the temperature is about 45° C. to about 55° C. In some embodiments, the temperature is about 45° C., about 50° C., about 55° C., about 60° C., about 65° C., about 70° C., about 75° C., or about 80° C.

[0111] In some embodiments, the solvent is heated to a temperature capable of inducing precipitation at a practical rate. In some embodiments, precipitation is complete within about 12 to about 24 hours, although longer and shorter periods are possible depending on the choice of precipitation solvent and temperature. In some embodiments, precipitation is complete within about 90 minutes.

[0112] In some embodiments, precipitation of the phosphate salt (about 1:3) is carried out by filtering the salt from the solution.

[0113] In some embodiments, the phosphate salt of Compound 1 (about 1:3) is amorphous.

[0114] Different forms of the same substance have different bulk properties, e.g., with respect to hygroscopicity, solubility, stability, etc. Forms with high melting points often have good thermodynamic stability, which is advantageous for extending the shelf life of drug formulations, including solid forms. Forms with low melting points are often less thermodynamically stable, but they are advantageous in that they result in higher water solubility, which in turn results in higher drug bioavailability. Forms with low hygroscopicity are desirable for stability to heat and humidity, and resist degradation during long-term storage.

[0115] In some embodiments, the salt of Compound 1 provided herein is crystalline. As used herein, "crystalline" or "crystal form" refers to a certain lattice configuration of a crystalline substance. Different crystal forms of the same substance typically have different crystal lattices (e.g., unit cells), which are due to the different physical properties inherent to each crystal form. In some cases, different lattice configurations have different water or solvent contents.

[0116] Different salt forms can be identified by solid state characterization methods such as X-ray powder diffraction (XRPD). Other characterization methods such as differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DVS), solid state NMR, etc., further aid in identifying the crystalline form, as well as determining stability and solvent / water content.

[0117] XRPD patterns of reflections (peaks) are typically considered as fingerprints of a particular crystalline form. It is well known that the relative intensities of XRPD peaks can vary widely depending on, among other things, the sample preparation technique, the distribution of crystal sizes, the various filters used, the sample mounting procedure, and the particular instrument employed. In some instances, new peaks may be observed or existing peaks may disappear, depending on the type or settings of the instrument. As used herein, the term "peak" refers to a reflection having a relative height / intensity of at least about 4% of the maximum peak height / intensity. Furthermore, instrumental variations and other factors may affect the 2-theta values. Thus, peak assignments such as those reported herein may vary by plus or minus about 0.2° (2-theta), and the terms "substantially" and "about" as used herein in the context of XRPD are meant to encompass the above-mentioned variations.

[0118] Similarly, temperature readings for DSC, TGA, or other thermal experiments may vary by about ±3° C. depending on the instrument, the particular settings, sample preparation, etc. Thus, the crystalline forms reported herein having DSC thermograms "substantially" as shown in any of the drawings or the term "about" are understood to accommodate such variations.

[0119] In some embodiments, the term "about" means ±10%. In some embodiments, the term "about" means ±5%.

[0120] In some embodiments, the salts described herein are substantially isolated. By "substantially isolated" it is meant that the salt is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, compositions enriched in the salts described herein. Substantial separation can include compositions that contain at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of the salts described herein or salts thereof. Methods for isolating salts are routine in the art.

[0121] The salts of the present invention may also include all isotopes of atoms present in the final salt or compound 1. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0122] In some embodiments, the salts may be found together with other substances such as water and solvents (eg, hydrates and solvates) or may be isolated.

[0123] The phrase "pharmacologically acceptable" is used herein to refer to salts, materials, compositions, and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio.

[0124] The salt formation reactions described herein can be carried out at any suitable temperature, which can be readily determined by one of ordinary skill in the art. The reaction temperature will depend, for example, on the melting and boiling points of the reagents and solvent (if present), the thermodynamics of the reaction (e.g., highly exothermic reactions may need to be carried out at lower temperatures), and the kinetics of the reaction (e.g., high activation energy barriers may require higher temperatures).

[0125] As used herein, the expressions "ambient temperature" and "room temperature" or "rt" are art-recognized and generally refer to a temperature, e.g., a reaction temperature approaching the temperature of the room in which the salt-forming reaction is carried out, e.g., about 20° C. to about 30° C.

[0126] The salt-forming reactions described herein can be carried out in air or under an inert atmosphere. Typically, reactions involving reagents or products that are substantially reactive with air can be carried out using air-sensitive synthetic techniques well known to those skilled in the art.

[0127] How to use The salts of the present disclosure can inhibit the activity of PD-1 / PD-L1 protein / protein interaction and are therefore useful in treating diseases and disorders associated with the activity of PD-1, as well as diseases and disorders associated with PD-L1, including its interaction with other proteins such as PD-1 and B7-1 (CD80). In certain embodiments, the salts of the present disclosure are useful for therapeutic administration to enhance, stimulate, and / or increase immunity in cancer, chronic infection, or sepsis, including enhancing responses to vaccinations. In some embodiments, the present disclosure provides a method of inhibiting PD-1 / PD-L1 protein / protein interaction. The method comprises administering to an individual or patient a salt of Formula 1 or any of the claims and described herein, or a pharma- ceutically acceptable salt or stereoisomer thereof. The salts of the present disclosure can be used alone, in combination with other agents or therapies, or as adjuvants or neoadjuvants for the treatment of diseases or disorders, including cancer or infectious diseases. Any of the compounds of the present disclosure, including any of its embodiments, may be used in the uses described herein.

[0128] The salts of the present disclosure inhibit PD-1 / PD-L1 protein / protein interaction, resulting in blockade of the PD-1 pathway. Blockade of PD-1 can enhance immune responses to cancer cells and infectious diseases in mammals, including humans. In some embodiments, the present disclosure provides for the treatment of an individual or patient using a salt of Compound 1 in vivo, such that the growth of cancerous tumors is inhibited. A salt of Compound 1, or any of the salts claimed and described herein, can be used to inhibit the growth of cancerous tumors. Alternatively, a salt of Compound 1, or any of the salts claimed and described herein, can be used in combination with other agents or standard cancer treatments, as described below. In one embodiment, the present disclosure provides a method of inhibiting the growth of tumor cells in vitro. The method includes contacting tumor cells in vitro with a salt of Compound 1, or any of the salts claimed and described herein. In another embodiment, the present disclosure provides a method of inhibiting the growth of tumor cells in an individual or patient. The method includes administering to an individual or patient in need thereof a therapeutically effective amount of a salt of Compound 1, or any of the salts claimed and described herein.

[0129] In some embodiments, a method of treating cancer is provided herein. The method comprises administering to a patient in need thereof a therapeutically effective amount of a salt of Compound 1, or any of the salts claimed and described herein. Examples of cancers include those whose growth can be inhibited using the salts of the present disclosure, and cancers that are typically responsive to immunotherapy.

[0130] In some embodiments, the disclosure provides a method of enhancing, stimulating, and / or increasing an immune response in a patient, the method comprising administering to a patient in need thereof a therapeutically effective amount of a salt of Compound 1, or any of the salts or compositions claimed and described herein.

[0131] Examples of cancers that can be treated using salts of the present disclosure include bone cancer, pancreatic cancer, skin cancer, cancer of the head and neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, endometrial cancer, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemia, e.g., acute myeloid leukemia, These include, but are not limited to, pulmonary fibrosis, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors of childhood, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or urethra, cancer of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumors, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancers, such as asbestos induced cancers, and combinations of such cancers. The salts of the present disclosure are also useful in the treatment of metastatic cancers, particularly metastatic cancers that express PD-L1.

[0132] In some embodiments, cancers treatable with the salts of the present disclosure include melanoma (e.g., metastatic malignant melanoma, cutaneous melanoma), renal cancer (e.g., clear cell carcinoma), prostate cancer (e.g., hormone refractory prostate adenocarcinoma), breast cancer (e.g., invasive breast cancer), colon cancer, lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), head and neck squamous cell carcinoma (e.g., squamous cell carcinoma of the head and neck), urothelial carcinoma (e.g., bladder cancer, non-muscle invasive bladder cancer (NMIBC)), and microsatellite instability high cancers (MSI high Additionally, the present disclosure includes refractory or recurrent malignancies whose growth may be inhibited using the salts of the present disclosure.

[0133] In some embodiments, cancers treatable using salts of the present disclosure include, but are not limited to, solid tumors (e.g., prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc.), blood cancers (e.g., lymphoma, leukemia, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), DLBCL, mantle cell lymphoma, non-Hodgkin's lymphoma (including relapsed or refractory NHL and relapsed follicular), Hodgkin's lymphoma, or multiple myeloma), as well as combinations of such cancers.

[0134] In some embodiments, cancers treatable using salts of the present disclosure include, but are not limited to, cholangiocarcinoma, bile duct carcinoma, biliary tract cancer, triple-negative breast cancer, rhabdomyosarcoma, small cell lung cancer, leiomyosarcoma, hepatocellular carcinoma, Ewing's sarcoma, brain cancer, brain tumor, astrocytoma, neuroblastoma, neurofibroma, basal cell carcinoma, chondrosarcoma, epithelioid sarcoma, eye cancer, fallopian tube cancer, gastrointestinal cancer, gastrointestinal stromal tumor, hairy cell leukemia, intestinal cancer, pancreatic islet cell carcinoma, oral cancer, mouth cancer, throat cancer, laryngeal cancer, lip cancer, mesothelioma, cervical cancer, nasal cavity cancer, eye cancer, ocular melanoma, pelvic cancer, rectal cancer, renal cell carcinoma, salivary gland cancer, paranasal sinus cancer, spinal cancer, tongue cancer, tubular cancer, urethral cancer, and ureteral cancer.

[0135] In some embodiments, salts of the present disclosure may be used to treat sickle cell disease and sickle cell anemia.

[0136] In some embodiments, diseases and indications treatable using salts of the present disclosure include, but are not limited to, hematological cancers, sarcomas, lung cancer, gastrointestinal cancer, genitourinary tract cancer, liver cancer, bone cancer, nervous system cancer, gynecological cancer, and skin cancer.

[0137] Exemplary hematological cancers include lymphomas and leukemias, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin's lymphoma (including relapsed or refractory NHL and relapsed follicular), Hodgkin's lymphoma, myeloproliferative disorders (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocytosis (ET)), myelodysplastic syndromes (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), and multiple myeloma (MM).

[0138] Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdomyosarcoma, fibroma, lipoma, hamartoma, and teratoma.

[0139] Exemplary lung cancers include non-small cell lung cancer (NSCLC) (e.g., squamous cell NSCLC), small cell lung carcinoma, bronchogenic carcinoma (squamous cell, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchial) carcinoma, bronchial adenoma, chondroitin hamartoma, and mesothelioma.

[0140] Exemplary gastrointestinal cancers include esophageal cancer (carcinoma, squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyosarcoma, adenocarcinoma), pancreatic cancer (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, VIPoma), small intestine cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colon cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), and colorectal cancer (e.g., colorectal adenocarcinoma).

[0141] Exemplary genitourinary cancers include cancer of the kidney (adenocarcinoma, Wilms' tumor [nephroblastoma]), cancer of the bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), cancer of the prostate (adenocarcinoma, sarcoma), and cancer of the testes (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous, and lipoma). In some embodiments, the cancer is a urological cancer (e.g., papillary renal carcinoma, testicular germ cell carcinoma, chromophobe renal cell carcinoma, clear cell renal carcinoma, or prostate adenocarcinoma).

[0142] Exemplary liver cancers include hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

[0143] Exemplary bone cancers include, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (retinal cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor.

[0144] Exemplary nervous system cancers include cancer of the skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), cancer of the meninges (meningiomas, meningeal sarcomas, gliomatosis), cancer of the brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), and cancer of the spinal cord (neurofibroma, meningioma, Glioma, sarcoma), as well as neuroblastoma and Lhermitte-Duclos disease.

[0145] Exemplary gynecological cancers include cancer of the uterus (endometrial carcinoma), cancer of the cervix (cervical carcinoma, preneoplastic cervical dysplasia), cancer of the ovaries (ovarian carcinoma (serous cystadenocarcinoma, serous adenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), cancer of the vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), cancer of the vagina (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (embryonal rhabdomyosarcoma), and cancer of the fallopian tubes (epithelial carcinoma).

[0146] Exemplary skin cancers include melanoma, basal cell carcinoma, squamous cell carcinoma (e.g., cutaneous squamous cell carcinoma), Kaposi's sarcoma, lenticular dysplastic nevus, lipoma, hemangioma, dermatofibroma, and keloids. In some embodiments, diseases and indications treatable using the salts of the present disclosure include, but are not limited to, sickle cell disease (e.g., sickle cell anemia), triple-negative breast cancer (TNBC), myelodysplastic syndrome, testicular cancer, cholangiocarcinoma, esophageal cancer, and urothelial cancer.

[0147] Blockade of the PD-1 pathway by the salts of the present disclosure may also be used to treat infectious diseases, such as viral, bacterial, fungal, and parasitic infections. The present disclosure provides a method for treating an infectious disease, such as a viral infection. The method comprises administering to a patient in need thereof a therapeutically effective amount of a salt of Compound 1, or any of the salts claimed and described herein. Examples of viruses causing infectious diseases treatable by the methods of the present disclosure include, but are not limited to, human immunodeficiency virus, human papillomavirus, influenza, hepatitis A, B, C, or D virus, adenovirus, poxvirus, herpes simplex virus, human cytomegalovirus, severe acute respiratory syndrome virus, Ebola virus, and measles virus. In some embodiments, viruses causing infectious diseases treatable by the methods of the present disclosure include, but are not limited to, hepatitis viruses (types A, B, or C), herpes viruses (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein-Barr virus), adenovirus, influenza virus, flavivirus, echovirus, rhinovirus, coxsackievirus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papilloma virus, infectious virus, poliovirus, rabies virus, JC virus, tuberculosis, and arboviral encephalitis virus.

[0148] The present disclosure provides a method for treating bacterial infection. The method comprises administering to a patient in need thereof a therapeutically effective amount of a salt of Compound 1 or any of the salts described in the claims and described herein. Non-limiting examples of pathogenic bacteria causing infections treatable by the methods of the present disclosure include Chlamydia, Rickettsia, Mycobacteria, Staphylococcus, Streptococcus, Pneumonococcus, Meningococcus and Conococcus, Klubsiella, Proteus, Serratia, Pseudomonas, Legionella, Diphtheria, Salmonella, Bacillus, Cholera, Tetanus, Botulism, Anthrax, Plague, Leptospirosis, and Lyme Disease.

[0149] The present disclosure provides a method for treating a fungal infection. The method includes administering to a patient in need thereof a therapeutically effective amount of a salt of Compound 1, or any of the salts described in the claims and described herein. Non-limiting examples of pathogenic fungi causing infections treatable by the methods of the present disclosure include Candida (albicans, krusei, glabrata, tropicalis, etc.), Cryptococcosis, Aspergillus (fumigatus, niger, etc.), Genus Mucorales (Mucor, Absidia, Rhizopus), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis, and Histoplasma capsulatum.

[0150] The present disclosure provides a method for treating a parasitic infection. The method comprises administering to a patient in need thereof a therapeutically effective amount of a salt of Compound 1, or any of the salts described in the claims and described herein. Non-limiting examples of pathogenic parasites causing infections treatable by the methods of the present disclosure include Entamoeba histolytica, Balantidium coli, Naegleria fowleri, Acanthamoeba spp., Giardia lambia, Cryptosporidium spp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, and Nippostrongylus brasiliensis.

[0151] The present disclosure provides a method for treating a neurodegenerative disease or disorder. The method comprises administering to a patient in need thereof a therapeutically effective amount of a salt of Compound 1, or any of the salts described in the claims and described herein. Non-limiting examples of neurodegenerative diseases or disorders include Alzheimer's disease, Parkinson's disease, Huntington's disease, prion disease, motor neuron disease, spinocerebellar ataxia, and spinal muscular atrophy.

[0152] It is believed that a salt of Compound 1, or any of its embodiments, may have a sufficient pharmacological profile and promising biopharmaceutical properties, such as toxicological profile, metabolic and pharmacokinetic properties, solubility, and permeability. It is understood that the determination of suitable biopharmaceutical properties is within the knowledge of one of ordinary skill in the art, such as the determination of cytotoxicity or inhibition of a given target or channel in a cell to determine potential toxicity.

[0153] The terms "individual" or "patient", used interchangeably, refer to any animal, including a mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, or primate, and most preferably a human.

[0154] The phrase "therapeutically effective amount" refers to that amount of active salt that elicits the biological or drug response in a tissue, system, animal, individual, or human that is desired by a researcher, veterinarian, physician, or other clinician.

[0155] As used herein, the term "treating" or "treatment" refers to one or more of: (1) inhibiting a disease, e.g., inhibiting a disease, condition or disorder in an individual experiencing or exhibiting a pathology or symptom of the disease, condition or disorder (i.e., preventing further progression of the pathology and / or symptoms), and (2) ameliorating a disease, e.g., ameliorating a disease, condition or disorder in an individual experiencing or exhibiting a pathology or symptom of the disease, condition or disorder (i.e., reversing the condition and / or symptoms), e.g., reducing the severity of the disease.

[0156] In some embodiments, the salts of the invention are useful for preventing or reducing the risk of developing any of the diseases mentioned herein; for example, for preventing or reducing the risk of developing a disease, condition, or disorder in an individual who may have a predisposition to the disease, condition, or disorder but has not yet experienced or exhibited any of the symptoms or symptoms of the disease.

[0157] Combination therapy Immune checkpoint therapy The salts of the present disclosure may be used in combination with one or more immune checkpoint inhibitors to treat diseases, such as cancer or infectious diseases. Exemplary immune checkpoint inhibitors include inhibitors against immune checkpoint molecules such as CBL-B, CD20, CD122, CD96, CD73, CD47, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, HPK1, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, TIGIT, CD112R, VISTA, PD-1, PD-L1, and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR, and CD137 (4-1BB). In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, TIGIT, and VISTA. In some embodiments, the salts provided herein can be used in combination with one or more agents selected from a KIR inhibitor, a TIGIT inhibitor, a LAIR1 inhibitor, a CD160 inhibitor, a 2B4 inhibitor, and a TGFbeta inhibitor.

[0158] In some embodiments, the salts provided herein may be used in combination with one or more agonists of immune checkpoint molecules, such as OX40, CD27, GITR, and CD137 (also known as 4-1BB).

[0159] In some embodiments, the agonist of an immune checkpoint molecule is an agonist of OX40, CD27, CD28, GITR, ICOS, CD40, TLR7 / 8, and CD137 (also known as 4-1BB).

[0160] In some embodiments, the agonist of CD137 is urelumab. In some embodiments, the agonist of CD137 is utomirumab.

[0161] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of CD40. In some embodiments, the agonist of CD40 is CP-870893, ADC-1013, CDX-1140, SEA-CD40, RO7009789, JNJ-64457107, APX-005M, or Chi Lob 7 / 4.

[0162] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of ICOS. In some embodiments, the agonist of ICOS is GSK-3359609, JTX-2011, or MEDI-570.

[0163] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of CD28. In some embodiments, the agonist of CD28 is ceralizumab.

[0164] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of CD27. In some embodiments, the agonist of CD27 is varlilumab.

[0165] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of TLR7 / 8. In some embodiments, the agonist of TLR7 / 8 is MEDI9197.

[0166] In some embodiments, the inhibitor of an immune checkpoint molecule is an anti-PD1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

[0167] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-1, for example, an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, cemiplimab, spartalizumab, camrelizumab, cetrelimab, toripalimab, sintilimab, SHR-1210, PDR001, MGA012, PDR001, AB122, AMP-224, JTX-4014, BGB-108, BCD-100, BAT1306, LZM009, AK105, HLX10, or TSR-042. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibody is pembrolizumab. In some embodiments, the anti-PD-1 monoclonal antibody is MGA012. In some embodiments, the anti-PD1 antibody is SHR-1210. Other anti-cancer agent(s) include antibody therapeutics such as 4-1BB (e.g., urelumab, utomirumab).

[0168] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-L1, such as an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), durvalumab (Imfinzi®), atezolizumab (Tecentriq®), avelumab (Bavencio®), MSB0010718C, tislelizumab, FAZ053, KN035, CS1001, SHR-1316, CBT-502, A167, STI-A101, CK-301, BGB-A333, MSB-2311, HLX20, or LY3300054. In some embodiments, the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736.

[0169] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1 and PD-L1, such as an anti-PD-1 / PD-L1 bispecific antibody, hi some embodiments, the anti-PD-1 / PD-L1 bispecific antibody is MCLA-136.

[0170] In some embodiments, the inhibitor is MCLA-145.

[0171] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CTLA-4, such as an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab, AGEN1884, or CP-675,206.

[0172] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1 and CTLA-4, e.g., an anti-PD-1 / CTLA-4 bispecific antibody. In some embodiments, the anti-PD-1 / CTLA-4 antibody is AK104.

[0173] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of LAG3, such as an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016, LAG525, INCAGN2385, or eftiragimodo alpha (IMP321).

[0174] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD73. In some embodiments, the inhibitor of CD73 is oleculab. In some embodiments, the inhibitor of CD73 is MEDI9447.

[0175] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of TIGIT. In some embodiments, the inhibitor of TIGIT is OMP-31M32.

[0176] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of VISTA. In some embodiments, the inhibitor of VISTA is JNJ-61610588 or CA-170.

[0177] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of B7-H3. In some embodiments, the inhibitor of B7-H3 is enoblituzumab, MGD009, or 8H9.

[0178] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of KIR. In some embodiments, the inhibitor of KIR is lirilumab or IPH4102.

[0179] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of A2aR. In some embodiments, the inhibitor of A2aR is CPI-444.

[0180] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of TGF-beta. In some embodiments, the inhibitor of TGF-beta is travedersen, galcertinib, or M7824.

[0181] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PI3K-gamma. In some embodiments, the inhibitor of PI3K-gamma is IPI-549.

[0182] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD47. In some embodiments, the inhibitor of CD47 is Hu5F9-G4 or TTI-621.

[0183] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD70. In some embodiments, the inhibitor of CD70 is cusatuzumab or BMS-936561.

[0184] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of TIM3, such as an anti-TIM3 antibody. In some embodiments, the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

[0185] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of GITR, such as an anti-GITR antibody. In some embodiments, the agonist is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228, BMS-986156, GWN323, MEDI1873, or MEDI6469.

[0186] In some embodiments, the agonist of immune checkpoint molecule is an agonist of OX40, for example, an OX40 agonist antibody or an OX40L fusion protein.In some embodiments, the anti-OX40 antibody is MEDI0562, MOXR-0916, PF-04518600, GSK3174988, BMS-986178, or 9B12.In some embodiments, the OX40L fusion protein is MEDI6383.

[0187] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD20, such as an anti-CD20 antibody. In some embodiments, the anti-CD20 antibody is obinutuzumab or rituximab.

[0188] The salts of the present disclosure can be used in combination with bispecific antibodies. In some embodiments, one of the domains of the bispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3, CD137, ICOS, CD3, or TGFβ receptor. In some embodiments, the bispecific antibody binds to PD-1 and PD-L1. In some embodiments, the bispecific antibody that binds to PD-1 and PD-L1 is MCLA-136. In some embodiments, the bispecific antibody binds to PD-L1 and CTLA-4. In some embodiments, the bispecific antibody that binds to PD-L1 and CTLA-4 is AK104.

[0189] In some embodiments, the salt of the present disclosure can be used in combination with one or more metabolic enzyme inhibitors.In some embodiments, the metabolic enzyme inhibitor is an inhibitor of IDO1, TDO, or arginase.Examples of IDO1 inhibitors include epacadostat, NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099, and LY338196.

[0190] As provided throughout, the additional compounds, inhibitors, agents, etc. may be combined with the salts of this invention in a single or consecutive dosage form, or they may be administered simultaneously or sequentially as separate dosage forms.

[0191] Cancer Therapy Cancer cell growth and survival can be affected by the dysfunction of multiple biological pathways. Therefore, it can be useful to combine inhibitors of different mechanisms, such as enzyme inhibitors, signal transduction inhibitors, chromatin dynamics inhibitors, or immune response regulators, to treat such conditions. Targeting more than one signal transduction pathway (or more than one biomolecule involved in a given signal transduction pathway) can reduce the possibility of drug resistance occurring in cell populations or reduce the toxicity of treatment.

[0192] The salts of the present disclosure may be used in combination with one or more other therapies for the treatment of diseases such as cancer or infectious diseases. Examples of diseases and indications treatable with combination therapy include those described herein. Examples of cancer include solid and non-solid tumors, such as liquid tumors, hematological cancers, and the like. Examples of infectious diseases include viral infections, bacterial infections, fungal infections, or parasitic infections. For example, the salts of the present disclosure may be combined with inhibitors of one or more of the following kinases for the treatment of cancer: Akt1, Akt2, Akt3, BCL2, CDK, TGF-βR, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IDH2, IGF-1R, IR-R, PDGFαR, PDGFβR, PI3K (alpha, beta, gamma, delta, and multiple or selective), CSF1R, KIT, FLK-II, KDR / FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, PARP, Ron, Sea, TRKA, TRKB, TRKC, TAM kinases (Axl, Mer, Tyro3), FLT3, VEGFR / Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK, and B-Raf. In some embodiments, the salts of the present disclosure may be combined with one or more of the following inhibitors to treat cancer or an infectious disease: Non-limiting examples of inhibitors that may be combined with salts of the present disclosure for the treatment of cancer and infectious diseases include FGFR inhibitors (FGFR1, FGFR2, FGFR3 or FGFR4, e.g., pemigatinib (INCY54828), INCB62079), EGFR (also known as ErB-1 or HER-1) inhibitors (e.g., erlotinib, gefitinib, vandetanib, olsimertinib, cetuximab, necitumumab, or panitumumab), VEGFR inhibitors or pathway blockers (e.g., bevacizumab, pazopanib, sunitinib, sorafenib, axitinib, regorafenib, ponatinib, cabozantinib, vandetanib, ramucirumab,lenvatinib, dib aflibercept), PARP inhibitors (e.g., olaparib, rucaparib, veliparib, or niraparib), JAK inhibitors (JAK1 and / or JAK2, e.g., ruxolitinib, baricitinib, or itacitinib (INCB39110)), IDO inhibitors (e.g., epacadostat, NLG919, or BMS-986205, MK7162), LSD1 inhibitors (e.g., INCB59872 and INCB60003), TDO inhibitors, PI3K-delta inhibitors (e.g., parsaparinib, and / or INCB50797), PI3K-gamma inhibitors such as PI3K-gamma selective inhibitors, Pim inhibitors (e.g., INCB53914), EGFR inhibitors (also known as ErB-1 or HER-1; e.g., erlotinib, gefitinib, vandetanib, osimertinib, cetuximab, necitumumab, or panitumumab), VEGFR inhibitors or pathway blockers (e.g., bevacizumab, pazopanib, sunitinib, sorafenib, axitinib, regorafenib, ponatinib, cabozantinib, vandetanib, histone deacetylase inhibitors (HDACs) such as tanib, ramucirumab, lenvatinib, dib aflibercept, PARP inhibitors (e.g., olaparib, rucaparib, veliparib, talazoparib, or niraparib), CSF1R inhibitors, TAM receptor tyrosine kinases (Tyro-3, Axl, and Mer), adenosine receptor antagonists (e.g., A2a / A2b receptor antagonists), HPK1 inhibitors, chemokine receptor inhibitors (e.g., CCR2 or CCR5 inhibitors), SHP1 / 2 phosphatase inhibitors, and HDAC8 inhibitors. ), angiogenesis inhibitors, interleukin receptor inhibitors, bromo and extra-terminal family member inhibitors (e.g., bromodomain inhibitors or BET inhibitors, e.g., INCB54329 and INCB57643), arginase inhibitors (INCB001158), PARP inhibitors (such as rucaparib or olaparib), sitravatinib, B-Raf inhibitor-MEK inhibitor combinations (such as encorafenib + binimetinib, dabrafenib + trametinib, or cobimetinib + vemurafenib), and adenosine receptor antagonists,or a combination thereof.

[0193] In some embodiments, a salt of the present disclosure may be combined with a TLR7 agonist (eg, imiquimod).

[0194] The salts of the present disclosure can also be used in combination with other methods of treating cancer, such as chemotherapy, radiation therapy, tumor-targeted therapy, adjuvant therapy, immunotherapy, or surgery. Examples of immunotherapy include cytokine therapy (e.g., interferon, GM-CSF, G-CSF, IL-2), CRS-207 immunotherapy, cancer vaccines, monoclonal antibodies, bispecific or multispecific antibodies, antibody-drug conjugates, adoptive T cell transfer, Toll receptor agonists, STING agonists, RIG-I agonists, oncolytic virus therapy, and immunomodulatory small molecules, including thalidomide or JAK1 / 2 inhibitors, PI3Kδ inhibitors, etc. The salts can be administered in combination with one or more anti-cancer drugs, such as chemotherapeutic agents. Examples of chemotherapeutic agents include abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, baricitinib, bleomycin, bortezomib, intravenous busulfan, oral busulfan, calcitinone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostate propionate, Nolon, eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alpha 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, mechlorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane,Mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin, paclitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib, streptomycin, serotoninib ... Putozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, and zoledronate.

[0195] Other anti-cancer agent(s) include antibody therapeutics such as trastuzumab (Herceptin), antibodies against costimulatory molecules such as CTLA-4 (e.g., ipilimumab), 4-1BB (e.g., urelumab, utomilumab), antibodies against PD-1 and PD-L1, or antibodies against cytokines (IL-10, TGF-β, etc.). Examples of PD-1 and / or PD-L1 antibodies that may be combined with salts of the present disclosure for the treatment of cancer or infectious diseases such as viral, bacterial, fungal, and parasitic infections include, but are not limited to, nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, and SHR-1210.

[0196] The salts of the present disclosure may further be used in combination with one or more anti-inflammatory agents, steroids, immunosuppressants, or therapeutic antibodies.

[0197] A salt of Compound 1, or any of the salts claimed and described herein, may be combined with another immunogenic agent, such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune stimulating cytokines. Non-limiting examples of tumor vaccines that may be used include peptides of melanoma antigens, such as peptides of gp100, MAGE antigens, Trp-2, MARTI, and / or tyrosinase, or tumor cells transfected to express the cytokine GM-CSF.

[0198] The salts of Compound 1, or any of the salts claimed and described herein, may be used in combination with vaccination protocols for the treatment of cancer. In some embodiments, tumor cells are transduced to express GM-CSF. In some embodiments, tumor vaccines include proteins from viruses implicated in human cancers, such as human papillomavirus (HPV), hepatitis viruses (HBV and HCV), and Kaposi's herpes sarcoma virus (KHSV). In some embodiments, the salts of the present disclosure may be used in combination with tumor-specific antigens, such as heat shock proteins isolated from the tumor tissue itself. In some embodiments, the salts of Compound 1, or any of the salts claimed and described herein, may be combined with dendritic cell immunity to activate a strong anti-tumor response.

[0199] The salts of the present disclosure can be used in combination with bispecific macrocyclic peptides that target Fe alpha or Fe gamma receptor expressing effector cells to tumor cells. The salts of the present disclosure can also be combined with macrocyclic peptides that activate host immune responsiveness.

[0200] Salts of the present disclosure may be used in conjunction with bone marrow transplantation for the treatment of various tumors of hematopoietic origin.

[0201] The salts of Compound 1 or any of the salts claimed and described herein may be used in combination with vaccines to stimulate immune responses against pathogens, toxins, and self-antigens. Examples of pathogens for which this therapeutic approach may be particularly useful include those for which there is currently no effective vaccine or for which traditional vaccines are not fully effective. These include, but are not limited to, HIV, Hepatitis (types A, B, and C), influenza, herpes, Giardia, Malaria, Leishmania, Staphylococcus aureus, and Pseudomonas Aeruginosa.

[0202] Viruses causing infectious diseases treatable by the methods of the present disclosure include, but are not limited to, human papillomavirus, influenza, hepatitis A, B, C, or D virus, adenovirus, poxvirus, herpes simplex virus, human cytomegalovirus, severe acute respiratory syndrome virus, Ebola virus, measles virus, herpes virus (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein-Barr virus), flavivirus, echovirus, rhinovirus, coxsackievirus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, infectious virus, poliovirus, rabies virus, JC virus, and arboviral encephalitis virus.

[0203] Pathogenic bacteria causing infections treatable by the methods of the present disclosure include, but are not limited to, Chlamydia, Rickettsia bacteria, Mycobacteria, Staphylococcus, Streptococcus, Pneumonococcus, Meningococcus and Conococcus, Klubsiella, Proteus, Serratia, Pseudomonas, Legionella, Diphtheria, Salmonella, Bacillus, Cholera, Tetanus, Botulism, Anthrax, Plague, Leptospirosis, and Lyme burgdorferi.

[0204] Pathogenic fungi causing infections treatable by the methods of the present disclosure include, but are not limited to, Candida (e.g., Candida albicans, Candida krusei, Candida glabrata, Candida tropicalis, etc.), Cryptococcus neoformans, Aspergillus (e.g., Candida fumigatus, Candida niger, etc.), Genus Mucorales (e.g., Mucor, Absidia, Rhizopus), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis, and Histoplasma capsulatum.

[0205] Examples of pathogenic parasites causing infections treatable by the methods of the present disclosure include, but are not limited to, Entamoeba histolytica, Balantidium coli, Naegleria fowleri, Acanthamoeba spp., Giardia lambia, Cryptosporidium spp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, and Nippostrongylus brasiliensis.

[0206] When more than one pharmaceutical agent is administered to a patient, they may be administered simultaneously, separately, sequentially, or in combination (eg, in the case of more than two agents).

[0207] Formulation, Dosage Forms, and Administration When used as a pharmaceutical, the salts of the present disclosure may be administered in the form of a pharmaceutical composition. Thus, the present disclosure provides compositions comprising a salt of Compound 1, or any of the salts described in the claims and described herein, or any of their embodiments, and at least one pharma- ceutically acceptable carrier or excipient. These compositions can be prepared by methods well known in the pharmaceutical art, and can be administered by various routes, depending on whether local or systemic treatment is indicated and the area to be treated. Administration can be topical (including delivery to mucous membranes, including transdermal, epidermal, ocular, and intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral, or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, or injection or infusion, or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose or, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

[0208] The present disclosure also includes pharmaceutical compositions that contain the salt of the present disclosure as an active ingredient in combination with one or more pharma- ceutically acceptable carriers or excipients. In some embodiments, the composition is suitable for topical administration. In making the composition of the present invention, the active ingredient is typically mixed with an excipient, diluted by an excipient, or enclosed in such a carrier, for example, in the form of a capsule, sachet, paper, or other container. When an excipient functions as a diluent, it can be a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition can be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or liquid medium), for example, an ointment containing up to 10% by weight of the active salt, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0209] When preparing the formulation, active salt can be milled to obtain a suitable particle size before combining with other components.If active salt is substantially insoluble, it can be milled to a particle size of less than 200 mesh.If active salt is substantially water-soluble, particle size can be adjusted by milling to obtain a substantially uniform distribution in the formulation, for example, about 40 mesh.

[0210] The salts of the invention may be milled using known milling procedures, such as wet milling, to obtain a particle size suitable for tablet formation and other formulation types. Finely divided (nanoparticulate) preparations of the salts of the invention may be prepared by processes known in the art (see, for example, WO 2002 / 000196).

[0211] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup and methylcellulose.The formulation can further comprise lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methylbenzoate and propylhydroxybenzoate; sweeteners; and flavoring agents.The composition of the present invention can be formulated to provide quick, sustained or delayed release of active ingredient after administration to patient by using methods known in the art.

[0212] In some embodiments, the pharmaceutical composition comprises silicified microcrystalline cellulose (SMCC) and at least one salt described herein. In some embodiments, the silicified microcrystalline cellulose comprises about 98% microcrystalline cellulose and about 2% silicon dioxide w / w.

[0213] In some embodiments, the composition is a sustained release composition comprising at least one salt as described herein and at least one pharma- ceutically acceptable carrier or excipient. In some embodiments, the composition comprises at least one salt as described herein and at least one component selected from microcrystalline cellulose, lactose monohydrate, hydroxypropyl methylcellulose, and polyethylene oxide. In some embodiments, the composition comprises at least one salt as described herein and microcrystalline cellulose, lactose monohydrate, and hydroxypropyl methylcellulose. In some embodiments, the composition comprises at least one salt as described herein and microcrystalline cellulose, lactose monohydrate, and polyethylene oxide. In some embodiments, the composition further comprises magnesium stearate or silicon dioxide. In some embodiments, the microcrystalline cellulose is AvicelPH102™. In some embodiments, the lactose monohydrate is Fast-flo 316™. In some embodiments, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208 K4M (e.g., Methocel K4 M Premier™) and / or hydroxypropyl methylcellulose 2208 K100LV (e.g., Methocel K00LV™). In some embodiments, the polyethylene oxide is polyethylene oxide WSR 1105 (e.g., Polyox WSR 1105™).

[0214] In some embodiments, the compositions are manufactured using a wet granulation process. In some embodiments, the compositions are manufactured using a dry granulation process.

[0215] The compositions may be formulated in unit dosage form, each dosage containing from about 5 to about 1000 mg (1 g), more usually from about 100 to about 500 mg, of the active ingredient. In some embodiments, each dosage contains about 10 mg of active ingredient. In some embodiments, each dosage contains about 50 mg of active ingredient. In some embodiments, each dosage contains about 25 mg of active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[0216] The ingredients used to formulate the pharmaceutical compositions are of high purity and substantially free of potentially harmful contaminants (e.g., at least national food grade, generally at least analytical grade, more typically at least pharmaceutical grade). In particular, for human consumption, the compositions are preferably manufactured or formulated in accordance with good manufacturing practice regulations as defined in applicable regulations of the U.S. Food and Drug Administration. For example, suitable formulations may be sterile and / or substantially isotonic, and / or in full compliance with all U.S. Food and Drug Administration good manufacturing practice regulations.

[0217] The active salts can be effective over a wide dosage range and are generally administered in a therapeutically effective amount. However, it will be understood that the amount of salt actually administered will usually be determined by the physician according to the relevant circumstances, including the condition being treated, the selected route of administration, the salt actually administered, the age, weight, and response of the individual patient, the severity of the patient's condition, and the like.

[0218] The therapeutic dosage of the salt of the invention may vary according to, for example, the particular application for which the treatment is being performed, the method of administration of the salt, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of the salt of the invention in a pharmaceutical composition may vary depending on many factors, including the dosage, chemical characteristics (e.g., hydrophobicity), and route of administration. For example, the salt of the invention may be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w / v of the salt for parenteral administration. Some typical dosage ranges are about 1 μg / kg to about 1 g / kg of body weight per day. In some embodiments, the dosage range is about 0.01 mg / kg to about 100 mg / kg of body weight per day. The dosage may depend on such variables as the type and extent of progression of the disease or disorder, the overall health of the particular patient, the relative biological availability of the selected salt, the excipient formulation, and its route of administration. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0219] To prepare solid compositions such as tablets, the primary active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of the salt of the present invention. When referring to these preformulation compositions as homogeneous, the active ingredient is typically evenly dispersed throughout the composition, and the composition can be readily divided into equally effective unit dosage forms such as tablets, pills, and capsules. This solid preformulation composition is then further divided into unit dosage forms of the type described above, for example, containing from about 0.1 to about 1000 mg of the active ingredient of the present invention.

[0220] The tablet or pill of the present invention can be coated or otherwise compounded to provide a dosage form that provides the advantage of long-term action.For example, the tablet or pill can comprise an inner dose and an outer dose component, the latter being in the form of an envelope on a forming agent.The two components can be separated by an enteric layer that resists disintegration in the stomach and allows the inner component to pass intact into the duodenum or to be delayed in release.Various materials can be utilized as such enteric layer or coating, including materials including a number of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0221] Liquid forms for oral or injectable administration into which the salts and compositions of the invention may be incorporated include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and flavored emulsions containing edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0222] Compositions for inhalation or insufflation include solutions and suspensions in pharma- ceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharma- ceutically acceptable excipients as described above. In some embodiments, the compositions are administered by oral or nasal respiratory route for local or systemic effect. Compositions may be nebulized by using inert gases. Nebulized solutions may be breathed directly from the nebulizing device, or the nebulizing device may be attached to a face mask, tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0223] Topical formulations may include one or more conventional carriers. In some embodiments, ointments may include water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white petrolatum, and the like. The carrier composition of creams may be based on glycerol and water in combination with one or more other ingredients, such as, for example, glycerol monostearate, PEG-glycerol monostearate, and cetylstearyl alcohol. Gels may be formulated using isopropyl alcohol and water, preferably in combination with other ingredients, such as, for example, glycerol, hydroxyethylcellulose, and the like. In some embodiments, topical formulations include at least about 0.1, at least about 0.25, at least about 0.5, at least about 1, at least about 2, or at least about 5% by weight of the salt of the invention. Topical formulations may be suitably packaged in 100 g tubes, optionally accompanied by instructions for treating a selected indication, such as, for example, psoriasis or other skin conditions.

[0224] The amount of salt or composition administered to a patient will vary depending on what is being administered, the purpose of the administration, such as prophylaxis or treatment, the condition of the patient, the method of administration, etc. In therapeutic applications, the compositions may be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dose will depend on the condition of the disease being treated, as well as the judgment of the attending clinician, based on factors such as the severity of the disease, the age, weight, and general health of the patient.

[0225] The compositions administered to patients may be in the form of pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques or may be sterile filtered. Aqueous solutions may be packaged or lyophilized for use as is, although lyophilized preparations are combined with a sterile aqueous carrier prior to administration. The pH of the formulations will typically be 3-11, more preferably 5-9, and most preferably 7-8.

[0226] The therapeutic dosage of the salt of the invention may vary according to, for example, the particular application for which the treatment is to be performed, the method of administration of the salt, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of the salt of the invention in a pharmaceutical composition may vary depending on many factors, including the dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, the salt of the invention may be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w / v of the salt for parenteral administration. Some typical dosages range from about 1 μg / kg body weight to about 1 g / kg body weight per day. In some embodiments, the dosage range is from about 0.01 mg / kg body weight to about 100 mg / kg body weight per day. The dosage may depend on such variables as the type and extent of progression of the disease or disorder, the overall health of the particular patient, the relative biological availability of the selected salt, the excipient formulation, and its route of administration. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0227] Labeled Compounds and Assay Methods The salts of the present disclosure may further be useful in investigating biological processes in normal and abnormal tissues. Accordingly, another aspect of the present invention relates to labeled salts of the present invention (radiolabeled, fluorescently labeled, etc.) that may be useful in imaging techniques as well as in both in vitro and in vivo assays for localizing and quantitating PD-1 or PD-L1 protein in tissue samples, including humans, and for identifying PD-L1 ligands by inhibitory binding of the labeled compounds. Thus, the present invention includes PD-1 / PD-L1 binding assays comprising such labeled salts.

[0228] The present invention further includes isotopically substituted salts of the present disclosure. An "isotopically substituted" salt is a salt of the present invention in which one or more atoms have been replaced or substituted by an atom having the same atomic number, but, for example, an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). It is to be understood that a "radiolabeled" salt is a salt incorporating at least one isotope (e.g., a radionuclide) that is radioactive. Suitable radionuclides that can be incorporated into the salt of the present invention include: 3 H (written as T for tritium), 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I, and 131 The radionuclide incorporated in the radiolabeled salts of the present invention will depend on the particular application of the radiolabeled salt. For example, in in vitro PD-L1 protein labeling and competition assays, 3 H, 14 C. 82 Br, 125 I, 131 I, 35 Salts incorporating S will generally be most useful. For radioimaging applications, 11 C. 18 F, 125 I, 123 I, 124 I, 131 I, 75 Br, 76 Br or 77 Br will generally be the most useful.

[0229] In some embodiments, the radionuclide is 3H, 14 C. 125 I, 35 S, and 82 Br. Synthetic methods for incorporating radioisotopes into organic compounds and salts are known in the art.

[0230] Specifically, the labeled salts of the present invention can be used in screening assays to identify and / or evaluate compounds. For example, a labeled newly synthesized or identified salt (i.e., a test salt) can be evaluated for its ability to bind to PD-L1 protein by monitoring its concentration change upon contact with PD-L1 protein through tracking of the label. For example, a (labeled) test salt can be evaluated for its ability to reduce the binding of another compound (i.e., a standard compound) known to bind to PD-L1 protein. Thus, the ability of the test salt to compete with the standard compound for binding to PD-L1 protein directly correlates with its binding affinity. Conversely, in some other screening assays, the standard salt is labeled and the test compound is not labeled. Thus, to evaluate the competition between the standard compound and the test salt, the concentration of the labeled standard salt is monitored, thereby ascertaining the relative binding affinity of the test salt.

[0231] kit The present disclosure also includes pharmaceutical kits useful for treating or preventing a disease or disorder associated with activity of PD-L1, including PD-1 and its interaction with other proteins such as B7-1 (CD80), e.g., cancer or infectious disease, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a salt of Compound 1, or any of its embodiments. As will be apparent to one of skill in the art, such kits can further include one or more of a variety of conventional pharmaceutical kit components, e.g., a container with one or more pharma- ceutically acceptable carriers, additional containers, etc. Instructions, either as a package insert or label, indicating amounts of components to be administered, administration guidelines, and / or guidelines for mixing the components, can also be included in the kit.

[0232] The following abbreviations may be used herein: aq. (aqueous); br (broad); d (doublet); dd (doublet of doublets); DCM (dichloromethane); DMF (N,N-dimethylformamide); Et (ethyl); EtOAc (ethyl acetate); g (gram(s); h (hour(s); HPLC (high performance liquid chromatography); Hz (hertz); J (coupling constant); LCMS (liquid chromatography-mass spectrometry); m (multiplet); M (molar); MS (mass spectrometry); Me (methyl); MeCN (acetonitrile); MeOH (methanol); m g (milligram(s); min. (minute(s); mL (milliliter(s); mmol (millimole(s); nM (nanomole); NMR (nuclear magnetic resonance spectroscopy); Ph (phenyl); rt (room temperature); s (singlet); t (triplet or tertiary); TBS (tert-butyldimethylsilyl); tert (tertiary); tt (triplet of triplets); TFA (trifluoroacetic acid); THF (tetrahydrofuran); μg (microgram(s); μL (microliter(s); μM (micromole); wt% (weight percent).

[0233] The present invention will be described in more detail by specific examples. The following examples are provided for illustrative purposes and are not intended to limit the present invention in any manner. Those skilled in the art will readily recognize a variety of non-critical parameters that can be changed or modified to yield essentially the same results. The salts of the examples have been found to inhibit the activity of PD-1 / PD-L1 protein / protein interaction by at least one assay described herein. EXAMPLES

[0234] Experimental Method In the following examples, X-ray powder diffraction analysis was performed on a Rigaku MiniFlex X-ray powder diffractometer (XRPD) instrument. The general experimental procedure for XRPD was as follows: (1) X-ray emission from copper at 1.054056 Å with Kβ filter, (2) X-ray power at 30 KV, 15 mA, and (3) sample powder was dispersed on a zero-background sample holder. The general measurement conditions for XRPD were as follows: start angle 3 degrees; stop angle 45 degrees; sampling 0.02 degrees; and scan speed 2 degrees / min.

[0235] Differential scanning calorimetry (DSC) was performed on a TA Instruments Differential Scanning Calorimeter, Model Q200, equipped with an autosampler. DSC instrument conditions were as follows: 30-300 °C at 10 °C / min, T-zero aluminum sample pan and lid, and nitrogen gas flow at 50 mL / min. Thermogravimetric analysis (TGA) was performed on a TA Instrument thermogravimetric analyzer, model Q500. General experimental conditions for the TGA were: ramp from 20° C. to 600° C. at 20° C. / min; nitrogen purge gas flow at 40 mL / min followed by balance of purge flow; sample purge flow at 60 mL / min; platinum sample pan. Purity was determined by HPLC using the conditions given below. [Table 1] [Table 2]

[0236] Example 1. Preparation of monomalonate of compound 1 A 500 mL round bottom flask equipped with a stir bar was charged with acetone (200 mL) followed by malonic acid (0.825 g, 7.93 mmol). The mixture was stirred at room temperature until completely homogenous.

[0237] A 100 mL round bottom flask equipped with a stir bar was charged with compound 1 (5.0 g, 7.21 mmol), methanol (5.0 mL), and dichloromethane (45.0 mL). The mixture was stirred until homogeneous.

[0238] The solution (slightly cloudy) was polish filtered directly into a 60 mL addition funnel using a syringe and filter disk. The round bottom flask was rinsed with 6 mL of 10% methanol / dichloromethane solution and the solution was filtered into the addition funnel. Compound 1 solution was added over 29 minutes. The addition funnel was rinsed with 4 mL of 10% methanol / dichloromethane and added to the slurry. The slurry was stirred at room temperature for 90 minutes.

[0239] The filter cake was rinsed with acetone (100 mL) and the solid was dried in a desiccator under high vacuum for 3.5 h. The recovered solid was 5.2 g and placed in a vacuum oven at 50° C. under nitrogen for 16 h. 5.1 g of product was recovered. HPLC purity 98.69%. Residual acetone (NMR): 940 ppm.

[0240] Example 2. Preparation of the monohydrobromide salt of compound 1 Hydrobromic acid (0.322 mL, 0.322 mmol, 1.0 M in isopropyl alcohol / water from a 48% aqueous solution, 1.05 equiv.) was added to a solution of compound 1 (212.62 mg, 0.306 mmol, 1.0 equiv.) in a 3:2 v / v mixture of methanol and dichloromethane (7.0 mL). The reaction mixture was stirred to give a thin slurry. The thin slurry was stirred for 1 h to give a slurry, and then stirred continuously overnight. The slurry was filtered to give the mother liquor and solid. The solid was dried under vacuum at 45-46 °C overnight to give the monohydrobromide salt of compound 1 as an amorphous solid (195 mg, 82% yield).

[0241] The stoichiometric ratio between compound 1 and hydrobromic acid was determined as 1:1 by HPLC. The monohydrobromide salt of compound 1 was characterized by XRPD (Figure 1). Analytical data collected on the product was obtained. The purity of the monohydrobromide salt was determined to be 99.4% by HPLC.

[0242] Example 3. Alternative preparation of the monohydrobromide salt of compound 1 Hydrobromic acid (0.097 mL, 0.097 mmol, 1.0 M in isopropyl alcohol / water from a 48% aqueous solution, 1.05 equiv.) was added dropwise to a solution of compound 1 (63.79 mg, 0.092 mmol, 1.0 equiv.) in tetrahydrofuran (1.6 mL). The reaction mixture was stirred to give a fine slurry. The slurry was stirred for 2 h and filtered. The solid was dried under vacuum at 40-41 °C overnight to give the monohydrobromide salt of compound 1 as an amorphous solid (63.70 mg, 89% yield).

[0243] The stoichiometric ratio between compound 1 and hydrobromic acid was determined as 1:1 by HPLC. The monohydrobromide salt of compound 1 was characterized by XRPD (FIG. 2). Analytical data collected on the product was obtained. The purity of the monohydrobromide salt was determined to be 99.7% by HPLC.

[0244] Example 4. Preparation of the monooxalate salt of compound 1 Oxalic acid (7.41 mg, 0.082 mmol, 1.05 equiv) was added to a solution of compound 1 (54.36 mg, 0.076 mmol, 1.0 equiv) in tetrahydrofuran (2.0 mL). The reaction mixture was stirred to give a slurry. The slurry was stirred for 2 h and filtered to give a mother liquor and a solid. The solid was dried under vacuum at 40-41 °C overnight to give the monooxalate salt of compound 1 as an amorphous solid (54.5 mg, 89% yield).

[0245] The stoichiometric ratio between compound 1 and oxalic acid was determined by elemental analysis to be 1:1 (C as theory). 43 H 41 N 7 O 8 2H 2O: C, 62.99; H, 5.53; N, 11.96, analytically C, 62.48; H, 5.33; N, 11.44). The monooxalate salt of compound 1 was characterized by XRPD (Figure 3). The TGA of the salt is shown in Figure 4. Analytical data collected on the product was obtained. The purity of the monooxalate salt was determined to be 99.3% by HPLC.

[0246] Example 5. Alternative preparation of the monooxalate salt of compound 1 A 50 mL round bottom flask equipped with a stir bar was charged with acetone (10.7 mL) followed by oxalic acid (77 mg, 0.851 mmol). The mixture was stirred at room temperature until completely homogenous.

[0247] A scintillation vial equipped with a stir bar was charged with Compound 1 (537 mg, 0.774 mmol), methanol (537 μL), and dichloromethane (4.83 mL). The mixture was stirred until homogeneous.

[0248] The solution of compound 1 was polish filtered using a syringe and filter disk directly into a clean scintillation vial. The solution of compound 1 was added dropwise via pipette over 3 minutes. The slurry was stirred at room temperature for 90 hours and the solid was filtered. The filter cake was rinsed with acetone (10 mL) and the solid was dried under high vacuum for 18 hours. 565 mg of product was recovered with a purity of 98.58%.

[0249] Example 6. Preparation of the monohydrochloride salt of compound 1 Hydrochloric acid (0.504 mL, 0.504 mmol, 1.0 M in isopropyl alcohol / water from a 37% aqueous solution, 1.05 equiv.) was added to a solution of compound 1 (332.80 mg, 0.480 mmol, 1.0 equiv.) in a 3:2 v / v mixture of methanol and dichloromethane (9.0 mL). The reaction mixture was stirred to obtain a clear solution and stirred continuously for 1 h. The dichloromethane was removed to obtain a slurry, and the slurry was stirred overnight. The slurry was filtered to obtain the mother liquor and solid. The solid was dried under vacuum at 45-46 °C overnight to obtain the monohydrochloride salt of compound 1 as an amorphous solid (287.7 mg, 82% yield).

[0250] The stoichiometric ratio between compound 1 and hydrochloric acid was determined as 1:1 by HPLC. The monohydrochloride salt of compound 1 was characterized by XRPD (FIG. 5). Analytical data collected on the product was obtained. The purity of the monohydrochloride salt was determined to be 99.0% by HPLC.

[0251] Example 7. Preparation of L-tartrate salt of compound 1 (1:1.5) [ka] L-Tartaric acid (11.74 mg, 0.078 mmol, 1.05 equiv.) was added to a solution of compound 1 (51.58 mg, 0.074 mmol) in tetrahydrofuran (1.6 mL). The reaction mixture was stirred for 25 min to give a slurry. The slurry was stirred continuously for 2 h and then filtered to give the mother liquor and solid. The solid was dried under vacuum at 40-41 °C overnight to give the L-tartrate salt of compound 1 as an amorphous solid (46.5 mg, 97% yield based on the moles of L-tartaric acid (limiting reactant) used).

[0252] The stoichiometric ratio between compound 1 and L-tartaric acid is 1 The ratio was 1:1.5 by H NMR (Figure 7). The L-tartrate salt of compound 1 was characterized by XRPD (Figure 6). Analytical data collected on the product was obtained. The purity of the L-tartrate salt was determined to be 99.3% by HPLC.

[0253] Example 8. Preparation of the dihydrobromide salt of compound 1 Hydrobromic acid (0.32 mL, 0.320 mmol, 1.0 M in isopropyl alcohol / water from a 48% aqueous solution, 2.30 equiv.) was added to a slurry of compound 1 (100 mg, 0.141 mmol, 1.0 equiv.) in methanol (2.0 mL). The reaction mixture was stirred to obtain a clear solution and then stirred continuously overnight. 0.5 mL of the slurry was filtered to obtain the mother liquor and solid sample 1. Isopropyl alcohol (1.0 mL) was added to the remaining slurry and stirred continuously for 4 h. The slurry was filtered to obtain the mother liquor and solid sample 2. Solid samples 1 and 2 were dried under vacuum at 45-46 °C overnight to obtain the dihydrobromide salt of compound 1 (32 mg sample 1 and 70 mg sample 2, 85% overall yield) as an amorphous solid.

[0254] The stoichiometric ratio between compound 1 and hydrobromic acid was determined as 1:2 by HPLC (sample 2). The dihydrobromide salt of compound 1 was characterized by XRPD (FIG. 8, samples 1 and 2). Analytical data collected on the product was obtained. The purity of the dihydrobromide salt was determined by HPLC to be 97.8% (sample 1) and 97.2% (sample 2).

[0255] Example 9. Alternative preparation of the dihydrobromide salt of compound 1 Hydrobromic acid (0.149 mL, 0.149 mmol, 1.0 M in IPA / water from a 48% aqueous solution, 2.04 equiv.) was added dropwise to a solution of compound 1 (50.59 mg, 0.073 mmol, 1.0 equiv.) in tetrahydrofuran (2.0 mL). The reaction mixture was stirred to give a fine slurry. The slurry was stirred at 25° C. for 2.5 h and filtered to give the mother liquor and solid. The solid was dried under vacuum at 40-41° C. overnight to give the dihydrobromide salt of compound 1 (56.5 mg, 91% yield) as an amorphous solid.

[0256] The stoichiometric ratio between compound 1 and hydrobromic acid was determined as 1:2 by HPLC. The dihydrobromide salt of compound 1 was characterized by XRPD (FIG. 9). Analytical data collected on the product was obtained. The purity of the dihydrobromide salt was determined to be 99.7% by HPLC.

[0257] Example 10. Preparation of the disoxalate salt of compound 1 Oxalic acid (20.11 mg, 0.223 mmol, 2.05 equiv.) was added to a solution of compound 1 (75.58 mg, 0.109 mmol, 1.0 equiv.) in tetrahydrofuran (2.0 mL). The reaction mixture was stirred to give a slurry. The slurry was continuously stirred for 2 h and filtered to give the mother liquor and solid. The solid was dried under vacuum at 40-41 °C overnight to give the disoxalate salt of compound 1 (89.5 mg, 94% yield) as a crystalline solid.

[0258] The stoichiometric ratio between compound 1 and oxalic acid was determined by elemental analysis to be 1:2 (C as theory). 45 H 43 N 7 O 12 100°C。 Analytical data was obtained. The purity of the dioxalate salt was determined to be 96.1% by HPLC.

[0259] [Table 3]

[0260] Example 11. Preparation of L-tartrate salt of compound 1 (1:1.7) [ka] L-Tartaric acid (31.52 mg, 0.210 mmol, 2.05 equiv.) was added to a solution of compound 1 (71.02 mg, 0.102 mmol) in tetrahydrofuran (2.0 mL). The reaction mixture was stirred for 30 min to give a slurry. The slurry was continuously stirred for 2 h and then filtered to give the mother liquor and solid. The solid was dried under vacuum at 40-41 °C overnight to give the L-tartrate salt of compound 1 (90.5 mg, 96% yield).

[0261] The stoichiometric ratio between compound 1 and L-tartaric acid is 1 The ratio was 1:1.7 by H NMR (Figure 14). The L-tartrate salt of compound 1 was characterized by XRPD (Figure 13). Analytical data collected on the product was obtained. The purity of the L-tartrate salt was determined to be 96.4% by HPLC.

[0262] Example 12. Preparation of the trihydrochloride salt of compound 1 A scintillation vial was charged with Compound 1 (500 mg, 0.721 mmol) and dimethylsulfoxide (4.0 mL).

[0263] A 50 mL round bottom flask equipped with a stir bar was charged with tetrahydrofuran (30.0 mL) and 4N hydrochloric acid / dioxane (721 uL, 4 equiv.). With stirring, the solution of compound 1 was added dropwise via pipettor to the tetrahydrofuran solution over 3 minutes. A solid precipitated from the solution and the slurry was pale yellow. The mixture was stoppered and stirred at room temperature overnight.

[0264] The slurry was filtered and the filter cake was rinsed with tetrahydrofuran (10.0 mL). The resulting solid was dried under vacuum. 598 mg of salt was recovered. HPLC purity was 98.5085%. Chloride analysis showed 2.89 equivalents of hydrochloric acid.

[0265] Example 13. Preparation of the phosphate salt of compound 1 (about 1:3) A 40 mL scintillation vial equipped with a stir bar was charged with acetone (15.0 mL) and phosphoric acid (0.151 mL, 2.162 mmol, 3 equiv). The mixture was stirred to obtain a clear solution. A 20 mL scintillation vial was charged with compound 1 (500 mg, 0.721 mmol), dichloromethane (4.50 mL), and methanol (0.50 mL). The mixture was stirred until homogeneous and then added dropwise to the phosphoric acid solution over 3-4 min. A yellow solid precipitated from the solution and the mixture was stirred at room temperature for 90 min and then filtered. The filter cake was washed with acetone (5.00 mL) and the solid was dried under high vacuum.

[0266] 722 mg of product was recovered. HPLC purity was 98.7%. The salt ratio was determined to be 1:2.78 by acid-base titration of the phosphate content.

[0267] Example 14. Preparation of the phosphate salt of compound 1 (about 1:2) A 40 mL scintillation vial equipped with a stir bar was charged with acetone (15.0 mL) and phosphoric acid (0.103 mL, 1.477 mmol, 2 equiv). The mixture was stirred to obtain a clear solution. A 20 mL scintillation vial was charged with compound 1 (500 mg, 0.721 mmol), dichloromethane (4.50 mL), and methanol (0.50 mL). The mixture was stirred until homogeneous and then added dropwise to the phosphoric acid solution over 3-4 min. A yellow solid precipitated from the solution and the mixture was stirred at room temperature for 90 min and then filtered. The filter cake was washed with acetone (5.00 mL) and the solid was dried under high vacuum.

[0268] 640 mg of product was recovered. HPLC purity was 98.7%. The salt ratio was determined to be 1:2.29 by acid-base titration of the phosphate content.

[0269] In addition to those described herein, various modifications of the present invention will become apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patents, patent applications, and publications cited in this application, is hereby incorporated by reference in its entirety. The present application also includes the following aspects. [Aspect 1] A salt selected from: (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid hydrobromide; (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid oxalate; (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid hydrochloride; (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid L-tartrate; (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid malonate; and (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid phosphate. [Aspect 2] The salt of embodiment 1, wherein the salt is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid hydrobromide. [Aspect 3] The salt of embodiment 2, wherein the salt is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid monohydrobromide. [Aspect 4] The salt of embodiment 2, wherein the salt is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid dihydrobromide. [Aspect 5] The salt of embodiment 1, wherein the salt is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid oxalate. [Aspect 6] The salt of embodiment 5, wherein the salt is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid monooxalate. [Aspect 7] The salt according to embodiment 6, having a thermogravimetric analysis (TGA) thermogram substantially as shown in FIG. [Aspect 8] The salt of embodiment 5, wherein the salt is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid disoxalate. [Aspect 9] The salt according to embodiment 8, having an X-ray powder diffraction pattern substantially as shown in FIG. 10. [Aspect 10] 9. The salt according to embodiment 8, having a DSC thermogram substantially as shown in FIG. [Aspect 11] The salt according to embodiment 8, having a thermogravimetric analysis (TGA) thermogram substantially as shown in FIG. 12. [Aspect 12] 9. The salt of embodiment 8, having at least one X-ray powder diffraction (XRPD) peak selected from 7.0±0.2 degrees, 11.4±0.2 degrees, 13.2±0.2 degrees, 14.9±0.2 degrees, and 17.0±0.2 degrees 2-theta. [Aspect 13] 9. The salt of embodiment 8, having at least two X-ray powder diffraction (XRPD) peaks selected from 7.0±0.2 degrees, 11.4±0.2 degrees, 13.2±0.2 degrees, 14.9±0.2 degrees, and 17.0±0.2 degrees 2-theta. [Aspect 14] 9. The salt of embodiment 8, having at least three X-ray powder diffraction (XRPD) peaks selected from 7.0±0.2 degrees, 11.4±0.2 degrees, 13.2±0.2 degrees, 14.9±0.2 degrees, and 17.0±0.2 degrees 2-theta. [Aspect 15] 9. The salt of embodiment 8, having at least four X-ray powder diffraction (XRPD) peaks selected from 7.0±0.2 degrees, 11.4±0.2 degrees, 13.2±0.2 degrees, 14.9±0.2 degrees, and 17.0±0.2 degrees 2-theta. [Aspect 16] The salt of embodiment 8, having characteristic X-ray powder diffraction (XRPD) peaks at 7.0±0.2 degrees, 11.4±0.2 degrees, 13.2±0.2 degrees, 14.9±0.2 degrees, and 17.0±0.2 degrees 2-theta. [Aspect 17] The salt according to embodiment 8, having an endothermic peak at a temperature of about 235±3° C. in a differential scanning calorimetry (DSC) thermogram. [Aspect 18] The salt of embodiment 1, wherein the salt is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid hydrochloride. [Aspect 19] The salt of embodiment 18, wherein the salt is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid monohydrochloride. [Aspect 20] The salt of embodiment 18, wherein the salt is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid trihydrochloride. [Aspect 21] The salt of embodiment 1, wherein the salt is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid L-tartrate. [Aspect 22] 22. The salt of claim 21, wherein the salt is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid L-tartrate (1:1.5). [Aspect 23] Substantially as shown in FIG. 1 23. The salt according to embodiment 22, having a H NMR spectrum. [Aspect 24] 22. The salt of claim 21, wherein the salt is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid L-tartrate (1:1.7). [Aspect 25] Substantially as shown in FIG. 1 25. The salt according to embodiment 24, having a H NMR spectrum. [Aspect 26] The salt of embodiment 1, wherein the salt is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid malonate. [Aspect 27] 27. The salt of embodiment 26, wherein the salt is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid monomalonate. [Aspect 28] The salt of embodiment 1, wherein the salt is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid phosphate. [Aspect 29] 29. The salt of embodiment 28, wherein the salt is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid phosphate (about 1:3). [Aspect 30] 29. The salt of embodiment 28, wherein the salt is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid phosphate (about 1:2). [Aspect 31] A pharmaceutical composition comprising the salt according to any one of aspects 1 to 30 and a pharma- ceutically acceptable carrier or excipient. [Aspect 32] A solid oral dosage form comprising the pharmaceutical composition according to embodiment 31. [Aspect 33] A method of inhibiting PD-1 / PD-L1 interaction comprising administering to a patient a salt according to any one of aspects 1 to 30. [Aspect 34] A method for treating a disease or disorder associated with inhibition of PD-1 / PD-L1 interaction, comprising administering to a patient in need thereof a therapeutically effective amount of a salt according to any one of aspects 1 to 30. [Aspect 35] A method of enhancing, stimulating, and / or increasing an immune response in a patient, comprising administering to said patient in need thereof a therapeutically effective amount of a salt according to any one of aspects 1-30.

Claims

1. A salt which is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid disoxalate, said salt being crystalline.

2. Figure 10 below: [Figure 10] 2. The salt of claim 1 having an X-ray powder diffraction pattern shown in

3. Figure 11 below: [Figure 11] 2. The salt of claim 1 having a DSC thermogram shown in

4. Figure 12 below: [Figure 12] 2. The salt of claim 1 having a thermogravimetric analysis (TGA) thermogram shown in

5. 2. The salt of claim 1 having at least one X-ray powder diffraction (XRPD) peak selected from 7.0±0.2 degrees, 11.4±0.2 degrees, 13.2±0.2 degrees, 14.9±0.2 degrees, and 17.0±0.2 degrees 2-theta.

6. 2. The salt of claim 1 having at least two X-ray powder diffraction (XRPD) peaks selected from 7.0±0.2 degrees, 11.4±0.2 degrees, 13.2±0.2 degrees, 14.9±0.2 degrees, and 17.0±0.2 degrees 2-theta.

7. 2. The salt of claim 1 having at least three X-ray powder diffraction (XRPD) peaks selected from 7.0±0.2 degrees, 11.4±0.2 degrees, 13.2±0.2 degrees, 14.9±0.2 degrees, and 17.0±0.2 degrees 2-theta.

8. 2. The salt of claim 1 having at least four X-ray powder diffraction (XRPD) peaks selected from 7.0±0.2 degrees, 11.4±0.2 degrees, 13.2±0.2 degrees, 14.9±0.2 degrees, and 17.0±0.2 degrees 2-theta.

9. 2. The salt of claim 1 having characteristic X-ray powder diffraction (XRPD) peaks at 7.0±0.2 degrees, 11.4±0.2 degrees, 13.2±0.2 degrees, 14.9±0.2 degrees, and 17.0±0.2 degrees 2-theta.

10. 2. The salt of claim 1, having an endothermic peak at a temperature of about 235±3° C. in a differential scanning calorimetry (DSC) thermogram.

11. The salt of claim 1, having at least one X-ray powder diffraction (XRPD) peak selected from 7.0±0.2 degrees, 11.4±0.2 degrees, 13.2±0.2 degrees, 14.9±0.2 degrees, and 17.0±0.2 degrees 2-theta, and exhibiting a differential scanning calorimetry (DSC) thermogram having an endothermic peak at a temperature of about 235±3° C.

12. The salt of claim 1, exhibiting a weight loss of about 0.7% up to about 100°C in a thermogravimetric analysis (TGA) thermogram.

13. A pharmaceutical composition comprising the salt according to any one of claims 1 to 12 and a pharma- ceutically acceptable carrier or excipient.

14. A solid oral dosage form comprising the pharmaceutical composition of claim 13.

15. The pharmaceutical composition according to claim 13 or the solid oral formulation according to claim 14, for inhibiting PD-1 / PD-L1 interaction.

16. The pharmaceutical composition of claim 13 or the solid oral formulation of claim 14 for treating a disease or disorder associated with inhibition of PD-1 / PD-L1 interaction.

17. The pharmaceutical composition or solid oral formulation of claim 16, wherein the disease or disorder is cancer or an infectious disease.

18. The pharmaceutical composition or solid oral formulation of claim 17, wherein the disease or disorder is an infectious disease, and the infectious disease is a viral infection.

19. The pharmaceutical composition or solid oral formulation of claim 17, wherein the disease or disorder is cancer.

20. The cancer is bone cancer, skin cancer, cancer of the head and neck, cutaneous or intraocular malignant melanoma, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemia, acute myeloid leukemia, chronic myeloid leukemia, solid tumors of childhood, lymphocytic lymphoma, cancer of the bladder, cancer of the renal pelvis, neoplasms of the central nervous system (CNS). , primary central nervous system (CNS) lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancers including asbestos-induced cancer, melanoma, metastatic malignant melanoma, cutaneous melanoma, renal carcinoma, hormone refractory prostate adenocarcinoma, invasive breast cancer, colon cancer, squamous cell carcinoma of the head and neck, squamous cell carcinoma of the head and neck, urothelial carcinoma, non-muscle invasive bladder cancer (NMIBC), microsatellite instability high (MSI) cancer high), solid tumors, prostate cancer, endometrial cancer, ovarian cancer, uterine cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, sarcoma, bladder cancer, blood cancer, lymphoma, leukemia, acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), non-Hodgkin's lymphoma, relapsed or refractory non-Hodgkin's lymphoma (NHL), relapsed follicular non-Hodgkin's lymphoma (NHL), multiple myeloma, bile duct cancer, biliary tract cancer, small cell lung cancer, leiomyosarcoma, brain cancer, astrocytoma, basal cell carcinoma, epithelioid sarcoma, eye cancer, gastrointestinal cancer, gastrointestinal stromal tumor, hairy cell leukemia, intestinal cancer, pancreatic islet cell carcinoma, oral cancer, oral cancer cancer), throat cancer, laryngeal cancer, lip cancer, neck cancer, nasal cancer, eye cancer, ocular melanoma, pelvic cancer, renal cell cancer, salivary gland cancer, paranasal sinus cancer, spinal cord cancer, tongue cancer, tubular cancer, urethral cancer, ureteral cancer, acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, Hodgkin's lymphoma, myeloproliferative disorders, primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET), myelodysplastic syndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), Ewing's sarcoma, rhabdomyosarcoma, angiosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdomyosarcoma, non-small cell lung cancer (NSCLC),Non-small cell squamous cell lung cancer (NSCLC), bronchogenic carcinoma, bronchogenic squamous cell carcinoma, bronchogenic undifferentiated small cell carcinoma, bronchogenic undifferentiated large cell carcinoma, bronchogenic adenocarcinoma, alveolar (bronchial) carcinoma, bronchial adenoma, chondroitin hamartoma, mesothelioma, carcinoma of the esophagus, squamous cell carcinoma of the esophagus, adenocarcinoma of the esophagus, leiomyosarcoma of the esophagus, lymphoma of the esophagus, carcinoma of the stomach, lymphoma of the stomach, leiomyosarcoma of the stomach, adenocarcinoma of the stomach, ductal adenocarcinoma of the pancreas, islet cell tumor, glucagonoma, gastrinoma, carcinoid tumor of the pancreas, VIP tumor, adenocarcinoma of the small intestine, lymphoma of the small intestine, carcinoid tumor of the small intestine, Leiomyoma, adenocarcinoma of the colon, tubular adenoma of the colon, villous adenoma of the colon, hamartoma of the colon, colorectal cancer, colorectal adenocarcinoma, genitourinary cancer, Wilms' tumor [nephroblastoma], squamous cell carcinoma of the bladder and urethra, transitional cell carcinoma of the bladder and urethra, adenocarcinoma of the bladder and urethra, adenocarcinoma of the prostate, sarcoma of the prostate, carcinoma of the testis, seminoma, teratoma of the testis, embryonal carcinoma of the testis, teratocarcinoma of the testis, choriocarcinoma of the testis, interstitial cell carcinoma of the testis, fibroma of the testis, fibroadenoma of the testis, adenomatous tumor of the testis, lipoma of the testis, urinary system cancer, papillary renal carcinoma, germ cell carcinoma of the testis, chromophobe renal cell carcinoma, clear cell renal carcinoma, adenocarcinoma of the prostate, hepatocellular Cancer, cholangiocarcinoma, hepatoblastoma, hepatocellular adenoma, hemangioma of the liver, osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, malignant lymphoma, retinal cell sarcoma, malignant giant cell tumor chordoma, osteochondroma, osteochondral exostosis, benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, giant cell tumor, skull cancer, skull osteoma, skull granuloma, skull xanthomas, osteitis deformans of the skull, meningeal cancer, meningioma, meningeal sarcoma, gliomatosis, brain cancer, medulloblastoma, ependymoma, germinoma, pinealoma, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, spinal cord cancer, spinal cord neurofibroma, spinal cord glioma, Breast cancer, Lhermitte-Duclos disease, gynecologic cancer, cancer of the uterus, cancer of the endometrium, cancer of the cervix, cervical cancer, preneoplastic cervical dysplasia, cancer of the ovary, ovarian cancer, serous cystadenocarcinoma of the ovary, serous adenocarcinoma of the ovary, mucinous cystadenocarcinoma of the ovary, unclassified carcinoma of the ovary, granulosa-theca cell tumor of the ovary, Sertoli-Leydig cell tumor, ovarian dysgerminoma, ovarian malignant teratoma, carcinoma of the vulva, carcinoma in situ of the vulva, carcinoma of the vagina, clear cell carcinoma of the vagina, sarcoma of the vagina botryoid, embryonal rhabdomyosarcoma of the vagina, carcinoma of the fallopian tube, squamous cell carcinoma of the skin, Kaposi's sarcoma, melanocytic nevus, hemangioma, dermatofibroma, keloid,20. The pharmaceutical composition or solid oral formulation of claim 19, wherein the cancer is selected from triple negative breast cancer (TNBC), esophageal cancer, and urothelial cancer.

21. The pharmaceutical composition or solid oral formulation of claim 19, wherein the cancer is a metastatic cancer that expresses PD-L1.

22. The pharmaceutical composition or solid oral formulation of claim 19, wherein the cancer is lung cancer.

23. The pharmaceutical composition or solid oral formulation of claim 22, wherein the lung cancer is small cell lung cancer.

24. The pharmaceutical composition or solid oral formulation of claim 22, wherein the lung cancer is non-small cell lung cancer.

25. The pharmaceutical composition or solid oral formulation of claim 19, wherein the cancer is liver cancer.

26. The pharmaceutical composition or solid oral formulation of claim 19, wherein the cancer is hepatocellular carcinoma.

27. The pharmaceutical composition or solid oral formulation of claim 19, wherein the cancer is melanoma.

28. The pharmaceutical composition or solid oral formulation of claim 19, wherein the cancer is bladder cancer.

29. The pharmaceutical composition or solid oral formulation of claim 19, wherein the cancer is cancer of the urethra.

30. The pharmaceutical composition or solid oral formulation of claim 19, wherein the cancer is renal cancer.

31. The pharmaceutical composition or solid oral formulation of claim 30, wherein the renal cancer is renal clear cell carcinoma.

32. The pharmaceutical composition or solid oral formulation of claim 19, wherein the cancer is cutaneous squamous cell carcinoma.

33. 15. A pharmaceutical composition according to claim 13 or a solid oral formulation according to claim 14 for enhancing, stimulating and / or increasing an immune response in a patient.

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