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 of related applications This application claims the rights of U.S. Provisional Application No. 62 / 884,996, filed on 9 August 2019, which is incorporated herein by reference in its entirety.

[0002] This application relates to a salt form of the PD-1 / PD-L1 inhibitor (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidine-1-yl)methyl)-1,7-naphthyridine-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-5-yl)methyl)pyrrolidine-3-carboxylic acid, and includes a method for preparing the same, the compound being useful in the treatment of various diseases, including infectious diseases and cancer. [Background technology]

[0003] The immune system plays a crucial role in controlling and eradicating diseases such as cancer. However, cancer cells often develop strategies to evade or suppress the immune system to gain an advantage in their proliferation. One such mechanism involves altering the expression of costimulatory and coinhibitory 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 a unique negative feedback mechanism to prevent T cell activation, which in turn reduces autoimmunity and promotes self-tolerance. Furthermore, 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 domain 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 modulates T cell receptor-mediated signaling. 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 have different expression patterns. The 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 via T cell receptor and B cell receptor signaling. PD-L1 is highly expressed in almost all tumor cells, and its expression further increases after IFN-γ treatment (Iwai et al, PNAS 2002, 99(19):12293-7; Blank et al, Cancer Res 2004, 64(3):1140-5). In fact, the PD-L1 expression status of tumors has been shown to be prognostic in several 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). The linkage of PD-1 to its ligands PD-L1 and PD-L2 on T cells generates signals that inhibit cell proliferation induced by the production of IL-2 and IFN-γ, as well as activation of T cell receptors (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 the recruitment of SHP-2 or SHP-1 phosphatases, which inhibit T cell receptor signaling, including the phosphorylation of Syk and Lck (Sharpe et al, Nat Immunol 2007, 8, 239-245). Activation of the PD-1 signaling axis also attenuates the activation of the NF-κB and AP1 pathways, as well as the phosphorylation of the PKC-θ activation loop, which is necessary for the production of cytokines 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 pieces of evidence from preclinical animal studies indicate that PD-1 and its ligands negatively regulate the immune response. 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 LCMV models of chronic infection, PD-1 / PD-L1 interactions have been shown to inhibit the activation, expansion, and acquisition of effector function in 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 the PD-1-mediated inhibitory signaling cascade to enhance or "rescue" the T cell response. Therefore, novel compounds and salts that block PD-1 / PD-L1 protein / protein interactions are needed. [Overview of the project]

[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. <9000079> The present disclosure further relates to the hydrobromide monohydrochloride, oxalate monohydrate, hydrochloride monohydrate, L-tartrate monohydrate, hydrobromide dihydrate, oxalate dihydrate, L-tartrate (1:1.5), hydrochloride (1:1.7), malonate monohydrate, phosphate (approx. 1:3), and phosphate (approx. 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 the crystalline forms of the salts described herein.

[0010] The present disclosure further relates to pharmaceutical compositions comprising the salts or crystalline forms described herein and at least one pharmaceutically acceptable carrier or excipient. The present disclosure further relates to solid dosage forms comprising the pharmaceutical composition.

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

[0012] The present disclosure further relates to treating a disease or disorder associated with inhibition of PD-1 / PD-L1 interaction, including administering to a patient a salt and crystalline form described herein. The present disclosure also provides the use of a salt and crystalline form 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 present disclosure also provides a salt and crystalline form 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, including administering to the patient a salt and crystalline form described herein. The present disclosure also provides the use of a salt and crystalline form 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 a salt and crystalline form described herein for use in enhancing, stimulating, and / or increasing an immune response in a patient.

[0014] The present invention further relates to a process for preparing a salt and crystalline form described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] [Figure 1] Shows the XRPD pattern of the hydrobromide salt of Compound 1. [Figure 2] Shows the XRPD pattern of the hydrobromide salt of Compound 1 prepared by an alternative method. [Figure 3] Shows the XRPD pattern of the monosuccinate salt of Compound 1. [[ID=!23]] [Figure 4] Shows the TGA thermogram of the monosuccinate salt of Compound 1. [Figure 5] ]]Shows the XRPD pattern of the hydrochloride salt of Compound 1. [Figure 6] Shows the XRPD pattern of the L-tartrate (1:1.5) salt of Compound 1. [Figure 7]The 1H NMR spectrum of the L-tartrate (1:1.5) of compound 1 is shown. [Figure 8] The XRPD patterns of two samples of the hydrobromide salt of compound 1 are shown. [Figure 9] The XRPD patterns of the hydrobromide salt of compound 1, prepared by an alternative method, are shown. [Figure 10] The XRPD pattern of the dioxalate of compound 1 is shown. [Figure 11] The DSC thermogram of compound 1's dioxalate is shown. [Figure 12] The TGA thermogram of compound 1's dioxalate is shown. [Figure 13] The XRPD pattern of the L-tartrate (1:1.7) of compound 1 is shown. [Figure 14] The 1H NMR spectrum of the L-tartrate (1:1.7) of compound 1 is shown. [Modes for carrying out the invention]

[0016] This disclosure relates, in particular, to a salt of (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidine-1-yl)methyl)-1,7-naphthyridine-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-5-yl)methyl)pyrrolidine-3-carboxylic acid (compound 1), where the salt is selected from the following: (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidine-1-yl)methyl)-1,7-naphthyridine-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-5-yl)methyl)pyrrolidine-3-carboxylic acid hydrobromide (hydrobromide of compound 1); (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidine-1-yl)methyl)-1,7-naphthyridine-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-5-yl)methyl)pyrrolidine-3-carboxylic acid oxalate (oxalate of compound 1); (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidine-1-yl)methyl)-1,7-naphthyridine-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-5-yl)methyl)pyrrolidine-3-carboxylate hydrochloride (hydrochloride of compound 1); (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidine-1-yl)methyl)-1,7-naphthyridine-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-5-yl)methyl)pyrrolidine-3-carboxylic acid L-tartrate (L-tartrate of compound 1); (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidine-1-yl)methyl)-1,7-naphthyridine-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-5-yl)methyl)pyrrolidine-3-carboxylic acid malonate (malonate of compound 1); and (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidine-1-yl)methyl)-1,7-naphthyridine-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-5-yl)methyl)pyrrolidine-3-carboxylic acid phosphate (phosphate of compound 1).

[0017] [ka]

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

[0019] Hydrobromide In some embodiments, the salt of compound 1 is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidine-1-yl)methyl)-1,7-naphthiridine-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-5-yl)methyl)pyrrolidine-3-carboxylic acid hydrobromide (hydrobromide of compound 1). In some embodiments, the hydrobromide of compound 1 is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidine-1-yl)methyl)-1,7-naphthiridine-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-5-yl)methyl)pyrrolidine-3-carboxylic acid monobromide (monobromide of compound 1). In some embodiments, the hydrobromide of compound 1 is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidine-1-yl)methyl)-1,7-naphthyridine-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-5-yl)methyl)pyrrolidine-3-carboxylic acid dibromide (dibromide of compound 1).

[0020] The mono-hydrobromide salt of compound 1 can be prepared by any suitable method 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 may 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. In some embodiments, the solvent includes tetrahydrofuran.

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

[0023] In some embodiments, the solvent is at approximately room temperature. In some embodiments, the solvent is heated to a temperature of about 50°C. In some embodiments, the temperature is between about 50°C and about 80°C. In some embodiments, the temperature is between about 40°C and about 60°C. In some embodiments, the temperature is between about 45°C and 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 at which precipitation can be induced at a practical rate. In some embodiments, precipitation is completed within about 12 to about 24 hours, but longer and shorter periods are possible depending on the choice of precipitation solvent and temperature. In some embodiments, precipitation is completed within about 12 hours. In some embodiments, precipitation is completed within about 2 hours.

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

[0026] In some embodiments, the monobromide salt of compound 1 can be characterized by an X-ray powder diffraction (XRPD) pattern, substantially as shown in Figure 1. In some embodiments, the monobromide salt of compound 1 can 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 suitable method 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 may 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 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 approximately room temperature. In some embodiments, the solvent is heated to a temperature of about 50°C. In some embodiments, the temperature is between about 50°C and about 80°C. In some embodiments, the temperature is between about 40°C and about 60°C. In some embodiments, the temperature is between about 45°C and 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 at which precipitation can be induced at a practical rate. In some embodiments, precipitation is completed within about 12 to about 24 hours, but longer and shorter periods are possible depending on the choice of precipitation solvent and temperature. In some embodiments, precipitation is completed within about 16 hours. In some embodiments, precipitation is completed within about 12 hours. In some embodiments, precipitation is completed within about 2.5 hours.

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

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

[0035] In some embodiments, the hydrobromide salt of compound 1 is amorphous.

[0036] Oxalate In some embodiments, the salt of compound 1 is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidine-1-yl)methyl)-1,7-naphthiridine-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-5-yl)methyl)pyrrolidine-3-carboxylic acid oxalate (oxalate of compound 1). In some embodiments, the oxalate of compound 1 is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidine-1-yl)methyl)-1,7-naphthiridine-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-5-yl)methyl)pyrrolidine-3-carboxylic acid monooxalate (monoxalate of compound 1). In some embodiments, the oxalate of compound 1 is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidine-1-yl)methyl)-1,7-naphthyridine-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-5-yl)methyl)pyrrolidine-3-carboxylic acid disoxalate (disoxalate of compound 1).

[0037] The monooxalate of compound 1 can be prepared by any suitable method for preparing oxalate addition salts. 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 may include any solvent or mixture of solvents that can at least partially dissolve compound 1. In some embodiments, the solvent may include 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 may include acetone, tetrahydrofuran, dichloromethane, methanol, ethanol, 1-propanol, or isopropanol. In some embodiments, the solvent may include acetone.

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

[0040] In some embodiments, the solvent is at approximately room temperature. In some embodiments, the solvent is heated to a temperature of about 50°C. In some embodiments, the temperature is between about 50°C and about 80°C. In some embodiments, the temperature is between about 40°C and about 60°C. In some embodiments, the temperature is between about 45°C and 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 at which precipitation can be induced at a practical rate. In some embodiments, precipitation is completed within about 12 to about 24 hours, but longer and shorter periods are possible depending on the choice of precipitation solvent and temperature. In some embodiments, precipitation is completed within about 2 hours. In some embodiments, precipitation is completed within about 90 minutes.

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

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

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

[0045] The dioxalate of compound 1 can be prepared by any suitable method for preparing oxalate addition salts. 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 may 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 approximately room temperature. In some embodiments, the solvent is heated to a temperature of about 50°C. In some embodiments, the temperature is between about 50°C and about 80°C. In some embodiments, the temperature is between about 40°C and about 60°C. In some embodiments, the temperature is between about 45°C and 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 at which precipitation and / or crystallization can be induced at a practical rate. In some embodiments, precipitation and / or crystallization is completed within about 12 to about 24 hours, but longer and shorter periods are possible depending on the choice of precipitation and / or crystallization solvent and temperature. In some embodiments, precipitation and / or crystallization is completed within about 2 hours.

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

[0051] In some embodiments, the dioxalate of compound 1 can be characterized substantially by an X-ray powder diffraction (XRPD) pattern, as shown in Figure 10.

[0052] In some embodiments, the dioxalate 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 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 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 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 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 of compound 1 has characteristic X-ray powder diffraction (XRPD) peaks at 7.0±0.2°, 11.4±0.2°, and 14.9±0.2° in the 2-theta region. In some embodiments, the dioxalate of compound 1 has characteristic X-ray powder diffraction (XRPD) peaks at 7.0±0.2°, 11.4±0.2°, 14.9±0.2°, and 17.0±0.2° in the 2-theta region. In some embodiments, the dioxalate of compound 1 has characteristic X-ray powder diffraction (XRPD) peaks at 7.0±0.2°, 11.4±0.2°, 13.2±0.2°, 14.9±0.2°, and 17.0±0.2° in the 2-theta region.

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

[0055] In some embodiments, the dioxalate of compound 1 exhibits a DSC thermogram with an endothermic peak at a temperature of 235±3°C. In some embodiments, the dioxalate of compound 1 has a DSC thermogram substantially as shown in Figure 11. In some embodiments, the dioxalate of compound 1 has a TGA thermogram substantially as shown in Figure 12.

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

[0057] In some embodiments, the dioxalate of compound 1 is amorphous. In some embodiments, the dioxalate of compound 1 is crystalline. In some embodiments, the dioxalate of compound 1 is a mixture containing both crystalline and amorphous forms.

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

[0059] The monohydrochloride salt of compound 1 can be prepared by any suitable method for preparing monohydrochloride 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 may 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. In some embodiments, the solvent includes methanol.

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

[0062] In some embodiments, the solvent is at approximately room temperature. In some embodiments, the solvent is heated to a temperature of about 50°C. In some embodiments, the temperature is between about 50°C and about 80°C. In some embodiments, the temperature is between about 40°C and about 60°C. In some embodiments, the temperature is between about 45°C and 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 at which precipitation can be induced at a practical rate. In some embodiments, precipitation is completed within about 12 to about 24 hours, but longer and shorter periods are possible depending on the choice of precipitation solvent and temperature. In some embodiments, precipitation is completed within about 12 hours.

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

[0065] In some embodiments, the monohydrochloride of compound 1 can be characterized substantially by an X-ray powder diffraction (XRPD) pattern, as shown in Figure 5.

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

[0067] The tri hydrochloride salt of compound 1 can be prepared by any suitable method for preparing a tri hydrochloride 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 may include any solvent or mixture of solvents that can at least partially dissolve compound 1. In some embodiments, the solvent may include 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 may include dioxane, dimethyl sulfoxide, acetone, tetrahydrofuran, dichloromethane, methanol, ethanol, 1-propanol, or isopropanol. In some embodiments, the solvent may include tetrahydrofuran.

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

[0070] In some embodiments, the solvent is at approximately room temperature. In some embodiments, the solvent is heated to a temperature of about 50°C. In some embodiments, the temperature is between about 50°C and about 80°C. In some embodiments, the temperature is between about 40°C and about 60°C. In some embodiments, the temperature is between about 45°C and 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 at which precipitation can be induced at a practical rate. In some embodiments, precipitation is completed within about 12 to about 24 hours, but longer and shorter periods are possible depending on the choice of precipitation solvent and temperature. In some embodiments, precipitation is completed within about 12 hours.

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

[0073] In some embodiments, the tri hydrochloride 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-hydroxypyrrolidine-1-yl)methyl)-1,7-naphthyridine-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-5-yl)methyl)pyrrolidine-3-carboxylic acid L-tartrate (L-tartrate of compound 1). In some embodiments, the L-tartrate of compound 1 is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidine-1-yl)methyl)-1,7-naphthyridine-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-5-yl)methyl)pyrrolidine-3-carboxylic acid L-tartrate (1:1.5) (L-tartrate of compound 1 (1:1.5)), where the ratio of compound 1 to L-tartaric acid is approximately 1:1.5. In some embodiments, the L-tartrate of compound 1 is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidine-1-yl)methyl)-1,7-naphthyridine-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-5-yl)methyl)pyrrolidine-3-carboxylic acid L-tartrate (1:1.7) (L-tartrate of compound 1 (1:1.7)), where the ratio of compound 1 to L-tartaric acid is approximately 1:1.7.

[0075] The L-tartrate (1:1.5) of compound 1 can be prepared by any suitable method for preparing L-tartrate addition salts. 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 may 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 approximately room temperature. In some embodiments, the solvent is heated to a temperature of at least 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.

[0079] In some embodiments, the solvent is heated to a temperature at which precipitation can be induced at a practical rate. In some embodiments, precipitation is completed within about 12 to about 24 hours, but longer and shorter periods are possible depending on the choice of precipitation solvent and temperature. In some embodiments, precipitation is completed within about 2 hours.

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

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

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

[0083] The L-tartrate salt (1:1.7) of compound 1 can be prepared by any suitable method for preparing L-tartrate addition salts. 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 may 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 approximately room temperature. In some embodiments, the solvent is heated to a temperature of at least 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.

[0087] In some embodiments, the solvent is heated to a temperature at which precipitation can be induced at a practical rate. In some embodiments, precipitation is completed within about 12 to about 24 hours, but longer and shorter periods are possible depending on the choice of precipitation solvent and temperature. In some embodiments, precipitation is completed within about 2 hours.

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

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

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

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

[0092] The monomalonate of compound 1 can be prepared by any suitable method for preparing monomalonate 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 may 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 approximately room temperature. In some embodiments, the solvent is heated to a temperature of about 50°C. In some embodiments, the temperature is between about 50°C and about 80°C. In some embodiments, the temperature is between about 40°C and about 60°C. In some embodiments, the temperature is between about 45°C and 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 at which precipitation can be induced at a practical rate. In some embodiments, precipitation is completed within about 12 to about 24 hours, but longer and shorter periods are possible depending on the choice of precipitation solvent and temperature. In some embodiments, precipitation is completed within about 1 to about 2 hours. In some embodiments, precipitation is completed within about 90 minutes.

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

[0098] In some embodiments, the monomalonate 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-hydroxypyrrolidine-1-yl)methyl)-1,7-naphthyridine-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-5-yl)methyl)pyrrolidine-3-carboxylic acid phosphate (phosphate of compound 1). In some embodiments, the phosphate of compound 1 is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidine-1-yl)methyl)-1,7-naphthyridine-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-5-yl)methyl)pyrrolidine-3-carboxylic acid phosphate (about 1:2) (phosphate of compound 1 (about 1:2)), where the ratio of compound 1 to phosphate is about 1:2. In some embodiments, the phosphate of compound 1 is (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidine-1-yl)methyl)-1,7-naphthyridine-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-5-yl)methyl)pyrrolidine-3-carboxylic acid phosphate (about 1:3) (phosphate of compound 1 (about 1:3)), where 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 may 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. 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 approximately room temperature. In some embodiments, the solvent is heated to a temperature of about 50°C. In some embodiments, the temperature is between about 50°C and about 80°C. In some embodiments, the temperature is between about 40°C and about 60°C. In some embodiments, the temperature is between about 45°C and 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 at which precipitation can be induced at a practical rate. In some embodiments, precipitation is completed within about 12 to about 24 hours, but longer and shorter periods are possible depending on the choice of precipitation solvent and temperature. In some embodiments, precipitation is completed within about 90 minutes.

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

[0106] In some embodiments, the phosphate of compound 1 (approximately 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 may include any solvent or mixture of solvents that can at least partially dissolve compound 1. In some embodiments, the solvent may include 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 may include acetone, tetrahydrofuran, dichloromethane, methanol, ethanol, 1-propanol, or isopropanol. In some embodiments, the solvent may include acetone.

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

[0110] In some embodiments, the solvent is at approximately room temperature. In some embodiments, the solvent is heated to a temperature of about 50°C. In some embodiments, the temperature is between about 50°C and about 80°C. In some embodiments, the temperature is between about 40°C and about 60°C. In some embodiments, the temperature is between about 45°C and 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 at which precipitation can be induced at a practical rate. In some embodiments, precipitation is completed within about 12 to about 24 hours, but longer and shorter periods are possible depending on the choice of precipitation solvent and temperature. In some embodiments, precipitation is completed within about 90 minutes.

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

[0113] In some embodiments, the phosphate of compound 1 (approximately 1:3) is amorphous.

[0114] Different forms of the same substance have different bulk properties, such as hygroscopicity, solubility, and stability. 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 have high water solubility, in other words, high bioavailability of the drug. Forms with low hygroscopicity are desirable in terms of stability against heat and humidity and can withstand degradation during long-term storage.

[0115] In some embodiments, the salts of compound 1 provided herein are crystalline. As used herein, “crystalline” or “crystalline form” means a particular lattice configuration of a crystalline substance. Different crystalline forms of the same substance typically have different crystal lattices (e.g., unit cells), which is due to the different physical properties unique to each crystalline form. In some cases, different lattice configurations have different water or solvent content.

[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), and solid-state NMR, further assist in identifying crystalline forms and, similarly, in determining stability and solvent / water content.

[0117] The XRPD pattern of reflections (peaks) is typically considered a fingerprint of a particular crystal morphology. It is well known that the relative intensity of XRPD peaks can vary widely depending, among other things, on the sample preparation technique, the distribution of crystal sizes, the various filters used, the sample mounting procedure, and the specific instrument used. In some cases, new peaks may be observed or existing peaks may disappear depending on the type or setting of the instrument. As used herein, the term “peak” refers to a reflection with a relative height / intensity of at least about 4% of the maximum peak height / intensity. Furthermore, instrument variations and other factors may affect the 2-theta value. 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” when used herein in the context of XRPD mean that the aforementioned variations are included.

[0118] Similarly, temperature readings for DSC, TGA, or other thermal experiments can vary by approximately ±3°C depending on the instrument, specific settings, sample preparation, etc. Therefore, any crystal morphology or term "approximately" reported herein with a DSC thermogram as shown in any of the drawings is understood to accept such variation.

[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. “Substantially isolated” means that the salt is separated at least partially or substantially from the environment in which it was formed or detected. Partial isolation may include, for example, a composition in which the salt described herein is concentrated. Substantial isolation may include a composition containing the salt described herein or 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 salt. Methods for isolating salts are commonplace in the art.

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

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

[0123] The term "pharmaceutically acceptable" is used herein to mean salts, substances, compositions, and / or dosage forms that are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit-to-risk ratio, within the bounds of reasonable medical judgment.

[0124] The salt-forming reactions described herein may be carried out at a suitable temperature that can be readily determined by those skilled 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., a highly exothermic reaction may need to be carried out at a lower temperature), and the kinetics of the reaction (e.g., a high activation energy barrier may require a high temperature).

[0125] As used herein, the terms “ambient temperature” and “room temperature” or “rt” are understood in the art and generally refer to a temperature, for example, the temperature of the room in which the salt formation reaction takes place, for example, a reaction temperature close to a temperature of about 20°C to about 30°C.

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

[0127] How to use The salts of this disclosure can inhibit the activity of the PD-1 / PD-L1 protein / protein interaction and are therefore useful in the treatment of diseases and disorders related to PD-1 activity, as well as diseases and disorders related to PD-L1, including its interaction with other proteins such as B7-1 (CD80). In certain embodiments, the salts of this disclosure are useful, when administered therapeutically, to enhance, stimulate, and / or increase immunity in cancer, chronic infection, or sepsis, including enhancing the response to vaccination. In some embodiments, this disclosure provides a method for inhibiting the PD-1 / PD-L1 protein / protein interaction. The method involves administering to an individual or patient a salt of Formula 1 or any of the salts described in any of the claims and described herein, or a pharmaceutically acceptable salt or stereoisomer thereof. The salts of this 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 this disclosure, including any of its embodiments, may be used in the uses described herein.

[0128] The salts of this disclosure inhibit the PD-1 / PD-L1 protein / protein interaction, resulting in blockade of the PD-1 pathway. Blockade of PD-1 can enhance the immune response to cancer cells and infectious diseases in mammals, including humans. In some embodiments, this disclosure provides the treatment of an individual or patient using a salt of compound 1 in vivo to inhibit the growth of cancerous tumors. Salts of compound 1, or salts described in any of the claims and herein, can be used to inhibit the growth of cancerous tumors. Alternatively, salts of compound 1, or salts described in any of the claims and herein, can be used in combination with other drugs or standard cancer treatments, as described below. In one embodiment, this disclosure provides a method for inhibiting the growth of tumor cells in vitro. This method involves contacting tumor cells in vitro with a salt of compound 1, or a salt described in any of the claims and herein. In another embodiment, this disclosure provides a method for inhibiting the growth of tumor cells in an individual or patient. The method comprises administering to an individual or patient in need of it a therapeutically effective amount of a salt of Compound 1, or a salt described in any of the claims and herein.

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

[0130] In some embodiments, the present disclosure provides methods for enhancing, stimulating, and / or increasing the immune response in a patient. The methods include administering to a patient in need a therapeutically effective amount of a salt of Compound 1, or a salt or composition described in any of the claims and herein.

[0131] Examples of cancers treatable with the salts of this disclosure include bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, gastric cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal gland cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia, such as acute myeloid leukemia. Examples of cancers that may be treated include, but are not limited to, diseases such as chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors in children, lymphocytic lymphoma, bladder cancer, kidney or urethral cancer, renal pelvis cancer, neoplasms of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axial tumors, brainstem gliomas, pituitary adenomas, Kaposi's sarcoma, epidermal carcinoma, squamous cell carcinoma, T-cell lymphoma, cancers induced by the environment, such as cancers induced by asbestos, and combinations of such cancers. The salts of this 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 this disclosure include melanoma (e.g., metastatic melanoma, cutaneous melanoma), renal cancer (e.g., clear cell carcinoma), prostate cancer (e.g., hormone-refractory adenocarcinoma of the prostate), 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 highly microsatellite-instability cancers (MSI). high ) are examples. Furthermore, this disclosure includes refractory or recurrent malignancies in which growth can be inhibited using the salts of this disclosure.

[0133] In some embodiments, cancers treatable with the salts of this 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.), hematological cancers (e.g., lymphoma, leukemia, e.g., acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), DLBCL, mantle cell lymphoma, non-Hodgkin lymphoma (including relapsed or refractory NHL and relapsed follicle), Hodgkin lymphoma or multiple myeloma), and combinations thereof.

[0134] In some embodiments, cancers treatable with the salts of the present disclosure include, but are not limited to, cholangiocarcinoma, bile duct cancer, 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, ocular cancer, fallopian tube cancer, gastrointestinal cancer, gastrointestinal stromal tumor, hairy cell leukemia, intestinal cancer, islet cell carcinoma, oral cancer, mouth cancer, pharyngeal 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 cord cancer, tongue cancer, tubular cancer, urethral cancer, and ureteral cancer.

[0135] In some embodiments, the 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 with the salts of this disclosure include, but are not limited to, hematological cancers, sarcomas, lung cancers, gastrointestinal cancers, urogenital tract cancers, liver cancers, bone cancers, nervous system cancers, gynecological cancers, and skin cancers.

[0137] Exemplary blood 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 lymphoma (including relapsed or refractory NHL and relapsed follicular lymphoma), Hodgkin 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, rhabdomyosarcoma, rhabdomyosarcoma, fibroma, lipoma, hamartoma, and teratoma.

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

[0140] Examples of gastrointestinal cancers include esophageal cancer (carcinoma, squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyosarcoma, adenocarcinoma), pancreatic cancer (ductal adenocarcinoma, islet cell tumor, glucagon-producing tumor, gastrin-producing tumor, carcinoid tumor, VIP-producing tumor), small intestine cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colorectal cancer (adenocarcinoma, tubular adenoma, chorioadenoma, hamartoma, leiomyoma), and colorectal cancer (e.g., colorectal adenocarcinoma).

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

[0142] Typical liver cancers include hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

[0143] Examples of bone cancers include, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (retinocellular sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondrosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor.

[0144] Examples of neurological cancers include cancers of the skull (osteoma, hemangioma, granuloma, xanthomas, osteoosteitis), cancers of the meninges (meningioma, meningiosarcoma, gliomas), cancers of the brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal glandoma), glioblastoma, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), and cancers of the spinal cord (neurofibroma, meningioma, sarcoma), as well as neuroblastoma and Lhermitt-Dukuro disease.

[0145] Examples of gynecological cancers include cancer of the uterus (endometrial cancer), cancer of the cervix (cervical cancer, preneoplastic cervical dysplasia), cancer of the ovaries (ovarian cancer (serous cystadenocarcinoma, serous adenocarcinoma, mucinous cystadenocarcinoma, unclassifiable cancer), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, undifferentiated germ cell tumor, 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, staphylosarcoma (embryonic rhabdomyosarcoma)), and cancer of the fallopian tubes (epithelial malignant tumors).

[0146] Exemplary skin cancers include melanoma, basal cell carcinoma, squamous cell carcinoma (e.g., cutaneous squamous cell carcinoma), Kaposi's sarcoma, dysplastic nevus moles, lipomas, hemangiomas, dermatofibromas, and keloids. In some embodiments, diseases and indications treatable with the salts of this 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 carcinoma.

[0147] Blocking the PD-1 pathway with the salts of this disclosure may also be used to treat infections such as viral, bacterial, fungal, and parasitic infections. This disclosure provides a method for treating infections such as viral infections. The method comprises administering to a patient in need a therapeutically effective amount of a salt of Compound 1, or a salt described in any of the claims and herein. Examples of viruses that cause infections treatable by the method of this disclosure include, but are not limited to, human immunodeficiency virus, human papillomavirus, influenza, hepatitis A, B, C, or D viruses, adenovirus, poxvirus, herpes simplex virus, human cytomegalovirus, severe acute respiratory syndrome virus, Ebola virus, and measles virus. In some embodiments, viruses that cause infections treatable by the methods of the present disclosure include, but are not limited to, hepatitis viruses (types A, B, or C), herpesviruses (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein-Barr virus), adenoviruses, influenza viruses, flaviviruses, echoviruses, rhinoviruses, coxsackieviruses, coronaviruses, respiratory syncytial viruses, Mampus viruses, rotaviruses, measles viruses, rubella viruses, parvoviruses, vaccinia viruses, HTLV viruses, dengue viruses, papillomaviruses, infectious viruses, polioviruses, rabies viruses, JC viruses, tuberculosis, and arboviral encephalitis viruses.

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

[0149] This disclosure provides a method for treating fungal infections. The method comprises administering to a patient in need a therapeutically effective amount of a salt of Compound 1, or a salt described in any of the claims and herein. Non-limiting examples of pathogenic fungi that cause infections treatable by the method of this disclosure include Candida (e.g., Candida albicans, Candida crusae, Candida glabrata, Candida tropicalis), cryptococcosis, Aspergillus (e.g., Aspergillus fumigatus, Aspergillus niger), Genus Mucorales (e.g., Mucor, Aspergillus absidia, Aspergillus rhizops), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis, and Histoplasma capsulatum.

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

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

[0152] Salts of compound 1, or any of its embodiments, are considered to have a sufficient pharmacological profile and promising biopharmaceutical properties, such as toxicological profile, metabolic and pharmacokinetic properties, solubility, and permeability. Determining appropriate biopharmaceutical properties is within the scope of the knowledge of those skilled in the art and is understood to be, for example, determining cytotoxicity in cells or inhibition of a given target or channel to determine potential toxicity.

[0153] The interchangeable terms “individual” or “patient” refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, most preferably humans.

[0154] The term "therapeutic effective dose" refers to the amount of active salt that elicits a biological or drug response in a tissue, system, animal, individual, or human, as determined by researchers, veterinarians, physicians, or other clinicians.

[0155] As used herein, the terms “to treat” or “to treat” mean one or more of the following: (1) inhibiting a disease, for example, inhibiting a disease, condition or disorder in an individual experiencing or exhibiting the pathology or symptoms of a disease, condition or disorder (i.e., preventing further progression of the pathology and / or symptoms); and (2) improving a disease, for example, improving a disease, condition or disorder in an individual experiencing or exhibiting the pathology or symptoms of a disease, condition or disorder (i.e., reversing the pathology and / or symptoms), for example, reducing the severity of the disease.

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

[0157] Combination therapy Immunotherapy (Immune Checkpoint Therapy) The salts of this disclosure may be used in combination with one or more immune checkpoint inhibitors to treat diseases such as cancer or infections. 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 stimulant 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 KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors, and TGF-beta inhibitors.

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

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

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

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

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

[0166] In some embodiments, the inhibitor of the 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 a PD-1 inhibitor, such as an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, semiprimab, spartalizumab, camrelizumab, cetrelimab, tripalimab, cintilimab, 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 anticancer agents include antibody therapies such as 4-1BB (e.g., urelumab, utomirumab).

[0168] In some embodiments, the inhibitor of the immune checkpoint molecule is a PD-L1 inhibitor, 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, tislerizumab, 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 the immune checkpoint molecule is an inhibitor of PD-1 and PD-L1, for example, an anti-PD-1 / PD-L1 bispecific antibody. In 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 the immune checkpoint molecule is an inhibitor of PD-1 and CTLA-4, for example, 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, for example, an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016, LAG525, INCAGN2385, or eftyragimod alfa (IMP321).

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

[0175] In some embodiments, the inhibitor of the 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 the 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 the immune checkpoint molecule is an inhibitor of B7-H3. In some embodiments, the inhibitor of B7-H3 is enobrituzumab, MGD009, or 8H9.

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

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

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

[0181] In some embodiments, the inhibitor of the 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 the immune checkpoint molecule is a CD47 inhibitor. In some embodiments, the CD47 inhibitor is Hu5F9-G4 or TTI-621.

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

[0184] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of TIM3, for example, 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 a GITR agonist, 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 the immune checkpoint molecule is an agonist of OX40, such as 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 the immune checkpoint molecule is a CD20 inhibitor, such as an anti-CD20 antibody. In some embodiments, the anti-CD20 antibody is obinutuzumab or rituximab.

[0188] The salts of this 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 the 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 salts of the present disclosure can be used in combination with one or more metabolic enzyme inhibitors. In some embodiments, the metabolic enzyme inhibitors are inhibitors 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, additional compounds, inhibitors, drugs, etc., may be combined with the salts of the present invention in single or sequential dosage forms, or they may be administered simultaneously or sequentially in separate dosage forms.

[0191] Cancer therapy The proliferation and survival of cancer cells can be affected by dysfunction of multiple biological pathways. Therefore, it may be useful to treat such conditions by combining inhibitors of different mechanisms, such as enzyme inhibitors, signaling inhibitors, chromatin dynamics inhibitors, or immune response modulators. Targeting one or more signaling pathways (or one or more biomolecules involved in a given signaling pathway) may reduce the potential for drug resistance to develop in cell populations or reduce the toxicity of treatment.

[0192] The salts of this disclosure may be used in combination with one or more other therapies for the treatment of diseases such as cancer or infections. Examples of diseases and indications treatable with combination therapy are those described herein. Examples of cancers include solid and non-solid tumors, such as humoral tumors and hematological malignancies. Examples of infections include viral infections, bacterial infections, fungal infections, or parasitic infections. For example, the salts of this disclosure may be used in combination with one or more inhibitors 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 kinase (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 infection. Non-limiting examples of inhibitors that may be combined with the salts of this 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, orsimertinib, cetuximab, nesitumumab, or panitumumab), VEGFR inhibitors or pathway blockers (e.g., bevacizumab, pazopanib, sunitinib, sorafenib, axitinib, regorafenib, ponatinib, cabozantinib, vandetanib, ramucirumab,Lenvatinib, dibuaflibercept), 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., Pulsa PI3K-gamma inhibitors such as crisib (INCB50465 and INCB50797), 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, nesitumumab, or panitumumab), VEGFR inhibitors or pathway blockers (e.g., bevacizumab, pazopanib, sunitinib, sorafenib, axitinib, regorafenib, ponatinib, cabozantinib, vandetanib) Histone deacetylase inhibitors such as tanib, ramucirumab, lenvatinib, dibuaflibercept, PARP inhibitors (e.g., olaparib, lucaparib, 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 (HDAC) ), 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 (e.g., rucaparib or olaparib), citravatinib, B-Raf inhibitor-MEK inhibitor combinations (e.g., encorafenib + binimetinib, dabrafenib + trametinib, or cobimetinib + vemurafenib), and adenosine receptor antagonists,Or a combination of those.

[0193] In some embodiments, the salts of the present disclosure can be combined with a TLR7 agonist (e.g., imiquimod).

[0194] The salts of this disclosure can also be used in combination with other methods of treating cancer, such as chemotherapy, radiotherapy, tumor-targeted therapy, adjuvant therapy, immunotherapy, or surgery. Examples of immunotherapies 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 may be administered in combination with one or more anticancer drugs, such as chemotherapeutic agents. Examples of chemotherapy agents include avalerix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, baricitinib, bleomycin, bortezomib, intravenous busulfan, oral busulfan, callussterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin difutitox, dexrazoxane, docetaxel, doxorubicin, and dromostalanine. 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 distosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisol, lomustine, mechloretamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane,Mitoxantrone, Nandrolone fenpropionate, Nelarabine, Nofetumomab, Oxaliplatin, Paclitaxel, Pamidronate, Panitumumab, Pegaspargase, Pegfilgrastim, Pemetrexed disodium, Pentostatin, Pipobroman, Plicamycin, Procarbazine, Quinacrine, Rasburicase, Rituximab, Ruxolitinib, Sorafenib, Stre Examples include ptozosin, sunitinib, sunitinib maleate, tamoxifen, temozolomide, teniposide, testactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tocitumomab, trastuzumab, tretinoin, uracil mustard, barrubicin, vinblastine, vincristine, vinorelbine, vorinostat, and zoledronate.

[0195] Other anticancer agents include antibody therapies such as trastuzumab (Herceptin), antibodies against costimulatory molecules such as CTLA-4 (e.g., ipilimumab) and 4-1BB (e.g., urelumab, utomirumab), antibodies against PD-1 and PD-L1, or antibodies against cytokines (e.g., IL-10, TGF-β). Examples of PD-1 and / or PD-L1 antibodies that may be combined with the salts of this disclosure for the treatment of cancer or infections 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 this disclosure can 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 salt described in any of the claims and herein, may be combined with other immunogenic agents, such as cancer cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immunostimulatory cytokines. Non-limiting examples of tumor vaccines that may be used include peptides of melanoma antigens such as gp100, MAGE antigen, Trp-2, MARTI, and / or tyrosinase peptides, or tumor cells transfected to express the cytokine GM-CSF.

[0198] Salts of Compound 1, or those described in any of the claims and 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, the tumor vaccine contains proteins derived from viruses associated with human cancer, such as human papillomavirus (HPV), hepatitis viruses (HBV and HCV), and Kaposi's herpes sarcoma virus (KHSV). In some embodiments, the salts of the Disclosure may be used in combination with tumor-specific antigens, such as heat shock proteins isolated from tumor tissue itself. In some embodiments, salts of Compound 1, or those described in any of the claims and herein, may be combined with dendritic cell immunity to activate a potent antitumor 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 the host immune response.

[0200] The salts of this disclosure may be used in combination with bone marrow transplantation for the treatment of various hematopoietic tumors.

[0201] Salts of Compound 1, or those described in any of the claims and herein, may be used in combination with vaccines to stimulate an immune response to pathogens, toxins, and autoantigens. Examples of pathogens for which this therapeutic approach may be particularly useful include pathogens for which there are currently no effective vaccines, or pathogens for which conventional vaccines are not entirely 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 that cause infections treatable by the methods of this disclosure include, but are not limited to, human papillomavirus, influenza, hepatitis A, B, C, or D viruses, adenovirus, poxvirus, herpes simplex virus, human cytomegalovirus, severe acute respiratory syndrome virus, Ebola virus, measles virus, herpesvirus (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein-Barr virus), flavivirus, echovirus, rhinovirus, coxsackievirus, coronavirus, respiratory syncytial virus, Mampus virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, infectious viruses, poliovirus, rabies virus, JC virus, and arboviral encephalitis virus.

[0203] Pathogenic bacteria that cause infections treatable by the methods of this disclosure include, but are not limited to, Chlamydia, Rickettsia, Mycobacteria, Staphylococcus, Streptococcus, Pneumonococcus, Menningcoccus and Conococcus, Curbusiera, Proteus, Serratia, Pseudomonas, Legionella, Diphtheria, Salmonella, Bacillus, Cholera, Tetanus, Botulism, Anthrax, Plague, Leptospirosis, and Lyme disease.

[0204] Pathogenic fungi that cause infections treatable by the methods disclosed herein include, but are not limited to, Candida (albicans, crusey, glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.), Genus Mucorales (mucor, absidia, rhizops), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis, and Histoplasma capsulatum.

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

[0206] When more than one medication is administered to a patient, they may be administered simultaneously, separately, sequentially, or in combination (for example, in the case of more than two medications).

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

[0208] The Disclosure also includes pharmaceutical compositions comprising a salt of the Disclosure as an active ingredient in combination with one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the compositions are suitable for topical administration. When preparing compositions of the Invention, the active ingredient is typically mixed with an excipient, diluted by the excipient, or encapsulated in such carriers, for example, in the form of capsules, sachets, paper or other containers. Where the excipient functions as a diluent, it may be a solid, semi-solid, or liquid material acting as a vehicle, carrier, or medium for the active ingredient. Thus, compositions may be in the form of tablets, pills, powders, lozenges, sachets, caches, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or liquid media), for example, ointments, soft and hard gelatin capsules, suppositories, sterile injection solutions, and sterile packaging powders containing up to 10% by weight of the active salt.

[0209] When preparing a formulation, the active salt can be ground to an appropriate particle size before being combined with other components. If the active salt is substantially insoluble, it can be ground to a particle size of less than 200 mesh. If the active salt is substantially water-soluble, the particle size can be adjusted by grinding to achieve a substantially uniform distribution in the formulation, for example, about 40 mesh.

[0210] The salt of the present invention may be ground using known grinding procedures, such as wet grinding, to obtain a particle size suitable for tablet formation and other formulation types. Finely divided (nanoparticle) formulations of the salt of the present invention may be prepared by processes known in the art (see, for example, WO2002 / 000196).

[0211] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulation may further include lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methyl benzoate and propyl hydroxybenzoate; sweeteners; and flavorings. Compositions of the present invention can be formulated using methods known in the art to provide rapid, sustained-release, or delayed release of the active ingredient after administration to a patient.

[0212] In some embodiments, the pharmaceutical composition comprises silicate microcrystalline cellulose (SMCC) and at least one salt described herein. In some embodiments, silicate 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 described herein and at least one pharmaceutically acceptable carrier or excipient. In some embodiments, the composition comprises at least one salt 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 described herein and microcrystalline cellulose, lactose monohydrate, and hydroxypropyl methylcellulose. In some embodiments, the composition comprises at least one salt 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, 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, polyethylene oxide is polyethylene oxide WSR 1105 (e.g., Polyox WSR 1105®).

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

[0215] The composition may be formulated in unit dosage forms, each dose containing approximately 5 to approximately 1000 mg (1 g) of the active ingredient, more typically approximately 100 to approximately 500 mg. In some embodiments, each dose contains approximately 10 mg of the active ingredient. In some embodiments, each dose contains approximately 50 mg of the active ingredient. In some embodiments, each dose contains approximately 25 mg of the active ingredient. The term "unit dosage form" refers to a physically distinct unit appropriate as a unit dose for human subjects and other mammals, each unit containing a predetermined amount of the active substance calculated to produce the desired therapeutic effect in conjunction with appropriate pharmaceutical excipients.

[0216] The components used to formulate the pharmaceutical composition are of high purity and substantially free from 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 composition is preferably manufactured or formulated in accordance with the provisions of the Pharmaceutical Manufacturing Control and Quality Control Standards as defined in the applicable provisions of the U.S. Food and Drug Administration. For example, a suitable formulation is sterile and / or substantially isotonic and / or fully compliant with all provisions of the U.S. Food and Drug Administration's Pharmaceutical Manufacturing Control and Quality Control Standards.

[0217] Active salts can be effective across a wide dosage range and are generally administered at therapeutically effective doses. However, it should be understood that the actual amount of salt administered is usually determined by the physician, taking into account relevant circumstances including the symptoms being treated, the chosen route of administration, the salt actually administered, the individual patient's age, weight, and response, and the severity of the patient's symptoms.

[0218] The therapeutic dose of the salt of the present invention may vary depending, for example, the specific use in which the treatment is performed, the method of administering the salt, the patient's health and condition, and the judgment of the prescribing physician. The proportion or concentration of the salt of the present invention in a pharmaceutical composition may vary depending on many factors, including the dose, chemical properties (e.g., hydrophobicity), and route of administration. For example, the salt of the present invention may be provided in a physiological buffered aqueous solution containing about 0.1 to about 10% w / v of the salt when administered parenterally. Some typical dose ranges are about 1 μg / kg body weight to about 1 g / kg body weight per day. In some embodiments, the dose range is about 0.01 mg / kg body weight to about 100 mg / kg body weight per day. The dose may depend on variables such as the type and progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the selected salt, the formulation of excipients, and its route of administration. The effective dose can be estimated from dose-response curves obtained from in vitro or animal model test systems.

[0219] To prepare solid compositions such as tablets, the main active ingredient is mixed with pharmaceutical excipients to form a solid preliminary formulation composition containing a homogeneous mixture of the salt of the present invention. When these preliminary formulation compositions are referred to as homogeneous, the active ingredient is typically evenly dispersed throughout the composition, and the composition can be easily divided into equally effective unit dosage forms such as tablets, pills, and capsules. Furthermore, this solid preliminary formulation composition can be divided into the above-described unit dosage forms, for example, containing about 0.1 to about 1000 mg of the active ingredient of the present invention.

[0220] The tablets or pills of the present invention may be coated or otherwise formulated to provide a dosage form that offers the advantage of long-lasting action. For example, the tablets or pills may contain internal and external dose components, the latter in the form of an envelope on a forming agent. The two components can be separated by an enteric coating that resists disintegration in the stomach and allows the internal component to pass intact into the duodenum or delays its release. Various substances, such as numerous polymer acids and mixtures of polymer acids with substances such as shellac, cetyl alcohol, and cellulose acetate, can be used as such enteric coatings or coatings.

[0221] Liquid forms for oral or injectable administration into which the salts and compositions of the present invention may be incorporated include aqueous solutions, appropriately 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 media.

[0222] Compositions for inhalation or inhalation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain the aforementioned preferred pharmaceutically acceptable excipients. In some embodiments, compositions are administered orally or via nasal respiratory routes for topical or systemic effects. Compositions may be sprayed using an inert gas. The sprayed solution may be inhaled directly from the spraying device, or the spraying device may be attached to a face mask, tent, or intermittent positive pressure respirator. Solutions, suspensions, or powder compositions can be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0223] Topical formulations may comprise one or more conventional carriers. In some embodiments, ointments may comprise water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white petrolatum, etc. Carrier compositions for creams may be based on water combined with glycerol and one or more other components such as, for example, glycerin monostearate, PEG-glycerin monostearate, and cetyl stearyl alcohol. Gels may be formulated using isopropyl alcohol and water, preferably in combination with other components such as glycerol, hydroxyethylcellulose, etc. In some embodiments, topical formulations may comprise 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 present invention. Topical formulations may be appropriately packaged in 100 g tubes, optionally accompanied by instructions for treating selected indications, such as 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 administration (e.g., prevention or treatment), the patient's condition, and the method of administration. In therapeutic applications, the composition may be administered to a patient already suffering from the disease in an amount sufficient to cure or at least partially suppress the symptoms of the disease and its complications. The effective dose depends on the judgment of the attending clinician, based on the state of the disease being treated, as well as factors such as the severity of the disease, the patient's age, weight, and general health.

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

[0226] The therapeutic dose of the salt of the present invention may vary depending on, for example, the specific use in which the treatment is performed, the method of administering the salt, the patient's health and condition, and the judgment of the prescribing physician. The proportion or concentration of the salt of the present invention in a pharmaceutical composition may vary depending on many factors, including the dose, chemical properties (e.g., hydrophobicity), and route of administration. For example, the salt of the present invention may be provided in a physiological buffered aqueous solution containing about 0.1 to about 10% w / v of the salt when administered parenterally. Some typical doses range from about 1 μg / kg body weight to about 1 g / kg body weight per day. In some embodiments, the dose range is about 0.01 mg / kg body weight to about 100 mg / kg body weight per day. The dose may depend on variables such as the type and progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the selected salt, the formulation of excipients, and its route of administration. The effective dose can be estimated from dose-response curves obtained from in vitro or animal model test systems.

[0227] Labeled compounds and assay methods The salts of this disclosure may also be useful for investigating biological processes in normal and abnormal tissues. Accordingly, another aspect of the present invention relates to labeled salts (radioactively labeled, fluorescently labeled, etc.) of the present invention which would be useful not only in imaging techniques but also in both in vitro and in vivo assays for localizing and quantifying PD-1 or PD-L1 proteins in tissue samples, including human, and for identifying PD-L1 ligands by inhibitory binding of labeled compounds. Accordingly, the present invention includes PD-1 / PD-L1 binding assays comprising such labeled salts.

[0228] The present invention further includes the isotope-substituted salts of the present disclosure. An "isotope-substituted" salt is a salt of the present invention in which one or more atoms have been replaced by atoms having the same atomic number but a different atomic weight or mass number than, for example, the atomic weight or mass number typically found in nature (i.e., naturally occurring). It should be understood that a "radioactive-labeled" salt is a salt incorporating at least one isotope (e.g., radionuclide) that is radioactive. Suitable radionuclides that can be incorporated into the salts of the present invention include 3 H (described as T for tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 35 S,​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​H, 14 C, 125 I, 35 S, and 82 The selection is made from the group consisting of Br. Synthetic methods for incorporating radioactive isotopes 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 newly synthesized or identified labeled salt (i.e., a salt of test) can be evaluated for its ability to bind to the PD-L1 protein by monitoring its concentration change upon contact with the PD-L1 protein through tracking the label. For example, a (labeled) salt of test can be evaluated for its ability to reduce the binding of another compound (i.e., a standard compound) known to bind to the PD-L1 protein. Thus, the ability of a salt of test to compete with a standard compound for binding to the PD-L1 protein is directly correlated to its binding affinity. Conversely, in some other screening assays, the standard salt is labeled and the test compound is not. Therefore, to evaluate the competition between the standard compound and the salt of test, the concentration of the labeled standard salt is monitored, thereby confirming the relative binding affinity of the salt of test.

[0231] kit The disclosure also includes pharmaceutical kits useful for the treatment or prevention of diseases or disorders related to the activity of PD-L1, including its interactions with other proteins such as PD-1 and B7-1 (CD80), such as cancer or infectious diseases, and which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a salt of compound 1 or any embodiment thereof. As will be apparent to those skilled in the art, such kits may further include one or more of a variety of conventional pharmaceutical kit components, such as containers having one or more pharmaceutically acceptable carriers, additional containers, etc. Instructions for use, indicating the amount of the component to be administered, guidelines for administration, and / or guidelines for mixing the components, may also be included in the kit, either as a package insert or label.

[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); Â (ethyl acetate); g (gram); h (hour); HPLC (high-performance liquid chromatography); Hz (Hertz); J (coupling constant); LCMS (liquid chromatography-mass spectrometry); m (multiplet); M (moles); MS (mass spectrometry); Me (methyl); MeCN (acetonitrile); MeOH (methanol); m g (milligrams); min. (minutes); mL (milliliters); mmol (millimoles); nM (nanomoles); 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 (micrograms); μL (microliters); μM (micromoles); wt% (weight percentage).

[0233] The present invention will be described in more detail by specific examples. The following examples are provided for illustrative purposes only and are not intended to limit the invention in any way. Those skilled in the art will readily recognize a variety of non-essential parameters that can be changed or modified to produce essentially the same results. The salts of the examples have been found to inhibit the activity of the 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 using a Rigaku MiniFlex X-ray powder diffractometer (XRPD). The general experimental procedure for the XRPD was as follows: (1) X-ray emission from copper at 1.054056 Å with a Kβ filter, (2) X-ray power at 30 KV and 15 mA, and (3) the sample powder dispersed on a zero-background sample holder. The general measurement conditions for the XRPD were as follows: start angle 3 degrees; stop angle 45 degrees; sampling 0.02 degrees; and scanning speed 2 degrees / min.

[0235] Differential scanning calorimetry (DSC) was performed using a TA Instruments differential scanning calorimeter, Model Q200, equipped with an autosampler. The 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 using a TA Instrument thermogravimetric analyzer, Model Q500. The general experimental conditions for the TGA were as follows: gradient from 20°C to 600°C at 20°C / min; equilibrium of purge flow followed by nitrogen purge gas flow at 40 mL / min; sample purge flow at 60 mL / min; platinum sample pan. The purity was determined by HPLC using the following conditions. [Table 1] [Table 2]

[0236] Example 1. Preparation of monomalonate of compound 1 In a 500 mL round-bottom flask equipped with a stirring rod, acetone (200 mL) was added, followed by malonic acid (0.825 g, 7.93 mmol). The mixture was stirred at room temperature until it was completely homogeneous.

[0237] Compound 1 (5.0 g, 7.21 mmol), methanol (5.0 mL), and dichloromethane (45.0 mL) were placed in a 100 mL round-bottom flask equipped with a stirring rod. The mixture was stirred until homogenized.

[0238] The solution (slightly cloudy) was filtered directly into a 60 mL addition funnel using a syringe and filter disc. The round-bottom flask was rinsed with 6 mL of 10% methanol / dichloromethane solution, and the solution was filtered and placed 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 filtered cake was rinsed with acetone (100 mL), and the solid was dried in a desiccator under high vacuum for 3.5 hours. 5.2 g of solid was recovered and placed in a vacuum oven at 50°C under a nitrogen atmosphere for 16 hours. 5.1 g of product was recovered. HPLC purity: 98.69%. Residual acetone (NMR): 940 ppm.

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

[0241] The stoichiometric ratio between compound 1 and hydrobromide was determined to be 1:1 by HPLC. The mono-hydrobromide of compound 1 was characterized by XRPD (Figure 1). Analytical data collected for the product were obtained. The purity of the mono-hydrobromide was determined to be 99.4% by HPLC.

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

[0243] The stoichiometric ratio between compound 1 and hydrobromide was determined to be 1:1 by HPLC. The mono-hydrobromide of compound 1 was characterized by XRPD (Figure 2). Analytical data collected for the product were obtained. The purity of the mono-hydrobromide was determined to be 99.7% by HPLC.

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

[0245] The stoichiometric ratio between compound 1 and oxalic acid was determined to be 1:1 by elemental analysis (theoretically, C 43 H 41 N7O8·2H2O:C, 62.99;H, 5.53;N, 11.96 (analytical results: C, 62.48;H, 5.33;N, 11.44). The monooxalate of compound 1 was characterized by XRPD (Figure 3). The TGA of the salt is shown in Figure 4. Analytical data collected for the product were obtained. The purity of the monooxalate was determined to be 99.3% by HPLC.

[0246] Example 5. Alternative preparation of monooxalate of compound 1 In a 50 mL round-bottom flask equipped with a stirring rod, acetone (10.7 mL) was added, followed by oxalic acid (77 mg, 0.851 mmol). The mixture was stirred at room temperature until it was completely homogeneous.

[0247] Compound 1 (537 mg, 0.774 mmol), methanol (537 μL), and dichloromethane (4.83 mL) were placed in a scintillation vial equipped with a stirring rod. The mixture was stirred until homogeneous.

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

[0249] Example 6. Preparation of monohydrochloride of compound 1 Hydrochloric acid (0.504 mL, 0.504 mmol, 1.0 M, 1.05 equivalents from 37% aqueous solution of isopropyl alcohol / water) was added to a solution of compound 1 (332.80 mg, 0.480 mmol, 1.0 equivalent) 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 hour. Dichloromethane was removed to obtain a slurry, which was stirred overnight. The slurry was filtered to obtain the mother liquor and solid. The solid was vacuum-dried overnight at 45-46°C 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 to be 1:1 by HPLC. The monohydrochloride of compound 1 was characterized by XRPD (Figure 5). Analytical data collected for the product were obtained. The purity of the monohydrochloride was determined to be 99.0% by HPLC.

[0251] Example 7. Preparation of L-tartrate (1:1.5) of Compound 1 [ka] L-tartaric acid (11.74 mg, 0.078 mmol, 1.05 equivalents) 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 minutes to obtain a slurry. The slurry was stirred continuously for 2 hours, then filtered to obtain the mother liquor and solid. The solid was vacuum-dried overnight at 40-41°C to obtain the L-tartrate of compound 1 as an amorphous solid (46.5 mg, 97% yield based on the number of moles of L-tartaric acid (limiting reactant) used).

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

[0253] Example 8. Preparation of dibromide salt of compound 1 Hydrobromic acid (0.32 mL, 0.320 mmol, 2.30 equivalents from isopropyl alcohol / 1.0 M in 48% aqueous solution) was added to a slurry of compound 1 (100 mg, 0.141 mmol, 1.0 equivalent) in methanol (2.0 mL). The reaction mixture was stirred to obtain a clear solution, which was 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 hours. The slurry was filtered to obtain the mother liquor and solid sample 2. Solid samples 1 and 2 were vacuum-dried overnight at 45-46°C to obtain the dihydrobromide salt of compound 1 (32 mg of sample 1 and 70 mg of sample 2, 85% total yield) as amorphous solids.

[0254] The stoichiometric ratio between Compound 1 and hydrobromic acid was determined to be 1:2 by HPLC (Sample 2). The dihydrobromide salt of Compound 1 was characterized by XRPD (Figure 8, Samples 1 and 2). Analytical data were obtained for the product. The purity of the dihydrobromide salt was determined to be 97.8% (Sample 1) and 97.2% (Sample 2) by HPLC.

[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 48% aqueous solution, 2.04 equivalents) was added dropwise to a solution of Compound 1 (50.59 mg, 0.073 mmol, 1.0 equivalent) in tetrahydrofuran (2.0 mL). The reaction mixture was stirred to obtain a good slurry. The slurry was stirred at 25 °C for 2.5 hours and filtered to obtain the mother liquor and the solid. The solid was dried under vacuum at 40 - 41 °C overnight to obtain 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 to be 1:2 by HPLC. The dihydrobromide salt of Compound 1 was characterized by XRPD (Figure 9). Analytical data were obtained for the product. The purity of the dihydrobromide salt was determined to be 99.7% by HPLC.

[0257] Example 10. Preparation of the Dioxalate Salt of Compound 1 Oxalic acid (20.11 mg, 0.223 mmol, 2.05 equivalents) was added to a solution of Compound 1 (75.58 mg, 0.109 mmol, 1.0 equivalent) in tetrahydrofuran (2.0 mL). The reaction mixture was stirred to obtain a slurry. The slurry was stirred continuously for 2 hours and filtered to obtain the mother liquor and the solid. The solid was dried under vacuum at 40 - 41 °C overnight to obtain the dioxalate 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 to be 1:2 by elemental analysis (theoretically C 45 H 43 N7O12 (C, 61.85; H, 4.96; N, 11.22; analytical results: C, 60.91; H, 5.21; N, 10.73). The crystallinity of the dioxalate was confirmed by XRPD (Figure 10, Table 1) and further confirmed by DSC (Figure 11), showing a salt with an onset temperature of 222.23°C and a peak at 235.26°C. The TGA of the dioxalate is shown in Figure 12. This showed a weight loss of approximately 0.7% up to approximately 100°C. Analytical data collected for the product were obtained. The purity of the dioxalate was determined to be 96.1% by HPLC.

[0259] [Table 3]

[0260] Example 11. Preparation of L-tartrate (1:1.7) of Compound 1 [ka] L-tartaric acid (31.52 mg, 0.210 mmol, 2.05 equivalents) 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 minutes to obtain a slurry. The slurry was stirred continuously for 2 hours, then filtered to obtain the mother liquor and solid. The solid was vacuum-dried overnight at 40-41°C to obtain the L-tartrate 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 1H NMR (Figure 14). The L-tartrate of compound 1 was characterized by XRPD (Figure 13). Analytical data collected for the product were obtained. The purity of the L-tartrate was determined to be 96.4% by HPLC.

[0262] Example 12. Preparation of the trihydrochloride salt of Compound 1 Compound 1 (500 mg, 0.721 mmol) and dimethyl sulfoxide (4.0 mL) were placed in a scintillation vial.

[0263] In a 50 mL round-bottom flask equipped with a stirring rod, 30.0 mL of tetrahydrofuran and 721 μL (4 equivalents) of 4N hydrochloric acid / dioxane were added. While stirring, the solution of compound 1 was added dropwise to the tetrahydrofuran solution via a pipette over 3 minutes. A solid precipitate formed from the solution, and the slurry was pale yellow. The mixture was stoppered and stirred overnight at room temperature.

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

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

[0266] 722 mg of product was recovered. The 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 phosphate of compound 1 (approximately 1:2) In a 40 mL scintillation vial equipped with a stirring rod, acetone (15.0 mL) and phosphoric acid (0.103 mL, 1.477 mmol, 2 equivalents) were added. The mixture was stirred to obtain a clear solution. In a 20 mL scintillation vial, compound 1 (500 mg, 0.721 mmol), dichloromethane (4.50 mL), and methanol (0.50 mL) were added. The mixture was stirred until homogeneous, and then added dropwise to the phosphoric acid solution over 3-4 minutes. A yellow solid precipitated from the solution, and the mixture was stirred at room temperature for 90 minutes, then filtered. The filtered cake was washed with acetone (5.00 mL), and the solid was dried under high vacuum.

[0268] 640 mg of product was recovered. The 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 be 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. All references, including all patents, patent applications, and publications cited herein, are incorporated herein by reference in their entirety.

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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