Solid forms of toll-like receptor modulators

Abstract

To provide a method for treating diseases.SOLUTION: There are provided crystalline forms, solvates, and hydrates of (R)-2-((2- amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol, and a method of producing the same. Compound I can adopt a variety of crystalline forms, including, but not limited to, Form I, an HCl salt, an HCl salt Form I, an HCl salt Form II, Compound I tartaric acid, Compound I maleic acid, Compound I fumaric acid, and Compound I methanesulfonic acid. Compound I can form a mixture of two or more crystalline forms, or form a single crystalline form substantially free of other crystalline forms. Compound 1 can also adopt a solid amorphous form.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 835,335, filed April 17, 2019, the entire contents of which are incorporated herein by reference.

[0002] Field FIELD OF THE INVENTION This application relates generally to Toll-like receptor modulator compounds, including pyrido[3,2 D]pyrimidine compounds, and in particular to pharmaceutical compositions that modulate Toll-like receptors (e.g., TLR-8), and methods of making and using them. [Background technology]

[0003] The Toll-like receptor (TLR) family plays a fundamental role in pathogen recognition and innate immune activation. Toll-like receptor 8 (TLR-8) is primarily expressed by myeloid immune cells, and activation of this receptor stimulates a wide range of immunological responses. TLR-8 agonists activate myeloid dendritic cells, monocytes, monocyte-derived dendritic cells, and Kupffer cells, leading to the production of proinflammatory cytokines and chemokines, such as interleukin-18 (IL-18), interleukin-12 (IL-12), tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ). Such agonists also activate costimulatory molecules, such as CD8 + It also promotes increased expression of major histocompatibility complex molecules (MAIT, NK cell) and chemokine receptors.

[0004] Collectively, activation of these innate and adaptive immune responses induces immune responses and provides therapeutic benefits in a variety of conditions, including autoimmunity, inflammation, allergy, asthma, graft rejection, graft-versus-host disease (GvHD), infection, cancer, and immunodeficiency. For example, in the context of hepatitis B, activation of TLR8 on professional antigen-presenting cells (pAPCs) and other intrahepatic immune cells is associated with the induction of IL-12 and proinflammatory cytokines, which are predicted to enhance HBV-specific T cell responses, activate intrahepatic NK cells, and drive antiviral immune reconstitution. See, for example, Wille-Reece, U. et al., J Exp Med 203, 1249-1258 (2006); Peng, G. et al., Science 309, 1380-1384 (2005); Jo, J. et al., PLoS Pathogens 10, e1004210 (2014), and Watashi, K. et al., J Biol Chem 288, 31715-31727 (2013). Given their potential for treating a wide variety of diseases, there remains a need for novel modulators of Toll-like receptors, such as TLR-8. Potent and selective modulators of TLR-8 with reduced potential for off-target propensity are particularly desirable. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Wille-Reece, U. et al., J Exp Med 203, 1249-1258 (2006) [Non-patent document 2] Peng, G. et al., Science 309, 1380-1384 (2005) [Non-patent document 3] Jo, J. et al., PLoS Pathogens, vol. 10, p. e1004210 (2014) [Non-patent document 4] Watashi, K. et al., J Biol Chem 288, 31715-31727 (2013) Summary of the Invention [Means for solving the problem]

[0006] In one embodiment, the disclosure provides a crystalline form of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (Compound I), Form I, characterized by an X-ray powder diffraction (XRPD) pattern containing three or more peaks at 10.9°, 11.5°, 13.2°, 14.7°, 15.5°, 21.4°, 21.9°, 23.2°, or 24.9°2θ (±0.2°2θ). [ka]

[0007] In another embodiment, the disclosure provides a crystalline form of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol hydrochloride, hydrochloride salt Form I, characterized by an XRPD pattern containing three or more peaks at 6.1°, 12.2°, 15.0°, 17.3°, 17.8°, 18.9°, 20.3°, 23.2°, or 24.1°2θ (±0.2°2θ). [ka]

[0008] In another embodiment, the disclosure provides a crystalline form of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol hydrochloride, hydrochloride salt Form II, characterized by an XRPD pattern containing three or more peaks at 7.1°, 9.7°, 14.3°, 15.3°, 16.1°, 19.1°, 22.5°, 24.0°, or 26.0°2θ (±0.2°2θ). [ka]

[0009] In another embodiment, the disclosure provides a crystalline form of Compound I tartaric acid, (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol tartaric acid, characterized by an XRPD pattern including three or more peaks at 6.3°, 9.9°, 12.5°, 17.7°, 18.3°, 19.2°, 23.4°, 25.7°, or 28.1°2θ (±0.2°2θ). Provides form. [ka]

[0010] In another embodiment, the disclosure provides a crystalline form of Compound I maleic acid, (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol maleic acid, characterized by an XRPD pattern including three or more peaks at 7.3°, 8.4°, 8.8°, 13.9°, 15.6°, 17.7°, 20.7°, 24.7°, or 27.4° 2θ (±0.2° 2θ). [ka]

[0011] In another embodiment, the disclosure provides a crystalline form of Compound I fumaric acid, (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol fumarate, characterized by an XRPD pattern including three or more peaks at 6.7°, 8.3°, 10.1°, 12.6°, 16.1°, 18.5°, 20.6°, 25.2°, or 27.6°2θ (±0.2°2θ). [ka]

[0012] In another embodiment, the disclosure provides a crystalline form of Compound I methanesulfonic acid, (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol methanesulfonic acid, characterized by an XRPD pattern including three or more peaks at 5.4°, 10.4°, 10.8°, 15.8°, 17.3°, 18.1°, 20.5°, 20.8°, or 23.9°2θ (±0.2°2θ). [ka]

[0013] In another embodiment, the present disclosure provides an amorphous solid form of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol. [ka] [Brief explanation of the drawings]

[0014] [Figure 1] FIG. 1 shows the XRPD pattern for Compound I Form I.

[0015] [Figure 2] FIG. 2 shows the DSC thermogram for Compound I Form I.

[0016] [Figure 3] FIG. 3 shows the TGA curve for Compound I Form I.

[0017] [Figure 4] FIG. 4 shows the DVS curve for Compound I Form I.

[0018] [Figure 5]FIG. 5 shows the XRPD pattern for Compound I HCl salt Form I.

[0019] [Figure 6] FIG. 6 shows the DSC thermogram for Compound I HCl salt Form I.

[0020] [Figure 7] FIG. 7 shows the TGA curve for Compound I HCl salt Form I.

[0021] [Figure 8] FIG. 8 shows the DVS curve for Compound I HCl salt Form I.

[0022] [Figure 9] FIG. 9 shows the XRPD pattern for Compound I HCl salt Form II.

[0023] [Figure 10] FIG. 10 shows the DSC thermogram for Compound I HCl salt Form II.

[0024] [Figure 11] FIG. 11 shows the TGA curve for Compound I HCl salt Form II.

[0025] [Figure 12] FIG. 12 shows the DVS curve for Compound I HCl salt Form II.

[0026] [Figure 13] FIG. 13 shows the XRPD pattern for Compound I tartaric acid.

[0027] [Figure 14] FIG. 14 shows the DSC thermogram for Compound I tartaric acid.

[0028] [Figure 15] FIG. 15 shows the TGA curve for Compound I tartaric acid.

[0029] [Figure 16] FIG. 16 shows the DVS curve for compound I tartaric acid.

[0030] [Figure 17] FIG. 17 shows the XRPD pattern for Compound I maleic acid.

[0031] [Figure 18] FIG. 18 shows the DSC thermogram for Compound I maleic acid.

[0032] [Figure 19] FIG. 19 shows the TGA curve for Compound I maleic acid.

[0033] [Figure 20] FIG. 20 shows the DVS curve for Compound I maleic acid.

[0034] [Figure 21] FIG. 21 shows the XRPD pattern for Compound I fumaric acid.

[0035] [Figure 22] FIG. 22 shows the DSC thermogram for Compound I fumaric acid.

[0036] [Figure 23] FIG. 23 shows the TGA curve for Compound I fumaric acid.

[0037] [Figure 24] FIG. 24 shows the DVS curve for compound I fumaric acid.

[0038] [Figure 25] FIG. 25 shows the XRPD pattern for Compound I methanesulfonic acid.

[0039] [Figure 26] FIG. 26 shows the DSC thermogram for Compound I methanesulfonic acid.

[0040] [Figure 27] FIG. 27 shows the TGA curve for Compound I methanesulfonic acid.

[0041] [Figure 28] FIG. 28 shows the DVS curve for Compound I methanesulfonic acid.

[0042] [Figure 29] FIG. 29 shows the XRPD pattern for amorphous Compound I.

[0043] [Figure 30] FIG. 30 shows the DSC curve for amorphous Compound I. DETAILED DESCRIPTION OF THE INVENTION

[0044] I. Overview The present disclosure provides a solid form of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (Compound I). [ka] and their salts, solvates, or co-crystals. Compound I can take on various crystalline forms, including, but not limited to, crystalline Compound I Form I, crystalline Compound I HCl Form I, crystalline Compound I HCl Form II, crystalline Compound I tartrate, crystalline Compound I maleate, crystalline Compound I fumarate, crystalline Compound I methanesulfonate, and amorphous Compound I. Compound I can form a mixture of two or more crystalline forms, or can form a single crystalline form substantially free of other crystalline forms.

[0045] The X-ray powder diffraction (XRPD) pattern of the solid form of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (Compound I) provided herein was collected using Cu Kα radiation. II. Definition

[0046] As used herein, the following words and phrases are generally intended to have the meanings set forth below, unless otherwise indicated by the context in which they are used.

[0047] "Hydrate" refers to the complex formed by combining Compound I and water. This term includes stoichiometric and non-stoichiometric hydrates.

[0048] "Solvate" refers to a complex formed by combining Compound I and a solvent.

[0049] "Desolvated" refers to a form of Compound I, a solvate as described herein, from which solvent molecules have been partially or completely removed. Desolvation techniques for producing desolvated forms include, but are not limited to, exposing a form of Compound I (a solvate) to a vacuum, exposing the solvate to elevated temperatures, exposing the solvate to a stream of gas, such as air or nitrogen, or any combination thereof. Thus, a desolvated form of Compound I can be anhydrous, i.e., completely free of solvent molecules, or can be partially solvated, where the solvent molecules are present in stoichiometric or non-stoichiometric amounts.

[0050] "Alcohol" refers to a solvent having a hydroxy group. Representative alcohols can have any suitable number of carbon atoms, e.g., C1-C6, and any suitable number of hydroxy groups, e.g., 1-3. Exemplary alcohols include, but are not limited to, methanol, ethanol, n-propanol, i-propanol, and the like.

[0051] A "therapeutically effective amount" refers to an amount sufficient to effect such treatment, as defined below, when administered to a mammal in need of treatment. The therapeutically effective amount varies depending on the subject being treated, the subject's weight and age, the severity of the disease state, the mode of administration, etc., and can be readily determined by one skilled in the art.

[0052] "Substantially free of other crystalline forms of Compound I" refers to a crystalline form of Compound I that contains less than 10% of other crystalline forms of Compound I. For example, substantially free can refer to a crystalline form of Compound I that contains less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of other crystalline forms of Compound I. Preferably, substantially free refers to a crystalline form of Compound I that contains less than 5% of other crystalline forms of Compound I. Preferably, substantially free refers to a crystalline form of Compound I that contains less than 1% of other crystalline forms of Compound I. III. Solid Forms of Compound I

[0053] The present disclosure provides solid forms of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (Compound I, see U.S. Pat. No. 9,670,205), including crystalline and amorphous forms, as well as salt, solvate, and hydrate forms. In some embodiments, the present disclosure provides compounds having the structure [ka] The present invention provides a crystalline form of Compound I having the formula:

[0054] Compound I can take various crystalline forms, including, but not limited to, Form I, HCl salt, HCl salt Form I, HCl salt Form II, Compound I tartrate, Compound I maleate, Compound I fumarate, and Compound I methanesulfonate. Compound I can form a mixture of two or more crystalline forms, or can form a single crystalline form substantially free of other crystalline forms. Compound 1 can also take a solid amorphous form.

[0055] In some embodiments, the present disclosure provides a crystalline form of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (Compound I). [ka] or a pharmaceutically acceptable salt or co-crystal thereof. The crystalline form of Compound I may be anhydrous, a salt, a solvate, or a co-crystal. In some embodiments, the crystalline form of Compound I may be a salt or a co-crystal. In some embodiments, the crystalline form of Compound I may be anhydrous or solvated. In some embodiments, the crystalline form of Compound I may be hydrated.

[0056] In some embodiments, the present disclosure provides (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol Form I, (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol HCl salt Form I, (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol HCl salt Form II, (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol HCl salt Form II, In some embodiments, the present disclosure provides a compound selected from the group consisting of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol tartaric acid, (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol maleic acid, (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol fumaric acid, and (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol methanesulfonic acid. In some embodiments, the present disclosure provides amorphous (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol. Form I

[0057] In some embodiments, the present disclosure provides (R)-2-((2-amino-7-fluoropyrido[ 3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol, wherein the crystalline form is Form I. In some embodiments, the present disclosure provides a crystalline form of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (Compound I), wherein the crystalline form is Form I, characterized by an X-ray powder diffraction (XRPD) pattern containing three or more peaks at 10.9°, 11.5°, 13.2°, 14.7°, 15.5°, 21.4°, 21.9°, 23.2°, or 24.9° 2θ (±0.2° 2θ). [ka]

[0058] In some embodiments, Form I is characterized by an XRPD pattern comprising 4, 5, 6, 7, 8, or 9 peaks at 10.9, 11.5, 13.2, 14.7, 15.5, 21.4, 21.9, 23.2, or 24.9°2θ (±0.2°2θ). In some embodiments, Form I is characterized by an XRPD pattern comprising 4 or more peaks at 10.9, 11.5, 13.2, 14.7, 15.5, 21.4, 21.9, 23.2, or 24.9°2θ (±0.2°2θ). In some embodiments, Form I is characterized by an XRPD pattern comprising five or more peaks at 10.9, 11.5, 13.2, 14.7, 15.5, 21.4, 21.9, 23.2, or 24.9°2θ (±0.2°2θ). In some embodiments, Form I is characterized by an XRPD pattern comprising six or more peaks at 10.9, 11.5, 13.2, 14.7, 15.5, 21.4, 21.9, 23.2, or 24.9°2θ (±0.2°2θ). In some embodiments, Form I is characterized by an XRPD pattern comprising 7 or more peaks at 10.9, 11.5, 13.2, 14.7, 15.5, 21.4, 21.9, 23.2, or 24.9°2θ (±0.2°2θ). In some embodiments, Form I is characterized by an XRPD pattern comprising 8 or more peaks at 10.9, 11.5, 13.2, 14.7, 15.5, 21.4, 21.9, 23.2, or 24.9°2θ (±0.2°2θ).

[0059] In some embodiments, Form I is characterized by an XRPD pattern comprising peaks at 15.5°, 21.4°, and 21.9° (±0.2° 2θ). In some embodiments, the XRPD pattern further comprises one, two, three, four, or more additional peaks at 10.9°, 11.5°, 13.2°, 14.7°, 23.2°, or 24.9° 2θ (±0.2° 2θ). In some embodiments, the XRPD pattern further comprises one or more additional peaks at 10.9°, 11.5°, 13.2°, 14.7°, 23.2°, or 24.9° 2θ (±0.2° 2θ). In some embodiments, the XRPD pattern further comprises two or more additional peaks at 10.9°, 11.5°, 13.2°, 14.7°, 23.2°, or 24.9°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises three or more additional peaks at 10.9°, 11.5°, 13.2°, 14.7°, 23.2°, or 24.9°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises four or more additional peaks at 10.9°, 11.5°, 13.2°, 14.7°, 23.2°, or 24.9°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises four or more additional peaks at 10.9°, 11.5°, 13.2°, 14.7°, 23.2°, or 24.9°2θ (±0.2°2θ). It further contains additional peaks at 13.2°, 14.7°, 23.2°, and 24.9° 2θ (±0.2° 2θ).

[0060] In some embodiments, Form I is characterized by an XRPD pattern comprising peaks at 10.9, 13.2, and 14.7 degrees 2θ (±0.2 degrees 2θ). In some embodiments, the XRPD pattern further comprises one, two, three, four, or more additional peaks at 11.5, 15.5, 21.4, 21.9, 23.2, or 24.9 degrees 2θ (±0.2 degrees 2θ). In some embodiments, the XRPD pattern further comprises one or more additional peaks at 11.5, 15.5, 21.4, 21.9, 23.2, or 24.9 degrees 2θ (±0.2 degrees 2θ). In some embodiments, the XRPD pattern further comprises two or more additional peaks at 11.5, 15.5, 21.4, 21.9, 23.2, or 24.9°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises three or more additional peaks at 11.5, 15.5, 21.4, 21.9, 23.2, or 24.9°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises four or more additional peaks at 11.5, 15.5, 21.4, 21.9, 23.2, or 24.9°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises additional peaks at 11.5°, 15.5°, 21.4°, 21.9°, 23.2°, and 24.9° 2θ (±0.2° 2θ).

[0061] In some embodiments, Form I is characterized by an XRPD pattern containing three or more peaks at 10.9°, 13.2°, 14.7°, 15.5°, 21.4°, or 21.9° (±0.2° 2θ). In some embodiments, Form I is characterized by an XRPD pattern containing four or more peaks at 10.9°, 13.2°, 14.7°, 15.5°, 21.4°, or 21.9° (±0.2° 2θ). In some embodiments, Form I is characterized by an XRPD pattern containing five or more peaks at 10.9°, 13.2°, 14.7°, 15.5°, 21.4°, or 21.9° (±0.2° 2θ). In some embodiments, Form I is characterized by an XRPD pattern comprising peaks at 10.9°, 13.2°, 14.7°, 15.5°, 21.4°, and 21.9° (±0.2° 2θ).

[0062] In some embodiments, Form I is characterized by an XRPD pattern comprising peaks at 10.9°, 11.5°, 13.2°, 14.7°, 15.5°, 21.4°, 21.9°, 23.2°, and 24.9°2θ (±0.2°2θ). In some embodiments, Form I is characterized by a unit cell with the following dimensions: a=8.0344(2) Å, b=8.0344(2) Å, c=23.7871(7) Å, α=90°, β=90°, and γ=90°, as determined by single crystal X-ray crystallography. In some embodiments, Form I is characterized by an XRPD pattern substantially as shown in FIG.

[0063] In some embodiments, Form I is characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 164° C. In some embodiments, Form I is characterized by a DSC thermogram substantially as shown in Figure 2. In some embodiments, Form I is characterized by the thermogravimetric analysis (TGA) curve of Figure 3. In some embodiments, Form I is characterized by the dynamic vapor sorption (DVS) curve of Figure 4.

[0064] In some embodiments, Form I has the following structural variations: (a) 10.9°, 11.5°, 13.2°, 14.7°, 15.5°, 21.4°, 21.9°, 23.2°, and 24.9°. (b) an XRPD pattern comprising a peak at θ (±0.2° 2θ); (b) a unit cell with the following dimensions, as determined by single crystal X-ray crystallography: a=8.0344(2) Å, b=8.0344(2) Å, c=23.7871(7) Å, α=90°, β=90°, and γ=90°; and (c) a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset temperature of about 164°C. In some embodiments, Form I is characterized by two or more of the following: (a) an XRPD pattern comprising peaks at 10.9°, 11.5°, 13.2°, 14.7°, 15.5°, 21.4°, 21.9°, 23.2°, and 24.9°2θ (±0.2°2θ); (b) a unit cell with the following dimensions, as determined by single crystal X-ray crystallography: a=8.0344(2)Å, b=8.0344(2)Å, c=23.7871(7)Å, α=90°, β=90°, and γ=90°; and (c) a differential scanning calorimetry (DSC) thermogram with an endotherm with an onset temperature of about 164°C. In some embodiments, Form I is characterized by the following: (a) an XRPD pattern comprising peaks at 10.9°, 13.2°, 14.7°, 15.5°, 21.4°, 21.9°, 23.2°, and 24.9°2θ (±0.2°2θ); (b) a unit cell with the following dimensions, as determined by single crystal X-ray crystallography: a=8.0344(2)Å, b=8.0344(2)Å, c=23.7871(7)Å, α=90°, β=90°, and γ=90°; and (c) a differential scanning calorimetry (DSC) thermogram with an endotherm with an onset temperature of about 164°C.

[0065] In some embodiments, Form I is characterized by one or more of the following: (a) an XRPD pattern substantially as shown in FIG. 1; (b) a unit cell with the following dimensions, as determined by single crystal X-ray crystallography: a=8.0344(2) Å, b=8.0344(2) Å, c=23.7871(7) Å, α=90°, β=90°, and γ=90°; (c) a DSC thermogram substantially as shown in FIG. 2; (d) a thermogravimetric analysis (TGA) curve substantially as shown in FIG. 3; and (e) a dynamic vapor sorption (DVS) curve substantially as shown in FIG. 4. In some embodiments, Form I is characterized by two or more of the following: (a) an XRPD pattern substantially as shown in FIG. 1; (b) a unit cell with the following dimensions, as determined by single crystal X-ray crystallography: a=8.0344(2) Å, b=8.0344(2) Å, c=23.7871(7) Å, α=90°, β=90°, and γ=90°; (c) a DSC thermogram substantially as shown in FIG. 2; (d) a thermogravimetric analysis (TGA) curve substantially as shown in FIG. 3; and (e) a dynamic vapor sorption (DVS) curve substantially as shown in FIG. 4. In some embodiments, Form I is characterized by the following: (a) an XRPD pattern substantially as shown in FIG. 1; (b) a unit cell with the following dimensions, as determined by single crystal X-ray crystallography: a=8.0344(2) Å, b=8.0344(2) Å, c=23.7871(7) Å, α=90°, β=90°, and γ=90°; (c) a DSC thermogram substantially as shown in FIG. 2; (d) a thermogravimetric analysis (TGA) curve substantially as shown in FIG. 3; and (e) a dynamic vapor sorption (DVS) curve substantially as shown in FIG. 4. HCl salt, Form I

[0066] In some embodiments, the disclosure provides a crystalline form of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol, wherein the crystalline form is HCl salt Form I. In some embodiments, the disclosure provides a crystalline form of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol hydrochloride that is hydrochloride salt Form I, characterized by an XRPD pattern including three or more peaks at 6.1°, 12.2°, 15.0°, 17.3°, 17.8°, 18.9°, 20.3°, 23.2°, or 24.1°2θ (±0.2°2θ). [ka]

[0067] In some embodiments, hydrochloride salt Form I is characterized by an XRPD pattern containing 4, 5, 6, 7, 8, or 9 peaks at 6.1, 12.2, 15.0, 17.3, 17.8, 18.9, 20.3, 23.2, or 24.1 °2θ (±0.2 °2θ). In some embodiments, hydrochloride salt Form I is characterized by an XRPD pattern containing 4 or more peaks at 6.1, 12.2, 15.0, 17.3, 17.8, 18.9, 20.3, 23.2, or 24.1 °2θ (±0.2 °2θ). In some embodiments, hydrochloride salt Form I is characterized by an XRPD pattern containing five or more peaks at 6.1°, 12.2°, 15.0°, 17.3°, 17.8°, 18.9°, 20.3°, 23.2°, or 24.1°2θ (±0.2°2θ). In some embodiments, hydrochloride salt Form I is characterized by an XRPD pattern containing six or more peaks at 6.1°, 12.2°, 15.0°, 17.3°, 17.8°, 18.9°, 20.3°, 23.2°, or 24.1°2θ (±0.2°2θ). In some embodiments, hydrochloride salt Form I is characterized by an XRPD pattern containing 7 or more peaks at 6.1°, 12.2°, 15.0°, 17.3°, 17.8°, 18.9°, 20.3°, 23.2°, or 24.1°2θ (±0.2°2θ). In some embodiments, hydrochloride salt Form I is characterized by an XRPD pattern containing 8 or more peaks at 6.1°, 12.2°, 15.0°, 17.3°, 17.8°, 18.9°, 20.3°, 23.2°, or 24.1°2θ (±0.2°2θ).

[0068] In some embodiments, hydrochloride salt Form I is characterized by an XRPD pattern comprising peaks at 6.1°, 15.0°, and 17.8°2θ (±0.2°2θ). In some embodiments, hydrochloride salt Form I is characterized by an XRPD pattern further comprising one or more additional peaks at 12.2°, 17.3°, 18.9°, 20.3°, 23.2°, or 24.1°2θ (±0.2°2θ). In some embodiments, hydrochloride salt Form I is characterized by an XRPD pattern further comprising two or more additional peaks at 12.2°, 17.3°, 18.9°, 20.3°, 23.2°, or 24.1°2θ (±0.2°2θ). In some embodiments, hydrochloride salt Form I is characterized by an XRPD pattern further comprising three or more additional peaks at 12.2°, 17.3°, 18.9°, 20.3°, 23.2°, or 24.1°2θ (±0.2°2θ). In some embodiments, hydrochloride salt Form I is characterized by an XRPD pattern further comprising four or more additional peaks at 12.2°, 17.3°, 18.9°, 20.3°, 23.2°, or 24.1°2θ (±0.2°2θ). In some embodiments, hydrochloride salt Form I is characterized by an XRPD pattern further comprising five or more additional peaks at 12.2°, 17.3°, 18.9°, 20.3°, 23.2°, or 24.1°2θ (±0.2°2θ).

[0069] In some embodiments, hydrochloride salt Form I is characterized by an XRPD pattern comprising peaks at 12.2°, 18.9°, and 24.1° 2θ (±0.2° 2θ). In some embodiments, hydrochloride salt Form I is characterized by an XRPD pattern further comprising one or more additional peaks at 6.1°, 15.0°, 17.3°, 17.8°, 20.3°, or 23.2°2θ (±0.2°2θ). In some embodiments, hydrochloride salt Form I is characterized by an XRPD pattern further comprising two or more additional peaks at 6.1°, 15.0°, 17.3°, 17.8°, 20.3°, or 23.2°2θ (±0.2°2θ). In some embodiments, hydrochloride salt Form I is characterized by an XRPD pattern further comprising three or more additional peaks at 6.1°, 15.0°, 17.3°, 17.8°, 20.3°, or 23.2°2θ (±0.2°2θ). In some embodiments, hydrochloride salt Form I is characterized by an XRPD pattern further comprising four or more additional peaks at 6.1°, 15.0°, 17.3°, 17.8°, 20.3°, or 23.2°2θ (±0.2°2θ). In some embodiments, hydrochloride salt Form I is characterized by an XRPD pattern further comprising five or more additional peaks at 6.1°, 15.0°, 17.3°, 17.8°, 20.3°, or 23.2°2θ (±0.2°2θ).

[0070] In some embodiments, hydrochloride salt Form I is characterized by an XRPD pattern comprising three or more peaks at 6.1°, 12.2°, 15.0°, 17.8°, 18.9°, or 24.1°2θ (±0.2°2θ). In some embodiments, hydrochloride salt Form I is characterized by an XRPD pattern comprising four or more peaks at 6.1°, 12.2°, 15.0°, 17.8°, 18.9°, or 24.1°2θ (±0.2°2θ). In some embodiments, hydrochloride salt Form I is characterized by an XRPD pattern comprising five or more peaks at 6.1°, 12.2°, 15.0°, 17.8°, 18.9°, or 24.1°2θ (±0.2°2θ). In some embodiments, hydrochloride salt Form I is characterized by an XRPD pattern comprising peaks at 6.1°, 12.2°, 15.0°, 17.8°, 18.9°, and 24.1° 2θ (±0.2° 2θ).

[0071] In some embodiments, hydrochloride salt Form I is characterized by an XRPD pattern comprising peaks at 6.1°, 12.2°, 15.0°, 17.3°, 17.8°, 18.9°, 20.3°, 23.2°, and 24.1°2θ (±0.2°2θ). In some embodiments, hydrochloride salt Form I is characterized by an XRPD pattern substantially as shown in FIG.

[0072] In some embodiments, hydrochloride salt Form I is characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset temperature of about 135° C. In some embodiments, hydrochloride salt Form I is characterized by a DSC thermogram substantially as shown in FIG. 6. In some embodiments, hydrochloride salt Form I is characterized by a thermogravimetric analysis (TGA) curve substantially as shown in FIG. 7. In some embodiments, hydrochloride salt Form I is characterized by a dynamic vapor sorption (DVS) curve substantially as shown in FIG. 8.

[0073] In some embodiments, hydrochloride salt Form I is characterized by (a) an XRPD pattern comprising peaks at 6.1°, 12.2°, 15.0°, 17.3°, 17.8°, 18.9°, 20.3°, 23.2°, and 24.1°2θ (±0.2°2θ), and (b) a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset temperature of about 135° C. In some embodiments, hydrochloride salt Form I is characterized by two or more of the following: (a) an XRPD pattern substantially as shown in FIG. 5, (b) a DSC thermogram substantially as shown in FIG. 6, (c) a thermogravimetric analysis (TGA) curve substantially as shown in FIG. 7, and (d) a dynamic vapor sorption (DVS) curve substantially as shown in FIG. 8. HCl salt, Form II

[0074] In some embodiments, the disclosure provides a crystalline form of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol, wherein the crystalline form is HCl salt Form II. In some embodiments, the disclosure provides a crystalline form of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol hydrochloride that is hydrochloride salt Form II, characterized by an XRPD pattern including three or more peaks at 7.1°, 9.7°, 14.3°, 15.3°, 16.1°, 19.1°, 22.5°, 24.0°, or 26.0°2θ (±0.2°2θ). [ka]

[0075] In some embodiments, hydrochloride salt Form II is characterized by 4, 5, 6, 7, 8, or 9 peaks at 7.1, 9.7, 14.3, 15.3, 16.1, 19.1, 22.5, 24.0, or 26.0°2θ (±0.2°2θ). In some embodiments, hydrochloride salt Form II is characterized by an XRPD pattern comprising 4 or more peaks at 7.1, 9.7, 14.3, 15.3, 16.1, 19.1, 22.5, 24.0, or 26.0°2θ (±0.2°2θ). In some embodiments, hydrochloride salt Form II is characterized by an XRPD pattern comprising five or more peaks at 7.1°, 9.7°, 14.3°, 15.3°, 16.1°, 19.1°, 22.5°, 24.0°, or 26.0°2θ (±0.2°2θ). In some embodiments, hydrochloride salt Form II is characterized by an XRPD pattern comprising six or more peaks at 7.1°, 9.7°, 14.3°, 15.3°, 16.1°, 19.1°, 22.5°, 24.0°, or 26.0°2θ (±0.2°2θ). In some embodiments, hydrochloride salt Form II is characterized by an XRPD pattern comprising 7 or more peaks at 7.1°, 9.7°, 14.3°, 15.3°, 16.1°, 19.1°, 22.5°, 24.0°, or 26.0°2θ (±0.2°2θ). In some embodiments, hydrochloride salt Form II is characterized by an XRPD pattern comprising 8 or more peaks at 7.1°, 9.7°, 14.3°, 15.3°, 16.1°, 19.1°, 22.5°, 24.0°, or 26.0°2θ (±0.2°2θ).

[0076] In some embodiments, the hydrochloride salt Form II is characterized by an XRPD pattern comprising peaks at 7.1°, 15.3°, and 24.0°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises one or more additional peaks at 9.7°, 14.3°, 16.1°, 19.1°, 22.5°, or 26.0°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises two or more additional peaks at 9.7°, 14.3°, 16.1°, 19.1°, 22.5°, or 26.0°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises three or more additional peaks at 9.7°, 14.3°, 16.1°, 19.1°, 22.5°, or 26.0°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises four or more additional peaks at 9.7°, 14.3°, 16.1°, 19.1°, 22.5°, or 26.0°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises four or more additional peaks at 9.7°, 14.3°, 16.1°, 19.1°, 22.5°, or 26.0°2θ (±0.2°2θ). It further includes 5 or more additional peaks at °2θ (±0.2 °2θ).

[0077] In some embodiments, hydrochloride salt Form II is characterized by an XRPD pattern comprising peaks at 14.3°, 16.1°, and 26.0°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises one or more additional peaks at 7.1°, 9.7°, 15.3°, 19.1°, 22.5°, or 24.0°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises two or more additional peaks at 7.1°, 9.7°, 15.3°, 19.1°, 22.5°, or 24.0°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises three or more additional peaks at 7.1°, 9.7°, 15.3°, 19.1°, 22.5°, or 24.0°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises four or more additional peaks at 7.1°, 9.7°, 15.3°, 19.1°, 22.5°, or 24.0°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises five or more additional peaks at 7.1°, 9.7°, 15.3°, 19.1°, 22.5°, or 24.0°2θ (±0.2°2θ).

[0078] In some embodiments, hydrochloride salt Form II is characterized by an XRPD pattern comprising three or more peaks at 7.1°, 14.3°, 15.3°, 16.1°, 24.0°, or 26.0°2θ (±0.2°2θ). In some embodiments, hydrochloride salt Form II is characterized by an XRPD pattern comprising four or more peaks at 7.1°, 14.3°, 15.3°, 16.1°, 24.0°, or 26.0°2θ (±0.2°2θ). In some embodiments, hydrochloride salt Form II is characterized by an XRPD pattern comprising five or more peaks at 7.1°, 14.3°, 15.3°, 16.1°, 24.0°, or 26.0°2θ (±0.2°2θ). In some embodiments, the hydrochloride salt Form II is characterized by an XRPD pattern comprising peaks at 7.1°, 14.3°, 15.3°, 16.1°, 24.0°, and 26.0° 2θ (±0.2° 2θ).

[0079] In some embodiments, hydrochloride salt Form II is characterized by an XRPD pattern comprising peaks at 7.1°, 9.7°, 14.3°, 15.3°, 16.1°, 19.1°, 22.5°, 24.0°, and 26.0°2θ (±0.2°2θ). In some embodiments, hydrochloride salt Form II is characterized by an XRPD pattern substantially as shown in FIG. 9. In some embodiments, hydrochloride salt Form II is characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset temperature of about 58°C. In some embodiments, hydrochloride salt Form II is characterized by a DSC thermogram substantially as shown in FIG. 10. In some embodiments, hydrochloride salt Form II is characterized by a thermogravimetric analysis (TGA) curve substantially as shown in FIG. 11. In some embodiments, hydrochloride salt Form II is characterized by a dynamic vapor sorption (DVS) curve substantially as shown in FIG.

[0080] In some embodiments, hydrochloride salt Form II is characterized by (a) an XRPD pattern comprising peaks at 7.1°, 9.7°, 14.3°, 15.3°, 16.1°, 19.1°, 22.5°, 24.0°, and 26.0°2θ (±0.2°2θ), and (b) a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset temperature of about 58° C. In some embodiments, hydrochloride salt Form II is characterized by two or more of the following: (a) an XRPD pattern substantially as shown in FIG. 9, (b) a DSC thermogram substantially as shown in FIG. 10, (c) a thermogravimetric analysis (TGA) curve substantially as shown in FIG. 11, and (d) a dynamic vapor sorption (DVS) curve substantially as shown in FIG. 12. Tartaric Acid

[0081] In some embodiments, the present disclosure provides a crystalline form of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol tartrate, wherein the crystalline form is a tartrate salt. In some embodiments, the present disclosure provides a crystalline form of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol, wherein the crystalline form is a co-crystal of Compound I tartaric acid. In some embodiments, the disclosure provides a crystalline form of Compound I tartaric acid, (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol tartaric acid, characterized by an XRPD pattern including three or more peaks at 6.3°, 9.9°, 12.5°, 17.7°, 18.3°, 19.2°, 23.4°, 25.7°, or 28.1°2θ (±0.2°2θ). [ka]

[0082] In some embodiments, Compound I tartrate is characterized by an XRPD pattern comprising four or more peaks at 6.3°, 9.9°, 12.5°, 17.7°, 18.3°, 19.2°, 23.4°, 25.7°, or 28.1°2θ (±0.2°2θ). In some embodiments, Compound I tartrate is characterized by an XRPD pattern comprising five or more peaks at 6.3°, 9.9°, 12.5°, 17.7°, 18.3°, 19.2°, 23.4°, 25.7°, or 28.1°2θ (±0.2°2θ). In some embodiments, Compound I tartrate is characterized by an XRPD pattern comprising six or more peaks at 6.3°, 9.9°, 12.5°, 17.7°, 18.3°, 19.2°, 23.4°, 25.7°, or 28.1°2θ (±0.2°2θ). In some embodiments, Compound I tartrate is characterized by an XRPD pattern comprising seven or more peaks at 6.3°, 9.9°, 12.5°, 17.7°, 18.3°, 19.2°, 23.4°, 25.7°, or 28.1°2θ (±0.2°2θ). In some embodiments, compound I tartaric acid is characterized by an XRPD pattern comprising 8 or more peaks at 6.3°, 9.9°, 12.5°, 17.7°, 18.3°, 19.2°, 23.4°, 25.7°, or 28.1°2θ (±0.2°2θ).

[0083] In some embodiments, Compound I tartaric acid is characterized by an XRPD pattern comprising peaks at 6.3°, 18.3°, and 23.4°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises one or more additional peaks at 9.9°, 12.5°, 17.7°, 19.2°, 25.7°, or 28.1°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises two or more additional peaks at 9.9°, 12.5°, 17.7°, 19.2°, 25.7°, or 28.1°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises three or more additional peaks at 9.9°, 12.5°, 17.7°, 19.2°, 25.7°, or 28.1°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises four or more additional peaks at 9.9°, 12.5°, 17.7°, 19.2°, 25.7°, or 28.1°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises four or more additional peaks at 9.9°, 12.5°, 17.7°, 19.2°, 25.7°, or 28.1°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises five or more additional peaks at 9.9°, 12.5°, 17.7°, 19.2°, 25.7°, and 28.1° 2θ (±0.2° 2θ).

[0084] In some embodiments, Compound I tartaric acid is characterized by an XRPD pattern comprising peaks at 9.9°, 12.5°, and 17.7°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises one or more additional peaks at 6.3°, 18.3°, 19.2°, 23.4°, 25.7°, or 28.1°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises two or more additional peaks at 6.3°, 18.3°, 19.2°, 23.4°, 25.7°, or 28.1°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises three or more additional peaks at 6.3, 18.3, 19.2, 23.4, 25.7, or 28.1 °2θ (±0.2 °2θ). In some embodiments, the XRPD pattern further comprises four or more additional peaks at 6.3, 18.3, 19.2, 23.4, 25.7, or 28.1 °2θ (±0.2 °2θ). In some embodiments, the XRPD pattern further comprises five or more additional peaks at 6.3, 18.3, 19.2, 23.4, 25.7, or 28.1 °2θ (±0.2 °2θ). In some embodiments, the XRPD pattern further comprises additional peaks at 6.3°, 18.3°, 19.2°, 23.4°, 25.7°, and 28.1° 2θ (±0.2° 2θ).

[0085] In some embodiments, Compound I tartrate is characterized by three or more XRPD peaks at 6.3°, 9.9°, 12.5°, 17.7°, 18.3°, or 23.4°2θ (±0.2°2θ). In some embodiments, Compound I tartrate is characterized by four or more XRPD peaks at 6.3°, 9.9°, 12.5°, 17.7°, 18.3°, or 23.4°2θ (±0.2°2θ). In some embodiments, Compound I tartrate is characterized by five or more XRPD peaks at 6.3°, 9.9°, 12.5°, 17.7°, 18.3°, or 23.4°2θ (±0.2°2θ). In some embodiments, Compound I tartaric acid is characterized by XRPD peaks at 6.3°, 9.9°, 12.5°, 17.7°, 18.3°, and 23.4° 2θ (±0.2° 2θ).

[0086] In some embodiments, compound I tartrate is characterized by an XRPD pattern comprising peaks at 6.3°, 9.9°, 12.5°, 17.7°, 18.3°, 19.2°, 23.4°, 25.7°, and 28.1°2θ (±0.2°2θ). In some embodiments, compound I tartrate is characterized by an XRPD pattern substantially as depicted in FIG. 13. In some embodiments, compound I tartrate is characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset temperature of about 157°C. In some embodiments, compound I tartrate is characterized by a DSC thermogram substantially as depicted in FIG. 14. In some embodiments, compound I tartrate is characterized by a DSC thermogram substantially as depicted in FIG. 15. In some embodiments, compound I tartrate is characterized by a dynamic vapor sorption (DVS) curve substantially as depicted in FIG. 16.

[0087] In some embodiments, Compound I tartrate is characterized by (a) an XRPD pattern comprising peaks at 6.3°, 9.9°, 12.5°, 17.7°, 18.3°, 19.2°, 23.4°, 25.7°, and 28.1°2θ (±0.2°2θ), and (b) a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset temperature of about 157° C. In some embodiments, Compound I tartrate is characterized by (a) an XRPD pattern substantially as shown in FIG. 14; (b) a DSC thermogram substantially as shown in FIG. 14; (c) a DSC thermogram substantially as shown in FIG. 15; or (d) a dynamic vapor sorption (DVS) curve substantially as shown in FIG. 16. Maleic Acid

[0088] In some embodiments, the present disclosure provides a crystalline form of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol, wherein the crystalline form is a maleate salt. In some embodiments, the present disclosure provides a crystalline form of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol, wherein the crystalline form is a co-crystal of Compound I maleate. In some embodiments, the disclosure provides a crystalline form of Compound I maleic acid, (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol maleic acid, characterized by an XRPD pattern including three or more peaks at 7.3°, 8.4°, 8.8°, 13.9°, 15.6°, 17.7°, 20.7°, 24.7°, or 27.4° 2θ (±0.2° 2θ). [ka]

[0089] In some embodiments, compound I maleic acid is characterized by an XRPD pattern comprising four or more peaks at 7.3°, 8.4°, 8.8°, 13.9°, 15.6°, 17.7°, 20.7°, 24.7°, or 27.4°2θ (±0.2°2θ). In some embodiments, compound I maleic acid is characterized by an XRPD pattern comprising five or more peaks at 7.3°, 8.4°, 8.8°, 13.9°, 15.6°, 17.7°, 20.7°, 24.7°, or 27.4°2θ (±0.2°2θ). In some embodiments, compound I maleic acid is characterized by an XRPD pattern comprising six or more peaks at 7.3°, 8.4°, 8.8°, 13.9°, 15.6°, 17.7°, 20.7°, 24.7°, or 27.4°2θ (±0.2°2θ). In some embodiments, compound I maleic acid is characterized by an XRPD pattern comprising seven or more peaks at 7.3°, 8.4°, 8.8°, 13.9°, 15.6°, 17.7°, 20.7°, 24.7°, or 27.4°2θ (±0.2°2θ). In some embodiments, Compound I maleic acid is characterized by an XRPD pattern comprising 8 or more peaks at 7.3°, 8.4°, 8.8°, 13.9°, 15.6°, 17.7°, 20.7°, 24.7°, or 27.4°2θ (±0.2°2θ).

[0090] In some embodiments, Compound I maleic acid is characterized by an XRPD pattern comprising peaks at 7.3°, 17.7°, and 24.7°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises one or more additional peaks at 8.4°, 8.8°, 13.9°, 15.6°, 20.7°, or 27.4°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises two or more additional peaks at 8.4°, 8.8°, 13.9°, 15.6°, 20.7°, or 27.4°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises three or more additional peaks at 8.4°, 8.8°, 13.9°, 15.6°, 20.7°, or 27.4°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises four or more additional peaks at 8.4°, 8.8°, 13.9°, 15.6°, 20.7°, or 27.4°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises five or more additional peaks at 8.4°, 8.8°, 13.9°, 15.6°, 20.7°, or 27.4°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises additional peaks at 8.4°, 8.8°, 13.9°, 15.6°, 20.7°, and 27.4°2θ (±0.2°2θ).

[0091] In some embodiments, compound I maleic acid is characterized by an XRPD pattern comprising peaks at 13.9°, 15.6°, and 27.4°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises one or more additional peaks at 7.3°, 8.4°, 8.8°, 17.7°, 20.7°, or 24.7°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises two or more additional peaks at 7.3°, 8.4°, 8.8°, 17.7°, 20.7°, or 24.7°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises three or more additional peaks at 7.3°, 8.4°, 8.8°, 17.7°, 20.7°, or 24.7°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises four or more additional peaks at 7.3°, 8.4°, 8.8°, 17.7°, 20.7°, or 24.7°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises five or more additional peaks at 7.3°, 8.4°, 8.8°, 17.7°, 20.7°, or 24.7°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises additional peaks at 7.3°, 8.4°, 8.8°, 17.7°, 20.7°, and 24.7°2θ (±0.2°2θ).

[0092] In some embodiments, compound I maleic acid is characterized by an XRPD pattern comprising three or more peaks at 7.3°, 13.9°, 15.6°, 17.7°, 24.7°, or 27.4°2θ (±0.2°2θ). In some embodiments, compound I maleic acid is characterized by an XRPD pattern comprising four or more peaks at 7.3°, 13.9°, 15.6°, 17.7°, 24.7°, or 27.4°2θ (±0.2°2θ). In some embodiments, compound I maleic acid is characterized by an XRPD pattern comprising five or more peaks at 7.3°, 13.9°, 15.6°, 17.7°, 24.7°, or 27.4°2θ (±0.2°2θ). In some embodiments, Compound I maleic acid is characterized by an XRPD pattern comprising peaks at 7.3°, 13.9°, 15.6°, 17.7°, 24.7°, and 27.4° 2θ (±0.2° 2θ).

[0093] In some embodiments, compound I maleic acid is characterized by an XRPD pattern comprising peaks at 7.3°, 8.4°, 8.8°, 13.9°, 15.6°, 17.7°, 20.7°, 24.7°, and 27.4°2θ (±0.2°2θ). In some embodiments, compound I maleic acid is characterized by an XRPD pattern substantially as depicted in FIG. 17. In some embodiments, compound I maleic acid is characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset temperature of about 143°C. In some embodiments, compound I maleic acid is characterized by a DSC thermogram substantially as depicted in FIG. 18. In some embodiments, compound I maleic acid is characterized by a thermogravimetric analysis (TGA) curve substantially as depicted in FIG. 19. In some embodiments, compound I maleic acid is characterized by a dynamic vapor sorption (DVS) curve substantially as depicted in FIG. 20.

[0094] In some embodiments, Compound I maleic acid is characterized by (a) an XRPD pattern comprising peaks at 7.3°, 8.4°, 8.8°, 13.9°, 15.6°, 17.7°, 20.7°, 24.7°, and 27.4° 2θ (±0.2° 2θ), and (b) a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset temperature of about 143° C. In some embodiments, Compound I maleic acid is characterized by two or more of: (a) an XRPD pattern substantially as shown in FIG. 17; (b) a DSC thermogram substantially as shown in FIG. 18; (c) a thermogravimetric analysis (TGA) curve substantially as shown in FIG. 19; or (d) a dynamic vapor sorption (DVS) curve substantially as shown in FIG. 20. Fumaric Acid

[0095] In some embodiments, the present disclosure provides a crystalline form of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol, wherein the crystalline form is a fumarate salt. In some embodiments, the present disclosure provides a crystalline form of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol, wherein the crystalline form is a co-crystal of Compound I fumaric acid. In some embodiments, the disclosure provides a crystalline form of Compound I fumaric acid, (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol fumaric acid, characterized by an XRPD pattern including three or more peaks at 6.7°, 8.3°, 10.1°, 12.6°, 16.1°, 18.5°, 20.6°, 25.2°, or 27.6°2θ (±0.2°2θ). [ka]

[0096] In some embodiments, compound I fumarate is characterized by an XRPD pattern comprising four or more peaks at 6.7°, 8.3°, 10.1°, 12.6°, 16.1°, 18.5°, 20.6°, 25.2°, or 27.6°2θ (±0.2°2θ). In some embodiments, compound I fumarate is characterized by an XRPD pattern comprising five or more peaks at 6.7°, 8.3°, 10.1°, 12.6°, 16.1°, 18.5°, 20.6°, 25.2°, or 27.6°2θ (±0.2°2θ). In some embodiments, compound I fumarate is characterized by an XRPD pattern comprising six or more peaks at 6.7°, 8.3°, 10.1°, 12.6°, 16.1°, 18.5°, 20.6°, 25.2°, or 27.6°2θ (±0.2°2θ). In some embodiments, compound I fumarate is characterized by an XRPD pattern comprising seven or more peaks at 6.7°, 8.3°, 10.1°, 12.6°, 16.1°, 18.5°, 20.6°, 25.2°, or 27.6°2θ (±0.2°2θ). In some embodiments, compound I fumaric acid is characterized by an XRPD pattern comprising 8 or more peaks at 6.7°, 8.3°, 10.1°, 12.6°, 16.1°, 18.5°, 20.6°, 25.2°, or 27.6° 2θ (±0.2° 2θ).

[0097] In some embodiments, compound I fumaric acid is characterized by an XRPD pattern comprising peaks at 6.7°, 8.3°, and 25.2° 2θ (±0.2° 2θ). In some embodiments, the XRPD pattern comprises one or more peaks at 10.1°, 12.6°, 16.1°, 18.5°, 20.6°, or 27.6° 2θ (±0.2° 2θ). In some embodiments, the XRPD pattern further comprises two or more additional peaks at 10.1°, 12.6°, 16.1°, 18.5°, 20.6°, or 27.6°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises three or more additional peaks at 10.1°, 12.6°, 16.1°, 18.5°, 20.6°, or 27.6°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises four or more additional peaks at 10.1°, 12.6°, 16.1°, 18.5°, 20.6°, or 27.6°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises five or more additional peaks at 10.1°, 12.6°, 16.1°, 18.5°, 20.6°, or 27.6°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises additional peaks at 10.1°, 12.6°, 16.1°, 18.5°, 20.6°, and 27.6°2θ (±0.2°2θ).

[0098] In some embodiments, compound I fumaric acid is characterized by an XRPD pattern comprising peaks at 18.5°, 20.6°, and 27.6°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises one or more additional peaks at 6.7°, 8.3°, 10.1°, 12.6°, 16.1°, or 25.2°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises two or more additional peaks at 6.7°, 8.3°, 10.1°, 12.6°, 16.1°, or 25.2°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises three or more additional peaks at 6.7°, 8.3°, 10.1°, 12.6°, 16.1°, or 25.2°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises four or more additional peaks at 6.7°, 8.3°, 10.1°, 12.6°, 16.1°, or 25.2°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises five or more additional peaks at 6.7°, 8.3°, 10.1°, 12.6°, 16.1°, or 25.2°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises additional peaks at 6.7°, 8.3°, 10.1°, 12.6°, 16.1°, or 25.2° 2θ (±0.2° 2θ).

[0099] In some embodiments, compound I fumaric acid is characterized by an XRPD pattern comprising three or more peaks at 6.7°, 8.3°, 18.5°, 20.6°, 25.2°, or 27.6°2θ (±0.2°2θ). In some embodiments, compound I fumaric acid is characterized by an XRPD pattern comprising four or more peaks at 6.7°, 8.3°, 18.5°, 20.6°, 25.2°, or 27.6°2θ (±0.2°2θ). In some embodiments, compound I fumaric acid is characterized by an XRPD pattern comprising five or more peaks at 6.7°, 8.3°, 18.5°, 20.6°, 25.2°, or 27.6°2θ (±0.2°2θ). In some embodiments, Compound I fumaric acid is characterized by an XRPD pattern comprising peaks at 6.7°, 8.3°, 18.5°, 20.6°, 25.2°, and 27.6° 2θ (±0.2° 2θ).

[0100] In some embodiments, compound I fumaric acid is characterized by an XRPD pattern comprising peaks at 6.7°, 8.3°, 10.1°, 12.6°, 16.1°, 18.5°, 20.6°, 25.2°, and 27.6° 2θ (±0.2° 2θ). In some embodiments, compound I fumaric acid is characterized by an XRPD pattern substantially as shown in Figure 21. In some embodiments, compound I fumaric acid is characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset temperature of about 70°C. In some embodiments, the DSC thermogram has a second endotherm with an onset temperature of about 167° C. In some embodiments, compound I fumaric acid is characterized by a DSC thermogram substantially as shown in FIG. 22. In some embodiments, compound I fumaric acid is characterized by a thermogravimetric analysis (TGA) curve substantially as shown in FIG. 23. In some embodiments, compound I fumaric acid is characterized by a dynamic vapor sorption (DVS) curve substantially as shown in FIG. 24.

[0101] In some embodiments, compound I fumarate is characterized by (a) an XRPD pattern comprising peaks at 6.7°, 8.3°, 10.1°, 12.6°, 16.1°, 18.5°, 20.6°, 25.2°, and 27.6°2θ (±0.2°2θ), and (b) a differential scanning calorimetry (DSC) thermogram having an endotherm with a first onset temperature of about 70° C. and a second onset temperature of about 167° C. In some embodiments, compound I fumarate is characterized by two or more of: (a) an XRPD pattern substantially as shown in FIG. 21; (b) a DSC thermogram substantially as shown in FIG. 22; (c) a thermogravimetric analysis (TGA) curve substantially as shown in FIG. 23; or (d) a dynamic vapor sorption (DVS) curve substantially as shown in FIG. 24. methanesulfonic acid

[0102] In some embodiments, the present disclosure provides a crystalline form of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol, wherein the crystalline form is a mesylate salt. In some embodiments, the present disclosure provides a crystalline form of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol, wherein the crystalline form is a co-crystal of Compound I methanesulfonic acid. In some embodiments, the disclosure provides a crystalline form of Compound I methanesulfonic acid, (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol methanesulfonic acid, characterized by an XRPD pattern including three or more peaks at 5.4°, 10.4°, 10.8°, 15.8°, 17.3°, 18.1°, 20.5°, 20.8°, or 23.9°2θ (±0.2°2θ). [ka]

[0103] In some embodiments, compound I methanesulfonic acid is characterized by an XRPD pattern comprising four or more peaks at 5.4°, 10.4°, 10.8°, 15.8°, 17.3°, 18.1°, 20.5°, 20.8°, or 23.9°2θ (±0.2°2θ). In some embodiments, compound I methanesulfonic acid is characterized by an XRPD pattern comprising five or more peaks at 5.4°, 10.4°, 10.8°, 15.8°, 17.3°, 18.1°, 20.5°, 20.8°, or 23.9°2θ (±0.2°2θ). In some embodiments, compound I methanesulfonic acid is characterized by an XRPD pattern comprising six or more peaks at 5.4°, 10.4°, 10.8°, 15.8°, 17.3°, 18.1°, 20.5°, 20.8°, or 23.9°2θ (±0.2°2θ). In some embodiments, compound I methanesulfonic acid is characterized by an XRPD pattern comprising seven or more peaks at 5.4°, 10.4°, 10.8°, 15.8°, 17.3°, 18.1°, 20.5°, 20.8°, or 23.9°2θ (±0.2°2θ). In some embodiments, Compound I methanesulfonic acid is characterized by an XRPD pattern comprising 8 or more peaks at 5.4°, 10.4°, 10.8°, 15.8°, 17.3°, 18.1°, 20.5°, 20.8°, or 23.9° 2θ (±0.2° 2θ).

[0104] In some embodiments, compound I methanesulfonic acid is characterized by an XRPD pattern comprising peaks at 5.4°, 18.1°, and 20.5°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises one or more additional peaks at 10.4°, 10.8°, 15.8°, 17.3°, 20.8°, or 23.9°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises two or more additional peaks at 10.4°, 10.8°, 15.8°, 17.3°, 20.8°, or 23.9°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises three or more additional peaks at 10.4°, 10.8°, 15.8°, 17.3°, 20.8°, or 23.9°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises four or more additional peaks at 10.4°, 10.8°, 15.8°, 17.3°, 20.8°, or 23.9°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises five or more additional peaks at 10.4°, 10.8°, 15.8°, 17.3°, 20.8°, or 23.9°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises additional peaks at 10.4°, 10.8°, 15.8°, 17.3°, 20.8°, and 23.9° 2θ (±0.2° 2θ).

[0105] In some embodiments, compound I methanesulfonic acid is characterized by an XRPD pattern comprising peaks at 15.8°, 20.8°, and 23.9°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises one or more additional peaks at 5.4°, 10.4°, 10.8°, 17.3°, 18.1°, or 20.5°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises two or more additional peaks at 5.4°, 10.4°, 10.8°, 17.3°, 18.1°, or 20.5°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises three or more additional peaks at 5.4°, 10.4°, 10.8°, 17.3°, 18.1°, or 20.5°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises four or more additional peaks at 5.4°, 10.4°, 10.8°, 17.3°, 18.1°, or 20.5°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises five or more additional peaks at 5.4°, 10.4°, 10.8°, 17.3°, 18.1°, or 20.5°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises additional peaks at 5.4°, 10.4°, 10.8°, 17.3°, 18.1°, and 20.5° 2θ (±0.2° 2θ).

[0106] In some embodiments, compound I methanesulfonic acid is characterized by an XRPD pattern comprising three or more peaks at 5.4°, 18.1°, 15.8°, 20.5°, 20.8°, or 23.9°2θ (±0.2°2θ). In some embodiments, compound I methanesulfonic acid is characterized by an XRPD pattern comprising four or more peaks at 5.4°, 18.1°, 15.8°, 20.5°, 20.8°, or 23.9°2θ (±0.2°2θ). In some embodiments, compound I methanesulfonic acid is characterized by an XRPD pattern comprising five or more peaks at 5.4°, 18.1°, 15.8°, 20.5°, 20.8°, or 23.9°2θ (±0.2°2θ). In some embodiments, compound I methanesulfonic acid is characterized by an XRPD pattern comprising five or more peaks at 5.4°, 18.1°, 15.8°, 20.5°, 20.8°, or 23.9°2θ (±0.2°2θ). The sulfonic acid is characterized by an XRPD pattern containing peaks at 5.4°, 18.1°, 15.8°, 20.5°, 20.8°, and 23.9° 2θ (±0.2° 2θ).

[0107] In some embodiments, compound I methanesulfonic acid is characterized by an XRPD pattern comprising peaks at 5.4°, 10.4°, 10.8°, 15.8°, 17.3°, 18.1°, 20.5°, 20.8°, and 23.9°2θ (±0.2°2θ). In some embodiments, compound I methanesulfonic acid is characterized by an XRPD pattern substantially as depicted in FIG. 25. In some embodiments, compound I methanesulfonic acid is characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset temperature of about 30°C. In some embodiments, the DSC thermogram has a second endotherm with an onset temperature of about 147°C. In some embodiments, compound I methanesulfonic acid is characterized by a DSC thermogram substantially as depicted in FIG. 26. In some embodiments, compound I methanesulfonic acid is characterized by a thermogravimetric analysis (TGA) curve substantially as depicted in FIG. 27. In some embodiments, Compound I methanesulfonic acid is characterized by a dynamic vapor sorption (DVS) curve substantially as shown in FIG.

[0108] In some embodiments, compound I methanesulfonic acid is characterized by (a) an XRPD pattern comprising peaks at 5.4°, 10.4°, 10.8°, 15.8°, 17.3°, 18.1°, 20.5°, 20.8°, and 23.9°2θ (±0.2°2θ), and (b) a differential scanning calorimetry (DSC) thermogram having a first endotherm with an onset temperature of about 30° C. and a second endotherm with an onset temperature of about 147° C. In some embodiments, compound I methanesulfonic acid is characterized by two or more of: (a) an XRPD pattern substantially as shown in FIG. 25; (b) a DSC thermogram substantially as shown in FIG. 26; (c) a thermogravimetric analysis (TGA) curve substantially as shown in FIG. 27; or (d) a dynamic vapor sorption (DVS) curve substantially as shown in FIG. 28. Amorphous Compound I

[0109] In some embodiments, the present disclosure provides an amorphous solid form of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol. [ka]

[0110] In some embodiments, amorphous Compound I is characterized by an XRPD pattern substantially as shown in Figure 29. In some embodiments, amorphous Compound I is characterized by a DSC thermogram substantially as shown in Figure 30. In some embodiments, amorphous Compound I is characterized by one or more of: (a) an XRPD pattern substantially as shown in Figure 29, or (b) a DSC thermogram substantially as shown in Figure 30. IV. Methods for Preparing Solid Forms of Compound I

[0111] Solid forms of Compound I can be prepared by a variety of methods. For example, Compound I can be dissolved and crystallized in a single solvent system. Alternatively, Compound I can be crystallized from a two-solvent system by dissolving Compound I in a solvent (good solvent) and then adding an antisolvent (bad solvent) to the mixture to crystallize Compound I. It is possible.

[0112] The solvent may be any solvent suitable for forming a solution. Typically, the solvent may be a polar solvent, which in some embodiments is a protic solvent. Other suitable solvents include non-polar solvents. Suitable solvents include, but are not limited to, water, alkanes such as heptane, hexane, and cyclohexane, petroleum ether, C1-C3 alcohols (methanol, ethanol, propanol, isopropanol), ethylene glycol and polyethylene glycols such as PEG400, alkanoates such as ethyl acetate, propyl acetate, isopropyl acetate, and butyl acetate, acetonitrile, alkanones such as acetone, butanone, methyl ethyl ketone (MEK), methyl propyl ketone (MPK), and methyl iso-butyl ketone (MIBK), ethers such as diethyl ether, methyl t-butyl ether, tetrahydrofuran, methyl-tetrahydrofuran, 1,2-dimethoxyethane, and 1,4-dioxane, aromatics such as benzene and toluene, halogenated solvents such as methylene chloride, chloroform, and carbon tetrachloride, dimethyl sulfoxide (DMSO), and dimethylformamide (DMF). Suitable solvents also include, but are not limited to, halogenated C1-C3 alcohols (trifluoromethanol, trifluoroethanol (TFE), hexafluoroisopropanol (HFIPA)). For example, the solvent may be a polar aprotic solvent, such as dichloromethane, N-methylpyrrolidone, tetrahydrofuran, ethyl acetate, acetone, methyl ethyl ketone, dimethylformamide (DMF), acetonitrile (AcCN), or dimethyl sulfoxide (DMSO), among others. The solvent may also be a polar protic solvent, such as t-butanol, n-propanol, isopropanol, ethanol, methanol, acetic acid, or water, among others. The solvent may also be a nonpolar solvent, such as hexane, pentane, petroleum ether, benzene, toluene, diethyl ether, methyl t-butyl ether, tetrahydrofuran, methyl tetrahydrofuran, 1,2-dimethoxyethane and 1,4-dioxane, chloroform, or carbon tetrachloride.

[0113] Two or more solvents can be used in any suitable ratio of solvent mixture, for example, the ratio of the first solvent to the second solvent can be 10:1 to about 1:10 (volume / volume or weight / weight), or about 10:1 to 1:5, or about 10:1 to 1:1, or about 10:1 to 5:1, or about 5:1 to 1:5, or about 5:1 to 1:1, or about 4:1 to 1:1, or about 3:1 to 1:1, or about 2:1 to 1:1. Other solvent ratios include about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9 or about 1:10 (volume / volume or weight / weight).

[0114] The method for preparing a solid form of Compound I can be carried out under any suitable reaction conditions. For example, the method for preparing a crystalline form of Compound I can be carried out at any suitable temperature, including, but not limited to, below room temperature, at room temperature, or above room temperature. In some embodiments, the temperature can be about -78°C to about 100°C, or about 0°C to about 50°C, or about 10°C to about 30°C. For example, the reaction mixture can be at a temperature of about 20°C, or about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C, or about 100°C. The reaction mixture may also be at a temperature of about 20°C, about 15°C, about 10°C, about 5°C, about 0°C, about -5°C, about -10°C, about -20°C, about -30°C, about -40°C, about -50°C, about -60°C, about -70°C, or about -78°C. In some embodiments, the temperature may be the reflux temperature of the particular solvent used in the method. In other embodiments, the crystalline forms of Compound I may be formed such that one crystalline form of Compound I forms a second crystalline form of Compound I. For example, the temperature can be increased above about 100°C.

[0115] The method for preparing a solid form of Compound I can include various other steps. For example, the solvent can be evaporated, seed crystals can be added to the mixture, the mixture can be heated and cooled, either once or repeatedly, etc. For example, the method can include heating the reaction mixture to a temperature of about 20°C, or about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C, or about 100°C. The method can also include cooling the reaction mixture to a temperature of about 20°C, about 15°C, about 10°C, about 5°C, about 0°C, about -5°C, about -10°C, about -20°C, about -30°C, about -40°C, about -50°C, about -60°C, about -70°C, or about -78°C. The temperature of the reaction mixture can be changed at any suitable rate, for example, from about 0.1°C / min to about 10°C / min.

[0116] The method for preparing the crystalline form of Compound I can be carried out for any suitable time. For example, the time can be several minutes, several hours or several days. In some embodiments, the time can be several hours, for example, overnight. The method for preparing the crystalline form of Compound I can also be carried out at any suitable pressure. For example, the pressure can be below atmospheric pressure, about atmospheric pressure, or above atmospheric pressure.

[0117] Crystallization can be induced by methods known in the art, for example, by mechanical means, such as by scraping or rubbing the contact surface of the reaction vessel with, for example, a glass rod. If necessary, the saturated or supersaturated solution can be inoculated with seed crystals. The method for preparing the solid form of Compound I can also include seed crystals of crystalline Compound I.

[0118] Isolation of the desired crystalline form can be achieved by removing the solvent from the crystals and precipitating the solvent. Generally, this is done by known methods, such as filtration, suction filtration, decantation or centrifugation. Further isolation can be achieved by removing any excess solvent(s) from the crystalline form by methods known to those skilled in the art, such as applying a vacuum and / or by heating. Form I

[0119] Crystalline Compound I Form I can be prepared by various methods using various solvents and solvent combinations.For example, Compound I Form I can be prepared using hexane, n-heptane, methanol, ethanol, n-propanol, isopropanol, water, tetrahydrofuran, 2-methyl-tetrahydrofuran, tert-butyl methyl ether, ethyl acetate, methyl isobutyl ketone, acetonitrile, toluene, and combinations thereof.In some embodiments, Compound I Form I can be prepared using n-heptane, methanol, ethanol, isopropanol, water, tetrahydrofuran, 2-methyl-tetrahydrofuran, tert-butyl methyl ether, ethyl acetate, methyl isobutyl ketone, acetonitrile, toluene, and combinations thereof.The solvent combinations useful in the method for preparing Compound I Form I include, but are not limited to, isopropanol and water, ethanol and n-heptane, tetrahydrofuran and n-heptane, acetone and water, methanol and water, ethanol and water, 2-methyltetrahydrofuran and n-heptane, etc. In some embodiments, the solvent combination may include ethanol and water, and 2-methyltetrahydrofuran and n-heptane. When two or more solvents are used in combination, they can be present in any suitable ratio as described above. In some embodiments, the solvents are isopropanol:water (9:1), ethanol:n-heptane (1:2), tetrahydrofuran:n-heptane, acetone:water (9:1), methanol:water (9:1). In some embodiments, the solvent may be ethanol:water (2:1), ethanol:water (1:1), ethanol:water (1:2), ethanol:water (1:3), 2-methyltetrahydrofuran:n-heptane (2:1), 2-methyltetrahydrofuran:n-heptane (1:1), 2-methyltetrahydrofuran:n-heptane (1:2), or 2-methyltetrahydrofuran:n-heptane (1:3). In some embodiments, the solvent may be ethanol:water (2:1), ethanol:water (1:1), ethanol:water (1:2), ethanol:water (1:3), 2-methyltetrahydrofuran:n-heptane (2:1), 2-methyltetrahydrofuran:n-heptane (1:1), 2-methyltetrahydrofuran:n-heptane (1:2), or 2-methyltetrahydrofuran:n-heptane (1:3).

[0120] In some embodiments, the present disclosure provides a method for preparing crystalline Compound I Form I of the present disclosure, comprising forming a mixture of Compound I of the present disclosure and a solvent under conditions suitable for preparing Form I. In some embodiments, Compound I is dissolved in a solvent. In some embodiments, the solvent can be a polar aprotic solvent. In some embodiments, the solvent can be ethyl acetate.

[0121] The method of preparing Compound I Form I can include various other steps. In some embodiments, the reaction mixture can be heated to a temperature of about 85° C. In some embodiments, the method includes cooling the reaction mixture to a temperature of about 20° C. In some embodiments, the method of preparing Compound I Form I also includes heating the mixture to dissolve Compound I and cooling the mixture. In some embodiments, the method of preparing Compound I Form I includes forming a mixture of Compound I and ethyl acetate, heating the mixture to dissolve Compound I, and cooling the mixture, thereby forming Compound I Form I.

[0122] In some embodiments, the present disclosure provides a method for preparing crystalline Compound I Form I of the present disclosure, comprising forming a mixture of Compound I of the present disclosure and a solvent under conditions suitable for preparing Form I. In some embodiments, Compound I is dissolved in a solvent. In some embodiments, the solvent can be a polar protic solvent. In some embodiments, the solvent can be ethanol.

[0123] The method of preparing Compound I Form I can include various other steps. In some embodiments, the reaction mixture can be heated to a temperature of about 75° C. In some embodiments, the method also includes cooling the reaction mixture to a temperature of about 0° C. In some embodiments, the method of preparing Compound I Form I also includes heating the mixture to dissolve Compound I and cooling the mixture. In some embodiments, the method of preparing Compound I Form I includes forming a mixture of Compound I and ethanol, heating the mixture to dissolve Compound I, and cooling the mixture to a temperature of about 0° C., thereby forming Compound I Form I.

[0124] In some embodiments, the present disclosure provides a method for preparing crystalline Compound I Form I of the present disclosure, comprising forming a mixture of Compound I of the present disclosure and a first solvent under conditions suitable for preparing Form I, and adding a second solvent to the mixture. In some embodiments, Compound I is dissolved in the first solvent, which is a good solvent. In some embodiments, the first solvent may be a polar protic solvent. In some embodiments, the first solvent may be ethanol. In some embodiments, the second solvent is an antisolvent. In some embodiments, the second solvent may be water.

[0125] The mixture can include any suitable ratio of the first solvent to the second solvent, for example, the ratio of the first solvent to the second solvent can be 10:1 to about 1:10 (volume / volume or weight / weight), or about 10:1 to 1:5, or about 10:1 to 1:1, or about 10:1 to 5. The solvent ratio may be about 1:1, or about 5:1 to 1:5, or about 5:1 to 1:1, or about 4:1 to 1:1, or about 3:1 to 1:1, or about 2:1 to 1:1. Other solvent ratios include about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, or about 1:10 (volume / volume or weight / weight). In some embodiments, the ratio of the first solvent to the second solvent may be about 2:1 (weight / weight). In some embodiments, the ratio of the first solvent to the second solvent may be about 1:1 (weight / weight). In some embodiments, the ratio of ethanol to water is about 2:1 (weight / weight). In some embodiments, the ratio of ethanol and water is about 1:1 (wt / wt).

[0126] The method of preparing Compound I Form I can include various other steps. In some embodiments, the reaction mixture can be heated to a temperature of about 75° C. In some embodiments, the method also includes cooling the reaction mixture to a temperature of about 22° C. In some embodiments, the method of preparing Compound I Form I also includes heating the mixture to dissolve Compound I and cooling the mixture. In some embodiments, the method of preparing Compound I Form I includes forming a mixture of Compound I and ethanol, heating the mixture to dissolve Compound I, adding water to the mixture, and cooling the mixture to room temperature, thereby forming Compound I Form I. HCl salt form I

[0127] Compound I HCl salt Form I can be prepared from Compound I Form I by mixing with hydrochloric acid in a solvent to form Compound I HCl salt Form I. In some embodiments, the present disclosure provides a method of forming Compound I HCl salt Form I, comprising forming a reaction mixture of Compound I Form I, hydrochloric acid, and a solvent, thereby preparing Compound I HCl salt Form I. In some embodiments, the solvent can be a polar aprotic solvent. In some embodiments, the solvent can be methyl ethyl ketone.

[0128] The method can include various other steps. In some embodiments, the reaction mixture can be heated to a temperature of about 50° C. In some embodiments, the reaction mixture can be cooled to ambient temperature. In some embodiments, the reaction mixture can be cooled to a temperature of about 10° C. In some embodiments, the method can include multiple heating and cooling steps. HCl salt form II

[0129] Compound I HCl salt Form II can be prepared from Compound I HCl salt Form I by exposing Compound I HCl salt Form I to an environment where the relative humidity is changed. In some embodiments, the present disclosure provides a method for preparing Compound I HCl salt Form II by exposing Compound I HCl salt Form I to a low relative humidity atmosphere and increasing the relative humidity to form a high relative humidity atmosphere, thereby preparing Compound I HCl salt Form II. A low relative humidity atmosphere can be less than 50%, including about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, and about 45% relative humidity. A high relative humidity atmosphere can be greater than 50%, including about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% relative humidity. In some embodiments, a low relative humidity atmosphere has a relative humidity of about 5%. In some embodiments, the high relative humidity atmosphere has a relative humidity of about 95%. tartaric acid

[0130] Crystalline Compound I tartaric acid can be prepared from Compound I Form I by dissolving Compound I Form I in a solvent with tartaric acid. In some embodiments, the present disclosure provides a method for preparing crystalline Compound I tartaric acid. The present invention provides a method for preparing a polar compound I tartaric acid, comprising forming a mixture of compound I Form I, tartaric acid, and a solvent under conditions suitable for preparing compound I tartaric acid. In some embodiments, compound I Form I is dissolved in a solvent. In some embodiments, the solvent can be a polar aprotic solvent. In some embodiments, the solvent can be ethyl acetate.

[0131] The method can include various other steps. In some embodiments, the reaction mixture can be heated to a temperature of about 50° C. In some embodiments, the reaction mixture can be cooled to ambient temperature. In some embodiments, the reaction mixture can be cooled to a temperature of about 10° C. In some embodiments, the method can include multiple heating and cooling steps.

[0132] Another step of the method can include adding a second solvent to the reaction mixture. In some embodiments, a non-polar solvent is added to the reaction mixture. In some embodiments, heptane is added to the reaction mixture. Maleic Acid

[0133] Crystalline Compound I maleic acid can be prepared from Compound I Form I by dissolving Compound I Form I in a solvent together with maleic acid. In some embodiments, the present disclosure provides a method for preparing crystalline Compound I maleic acid, comprising forming a mixture of Compound I Form I, maleic acid, and a solvent under conditions suitable for preparing Compound I maleic acid. In some embodiments, Compound I Form I is dissolved in a solvent. In some embodiments, the solvent may be a polar aprotic solvent. In some embodiments, the solvent may be ethyl acetate.

[0134] The method can include various other steps. In some embodiments, the reaction mixture can be heated to a temperature of about 50° C. In some embodiments, the reaction mixture can be cooled to ambient temperature. In some embodiments, the reaction mixture can be cooled to a temperature of about 10° C. In some embodiments, the method can include multiple heating and cooling steps. Fumaric acid

[0135] Crystalline Compound I fumarate can be prepared from Compound I Form I by dissolving Compound I Form I in a solvent together with fumaric acid. In some embodiments, the present disclosure provides a method for preparing crystalline Compound I fumarate, comprising forming a mixture of Compound I Form I, fumaric acid, and a solvent under conditions suitable for preparing Compound I fumarate. In some embodiments, Compound I Form I is dissolved in a solvent. In some embodiments, the solvent can be a polar aprotic solvent. In some embodiments, the solvent can be acetone.

[0136] The method can include various other steps. In some embodiments, the reaction mixture can be heated to a temperature of about 50° C. In some embodiments, the reaction mixture can be cooled to ambient temperature. In some embodiments, the reaction mixture can be cooled to a temperature of about 10° C. In some embodiments, the method can include multiple heating and cooling steps. methanesulfonic acid

[0137] Crystalline Compound I methanesulfonic acid can be prepared from Compound I Form I by dissolving Compound I Form I in a solvent with methanesulfonic acid. In some embodiments, the present disclosure provides a method for preparing crystalline Compound I methanesulfonic acid, comprising: The present invention provides a method for preparing methanesulfonic acid by forming a mixture of Compound I Form I, methanesulfonic acid, and a solvent under conditions suitable for preparing methanesulfonic acid. In some embodiments, Compound I Form I is dissolved in a solvent. In some embodiments, the solvent can be a polar aprotic solvent. In some embodiments, the solvent can be ethyl acetate.

[0138] The method can include various other steps. In some embodiments, the reaction mixture can be heated to a temperature of about 50° C. In some embodiments, the reaction mixture can be cooled to ambient temperature. In some embodiments, the reaction mixture can be cooled to a temperature of about 10° C. In some embodiments, the method can include multiple heating and cooling steps. Amorphous Compound I

[0139] Amorphous Compound I can also be prepared by the methods of the present disclosure. For example, Compound I Form I can be dissolved in a solvent and freeze-dried to form amorphous Compound I. In some embodiments, the present disclosure provides a method for preparing amorphous Compound I, comprising forming a mixture of Compound I and a solvent under conditions suitable for preparing Form I. In some embodiments, Compound I is dissolved in a solvent.

[0140] In some embodiments, the solvent may be a polar protic solvent. In some embodiments, the solvent may be t-butanol, n-propanol, isopropanol, ethanol, or methanol. In some embodiments, the solvent may be t-butanol.

[0141] The method can be carried out under any suitable reaction conditions. For example, the reaction mixture can be at a temperature of about 0° C., about −40° C., or about −78° C. In some embodiments, the reaction mixture can be at a temperature of about −78° C. V. Pharmaceutical Compositions

[0142] The solid form of Compound I provided herein can be administered in the form of a pharmaceutical composition.The present disclosure provides pharmaceutical compositions containing one or more of the solid forms of Compound I described as active ingredients, or its pharmaceutically acceptable salts or esters, and one or more pharmaceutically acceptable excipients, carriers including inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants.The pharmaceutical composition can be administered alone or in combination with other therapeutic agents (shown in the following combination therapy section).Such compositions are prepared in a manner well known in the pharmaceutical arts (see, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, PA 17th Ed. (1985) and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (GS Banker & CT Rhodes, Eds.)).

[0143] The pharmaceutical compositions can be administered in either single or multiple doses by any of the approved methods of administration for drugs having similar utilities, including rectal, oral buccal, intranasal and transdermal routes, by intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous oral, topical, as an inhalant, or via an impregnated or coated device, such as a stent, or a cylindrical polymer inserted into an artery, for example, as described in the patents and patent applications incorporated by reference.

[0144] One mode of administration is parenterally, particularly by injection. Forms that can be incorporated for administration by injection include aqueous or oily suspensions or emulsions, including sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions and similar pharmaceutical vehicles. Aqueous saline solutions are also conventionally used for injection, but are less preferred in the context of the present disclosure. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be used. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0145] Sterile injectable solution is prepared by incorporating the compound of the present disclosure in the required amount into a suitable solvent with various other ingredients as listed above, if necessary, and then sterile filtered.Generally, dispersion is prepared by incorporating various sterilized active ingredients into a sterile vehicle that contains a basic dispersion medium and other ingredients as listed above that are required.For the sterile powder used to prepare sterile injectable solution, the general preparation method is vacuum drying and freeze-drying technology, thereby obtaining the powder of active ingredient and any additional desired ingredients from its solution that has been previously sterile filtered.

[0146] Oral administration is another route of administration of the compounds according to the present disclosure. Administration can be via capsules or enteric-coated tablets, etc. In preparing pharmaceutical compositions containing at least one compound described herein, the active ingredient is usually diluted with an excipient and / or enclosed in a carrier, which can be in the form of a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material (as described above) that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition can be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), for example, an ointment containing up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injection solutions, and sterile packaged powders.

[0147] 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, sterilized water, syrup and methylcellulose.Preparation can further comprise lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl benzoate and propyl hydroxybenzoate; sweeteners; and flavoring agents.

[0148] The compositions of the present disclosure can be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to a patient by using procedures known in the art.Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations.Examples of controlled release systems are shown in U.S. Patent Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345.Another formulation for use in the methods of the present disclosure uses transdermal delivery devices ("patches").Such transdermal patches can be used to provide continuous or discontinuous infusion of the compounds of the present disclosure in controlled amounts.The construction and use of transdermal patches for delivering pharmaceuticals is well known in the art.See, for example, U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139.Such Patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0149] In some embodiments, the compositions are formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect, in association with an appropriate pharmaceutical excipient (e.g., tablet, capsule, ampoule). The compounds are generally administered in pharmaceutically effective amounts. In some embodiments, each dosage unit contains 1 mg to 2 g of a compound described herein, and for parenteral administration, in some embodiments, 0.1 to 700 mg of a compound described herein. However, it will be understood that the amount of compound actually administered will typically be determined by a physician in light of relevant circumstances, including the condition to be treated, the selected route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0150] To prepare solid compositions such as tablets, the active ingredient is mixed with a pharmaceutical excipient to form a solid pre-formulation composition containing a homogeneous mixture of the compounds of the present disclosure. When these pre-formulation compositions are referred to as homogeneous, it is meant that the active ingredient is evenly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0151] The tablets or pills of the present disclosure may be coated or otherwise formulated to provide a dosage form offering the advantage of prolonged action or to protect against the acidic conditions of the stomach. For example, the tablets or pills may comprise an inner dosage component and an outer dosage component, the outer dosage component being in the form of an envelope surrounding the inner dosage component. The two components may be separated by an enteric layer that serves to resist disintegration in the stomach and allows the inner component to pass intact into the duodenum or be delayed in release. A variety of materials can be used for such enteric layers or coatings, including several polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0152] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the compositions are administered by oral or nasal respiratory route for local or systemic effect. Compositions, preferably in pharmaceutically acceptable solvents, can be nebulized by the use of inert gases. Nebulized solutions can be inhaled directly from the nebulizing device, or the nebulizing device can be attached to a face mask tent or intermittent positive pressure breathing machine. In some embodiments, solution, suspension, or powder compositions can be administered orally or nasally from a device that appropriately delivers the formulation.

[0153] In one embodiment, the present disclosure relates to a pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier and a therapeutically effective amount of a compound of Compound I described above, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer, or hydrate thereof. VI.How to use

[0154] The solid forms of Compound I described herein can be administered to subjects suffering from viral infections, such as, but not limited to, hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV), in either single or multiple doses by any of the approved administration methods known to those of skill in the art and detailed above.

[0155] As used herein, an "agonist" is a substance that stimulates its binding partner, typically a receptor. Stimulation may be defined in the context of a particular assay or may be evident in the literature from the discussion herein, comparing factors or substances that are accepted as "agonists" or "antagonists" of a particular binding partner under substantially similar circumstances as understood by those skilled in the art. Stimulation may be defined in terms of an increase in a particular effect or function induced by the interaction of an agonist or partial agonist with a binding partner, which may include allosteric effects.

[0156] As used herein, an "antagonist" is a substance that inhibits its binding partner, typically a receptor. Inhibition may be defined in the context of a particular assay, or may be evident in the literature from the discussion herein, comparing factors or substances that are accepted as "agonists" or "antagonists" of a particular binding partner under substantially similar circumstances as understood by those skilled in the art. Inhibition may be defined in terms of a reduction in a particular effect or function induced by the interaction of the antagonist with the binding partner, which may include allosteric effects.

[0157] As used herein, a "partial agonist" or "partial antagonist" is a substance that provides a level of stimulation or inhibition, respectively, to its binding partner that is not fully or completely agonistic or antagonistic, respectively. It will be understood that stimulation, and therefore inhibition, is inherently defined with respect to any substance or category of substance defined as an agonist, antagonist, or partial agonist.

[0158] As used herein, "intrinsic activity" or "potency" refers to some measure of the biological effectiveness of a binding partner complex. With respect to receptor pharmacology, the context in which intrinsic activity or potency is to be defined depends on the context of the binding partner (e.g., receptor / ligand) complex and a consideration of the activity related to a particular biological outcome. For example, in some situations, intrinsic activity may vary depending on the particular second messenger system involved. It will be clear to one of skill in the art where such context-specific assessments are relevant and how they may relate to the context of the present disclosure.

[0159] As used herein, modulation of a receptor includes agonism, partial agonism, antagonism, partial antagonism, or inverse agonism of the receptor.

[0160] As will be appreciated by those skilled in the art, when treating a viral infection, such as HCV, HBV, or HIV, such treatment can be characterized in a variety of ways and measured by a variety of endpoints, and the scope of the present disclosure is intended to encompass all such characterizations.

[0161] In one embodiment, the method can be used to induce an immune response against multiple epitopes of a viral infection in a human. The induction of an immune response against a viral infection can be assessed using any technique known to those skilled in the art for determining whether an immune response has occurred. Suitable methods for detecting an immune response in the context of the present disclosure include, among others, detecting a reduction in viral load or antigen in a subject's serum, detecting IFN-gamma secreting peptide-specific T cells, and detecting elevated levels of one or more liver enzymes, such as alanine transferase (ALT) and aspartate transferase (AST). In one embodiment, detection of IFN-gamma secreting peptide-specific T cells is achieved using an ELISPOT assay. Another embodiment includes reducing the viral load associated with HBV infection, including as measured by PCR testing.

[0162] In some embodiments, the present disclosure provides a method of treating a viral infection, the method comprising administering a therapeutically effective amount of a crystalline form of Compound I or a pharmaceutical composition of the present disclosure to a human in need thereof. In some embodiments, the present disclosure provides a crystalline form of Compound I for use in treating a viral infection, comprising administering a therapeutically effective amount of a crystalline form of Compound I or a pharmaceutical composition of the present disclosure. In some embodiments, the present disclosure provides a use of a crystalline form of Compound I for treating a viral infection. In some embodiments, the present disclosure provides a use of a crystalline form of Compound I for the manufacture of a medicament for treating a viral infection.

[0163] In another aspect, the disclosure provides methods for treating hepatitis B or C virus infection, each of the methods comprising administering to a human subject infected with hepatitis B or C virus a therapeutically effective amount of a crystalline form of Compound I. Typically, the human subject has a chronic hepatitis B or C infection, although the scope of the disclosure also includes treating humans acutely infected with HBV or HCV.

[0164] In some embodiments, the present disclosure provides a crystalline form of Compound I for use in treating hepatitis B virus infection or hepatitis C virus infection. In some embodiments, the present disclosure provides a use of a crystalline form of Compound I for the manufacture of a medicament for the treatment of hepatitis B virus infection or hepatitis C virus infection.

[0165] In some embodiments, the present disclosure provides a crystalline form of Compound I for use in treating hepatitis B virus infection. In some embodiments, the present disclosure provides a use of a crystalline form of Compound I for the manufacture of a medicament for the treatment of hepatitis B virus infection.

[0166] Treatment according to the present disclosure typically results in the stimulation of an immune response against HBV or HCV in humans infected with HBV or HCV, respectively, resulting in a reduction in the HBV or HCV viral load in the infected individual. Examples of immune responses include the production of antibodies (e.g., IgG antibodies) and / or the production of cytokines, such as interferons, which regulate the activity of the immune system. The immune system response may be a newly induced response or an enhancement of an existing immune response. In particular, the immune system response may be a seroconversion of one or more HBV or HCV antigens. It can be a version.

[0167] Viral load can be determined by measuring the amount of HBV DNA or HCV DNA present in blood. For example, serum HBV DNA can be quantified using the Roche COBAS Amplicor Monitor PCR assay (version 2.0; lower limit of quantification, 300 copies / mL [57 IU / mL]) and Quantiplex bDNA assay (lower limit of quantification, 0.7 MEq / mL; Bayer Diagnostics, formerly Chiron Diagnostics, Emeryville, CA). The amount of antibodies to specific HBV or HCV antigens (e.g., hepatitis B surface antigen (HBsAG)) can be measured using art-recognized techniques such as enzyme-linked immunosorbent assay and enzyme-linked immunosorbent assay. For example, the amount of antibodies to specific HBV or HCV antigens can be measured using the Abbott AxSYM microparticle enzyme immunoassay system (Abbott Laboratories, North Chicago, IL).

[0168] Compound I can be administered by any useful route and means, for example, orally or parenterally (e.g., intravenously). A therapeutically effective amount of Compound I is about 0.000 0.01 mg / kg body weight / day to about 10 mg / kg body weight / day, for example, about 0.0001 mg / kg body weight / day to about 10 mg / kg body weight / day, or for example, about 0.001 mg / kg body weight / day to about 1 mg / kg body weight / day, or for example, about 0.01 mg / kg body weight / day to about 1 mg / kg body weight / day, or for example, about 0.05 mg / kg body weight / day to about 0.5 mg / kg body weight / day, or for example, about 0.3 μg to about 30 mg / day, or for example, about 30 μg to about 300 μg / day.

[0169] The therapeutically effective amount of Compound 1 is also about 0.01 mg per dose to about 1000 mg per dose, for example, about 0.01 mg per dose to about 100 mg per dose, or for example, about 0.1 mg per dose to about 100 mg per dose, or for example, about 1 mg per dose to about 100 mg per dose, or for example, about 1 mg per dose to about 10 mg per dose. Other therapeutically effective amounts of Compound 1 are about 1 mg per dose, about 1.5 mg per dose, about 2 mg per dose, about 2.5 mg per dose, about 3 mg per dose, or about 3.5 mg per dose, or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or about 100 mg per dose. Other therapeutically effective amounts of Compound 1 are about 100 mg per dose, or about 125, 150, 175, 200, 225, 250, 275, 300, 350, 400, 450, or about 500 mg per dose. A single dose can be administered hourly, daily, or weekly. For example, a single dose can be administered every 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours, or 24 hours. A single dose can also be administered every 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days. A single dose can also be administered every 1 week, 2 weeks, 3 weeks, or 4 weeks. A single dose can also be administered once a month.

[0170] The frequency of administration of Compound I is determined by the needs of individual patients, and can be, for example, once a day, twice a day, or more. Administration of Compound I continues as long as necessary to treat HBV or HCV infection. For example, Compound I can be administered to a person infected with HBV or HCV for a period of 20 to 180 days, or for example, for a period of 20 to 90 days, or for example, for a period of 30 to 60 days.

[0171] Administration can be intermittent, with the patient receiving a daily dose of Compound I for a period of several days or more, followed by a period of several days or more, during which the patient does not receive a daily dose of Compound I. For example, the patient can receive a dose of Compound I every other day or three times a week. Also illustratively, the patient can receive a dose of Compound I daily for a period of 1-14 days, followed by a period of 7-21 days during which the patient does not receive a dose of Compound I, followed by a subsequent period (e.g., 1-14 days) during which the patient again receives a daily dose of Compound I. Alternating periods of Compound I administration followed by periods without Compound I administration can be repeated as clinically needed to treat the patient.

[0172] As described more fully herein, a crystalline form of Compound I can be administered to a human infected with hepatitis B virus or hepatitis C virus together with one or more additional therapeutic agents. The additional therapeutic agent(s) can be administered to the infected human simultaneously with the crystalline form of Compound I, or before or after administration of the crystalline form of Compound I. In some embodiments, the present disclosure provides a crystalline form of Compound I for use in a method of treating or preventing hepatitis B virus infection, wherein the crystalline form of Compound I is administered simultaneously, separately, or sequentially with one or more additional therapeutic agents for treating hepatitis B virus infection. In some embodiments, the present disclosure provides a use of a crystalline form of Compound I for manufacturing a medicament for treating hepatitis B virus infection, wherein the crystalline form of Compound I is administered simultaneously, separately, or sequentially with one or more additional therapeutic agents for treating hepatitis B virus infection.

[0173] In another aspect, the present disclosure provides a method for ameliorating symptoms associated with HBV or HCV infection, the method comprising administering to a human subject infected with hepatitis B virus or hepatitis C virus a therapeutically effective amount of a crystalline form of Compound I, the therapeutically effective amount being sufficient to ameliorate symptoms associated with HBV or HCV infection, including the presence of HBV virions (or HCV virions) in the blood, hepatitis, jaundice, muscle pain, weakness, and fatigue.

[0174] In some embodiments, the disclosure provides a crystalline form of Compound I for use in ameliorating symptoms associated with HBV or HCV infection, the method comprising administering a therapeutically effective amount of the crystalline form of Compound I to a human subject infected with Hepatitis B virus or Hepatitis C virus, wherein the therapeutically effective amount is sufficient to ameliorate symptoms associated with HBV or HCV infection. In some embodiments, the disclosure provides a use of a crystalline form of Compound I for the manufacture of a medicament for ameliorating symptoms associated with HBV or HCV infection, the method comprising administering a therapeutically effective amount of the crystalline form of Compound I to a human subject infected with Hepatitis B virus or Hepatitis C virus, wherein the therapeutically effective amount is sufficient to ameliorate symptoms associated with HBV or HCV infection.

[0175] In a further aspect, the present disclosure provides a method for reducing the rate of progression of hepatitis B or C virus infection in a human, the method comprising administering a therapeutically effective amount of Compound I to a human subject infected with hepatitis B or C virus, the therapeutically effective amount being sufficient to reduce the rate of progression of the hepatitis B or C virus infection. The rate of progression of the infection can be monitored by measuring the amount of HBV or HCV viral particles in the blood.

[0176] In another aspect, the present disclosure provides a method for reducing viral load associated with HBV or HCV infection, the method comprising administering a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, to a human infected with HBV or HCV, wherein the therapeutically effective amount is sufficient to reduce the HBV viral load or HCV viral load in the human.

[0177] In a further aspect, the present disclosure provides a method for inducing or enhancing an immune response to hepatitis B virus or hepatitis C virus in a human, the method comprising administering a therapeutically effective amount of Compound I to the human, wherein a new immune response to hepatitis B virus or hepatitis C virus is induced in the human, or an existing immune response to hepatitis B virus or hepatitis C virus is enhanced in the human. Seroconversion to HBV or HCV can be induced in the human. Examples of immune responses include the production of antibodies, such as IgG antibody molecules, and / or the production of cytokine molecules that regulate the activity of one or more components of the human immune system.

[0178] The induction of seroconversion to HCV or HBV viruses in patients chronically infected with either of these viruses is an unexpected property of Compound I. In clinical practice, HBV or HCV patients are treated with Compound I alone or in combination with one or more other therapeutic agents until an immune response to HBV or HCV is induced or enhanced and the HBV or HCV viral load is reduced. Thereafter, although the HBV or HCV virus may persist in a latent form in the patient's body, treatment with Compound I can be stopped and the patient's own immune system can suppress further viral replication. In patients treated according to the present disclosure and already receiving treatment with an antiviral agent that suppresses HBV or HCV viral replication, the antiviral agent(s) During treatment with HBV or HCV, few or no detectable viral particles can be present in the patient's body. In these patients, seroconversion becomes evident when the patient is no longer administered the antiviral agent(s) and the HBV or HCV viral load does not increase.

[0179] In practicing the present disclosure, an immune response can be induced against one or more antigens of HBV or HCV. For example, an immune response can be induced against HBV surface antigen (HBsAg), or against a small form of HBV surface antigen (small S antigen), or against a medium form of HBV surface antigen (medium S antigen), or a combination thereof. Again, by way of example, an immune response can be induced against HBV surface antigen (HBsAg), as well as against other HBV-derived antigens, such as core polymerase or x protein.

[0180] The induction of immune response against HCV or HBV can be evaluated using any technique known to those skilled in the art to determine whether an immune response has occurred.Suitable methods for detecting immune response in the present disclosure include, inter alia, detecting a reduction in the viral load in the serum of a subject, for example, by measuring the amount of HBV DNA or HCV DNA in the blood of a subject using a PCR assay, and / or by measuring the amount of anti-HBV antibody or anti-HCV antibody in the blood of a subject using a method such as ELISA.

[0181] Additionally, the compounds of the present disclosure may be useful in treating cancers or tumors (including dysplasias, such as uterine dysplasia). These include hematological malignancies, oral cancers (e.g., of the lip, tongue, or pharynx), digestive tract (e.g., esophagus, stomach, small intestine, colon, large intestine, or rectum), liver and biliary tract, pancreas, respiratory tract such as larynx or lung (small cell and non-small cell), bone, connective tissue, skin (e.g., melanoma), breast, reproductive tract (uterus, cervix, testicles, ovaries, or prostate), urinary tract (e.g., bladder or kidney), brain, and endocrine glands such as the thyroid gland. In summary, the compounds of the present disclosure can be used to treat any neoplasm, including not only hematological malignancies but also all types of solid tumors.

[0182] Hematological malignancies are broadly defined as proliferative disorders of blood cells and / or their precursors, resulting in uncontrolled proliferation of these cells. Anatomically, hematological malignancies are divided into two major groups: lymphomas—malignant tumors of lymphoid cells, primarily, but not exclusively, in lymph nodes, and leukemias—neoplasms that typically arise from lymphoid or myeloid cells and primarily affect the bone marrow and peripheral blood. Lymphomas can be subdivided into Hodgkin's disease and non-Hodgkin's lymphoma (NHL). The latter group includes several distinct entities that can be distinguished clinically (e.g., aggressive lymphoma, indolent lymphoma), histologically (e.g., follicular lymphoma, mantle cell lymphoma), or based on the origin of the malignant cells (e.g., B lymphocyte, T lymphocyte). Leukemia and related malignancies include acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), and chronic lymphocytic leukemia (CLL). Other hematologic malignancies include plasma cell dyscrasias, including multiple myeloma, and myelodysplastic syndromes. VII. Combination Therapy

[0183] In certain embodiments, a method of treating or preventing an infectious disease, a viral infection, a hepatitis B infection, an HIV infection, cancer, or a hyperproliferative disease in a human having or at risk of having the disease comprises combining a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, with a therapeutically effective amount of one or more (e.g., 1, 2, 3, 4, 1 or 2, 1-3, or 1-4) additional therapeutic agents. In one embodiment, a method is provided for treating an infectious disease, a viral infection, a hepatitis B infection, an HIV infection, cancer, or a hyperproliferative disease in a human having or at risk of having the disease, comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with therapeutically effective amounts of one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents.

[0184] In certain embodiments, the present disclosure provides a method for treating a viral infection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with therapeutically effective amounts of one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents suitable for treating the viral infection. In some embodiments, the viral infection is a hepatitis B infection. In some embodiments, the viral infection is an HIV infection.

[0185] In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with one, two, three, four, or more additional therapeutic agents. In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with two additional therapeutic agents. In other embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with three additional therapeutic agents. In further embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with four additional therapeutic agents. The one, two, three, four, or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, and / or the therapeutic agents can be selected from different classes of therapeutic agents. Administration of Combination Therapy

[0186] In certain embodiments, the compound disclosed herein is administered with one or more additional therapeutic agents.The co-administration of the compound disclosed herein and one or more additional therapeutic agents generally refers to the simultaneous or sequential administration of the compound disclosed herein and one or more additional therapeutic agents, so that therapeutically effective amounts of the compound disclosed herein and one or more additional therapeutic agents are both present in the body of subject.When administered sequentially, the combination can be administered in two or more doses.

[0187] Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to the simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents such that a therapeutically effective amount of each agent is present in the patient's body.

[0188] In certain embodiments, the compounds disclosed herein can be combined with one or more (e.g., 1, 2, 3, 4, 1 or 2, 1-3, or 1-4) additional therapeutic agents at any dosage of the compound (e.g., 10 mg to 1000 mg of compound).

[0189] Co-administration includes administering a unit dosage of a compound disclosed herein before or after administering a unit dosage of one or more additional therapeutic agents.The compound disclosed herein may be administered within seconds, minutes, or hours after administering one or more additional therapeutic agents.For example, in some embodiments, a unit dosage of a compound disclosed herein is administered first, followed by a unit dosage of one or more additional therapeutic agents within seconds or minutes.Alternatively, in other embodiments, a unit dosage of one or more additional therapeutic agents is administered first, followed by a unit dosage of a compound disclosed herein within seconds or minutes. In some embodiments, a unit dose of a compound disclosed herein is administered first, followed after a period of several hours (e.g., 1-12 hours) by a unit dose of one or more additional therapeutic agents. In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed after a period of several hours (e.g., 1-12 hours) by a unit dose of a compound disclosed herein.

[0190] In certain embodiments, the compounds disclosed herein are combined with one or more additional therapeutic agents in a single dosage form for simultaneous administration to a subject, e.g., as a solid dosage form for oral administration.

[0191] In certain embodiments, the compound described herein is formulated as a tablet, which can optionally contain one or more other compounds useful for treating the disease being treated.In certain embodiments, the tablet can contain other active ingredients for treating viral diseases, such as hepatitis B virus, HIV.

[0192] In certain embodiments, such tablets are suitable for once-daily dosing.

[0193] In one embodiment, a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof is provided in combination with one or more (e.g., 1, 2, 3, 1 or 2, or 1 to 3) additional therapeutic agents, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0194] In one embodiment, a kit is provided that includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., 1, 2, 3, 4, 1 or 2, or 1 to 3, or 1 to 4) additional therapeutic agents. Combination viral therapy

[0195] The compounds described herein include abacavir, acyclovir, adefovir, amantadine, amprenavir, arbidol, atazanavir, atripla, brivudine, cidofovir, combivir, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, fomvirsen, fosamprenavir, foscarnet, phosphonet, ganciclovir, gardasil, ibacitabine, immunovir, idoxuridine, imiquimod, indinavir, inosine, integrase inhibitors, interferons including interferon type III, interferon type II, and interferon type I, lamivudine, lopinavir, loviride, ide), MK-0518, maraviroc, moroxydine, nelfinavir, nevirapine, nexavir, nucleoside analogs, oseltamivir, penciclovir, peramivir, pleconaril, podophyllotoxin, protease inhibitors, reverse transcriptase inhibitors, ribavirin, rimantadine, ritonavir, saquinavir, stavudine, tenofovir, tenofovir disoproxil, tipranavir, trifluridine, trizivir, tromantadine, truvada, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir, zidovudine, and combinations thereof.

[0196] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 5-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 5-10 mg, 5-15 mg, 5-20 mg, 5-25 mg, 25-30 mg, 20-30 mg, 15-30 mg, or 10-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. The compounds disclosed herein can be combined with the agents provided herein in any dosage amount (e.g., 50 mg to 500 mg of the compound), as if each combination of dosage amounts were specifically and individually listed.

[0197] In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 100 to 400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 100-150; 100-200, 100-250; 100-300; 100-350; 150-200; 150-250; 150-300; 150-350; 150-400; 200-250; 200-300; 200-350; 200-400; 250-350; 250-400; 350-400, or 300-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 300 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 250 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 150 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. The disclosed compounds can be combined with agents provided herein in any dosage amount of the compound (e.g., 50 mg to 500 mg of the compound), as if each dosage combination were specifically and individually listed. HIV combination therapy

[0198] In certain embodiments, provided are methods for treating or preventing HIV infection in a human or animal having or at risk of having HIV infection, comprising administering to the human or animal a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with therapeutically effective amounts of one or more (e.g., 1, 2, 3, 1 or 2, or 1 to 3) additional therapeutic agents. In one embodiment, provided are methods for treating HIV infection in a human or animal having or at risk of having HIV infection, comprising administering to the human or animal a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with therapeutically effective amounts of one or more (e.g., 1, 2, 3, 1 or 2, or 1 to 3) additional therapeutic agents.

[0199] In certain embodiments, the present disclosure provides a method of treating an HIV infection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents suitable for treating HIV infection.

[0200] In certain embodiments, the compounds disclosed herein are useful for treating HIV in need thereof. In certain embodiments, the tablet may contain another active ingredient for treating HIV, such as an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitor, an HIV nucleoside or nucleotide reverse transcriptase inhibitor, an HIV integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, a pharmacokinetic enhancer, and combinations thereof.

[0201] In certain embodiments, such tablets are suitable for once-daily administration.

[0202] In the above embodiments, the additional therapeutic agent can be an anti-HIV agent. In some embodiments, the additional therapeutic agent is an HIV combination drug, an HIV protease inhibitor, an HIV non-nucleosidic or non-nucleotide reverse transcriptase inhibitor, an HIV nucleosidic or nucleotide reverse transcriptase inhibitor, an HIV integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, an HIV entry inhibitor, an HIV maturation inhibitor, an immunomodulator, an immunotherapeutic agent, an antibody-drug conjugate, a gene modifying agent, a gene editing agent (such as CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs, etc.), a cell therapy (chimeric antigen receptor T cells, CAR-T and engineered T cell receptors, TCR-T), a latent infection reactivator, a compound targeting the HIV capsid (including capsid inhibitors), an immune-based therapy, a phosphatidylinositol 3-kinase (PI3K) inhibitor, an alpha4 / beta7 antagonist, an HIV antibody, a bispecific antibody and an "antibody-like" therapeutic protein, an HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nuclear protein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic cell ICAM-3-binding nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV Selected from the group consisting of POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapies, HIV vaccines and other HIV therapeutics, and combinations thereof.

[0203] In some embodiments, the additional therapeutic agent is selected from the group consisting of combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reactivators, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies and bispecific antibodies and "antibody-like" therapeutic proteins, and combinations thereof. HIV combination drugs

[0204] Examples of combination drugs include ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, covicis) TDF, tenofovir disoproxil fumarate and emtricitabine; TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat and elvitegravir); BIKTARVY® (Victavir) Gravir, Emtricitabine, Tenofovir Alafenamide); Darunavir, Tenofovir Alafenamide Hemifumarate, Emtricitabine and Cobicistat; Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate; Lamivudine and Tenofovir Disoproxil Fumarate; Tenofovir and Lamivudine; Tenofovir Alafenamide and Emtricitabine; Tenofovir Alafenamide Hemifumarate and Emtricitabine; Tenofovir Alafenamide Hemifumarate, Emtricitabine and Rilpivirine; Tenofovir Alafenamide Rafenamide hemifumarate, emtricitabine, cobicistat, and elvitegravir; COMBIVIR® (zidovudine and lamivudine; AZT + 3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC + 3TC); KALETRA® (ALUVIA®; lopinavir and ritonavir); TRIUMEQ® (dolutegravir, abacavir, and lamivudine); TRIZIVIR® (abacavir sulfate, zidovudine, and lamivudine) Mivudine; ABC+AZT+3TC); Atazanavir and Cobicistat; Atazanavir sulfate and Cobicistat; Atazanavir sulfate and Ritonavir; Darunavir and Cobicistat; Dolutegravir and Rilpivirine; Dolutegravir and Rilpivirine Hydrochloride; Dolutegravir, Abacavir Sulfate and Lamivudine; Lamivudine, Nevirapine and Zidovudine; Raltegravir and Lamivudine; Doravirine, Lamivudine and Tenofovir Disoproxil Fumarate; Doravirine, Lamivudine and Tenofovir Disoproxil;These include dolutegravir + lamivudine, lamivudine + abacavir + zidovudine, lamivudine + abacavir, lamivudine + tenofovir disoproxil fumarate, lamivudine + zidovudine + nevirapine, lopinavir + ritonavir; lopinavir + ritonavir + abacavir + lamivudine, lopinavir + ritonavir + zidovudine + lamivudine, tenofovir + lamivudine, and tenofovir disoproxil fumarate + emtricitabine + rilpivirine hydrochloride, lopinavir, ritonavir, zidovudine, and lamivudine; Vacc-4x and romidepsin; and APH-0812. HIV protease inhibitors

[0205] Examples of HIV protease inhibitors include amprenavir, atazanavir, brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, tipranavir, DG-17, TMB-657 (PPL-100), T-169, BL-008, and TMC-310911. HIV reverse transcriptase inhibitors

[0206] Examples of HIV non-nucleoside or non-nucleoside reverse transcriptase inhibitors include dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, nevirapine, rilpivirine, ACC-007, AIC-292, KM-023, PC-1005, and VM-1500.

[0207] Examples of HIV nucleoside or nucleotide reverse transcriptase inhibitors include adefovir, adefovir dipivoxil, azuvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemiacetate, and tenofovir alafenamide hemiacetate. fumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, VIDEX® and VIDEX EC® (didanosine, ddl), abacavir, abacavir sulfate, alovudine, apricitabine, censavudine, didanosine, elvucitabine, festinavir, fosalvudine tidoxil, CMX-157, dapivirine, doravirine, etravirine, OCR-5753, tenofovir disoproxil orotate, fozivudine tidoxil, lamivudine, phosphazide, stavudine, zalcitabine, zidovudine, GS-9131, GS-9148, MK-8504, and KP-1461. HIV integrase inhibitors

[0208] Examples of HIV integrase inhibitors include elvitegravir, curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, raltegravir, dolutegravir, and JTK. -351, bictegravir, AVX-15567, cabotegravir (depot injection), diketoquinoline-4-one derivatives, integrase-LEDGF inhibitors, ledgin, M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbene disulfonic acid, T-169, and cabotegravir.

[0209] Examples of HIV non-catalytic or allosteric integrase inhibitors (NCINI) include CX-05045, CX-05168 and CX-14442. HIV entry inhibitors

[0210] Examples of HIV entry (fusion) inhibitors include cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 adhesion inhibitors, gp120 inhibitors and CXCR4 inhibitors.

[0211] Examples of CCR5 inhibitors include aplaviroc, vicriviroc, maraviroc, cenicriviroc, PRO-140, adaptavir (RAP-101), nifeviroc (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptide C25P, TD-0680, and vMIP (Haimipu).

[0212] Examples of gp41 inhibitors include albuvirtide, enfuvirtide, BMS-986197, enfuvirtide biobetter, enfuvirtide biosimilar, HIV-1 fusion inhibitor (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer, and sifuvirtide.

[0213] Examples of CD4 adhesion inhibitors include ibalizumab and CDA analogs.

[0214] Examples of gp120 inhibitors include Radha-108(receptor)3B3-PE38, BanLec, bentonite-based nanomedicine, fostemsavir tromethamine, IQP-0831, and BMS-663068.

[0215] Examples of CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide and vMIP (Haimipu). HIV maturation inhibitors

[0216] Examples of HIV maturation inhibitors include BMS-955176 and GSK-2838232. Latent infection reactivator

[0217] Examples of latent infection reactivators include histone deacetylase (HDAC) inhibitors, proteasome inhibitors such as Velcade, protein kinase C (PKC) activators, Smyd2 inhibitors, BET-bromodomain 4 (BRD4) inhibitors, ionomycin, PMA, SAHA (suberoylanilide hydroxamic acid or suberoyl, anilide and hydroxamic acid), AM-0015, ALT-803, NIZ-985, NKTR-255, IL-15 modulating antibodies, JQ1, disulfiram, amphotericin B and ubiquitin inhibitors such as largazole analogs, and GSK-343.

[0218] Examples of HDAC inhibitors include romidepsin, vorinostat, and panobinostat.

[0219] Examples of PKC activators include indolactam, prostratin, ingenol B and DAG-lactone. Capsid inhibitors

[0220] Examples of capsid inhibitors include capsid polymerization inhibitors or capsid-disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibitors such as azodicarbonamide, HIV p24 capsid protein inhibitors, AVI-621, AVI-101, AVI-201, AVI-301 and the AVI-CAN1-15 series. Immune-Based Therapies

[0221] Examples of immune-based therapies include toll-like receptor modulators, such as TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13; programmed cell death protein 1 (Pd-1) modulators; programmed death-ligand 1 (Pd-L1) modulators; IL-15 modulators; DermaVir; interleukin-7; Plaquenil (hydroxychloroquine); Proleukin (aldesleukin, IL-2); interferon alpha; interferon alpha-2b; interferon alpha-n3; pegylated interferon alpha; interferon ga These include ribavirin; hydroxyurea; mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF); ribavirin; lintatolimod, the polymer polyethyleneimine (PEI); gepone; lintatolimod; IL-12; WF-10; VGV-1; MOR-22; BMS-936559; CYT-107; interleukin-15 / Fc fusion protein; normferon; pegylated interferon alfa-2a; pegylated interferon alfa-2b; recombinant interleukin-15; RPI-MN; GS-9620; STING modulators; RIG-I modulators; NOD2 modulators; and IR-103.

[0222] Examples of TLR8 modulators include motolimod, resiquimod, 3M-051, 3M-052, MCT-465, IMO-4200, VTX-763, VTX-1463, and the compounds described in U.S. Patent Application Publication No. 20140045849 (Janssen), U.S. Patent Application Publication No. 20140073642 (Janssen), WO 2014 / 056953 (Janssen), WO 2014 / 076221 (Janssen), WO 2014 / 128189 (Janssen), U.S. Patent Application Publication No. 20140350031 (Janssen), WO 2014 / 023813 (Janssen), and the compounds described in U.S. Patent Application Publication No. 20140045849 (Janssen), U.S. Patent Application Publication No. 20140073642 (Janssen), WO 2014 / 056953 (Janssen), WO 2014 / 076221 (Janssen), WO 2014 / 128189 (Janssen), U.S. Patent Application Publication No. 20140350031 (Janssen), WO 2014 / 023813 (Janssen). en), U.S. Patent Application Publication No. 20080234251 (Array Biopharma), U.S. Patent Application Publication No. 20080306050 (Array Biopharma), U.S. Patent Application Publication No. 20100029585 (Ventirx Pharma), U.S. Patent Application Publication No. 20110092485 (Ventirx Pharma), U.S. Patent Application Publication No. 20110118235 (Ventirx Pharma), U.S. Patent Application Publication No. 20120082658 (Ventirx Pharma), U.S. Patent Application Publication No. 20120219615 (Ventirx Pharma), U.S. Patent Application Publication No. 20140066432 (Ventirx No. 20130251673 (Novira therapeutics), U.S. Patent No. 9,670,205 (Gilead Sciences Inc.), U.S. Patent Application Publication No. 20160289229 (Gilead Sciences Inc.), U.S. Patent Application No. 15 / 692,161 (Gilead Sciences Inc.), and U.S. Patent Application No. 15 / 692,093 (Gilead Sciences Inc.). Phosphatidylinositol 3-kinase (PI3K) inhibitors

[0223] Examples of PI3K inhibitors include idelalisib, alpelisib, buparlisib, CAI orotate, copanlisib, duvelisib, gedatrisib, neratinib, panulisib, perifosine, pictilisib, pilalalisib, pukitinib mesylate, rigosertib, rigosertib sodium, sonolic acid, taselisib, AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, and D S-7423, EN-3342, GSK-2126458, GSK-2269577, GSK-2636771, INCB-040093, LY-3023414, MLN-1117, PQR-309, RG-7666, RP-6530, RV-1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857, VS-5584, XL-765, and ZSTK-474. Alpha 4 / beta 7 antagonists

[0224] Examples of integrin alpha4 / beta7 antagonists include PTG-100, TRK-170, abrilumab, etrolizumab, carotegrast methyl, and vedolizumab. HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins

[0225] Examples of HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins include DART®, DUOBODIES®, BITES®, XmAb®, TandAb®, Fab derivatives, bnABs (broadly neutralizing HIV-1 antibodies), BMS-936559, TMB-360, and those targeting HIV gp120 or gp41, antibody recruiting molecules targeting HIV, anti-CD63 monoclonal antibodies, anti-GB virus C antibodies, anti-GP120 / CD4, CCR5 bispecific antibodies, anti-nef single domain antibodies, anti-Rev antibodies, camelid-derived anti-CD18 antibodies, camelid-derived anti-ICAM-1 antibodies, DCVax-001, gp140-targeting antibodies, gp41-based HIV therapeutic antibodies, human recombinant mAb (PGT-121), ibalizumab, Immuglo, and MB-66.

[0226] Examples of drugs targeting HIV in such a way include bavituximab, UB-421, C2F5, 2G12, C4E10, C2F5+C2G12+C4E10, 8ANC195, 3BNC117, 3BNC60, 10-1074, PGT145, PGT121, PGT-151, PGT-133, MDX010 (ipilimumab), DH511, N6, Examples of HIV bispecific antibodies include VRC01, PGDM1400, A32, 7B2, 10E8, 10E8v4, CAP256-VRC26.25, DRVIA7, VRC-07-523, VRC-HIVMAB080-00-AB, VRC-HIVMAB060-00-AB, MGD-014, and VRC07. Examples of HIV bispecific antibodies include MGD014. Pharmacokinetic Enhancers

[0227] Examples of pharmacokinetic enhancers include cobicistat and ritonavir. HIV vaccines

[0228] Examples of HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, CD4-derived peptide vaccines, vaccine combinations, rgp120 (AIDSVAX), ALVAC HIV (vCP1521) / AIDSVAX B / E (gp120) (RV144), monomeric gp120 HIV-1 subtype C vaccine, Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, VAC-3S, multiclade DNA recombinant adenovirus-5 (rAd5), Pennvax-G, Pennvax-GP, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, and NAcGM3 / VSSP. ISA-51, polyICLC adjuvanted vaccine, TatImmune, GTU-MultiHIV (FIT-06), gp140[delta]V2.TV1+MF-59, rVSVIN HIV-1 gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin / ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV1-PG9DP, GOVX-B11, GOVX-B21, TVI-HIV-1, Ad-4 (Ad4-env clade C+Ad4-mGag), EN41-UGR7C, EN41-FPA2, PreVaxTat, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, DNA-Ad5 gag / pol / nef / nev(HVTN505), MVATG-17401, ETV-01, CDX-1401, rcAD26.MOS1.HIV-Env, Ad26.Mod.HIV vaccines, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, IHV-001, and virus-like particle vaccines, such as pseudovirion vaccines, CombiVICHvac, LFn-p24 B / C fusion vaccines, GTU-based DNA vaccines, HIV gag / pol / nef / env DNA vaccines, anti-TAT HIV vaccines, conjugate polypeptide vaccines, dendritic cell vaccines, gag-based DNA vaccines, GI-2010, gp41 HIV-1 vaccines, HIV vaccines (PIKA adjuvants), Ii-key / MHC class II epitope hybrid peptide vaccines, ITV-2, ITV-3, ITV-4, LIPO-5, multiclade Env vaccines, MVA vaccines, Pennvax-GP, pp71-deficient HCMV vector HIV These include gag vaccine, recombinant peptide vaccine (HIV infection), NCI, rgp160 HIV vaccine, RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, therapeutic HIV vaccine, UBI HIV gp120, Vacc-4x + romidepsin, mutant gp120 polypeptide vaccine, rAd5 gag-pol env A / B / C vaccine, DNA.HTI, and MVA.HTI. Additional HIV treatments

[0229] Examples of additional HIV therapeutic agents include those described in WO 2004 / 096286 (Gilead Sciences), WO 2006 / 015261 (Gilead Sciences), and others. ences), WO 2006 / 110157 (Gilead Sciences), WO 2012 / 003497 (Gilead Sciences), WO 2012 / 003498 (Gilead Sciences), WO 2012 / 145728 (Gilead Sciences), WO 2013 / 006738 (Gilead Sciences), WO 2013 / 159064 (Gilead Sciences), WO 2014 / 100323 (Gilead Sciences), U.S. Patent Application Publication No. 2013 / 0165489 (University of Pennsylvania), U.S. Patent Application Publication No. 2014 / 0221378 (Japan Tobacco), U.S. Patent Application Publication No. 2014 / 0221380 (Japan Tobacco), WO 2009 / 062285 (Boehringer Ingelheim), WO 2010 / 130034 (Boehringer Ingelheim), WO 2013 / 006792 (Pharma Resources), U.S. Patent Application Publication No. 20140221356 (Gilead Sciences), U.S. Patent Application Publication No. 20100143301 (Gilead Sciences), and WO 2013 / 091096 (Boehringer Ingelheim).

[0230] Examples of other drugs for treating HIV include acemannan, alisporivir, BanLec, deferiprone, Gamimune, metenkefalin, naltrexone, Prolastin, REP 9, RPI-MN, VSSP, H1viral, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, AAV-eCD4-Ig gene therapy, MazF gene therapy, BlockAide, ABX-464, AG-1105, APH-0812, BIT-225, CYT-107, HGTV-43, HPH-116, HS-10234, IMO -3100, IND-02, MK-1376, MK-8507, MK-8591, NOV-205, PA-1050040 (PA-040), PGN-007, SCY-635, SB-9200, SCB-719, TR-452, TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, Immuglo, and VIR-576. Gene and Cell Therapy

[0231] Gene and cell therapies include genetic modifications to silence genes; genetic approaches that directly kill infected cells; infusion of immune cells designed to replace much of the subject's own immune system and mount an immune response against infected cells or activate the subject's own immune system to kill infected cells, or to find and kill infected cells; and genetic approaches that modify cellular activity to further alter endogenous immune responsiveness to infection.

[0232] An example of a dendritic cell therapy is AGS-004. gene editing agents

[0233] Examples of gene editing systems include CRISPR / Cas9 systems, zinc finger nuclease systems, TALEN systems, homing endonuclease systems and meganuclease systems.

[0234] An example of an HIV-targeting CRISPR / Cas9 system is EBT101. CAR-T cell therapy

[0235] CAR-T cell therapy involves a population of immune effector cells engineered to express a chimeric antigen receptor (CAR), which contains an HIV antigen-binding domain. The HIV antigen can be an HIV envelope protein or a portion thereof, gp120 or a portion thereof, or gp120. Examples of immune effector cells include the CD4 binding site on gp120, the CD4-inducible binding site on gp120, the N-glycan on gp120, V2 of gp120, and the membrane proximal region on gp41. The immune effector cells are T cells or NK cells. In some embodiments, the T cells are CD4+ T cells, CD8+ T cells, or a combination thereof.

[0236] An example of an HIV CAR-T is VC-CAR-T. TCR-T cell therapy

[0237] TCR-T cell therapy involves T cells engineered to target HIV-derived peptides present on the surface of virus-infected cells.

[0238] It will be appreciated by those skilled in the art that the additional therapeutic agents listed above may fall into more than one of the above-listed classes. The particular classes are not intended to limit the functionality of the compounds listed in those classes.

[0239] In a specific embodiment, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with an HIV nucleoside or nucleotide reverse transcriptase inhibitor and an HIV non-nucleoside reverse transcriptase inhibitor. In another specific embodiment, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with an HIV nucleoside or nucleotide reverse transcriptase inhibitor and an HIV protease inhibitor compound. In an additional embodiment, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with an HIV nucleoside or nucleotide reverse transcriptase inhibitor, an HIV non-nucleoside reverse transcriptase inhibitor, and a pharmacokinetic enhancer. In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with at least one HIV nucleoside reverse transcriptase inhibitor, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with two HIV nucleoside or nucleotide reverse transcriptase inhibitors.

[0240] In certain embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are selected from the group consisting of ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); BIKTA RVY® (bictegravir, emtricitabine, tenofovir alafenamide); adefovir; adefovir dipivoxil; cobicistat; emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate; TRIUMEQ® (dolutegravir, abacavir and lamivudine); dolutegravir, abacavir sulfate and lamivudine; Ral Tegravir; Raltegravir and Lamivudine; Maraviroc; Enfuvirtide; ALUVIA® (KALETRA®; Lopinavir and Ritonavir); COMBIVIR® (Zidovudine and Lamivudine; AZT + 3TC); EPZICOM® (LIVEXA®; Abacavir Sulfate and Lamivudine; ABC + 3TC); TRIZIVIR® (Abacavir Sulfate, Zidovudine, and Lamivudine; AB C+AZT+3TC); Rilpivirine; Rilpivirine hydrochloride; Atazanavir sulfate and cobicistat; Atazanavir and cobicistat; Darunavir and cobicistat; Atazanavir; Atazanavir sulfate; Dolutegravir; Elvitegravir; Ritonavir; Atazanavir sulfate and ritonavir; Darunavir; Lamivudine; Prolastin; Fosamprenavir; Fosamprenavir calcium; Efavirenz; Etravirine; Nelfinavir; Nelfinavir mesylate; Interferon; Didanosine; Stavudine; Indinavir; Indinavir sulfate; Te Combined with one, two, three, four or more additional therapeutic agents selected from nevirapine and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (receptol); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine and tenofovir disoproxil fumarate; phosphazide; lamivudine, nevirapine and zidovudine; abacavir; and abacavir sulfate.

[0241] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, or bictegravir.

[0242] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, or bictegravir.

[0243] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, and bictegravir, and a second additional therapeutic agent selected from the group consisting of emtricitabine and lamivudine.

[0244] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, and bictegravir, and a second additional therapeutic agent which is emtricitabine.

[0245] In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 5-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 5-10, 5-15, 5-20, 5-25, 25-30, 20-30, 15-30, or 10-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine. The compound disclosed herein is , can be combined with the agents provided herein in any dosage amount of the compound (e.g., 1 mg to 500 mg of the compound), as if each combination of dosage amounts were specifically and individually recited.

[0246] In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 200-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 200-250, 200-300, 200-350, 250-350, 250-400, 350-400, 300-400, or 250-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 300 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg of emtricitabine. The compounds disclosed herein can be combined with agents provided herein at any dosage of the compound (e.g., 1 mg to 500 mg of the compound), as if each dosage combination were specifically and individually recited. HBV combination therapy

[0247] In certain embodiments, methods are provided for treating or preventing HBV infection in a human infected with or at risk of HBV infection, comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with therapeutically effective amounts of one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents. In one embodiment, methods are provided for treating HBV infection in a human infected with or at risk of HBV infection, comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with therapeutically effective amounts of one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents.

[0248] In certain embodiments, the present disclosure provides methods for treating HBV infection, comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents suitable for treating HBV infection.

[0249] The compounds described herein can be used or combined with one or more of chemotherapeutic agents, immunomodulators, immunotherapeutic agents, therapeutic antibodies, therapeutic vaccines, bispecific antibodies and "antibody-like" therapeutic proteins (DART®, Duobodies®, Bites®, XmAb®, TandAb®, Fab derivatives, etc.), antibody-drug conjugates (ADCs), gene modifying or gene editing agents (CRISPR Cas9, zinc finger nucleases, homing endonucleases, synthetic nucleases, TALENs, etc.), cell therapy agents such as CAR-T (chimeric antigen receptor T cell) and TCR-T (modified T cell receptor) agents, or any combination thereof.

[0250] In certain embodiments, the compounds described herein are formulated as tablets that may optionally contain one or more other compounds useful for treating HBV. In certain embodiments, the tablets contain another active ingredient for treating HBV, such as 3- dioxygenase (IDO) inhibitors, apolipoprotein A1 modulators, arginase inhibitors, B- and T-lymphocyte attenuator inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, CCR2 chemokine antagonists, CD137 inhibitors, CD160 inhibitors, CD305 inhibitors, CD4 agonists and modulators, compounds targeting HBcAg, compounds targeting hepatitis B core antigen (HBcAg), core protein allosteric modulators, covalently closed circular DNA (cccDNA) inhibitors, cyclophilin inhibitors, cytotoxic T lymphocyte-associated protein 4 (ipi4) inhibitors, DNA polymerase inhibitors, endonuclease modulators, epigenetic modifiers, farnesoid X receptor agonists, HBsAg inhibitors, HBsAg secretion or association inhibitors, HBV DNA polymerase inhibitors, HBV replication inhibitors, HBVRNAse inhibitors, HBV virus entry inhibitors, HBx inhibitors, hepatitis B large envelope protein modulators, hepatitis B large envelope protein stimulators, hepatitis B structural protein modulators, hepatitis B surface antigen (HBsAg) inhibitors, hepatitis B surface antigen (HBsAg) secretion or association inhibitors, hepatitis B virus E antigen inhibitors, hepatitis B virus replication inhibitors, hepatitis virus structural protein inhibitors, HIV-1 reverse transcriptase inhibitors, hyaluronidase inhibitors, IAP inhibitors, IL-2 agonists, IL-7 agonists, immunomodulators, indoleamine-2 inhibitors, inhibitors of ribonucleotide reductase, interleukin-2 ligand, ipi4 inhibitors, lysine demethylase inhibitors, histone demethylase inhibitors, KDM1 inhibitors, KDM5 inhibitors, killer cell lectin-like receptor subfamily G member 1 inhibitors, lymphocyte-activation gene 3 inhibitors, lymphotoxin beta receptor activators, modulators of Axl, B7-H3 modulators, B7-H4 modulators, CD160 modulators, CD161 modulators, CD27 modulators, CD47 modulators, CD70 modulators, GITR modulators, HEVEM modulators, ICOS modulators, Mer modulators, NKG2A modulators, NKG2D modulators, OX40 modulators, SIRP alpha modulators, TIGIT modulators, Tim-4 modulators, Tyro modulators, taurocholate Na+ cotransporting polypeptide (NTCP) inhibitors, natural killer cell receptor 2B4 inhibitors, NOD2 gene stimulators, nuclear protein inhibitors, nuclear protein modulators, PD-1 inhibitors, PD-L1 inhibitors, peptidyl prolyl isomerase inhibitors, phosphatidylinositol-3 kinase (PI3K) inhibitors, retinoic acid-inducible gene 1 stimulators, reverse transcriptase inhibitors, ribonuclease inhibitors, RNAThese agents may include DNA polymerase inhibitors, SLC10A1 gene inhibitors, SMAC mimetics, Src tyrosine kinase inhibitors, stimulators of interferon genes (STING) agonists, stimulators of NOD1, T cell surface glycoprotein CD28 inhibitors, T cell surface glycoprotein CD8 modulators, thymosin agonists, thymosin alpha 1 ligands, Tim-3 inhibitors, TLR-3 agonists, TLR-7 agonists, TLR-9 agonists, TLR9 gene stimulators, toll-like receptor (TLR) modulators, viral ribonucleotide reductase inhibitors, and combinations thereof. HBV combination drugs

[0251] Examples of drug combinations for treating HBV include TRUVADA® (tenofovir disoproxil fumarate and emtricitabine); ABX-203, lamivudine and PEG-IFN-alpha; ABX-203 adefovir and PEG-IFN-alpha; and INO-1800 (INO-9112 and RG7944). Other HBV drugs

[0252] Examples of other drugs for treating HBV include alpha-hydroxytropolone, amdoxovir, beta-hydroxycytosine nucleosides, AL-034, CCC-09 75, elvucitabine, ezetimibe, cyclosporine A, gentiopicrin (gentiopicroside), JNJ-56136379, nitazoxanide, birinapant, NJK14047, NOV-205 (Morixan, BAM-205), oligotide, mibotylate, Feron, GST-HG-131, levamisole, Ka Shu Ning, alloferon, WS-007, Y-101 (Ti Fen Tai), rSIFN-co, PEG-IIFNm, KW-3, BP-Inter-014, oleanolic acid, HepB-nRNA, cTP-5 (rTP-5), HSK-II-2, HEISCO-106-1, HEISCO-106, Hepbarna, IBPB-006IA, Hepuyinfen, DasKloster 0014-01, ISA-204, Jiangantai (Ganxikang), MIV-210, OB-AI-004, PF-06, picroside, DasKloster-0039, Heplantai, IMB-2613, TCM-800B, reduced glutathione, RO-6864018, RG-7834, UB-551, and ZH-2N, as well as U.S. Patent Application Publication No. 20150210682 (Roche), U.S. Patent Application Publication No. 2016 / 0122344 (Roche), WO 2015173164, WO 2016023877, and U.S. Patent Application Publication No. 2015252057 No. (Roche), WO 16128335 (Roche), WO 16120186 (Roche), U.S. Patent Application Publication No. 2016237090 (Roche), WO 16107833 (Roche), WO 16107832 (Roche), U.S. Patent Application Publication No. 2016176899 (Roche), WO 16102438 (Roche), WO 16012470 (Roche), U.S. Patent Application Publication No. 2016220586 (Roche), and U.S. Patent Application Publication No. 2015031687 (Roche). HBV vaccine

[0253] HBV vaccines include both prophylactic and therapeutic vaccines. Examples of HBV prophylactic vaccines include Vaxelis, Hexaxim, Heplisav, Mosquirix, DTwP-HBV vaccine, Bio-Hep-B, D / T / P / HBV / M (LBVP-0101; LBVW-0101), DTwP-HepB-Hib-IPV vaccine, Heberpenta L, DTwP-HepB-Hib, V-419, CVI-HBV-001, Tetrabhay, hepatitis B vaccine (Advax Super D), Hepatrol-07, GSK-223192A, and ENGERIX. B®, Recombinant Hepatitis B Vaccine (Intramuscular, Kangtai Biological Products), Recombinant Hepatitis B Vaccine (Hansenual polymorpha Yeast, Intramuscular, Hualan Biological Engineering), Recombinant Hepatitis B Surface Antigen Vaccine, Bimmugen, Euforavac, Eutravac, anrix-DTaP-IPV-Hep B, HBAI-20, Infanrix-DTaP-IPV-Hep B-Hib, Pentabio Vaksin These include DTP-HB-Hib, Comvac 4, Twinrix, Euvax-B, Tritanrix HB, Infanrix Hep B, Comvax, DTP-Hib-HBV vaccine, DTP-HBV vaccine, Yi Tai, Heberbiovac HB, Trivac HB, GerVax, DTwP-Hep B-Hib vaccine, Bilive, Hepavax-Gene, SUPERVAX, Comvac5, Shanvac-B, Hebsulin, Recombivax HB, Revac B mcf, Revac B+, Fendrix, DTwP-HepB-Hib, DNA-001, Shan5, Shan6, rhHBsAG vaccine, HBI pentavalent vaccine, LBVD, Infanrix HeXa, and DTaP-rHB-Hib vaccine.

[0254] Examples of HBV therapeutic vaccines include HBsAG-HBIG conjugate, ARB-1598, Bio-Hep-B, NASVAC, abi-HB (intravenous), ABX-203, Tetrabhay, GX-110E, GS-4774, and peptide vaccine (Epsilon PA). -44), Hepatrol-07, NASVAC (NASTERAP), IMP-321, BEVAC, Revac B mcf, Revac B+, MGN-1333, KW-2, CVI-HBV-002, AltraHepB, VGX-6200, FP-02, FP-02.2, TG-1050, NU-500, HBVax, im / TriGrid / antigen vaccine, Mega-CD40L-adjuvanted vaccine, HepB-v, RG7944 (INO-1800), recombinant VLP-based therapeutic vaccine (HBV infection, VLP Biotech), AdTG-17909, AdTG-17910, AdTG-18202, ChronVac-B, TG-1050, and Lm HBV. HBV DNA polymerase inhibitors

[0255] Examples of HBV DNA polymerase inhibitors include adefovir (HEPSERA®), emtricitabine (EMTRIVA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir dipivoxil, tenofovir dipivoxil fumarate, tenofovir octadecyloxyethyl ester, CMX-157, besifovir, and entefloxacin. Immunomodulators include bacil (BARACLUDE®), entecavir maleate, telbivudine (TYZEKA®), filocillovir, pradefovir, clevudine, ribavirin, lamivudine (EPIVIR-HBV®), phosphazide, famciclovir, fusorin, metacavir, SNC-019754, FMCA, AGX-1009, AR-II-04-26, HIP-1302, tenofovir disoproxil aspartate, tenofovir disoproxil orotate, and HS-10234.

[0256] Examples of immunomodulators include lintatolimod, imidole hydrochloride, ingaron, dermaVir, Plaquenil (hydroxychloroquine), proleukin, hydroxyurea, mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF), JNJ-440, WF-10, AB-452, ribavirin, IL-12, INO-9112, the polymer polyethyleneimine (PEI), Gepon, VGV-1, MOR-22, CRV-431, JNJ-0535, TG-1050, ABI-H2158, BMS-936559, RO-7011785, RG-7854, AB-506, RO-6871765, AIC-649, and IR-103. Toll-like receptor (TLR) modulators

[0257] TLR modulators include modulators of TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13. Examples of TLR3 modulators include lintatolimod, poly-ICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH-33, MCT-465, MCT-475, and ND-1.1.

[0258] Examples of TLR7 modulators include GS-9620, GSK-2245035, imiquimod, resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, Limtop, D, telluritolimod, SP-0509, TMX-30X, TMX-202, RG-7863, RG-7795, LHC-165, RG-7854, and compounds disclosed in U.S. Patent Application Publication No. 20100143301 (Gilead Sciences), U.S. Patent Application Publication No. 20110098248 (Gilead Sciences), and U.S. Patent Application Publication No. 20090047249 (Gilead Sciences). Examples include compounds.

[0259] Examples of TLR8 modulators include motolimod, resiquimod, 3M-051, 3M-052, MCT-465, IMO-4200, VTX-763, VTX-1463, and the compounds disclosed in U.S. Patent Application Publication No. 20140045849 (Janssen), U.S. Patent Application Publication No. 20140073642 (Janssen), WO 2014 / 056953 (Janssen), WO 2014 / 076221 (Janssen), WO 2014 / 128189 (Janssen), U.S. Patent Application Publication No. 20140350031 (Janssen), WO 2014 / 023813 (Janssen), U.S. Patent Application Publication No. 20080234251 (Array Biopharma), U.S. Patent Application Publication No. 20080306050 (Array Biopharma), U.S. Patent Application Publication No. 20100029585 (Ventirx Pharma), U.S. Patent Application Publication No. 20110092485 (Ventirx Pharma), U.S. Patent Application Publication No. 20110118235 (Ventirx Pharma), U.S. Patent Application Publication No. 20120082658 (Ventirx Pharma), U.S. Patent Application Publication No. 20120219615 (Ventirx Pharma), U.S. Patent Application Publication No. 20140066432 (Ventirx Pharma), U.S. Patent Application Publication No. 20140088085 (Ventirx Pharma), U.S. Patent Application Publication No. 20140275167 (Novira No. 20130251673 (Novira Therapeutics), U.S. Patent Application Publication No. 9,670,205, U.S. Patent Application Publication No. 20160289229, U.S. Patent Application No. 15 / 692161, and U.S. Patent Application No. 15 / 692093.

[0260] Examples of TLR9 modulators include BB-001, BB-006, CYT-003, IMO-2055, IMO-2125, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, leftolimod (MGN-1703), ritenimod, and CYT-003-QbG10.

[0261] Examples of TLR7, TLR8, and TLR9 modulators are described in WO 2017047769 (Teika Seiyaku), WO 2015014815 (Janssen), WO 2018045150 (Gilead Sciences Inc.), WO 2018045144 (Gilead Sciences Inc.), WO 2015162075 (Roche), WO 2017034986 (University of Kansas), WO 2018095426 (Jiangsu Hengrui Medicine Co Ltd), WO 2016091698 (Roche), WO 2016075661 (GlaxoSmithKline Biologicals), WO 2016180743 (Roche), WO 2018089695 (Dynavax Technologies), WO 2016055553 (Roche), WO 2015168279 (Novartis), WO 2016107536 (Medshine Discovery), WO 2018086593 (Livo (Shanghai) Pharmaceutical), WO 2017106607 (Merck), WO 2017061532 (Sumitomo Dainippon Pharma), WO 2016023511 (Chia Tai Tianqing Pharmaceutical), WO 2017076346 (Chia Tai Tianqing Pharmaceutical), WO 2017046112 (Roche), WO 2018078149 (Roche), WO 2017040233 (3M Co), WO 20161 41092 (Gilead Sciences), WO 2018049089 (Bristol Myers Squibb), WO 2015057655 (Eisai Co Ltd), WO 2017001307 (Roche), WO 2018005586 (Bristol Myers Squibb), WO 201704023 (3M Co), WO 2017163264 (Council of Scientific and Industrial Research (India)), WO 2018046460 (GlaxoSmithKline Biologicals), WO 2018047081 (Novartis), WO 2016142250 (Roche), WO 2015168269 (Novartis), WO 201804163 (Roche), WO 2018038877 (3M Co), WO 2015057659 (Eisai Co Ltd), WO 2017202704 (Roche), WO 2018026620 (Bristol Myers Squibb), WO 2016029077 (Janus Biotherapeutics), WO 201803143 (Merck), WO 2016096778 (Roche), WO 2017190669 (Shanghai De Novo Pharmatech), U.S. Pat. No. 09884866 (University of Minnesota), WO 2017219931 (Sichuan KelunBiotech Biopharmaceutical), WO 2018002319 (Janssen Sciences), WO 2017216054 (Roche), WO 2017202703 (Roche), WO 2017184735 (IFM Therapeutics), WO 2017184746 (IFM Therapeutics), International Publication No. 2015088045 (Takeda Pharmaceutical), International Publication No. 2017038909 (Takeda Examples of compounds disclosed in International Publication No. WO 2015095780 (University of Kansas), and International Publication No. WO 2015023958 (University of Kansas) are also disclosed. Interferon alpha receptor ligand

[0262] Examples of interferon alpha receptor ligands include interferon alpha-2b (INTRON A®), pegylated interferon alpha-2a (PEGASYS®), pegylated interferon alpha-1b, interferon alpha 1b (HAPGEN®), Veldona, Infradure, Roferon-A, YPEG-interferon alpha-2a (YPEG-rhIFN alpha-2a), P-1101, Algeron, Alfarona, Ingaron (interferon gamma), rSIFN-co (recombinant super compound interferon), interferon), Y pegylated interferon alfa-2b (YPEG-rhIFN alfa-2b), MOR-22, pegylated interferon alfa-2b (PEG-INTRON®), Bioferon, Novaferon, Inmutag (Inferon), MULTIFERON®, interferon alfa-n1 (HUMOFERON®), interferon beta-1a (AVONEX®), Shaferon, interferon alfa-2b (Axxo), Alfaferone, interferon alfa-2b (BioGeneric Pharma), interferon alfa-2 (CJ), Laferonum, VIPEG, BLAUFERON-A, BLAUFERON-B, Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-B, interferon alfa-2b (IFN, Laboratorios Bioprofarma), alpha interferon a 2b, Kalferon, Pegnano, Feronsure, PegiHep, interferon alfa 2b (Zydus-Cadila), interferon alfa rHSA-IFN alpha-2a, Optipeg A, Realfa 2B, Reliferon, interferon alpha-2b (Amega), interferon alpha-2b (Virchow), pegylated interferon alpha-2b, rHSA-IFN alpha-2a (recombinant human serum albumin interferon alpha-2a fusion protein), rHSA-IFN alpha 2b, recombinant human interferon alpha-(1b, 2a, 2b), pegylated interferon alpha-2b (Amega), pegylated interferon alpha-2a, Reliferon-EC, Proquiferon, Uniferon, Urifron, interferon alpha-2b (Changchun Institute of Biological Products), Anterferon, Shanferon, Layfferon, Shang Sheng Lei Tai, INTEFEN, SINOGEN, Fukangtai, Pegstat, rHSA-IFN alpha-2b, SFR-9216, and Interapo (Interapa). hyaluronidase inhibitors

[0263] Examples of hyaluronidase inhibitors include astodrimer. Hepatitis B surface antigen (HBsAg) inhibitors

[0264] Examples of HBsAg inhibitors include HBF-0259, PBHBV-001, PBHBV-2-15, PBHBV-2-1, REP-9AC, REP-9C, REP-9, REP-2139, REP-2139-Ca, REP-2165, REP-2055, REP-2163, REP-2165, REP-2053, REP-2031 and REP-006, and REP-9AC'.

[0265] An example of an HBsAg secretion inhibitor is BM601. Cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitor

[0266] Examples of cytotoxic T lymphocyte-associated protein 4 (ipi4) inhibitors include AGEN-2041, AGEN-1884, ipilimumab, belatacept, PSI-001, PRS-010, Probody mAbs, tremelimumab, and JHL-1155. Cyclophilin inhibitors

[0267] Examples of cyclophilin inhibitors include CPI-431-32, EDP-494, OCB-030, SCY-635, NVP-015, NVP-018, NVP-019, STG-175, and compounds disclosed in U.S. Patent No. 8,513,184 (Gilead Sciences), U.S. Patent Application Publication No. 20140030221 (Gilead Sciences), U.S. Patent Application Publication No. 20130344030 (Gilead Sciences), and U.S. Patent Application Publication No. 20130344029 (Gilead Sciences). HBV virus entry inhibitor

[0268] An example of an HBV viral entry inhibitor is Myrcludex B. Antisense oligonucleotides targeting viral mRNA

[0269] Examples of antisense oligonucleotides targeting viral mRNA include ISIS-HBVRx, IONIS-HBVRx, IONIS-GSK6-LRx, GSK-3389404, and RG-6004. Short interfering RNA (siRNA) and ddRNAi

[0270] Examples of siRNA include TKM-HBV (TKM-HepB), ALN-HBV, and S R-008, HepB-nRNA, and ARC-520, ARC-521, ARB-1740, and ARB-1467.

[0271] An example of DNA-directed RNA interference (ddRNAi) is BB-HB-331. Endonuclease Modulators

[0272] An example of an endonuclease modulator is PGN-514. Ribonucelotide reductase inhibitors

[0273] An example of an inhibitor of ribonucleotide reductase is Trimidox. HBV E antigen inhibitors

[0274] An example of an HBV E antigen inhibitor is wogonin. Covalently closed circular DNA (cccDNA) inhibitors

[0275] Examples of cccDNA inhibitors include BSBI-25 and CHR-101. Farnesoid X receptor agonists

[0276] Examples of farnesoid x receptor agonists include EYP-001, GS-9674, EDP-305, MET-409, Tropifexor, AKN-083, RDX-023, BWD-100, LMB-763, INV-3, NTX-023-1, EP-024297, and GS-8670. HBV antibody

[0277] Examples of HBV antibodies that target the surface antigen of the hepatitis B virus include GC-1102, XTL-17, XTL-19, KN-003, IV Hepabulin SN, and Fully Human Monoclonal Antibody Therapy (Hepatitis B Virus Infection, Humabs BioMed).

[0278] Examples of HBV antibodies, including monoclonal and polyclonal antibodies, include Zutectra, Shang Sheng Gan Di, Uman Big (Hepatitis B Hyperimmune), Omri-Hep-B, Nabi-HB, Hepatect CP, HepaGam B, Igantibe, Niuliva, CT-P24, Hepatitis B Immune Globulin (Intravenous, pH4, HBV Infection, Shanghai RAAS Blood Products), and Fovepta (BT-088).

[0279] An example of a fully human monoclonal antibody is HBC-34. CCR2 chemokine antagonists

[0280] Examples of CCR2 chemokine antagonists include propagermanium. Thymosin agonists

[0281] Examples of thymosin agonists include thymalfasin, recombinant thymosin alpha 1 (GeneScience). cytokines

[0282] Examples of cytokines include recombinant IL-7, CYT-107, interleukin-2 (IL-2, Immunex), recombinant human interleukin-2 (Shenzhen Neptunus), IL-15, IL-21, IL-24, and celmoleukin. Nuclear protein modulators

[0283] The nucleoprotein modulator can be either an HBV core or capsid protein inhibitor.Examples of nucleoprotein modulators include GS-4882, AB-423, AT-130, GLS4, NVR-1221, NVR-3778, AL-3778, BAY41-4109, morphotiazine mesylate, ARB-168786, ARB-880, JNJ-379, RG-7907, HEC-72702, AB-506, ABI-H0731, JNJ-440, ABI-H2158 and DVR-23.

[0284] Examples of capsid inhibitors include those disclosed in U.S. Patent Application Publication No. 20140275167 (Novira Therapeutics), U.S. Patent Application Publication No. 20130251673 (Novira Therapeutics), U.S. Patent Application Publication No. 20140343032 (Roche), WO 2014037480 (Roche), U.S. Patent Application Publication No. 20130267517 (Roche), WO 2014131847 (Janssen), WO 2014033176 (Janssen), WO 2014033170 (Janssen), WO 2014033167 (Janssen), WO 2015 / 059212 (Janssen), and WO 2015 / 059212 (Janssen). en), WO 2015118057 (Janssen), WO 2015011281 (Janssen), WO 2014184365 (Janssen), WO 2014184350 (Janssen), WO 2014161888 (Janssen), WO 2013096744 (Novira), U.S. Patent Application Publication No. 20150225355 (Novira), U.S. Patent Application Publication No. 20140178337 (Novira), U.S. Patent Application No. Patent Application Publication No. 20150315159 (Novira), U.S. Patent Application Publication No. 20150197533 (Novira), U.S. Patent Application Publication No. 20150274652 (Novira), U.S. Patent Application Publication No. 20150259324 (Novira), U.S. Patent Application Publication No. 20150132258 (Novira), U.S. Patent No. 9,181,288 (Novira), WO 2014184350 (Janssen), WO 2013144129 (Roche), WO 2014184350 (Janssen), WO 2014184350 (Roche ... 017198744 (Roche), U.S. Patent Application Publication No. 20170334882 (Novira), U.S. Patent Application Publication No. 20170334898 (Roche), WO 2017202798 (Roche), WO 2017214395 (Enanta), WO 2018001944 (Roche), WO 2018001952 (Roche), WO 2018005881 (Novira), WO 2018005883 (Novira),WO 2018011100 (Roche), WO 2018011160 (Roche), WO 2018011162 (Roche), WO 2018011163 (Roche), WO 2018036941 (Roche), WO 2018043747 (Kyoto Univ), U.S. Patent Application Publication No. 20180065929 (Janssen), WO 2016168619 (Indiana University), WO 2016195982 (The Penn State Foundation), WO 2017001655 (Janssen), WO 2017048950 (Assembly Biosciences), WO 2017048954 (Assembly Examples of compounds disclosed in International Publication No. 2017048962 (Assembly Biosciences), U.S. Patent Application Publication No. 20170121328 (Novira), and U.S. Patent Application Publication No. 20170121329 (Novira).

[0285] Examples of transcription inhibitors include those disclosed in International Publication No. 2017013046 (Roche), International Publication No. 2017016960 (Roche), International Publication No. 2017017042 (Roche), International Publication No. 2017017043 (Roche), International Publication No. 2017061466 (Toyoma chemicals), International Publication No. 2016177655 (Roche), International Publication No. 2016161268 (Enanta), and International Publication No. 2017001853 (Redex Pharma), WO 2017211791 (Roche), WO 2017216685 (Novartis), WO 2017216686 (Novartis), WO 2018019297 (Ginkgo Pharma), WO 2018022282 (Newave Pharma), U.S. Patent Application Publication No. 20180030053 (Novartis), and WO 2018045911 (Zhejiang Pharma). Retinoic acid-inducible gene 1 stimulator

[0286] Examples of stimulators of retinoic acid-inducible gene 1 include SB-9200, SB-40, SB-44, ORI-7246, ORI-9350, ORI-7537, ORI-9020, ORI-9198, and ORI-7170, RGT-100. NOD2 stimulators

[0287] Examples of NOD2 stimulators include SB-9200. Phosphatidylinositol 3-kinase (PI3K) inhibitors

[0288] Examples of PI3K inhibitors include idelalisib, ACP-319, AZD-8186, AZD-8835, buparlisib, CDZ-173, CLR-457, pictilisib, neratinib, rigosertib, rigosertib sodium, EN-3342, TGR-1202, alpelisib, duvelisib, IPI-549, UCB-5857, taselisib, XL-765, gedatricisib, ME-401, VS-5584, copanlisib, orotate CAI, perifosine, RG-7666, GSK-2636771, and DS- 7423, panulisib, GSK-2269557, GSK-2126458, CUDC-907, PQR-309, INCB-40093, pilaralisib, BAY-1082439, pukitinib mesylate, SAR-245409, AMG-319, RP-6530, ZSTK-474, MLN-1117, SF-1126, RV-1729, sonolisib, LY-3023414, SAR-260301, TAK-117, HMPL-689, tenalisib, voxtalisib, and CLR-1401. Indoleamine 2,3-dioxygenase (IDO) pathway inhibitors

[0289] Examples of IDO inhibitors include epacadostat (INCB24360), resminostat (4SC-201), indoximod, F-001287, SN-35837, NLG-919, GDC-0919, GBV-1028, GBV-1012, NKTR-218, and compounds disclosed in U.S. Patent Application Publication No. 20100015178 (Incyte), U.S. Patent Application Publication No. 2016137652 (Flexus Biosciences, Inc.), WO 2014073738 (Flexus Biosciences, Inc.), and WO 2015188085 (Flexus Biosciences, Inc.). PD-1 inhibitors

[0290] Examples of PD-1 inhibitors include cemiplimab, nivolumab, pembrolizumab, pidilizumab, BGB-108, STI-A1014, SHR-1210, PDR-001, PF-06801591, IBI-308, GB-226, STI-1110, and JNJ- 63723283, CA-170, durvalumab, atezolizumab, and mDX-400, JS-001, camrelizumab, sintilimab, tislelizumab, BCD-100, BGB-A333, JNJ-63723283, GLS-010 (WBP-3055), CX-072, AGEN-2034, GNS-1480 (epidermal growth factor receptor antagonist; programmed cell death ligand 1 inhibitor), CS-1001, M-7824 (PD-L1 / TGF-β bifunctional fusion protein), genolizumab, BMS-936559. PD-L1 inhibitors

[0291] Examples of PD-L1 inhibitors include atezolizumab, avelumab, AMP-224, MEDI-0680, RG-7446, GX-P2, durvalumab, KY-1003, KD-033, MSB-0010718C, TSR-042, ALN-PDL, STI-A1014, GS-4224, CX-072, and BMS-936559.

[0292] Examples of PD-1 inhibitors include those disclosed in WO 2017112730 (Incyte Corp), WO 2017087777 (Incyte Corp), WO 2017017624, WO 2014151634 (Bristol Myers Squibb Co), WO 201317322 (BristolMyers Squibb Co), WO 2018119286 (Incyte Corp), WO 2018119266 (Incyte Corp), WO 2018119263 (Incyte Corp), WO 2018119236 (Incyte Corp), WO 2018119221 (Incyte Corp), WO 2018118848 (BristolMyers Squibb Co), Co), WO 20161266460 (BristolMyers Squibb Co), WO 2017087678 (BristolMyers Squibb Co), WO 2016149351 (BristolMyers Squibb Co), WO 2015033299 (Aurigene Discovery Technologies Ltd), WO 2015179615 (Eisai Co Ltd; Eisai Research Institute), WO 2017066227 (BristolMyers Squibb Co), WO 2016142886 (Aurigene Discovery Technologies Ltd), WO 2016142852 (Aurigene Discovery Technologies Ltd), WO 2016142835 (Aurigene Discovery Technologies Ltd; individual), International Publication No. 2016142833 (Aurigene Discovery Technologies Ltd), WO 2018085750 (BristolMyers Squibb Co), WO 2015033303 (Aurigene Discovery Technologies Ltd), WO 2017205464 (Incyte Corp), WO 2016019232 (3M Co; individual; Texas A&M University System), WO 2015160641 (BristolMyers Squibb Co), WO 2017079669 (Incyte Corp), WO 2015033301 (Aurigene Discovery Technologies Ltd), WO 2015034820 (BristolMyers Squibb Co), International Publication No. 2018073754 (Aurigene Discovery Technologies Ltd), WO 2016077518 (BristolMyers Squibb Co), WO 2016057624 (BristolMyers Squibb Co), WO 2018044783 (Incyte Corp), WO 2016100608 (BristolMyers Squibb Co), International Publication No. 2016100285 (BristolMyer s Squibb Co), WO 2016039749 (BristolMyers Squibb Co), WO 2015019284 (Cambridge Enterprise Ltd), WO 2016142894 (Aurigene Discovery Technologies Ltd), WO 2015134605 (BristolMyers Squibb Co), WO 2018051255 (Aurigene Discovery Technologies Ltd), WO 2018051254 (Aurigene Discovery Technologies Ltd), WO 2017222976 (Incyte Corp), WO 2017070089 (Incyte Corp), WO 2018044963 (BristolMyers Squibb Co), WO 2013144704 (Aurigene Discovery Technologies Ltd), WO 2018013789 (Incyte Corp), WO 2017176608 (BristolMyers Squibb Co), WO 2018009505 (BristolMyers Squibb Co), WO 2011161699 (Aurigene Discovery Technologies Ltd), WO 2015119944 (Incyte Corp; Merck Sharp & Dohme Corp), WO 2017192961 (Incyte Corp), WO 2017106634 (Incyte Corp), WO 2013132317 (Aurigene Discovery Technologies Ltd), WO 2012168944 (Aurigene Discovery Technologies Ltd), WO 2015036927 (Aurigene Discovery Technologies Ltd), WO 2015044900 (Aurigene Discovery Technologies Ltd), and WO 2018026971 (Arising International). Recombinant Thymosin Alpha-1

[0293] Examples of recombinant thymosin alpha-1 include NL-004 and pegylated thymosin alpha-1. Bruton's tyrosine kinase (BTK) inhibitors

[0294] Examples of BTK inhibitors include ABBV-105, acalabrutinib (ACP-196), ARQ-531, BMS-986142, dasatinib, ibrutinib, GDC-0853, PRN-1008, SNS-062, ONO-4059, BGB-3111, ML-319, MSC-2364447, RDX-022, X-022, AC-058, RG-7845, spebrutinib, TAS-5315, TP-0158, TP-4207, HM-71224, KBP-7536, M-2951, TAK-020, AC-0025, and the compounds described in U.S. Patent Application Publication No. 20140330015 (Ono). Examples of compounds disclosed in U.S. Patent Application Publication No. 20130079327 (Ono Pharmaceutical), and U.S. Patent Application Publication No. 20130217880 (Ono Pharmaceutical). KDM inhibitors

[0295] Examples of KDM5 inhibitors include those disclosed in International Publication No. 2016057924 (Genentech / Constellation Pharmaceuticals), U.S. Patent Application Publication No. 20140275092 (Genentech / Constellation Pharmaceuticals), U.S. Patent Application Publication No. 20140371195 (Epitherapeutics), and U.S. Patent Application Publication No. 20140371214 (Epitherapeutics), U.S. Patent Application Publication No. 20160102096 (Episode 1), and U.S. Patent Application Publication No. 20160102096 (Episode 2), and U.S. Patent Application Publication No. 20140371195 (Epitherapeutics), and U.S. Patent Application Publication No. 20140371214 (Epitherapeutics), and U.S. Patent Application Publication No. 20160102096 (Episode 3), and U.S. Patent Application Publication No. 20140371195 (Epitherapeutics), and U.S. Patent Application Publication No. 20140371214 (Epitherapeutics), and U.S. Patent Application Publication No. 20160102096 (Episode 4), and U.S. Patent Application Publication No. 20140371195 (Epitherapeutics), and U.S. Patent Application Publication No. 20140371214 (Epitherapeutics), and U.S. Patent Application Publication No. 20140371195 ... and compounds disclosed in U.S. Patent Application Publication No. 20140194469 (Quanticel), U.S. Patent Application Publication No. 20140171432, U.S. Patent Application Publication No. 20140213591 (Quanticel), U.S. Patent Application Publication No. 20160039808 (Quanticel), U.S. Patent Application Publication No. 20140275084 (Quanticel), and WO 2014164708 (Quanticel).

[0296] Examples of KDM1 inhibitors include compounds disclosed in US Pat. No. 9,186,337 (Oryzon Genomics), GSK-2879552, and RG-6016. STING agonists

[0297] Examples of STING agonists include SB-11285, AdVCA0848, STINGVAX, and those disclosed in WO 2018065360 (Biolog Life Science Institute Forschungslabor und Biochemica-Vertrieb GmbH, Germany), WO 2018009466 (Aduro Biotech), WO 2017186711 (InvivoGen), WO 2017161349 (Immune Sensor), WO 2017106740 (Aduro Biotech), U.S. Patent Application Publication No. 20170158724 (GlaxoSmithkline), WO 2017075477 (Aduro and compounds disclosed in U.S. Patent Application Publication No. 20170044206 (Merck), WO 2014179760 (University of California), WO 2018098203 (Janssen), WO 2018118665 (Merck), WO 2018118664 (Merck), WO 2018100558 (Takeda), WO 2018067423 (Merck), and WO 2018060323 (Boehringer). Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

[0298] Examples of NNRTIs include compounds disclosed in WO2018118826 (Merck), WO2018080903 (Merck), WO2018119013 (Merck), WO2017100108 (Idenix), WO2017027434 (Merck), WO2017007701 (Merck), WO2008005555 (Gilead). HBV replication inhibitors

[0299] Examples of hepatitis B virus replication inhibitors include isothiafluridine, IQP-HBV, RM-5038, and Xingantie. Arginase inhibitors

[0300] Examples of arginase inhibitors include CB-1158, C-201 and resminostat. Gene and Cell Therapy

[0301] Gene and cell therapies include genetic modifications to silence genes; genetic approaches that directly kill infected cells; infusion of immune cells designed to replace much of the patient's own immune system and mount an immune response against infected cells or activate the patient's own immune system to kill infected cells, or to find and kill infected cells; and genetic approaches that modify cellular activity to further alter the endogenous immune responsiveness to infection. gene editing agents

[0302] Examples of genome editing systems include CRISPR / Cas9 systems, zinc finger nuclease systems, TALEN systems, homing endonuclease systems and meganuclease systems; cccDNA elimination via, for example, targeted cleavage, and modification of one or more hepatitis B virus (HBV) viral genes. Modification (e.g., knockout and / or knockdown) of a PreC, C, X, PreSI, PreS2, S, P, or SP gene refers to (1) reducing or eliminating PreC, C, X, PreSI, PreS2, S, P, or SP gene expression, (2) interfering with precore, core, X protein, long surface protein, middle surface protein, S protein (also known as HBsAg and HBsAg), polymerase protein, and / or hepatitis B splicing protein function (HBe, HBc, HBx, PreS1, PreS2, S, Pol, and / or HBSP), or (3) reducing or eliminating intracellular, serum, and / or intraparenchymal levels of HBe, HBc, HBx, LHBs, MHBs, SHBs, Pol, and / or HBSP proteins. Knockdown of one or more of the PreC, C, X, PreSI, PreS2, S, P and / or SP genes is achieved by targeting genes within the HBV cccDNA and / or integrated HBV DNA. CAR-T cell therapy

[0303] CAR T cell therapy comprises a population of immune effector cells engineered to express chimeric antigen receptors (CARs), where the CARs comprise HBV antigen binding domains. The immune effector cells are T cells or NK cells. In some embodiments, the T cells are CD4+ T cells, CD8+ T cells, or a combination thereof. The cells can be autologous or allogeneic. TCR-T cell therapy

[0304] TCR T cell therapy involves T cells expressing HBV-specific T cell receptors. The TCR-T cells are engineered to target HBV-derived peptides displayed on the surface of virus-infected cells. In some embodiments, the T cells express HBV surface antigen (HBsAg)-specific TCRs. An example of a TCR-T therapy for the treatment of HBV is LTCR-H2-1.

[0305] In another specific embodiment, a compound disclosed herein or a pharmaceutically acceptable salt thereof is selected from the group consisting of an HBV DNA polymerase inhibitor, an immunomodulator, a TLR modulator, an HBsAg inhibitor, an HBsAg secretion or association inhibitor, an HBV therapeutic vaccine, an HBV antibody including an HBV antibody targeting the surface antigen of the hepatitis B virus and a bispecific antibody and an "antibody-like" therapeutic protein (such as DART®, DUOBODIES®, BITES®, XmAb®, TandAb®, a Fab derivative or a TCR-like antibody), a cyclophilin inhibitor, a stimulator of retinoic acid-inducible gene 1, and a stimulator of RIG-I-like receptors. , one or two additional therapeutic agents selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, an arginase inhibitor, a PI3K inhibitor, an IDO inhibitor, and a NOD2 stimulator, and one or two additional therapeutic agents selected from the group consisting of an HBV viral entry inhibitor, an NTCP inhibitor, an HBx inhibitor, a cccDNA inhibitor, an HBV antibody targeting the surface antigen of the hepatitis B virus, an siRNA, an miRNA gene therapy agent, an sshRNA, a KDM5 inhibitor, and a nucleoprotein modulator (HBV core or capsid protein modulator).

[0306] In another specific embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are used in combination with HBV DNA polymerase inhibitors, immunomodulators, TLR modulators, HBsAg inhibitors, HBV therapeutic vaccines, hepatitis B virus surface antigens, and the like. and at least a second additional therapeutic agent selected from the group consisting of HBV antibodies and bispecific antibodies and "antibody-like" therapeutic proteins (such as DART®, DUOBODIES®, BITES®, XmAb®, TandAb®, Fab derivatives or TCR-like antibodies), cyclophilin inhibitors, stimulators of retinoic acid-inducible gene 1, stimulators of RIG-I-like receptors, PD-1 inhibitors, PD-L1 inhibitors, arginase inhibitors, PI3K inhibitors, IDO inhibitors, and stimulators of NOD2.

[0307] In another specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HBV DNA polymerase inhibitor and at least a second additional therapeutic agent selected from the group consisting of an HBV viral entry inhibitor, an NTCP inhibitor, an HBx inhibitor, a cccDNA inhibitor, an HBV antibody targeting the surface antigen of the hepatitis B virus, an siRNA, an miRNA gene therapy agent, an sshRNA, a KDM5 inhibitor, and a nucleoprotein modulator (an HBV core or capsid protein inhibitor).

[0308] In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are disclosed in U.S. Patent Application Publication No. 2010 / 0143301 (Gilead Sciences), U.S. Patent Application Publication No. 2011 / 0098248 (Gilead Sciences), U.S. Patent Application Publication No. 2009 / 0047249 (Gilead Sciences), U.S. Patent No. 8,722,054 ... Sciences), U.S. Patent Application Publication No. 2014 / 0045849 (Janssen), U.S. Patent Application Publication No. 2014 / 0073642 (Janssen), WO 2014 / 056953 (Janssen), WO 2014 / 076221 (Janssen), WO 2014 / 128189 (Janssen), U.S. Patent Application Publication No. 2014 / 0350031 (Janssen), WO 2014 / 023813 (Janssen), U.S. Patent Application Publication No. 2008 / 0234251 (Array Biopharma), U.S. Patent Application Publication No. 2008 / 0306050 (Array Biopharma), U.S. Patent Application Publication No. 2010 / 0029585 (Ventirx Pharma), U.S. Patent Application Publication No. 2011 / 0092485 (Ventirx Pharma), U.S. Patent Application Publication No. 2011 / 0118235 (Ventirx Pharma), U.S. Patent Application Publication No. 2012 / 0082658 (Ventirx Pharma), U.S. Patent Application Publication No. 2012 / 0219615 (Ventirx Pharma), U.S. Patent Application Publication No. 2014 / 0066432 (Ventirx Pharma), U.S. Patent Application Publication No. 2014 / 0088085 (Ventirx Pharma), U.S. Patent Application Publication No. 2014 / 0275167 (Novira Therapeutics), U.S. Patent Application Publication No. 2013 / 0251673 (Novira Therapeutics), U.S. Patent No. 8,513,184 (Gilead Sciences), U.S. Patent Application Publication No. 2014 / 0030221 (Gilead Sciences), U.S. Patent Application Publication No. 2013 / 0344030 (Gilead Sciences), U.S. Patent Application Publication No. 2013 / 0344029 (GileadSciences), U.S. Patent Application Publication No. 20140275167 (Novira Therapeutics), U.S. Patent Application Publication No. 20130251673 (Novira Therapeutics), U.S. Patent Application Publication No. 2014 / 0343032 (Roche), WO 2014037480 (Roche), U.S. Patent Application Publication No. 2013 / 0267517 (Roche), WO 2014131847 (Janssen), WO 2014033176 (Janssen), WO 2014033170 (Jan ssen), WO 2014033167 (Janssen), WO 2015 / 059212 (Janssen), WO 2015118057 (Janssen), WO 2015011281 (Janssen), WO 2014184365 (Janssen), WO 2014184350 (Janssen), WO 20 No. 14161888 (Janssen), WO 2013096744 (Novira), U.S. Patent Application Publication No. 20150225355 (Novira), U.S. Patent Application Publication No. 20140178337 (Novira), U.S. Patent Application Publication No. 20150315159 (Novira), U.S. Patent Application Publication No. 20150197533 (Novira), U.S. Patent Application Publication No. 20150274652 (Novira) a), U.S. Patent Application Publication No. 20150259324 (Novira), U.S. Patent Application Publication No. 20150132258 (Novira), U.S. Patent No. 9,181,288 (Novira), WO 2014184350 (Janssen), WO 2013144129 (Roche), U.S. Patent Application Publication No. 20100015178 (Incyte), U.S. Patent Application Publication No. 2016137652 (Flexus Biosciences, Inc.), WO 2014073738 (Flexus Biosciences, Inc.), WO 2015188085 (Flexus Biosciences, Inc.), U.S. Patent Application Publication No. 2014 / 0330015 (Ono Pharmaceutical), U.S. Patent Application Publication No. 2013 / 0079327 (Ono Pharmaceutical), U.S. Patent Application Publication No. 2013 / 0217880 (Ono Pharmaceutical), International Publication No. 2016057924 (Genentech / Constellation Pharmaceuticals), U.S. Patent Application Publication No. 20140275092 (Genentech / Constellation Pharmaceuticals), U.S. Patent Application Publication No. 20140371195 (Epitherapeutics) and U.S. Patent Application Publication No. 20140371214 (Epitherapeutics), U.S. Patent Application Publication No. 20160102096 (Epitherapeutics), U.S. Patent Application Publication No. 20140194469 (Quanticel), U.S. Patent Application Publication No. 20140171432, U.S. Patent Application Publication No. 20140213591 (Quanticel), U.S. Patent Application Publication No. 20160039808 (Quanticel), U.S. Patent Application Publication No. 20140275084 (Quanticel), WO 2014164708 (Quanticel), U.S. Patent No. 9,186,337 (Oryzon and other drugs for treating HBV, as well as combinations thereof. Cancer Combination Therapy

[0309] In one embodiment, the compounds of the present disclosure may be used in conjunction with other therapeutic methods for the treatment of cancer. Preferably, combination therapy with chemotherapy, hormones, antibodies, surgery and / or radiation treatments is contemplated.

[0310] In some embodiments, the additional anti-cancer treatment is surgery and / or radiation therapy.

[0311] In some embodiments, the additional anti-cancer treatment is at least one additional cancer medicament.

[0312] In some embodiments, a combination is provided comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and at least one additional cancer medicament.

[0313] In some embodiments, there is provided a combination comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and at least one additional cancer medicament, for use in therapy.

[0314] In some embodiments, there is provided the use of a combination comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and at least one cancer medicament in the manufacture of a medicament for treating cancer.

[0315] Further examples of cancer medications include intercalating agents such as anthracyclines, doxorubicin, idarubicin, epirubicin, and daunorubicin; topoisomerase inhibitors such as irinotecan, topotecan, camptothecin, lamellarin D, etoposide, teniposide, mitoxantrone, amsacrine, ellipticine, and aurintricarboxylic acid; nitrosoureas such as carmustine (BCNU), lomustine (CCNU), and streptozocin. nitrogen mustards such as cyclophosphamide, mechlorethamine, uramustine, bendamustine, melphalan, chlorambucil, mafosfamide, trofosfamide, and ifosfamide; alkyl sulfonates such as busulfan and treosulfan; alkylating agents such as procarbazine, dacarbazine, temozolomide, and thiotepa; cisplatin, carboplatin, nedaplatin, oxaliplatin, satraplatin, and triplatin tetranitrate Platinum analogues such as; microtubule disrupting drugs such as vinblastine, colcemid and nocodazole; antifolates such as methotrexate, aminopterin, dichloromethotrexate, pemetrexed, raltitrexed and pralatrexate; purine analogues such as azathioprine, mercaptopurine, thioguanine, fludarabine, fludarabine phosphate, pentostatin and cladribine; 5-fluorouracil, floxuridine, cytarabine, 6-azathioprine, mercaptopurine, thioguanine, fludarabine phosphate, pentostatin and cladribine; pyrimidine analogs such as uracil, gemcitabine; gestagens, androgens, glucocorticoids, steroids such as dexamethasone, prednisolone and prednisone; monoclonal antibodies, for example alemtuzumab, apolizumab, cetuximab, epratuzumab, galiximab, gemtuzumab, ipilimumab, labetuzumab, panitumumab, rituximab, trastuzumab, nimotuzumab, mapatumumab, matuzumab, rhMab ICR62 and pertuzumab, anti-cancer antibodies such as radiolabeled antibodies and antibody-drug conjugates; anti-cancer peptides such as radiolabeled peptides and peptide-drug conjugates; and taxanes and taxane analogs such as paclitaxel and docetaxel.

[0316] In certain embodiments, methods are provided for treating or preventing a hyperproliferative disease or cancer in a human or animal having or at risk of having the hyperproliferative disease or cancer, comprising administering to the human or animal a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with therapeutically effective amounts of one or more (e.g., 1, 2, 3, 1 or 2, or 1 to 3) additional therapeutic agents. In one embodiment, methods are provided for treating a hyperproliferative disease or cancer in a human or animal having or at risk of having the hyperproliferative disease or cancer, comprising administering to the human or animal a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with therapeutically effective amounts of one or more (e.g., 1, 2, 3, 1 or 2, or 1 to 3) additional therapeutic agents.

[0317] In certain embodiments, the present disclosure provides a method of treating a hyperproliferative disease or cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents suitable for treating the hyperproliferative disease or cancer.

[0318] The compounds described herein include chemotherapeutic agents, anti-cancer agents, anti-angiogenic agents, anti-fibrotic agents, immunotherapeutic agents, therapeutic antibodies, bispecific antibodies and "antibody-like" therapeutic proteins (DART®, Duobody®, Bite®, XmAb®, TandAb®, Fab derivatives, etc.), antibody-drug conjugates (ADCs), radiotherapeutic agents, anti-cancer agents, anti-proliferative agents, oncolytic viruses, gene modifying or editing agents (CRISPR / Cas9, zinc finger nucleases or synthetic nucleases, TALENs, etc.), CAR (chimeric antigen receptor) T-cell immunotherapeutics, engineered The therapeutic agent may be used or combined with one or more of the T cell receptor (TCR-T) receptors or any combination thereof. These therapeutic agents may be in the form of a compound, an antibody, a polypeptide, or a polynucleotide. In one embodiment, provided herein is a product comprising a compound described herein and an additional therapeutic agent as a combined preparation for simultaneous, separate, or sequential use in therapy.

[0319] The one or more therapeutic agents include, but are not limited to, inhibitors, agonists, antagonists, ligands, modulators, stimulators, blockers, gene activators or repressors, ligands, receptors, proteins, or factors. Non-limiting examples of additional therapeutic agents include: Abelson murine leukemia viral oncogene homolog 1 gene (ABL, such as ABL1), acetyl-CoA carboxylase (such as ACC1 / 2), activated CDC kinase (ACK, such as ACK1), adenosine deaminase, adenosine receptors (such as A2B, A2a, and A3), adenylate cyclase, ADP-ribosyl cyclase-1, adrenocorticotropic hormone receptor (ACTH), aerolysin, AKT1 gene, Alk-5 protein kinase, alkaline phosphatase, alpha-1 adrenergic receptor, alpha-2 adrenergic receptor, alpha-ketoconazole, and alpha-ketoconazole. Glutarate dehydrogenase (KGDH), aminopeptidase N, AMP-activated protein kinase, anaplastic lymphoma kinase (ALK, such as ALK1), androgen receptor, angiopoietin (ligand-1, ligand-2, etc.), angiotensinogen (AGT) gene, murine thymoma viral oncogene homolog 1 (AKT) protein kinase (AKT1, AKT2, AKT3, etc.), apolipoprotein AI (APOA1) gene, apoptosis-inducing factor, apoptosis protein (1, 2, etc.), apoptosis signal-regulating kinase (A ASK (e.g., SK1), arginase (I), arginine deiminase, aromatase, asteroid homolog 1 (ASTE1) gene, ataxia-telangiectasia and Rad3-related (ATR) serine / threonine protein kinase, Aurora protein kinases (e.g., 1, 2), Axl tyrosine kinase receptor, baculovirus IAP repeat-containing 5 (BIRC5) gene, basigin, B-cell lymphoma 2 (BCL2) gene, Bcl2-binding component 3, Bcl2 protein, BCL2L11 gene, BCR (breakpoint cluster region) Proteins and genes, beta-adrenergic receptor, beta-catenin, B-lymphocyte antigen CD19, B-lymphocyte antigen CD20, B-lymphocyte cell adhesion molecule, B-lymphocyte stimulatory factor ligand, bone morphogenetic protein-10 ligand, bone morphogenetic protein-9 ligand modulator, Brachyury protein, bradykinin receptor, B-Raf proto-oncogene (BRAF), Brc-Abl tyrosine kinase, bromodomain and ectodomain (BET) bromodomain-containing proteins (e.g., BRD2, BRD3, BRD4), Bruton's tyrosine kinase (BTK),Calmodulin, calmodulin-dependent protein kinase (CaMK such as CAMKII), cancer-testis antigen 2, cancer-testis antigen NY-ESO-1, cancer / testis antigen 1B (CTAG1) gene, cannabinoid receptors (CB1, CB2, etc.), carbonic anhydrase, casein kinases (CKI, CKII, etc.), caspases (caspase-3, caspase-7, caspase-9, etc.), caspase-8 apoptosis-associated cysteine ​​peptidase CASP8-FADD-like regulator, caspase recruitment domain protein-15, cathepsin G, CCR5 gene, CDK-activating kinase (CAK), checkpoint kinases (CHK1, CHK2, etc.), chemokines (C-C motif) receptors (CCR2, CCR4, CCR5, etc.), chemokine (C-X-C motif) receptors (CXCR4, CXCR1 and CXCR2, etc.), chemokine CC21 ligand, cholecystokinin CCK2 receptor, chorionic gonadotropin, c-Kit (tyrosine protein kinase Kit or CD117), claudins (6, 18, etc.), cluster of differentiation (CD) antigens such as CD4, CD27, CD29, CD30, CD33, CD37, CD40, CD40 ligand receptor, CD40 ligand, CD40LG gene, CD44, CD45, CD47, CD49b, CD51, CD52, CD55, CD58, CD66e, CD70 gene, CD74, C, D79, CD79b, CD79B genes, CD80, CD95, CD99, CD117, CD122, CDw123, CD134, CDw137, CD158a, CD158b1, CD158b2, CD223, CD276 antigens; clusterin (CLU) gene, clusterin, c-Met (hepatocyte growth factor receptor (HGFR)), complement C3, connective tissue growth factor, COP9 signalosome subunit 5, C SF-1 (colony-stimulating factor 1 receptor), CSF2 gene, CTLA-4 (cytotoxic T-lymphocyte protein 4) receptor, cyclin D1, cyclin G1, cyclin-dependent kinases (CDKs such as CDK1, CDK1B, and CDK2-9), cyclooxygenases (1, 2, etc.), CYP2B1 gene, cysteine ​​palmitoyltransferase (porcupine), cytochrome P450 11B2, cytochrome P450 17, cytochrome P450 17A1, cytochrome P450 2D6, cytochrome P450 3A4, cytochrome P450 reductase, cytokine signaling-1, cytokine signaling-3, cytoplasmic isocitrate dehydrogenase, cytosine deaminase, cytosine DNA methyltransferase, cytotoxic T lymphocyte protein-4, DDR2 gene, delta-like protein ligands (e.g., 3, 4), deoxyribonuclease, Dickkopf-1 ligand, dihydrofolate reductase (DHFR), dihydropyrimidine dehydrogenase, dipeptidyl peptidase IV, discoidin domain receptors (DDRs) such as DDR1, DNA-binding proteins (e.g., HU-beta), DNA-dependent protein kinases Protein kinase, DNA gyrase, DNA methyltransferase, DNA polymerase (alpha, etc.), DNA primase, dUTP pyrophosphatase, L-dopachrome tautomerase, echinoderm microtubule-like protein 4, EGFR tyrosine kinase receptor, elastase, elongation factor 1 alpha 2, elongation factor 2, endoglin, endonuclease, endoplasmin, endosialin, endostatin, endothelin (ET-A, ET-B, etc.), enhancer of zeste homolog 2 (EZH2), ephrin (EPH) tyrosine kinase (Epha3, Ephb4, etc.), ephrin B2 ligand, epidermal growth factor,Epidermal growth factor receptor (EGFR), epidermal growth factor receptor (EGFR) gene, epigen, epithelial cell adhesion molecule (EpCAM), Erb-b2 (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2) tyrosine kinase receptor, Erb-b3 tyrosine kinase receptor, Erb-b4 tyrosine kinase receptor, E-selectin, estradiol 17 beta dehydrogenase, estrogen receptor (alpha, beta, etc.), estrogen-related receptor, eukaryotic translation initiation factor 5A (EIF5A) gene, exportin 1, extracellular signal-related kinases (e.g., 1 and 2), extracellular signal-regulated kinases (ERK), factors (e.g., factor Xa, factor VIIa), farnesoid x receptor (FXR), Fas ligand, fatty acid synthase (FASN), ferritin, FGF-2 ligand, FGF-5 ligand, fibroblast growth factors (FGFs such as FGF1, FGF2, and FGF4), fibronectin, Fms-related tyrosine kinase 3 (Flt3), focal adhesion kinase (FAKs such as FAK2), folate hydrolase, prostate-specific membrane antigen 1 (FOLH1), folate receptor receptors (such as alpha), folate, folate transporter 1, FYN tyrosine kinase, basic amino acid pair cleaving enzyme (furin), beta-glucuronidase, galactosyltransferase, galectin-3, ganglioside GD2, glucocorticoids, glucocorticoid-inducible TNFR-related protein GITR receptor, glutamate carboxypeptidase II, glutaminase, glutathione S-transferase P, glycogen synthase kinase (GSK such as 3-beta), glypican 3 (GPC3), gonadotropins Glycoside-releasing hormone (GNRH), granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor, granulocyte colony-stimulating factor (GCSF) ligand, growth factor receptor-bound protein 2 (GRB2), Grp78 (78kDa glucose-regulated protein) calcium-binding protein, molecular chaperone groEL2 gene, heat shock proteins (27, 70, 90 alpha, beta, etc.), heat shock protein genes, heat-stable enterotoxin receptor, hedgehog protein, heparanase, hepatocyte growth factor, HERV-H LTR-related protein 2, hexose kinase, histamine H2 receptor,Histone methyltransferase (DOT1L), His, Deacetylases (HDACs such as 1, 2, 3, 6, 10, and 11), histone H1, histone H3, HLA class I antigen (A-2 alpha), HLA class II antigen, homeobox protein NANOG, HSPB1 gene, human leukocyte antigen (HLA), human papillomavirus (E6, E7, etc.) proteins, hyaluronic acid, hyaluronidase, hypoxia inducible factor-1 alpha (HIF1α), imprinted maternally expressed transcripts (Imprinted Maternally Expressed Transcripts), and cytochrome P450 (CYP450) are also involved. Transcript) (H19) gene, mitogen-activated protein kinase 1 (MAP4K1), tyrosine-protein kinase HCK, I-kappa-B kinase (IKK, such as IKKbe), IL-1 alpha, IL-1 beta, IL-12, IL-12 gene, IL-15, IL-17, IL-2 gene, IL-2 receptor alpha subunit, IL-2, IL-3 receptor, IL-4, IL-6, IL-7, IL-8, immunoglobulin (G, G1, G2, K, M, etc.), immunoglobulin Fc receptor, immunoglobulin gamma Fc receptor (I, III, IIIA, etc.), indoleamine 2,3-dioxygenase (IDO, such as IDO1), indoleamine pyrrole 2,3-dioxygenase 1 inhibitor, insulin receptor, insulin-like growth factor (e.g., 1, 2), integrin alpha-4 / beta-1, integrin alpha-4 / beta-7, integrin alpha-5 / beta-1, integrin alpha-V / beta-3, integrin alpha-V / beta-5, integrin alpha-V / beta-6, intercellular adhesion molecule 1 (ICAM-1), interferons (e.g., alpha, alpha 2, beta, gamma), interferon-inducible protein 2 (AIM2) absent in melanoma, interferon type I receptor, interleukin-1 ligand, interleukin-13 receptor alpha 2, interleukin-2 ligand, interleukin-1 receptor-associated kinase 4 (IRAK4), interleukin-2, interleukin-29 ligand, isocitrate dehydrogenase (e.g., IDH1, IDH2), Janus kinases (JAKs such as JAK1 and JAK2), Jun N-terminal kinase, kallikrein-related peptidase 3 (KLK3) gene, killer cell Ig-like receptor, kinase insert domain receptor (KDR), kinesin-like protein KIF11, Kirsten rat sarcoma viral oncogene homolog (KRAS) gene, kisspeptin (KiSS-1) receptor, KIT gene, v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) tyrosine kinase, lactoferrin, lanosterol-14 demethylase, LDL receptor-related protein-1, leukotriene A4 hydrolase, listeriolysin, L-selectin, luteinizing hormone receptor, lyase, lymphocyte activation gene 3 protein Protein (LAG-3), lymphocyte antigen 75, lymphocyte functional antigen-3 receptor, lymphocyte-specific protein tyrosine kinase (LCK), lymphotactin, Lyn (Lck / Yes novel) tyrosine kinase, lysine demethylases (KDM1, KDM2, KDM4, KDM5, KDM6, A / B / C / D, etc.), lysophosphatidic acid-1 receptor, lysosome-associated membrane protein family (LAMP) genes, lysyl oxidase homolog 2, lysyl oxidase protein (LOX), lysyl oxidase-like protein (LOXL, such as LOXL2), hematopoietic progenitor kinase 1 (HPK1), hepatocyte growth factor receptor (MET) gene, macrophage colony Macrophage migration inhibitory factor (MCSF) ligand, MAGEC1 gene, MAGEC2 gene, major vault protein, MAPK-activated protein kinase (e.g., MK2), Mas-related G protein-coupled receptor, matrix metalloproteinases (MMPs such as MMP2 and MMP9), Mcl-1 differentiation protein, Mdm2 p53-binding protein, Mdm4 protein, melan-A (MART-1) melanoma antigen, melanocyte protein Pmel 17, melanocyte-stimulating hormone ligand, melanoma antigen family A3 (MAGEA3) gene, melanoma-associated antigens (e.g., 1, 2, 3, 6), membrane copper amine oxidase, mesothelin, MET tyrosine kinase, metabotropic glutamate receptor 1, metalloreductase STEAP1 (six-transmembrane epithelial antigen of the prostate 1), metastin, methionine aminopeptidase-2, methyltransferase, mitochondrial 3-ketoacyl-CoA thiolase, mitogen-activated protein kinase (MAPK), mitogen-activated protein kinase (MEK, such as MEK1, MEK2), mTOR (mechanistic target of rapamycin (serine / threonine kinase)), mTOR complex (e.g., 1, 2), mucins (e.g., 1, 5A, 16), mut T homologs (MTH, such as MTH1), Myc proto-oncogene protein, myeloid cell leukemia 1 (MCL1) gene, myristoylated alanine-rich protein kinase C substrate (MARCKS) protein, NAD ADP-ribosyltransferase, natriuretic peptide receptor C, neural cell adhesion molecule 1, neurokinin 1 (NK1) receptor, neurokinin receptor, neuropilin 2, NF-kappa B-activating protein, NIMA-related kinase 9 (NEK9), nitric oxide synthase, NK cell receptor, NK3 receptor, NKG2 AB-activated NK receptor, norepinephrine transporter, Notch (e.g., Notch-2 receptor, Notch-3 receptor, Notch-4 receptor), nuclear erythroid 2-related factor 2, nuclear factor (NF) kappa B, nucleolin, nucleophosmin, nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), 2-oxoglutarate dehydrogenase, 2,5-oligoadenylate synthetase, O-methylguanine DNA methyltransferase, opioid receptors (e.g., delta), ornithine decarboxylase, orotate phosphoribosyltransferase, orphan nuclear hormone receptor NR4A1, osteocalcin, osteoclast differentiation factor, osteopontin, OX-40 (tumor necrosis factor receptor superfamily member 4 TNFRSF4, or CD134) receptor, P3 protein, p38 kinase, p38MAP kinase, p53 tumor suppressor protein, parathyroid hormone ligand, peroxisome proliferator-activated receptors (PPARs, such as alpha, delta, and gamma), P-glycoprotein (e.g., 1), phosphatase and tensin homolog (PTEN), phosphatidylinositol 3-kinase (PI3K), phosphoinositide-3 kinase (PI3K, such as alpha, delta, and gamma), phosphorylase kinase (PK), PKN3 gene, placental growth factor, platelet-derived growth factor (PDGF, such as alpha and beta), platelet-derived growth factor (PDGF, such as alpha and beta), multidrug resistance transporter, plexin B1, PLK1 gene, polo-like kinase (PLK), polo-like kinase 1, poly ADP-ribose polymerase (PARP, such as PARP1, 2, and 3), antigen preferentially expressed in melanoma (PRAME) gene, prenyl-binding protein (PrPB), putative transcription factor PML, progenitor factor 1 (PMP), progenitor factor 2 (PMP), progenitor factor 3 (PMP), progenitor factor 4 (PMP), progenitor factor 5 (PMP), progenitor factor 6 (PMP), progenitor factor 7 (PMP), progenitor factor 8 (PMP), progenitor factor 9 (PMP), progenitor factor 10 (PMP), progenitor factor 11 (PMP), progenitor factor 12 (PMP), progenitor factor 13 (PMP), progenitor factor 14 (PMP), progenitor factor 15 (PMP), progenitor factor 16 (PMP), progenitor factor 17 (PMP), progenitor factor 18 (PMP), progenitor factor 19 (PMP), progenitor factor 19 (PMP), progenitor factor 19 (PMP), pro Steroid receptor, programmed cell death 1 (PD-1), programmed cell death ligand 1 inhibitor (PD-L1), prosaposin (PSAP) gene, prostanoid receptor (EP4), prostate-specific antigen, prostatic acid phosphatase, proteasome, protein E7, protein farnesyltransferase, protein kinases (PKs such as A, B, and C), protein tyrosine kinase, protein tyrosine phosphatase beta, proto-oncogene serine / threonine-protein kinases (PIMs such as PIM-1, PIM-2, and PIM-3), P-selectin, purine nucleoside phosphorylase, purinergic receptor P2X ligand-gated ion channel 7 (P2X7), pyruvate dehydrogenase (PDH), pyruvate dehydrogenase kinase, pyruvate kinase (PYK), 5-alpha-reductase, Raf protein kinases (such as 1 and B), RAF1 gene, Ras gene, RasGTPase, RET gene, Ret tyrosine kinase receptor, retinoblastoma-related protein, retinoic acid receptor (gamma, etc.), retinoid X receptor, Rheb (brain-enriched Ras homolog) GTPase, Rho (Ras homolog)-related protein kinase 2, ribonuclease, ribonucleotide reductase (M2 subunit, etc.), ribosomal protein S6 kinase, RNA polymerase (I, II, etc.), Ron (Recepteur d'Origine Nantais) tyrosine kinase, ROS1 (ROS proto-oncogene 1, receptor tyrosine kinase) gene, Ros1 tyrosine kinase, Runt-related transcription factor 3, gamma-secretase, S100 calcium-binding protein A9, sarcoplasmic reticulum calcium ATPase, second mitochondrial-derived caspase activator (SMAC) protein, secreted frizzled-associated protein-2, semaphorin -4D, serine proteases, serine / threonine kinases (STKs), serine / threonine-protein kinases (TBKs such as TBK1), signal transduction and transcription (STATs such as STAT-1, STAT-3, and STAT-5), signaling lymphocyte activation molecule (SLAM) family member 7, six-transmembrane epithelial antigen of the prostate (STEAP) gene, SL cytokine ligand, smoothened (SMO) receptor, sodium iodide symporter, sodium phosphate symporter 2B, somatostatin receptors (1, 2, 3, 4, 5, etc.), sonic hedge Hog protein, Son of Sevenless (SOS), specific protein 1 (Sp1) transcription factor, sphingomyelin synthase, sphingosine kinase (1, 2, etc.), sphingosine-1-phosphate receptor-1, spleen tyrosine kinase (SYK), SRC gene, Src tyrosine kinase, STAT3 gene, steroid sulfatase, stimulator of interferon genes (STING) receptor, stimulator of interferon genes protein, stromal cell-derived factor 1 ligand, SUMO (small ubiquitin-like modifier), superoxide dismutase, survivability bin protein, synapsin 3, syndecan-1, synuclein alpha, T cell surface glycoprotein CD28, tank-binding kinase (TBK), TATA box-binding protein-associated factor RNA polymerase I subunit B (TAF1B) gene, T cell CD3 glycoprotein zeta chain, T cell differentiation antigen CD6, T cell immunoglobulin and mucin domain-containing-3 (TIM-3), T cell surface glycoprotein CD8, Tec protein tyrosine kinase, Tek tyrosine kinase receptor, telomerase, telomerase reverse transcriptase (TERT) gene, Te Nascin, TGF beta 2 ligand, thrombopoietin receptor, thymidine kinase, thymidine phosphorylase, thymidylate synthase, thymosin (alpha 1, etc.), thyroid hormone receptor, thyrotropin receptor, tissue factor, TNF-related apoptosis-inducing ligand, TNFR1-associated death domain protein, TNF-related apoptosis-inducing ligand (TRAIL) receptor, TNFSF11 gene, TNFSF9 gene, Toll-like receptor (TLR, such as TLR1-13), topoisomerase (I, II, III, etc.), transcription factors, transferases,Transferrin, transforming growth factor (TGF, e.g., beta) kinase, transforming growth factor TGF-beta receptor kinase, transglutaminase, translocation-associated protein, transmembrane glycoprotein NMB, Trop-2 calcium signal transducer, trophoblast glycoprotein (TPBG) gene, trophoblast glycoprotein, tropomyosin receptor kinase (Trk) receptor (e.g., TrkA, TrkB, TrkC), tryptophan 5-hydroxylase, tubulin, tumor necrosis factor (TNF, e.g., alpha, beta), tumor necrosis factor 13C receptor, tumor progression locus 2 (TPL2), tumor protein 53 (TP53) gene, tumor suppressor candidate 2 (TUSC2) gene, tyrosinase, tyrosine hydroxylase, tyrosine kinase (TK), tyrosine kinase receptor, tyrosine kinase with immunoglobulin-like and EGF-like domains ubiquitin kinase (TIE) receptor, tyrosine protein kinase ABL1 inhibitor, ubiquitin, ubiquitin carboxyl hydrolase isozyme L5, ubiquitin thioesterase-14, ubiquitin conjugating enzyme E2I (UBE2I, UBC9), urease, urokinase-type plasminogen activator, uteroglobin, vanilloid VR1, vascular cell adhesion protein 1, vascular endothelial growth factor receptor (VEGFR), V-domain Ig inhibitor of T-cell activation (VISTA), VEGF-1 receptor, VEGF-2 receptor, VEGF-3 receptor, VEGF-A, VEGF-B, vimentin, vitamin D3 receptor, proto-oncogene tyrosine-protein kinase Yes, Wee-1 protein kinase, Wilms tumor antigen 1, Wilms tumor protein, X-linked inhibitor of apoptosis protein, zinc finger protein transcription factor, or any combination thereof.

[0320] Drugs can be classified according to their mechanism of action, for example, into the following groups: -Antimetabolites / anticancer drugs, such as the pyrimidine analogue floxuridine, capecitabine, cytarabine, CPX-351 (liposomal cytarabine, daunorubicin), and TAS-118; - purine analogues, folate antagonists (such as pralatrexate) and related inhibitors; - antiproliferative / antimitotic agents including natural products, such as vinca alkaloids (vinblastine, vincristine) and microtubule disrupting agents, such as taxanes (paclitaxel, docetaxel), vinblastine, nocodazole, epothilones, vinorelbine (NAVELBINE®) and epipodophyllotoxins (etoposide, teniposide); DNA damaging agents such as actinomycin, amsacrine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide (CYTOXAN®), dactinomycin, daunorubicin, doxorubicin, epirubicin, ifosphamide, melphalan, merchlorethamine, mitomycin C, mitoxantrone, nitrosoureas, procarbazine, taxol, taxotere, teniposide, etoposide, and triethylenethiophosphoramide; - DNA hypomethylating agents, such as guadecitabine (SGI-110), ASTX727; - Antibiotics, such as dactinomycin, daunorubicin, doxorubicin, idarubicin, anthracyclines, mitoxantrone, bleomycin, plicamycin (mithramycin); - Enzymes that metabolize L-asparagine systemically and eliminate cells that do not have the ability to synthesize their own asparagine, such as L-asparaginase; - antiplatelet agents; - DNAi oligonucleotides targeting Bcl-2, e.g., PNT2258; - Drugs that activate or reactivate latent human immunodeficiency virus (HIV), such as panobinostat and romidepsin; - asparaginase stimulators, such as crisantaspase (Erwinase®) and GRASPA (ERY-001, ERY-ASP), calaspargase pegol; - pan-Trk, ROS1 and ALK inhibitors, such as entrectinib, TPX-0005; - anaplastic lymphoma kinase (ALK) inhibitors, such as alectinib and ceritinib; - Antiproliferative / antimitotic alkylating agents, such as nitrogen mustard cyclophosphamide and analogues (melphalan, chlorambucil, hexamethylmelamine, thiotepa), alkylnitrosoureas (carmustine) and analogues, streptozocin and triazenes (dacarbazine); - Antiproliferative / antimitotic antimetabolites, e.g., folic acid analogues (methotrexate); - platinum coordination complexes (cisplatin, oxiloplatin and carboplatin), procarbazine, hydroxyurea, mitotane and aminoglutethimide; - Hormones, hormone analogues (estrogens, tamoxifen, goserelin, bicalutamide and nilutamide) and aromatase inhibitors (letrozole and anastrozole); - Anticoagulants, such as heparin, synthetic heparin salts, and other inhibitors of thrombin; - Thrombolytic agents, such as tissue plasminogen activator, streptokinase, urokinase, aspirin, dipyridamole, ticlopidine and clopidogrel; - antimigratory agents; - Antisecretory agents (breveldin); - immunosuppressants, such as tacrolimus, sirolimus, azathioprine and mycophenolate; - Growth factor inhibitors and vascular endothelial growth factor inhibitors; - fibroblast growth factor inhibitors, e.g. FPA14; - Anti-VEGFR antibodies, e.g., IMC-3C5, GNR-011, tanibirumab; - anti-VEGF / DDL4 antibodies, such as ABT-165; - anti-cadherin antibodies, e.g., HKT-288; - anti-CD70 antibodies, such as AMG-172; anti-leucine-rich repeat-containing 15 (LRRC15) antibodies, such as ABBV-085, ARGX-110; - Angiotensin receptor blockers, nitric oxide donors; - antisense oligonucleotides, such as AEG35156, IONIS-KRAS-2.5Rx, EZN-3042, RX-0201, IONIS-AR-2.5Rx, BP-100 (plexigenesen), IONIS-STAT3-2.5Rx; - DNA interference oligonucleotides, such as PNT2258, AZD-9150; - anti-ANG-2 antibodies, such as MEDI3617 and LY3127804; - anti-ANG-1 / ANG-2 antibodies, such as AMG-780; - anti-MET / EGFR antibodies, e.g., LY3164530; - Anti-EGFR antibodies, such as ABT-414, AMG-595, necitumumab, ABBV-221, depatuxizumab mafodotin (ABT-414), tomzotuximab, ABT-806, Vectibix, modotuximab, RM-1929; - anti-CSF1R antibodies, such as emactuzumab, LY3022855, AMG-820, FPA-008 (caviralizumab); - anti-CD40 antibodies, such as RG7876, SEA-CD40, APX-005M, ABBV-428; - Anti-endoglin antibodies, e.g. TRC105 (carotuximab); - anti-CD45 antibodies, such as 131I-BC8 (lomab-B); - anti-HER3 antibodies, such as LJM716, GSK2849330; - anti-HER2 antibodies, such as margetuximab, MEDI4276, BAT-8001; - anti-HLA-DR antibodies, such as IMMU-114; - anti-IL-3 antibodies, such as JNJ-56022473; - anti-OX40 antibodies, such as MEDI6469, MEDI6383, MEDI0562 (tabolixizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368; - anti-EphA3 antibodies, such as KB-004; - anti-CD20 antibodies, e.g., obinutuzumab, IGN-002; - anti-CD20 / CD3 antibodies, such as RG7828; - anti-CD37 antibodies, e.g., AGS67E, otlertuzumab (TRU-016); - anti-ENPP3 antibodies, e.g., AGS-16C3F; - anti-FGFR-3 antibodies, such as LY3076226, B-701; - anti-FGFR-2 antibodies, e.g., GAL-F2; - anti-C5 antibodies, such as ALXN-1210; - anti-CD27 antibodies, such as varlilumab (CDX-1127); - anti-TROP-2 antibodies, such as IMMU-132; - Anti-NKG2a antibodies, e.g., monalizumab; - anti-VISTA antibodies, e.g. HMBD-002; - Anti-PVRIG antibodies, e.g. COM-701; - anti-EpCAM antibodies, e.g. VB4-845; - anti-BCMA antibodies, e.g. GSK-2857916; - anti-CEA antibodies, e.g., RG-7813; - anti-cluster of differentiation 3 (CD3) antibodies, e.g., MGD015; - Anti-folate receptor alpha antibodies, e.g. IMGN853; - MCL-1 inhibitors, such as AMG-176, S-64315, and AZD-5991, 483-LM, A-1210477, UMI-77, JKY-5-037; - epha2 inhibitors, e.g. MM-310; - anti-LAG-3 antibodies, such as leratolimab (ONO-4482), LAG-525, MK-4280, REGN-3767; - Raf kinase / VEGFR inhibitors, e.g. RAF-265; - Polycomb protein (EED) inhibitors, such as MAK683; - anti-fibroblast activation protein (FAP) / IL-2R antibodies, such as RG7461; - anti-fibroblast activation protein (FAP) / TRAIL-R2 antibodies, such as RG7386; - anti-fucosyl-GM1 antibodies, e.g. BMS-986012; - p38 MAP kinase inhibitors, e.g., ralimetinib; - PRMT1 inhibitors, e.g. MS203; - Sphingosine kinase 2 (SK2) inhibitors, such as opaganib; - FLT3-ITD inhibitors, such as BCI-332; - Nuclear erythroid 2-related factor 2 stimulators, such as omaveloxolone (RTA-408); - Tropomyosin receptor kinase (TRK) inhibitors, such as LOXO-195, ONO-7579; - anti-ICOS antibodies, e.g. JTX-2011, GSK3359609; - anti-DR5 (TRAIL2) antibodies, such as DS-8273; - anti-GD2 antibodies, such as APN-301; - anti-interleukin-17 (IL-17) antibodies, such as CJM-112; - Anti-carbonic anhydrase IX antibodies, e.g., TX-250; - anti-CD38 attenuins, e.g., TAK573; - Anti-mucin 1 antibodies, e.g. gatipotuzumab; - Mucin 1 inhibitors, e.g. GO-203-2C; - MARCKS protein inhibitors, for example BIO-11006; - Folic acid antagonists, e.g. arfolitixoline; - Galectin-3 inhibitors, e.g. GR-MD-02; - P68 phosphorylation inhibitors, such as RX-5902; - CD95 / TNF modulators, for example ofranergen obadenovec; - PI3K / Akt / mTOR inhibitors, e.g., ABTL-0812; - pan-PIM kinase inhibitors, such as INCB-053914; - IL-12 gene stimulators, such as EGEN-001, taboquinogen terce plasmid; - Heat shock protein HSP90 inhibitors, such as TAS-116, PEN-866;- VEGF / HGF antagonists, such as MP-0250; - SYK tyrosine kinase / FLT3 tyrosine kinase inhibitors, such as TAK-659; - SYK tyrosine kinase / JAK tyrosine kinase inhibitors, such as ASN-002;- FLT3 tyrosine kinase inhibitors, such as FF-10101; - FLT3 tyrosine kinase agonists, such as CDX-301; - FLT3 / MEK1 inhibitors, such as E-6201; - IL-24 antagonists, such as AD-IL24; - RIG-I agonists, such as RGT-100; - Aerolysin stimulants, such as topsalisin; - P-glycoprotein 1 inhibitors, such as HM-30181A; - CSF-1 antagonists, such as ARRY-382, BLZ-945; - Anti-mesothelin antibodies, e.g., SEL-403; - Thymidine kinase stimulators, such as agratimagenbesadenovec; - Polo-like kinase 1 inhibitors, such as PCM-075; - TLR-7 agonists, such as TMX-101 (imiquimod); - NEDD8 inhibitors, e.g., pevonedistat (MLN-4924), TAS-446 4; - pleiotropic pathway modulators, such as avadomide (CC-122); - FoxM1 inhibitors, e.g. thiostrepton; - anti-MUC1 antibodies, such as Mab-AR-20.5; - anti-CD38 antibodies, e.g., isatuximab, MOR-202; - UBA1 inhibitors, such as TAK-243; - Src tyrosine kinase inhibitors, such as VAL-201; - VDAC / HK inhibitors, e.g. VDA-1102; - BRAF / PI3K inhibitors, e.g., ASN-003; - Elf4a inhibitors, e.g., rohitinib, eFT226; - TP53 gene stimulators, e.g. ad-p53; - PD-L1 / EGFR inhibitors, such as GNS-1480; - retinoic acid receptor alpha (RARα) inhibitors, such as SY-1425; - SIRT3 inhibitors, e.g. YC8-02; - stromal cell-derived factor 1 ligand inhibitors, such as olaptesed pegol (NOX-A12); - IL-4 receptor modulators, such as MDNA-55; - Arginase-I stimulators, e.g., pegdilarginase; - Topoisomerase I inhibitors / hypoxia inducible factor-1 alpha inhibitors, e.g. PEG-SN38 (filtecampegol); - Hypoxia-inducible factor-1 alpha inhibitors, such as PT-2977, PT-2385; - CD122 agonists, such as NKTR-214; - p53 tumor suppressor protein stimulators, such as kebetrin; - Mdm4 / Mdm2 p53-binding protein inhibitors, such as ALRN-6924; - Kinesin spindle protein (KSP) inhibitors, such as filanesib (ARRY-520); - CD80-fc fusion protein inhibitors, such as FPT-155; - Menin and mixed lineage leukemia (MLL) inhibitors, such as KO-539; - liver x receptor agonists, e.g. RGX-104; - IL-10 agonists, such as AM-0010; - EGFR / ErbB-2 inhibitors, e.g., varlitinib; - VEGFR / PDGFR inhibitors, e.g., borolanib; - IRAK4 inhibitors, such as CA-4948; - anti-TLR-2 antibodies, such as OPN-305; - calmodulin modulators, such as CBP-501; - Glucocorticoid receptor antagonists, such as relacorilant (CORT-125134); - a second mitochondrial-derived caspase activator (SMAC) protein inhibitor, such as BI-891065; - lactoferrin modulators, such as LTX-315; - Kit tyrosine kinase / PDGF receptor alpha antagonists, e.g. DCC-2618; - KIT inhibitors, such as PLX-9486; - Exportin 1 inhibitors, e.g. ertanexor; - EGFR / ErbB2 / Ephb4 inhibitors, e.g. tesevatinib; - anti-CD33 antibodies, e.g., IMGN-779; - anti-KMA antibodies, e.g., MDX-1097; - anti-TIM-3 antibodies, such as TSR-022, LY-3321367, MBG-453; - anti-CD55 antibodies, e.g. PAT-SC1; - Anti-PSMA antibodies, e.g., ATL-101; - anti-CD100 antibodies, e.g. VX-15; - anti-EPHA3 antibodies, e.g., fivatuzumab; - anti-Erbb antibodies, e.g. CDX-3379, HLX-02, seribantumab; - anti-APRIL antibodies, e.g., BION-1301; - anti-Tigit antibodies, e.g. BMS-986207, RG-6058; - CHST15 gene inhibitors, such as STNM-01; - RAS inhibitors, e.g. NEO-100; - somatostatin receptor antagonists, such as OPS-201; - CEBPA gene stimulators, such as MTL-501; - DKK3 gene modulators, such as MTG-201; - p70s6k inhibitors, for example MSC2363318A; - methionine aminopeptidase 2 (MetAP2) inhibitors, such as M8891, APL-1202; - arginine N-methyltransferase 5 inhibitors, such as GSK-3326595; - anti-programmed cell death protein 1 (anti-PD-1) antibodies, such as nivolumab (OPDIVO®, BMS-936558, MDX-1106), pembrolizumab (KEYTRUDA®, MK-3477, SCH-900475, lambrolizumab, CAS Registry Number 1374853-91-4), pidilizumab, PF-06801591, BGB-A317, GLS-010 (WBP-3055), AK-103 (HX-008), MGA-012, BI-754091, REGN-2810 (cemiplimab), AGEN-2034, JS-001, JNJ-63723283, genolimuzumab (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, BAT-1306 and anti-programmed death-ligand 1 (anti-PD-L1) antibodies, such as BMS-936559, atezolizumab (MPDL3280A), durvalumab (MEDI4736), avelumab, CK-301, (MSB0010718C), MEDI0680, CX-072, CBT-502, PDR-001 (spartalizumab), TSR-042 (dostallimab), JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155, KN-035, IBI-308, FAZ-053 and MDX1105-01; - PD-L1 / VISTA antagonists, such as CA-170; - anti-PD-L1 / TGFβ antibodies, e.g., M7824; - anti-transferrin antibodies, e.g., CX-2029; - anti-IL-8 (interleukin-8) antibodies, such as HuMax-Inflam; - ATM (ataxia telangiectasia) inhibitors, such as AZD0156; - CHK1 inhibitors, such as GDC-0575, LY2606368 (prexasertib), SRA737, RG7741 (CHK1 / 2); - CXCR4 antagonists, such as BL-8040, LY2510924, blixafol (TG-0054), X4P-002, X4P-001-IO; - EXH2 inhibitors, e.g. GSK2816126; - HER2 inhibitors, e.g. neratinib, tucatinib (ONT-380); - KDM1 inhibitors, such as ORY-1001, IMG-7289, INCB-59872, GSK-2879552; - CXCR2 antagonists, such as AZD-5069; - GM-CSF antibodies, e.g. lenzilumab; - DNA-dependent protein kinase inhibitors, such as MSC2490484A (nezisertib), VX-984, AsiDNA (DT-01); - Protein kinase C (PKC) inhibitors, e.g., LXS-196, sotrastaurin ; - selective estrogen receptor downregulators (SERDs), such as fulvestrant (Faslodex®), RG6046, RG6047, elacestrant (RAD-1901) and AZD9496; - selective estrogen receptor covalent antagonists (SERCA), such as H3B-6545; - selective androgen receptor modulators (SARMs), such as GTX-024, darolutamide; - Transforming growth factor-beta (TGF-beta) kinase antagonists, such as galunisertib; - anti-transforming growth factor-beta (TGF-beta) antibodies, such as LY3022859, NIS793, XOMA 089; - bispecific antibodies, such as MM-141 (IGF-1 / ErbB3), MM-111 (Erb2 / Erb3), JNJ-64052781 (CD19 / CD3), PRS-343 (CD-137 / HER2), AFM26 (BCMA / CD16A), JNJ-61186372 (EGFR / cMET), AMG-211 (CEA / CD3), RG7802 (CEA / CD3), ERY-974 (CD3 / GPC3), vancizumab (angiopoietin / VEGF), PF-06671008 (cadherin / CD3), AFM-13 (CD16 / CD30), APVO436 (CD123 / CD3), and flotetuzumab (CD123 / CD3), REGN-1979(CD20 / CD3), MCLA-117(CD3 / CLEC12A), MCLA-128(HER2 / HER3), JNJ-0819, JNJ-7564(CD3 / heme), AMG-757(DLL3-CD3), MGD-013(PD-1 / LAG-3), AK-104 (CTLA-4 / PD-1), AMG-330 (CD33 / CD3), AMG-420 (BCMA / CD3), BI-836880 (VEF G / ANG2), JNJ-63709178(CD123 / CD3), MGD-007(CD3 / gpA33), MGD-009(CD3 / B7H3); - Mutation-selective EGFR inhibitors, such as PF-06747775, EGF816 (nazartinib), ASP8273, ACEA-0010, BI-1482694; - anti-GITR (glucocorticoid-induced tumor necrosis factor receptor-related protein) antibodies, such as MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323; - anti-delta-like protein ligand 3 (DDL3) antibody, rovalpituzumab tesirine; - anti-clusterin antibodies, e.g., AB-16B5; - anti-ephrin-A4 (EFNA4) antibodies, such as PF-06647263; - Anti-RANKL antibodies, e.g., denosumab; - anti-mesothelin antibodies, e.g., BMS-986148, anti-MSLN-MMAE; - Anti-sodium phosphate cotransporter 2B (NaP2B) antibodies, e.g., rifastuzumab; - anti-c-Met antibodies, e.g., ABBV-399; - adenosine A2A receptor antagonists, such as CPI-444, AZD-4635, preladenant, PBF-509; - alpha-ketoglutarate dehydrogenase (KGDH) inhibitors, such as CPI-613; - XPO1 inhibitors, such as selinexor (KPT-330); - isocitrate dehydrogenase 2 (IDH2) inhibitors, such as enasidenib (AG-221); - IDH1 inhibitors, such as AG-120 and AG-881 (IDH1 and IDH2), IDH-305, BAY-1436032; - interleukin-3 receptor (IL-3R) modulators, such as SL-401;- arginine deiminase stimulators, such as PEG-arginase (ADI-PEG-20); - antibody-drug conjugates, such as MLN0264 (anti-GCC, guanylyl cyclase C), T-DM1 (trastuzumab emtansine, Kadcycla), milatuzumab-doxorubicin (hCD74-DOX), brentuximab vedotin, DCDT2980S, polatuzumab vedotin, SGN-CD70A, SGN-CD19A, inotuzumab ozogamicin, lorvotuzumab mertansine, SAR3419, isactuzumab govitecan govitecan), enfortumab vedotin (ASG-22ME), ASG-15ME, DS-8201 (trastuzumab deruxtecan), 225Ac-lintuzumab, U3-1402, 177Lu-tetraxetan-tetuloma, tisotumab vedotin, anetuzumab ravtansine, CX-2009, SAR-566658, W-0101, polatuzumab vedotin, ABBV-085; - Claudin-18 inhibitors, e.g. claudiximab; - β-catenin inhibitors, e.g. CWP-291; - anti-CD73 antibodies, such as MEDI-9447 (oleculab), CPX-006, IPH-53, BMS-986179; - CD73 antagonists, such as AB-680, PSB-12379, PSB-12441, PSB-12425; - CD39 / CD73 antagonists, such as PBF-1662; - Chemokine receptor 2 (CCR) inhibitors, such as PF-04136309, CCX-872, BMS-813160 (CCR2 / CCR5); - thymidylate synthase inhibitors, such as ONX-0801; - ALK / ROS1 inhibitors, e.g. lorlatinib; - Tankyrase inhibitors, e.g. G007-LK; - Mdm2 p53 binding protein inhibitors, such as CMG-097, HDM-201; - c-PIM inhibitors, such as PIM447; - BRAF inhibitors, such as dabrafenib, vemurafenib, encorafenib (LGX818), PLX8394; - sphingosine kinase-2 (SK2) inhibitors, such as Yeliva® (ABC294640); - Cell cycle inhibitors, such as selumetinib (MEK1 / 2) and sapacitabine; - AKT inhibitors, such as MK-2206, ipatasertib, afuresertib, AZD5363, and ARQ-092, capivasertib, triciribine; - anti-CTLA-4 (cytotoxic T-lymphocyte protein-4) inhibitors, such as tremelimumab, AGEN-1884, BMS-986218; - c-MET inhibitors, such as AMG-337, savolitinib, tivantinib (ARQ-197), capmatinib and tepotinib, ABT-700, AG213, AMG-208, JNJ-38877618 (OMO-1), merestinib, HQP-8361; - c-Met / VEGFR inhibitors, e.g., BMS-817378, TAS-115; - c-MeT / RON inhibitors, e.g. BMS-777607; - BRAF / EGFR inhibitors, e.g. BGB-283; - bcr / abl inhibitors, such as rebastinib and asciminib; - MNK1 / MNK2 inhibitors, e.g. eFT-508; - mTOR inhibitors / cytochrome P450 3A4 stimulators, e.g. TYME-88; - lysine-specific demethylase-1 (LSD1) inhibitors, such as CC-90011; - pan-RAF inhibitors, such as LY3009120, LXH254, TAK-580; - Raf / MEK inhibitors, e.g. RG7304; - CSF1R / KIT and FLT3 inhibitors, such as pexidartinib (PLX3397); - Kinase inhibitors, e.g. vandetanib; - E-selectin antagonists, such as GMI-1271; - Differentiation inducers, such as tretinoin; - Epidermal growth factor receptor (EGFR) inhibitors, such as osimertinib (AZD-9291); - topoisomerase inhibitors, such as doxorubicin, daunorubicin, dactinomycin, eniposide, epirubicin, etoposide, idarubicin, irinotecan, mitoxantrone, pixantrone, sobuzoxane, topotecan, irinotecan, MM-398 (liposomal irinotecan), vosaroxin and GPX-150, aldoxorubicin, AR-67, mavereltinib, AST-2818, avitinib (ACEA-0010), irofulven (MGI-114); - Corticosteroids, such as cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisone, prednisolone; - Growth factor signaling kinase inhibitors; - nucleoside analogues, e.g. DFP-10917; - Axl inhibitors, e.g., BGB-324 (bemcentinib), SLC-0211; - BET inhibitors, such as INCB-054329, INCB057643, TEN-010, AZD-5153, ABT-767, BMS-986158, CC-90010, GSK525762 (molybreceptor), NHWD-870, ODM-207, GSK-2820151, GSK-1210151A, ZBC246, ZBC260, ZEN3694, FT-1101, RG-6146, CC-90010, mibebrexit, BI-894999, PLX-2853, PLX-51107, CPI-0610, GS-5829; - PARP inhibitors, such as olaparib, rucaparib, veliparib, talazoparib, ABT-767, BGB-290; - proteasome inhibitors, such as ixazomib, carfilzomib (Kyprolis®), marizomib; - glutaminase inhibitors, e.g. CB-839; - vaccines, such as peptide vaccines TG-01 (RAS), GALE-301, GALE-302, neripepimto-s, SurVaxM, DSP-7888, TPIV-200, PVX-410, VXL-100, DPX-E7, ISA-101, 6MHP, OSE-2101, galinpepimto-S, SVN53-67 / M57-KLH, IMU-131; bacterial vector vaccines, such as CRS- 207 / GVAX, axalimogene filorisvac (ADXS11-001); adenovirus vector vaccines, e.g., nadofalagene filadenovec; autologous Gp96 vaccines; dendritic cell vaccines, e.g., CVactm, staprudencel-T, eltraprudencel-T, SL-701, BSK01™, rocaprudencel-T (AGS-003), DCVAC, CVac™, staprudencel-T, eltraprudencel-T, SL-701, BSK01™, ADXS31-142; oncolytic vaccines, e.g., talimogene laherparepvec, pexastimogene devasilepvec, GL-ONC1, MG1-MA3, parvovirus H-1, ProstAtak, enadenotsileb, MG1MA3, ASN-002 (TG-1042); therapeutic vaccines, e.g., CVAC-301, CMP-001, PF-06753512, VBI-1901, TG-4010, ProscaVax™; tumor cell vaccines, e.g., Vigil® (IND-14205), Oncoquest-L vaccine; live attenuated, recombinant, serotype 1 poliovirus vaccines, e.g., PVS-RIPO; adagloxadrimorenin; MEDI-0457; DPV-001 tumor-derived, autophagosome-enriched cancer vaccine; RNA vaccines, e.g., CV-9209, LV-305; DNA vaccines, e.g., MEDI-0457, MVI-816, INO-5401; modified vaccinia virus Ankara vaccines expressing p53, e.g., MVA-p53; DPX-Survivac; BriaVax™; GI-6301; GI-6207; GI-4000; - anti-DLL4 (delta-like ligand 4) antibodies, such as demcizumab; - STAT-3 inhibitors, such as napabucasin (BBI-608); - ATPase p97 inhibitors, such as CB-5083; - Smoothened (SMO) receptor inhibitors, such as Odomzo® (sonidegib, formerly LDE-225), LEQ506, vismodegib (GDC-0449), BMS-833923, glasdegib (PF-04449913), LY2940680 and itraconazole; - interferon alpha ligand modulators, such as interferon alpha-2b, interferon alpha-2a biosimilars (Biogenomics), ropeginterferon alpha-2b (AOP-2014, P-1101, PEG IFN alpha-2b), Multiferon (Alfanative, Viragen), interferon alpha 1b, Roferon-A (Canferon, Ro-25-3036), interferon alpha-2a follow-on biologic (Biosidus) (Inmutag, Inter 2A), interferon alpha-2b follow-on biologic (Biosidus-Bioferon, Citopheron, Ganapar, Beijing Kawin) Technology-Kaferon), Alfaferone, pegylated interferon alfa-1b, pegylated interferon alfa-2b post-development formulation (Amega), recombinant human interferon alfa-1b, recombinant human interferon alfa-2a, recombinant human interferon alfa-2b, veltuzumab-IFN alfa 2b conjugate, Dynavax (SD-101) and interferon alfa-n1 (Humoferon, SM-10500, Sumiferon); - interferon gamma ligand modulators, such as interferon gamma (OH-6000, Ogamma100); - IL-6 receptor modulators, such as tocilizumab, siltuximab, AS-101 (CB-06-02, IVX-Q-101); - telomerase modulators, such as tertomotide (GV-1001, HR-2802, Riavax) and imetelstat (GRN-163, JNJ-63935937); - DNA methyltransferase inhibitors, such as temozolomide (CCRG-81045), decitabine, guadecitabine (S-110, SGI-110), KRX-0402, RX-3117, RRx-001 and azacitidine; - DNA gyrase inhibitors, such as pixantrone and sobuzoxane; - Bcl-2 family protein inhibitors, such as ABT-263, venetoclax (ABT-199), ABT-737 and AT-101; - Notch inhibitors, such as LY3039478 (crenigacestat), tarextumab (anti-Notch2 / 3), BMS-906024; - anti-myostatin inhibitors, such as landogrozumab; - hyaluronidase stimulators, such as PEGPH-20; - Wnt pathway inhibitors, such as SM-04755, PRI-724, WNT-974; - gamma-secretase inhibitors, such as PF-03084014, MK-0752, RO-4929097; - Grb-2 (growth factor receptor-binding protein-2) inhibitors, such as BP1001; - TRAIL pathway-inducing compounds, such as ONC201, ABBV-621; - focal adhesion kinase inhibitors, such as VS-4718, defactinib, GSK2256098; - hedgehog inhibitors, such as saridegib, sonidegib (LDE225), glasdegib and vismodegib; - Aurora kinase inhibitors, such as alisertib (MLN-8237), and AZD-2811, AMG-900, barasertib, ENMD-2076; - HSPB1 modulators (heat shock protein 27, HSP27), such as brivudin, apatrusen; - ATR inhibitors, such as BAY-937, AZD6738, AZD6783, VX-803, VX-970 (berzosertib) and VX-970; - mTOR inhibitors, such as sapanisertib and bistusertib (AZD2014), ME-344; - mTOR / PI3K inhibitors, e.g., gedatolisib, GSK2141795, omipalisib, RG6114; - Hsp90 inhibitors, such as AUY922, onarespib (AT13387), SNX-2112, SNX5422; - Mouse double minute chromosome (mdm2) oncogene inhibitors, such as DS-3032b, RG7775, AMG-232, HDM201 and idasanutlin (RG7388); - CD137 agonists, e.g., urelumab, utomilumab (PF-05082566); - STING agonists, such as ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291; - FGFR inhibitors, such as FGF-401, INCB-054828, BAY-1163877, AZD4547, JNJ-42756493, LY2874455, Debio-1347; - fatty acid synthase (FASN) inhibitors, such as TVB-2640; - anti-KIR monoclonal antibodies, such as lirilumab (IPH-2102), IPH-4102; - antigen CD19 inhibitors, such as MOR208, MEDI-551, AFM-11, inebilizumab; - CD44 binders, such as A6; - protein phosphatase 2A (PP2A) inhibitors, such as LB-100; - CYP17 inhibitors, such as seviteronel (VT-464), ASN-001, ODM-204, CFG920, abiraterone acetate; - RXR agonists, such as IRX4204; - Hedgehog / Smoothened (hh / Smo) antagonists, such as taladegib, pachdegib; - Complement C3 modulators, such as Imprime PGG; - IL-15 agonists, such as ALT-803, NKTR-255 and hetIL-15; - EZH2 (enhancer of zeste homolog 2) inhibitors, such as tazemetostat, CPI-1205, GSK-2816126; - Oncolytic viruses, such as Peraleorep, CG-0070, MV-NIS therapy, HSV-1716, DS-1647, VCN-01, ONCOS-102, TBI-1401, Tasadenotulev (DNX-2401), Bossimazine amireterorepvec, RP-1, CVA21, Celyvir, LOAd-703, OBP-301; - DOT1L (histone methyltransferase) inhibitors, such as pinometostat (EPZ-5676); - toxins, such as cholera toxin, ricin, Pseudomonas exotoxin, Bordetella pertussis adenylate cyclase toxin, diphtheria toxin and caspase activators; - DNA plasmids, e.g. BC-819; - PLK inhibitors of PLK1, 2 and 3, e.g. volasertib (PLK1); - WEE1 inhibitors, such as AZD1775 (adavosertib); - Rho kinase (ROCK) inhibitors, such as AT13148, KD025; - ERK inhibitors, such as GDC-0994, LY3214996, MK-8353; - IAP inhibitors, e.g., ASTX660, Debio-1143, Birinapant, APG- 1387, LCL-161; - RNA polymerase inhibitors, such as lurbinectedin (PM-1183), CX-5461; - tubulin inhibitors, such as PM-184, BAL-101553 (risabambambulin), and OXI-4503, fluolapacin (AC-0001), plinabulin; - toll-like receptor 4 (TL4) agonists, such as G100, GSK1795091 and PEPA-10; - elongation factor 1 alpha 2 inhibitors, such as plitidepsin; - CD95 inhibitors, such as APG-101, APO-010, asnercept; - WT1 inhibitors, such as DSP-7888; - splicing factor 3B subunit 1 (SF3B1) inhibitors, such as H3B-8800; - PDGFR alpha / KIT mutation-specific inhibitors, e.g., BLU-285; - SHP-2 inhibitors, such as TNO155 (SHP-099), RMC-4550; and - retinoid Z receptor gamma (RORγ) agonists, such as LYC-55716;

[0321] In some embodiments, a method of treating or preventing a hyperproliferative disease or cancer in a human or animal having or at risk of having the hyperproliferative disease or cancer comprises administering a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to a human or animal having or at risk of having the hyperproliferative disease or cancer, in combination with a therapeutically effective amount of one or more (e.g., 1, 2, 3, 1 or 2, or 1 to 3) apoptosis signal-regulating kinase (ASK) inhibitors; Bruton's tyrosine kinase (BTK) inhibitors; cluster of differentiation 47 (CD47) inhibitors; cyclin-dependent kinase (CDK) inhibitors; discoidin domain receptor (DDR) inhibitors; histone deacetylase (HDAC) inhibitors; indoleamine-pyrrole- Provided herein are methods comprising administering to a human or animal in combination with an additional therapeutic agent or a pharmaceutically acceptable salt thereof selected from the group consisting of a 2,3-dioxygenase (IDO1) inhibitor; a Janus kinase (JAK) inhibitor; a lysyl oxidase-like protein (LOXL) inhibitor; a matrix metalloproteinase (MMP) inhibitor; a mitogen-activated protein kinase (MEK) inhibitor; a phosphatidylinositol 3-kinase (PI3K) inhibitor; a spleen tyrosine kinase (SYK) inhibitor; a toll-like receptor 8 (TLR8) inhibitor; a toll-like receptor 9 (TLR9) inhibitor; a tyrosine kinase inhibitor (TKI), and any combination thereof. Non-limiting examples include: - Apoptosis signal-regulating kinase (ASK) inhibitors: ASK inhibitors include ASK1 inhibitors. Examples of ASK1 inhibitors include, but are not limited to, those described in WO 2011 / 008709 (Gilead Sciences) and WO 2013 / 112741 (Gilead Sciences); - Bruton's tyrosine kinase (BTK) inhibitors: examples of BTK inhibitors include, but are not limited to, (S)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one, acalabrutinib (ACP-196), BGB-3111, CB988, HM71224, ibrutinib, M-2951 (evobrutinib), M7583, tirabrutinib (ONO-4059), PRN-1008, spebrutinib (CC-292), TAK-020, becabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, TAS-5315; Cluster of differentiation 47 (CD47) inhibitors: Examples of CD47 inhibitors include anti-CD47 mAb (Vx-1004), anti-human CD47 mAb (CNTO-7108), CC-90002, CC-90002-ST-001, humanized anti-CD47 antibody (Hu5F9-G4), NI-1701, NI-1801, RCT-1938, and TTI-621. Including, but not limited to; - cyclin-dependent kinase (CDK) inhibitors: CDK inhibitors include inhibitors of CDK1, 2, 3, 4, 6, 7 and 9, such as abemaciclib, alvocidib (HMR-1275, flavopiridol), AT-7519, dinaciclib, ibrance, FLX-925, LEE001, palbociclib, ribociclib, rigosertib, selinexor, UCN-01, SY1365, CT-7001, SY-1365, G1T38, mirciclib, trilaciclib and TG-02; Discoidin Domain Receptor (DDR) Inhibitors: DDR inhibitors include inhibitors of DDR1 and / or DDR2. Examples of DDR inhibitors include, but are not limited to, those disclosed in WO2014 / 047624 (Gilead Sciences), US Patent Application Publication No. 2009-0142345 (Takeda Pharmaceutical), US Patent Application Publication No. 2011-0287011 (Oncomed Pharmaceuticals), WO2013 / 027802 (Chugai Pharmaceutical), and WO2013 / 034933 (Imperial Innovations); Histone deacetylase (HDAC) inhibitors: Examples of HDAC inhibitors include, but are not limited to, abexinostat, ACY-241, AR-42, BEBT-908, belinostat, CKD-581, CS-055 (HBI-8000), CUDC-907 (fimepinostat), entinostat, gibinostat, mocetinostat, panobinostat, pracinostat, xinostat (JNJ-26481585), resminostat, licorinostat, SHP-141, valproic acid (VAL-001), vorinostat, tinostamustine, remetinostat, entinostat; - Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors: examples of IDO1 inhibitors include, but are not limited to, BLV-0801, epacadostat, F-001287, GBV-1012, GBV-1028, GDC-0919, indoximod, NKTR-218, NLG-919-based vaccines, PF-06840003, pyranonaphthoquinone derivatives (SN-35837), resminostat, SBLK-200802, BMS-986205 and shIDO-ST, EOS-200271, KHK-2455, LY-3381916; - Janus kinase (JAK) inhibitors: JAK inhibitors inhibit JAK1, JAK2 and / or JAK3. Examples of JAK inhibitors include, but are not limited to, AT9283, AZD1480, baricitinib, BMS-911543, fedratinib, filgotinib (GLPG0634), gandotinib (LY2784544), INCB039110 (itacitinib), lestaurtinib, momelotinib (CYT0387), NS-018, pacritinib (SB1518), peficitinib (ASP015K), ruxolitinib, tofacitinib (formerly tasocitinib), INCB052793, and XL019; Lysyl oxidase-like protein (LOXL) inhibitors: LOXL inhibitors include inhibitors of LOXL1, LOXL2, LOXL3, LOXL4, and / or LOXL5. Examples of LOXL inhibitors include, but are not limited to, the antibodies described in WO2009 / 017833 (Arresto Biosciences). Examples of LOXL2 inhibitors include, but are not limited to, the antibodies described in WO2009 / 017833 (Arresto Biosciences), WO2009 / 035791 (Arresto Biosciences), and WO2011 / 097513 (Gilead Biologics); - Matrix metalloproteinase (MMP) inhibitors: MMP inhibitors include inhibitors of MMP1 to 10. Examples of MMP9 inhibitors include marimastat (BB-2516), cipemastat (Ro32-3555), GS-5745 (andecaliximab) and WO2012 / 027721 (Gilead Biosciences). These include, but are not limited to, those described in the FDA (FDA-approved ... - Mitogen-activated protein kinase (MEK) inhibitors: MEK inhibitors include antroquinonol, binimetinib, cobimetinib (GDC-0973, XL-518), MT-144, selumetinib (AZD6244), sorafenib, trametinib (GSK1120212), uprosertib plus trametinib, PD-0325901, pimasertib, LTT462, AS703988, CC-90003, and refametinib; - Phosphatidylinositol 3-kinase (PI3K) inhibitors: PI3K inhibitors include inhibitors of PI3Kγ, PI3Kδ, PI3Kβ, PI3Kα and / or pan-PI3K. Examples of PI3K inhibitors include ACP-319, AEZA-129, AMG-319, AS252424, AZD8186, BAY10824391, BEZ235, buparlisib (BKM120), BYL719 (alpelisib), CH5132799, copanlisib (BAY80-6946), duvelisib, GDC-0032, GDC-0077, GDC-0941, GDC-0980, GSK2636771, GSK2269557, idelalisib (Zydelig®), INCB50465, IPI-145, and IPI-443. , IPI-549, KAR4141, LY294002, LY3023414, MLN1117, OXY111A, PA799, PX-866, RG7604, rigosertib, RP5090, RP6530, SRX3177, taselisib, TG100115, TGR-1202 (umbralisib), TGX221, WX-037, X-339, X-414, XL147 (SAR245408), XL499, XL756, wortmannin, ZSTK474, and WO2005 / 113556 (ICOS), WO2013 / 052699 (Gilead Calistoga), WO2013 / 116562 (Gilead Calistoga), WO2014 / 100765 (Gilead Calistoga), WO2014 / 100767 (Gilead Calistoga) and WO2014 / 201409 (Gilead Sciences); - spleen tyrosine kinase (SYK) inhibitors: examples of SYK inhibitors include, but are not limited to, 6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine, BAY-61-3606, cerdulatinib (PRT-062607), entospletinib, fostamatinib (R788), HMPL-523, NVP-QAB205AA, R112, R343, tamatinib (R406) and those described in U.S. Pat. No. 8,450,321 (Gilead Connecticut) and U.S. Patent Application Publication No. 2015 / 0175616; - Toll-like receptor 8 (TLR8) inhibitors: examples of TLR8 inhibitors include, but are not limited to, E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, resiquimod, VTX-1463 and VTX-763; - toll-like receptor 9 (TLR9) inhibitors: examples of TLR9 inhibitors include, but are not limited to, AST-008, IMO-2055, IMO-2125, lefitolimod, ritenimod, MGN-1601, and PUL-042; and - Tyrosine-kinase inhibitors (TKIs): TKIs can target the epidermal growth factor receptor (EGFR) and receptors for fibroblast growth factor (FGF), platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). Examples of TKIs include afatinib, ARQ-087 (derazantinib), asp5878, AZD3759, AZD4547, bosutinib, brigatinib, cabozantinib, cediranib, crenolanib, dacomitinib, dasatinib, dovitinib, E-6201, erdafitinib, erlotinib, gefitinib, gilteritinib (ASP-2215), FP-1039, HM61713, icotinib, imatinib, KX2-391 (Src), lapatinib, lestaurtinib, lenvatinib, midostaurin, nintedanib, ODM-203, osimertinib (AZD-929 1), ponatinib, poziotinib, quizartinib, radotinib, rociletinib, surufatinib (HMPL-012), sunitinib, tivoanib, and TH-4000, MEDI-575 (anti-PDGFR antibodies).

[0322] As used herein, "chemotherapeutic agent" or "chemotherapeutic" (or in the case of treatment with a chemotherapeutic agent, "chemotherapy") is intended to encompass any non-proteinaceous (i.e., non-peptidic) chemical compound useful in the treatment of cancer. Examples of chemotherapeutic agents include alkylating agents, such as thiotepa and cyclophosphamide (CYTOXAN®); alkyl sulfonates, such as busulfan, improsulfan, and piposulfan; aziridines, such as benzodepa, carboquone, meturedepa, and uredepa; ethylenimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimemylolomelamine; acetogenins, particularly bullatacin and bullatacinone; camptothecin, including the synthetic analog topotecan; bryostatin, kallistatin; and CC-antigens, including their synthetic analogs adozelesin, carzelesin, and biceresin. 1065; cryptophycins, especially cryptophycin 1 and cryptophycin 8; dolastatins; duocarmycins, including synthetic analogs KW-2189 and CBI-TMI; eleutherobin; 5-azacytidine; pancratistatin; sarcodictyin; spongistatins; nitrogen mustards, such as chlorambucil, chlornaphazine, cyclophosphamide, glufosfamide, evofosfamide, bendamustine, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobembine, fenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosoureas, such as carmustine, chlorozotocin, foremustine, lomustine, nimustine, and ranimustine;Antibiotics, such as enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gamma II and calicheamicin phiIl), dynemicins, including dynemicin A, bisphosphonates, such as clodronate, esperamicin, neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromomophores, aclacinomycin, actinomycin, ausramycin, azaserine, bleomycin, kalamycin, Cactinomycin, carabicin, carminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, e.g. anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as demopterin, methotrexate, pteropterin, and trimetrexate; purine analogs pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine and floxuridine; androgens such as calusterone, dromostanolone propionate, epithiostanol, mepitiostane and testolactone; anti-adrenal agents such as aminoglute; thymide, mitotane, and trilostane; folic acid replinishers, such as folinic acid; radiotherapeutic agents, such as radium-223; trichothecenes, especially T-2 toxin, veraculin A, roridin A, and anguidine; taxoids, such as paclitaxel (TAXOL®), Abraxane, docetaxel (TAXOTERE®), cabazitaxel, BIND-014, tesetaxel; platinum analogs, such as cisplatin and carboplatin, NC-6004 nanoplatin; aceglatone; aldophosphamide glycosides; aminolevulinic acid; carboxylic acid; eniluracil; amsacrine; hestravcil; bisantrene; edatraxate; defofamine; demecolcine; diaziconazole; elformthine; elliptinium acetate; epothilone; etoglucide; gallium nitrate; hydroxyurea; lentinan; leucovorin; lonidamine; maytansinoids, such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; fenamet; pirarubicin; rosoxantro Fluoropyrimidine; Folinic acid; Podophyllic acid; 2-Ethylhydrazide; Procarbazine; Polysaccharide-K (PSK); Razoxane; Rhizoxin; Sizofiran; Spirogermanium; Tenuazonic acid; Trabectedin, Triaziquone; 2,2',2"-Trichlorotriemylamine; Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitolactol; Pipobroman; Gacytosine; Arabinoside ("Ara-C"); Cyclophosphatase amide; thiotepa; chlorambucil; gemcitabine (GEMZAR®); 6-thioguanine; mercaptopurine; methotrexate; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vancristine; vinorelbine (NAVELBINE®); novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeoloda; ibandronate; CPT-11;These include, but are not limited to, the topoisomerase inhibitor RFS2000; difluoromethylornithine (DFMO); retinoids, such as retinoic acid; capecitabine; NUC-1031; FOLFIRI (fluorouracil, leucovorin, and irinotecan); and pharmaceutically acceptable salts, acids, or derivatives of any of the above.

[0323] Also included within the definition of "chemotherapeutic agent" are antihormonal agents, such as antiestrogens and selective estrogen receptor modulators (SERMs), inhibitors of the enzyme aromatase, antiandrogens, and pharmaceutically acceptable salts, acids, or derivatives of any of the above that regulate or inhibit hormone action on tumors.

[0324] Antihormonal drugs Examples of antiestrogens and SERMs include, for example, tamoxifen (including NOLVADEX™), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (FARESTON®).

[0325] Inhibitors of the enzyme aromatase regulate estrogen production in the adrenal glands. Examples include 4(5)-imidazole, aminoglutethimide, megestrol acetate (MEGACE®), exemestane, formestane, fadrozole, vorozole (RIVISOR®), letrozole (FEMARA®), and anastrozole (ARIMIDEX®).

[0326] Examples of antiandrogens include apalutamide, abiraterone, enzalutamide, flutamide, galeterone, nilutamide, bicalutamide, leuprolide, goserelin, ODM-201, APC-100, and ODM-204.

[0327] An example of a progesterone receptor antagonist is onapristone.

[0328] Antiangiogenic agents Antiangiogenic agents include retinoid acid and its derivatives, 2-methoxyestradiol, ANGIOSTATIN®, ENDOSTATIN®, regorafenib, necuranib, suramin, squalamine, tissue inhibitor of metalloproteinase-1, tissue inhibitor of metalloproteinase-2, plasminogen activator inhibitor-1, plasminogen activator inhibitor (inhibitor)-2, cartilage-derived inhibitor, paclitaxel (nab-paclitaxel), platelet factor 4, protamine sulfate (clupein), sulfated chitin derivatives (snow crab (queen) crab shells), sulfated polysaccharide peptidoglycan complex (sp-pg), staurosporine, modulators of matrix metabolism including proline analogues such as l-azetidine-2-carboxylic acid (LACA), cis-hydroxyproline, d,l-3,4-dehydroproline, thiaproline, α,α'-dipyridyl, beta-aminopropionitrile fumarate, 4-propyl-5-(4-pyridinyl)-2(3h)-oxazolone, methotrexate, mitoxantrone, heparin, interferon, serum macroglobulin 2, chicken inhibitor of metalloproteinase-3 metalloproteinase-3 (ChIMP-3), chymostatin, beta-cyclodextrin tetradecasulfate, eponemycin, fumagillin, sodium gold thiomalate, d-penicillamine, beta-1-anticollagenase serum, alpha-2-antiplasmin, bisantrene, lobenzarit disodium, n-2-carboxyphenyl-4-chloroanthronilic acid disodium ("CCA"), thalidomide, antiangiogenic steroids, carboxyaminoimidazoles, metalloproteinase inhibitors such as BB-94, and inhibitors of S100A9 such as tasquinimod.Other anti-angiogenic agents include, but are not limited to, antibodies, preferably monoclonal antibodies, against these angiogenic growth factors: beta-FGF, alpha-FGF, FGF-5, VEGF isoforms, VEGF-C, HGF / SF, and Ang-1 / Ang-2.

[0329] antifibrotic agents Antifibrotic agents include, but are not limited to, compounds such as beta-aminoproprionitrile (BAPN) and the compounds disclosed in U.S. Pat. No. 4,965,288 relating to inhibitors of lysyl oxidase and their use in treating diseases and conditions associated with the abnormal deposition of collagen, and U.S. Pat. No. 4,997,854 relating to compounds that inhibit LOX for the treatment of various pathological fibrotic conditions, which are incorporated herein by reference. Other exemplary inhibitors are described in U.S. Pat. No. 4,943,593 for compounds such as 2-isobutyl-3-fluoro-, chloro-, or bromo-allylamine, and in U.S. Pat. Nos. 5,021,456, 5,059,714, 5,120,764, 5,182,297, and 5,252,608 for 2-(1-naphthyloxymemyl)-3-fluoroallylamine, and in U.S. Patent Application Publication No. 2004-0248,871, which are incorporated herein by reference.

[0330] Exemplary antifibrotic agents are primary amines that react with the carbonyl group of the active site of lysyl oxidase, more particularly, the products that bind to the carbonyl and are stabilized by resonance, such as the following primary amines: ethylenediamine, hydrazine, phenylhydrazine and their derivatives; semicarbazide and urea derivatives; aminonitriles, such as BAPN or 2-nitroethylamine; unsaturated or saturated haloamines; Also included are those which produce amines such as 2-bromo-ethylamine, 2-chloroethylamine, 2-trifluoroethylamine, 3-bromopropylamine and p-halobenzylamines; and selenohomocysteine ​​lactones.

[0331] Other anti-fibrotic agents are cell-permeable or non-permeable copper chelators. Exemplary compounds also include indirect inhibitors that block the aldehyde derivatives derived from the oxidative deamination of lysyl and hydroxylysyl residues by lysyl oxidase. Examples include thiolamine, particularly D-penicillamine and its analogs, such as 2-amino-5-mercapto-5-methylhexanoic acid, D-2-amino-3-methyl-3-((2-acetamidoethyl)dithio)butanoic acid, p-2-amino-3-methyl-3-((2-aminoethyl)dithio)butanoic acid, sodium-4-((p-1-dimethyl-2-amino-2-carboxyethyl)dithio)butanesulfurate, 2-acetamidoethyl-2-acetamidoethanethiolsulfanate, and sodium-4-mercaptobutanesulfinate trihydrate.

[0332] immunotherapy agents Examples of immunotherapeutic agents include, but are not limited to, therapeutic antibodies suitable for treating a subject. Some examples of therapeutic antibodies include abagovomab, ABP-980, adecatumumab, afutuzumab, alemtuzumab, altumomab, amatuximab, anatumomab, arcitumomab, bavituximab, bectumomab, bevacizumab, bivatuzumab, blinatumomab, brentuximab, cantuzumab, catumaxomab, CC49, cetuximab, sitatuzumab (ci) tatuzumab, cizutuzumab, clivatuzumab, conatumumab, dacetuzumab, darotuzumab, daratumumab, detumomab, dinutuximab, drozitumab, durigotumab, dusigitumab, ecromeximab, elotuzumab, emibetuzumab, ensituximab, ertumaxomab , etaracizumab, farletuzumab, ficlatuzumab, figitumumab, flanvotumab, futuximab, ganitumab, gemtuzumab, girentuximab, glembatumumab, ibritumomab, igovomab, imgatuzumab, indatuximab, inotuzumab, in intetumumab, ipilimumab (YERVOY® MDX-010, BMS-734016 and MDX-101), iratumumab, labetuzumab, lexatumumab, lintuzumab, lorvotuzumab, lucatumumab, mapatuzumab, matuzumab, milatuzumab, minretumomab, mitumomab, mogamulizumab, moxetumomab,Naptumomab, narnatumab, necitumumab, nimotuzumab, nofetumomab, OBI-833, obinutuzumab, ocaratuzumab, ofatumumab, olaratuzumab, onartuzumab, oportuzumab, oregovomab, panitumumab, parsatuzumab, pa Pasudotox, patritumab, pemtumomab, pertuzumab, pintumomab, pritumumab, racotumomab, radretumab, ramucirumab (Cyramza®), rilotumumab, rituximab, lobatum, These include robatumumab, samalizumab, satumomab, sibrotuzumab, siltuximab, solitomab, simtuzumab, tacatuzumab, taplitumomab, tenatumomab, teprotumumab, tigatuzumab, tositumomab, trastuzumab, tucotuzumab, ublituximab, veltuzumab, vorsetuzumab, votumumab, zalutumumab, and 3F8. Rituximab can be used to treat indolent B-cell cancers, including marginal zone lymphoma, WM, CLL, and small lymphocytic lymphoma. The combination of rituximab with chemotherapy agents is particularly effective.

[0333] The exemplified therapeutic antibodies may be further labeled with or combined with radioisotope particles such as indium-111, yttrium-90 (90Y-clivatuzumab) or iodine-131.

[0334] Cancer Gene Therapy and Cell Therapy Cancer gene and cell therapy includes the insertion of normal genes into cancer cells to replace mutated or altered genes; genetic modifications to silence mutated genes; the infusion of immune cells designed to replace large portions of a subject's own immune system to enhance the immune response to cancer cells or to activate the subject's own immune system (T cells or natural killer cells) to kill cancer cells or to find and kill cancer cells; genetic approaches to directly kill cancer cells; and genetic approaches to modify cellular activity to further alter the endogenous immune responsiveness to cancer. gene editing agents

[0335] Examples of genome editing systems include CRISPR / Cas9 systems, zinc finger nuclease systems, TALEN systems, homing endonuclease systems and meganuclease systems. CAR-T cell therapy and TCR-T cell therapy

[0336] CAR-T cell therapy involves a population of immune effector cells engineered to express a chimeric antigen receptor (CAR), which contains a tumor antigen-binding domain. The immune effector cells are T cells or NK cells. TCR-T cell therapy involves TCR-T cells engineered to target tumor-derived peptides present on the surface of tumor cells. The cells can be autologous or allogeneic.

[0337] In some embodiments, the CAR comprises an antigen-binding domain, a transmembrane domain, and an intracellular signaling domain.

[0338] In some embodiments, the intracellular domain comprises a primary signaling domain, a costimulatory domain, or both a primary signaling domain and a costimulatory domain.

[0339] In some embodiments, the primary signaling domain comprises a functional signaling domain of one or more proteins selected from the group consisting of CD3 zeta, CD3 gamma, CD3 delta, CD3 epsilon, common FcR gamma (FCERIG), FcR beta (Fc epsilon R1b), CD79a, CD79b, Fc gamma RIIa, DAP10, and DAP12.

[0340] In some embodiments, the costimulatory domain is selected from the group consisting of CD27, CD28, 4-1BB (CD13 7), OX40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-I), CD2, CD7, LIGHT, NKG2C, B7-H3, CD83 specific binding ligand, CDS, ICAM-1, GITR, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRFI), CD160, CD19, CD4, CD8 alpha, CD8 beta, IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD 1 ld, ITGAE, CD103, ITGAL, CD 1 la, LFA-1, ITGAM, CD1 lb, ITGAX, CD1 The functional domains comprise one or more proteins selected from the group consisting of lc, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, TNFR2, TRANCE / RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​LAT, GADS, SLP-76, PAG / Cbp, NKp44, NKp30, NKp46, and NKG2D.

[0341] In some embodiments, the transmembrane domain is selected from the group consisting of the alpha, beta, or zeta chain of the T cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154, KIRDS2, OX40, CD2, CD27, LFA-1 (CD11a, CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD40, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), CD160, CD19, IL2R beta, IL2R gamma, IL7R u, ITGA1, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD1 ld, ITGAE, CD103, ITGAL, CD1 la, LFA-1, ITGAM, CD1 lb, ITGAX, CD1 The transmembrane domain of a protein selected from the group consisting of lc, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, TNFR2, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​PAG / Cbp, NKp44, NKp30, NKp46, NKG2D, and NKG2C.

[0342] In some embodiments, the antigen binding domain binds to a tumor antigen.

[0343] In some embodiments, the tumor antigen is CD19; CD123; CD22; CD30; CD171; CS-1 (CD2 subset 1, also known as CRACC, SLAMF7, CD319, and 19A24); C-type lectin-like molecule-1 (CLL-1 or CLECLI); CD33; epidermal growth factor receptor variant III (EGFRvlll); ganglioside G2 (GD2); ganglioside GD3 (aNeuSAc(2-8)aNeuSAc(2-3)bDGaip(1-4)bDGIcp(1-1)Cer); TNF receptor family member B-cell maturation (BCMA); Tn antigen ((Tn Ag) or (GaINAcu-Ser / Thr)); prostate-specific membrane antigen (PSMA); receptor tyrosine kinase-like orphan receptor 1 (RORI); Fms-like tyrosine kinase 3 (FLT3); tumor-associated glycoprotein 72 (TAG72); CD38; CD44v6; carcinoembryonic antigen (CEA); epithelial cell adhesion molecule (EPCAM); B7H3 (CD276); KIT (CD117); Interleukin-13 receptor subunit alpha-2 (IL-13Ra2 or CD213A2); mesothelin; interleukin-11 receptor alpha (IL-11Ra); prostate stem cell antigen (PSCA); protease serine 21 (testisin or PRSS21); vascular endothelial growth factor receptor 2 (VEGFR2); Lewis (Y) antigen; CD24; platelet-derived growth factor receptor beta (PDGFR-beta); stage-specific fetal antigen-4 (SSEA-4); CD20; delta-like 3 (DLL3); folate receptor alpha; receptor tyrosine kinase inhibitor (TIK-1). Protein kinase, ERBB2 (Her2 / neu); mucin 1, cell surface associated (MUC1); epidermal growth factor receptor (EGFR); neural cell adhesion molecule (NCAM); prostate; prostatic acid phosphatase (PAP); elongation factor 2 mutated (ELF2M); ephrin B2; fibroblast activation protein alpha (FAP); insulin-like growth factor 1 receptor (IGF-I receptor), carbonic anhydrase IX (CAIX); proteasome (prosome, macropain) subunit, beta, 9 (LMP2); glycoprotein 100 (gp100); breakpoint cluster Oncogene fusion protein (bcr-abl) consisting of the BCR region and Abelson murine leukemia viral oncogene homolog 1 (Abl); tyrosinase; ephrin type A receptor 2 (EphA2); fucosyl GM1; sialyl Lewis adhesion molecule (sLe); ganglioside GM3 (aNeuSAc(2-3)bDGalp(1-4)bDGlcp(1-1)Cer); transglutaminase 5 (TGS5); high-molecular-weight melanoma-associated antigen (HMWMAA); o-acetyl-GD2 ganglioside (OAcGD2); folate receptor beta; tumor vascular endothelial marker -1 (TEM1 / CD248); tumor endothelial marker 7-related (TEM7R); prostate six-transmembrane epithelial antigen I (STEAP1); claudin 6 (CLDN6); thyroid-stimulating hormone receptor (TSHR); G protein-coupled receptor class C group 5, member D (GPRCSD); X chromosome open reading frame 61 (CXORF61); CD97; CD179a; anaplastic lymphoma kinase (ALK); polysialic acid; placenta-specific 1 (PLAC1); hexasaccharide moiety of globo-H glycoceramide (GloboH); mammary differentiation antigen (NY-BR-1);Uroplakin 2 (UPK2); Hepatitis A virus cellular receptor 1 (HAVCR1); Adrenergic receptor beta 3 (ADRB3); Pannexin 3 (PANX3); G protein-coupled receptor 20 (GPR20); Lymphocyte antigen 6 complex, locus K9 (LY6K); Olfactory receptor 51E2 (ORSIE2); TCR gamma alternative reading frame protein (TARP); Wilms tumor protein (WT1); Cancer / Testis antigen 1 (NY-ESO-1); Cancer / Testis antigen 2 (LAGE-1a); Melanoma-associated antigen 1 (MAGE-A1); ETS translocation variant gene 6, located on chromosome 12p (ETV6-AML); Sperm protein 17 (SPA17); X antigen family, member 1A (XAGE1); Angiopoietin-binding cell surface receptor 2 (Tie2); Melanoma cancer-testis antigen-1 (MADCT-1); Melanoma cancer-testis antigen-2 (MAD-CT-2); F os-related antigen 1; tumor protein p53 (p53); p53 mutant; prostein; survivin; telomerase; prostate cancer tumor antigen-1 (PCTA-1 or galectin-8); melanoma antigen 1 recognized by T cells (MelanA or MARTI); rat sarcoma (Ras) mutant; human telomerase reverse transcriptase (hTERT); sarcoma translocation breakpoint; melanoma inhibitor of apoptosis (ML-IAP); ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene); N-acetylglucosaminyl-transferase V (NA17); paired box protein Pax-3 (PAX3); androgen receptor; cyclin B1; v-myc avian myelocytomatosis viral oncogene neuroblastoma-derived homolog (MYCN); Ras homolog family member C (RhoC); tyrosinase-related protein 2 (TRP-2); cytochrome P450 1B1 (CYP IBI); CCCTC-binding factor (zinc finger protein)-like (sibling of BORIS or regulator of imprinted sites), squamous cell carcinoma antigen 3 recognized by T cells (SART3); paired box protein Pax-5 (PAX5); proacrosin-binding protein sp32 (OY-TES I); lymphocyte-specific protein tyrosine kinase (LCK); A-kinase anchor protein 4 (AKAP-4); synovial sarcoma, X breakpoint 2 (SSX2); end; Receptor for advanced glycation end products (RAGE-I); Renal ubiquitous 1 (RUI); Renal ubiquitous 2 (RU2); Legumain; Human papillomavirus E6 (HPV E6); Human papillomavirus E7 (HPV E7); Intestinal carboxylesterase; Heat shock protein 70-2 mutant (mut hsp70-2); CD79a; CD79b; CD72; leukocyte-associated immunoglobulin-like receptor 1 (LAIRI); Fc fragment of IgA receptor (FCAR or CD89); leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2); CD300 molecule-like family member f (CD300LF); C-type lectin domain family 12 member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2); lymphocyte antigen 75 (LY75); glypican-3 (GPC3); Fc receptor-like 5 (FCRL5); and immunoglobulin lambda-like polypeptide 1 (IGLL1).

[0344] In some embodiments, the tumor antigen is CD150, 5T4, ActRIIA, B7, BMCA, CA-125, CCNA1, CD123, CD126, CD138, CD14, CD148, CD15, CD19, CD20, CD200, CD21, CD22, CD23, CD24, CD25, CD26, CD261, CD262, CD30, CD33, CD362, CD37, CD38, CD4, CD40, CD40L, CD44, CD46, CD5, CD52, CD53, CD5 4, CD56, CD66a-d, CD74, CD8, CD80, CD92, CE7, CS-1, CSPG4, ED-B fibronectin, EGFR, EGFRvIII, EGP-2, EGP-4, EPHa2, ErbB2, ErbB3, ErbB4, FBP, GD2, GD3, combined HER1-HER2, combined HER2-HER3, HERV-K, HIV-1 envelope glycoprotein gp120, HIV-1 envelope glycoprotein gp41, HLA-DR, HM1.24, HMW-MAA, Her2, Her2 / neu, IGF-1R, IL-11Ralpha, IL-13R-alpha2, IL-2, IL-22R-alpha, IL-6, IL-6R, Ia, Ii, L1-CAM, L1-cell adhesion molecule, Lewis Y, Ll-CAM, MAGE A3, MAGE-A1, MART-1, MUC1, NKG2C ligand, NKG2D ligand, NYESO-1, OEPHa2, PIGF, PSCA, PSMA, ROR1, T101, TAC, TAG72, TIM-3, TRAIL-R1, TRAIL-Rl (DR4), TRAIL-R2 (DR5), VEGF, VEGFR2, WT-I, G protein-coupled receptor, alpha-fetoprotein (AFP), angiogenic factors, exogenous cognate binding molecule (ExoCBM), oncogene product, antifolate receptor, c-Met, carcinoembryonic antigen (CEA), cyclin ( D1), ephrin B2, epithelial tumor antigen, estrogen receptor, fetal acetylcholine receptor, folate-binding protein, gp100, hepatitis B surface antigen, kappa chain, kappa light chain, kdr, lambda chain, livin, melanoma-associated antigen, mesothelin, mouse double minute 2 homolog (MDM2), mucin 16 (MUC16), mutant p53, mutant ras, necrosis antigen, carcinoembryonic antigen, ROR2, progesterone receptor, prostate-specific antigen, tEGFR, tenascin, P2-microglobulin, and Fc receptor-like 5 (FcRL5).

[0345] Non-limiting examples of cell therapies include Argenpantocel-L, Sipuleucel-T, (BPX-501) Ribogenlecleucel, U.S. Pat. No. 9,089,520, WO 2016100236, AU-105, ACTR-087, activated allogeneic natural killer cells CNDO-109-AANK, MG-4101, AU-101, BPX-601, FATE-NK100, LFU-835 hematopoietic stem cells, and Imiclo. Isel-T, valtaleucel-T, PNK-007, UCARTCS1, ET-1504, ET-1501, ET-1502, ET-190, CD19-ARTEMIS, ProHema, FT-1050-treated bone marrow stem cell therapy, CD4CARNK-92 cells, CryoStim, AlloStim, lentiviral-transduced huCART-meso cells, CART-22 cells, EGFRt / 19-28z / 4-1BBL CAR T cells, autologous 4H11-28z / fIL-12 / E These include FGRt T cells, CCR5-SBC-728-HSPC, CAR4-1BBZ, CH-296, dnTGFbRII-NY-ESOc259T, Ad-RTS-IL-12, IMA-101, IMA-201, CARMA-0508, TT-18, CMD-501, CMD-503, CMD-504, CMD-502, CMD-601, CMD-602, and CSG-005.

[0346] In some embodiments, tumor-targeting antigens include: alpha-fetoprotein, e.g., ET-1402 and AFP-TCR; anthrax toxin receptor 1, e.g., anti-TEM8 CAR T cell therapy; B cell maturation antigen (BCMA), e.g., bb-2121, UCART-BCMA, ET-140, KITE-585, MCM-998, LCAR-B38M, CART-BCMA, SEA-BCMA, BB212, UCART-BCMA, ET-140, P-BCMA-101, AUTO-2 (APRIL-CAR); anti-CLL-1 antibodies, e.g., KITE-796; B7 homolog 6, e.g., CAR-NKp30 and CAR-B7H6; B lymphocyte antigen CD19, e.g., TBI-1501, CTL-119 huCART-19 T cells, JCAR-015 U.S. Patent No. 7446190, JCAR-014, JCAR-017 (WO 2016196388, WO 2016033570, WO 2015157386), axicabtagene ciloleucel (KTE-C19), U.S. Patent No. 7741465, U.S. Patent No. 6319494, UCART-19, EBV-CTL, Ttisagenlecleucel-T (CTL019), WO 2012079000, WO 2017049166, CD19CAR-CD28-CD3 zeta-EGFRt-expressing T cells, CD19 / 4-1BBL armored CAR T cell therapy, C-CAR-011, CIK-CAR.CD19, CD19CAR-28 Zeta T cells, PCAR-019, MatchCART, DSCAR-01, IM19 CAR-T; B lymphocyte antigen CD20, e.g., ATTCK-20; B lymphocyte cell adhesion, e.g., UCART-22, JCAR-018 (WO 20160090190); NY-ESO-1, e.g., GSK-3377794, TBI-1301; carbonic anhydrase, e.g., DC-Ad-GMCAIX; caspase 9 suicide gene, e.g., CaspaCIDe DLI, BPX-501; CCR5, e.g., SB-728; CDw123, e.g., MB-102, UCART-123; CD20m, e.g., CBM-C20.1; CD4, e.g., ICG-122; CD30, e.g., CART30 (CBM-C30.1); CD33, e.g., CIK-CAR.CD33; CD38, e.g., T-007, UCART-38; CD40 ligand, e.g., BPX-201; CEACAM protein 4 modulator, e.g., MG7-CART; Claudin 6, e.g., CSG-002; EBV targeting, e.g., CMD-003; EGFR, e.g., autologous 4H11-28z / fIL-12 / EFGRt T cells; endonucleases, e.g., PGN-514, PGN-201; Epstein-Barr virus-specific T lymphocytes, e.g., TT-10; Erbb2, e.g., CST-102, CIDeCAR; ganglioside (GD2), e.g., 4SCAR-GD2; glutamic acid carboxypeptidase II, e.g., CIK-CAR. PSMA, CART-PSMA-TGFβRDN, P-PSMA-101; glypican-3 (GPC3), e.g., TT-16, GLYCAR; hemoglobin, e.g., PGN-236; hepatocyte growth factor receptor, e.g., anti-cMet RNA CAR T; human papillomavirus E7 protein, e.g., KITE-439; immunoglobulin gamma Fc receptor III, e.g., ACTR087; IL-12, e.g., DC-RTS-IL-12; IL-12 agonist / mucin 16, e.g., JCAR-020; IL-13 alpha 2, e.g., MB-101; IL-2, e.g., CST-101; K-Ras GTPase, e.g., anti-KRAS G12V mTCR cell therapy; neural cell adhesion molecule L1 L1CAM (CD171), e.g., JCAR-023; latent infection membrane protein 1 / latent infection membrane protein 2, e.g., Ad5f35-LMPd1-2 transduced autologous dendritic cells; melanoma associated antigen 10, e.g., MAGE-A10C796T, MAGE-A10 TCR; melanoma associated antigen 3 / melanoma associated antigen 6 (MAGE A3 / A6), e.g., KITE-718; mesothelin, e.g., CSG-MESO, TC-210; NKG 2D, such as NKR-2; Ntrkr1 tyrosine kinase receptors, such as JCAR-024; T cell receptors, such as BPX-701, IMCgp100; T lymphocytes, such as TT-12; tumor-infiltrating lymphocytes, such as LN-144, LN-145; and Wilms tumor proteins, such as JTCR-016, WT1-CTL. Lymphoma or leukemia combination therapy

[0347] In some embodiments, the additional therapeutic agent is suitable for treating lymphoma or leukemia. These agents include aldesleukin, alvocidib, amifostine trihydrate, aminocamptothecin, antineoplaston A10, antineoplaston AS2-1, antithymocyte globulin, arsenic trioxide, Bcl-2 family protein inhibitor ABT-263, beta-arretin, BMS-345541, bortezomib (VELCADE®), bortezomib (VELCADE®, PS-341), bryostatin 1, busulfan, campath-1H, carboplatin, carfilzomib (Kyproliin), and the like. (registered trademark), carmustine, caspofungin acetate, CC-5103, chlorambucil, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), cisplatin, cladribine, clofarabine, curcumin, CVP (cyclophosphamide, vincristine, and prednisone), cyclophosphamide, cyclosporine, cytarabine, denileukin diftitox, dexamethasone, docetaxel, dolastatin 10, doxorubicin, doxorubicin hydrochloride, DT-PACE (dexamethasone cisplatin, thalidomide, cisplatin, doxorubicin, cyclophosphamide and etoposide), enzastaurin, epoetin alfa, etoposide, everolimus (RAD001), FCM (fludarabine, cyclophosphamide and mitoxantrone), FCR (fludarabine, cyclophosphamide and rituximab), fenretinide, filgrastim, flavopiridol, fludarabine, FR (fludarabine and rituximab), geldanamycin (17-AAG), hyperCVAD (hyperfractionated cyclophosphamide), , vincristine, doxorubicin, dexamethasone, methotrexate, and cytarabine), ICE (ifosfamide, carboplatin, and etoposide), ifosfamide, irinotecan hydrochloride, interferon alfa-2b, ixabepilone, lenalidomide (REVLIMID®, CC-5013), lymphokine-activated killer cells, MCP (mitoxantrone, chlorambucil, and prednisolone), melphalan, mesna, methotrexate, mitoxantrone hydrochloride, motexafine gadolinium,Mycophenolate mofetil, nelarabine, obatoclax (GX15-070), oblimersen, octreotide acetate, omega-3 fatty acids, Omr-IgG-am (WNIG, Omrix), oxaliplatin, paclitaxel, palbociclib (PD0332991), pegfilgrastim, pegylated liposomal doxorubicin hydrochloride, perifosine, prednisolone, prednisone, recombinant flt3 ligand, recombinant human thrombopoietin, recombinant interferon alpha, recombinant interleukin-11, recombinant interleukin-12, rituximab, R-CHOP (rituximab and CHOP), R-CVP (rituximab and CVP), R-FCM (Ritux) R-ICE (rituximab and FCM), R-ICE (rituximab and ICE) and R-MCP (rituximab and MCP), R-roscovitine (seliciclib, CYC202), sargramostim, sildenafil citrate, simvastatin, sirolimus, styryl sulfone, tacrolimus, tanespimycin, temsirolimus (CCI-779), thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tipifarnib, vincristine, vincristine sulfate, vinorelbine bitartrate, SAHA (suberoylanilide hydroxamic acid or suberoyl, anilide and hydroxamic acid), vemurafenib (Zelboraf®), venetoclax (ABT-199),

[0348] One modified approach is radioimmunotherapy, which combines monoclonal antibodies with radioisotope particles such as indium-111, yttrium-90, and iodine-131. Examples of combination therapies include, but are not limited to, iodine-131 tositumomab (BEXXAR®), yttrium-90 ibritumomab tiuxetan (ZEVALIN®), and BEXXAR® together with CHOP.

[0349] The above-mentioned therapies can supplement or be combined with stem cell transplantation or treatment. Therapeutic approaches include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, total body irradiation, stem cell infusion, myeloablative with stem cell support, in vitro treated peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzymatic techniques, low-LET cobalt-60 gamma therapy, bleomycin, conventional surgery, radiation therapy, and non-myeloablative allogeneic hematopoietic stem cell transplantation.

[0350] Non-Hodgkin's Lymphoma Combination Therapy In some embodiments, the additional therapeutic agent is suitable for treating non-Hodgkin's lymphoma (NHL), particularly those of B-cell origin, and includes monoclonal antibodies, standard chemotherapy approaches (e.g., CHOP, CVP, FCM, MCP, etc.), radioimmunotherapy, and combinations thereof, particularly the integration of antibody therapy with chemotherapy.

[0351] Examples of unconjugated monoclonal antibodies for treating NHL / B-cell cancer include rituximab, alemtuzumab, human or humanized anti-CD20 antibodies, lumiliximab, anti-TNF-related apoptosis-inducing ligand (anti-TRAIL), bevacizumab, galiximab, epratuzumab, SGN-40, and anti-CD74.

[0352] Examples of experimental antibody agents used in the treatment of NHL / B-cell cancers include ofatumumab, ha20, PRO131921, alemtuzumab, galiximab, SGN-40, CHIR-12.12, epratuzumab, lumiliximab, apolizumab, milatuzumab, and bevacizumab.

[0353] Examples of standard regimens of chemotherapy for NHL / B-cell cancer include CHOP, FCM, CVP, MCP, R-CHOP, R-FCM, R-CVP, and R-MCP.

[0354] Examples of radioimmunotherapies for NHL / B-cell cancer include yttrium-90 ibritumomab tiuxetan (ZEVALIN®) and iodine-131 tositumomab (BEXXAR®).

[0355] Mantle cell lymphoma combination therapy In some embodiments, the additional therapeutic agent is suitable for treating mantle cell lymphoma (MCL) and includes combination chemotherapy, such as CHOP, hyperCVAD, and FCM. These regimens can also be supplemented with the monoclonal antibody rituximab to form the combination therapies R-CHOP, hyperCVAD-R, and R-FCM. Any of the above-mentioned therapies can be combined with stem cell transplantation or ICE to treat MCL.

[0356] Other examples of therapeutic agents suitable for treating MCL include: - immunotherapy, e.g., monoclonal antibodies (such as rituximab), and cancer vaccines based on the genetic makeup of an individual subject's tumor, e.g., GTOP-99 - radioimmunotherapy, in which monoclonal antibodies are combined with radioisotope particles, such as iodine-131 tositumomab (BEXXAR®), yttrium-90 ibritumomab tiuxetan (ZEVALIN®), and BEXXAR® in sequential treatment with CHOP; - Autologous stem cell transplant in combination with high-dose chemotherapy and administration of proteasome inhibitors such as bortezomib (VELCADE® or PS-341), or administering antiangiogenic agents such as thalidomide in combination with tuximab; - Drugs that lead to the degradation of the Bcl-2 protein and increase the sensitivity of cancer cells to chemotherapy, for example, oblimersen in combination with other chemotherapy agents; mTOR inhibitors, which can lead to cell growth inhibition and even cell death. Non-limiting examples are RITUXAN®, VELCADE®, or sirolimus, temsirolimus (TORISEL®, CCI-779), CC-115, CC-223, SF-1126, PQR-309 (bimiralisib), voxtalisib, GSK-2126458, and temsirolimus in combination with other chemotherapeutic agents; - other agents, such as flavopiridol, palbociclib (PD0332991), R-roscovitine (selicicilib, CYC202), styryl sulfones, obatoclax (GX15-070), TRAIL, anti-TRAIL death receptor DR4 and DR5 antibodies, temsirolimus (TORISEL®, CC1-779), everolimus (RAD001), BMS-345541, curcumin, SAHA, thalidomide, lenalidomide (REVLIMID®, CC-5013), and geldanamycin (17-AAG).

[0357] Waldenström's macroglobulinemia combination therapy In some embodiments, the additional therapeutic agent is suitable for treating Waldenstrom's Macroglobulinemia (WM) and includes aldesleukin, alemtuzumab, alvocidib, amifostine trihydrate, aminocamptothecin, antineoplaston A10, antineoplaston AS2-1, antithymocyte globulin, arsenic trioxide, autologous human tumor-derived HSPPC-96, Bcl-2 family protein inhibitor ABT-263, beta-arretin, bortezomib (VELCADE®), bryostatin 1, busulfan, campath-1H, Carboplatin, carmustine, caspofungin acetate, CC-5103, cisplatin, clofarabine, cyclophosphamide, cyclosporine, cytarabine, denileukin diftitox, dexamethasone, docetaxel, dolastatin 10, doxorubicin hydrochloride, DT-PACE, enzastaurin, epoetin alfa, epratuzumab (hLL2-anti-CD22 humanized antibody), etoposide, everolimus, fenretinide, filgrastim, fludarabine, ifosfamide, indium-111 monoclonal antibody MN-14, Iodine-131 tositumomab, irinotecan hydrochloride, ixabepilone, lymphokine-activated killer cells, melphalan, mesna, methotrexate, mitoxantrone hydrochloride, monoclonal antibody CD19 (such as tisagenlecleucel-T, CART-19, and CTL-019), monoclonal antibody CD20, motexafin gadolinium, mycophenolate mofetil, nelarabine, oblimersen, octreotide acetate, omega-3 fatty acids, oxaliplatin, paclitaxel, pegfilgrastim, and pegylated liposomal doxorubicin hydrochloride salt, pentostatin, perifosine, prednisone, recombinant flt3 ligand, recombinant human thrombopoietin, recombinant interferon alpha, recombinant interleukin-11, recombinant interleukin-12, rituximab, sargramostim, sildenafil citrate (VIAGRA®), simvastatin, sirolimus, tacrolimus, tanespimycin, thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tipifarnib, tositumomab, veltuzumab, vincristine sulfate, vinorelbine bitartrate, vorinostat, WT1126-134 peptide vaccine, WT-1 analog peptide vaccine, yttrium-90 ibritumomab tiuxetan, yttrium-90 humanized epratuzumab, and any combination thereof.

[0358] Other examples of therapeutic approaches used to treat WM include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, total body irradiation, stem cell infusion, myeloablation with stem cell support, in vitro treated peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzymatic techniques, low-LET cobalt-60 gamma radiation therapy, bleomycin, conventional external steroid therapy, and steroid therapy. These include endoscopic surgery, radiation therapy, and non-myeloablative allogeneic hematopoietic stem cell transplantation.

[0359] Diffuse large B-cell lymphoma combination therapy In some embodiments, the additional therapeutic agent is suitable for treating diffuse large B-cell lymphoma (DLBCL) and includes cyclophosphamide, doxorubicin, vincristine, prednisone, anti-CD20 monoclonal antibodies, etoposide, bleomycin, many of the agents listed for WM, and any combination thereof, such as ICE and R-ICE.

[0360] Chronic lymphocytic leukemia combination therapy In some embodiments, the additional therapeutic agent is suitable for treating chronic lymphocytic leukemia (CLL) and includes chlorambucil, cyclophosphamide, fludarabine, pentostatin, cladribine, doxorubicin, vincristine, prednisone, prednisolone, alemtuzumab, many of the agents listed for WM, and combination chemotherapy and chemoimmunotherapy, including the following common combination regimens: CVP, R-CVP, ICE, R-ICE, FCR, and FR.

[0361] Myelofibrosis combination therapy In some embodiments, the additional therapeutic agent is suitable for treating myelofibrosis and includes a hedgehog inhibitor, a histone deacetylase (HDAC) inhibitor, and a tyrosine kinase inhibitor. Non-limiting examples of hedgehog inhibitors are saridegib and vismodegib.

[0362] Examples of HDAC inhibitors include, but are not limited to, pracinostat and panobinostat.

[0363] Non-limiting examples of tyrosine kinase inhibitors are lestaurtinib, bosutinib, imatinib, gilteritinib, radotinib, and cabozantinib. Combination hyperproliferative disease therapy

[0364] In some embodiments, the additional therapeutic agent is suitable for treating a hyperproliferative disease and includes gemcitabine, nab-paclitaxel, and gemcitabine / nab-paclitaxel with a JAK inhibitor and / or a PI3Kδ inhibitor. Bladder cancer combination therapy

[0365] In some embodiments, the additional therapeutic agent is suitable for treating bladder cancer and includes atezolizumab, carboplatin, cisplatin, docetaxel, doxorubicin, fluorouracil (5-FU), gemcitabine, ifosfamide, interferon alpha-2b, methotrexate, mitomycin, nab-paclitaxel, paclitaxel, pemetrexed, thiotepa, vinblastine, and any combination thereof. Breast cancer combination therapy

[0366] In some embodiments, the additional therapeutic agent is suitable for treating breast cancer and includes albumin-bound paclitaxel, anastrozole, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, epirubicin, everolimus, exemestane, fluorouracil, fulvestrant, gemcitabine, ixabepilone, lapatinib, letrozole, methotrexate, mitoxantrone, paclitaxel, pegylated liposomal doxorubicin, pertuzumab, tamoxifen, toremifene, trastuzumab, vinorelbine, and any combination thereof. Triple-negative breast cancer combination therapy

[0367] In some embodiments, the additional therapeutic agent is suitable for treating triple-negative breast cancer and includes cyclophosphamide, docetaxel, doxorubicin, epirubicin, fluorouracil, paclitaxel, and combinations thereof. Colorectal Cancer Combination Therapy

[0368] In some embodiments, the additional therapeutic agent is suitable for treating colorectal cancer and includes bevacizumab, capecitabine, cetuximab, fluorouracil, irinotecan, leucovorin, oxaliplatin, panitumumab, ziv-aflibercept, and any combination thereof.

[0369] In some embodiments, the additional therapeutic agent is suitable for treating castration-resistant prostate cancer and includes abiraterone, cabazitaxel, docetaxel, enzalutamide, prednisone, sipuleucel-T, and any combination thereof. Combination therapy for esophageal and esophagogastric junction cancer

[0370] In some embodiments, the additional therapeutic agent is suitable for treating esophageal and esophageal-gastric junction cancer and includes capecitabine, carboplatin, cisplatin, docetaxel, epirubicin, fluoropyrimidines, fluorouracil, irinotecan, leucovorin, oxaliplatin, paclitaxel, ramucirumab, trastuzumab, and any combination thereof. Gastric cancer combination therapy

[0371] In some embodiments, the additional therapeutic agent is suitable for treating gastric cancer and includes capecitabine, carboplatin, cisplatin, docetaxel, epirubicin, fluoropyrimidines, fluorouracil, irinotecan, leucovorin, mitomycin, oxaliplatin, paclitaxel, ramucirumab, trastuzumab, and any combination thereof.

[0372] In some embodiments, the additional therapeutic agent is suitable for treating head and neck cancer and includes afatinib, bleomycin, capecitabine, carboplatin, cetuximab, cisplatin, docetaxel, fluorouracil, gemcitabine, hydroxyurea, methotrexate, nivolumab, paclitaxel, pembrolizumab, vinorelbine, and any combination thereof. Hepatobiliary tract cancer combination therapy

[0373] In some embodiments, the additional therapeutic agent is suitable for treating hepatobiliary cancer and includes capecitabine, cisplatin, fluoropyrimidines, 5-fluorourcil, gemcitabine, oxaliplatin, sorafenib, and any combination thereof. Hepatocellular carcinoma combination therapy

[0374] In some embodiments, the additional therapeutic agent is suitable for treating hepatocellular carcinoma and includes capecitabine, doxorubicin, gemcitabine, sorafenib, and any combination thereof. Non-small cell lung cancer combination therapy

[0375] In some embodiments, the additional therapeutic agent is suitable for treating non-small cell lung cancer (NSCLC) and is selected from the group consisting of afatinib, albumin-bound paclitaxel, alectinib, bevacizumab, and the like. rivaroxaban, bevacizumab, cabozantinib, carboplatin, cisplatin, crizotinib, dabrafenib, docetaxel, erlotinib, etoposide, gemcitabine, nivolumab, paclitaxel, pembrolizumab, pemetrexed, ramucirumab, trametinib, trastuzumab, vandetanib, vemurafenib, vinblastine, vinorelbine, and any combination thereof. Small cell lung cancer combination therapy

[0376] In some embodiments, the additional therapeutic agent is suitable for treating small cell lung cancer (SCLC) and includes bendamustine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, etoposide, gemcitabine, ipilimumab, irinotecan, nivolumab, paclitaxel, temozolomide, topotecan, vincristine, vinorelbine, and any combination thereof. Melanoma combination therapy

[0377] In some embodiments, the additional therapeutic agent is suitable for treating melanoma and includes albumin-bound paclitaxel, carboplatin, cisplatin, cobimetinib, dabrafenib, daclavadine, IL-2, imatinib, interferon alpha-2b, ipilimumab, nitrosoureas, nivolumab, paclitaxel, pembrolizumab, pilimumab, temozolomide, trametinib, vemurafenib, vinblastine, and any combination thereof. Ovarian cancer combination therapy

[0378] In some embodiments, the additional therapeutic agent is suitable for treating ovarian cancer and includes 5-fluorouracil, albumin-bound paclitaxel, altretamine, anastrozole, bevacizumab, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, etoposide, exemestane, gemcitabine, ifosfamide, irinotecan, letrozole, leuprolide acetate, liposomal doxorubicin, megestrol acetate, melphalan, olaparib, oxaliplatin, paclitaxel, pazopanib, pemetrexed, tamoxifen, topotecan, vinorelbine, and any combination thereof. Pancreatic cancer combination therapy

[0379] In some embodiments, the additional therapeutic agent is suitable for treating pancreatic cancer and includes 5-fluorouracil, albumin-bound paclitaxel, capecitabine, cisplatin, docetaxel, erlotinib, fluoropyrimidines, gemcitabine, irinotecan, leucovorin, oxaliplatin, paclitaxel, and any combination thereof. Renal cell carcinoma combination therapy

[0380] In some embodiments, the additional therapeutic agent is suitable for treating renal cell carcinoma and includes axitinib, bevacizumab, cabozantinib, erlotinib, everolimus, levantinib, nivolumab, pazopanib, sorafenib, sunitinib, temsirolimus, and any combination thereof. VIII. Kit

[0381] The present disclosure provides a kit comprising the compound of the present disclosure or its pharmaceutically acceptable salt.The kit may further comprise instructions for use, such as for treating viral infections.The instructions are generally written instructions, but electronic storage media (for example, magnetic diskettes or optical disks) containing instructions are also acceptable.

[0382] The present disclosure provides one or more pharmaceutical compositions containing a compound of the present disclosure or a pharmaceutically acceptable salt thereof. Pharmaceutical kits are also provided, including a number of containers. If necessary, such container(s) may be accompanied by a notice in a form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, reflecting approval by the government agency for manufacture, use, or sale for human administration. Each component (if multiple components are present) may be packaged in a separate container, or several components may be combined in a single container, provided cross-reactivity and shelf life permit. Kits may be in unit dosage form, bulk packaged (e.g., multi-dose package), or subunit dose. Kits may include multiple unit doses of the compound and instructions and may be packaged in an amount sufficient for storage and use in a pharmacy (e.g., hospital pharmacy and compounding pharmacy).

[0383] Also, a product containing a unit dosage of the disclosed compound or its pharmaceutically acceptable salt is provided in a package suitable for use in the methods described herein.Suitable packages are known in the art and include, for example, vials, containers, ampoules, bottles, jars, flexible packaging, etc.The product can be further sterilized and / or sealed. [Example]

[0384] The abbreviations used herein have the following meanings: [Table A-1] [Table A-2]

[0385] The solid forms (polymorphs, solvates and hydrates) of Compound I were characterized by various methods as follows.

[0386] XRPD patterns were collected on a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu Kα radiation generated using a long fine focus source and a nickel filter. The diffractometer has a symmetric Bragg-Brentano geometry. The structure used was constructed. Prior to analysis, a silicon specimen (NIST SRM 640e) was analyzed to verify that the observed Si 111 peak position matched the NIST-certified position. The sample specimen was prepared as a thin annular layer centered on a silicon zero-background substrate. An anti-scatter slit (SS) was used to minimize background caused by air. Soller slits were used on the incident and diffracted beams to minimize off-axis divergence. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) positioned 240 mm from the sample and Data Collector software v.2.2b.

[0387] Differential scanning calorimetry (DSC) data were collected using TA Instruments 2920 and Q2000 differential scanning calorimeters. Temperature calibration was performed using NIST-traceable indium metal. Samples were placed in T-zero aluminum DSC pans, covered with lids, and crimped. The weight was then accurately recorded. A weighed aluminum pan configured as the sample pan was placed on the reference side of the cell. Samples were heated from -30°C to 250°C at 10°C / min.

[0388] Thermogravimetric analysis (TGA) data were collected using a TA Instruments Discovery thermogravimetric analyzer. Temperature calibration was performed using nickel and Alumel™. Each sample was placed in an aluminum pan and inserted into a TG furnace. The furnace was heated under a nitrogen purge. Samples were heated from ambient temperature to 350°C at 10°C / min.

[0389] Moisture sorption / desorption data were collected on a VTI SGA-100 vapor sorption analyzer. NaCl and PVP were used as calibration standards. Samples were not dried prior to analysis. Sorption and desorption data were collected under a nitrogen purge at 10% RH increments over a RH range of 5% to 95%. The equilibration criteria used for analysis were a weight change of less than 0.0100% in 5 minutes, with a maximum equilibration time of 3 hours. Weight percentages reported in the data section are relative to the total sample mass introduced prior to equilibration at 5% RH, as measured by the instrument. Example 1 Preparation of Compound I [ka]

[0390] A 50 L jacketed reactor flushed with nitrogen was charged with Compound A (2.69 kg, 6.07 mol, 1.0 equiv.). This was followed by the addition of dichloromethane (10.13 L, 13.44 kg). The agitation was set to 175 RPM, and the contents were stirred until a solution was observed. Trifluoroacetic acid (4.53 L, 6.75 kg) was charged at a rate such that the internal temperature did not exceed 35°C (approximately 30 minutes). After the trifluoroacetic acid was added, the jacket was set to 46°C (to maintain a gentle reflux). The contents were stirred at this temperature for 3 hours, and then the jacket was set to 15°C. Once the internal temperature reached 20°C, ethanol (denatured from n-heptane) (8.56 L, 6.75 kg) was charged, and the contents were stirred at 20°C for 14 hours. After this time, the heterogeneous contents were filtered through a benchtop poly filter into a nitrogen flushed 100 L jacketed reactor.

[0391] Dichloromethane (5.21 L, 6.91 kg) was charged to a 50 L reactor, and the solution was rinsed through a filter into the 100 L reactor. The 100 L reactor was then charged with water (15.5 L, 15.5 kg) and ethyl acetate (19.0 L, 17.0 kg). The agitation was set to 175 RPM and the jacket was set to 87°C. The contents were heated to reflux for 30 minutes. After this time, the jacket was set to 20°C. The aqueous layer was discarded. The reactor was charged with water (18.4 L, 18.4 kg) and the agitation was set to 200 RPM. 30% w / w NaOH (8.61 kg) was charged, and the contents were agitated at 30°C for 30 minutes (jacket set to 40°C). Ethyl acetate (45.0 L, 40.4 kg) was then charged, and the jacket was set to 55°C. Once the internal temperature reached 45°C, the contents were agitated at 200 RPM for 30 minutes. After this time, agitation was stopped, the phases were allowed to separate, and the aqueous layer was discarded. A 4.5% w / w aqueous sodium bicarbonate solution (prepared from 605 g sodium bicarbonate and 12.8 kg water) was charged, and the contents were agitated at 200 RPM for 30 minutes at an internal temperature of 45°C. After this time, agitation was stopped, and the layers were allowed to separate. The aqueous layer was removed, and the jacket was set to 20°C. The contents were aged at this temperature under nitrogen for 14 hours. The jacket was then set to 55°C. Once the internal temperature reached 45°C, 4.5% w / w aqueous sodium bicarbonate (prepared from 605 g sodium bicarbonate and 12.8 kg water) was charged, and the contents were agitated (200 RPM) for 30 minutes at 45°C. Agitation was then stopped, the phases were allowed to separate, and the aqueous layer was discarded. 4.5% w / w aqueous sodium bicarbonate (prepared from 605 g sodium bicarbonate and 12.8 kg water). The contents were agitated (200 RPM) for 30 minutes at 45°C. Agitation was then stopped, the phases were allowed to separate, and the aqueous layer was discarded. Water (13.6 L, 13.6 kg) was added and the contents were agitated (150 RPM) for 30 minutes at 45°C. After this time, agitation was stopped, the phases were allowed to separate, and the aqueous layer was discarded.

[0392] Alternatively, a nitrogen-flushed reaction vessel was charged with Compound A (scale factor 1.0 part). This was followed by the addition of dichloromethane (2.5 parts). The contents were stirred until a homogeneous solution was observed. Trifluoroacetic acid (2.0 parts) was charged at a rate such that the internal temperature did not exceed 35°C (approximately 30 minutes). After the trifluoroacetic acid was added, the jacket was set to maintain an internal temperature of approximately 30°C. The contents were stirred at this temperature for approximately 10 hours, and then the jacket was set to 22°C. Once the internal temperature reached 22°C, ethanol (2.0 parts) was charged and the contents were stirred at 22°C for 14 hours. After this time, the contents were filtered. The filter was rinsed with ethanol (2.0 parts), and the contents were distilled to approximately 3 L / kg. The contents were cooled to 22°C, and ethanol (1 part) and water (1 part) were charged to the contents. To this was charged 50% wt / wt aqueous sodium hydroxide (approximately 0.7 parts) until a pH of 12-14 was achieved. The internal temperature of the contents was adjusted to 22°C, and water (3.0 parts) was charged over 30 minutes. The contents were cooled to approximately 0°C over 2 hours and held at this temperature for 2 hours. The slurry was filtered, and the cake was rinsed with a 1:1 wt / wt ratio of water and ethanol (2 parts). The contents were dried at 45°C until a constant weight was achieved. Compound I (Form I) was removed and packaged. Example 2 Form I (Ethyl Acetate)

[0393] The reactor was configured for vacuum distillation, the jacket was set to 70°C, and the agitation was set to 150 RPM. Solvent was removed by vacuum distillation to approximately 30 L. The jacket was set to 35°C, and the reactor was backfilled with nitrogen. Ethyl acetate (45 L, 40.4 kg) was charged, the reactor was heated to 70°C, the agitation was set to 150 RPM, and the pressure was reduced. Solvent was removed by vacuum distillation to approximately 30 L. The jacket was set to 35°C, and the reactor was backfilled with nitrogen. The ethyl acetate distillation sequence was repeated five times as described. The final volume for the five distillations was approximately 30 L after charging 45 L of ethyl acetate per sequence. The contents were sampled for water content (target <0.5% HO). After passing the water content criteria, the jacket was heated to 70°C, the agitation was set to 150 RPM, the pr...

Claims

1. 2. Compound I tartaric acid, (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol tartaric acid, characterized by an X-ray powder diffraction (XRPD) pattern containing three or more peaks at 6.3°, 9.9°, 12.5°, 17.7°, 18.3°, 19.2°, 23.4°, 25.7°, or 28.1° 2θ (±0.2° 2θ). 【Chemistry 24】 Crystals.

2. 2. The crystal of claim 1, characterized by an XRPD pattern comprising four or more peaks at 6.3°, 9.9°, 12.5°, 17.7°, 18.3°, 19.2°, 23.4°, 25.7°, or 28.1°2θ (±0.2°2θ).

3. 3. The crystal of claim 1 or claim 2, characterized by an XRPD pattern comprising peaks at 6.3°, 18.3°, and 23.4° 2θ (±0.2° 2θ).

4. 4. The crystal of claim 3, wherein the XRPD pattern further comprises one or more additional peaks at 9.9°, 12.5°, 17.7°, 19.2°, 25.7°, or 28.1° 2θ (±0.2° 2θ).

5. 5. The crystal of claim 3 or claim 4, wherein the XRPD pattern further comprises two or more additional peaks at 9.9°, 12.5°, 17.7°, 19.2°, 25.7°, or 28.1°2θ (±0.2°2θ).

6. 3. The crystal of claim 1 or claim 2, characterized by an XRPD pattern comprising peaks at 9.9°, 12.5°, and 17.7° 2θ (±0.2° 2θ).

7. 7. The crystal of claim 6, wherein the XRPD pattern further comprises one or more additional peaks at 6.3°, 18.3°, 19.2°, 23.4°, 25.7°, or 28.1° 2θ (±0.2° 2θ).

8. 8. The crystal of claim 6 or claim 7, wherein the XRPD pattern further comprises two or more additional peaks at 6.3°, 18.3°, 19.2°, 23.4°, 25.7°, or 28.1°2θ (±0.2°2θ).

9. 9. The crystal of any one of claims 1 to 8, characterized by an XRPD pattern comprising peaks at 6.3°, 9.9°, 12.5°, 17.7°, 18.3°, 19.2°, 23.4°, 25.7°, and 28.1°2θ (±0.2°2θ).

10. A crystal described in any one of claims 1 to 9, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset temperature of 157°C.

11. 2. Compound I maleic acid, (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol maleic acid, characterized by an XRPD pattern containing three or more peaks at 7.3°, 8.4°, 8.8°, 13.9°, 15.6°, 17.7°, 20.7°, 24.7°, or 27.4° 2θ (±0.2° 2θ). 【Chemistry 25】 Crystals.

12. 12. The crystal of claim 11, characterized by an XRPD pattern comprising four or more peaks at 7.3°, 8.4°, 8.8°, 13.9°, 15.6°, 17.7°, 20.7°, 24.7°, or 27.4° 2θ (±0.2° 2θ).

13. 13. The crystal of claim 11 or 12, characterized by an XRPD pattern comprising peaks at 7.3°, 17.7°, and 24.7° 2θ (±0.2° 2θ).

14. 14. The crystal of claim 13, wherein the XRPD pattern further comprises one or more additional peaks at 8.4°, 8.8°, 13.9°, 15.6°, 20.7°, or 27.4° 2θ (±0.2° 2θ).

15. 15. The crystal of claim 13 or claim 14, wherein the XRPD pattern further comprises two or more additional peaks at 8.4°, 8.8°, 13.9°, 15.6°, 20.7°, or 27.4° 2θ (±0.2° 2θ).

16. Peaks at 13.9°, 15.6°, and 27.4° 2θ (±0.2° 2θ) 13. The crystal of claim 11 or claim 12, characterized by an XRPD pattern comprising:

17. 17. The crystal of claim 16, wherein the XRPD pattern further comprises one or more additional peaks at 7.3°, 8.4°, 8.8°, 17.7°, 20.7°, or 24.7° 2θ (±0.2° 2θ).

18. 18. The crystal of claim 16 or 17, wherein the XRPD pattern further comprises two or more additional peaks at 7.3°, 8.4°, 8.8°, 17.7°, 20.7°, or 24.7°2θ (±0.2°2θ).

19. 19. The crystal of any one of claims 11 to 18, characterized by an XRPD pattern comprising peaks at 7.3°, 8.4°, 8.8°, 13.9°, 15.6°, 17.7°, 20.7°, 24.7°, and 27.4°2θ (±0.2°2θ).

20. A crystal described in any one of claims 11 to 19, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset temperature of 143°C.

21. 2. Compound I fumaric acid, (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol fumaric acid, characterized by an XRPD pattern containing three or more peaks at 6.7°, 8.3°, 10.1°, 12.6°, 16.1°, 18.5°, 20.6°, 25.2° or 27.6° 2θ (±0.2° 2θ). 【Chemistry 26】 Crystals.

22. 22. The crystal of claim 21, characterized by an XRPD pattern comprising four or more peaks at 6.7°, 8.3°, 10.1°, 12.6°, 16.1°, 18.5°, 20.6°, 25.2° or 27.6° 2θ (±0.2° 2θ).

23. 23. The crystal of claim 21 or claim 22, characterized by an XRPD pattern comprising peaks at 6.7°, 8.3°, and 25.2° 2θ (±0.2° 2θ).

24. 24. The crystal of claim 23, wherein the XRPD pattern further comprises one or more additional peaks at 10.1°, 12.6°, 16.1°, 18.5°, 20.6°, or 27.6°2θ (±0.2°2θ).

25. 25. The crystal of claim 23 or claim 24, wherein the XRPD pattern further comprises two or more additional peaks at 10.1°, 12.6°, 16.1°, 18.5°, 20.6°, or 27.6°2θ (±0.2°2θ).

26. 23. The crystal of claim 21 or claim 22, characterized by an XRPD pattern comprising peaks at 18.5°, 20.6°, and 27.6° 2θ (±0.2° 2θ).

27. 26. The crystal of claim 25, wherein the XRPD pattern further comprises one or more additional peaks at 6.7°, 8.3°, 10.1°, 12.6°, 16.1°, or 25.2° 2θ (±0.2° 2θ).

28. 28. The crystal of claim 26 or claim 27, wherein the XRPD pattern further comprises two or more additional peaks at 6.7°, 8.3°, 10.1°, 12.6°, 16.1°, or 25.2° 2θ (±0.2° 2θ).

29. 29. The crystal of any one of claims 21 to 28, characterized by an XRPD pattern comprising peaks at 6.7°, 8.3°, 10.1°, 12.6°, 16.1°, 18.5°, 20.6°, 25.2° and 27.6° 2θ (±0.2° 2θ).

30. A crystal described in any one of claims 21 to 29, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset temperature of 70°C.

31. 31. The crystal of claim 30, wherein the DSC thermogram has a second endotherm with an onset temperature of 167°C.

32. 32. A pharmaceutical composition comprising a crystal according to any one of claims 1 to 31 and one or more pharma- ceutically acceptable excipients.

33. The pharmaceutical composition according to claim 32, wherein the crystal is a crystal of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol tartaric acid.

34. The pharmaceutical composition according to claim 32, wherein the crystal is a crystal of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol maleic acid.

35. The pharmaceutical composition according to claim 32, wherein the crystal is a crystal of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol fumaric acid.

36. A composition comprising a crystal described in any one of claims 1 to 31 or a pharmaceutical composition described in claim 32 for treating or preventing HBV infection in a subject in need of such treatment or prevention.

37. 36. Use of a crystal according to any one of claims 1 to 31 or a pharmaceutical composition according to claim 32 in the manufacture of a medicament for treating or preventing HBV infection.

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