Solid forms of Toll-like receptor modulators

Abstract

The present application provides crystalline forms, solvates and hydrates of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexane-1-ol, and methods for preparing the same.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 62 / 835,335, filed on April 17, 2019, the entire contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present application generally relates to Toll-like receptor modulator compounds, including diaminopyrido[3,2-d]pyrimidine compounds, among others, and pharmaceutical compositions thereof that modulate Toll-like receptors (eg, TLR-8), and methods of making and using the same. Background Art

[0004] The Toll-like receptor (TLR) family plays a fundamental role in pathogen recognition and innate immune activation. Toll-like receptor 8 (TLR-8) is mainly expressed by bone marrow immune cells, and activation of this receptor stimulates a wide range of immune responses. TLR-8 agonists activate bone marrow 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-α (TNF-α), and interferon-γ (IFN-γ). Such agonists also promote increased expression of co-stimulatory molecules such as CD8+ cells, major histocompatibility complex molecules (MAIT, NK cells), and chemokine receptors.

[0005] Collectively, activation of these innate and adaptive immune responses induces immune responses and provides therapeutic benefits in a variety of conditions involving autoimmunity, inflammation, allergy, asthma, transplant rejection, graft-versus-host disease (GvHD), infection, cancer, and immunodeficiency. For example, with respect to 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 expected to enhance HBV-specific T cell responses, activate intrahepatic NK cells, and drive reconstitution of antiviral immunity. See, e.g., 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).

[0006] Given the potential for treating a variety of diseases, there remains a need for new 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. Summary of the invention

[0007] In one embodiment, 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):

[0008]

[0009] Characterized by an X-ray powder diffraction (XRPD) pattern comprising three or more 2θ peaks (±0.2° 2θ) located at 10.9°, 11.5°, 13.2°, 14.7°, 15.5°, 21.4°, 21.9°, 23.2° or 24.9°, Form I.

[0010] In another embodiment, 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 hydrochloride:

[0011]

[0012] It is characterized in that the X-ray powder diffraction (XRPD) pattern contains three or more 2θ peaks (±0.2°2θ) located at 6.1°, 12.2°, 15.0°, 17.3°, 17.8°, 18.9°, 20.3°, 23.2° or 24°, hydrochloride salt form I.

[0013] In another embodiment, 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 hydrochloride:

[0014]

[0015] It is characterized in that the X-ray powder diffraction (XRPD) pattern contains three or more 2θ peaks (±0.2°2θ) located at 7.1°, 9.7°, 14.3°, 15.3°, 16.1°, 19.1°, 22.5°, 24.0° or 26.0°, hydrochloride form II.

[0016] In another embodiment, 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 tartaric acid:

[0017]

[0018] It is characterized in that the X-ray powder diffraction (XRPD) pattern contains three or more 2θ peaks (±0.2°2θ) located at 6.3°, 9.9°, 12.5°, 17.7°, 18.3°, 19.2°, 23.4°, 25.7° or 28.1°, and compound I is tartaric acid.

[0019] In another embodiment, 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 maleic acid:

[0020]

[0021] It is characterized in that the X-ray powder diffraction (XRPD) pattern contains three or more 2θ peaks (±0.2°2θ) located at 7.3°, 8.4°, 8.8°, 13.9°, 15.6°, 17.7°, 20.7°, 24.7° or 27.4°, and the compound I is maleic acid.

[0022] In another embodiment, 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 fumaric acid:

[0023]

[0024] It is characterized in that the X-ray powder diffraction (XRPD) pattern contains three or more 2θ peaks (±0.2°2θ) located at 6.7°, 8.3°, 10.1°, 12.6°, 16.1°, 18.5°, 20.6°, 25.2° or 27.6°, and compound I is fumaric acid.

[0025] In another embodiment, 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 methanesulfonic acid:

[0026]

[0027] It is characterized in that the X-ray powder diffraction (XRPD) pattern contains three or more 2θ peaks (±0.2° 2θ) located at 5.4°, 10.4°, 10.8°, 15.8°, 17.3°, 18.1°, 20.5°, 20.8° or 23.9°.

[0028] 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:

[0029] BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 The XRPD pattern of Compound 1 Form I is shown.

[0031] Figure 2 The DSC thermogram of Compound 1 Form I is shown.

[0032] Figure 3 The TGA curve of Compound 1 Form I is shown.

[0033] Figure 4 The DVS curve of Compound 1 Form I is shown.

[0034] Figure 5 The XRPD pattern of Compound 1 HCl salt Form I is shown.

[0035] Figure 6 Shown is the DSC thermogram of Compound 1 HCl salt Form I.

[0036] Figure 7 The TGA curve of Compound 1 HCl salt Form I is shown.

[0037] Figure 8 The DVS curve of Compound I HCl salt Form I is shown.

[0038] Fig. 9 The XRPD pattern of Compound I HCl salt Form II is shown.

[0039] Fig.10 DSC thermogram showing Compound I HCl salt Form II

[0040] Fig.11 TGA curve showing Compound I HCl salt Form II

[0041] Fig.12 The DVS curve of Compound I HCl salt Form II is shown.

[0042] Fig.13 The XRPD pattern of Compound 1 tartrate salt is shown.

[0043] Fig.14 The DSC thermogram of Compound 1 tartrate salt is shown.

[0044] Fig.15The TGA curve of Compound 1 tartrate salt is shown.

[0045] Fig.16 The DVS curve of Compound 1 tartrate salt is shown.

[0046] Fig.17 The XRPD pattern of Compound 1 maleate salt is shown.

[0047] Fig.18 Shown is the DSC thermogram of Compound 1 maleate salt.

[0048] Fig.19 The TGA curve of Compound 1 maleate salt is shown.

[0049] Fig. 20 The DVS curve of Compound 1 maleate salt is shown.

[0050] Fig.21 The XRPD pattern of Compound 1 fumarate salt is shown.

[0051] Fig. 22 Shown is the DSC thermogram of Compound 1 fumarate salt.

[0052] Fig.23 The TGA curve of Compound 1 fumarate salt is shown.

[0053] Fig.24 The DVS curve of Compound 1 fumarate salt is shown.

[0054] Fig.25 The XRPD pattern of Compound 1 mesylate salt is shown.

[0055] Fig.26 Shown is the DSC thermogram of Compound 1 mesylate salt.

[0056] Fig. 27 The TGA curve of Compound 1 mesylate salt is shown.

[0057] Fig.28 The DVS curve of Compound 1 mesylate salt is shown.

[0058] Fig.29 The XRPD pattern of amorphous Compound 1 is shown.

[0059] Fig.30 The DSC curve of amorphous Compound I is shown. DETAILED DESCRIPTION OF THE INVENTION

[0061] I. Overview

[0062] The present disclosure arises from the surprising discovery that solid forms of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (Compound I)

[0063]

[0064] and salts, solvates or co-crystals thereof. Compound I may adopt a variety of crystalline forms, including but not limited to Compound I crystalline form I, Compound I HCl crystalline form I, Compound I HCl crystalline form II, Compound I tartaric acid crystalline form, Compound I maleic acid crystalline form, Compound I fumaric acid crystalline form, Compound I methanesulfonic acid crystalline form and amorphous Compound I. Compound I may form a mixture of two or more crystalline forms, or form a single crystalline form that is substantially free of other crystalline forms.

[0065] The X-ray powder diffraction (XRPD) pattern of a 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 Ka radiation.

[0066] II. Definitions

[0067] As used in this specification, the following words and phrases are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0068] "Hydrate" refers to a complex formed by the combination of Compound I and water. The term includes stoichiometric and non-stoichiometric hydrates.

[0069] "Solvate" refers to a complex formed by the combination of Compound I and a solvent.

[0070] "Desolvated" refers to a solvate of a Compound 1 form as described herein and from which solvent molecules have been partially or completely removed. Desolvation techniques that produce a desolvated form include, but are not limited to, exposing a Compound 1 form (solvate) to a vacuum, subjecting the solvate to an elevated temperature, exposing the solvate to a gas stream, such as air or nitrogen, or any combination thereof. Thus, a desolvated Compound 1 form can be anhydrous, i.e., completely devoid of solvent molecules, or partially solvated, wherein the solvent molecules are present in stoichiometric or non-stoichiometric amounts.

[0071] "Alcohol" refers to a solvent having a hydroxyl group. Representative alcohols may have any suitable number of carbon atoms, such as C 1 -C 6 , and any suitable number of hydroxyl groups, such as 1 to 3. Exemplary alcohols include, but are not limited to, methanol, ethanol, n-propanol, isopropanol, and the like.

[0072] A "therapeutically effective amount" refers to an amount sufficient to effect treatment, as defined below, when administered to a mammal in need of such treatment. The therapeutically effective amount will vary depending on the subject being treated, the subject's weight and age, the subject's weight and age, the severity of the disease condition, the mode of administration, etc., and can be readily determined by one of ordinary skill in the art.

[0073] "Substantially free of other crystalline forms of Compound I" means a crystalline form of Compound I that contains less than 10% of other crystalline forms of Compound I. For example, substantially free can mean a crystalline form of Compound I that contains less than 9, 8, 7, 6, 5, 4, 3, 2, or 1% of other crystalline forms of Compound I. Preferably, substantially free means a crystalline form of Compound I that contains less than 5% of other crystalline forms of Compound I. Substantially free means a crystalline form of Compound I that contains less than 1% of other crystalline forms of Compound I.

[0074] III. Solid Form of Compound I

[0075] The present invention 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 salts, solvates and hydrates. In some embodiments, the present disclosure provides a crystalline form of Compound I having the following structure:

[0076]

[0077] and its salts, solvates or hydrates.

[0078] Compound 1 can adopt a variety of crystalline forms, including but not limited to Form I, HCl salt, HCl salt crystalline form I, HCl salt crystalline form II, Compound 1 tartrate, Compound 1 maleate, Compound 1 fumarate and Compound 1 methanesulfonate. Compound 1 can form a mixture of two or more crystalline forms, or form a single crystalline form that is substantially free of other crystalline forms. Compound 1 can also adopt a solid amorphous form.

[0079] 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):

[0080]

[0081] Or a pharmaceutically acceptable salt or co-crystal thereof. The crystalline form of Compound 1 may be an anhydrate, a salt, a solvate, or a co-crystal. In some embodiments, the crystalline form of Compound 1 may be a salt or a co-crystal. In some embodiments, the crystalline form of Compound 1 may be anhydrous or solvated. In some embodiments, the crystalline form of Compound 1 may be hydrated.

[0082] In some embodiments, the present invention provides a compound selected from the following: (R)-2-((2-amino-7-fluoropyrido [3,2-d] pyrimidin-4-yl) amino)-2-methylhexan-1-ol crystalline form I; (R)-2-((2-amino-7-fluoropyrido [3,2-d] pyrimidin-4-yl) amino)-2-methylhexan-1-ol HCl salt crystalline form I; (R)-2-((2-amino-7-fluoropyrido [3,2-d] pyrimidin-4-yl) amino)-2-methylhexan-1-ol HCl salt crystalline form I; (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol tartrate; (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol maleate; (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol fumarate; and

[0083] (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol methanesulfonate. 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.

[0084] Crystal form I

[0085] 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 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):

[0086]

[0087] Characterized by an X-ray powder diffraction (XRPD) pattern comprising three or more 2θ peaks located at 10.9°, 11.5°, 13.2°, 14.7°, 15.5°, 21.4°, 21.9°, 23.2°, or 24.9° (±0.2° 2θ), Form I. In some embodiments, Form I is characterized by an XRPD pattern comprising four, five, six, seven, eight, or nine peaks located at 10.9°, 11.5°, 13.2°, 14.7°, 15.5°, 21.4°, 21.9°, 23.2°, or 24.9° 2θ (±0.2° 2θ).

[0088] In some embodiments, Form I is characterized by an XRPD pattern comprising four or more peaks located 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 located 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 located at 10.9°, 11.5°, 13.2°, 14.7°, 15.5°, 21.4°, 21.9°, 23.2°, or 24.9° 2θ peaks (±0.2° 2θ). In some embodiments, Form I is characterized by an XRPD pattern comprising seven or more peaks located 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 eight or more peaks located at 10.9°, 11.5°, 13.2°, 14.7°, 15.5°, 21.4°, 21.9°, 23.2°, or 24.9° 2θ (±0.2° 2θ).

[0089] In some embodiments, Form I is characterized in that the XRPD pattern includes peaks at 15.5°, 21.4°, and 21.9° (± 0.2° 2θ). In some embodiments, the XRPD pattern further includes 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 includes 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 includes 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 additional peaks at 10.9°, 11.5°, 13.2°, 14.7°, 23.2°, and 24.9° 2θ (± 0.2° 2θ).

[0090] In some embodiments, Form I is characterized in that the XRPD pattern includes peaks at 10.9°, 13.2°, and 14.7° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern also includes one, two, three, four, or more additional peaks located at 11.5°, 15.5°, 21.4°, 21.9°, 23.2°, or 24.9° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern also includes one or more additional peaks located at 11.5°, 15.5°, 21.4°, 21.9°, 23.2°, or 24.9° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern also includes two or more additional peaks located 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).

[0091] In some embodiments, Form I is characterized by an XRPD pattern including three or more peak XRPD patterns located 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 including four or more peak XRPD patterns located 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 including five or more peak XRPD patterns located 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).

[0092] 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 of the following dimensions as determined by single crystal X-ray crystallography: α = 90°; β = 90°; and γ = 90°. In some embodiments, Form I is characterized by being substantially as Figure 1 XRPD pattern shown in .

[0093] In some embodiments, Form I is characterized by having a differential scanning calorimetry (DSC) thermogram with an endotherm beginning at about 164°C. In some embodiments, Form I is characterized by being substantially as Figure 2 In some embodiments, Form I is characterized by Figure 3 In some embodiments, Form I is characterized by Figure 4 Dynamic vapor sorption (DVS) curves.

[0094] In some embodiments, Form I is characterized by one 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 having the following dimensions as determined by single crystal X-ray crystallography: α = 90°; β = 90°; and γ = 90°; and (c) a differential scanning calorimetry (DSC) thermogram having an endotherm starting at 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 having the following dimensions as determined by single crystal X-ray crystallography: α = 90°; β = 90°; and γ = 90°; and (c) a differential scanning calorimetry (DSC) thermogram having an endotherm onset at about 164°C. In some embodiments, Form I is characterized by: (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 having dimensions as determined by single crystal X-ray crystallography of α = 90°; β = 90°; and γ = 90°; and (c) a differential scanning calorimetry (DSC) thermogram having an endotherm onset at about 164°C.

[0095] In some embodiments, Form I is characterized by one or more of the following:

[0096] (a) The XRPD pattern is basically as follows Figure 1 (b) a unit cell having the following dimensions as determined by single crystal X-ray crystallography: α = 90°; β = 90°; and γ = 90°; (c) substantially as Figure 2 DSC thermogram shown; (d) substantially as Figure 3 Thermogravimetric analysis (TGA) curve shown; and (e) substantially as Figure 4 In some embodiments, Form I is characterized by two or more of the following: (a) substantially as Figure 1 (b) a unit cell having the following dimensions as determined by single crystal X-ray crystallography: α = 90°; β = 90°; and γ = 90°; (c) substantially as Figure 2 DSC thermogram shown; (d) substantially as Figure 3 Thermogravimetric analysis (TGA) curve shown; and (e) substantially as Figure 4 In some embodiments, Form I is characterized by the following: (a) substantially as Figure 1 (b) a unit cell having the following dimensions as determined by single crystal X-ray crystallography: α = 90°; β = 90°; and γ = 90°; (c) substantially as Figure 2 DSC thermogram shown; (d) substantially as Figure 3 Thermogravimetric analysis (TGA) curve shown; and (e) substantially as Figure 4 Dynamic vapor sorption (DVS) curves are shown.

[0097] HCl salt, Form I

[0098] 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 HCl salt 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 hydrochloride

[0099]

[0100] It is characterized in that the XRPD spectrum includes three or more peaks located at 6.1°, 12.2°, 15.0°, 17.3°, 17.8°, 18.9°, 20.3°, 23.2° or 24.1° 2θ (± 0.2° 2θ) XRPD spectrum hydrochloride salt form I.

[0101] In some embodiments, the hydrochloride salt Form I is characterized by an XRPD pattern comprising four, five, six, seven, eight or nine peaks at (±0.2° 2θ) at 6.1°, 12.2°, 15.0°, 17.3°, 17.8°, 18.9°, 20.3°, 23.2° or 24.1° 2θ, hydrochloride salt Form I. In some embodiments, the hydrochloride salt Form I is characterized by an XRPD pattern comprising four or more peaks at (±0.2° 2θ) at 6.1°, 12.2°, 15.0°, 17.3°, 17.8°, 18.9°, 20.3°, 23.2° or 24.1° 2θ, hydrochloride salt Form I. In some embodiments, the hydrochloride salt Form I is characterized by an XRPD pattern comprising 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), hydrochloride salt Form I. In some embodiments, the hydrochloride salt Form I is characterized by an XRPD pattern comprising 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, the hydrochloride salt Form I is characterized by an XRPD pattern comprising seven 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), hydrochloride salt Form I. In some embodiments, the hydrochloride salt Form I is characterized by an XRPD pattern comprising eight 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), XRPD pattern, hydrochloride salt Form I.

[0102] In some embodiments, the hydrochloride salt Form I is characterized in that the XRPD pattern includes peaks at 6.1°, 15.0°, and 17.8° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern of the hydrochloride salt Form I also includes 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, the XRPD pattern of the hydrochloride salt Form I also includes 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, the XRPD pattern of the hydrochloride salt form I also includes three or more additional peaks located at 12.2°, 17.3°, 18.9°, 20.3°, 23.2°, or 24.1° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern of the hydrochloride salt form I also includes four or more additional peaks located at 12.2°, 17.3°, 18.9°, 20.3°, 23.2°, or 24.1° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern of the hydrochloride salt form I also includes five or more additional peaks located at 12.2°, 17.3°, 18.9°, 20.3°, 23.2°, or 24.1° 2θ (± 0.2° 2θ).

[0103] In some embodiments, the hydrochloride salt form I is characterized in that the XRPD pattern includes peaks at 12.2°, 18.9°, and 24.1° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern of the hydrochloride salt form I also includes 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, the hydrochloride salt form I is an XRPD pattern that also includes two or additional peaks at 6.1°, 15.0°, 17.3°, 17.8°, 20.3°, or 23.2° 2θ (± 0.2° 2θ). In some embodiments, the hydrochloride salt form I is an XRPD pattern that also includes three or more additional peaks located at 6.1°, 15.0°, 17.3°, 17.8°, 20.3°, or 23.2° 2θ (± 0.2° 2θ). In some embodiments, the hydrochloride salt form I is an XRPD pattern that also includes four or more additional peaks located at 6.1°, 15.0°, 17.3°, 17.8°, 20.3°, or 23.2° 2θ (± 0.2° 2θ). In some embodiments, the hydrochloride salt form I is an XRPD pattern that also includes five or more additional peaks located at 6.1°, 15.0°, 17.3°, 17.8°, 20.3°, or 23.2° 2θ (± 0.2° 2θ).

[0104] In some embodiments, the hydrochloride salt form I is characterized in that the XRPD pattern includes three or more peaks located at 6.1°, 12.2°, 15.0°, 17.8°, 18.9°, or 24.1° 2θ 2θ (± 0.2° 2θ). In some embodiments, the hydrochloride salt form I is characterized in that the XRPD pattern includes four or more peaks located at 6.1°, 12.2°, 15.0°, 17.8°, 18.9°, or 24.1° 2θ 2θ (± 0.2° 2θ). In some embodiments, the hydrochloride salt form I is characterized in that the XRPD pattern includes five or more peaks located at 6.1°, 12.2°, 15.0°, 17.8°, 18.9°, or 24.1° 2θ 2θ (± 0.2° 2θ). In some embodiments, the 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 2θ (± 0.2° 2θ).

[0105] In some embodiments, the 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, the hydrochloride salt Form I is characterized by being substantially as Figure 5 XRPD pattern shown in .

[0106] In some embodiments, the hydrochloride salt Form I is characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm onset at about 135°C.

[0107] In some embodiments, the hydrochloride salt form I is characterized by being substantially as follows Figure 6 In some embodiments, the hydrochloride salt form I is characterized by being substantially as follows Figure 7 Thermogravimetric analysis (TGA) curve shown in FIG. In some embodiments, the hydrochloride salt form I is characterized by being substantially as follows Figure 8 Dynamic vapor sorption (DVS) curves shown in .

[0108] In some embodiments, the 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 thermogram (DSC) thermogram having an endotherm starting at about 135°C. In some embodiments, the hydrochloride salt Form I is characterized by two or more of the following: (a) substantially as Figure 5 (b) substantially as shown in Figure 6 DSC thermogram shown; (c) substantially as Figure 7 Thermogravimetric analysis (TGA) curve shown; and (d) substantially as Figure 8 Dynamic vapor sorption (DVS) curves are shown.

[0109] HCl salt, Form II

[0110] 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 HCl salt Form II. 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 hydrochloride:

[0111]

[0112] It is characterized in that the XRPD spectrum includes three or more peaks located at 7.1°, 9.7°, 14.3°, 15.3°, 16.1°, 19.1°, 22.5°, 24.0° or 26.0° 2θ (±0.2° 2θ), hydrochloride form II.

[0113] In some embodiments, the 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, the hydrochloride salt Form II is characterized by an XRPD pattern including four 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, the hydrochloride salt form II is characterized in that the XRPD pattern includes five or more peaks located 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, the hydrochloride salt form II is characterized in that the XRPD pattern includes six or more peaks located 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, the hydrochloride salt Form II is characterized in that the XRPD pattern includes seven or more peaks located 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, the hydrochloride salt Form II is characterized in that the XRPD pattern includes eight or more peaks located at 7.1°, 9.7°, 14.3°, 15.3°, 16.1°, 19.1°, 22.5°, 24.0°, or 26.0° 2θ (± 0.2° 2θ).

[0114] In some embodiments, the hydrochloride salt form II is characterized in that the XRPD pattern includes peaks at 7.1°, 15.3°, and 24.0° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern also includes 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 also includes 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 also includes 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 located 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 five or more additional peaks located at 9.7°, 14.3°, 16.1°, 19.1°, 22.5°, or 26.0° 2θ (± 0.2° 2θ).

[0115] In some embodiments, the hydrochloride salt form II is characterized in that the XRPD pattern includes peaks at 14.3°, 16.1°, and 26.0° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern also includes 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 also includes two or more additional peaks at 7.1°, 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 7.1°, 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 7.1°, 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 five or more additional peaks at 7.1°, 9.7°, 14.3°, 16.1°, 19.1°, 22.5°, or 26.0° 2θ (± 0.2° 2θ).

[0116] 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).

[0117] In some embodiments, the hydrochloride salt form II is characterized by including three or more XRPD patterns at 7.1°, 14.3°, 15.3°, 16.1°, 24.0°, or 26.0° 2θ (± 0.2° 2θ) peaks. In some embodiments, the hydrochloride salt form II is characterized by including four or more XRPD patterns at 7.1°, 14.3°, 15.3°, 16.1°, 24.0°, or 26.0° 2θ (± 0.2° 2θ) peaks. In some embodiments, the hydrochloride salt form II is characterized by including five or more XRPD patterns at 7.1°, 14.3°, 15.3°, 16.1°, 24.0°, or 26.0° 2θ (± 0.2° 2θ) peaks. 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).

[0118] In some embodiments, the 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, the hydrochloride salt form II is characterized by being substantially as Fig. 9 In some embodiments, the hydrochloride salt form II is characterized by a differential scanning calorimetry thermogram (DSC) thermogram having an endotherm starting at about 58°C. In some embodiments, the hydrochloride salt form II is characterized by being substantially as Fig.10 In some embodiments, the hydrochloride salt form II is characterized by being substantially as follows Fig.11Thermogravimetric analysis (TGA) curve shown in FIG. In some embodiments, the hydrochloride salt form II is characterized by being substantially as Fig.12 Dynamic vapor sorption (DVS) curves shown in .

[0119] In some embodiments, the 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 thermogram (DSC) thermogram having an endotherm starting at about 58°C. In some embodiments, the hydrochloride salt form II is characterized by two or more of the following: (a) substantially as Fig. 9 (b) substantially as shown in Fig.10 DSC thermogram shown; (c) substantially as Fig.11 Thermogravimetric analysis (TGA) curve shown; and (d) substantially as Fig.12 Dynamic vapor sorption (DVS) curves are shown.

[0120] tartaric acid

[0121] 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. 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 tartrate cocrystal of Compound I tartrate. 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:

[0122]

[0123] It is characterized in that the XRPD spectrum includes three or more peaks located at 6.3°, 9.9°, 12.5°, 17.7°, 18.3°, 19.2°, 23.4°, 25.7° or 28.1° 2θ (±0.2° 2θ), Compound I tartrate.

[0124] In some embodiments, the tartrate salt of Compound 1 is characterized by an XRPD pattern comprising four or more peaks located 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, the tartrate salt of Compound 1 is characterized by an XRPD pattern comprising five or more peaks located 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, the tartrate salt of Compound 1 is characterized by an XRPD pattern comprising six or more peaks located 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, the tartrate salt of Compound 1 is characterized by an XRPD pattern comprising seven or more peaks located 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, the Compound 1 tartrate salt is characterized by an XRPD pattern comprising eight or more peaks located at 6.3°, 9.9°, 12.5°, 17.7°, 18.3°, 19.2°, 23.4°, 25.7°, or 28.1° 2θ (±0.2° 2θ).

[0125] In some embodiments, the compound I tartrate salt is characterized in that the XRPD pattern includes peaks at 6.3°, 18.3°, and 23.4° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern also includes 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 also includes 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 also includes 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 also includes 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 also includes five 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 also includes additional peaks at 9.9°, 12.5°, 17.7°, 19.2°, 25.7°, and 28.1° 2θ (± 0.2° 2θ).

[0126] In some embodiments, the compound I tartrate salt is characterized in that the XRPD pattern includes peaks at 9.9 °, 12.5 °, and 17.7 ° 2θ (± 0.2 ° 2θ). In some embodiments, the XRPD pattern also includes 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 also includes 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 also includes 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 also includes 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 also includes 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 also includes additional peaks at 6.3°, 18.3°, 19.2°, 23.4°, 25.7°, and 28.1° 2θ (± 0.2° 2θ).

[0127] In some embodiments, the Compound I tartrate salt is characterized by three or more XRPD peaks located at 6.3°, 9.9°, 12.5°, 17.7°, 18.3°, or 23.4° 2θ (± 0.2° 2θ). In some embodiments, the Compound I tartrate salt is characterized by four or more XRPD peaks located at 6.3°, 9.9°, 12.5°, 17.7°, 18.3°, or 23.4° 2θ (± 0.2° 2θ). In some embodiments, the Compound I tartrate salt is characterized by five or more XRPD peaks located at 6.3°, 9.9°, 12.5°, 17.7°, 18.3°, or 23.4° 2θ (± 0.2° 2θ). In some embodiments, the Compound 1 tartrate salt is characterized by XRPD peaks at 6.3°, 9.9°, 12.5°, 17.7°, 18.3°, and 23.4° 2θ (± 0.2° 2θ).

[0128] In some embodiments, the tartrate salt of Compound 1 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, the tartrate salt of Compound 1 is characterized by being substantially as Fig.13 In some embodiments, the Compound I tartrate salt is characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm starting at about 157° C. In some embodiments, the Compound I tartrate salt is characterized by being substantially as Fig.14 In some embodiments, the tartrate salt of Compound 1 is characterized by being substantially as follows Fig.15 In some embodiments, the tartrate salt of Compound 1 is characterized by being substantially as follows Fig.16 Dynamic vapor sorption (DVS) curves shown in .

[0129] In some embodiments, the tartrate salt of Compound I 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 starting at about 157°C. In some embodiments, the tartrate salt of Compound I is characterized by two or more of the following: (a) substantially as Fig.13 (b) substantially as shown in Fig.14 DSC thermogram shown; (c) substantially as Fig.15 The DSC thermogram shown; or (d) substantially as Fig.16 Dynamic vapor sorption (DVS) curves are shown.

[0130] Maleic acid

[0131] 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 maleate co-crystal of Compound 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 maleate:

[0132]

[0133] Characterized in that the XRPD pattern includes three or more peaks located at 7.3°, 8.4°, 8.8°, 13.9°, 15.6°, 17.7°, 20.7°, 24.7° or 27.4° 2θ (±0.2° 2θ), Compound I maleate.

[0134] In some embodiments, the maleate salt of Compound 1 is characterized by an XRPD pattern comprising four or more peaks located 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, the maleate salt of Compound 1 is characterized by an XRPD pattern comprising five or more peaks located 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, the maleate salt of Compound 1 is characterized by an XRPD pattern comprising six or more peaks located 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, the maleate salt of Compound 1 is characterized by an XRPD pattern comprising seven or more peaks located 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, the maleate salt of Compound 1 is characterized by an XRPD pattern comprising eight or more peaks located at 7.3°, 8.4°, 8.8°, 13.9°, 15.6°, 17.7°, 20.7°, 24.7°, or 27.4° 2θ (±0.2° 2θ).

[0135] In some embodiments, the maleate salt of Compound I is characterized in that the XRPD pattern includes peaks at 7.3°, 17.7°, and 24.7° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern also includes 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 also includes 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 also includes 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).

[0136] In some embodiments, the maleate salt of Compound I is characterized in that the XRPD pattern includes peaks at 13.9°, 15.6°, and 27.4°2θ (±0.2°2θ). In some embodiments, the XRPD pattern also includes 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 also includes 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 also includes 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).

[0137] In some embodiments, the maleate salt of Compound I is characterized in that the XRPD pattern includes three or more peaks located at 7.3°, 13.9°, 15.6°, 17.7°, 24.7°, or 27.4° 2θ (± 0.2° 2θ). In some embodiments, the maleate salt of Compound I is characterized in that the XRPD pattern includes four or more peaks located at 7.3°, 13.9°, 15.6°, 17.7°, 24.7°, or 27.4° 2θ (± 0.2° 2θ). In some embodiments, the maleate salt of Compound I is characterized in that the XRPD pattern includes five or more peaks located at 7.3°, 13.9°, 15.6°, 17.7°, 24.7°, or 27.4° 2θ (± 0.2° 2θ). In some embodiments, the maleate salt of Compound 1 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).

[0138] In some embodiments, the maleic acid of Compound 1 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, the maleic acid salt of Compound 1 is characterized by being substantially as Fig.17 In some embodiments, the maleate salt of Compound I is characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm starting at about 143° C. In some embodiments, the maleate salt of Compound I is characterized by being substantially as Fig.18 In some embodiments, the maleate salt of Compound 1 is characterized by being substantially as follows Fig.19 Thermogravimetric analysis (TGA) curve shown in FIG. In some embodiments, the maleate salt of Compound 1 is characterized by being substantially as follows Fig. 20 Dynamic vapor sorption (DVS) curves are shown.

[0139] In some embodiments, the maleate salt of Compound 1 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). In some embodiments, the maleate salt of Compound 1 is characterized by two or more of the following: (a) substantially as Fig.17 The XRPD pattern shown; (b) substantially as Fig.18 DSC thermogram shown; (c) substantially as Fig.19 Thermogravimetric analysis (TGA) curve shown; or (d) substantially as Fig. 20 Dynamic vapor sorption (DVS) curves are shown.

[0140] Fumaric Acid

[0141] 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. 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 cocrystal of Compound 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 fumarate:

[0142]

[0143] It is characterized in that the XRPD spectrum includes three or more peaks located at 6.7°, 8.3°, 10.1°, 12.6°, 16.1°, 18.5°, 20.6°, 25.2° or 27.6° 2θ (± 0.2° 2θ), compound I fumarate.

[0144] In some embodiments, the fumarate salt of Compound 1 is characterized by an XRPD pattern comprising four or more peaks located 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, the fumarate salt of Compound 1 is characterized by an XRPD pattern comprising five or more peaks located 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, the fumarate salt of Compound 1 is characterized by an XRPD pattern comprising six or more peaks located 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, the fumarate salt of Compound 1 is characterized by an XRPD pattern comprising seven or more peaks located 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, the fumarate salt of Compound 1 is characterized by an XRPD pattern comprising eight or more peaks located at 6.7°, 8.3°, 10.1°, 12.6°, 16.1°, 18.5°, 20.6°, 25.2°, or 27.6° 2θ (±0.2° 2θ).

[0145] In some embodiments, the fumarate salt of Compound I is characterized in that the XRPD pattern includes peaks at 6.7°, 8.3°, and 25.2°2θ (±0.2°2θ). In some embodiments, the XRPD pattern also includes one 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 also includes 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 also includes 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 also includes 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 also includes 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 also includes additional peaks at 10.1°, 12.6°, 16.1°, 18.5°, 20.6°, and 27.6° 2θ (± 0.2° 2θ).

[0146] In some embodiments, Compound I fumaric acid is characterized in that the XRPD pattern includes peaks at 18.5°, 20.6°, and 27.6° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern also includes 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 also includes two or more additional peaks at 6.7°, 8.3°, 10.1°, 12.6°, 16.1°, or 25.2° 2θθ (± 0.2° 2θ). In some embodiments, the XRPD pattern also includes three or more additional peaks at 6.7°, 8.3°, 10.1°, 12.6°, 16.1°, or 25.2° 2θθ (± 0.2° 2θ). In some embodiments, the XRPD pattern also includes four or more additional peaks at 6.7°, 8.3°, 10.1°, 12.6°, 16.1°, or 25.2° 2θθ (± 0.2° 2θ). In some embodiments, the XRPD pattern also includes five or more additional peaks at 6.7°, 8.3°, 10.1°, 12.6°, 16.1°, or 25.2° 2θθ (± 0.2° 2θ). In some embodiments, the XRPD pattern also includes additional peaks at 6.7°, 8.3°, 10.1°, 12.6°, 16.1°, or 25.2° 2θθ (± 0.2° 2θ).

[0147] In some embodiments, the fumarate salt of Compound I is characterized in that the XRPD pattern includes three or more peaks located at 6.7°, 8.3°, 18.5°, 20.6°, 25.2°, or 27.6° 2θ (± 0.2° 2θ). In some embodiments, the fumarate salt of Compound I is characterized in that the XRPD pattern includes four or more peaks located at 6.7°, 8.3°, 18.5°, 20.6°, 25.2°, or 27.6° 2θ (± 0.2° 2θ). In some embodiments, the fumarate salt of Compound I is characterized in that the XRPD pattern includes five or more peaks located at 6.7°, 8.3°, 18.5°, 20.6°, 25.2°, or 27.6° 2θ (± 0.2° 2θ). In some embodiments, the fumarate salt of Compound 1 is characterized by an XRPD pattern comprising a peak at 6.7°, 8.3°, 18.5°, 20.6°, 25.2°, or 27.6° 2θ (±0.2° 2θ).

[0148] In some embodiments, the fumaric acid salt of Compound 1 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, the fumaric acid salt of Compound 1 is characterized by being substantially as Fig.21 In some embodiments, Compound I fumaric acid is characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm starting at about 70°C. In some embodiments, the DSC thermogram has a second endotherm starting at about 167°C. In some embodiments, Compound I fumaric acid is characterized by being substantially as Fig. 22 In some embodiments, Compound 1 fumaric acid is characterized by being substantially as follows Fig.23 Thermogravimetric analysis (TGA) curve shown. In some embodiments, Compound I fumaric acid is characterized by being substantially as Fig.24 Dynamic vapor sorption (DVS) curves are shown.

[0149] In some embodiments, Compound I fumaric acid 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 thermogram (DSC) thermogram having a first onset of about 70°C and a second onset of about 167°C endothermic peaks. In some embodiments, Compound I fumaric acid is characterized by two or more of the following: (a) substantially as Fig.21 (b) substantially as shown in Fig. 22 DSC thermogram shown; (c) substantially as Fig.23 Thermogravimetric analysis (TGA) curve shown; or (d) substantially as Fig.24 Dynamic vapor sorption (DVS) curves are shown.

[0150] Methanesulfonic acid

[0151] 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 methanesulfonate 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 Compound I methanesulfonic acid cocrystal. 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 methanesulfonic acid:

[0152]

[0153] It is characterized in that the XRPD spectrum includes three or more peaks located at 5.4°, 10.4°, 10.8°, 15.8°, 17.3°, 18.1°, 20.5°, 20.8° or 23.9° 2θ (±0.2° 2θ), compound I methanesulfonic acid.

[0154] In some embodiments, Compound 1 methanesulfonic acid is characterized in that its XRPD pattern includes four or more peaks located 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 1 methanesulfonic acid is characterized in that its XRPD pattern includes five or more peaks located 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 1 methanesulfonic acid is characterized in that its XRPD pattern includes six or more peaks located 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 1 methanesulfonic acid is characterized in that its XRPD pattern includes seven or more peaks located 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 1 methanesulfonic acid is characterized in that its XRPD pattern includes eight or more peaks located at 5.4°, 10.4°, 10.8°, 15.8°, 17.3°, 18.1°, 20.5°, 20.8°, or 23.9° 2θ (±0.2° 2θ).

[0155] In some embodiments, the mesylate salt of Compound I is characterized in that the XRPD pattern includes peaks at 5.4°, 18.1°, and 20.5° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern also includes 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 also includes 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 includes 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).

[0156] In some embodiments, the mesylate salt of Compound I is characterized in that the XRPD pattern includes peaks at 15.8°, 20.8°, and 23.9° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern also includes 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 also includes 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 also includes 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).

[0157] In some embodiments, the mesylate salt of Compound 1 is characterized in that the XRPD pattern includes three or more peaks located at 5.4°, 18.1°, 15.8°, 20.5°, 20.8°, or 23.9° 2θ (± 0.2° 2θ). In some embodiments, the mesylate salt of Compound 1 is characterized in that the XRPD pattern includes four or more peaks located at 5.4°, 18.1°, 15.8°, 20.5°, 20.8°, or 23.9° 2θ (± 0.2° 2θ). In some embodiments, the mesylate salt of Compound 1 is characterized in that the XRPD pattern includes five or more peaks located at 5.4°, 18.1°, 15.8°, 20.5°, 20.8°, or 23.9° 2θ (± 0.2° 2θ). In some embodiments, the mesylate salt of Compound 1 is characterized by an XRPD pattern comprising peaks at 5.4°, 18.1°, 15.8°, 20.5°, 20.8°, and 23.9° 2θ (± 0.2° 2θ).

[0158] In some embodiments, the mesylate salt of Compound 1 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, the mesylate salt of Compound 1 is characterized by being substantially as Fig.25 In some embodiments, the mesylate salt of Compound I is characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm starting at about 30°C. In some embodiments, the DSC thermogram has a second endotherm starting at about 147°C. In some embodiments, the mesylate salt of Compound I is characterized by being substantially as Fig.26 In some embodiments, the mesylate salt of Compound 1 is characterized by being substantially as follows Fig. 27 Thermogravimetric analysis (TGA) curve shown in FIG. In some embodiments, the mesylate salt of Compound I is characterized by being substantially as follows Fig.28 Dynamic vapor sorption (DVS) curves shown in .

[0159] In some embodiments, the mesylate salt of Compound I 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 thermogram (DSC) thermogram having a first endotherm starting at about 30°C and a second endotherm starting at about 147°C. In some embodiments, the mesylate salt of Compound I is characterized by two or more of the following: (a) substantially as Fig.25 (b) substantially as shown in Fig.26 DSC thermogram shown; (c) substantially as Fig. 27 Thermogravimetric analysis (TGA) curve shown; or (d) substantially as Fig.28 Dynamic vapor sorption (DVS) curves are shown.

[0160] Amorphous Compound I

[0161] 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:

[0162]

[0163] In some embodiments, amorphous Compound 1 is characterized by an XRPD pattern substantially as follows Fig.29In some embodiments, amorphous Compound 1 is characterized by being substantially as Fig.30 In some embodiments, amorphous Compound 1 is characterized by one or more of the following: Fig.29 or (b) substantially as shown in Fig.30 DSC thermogram shown.

[0164] IV. Methods for Preparing Solid Forms of Compound I

[0165] Solid forms of Compound 1 can be prepared by a variety of methods. For example, Compound 1 can be dissolved in a single solvent system and allowed to crystallize. Alternatively, Compound 1 can be crystallized from a dual solvent system by dissolving Compound 1 in a solvent (good solvent) and then adding an anti-solvent (poor solvent) to the mixture to allow Compound 1 to crystallize.

[0166] 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, C 1 -C 3 Alcohols (methanol, ethanol, propanol, isopropanol), ethylene glycol and polyethylene glycol such as PEG400, alkanoates such as ethyl acetate, propyl acetate, isopropyl acetate and butyl acetate, acetonitrile, alkanoates such as acetone, butanone, methyl ethyl ketone (MEK), methyl propyl ketone (MPK) and methyl isobutyl ketone (MIBK), ethers such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran, 1,2-dimethoxyethane and dioxane, aromatic compounds such as benzene and toluene, halogenated solvents such as dichloromethane, chloroform and carbon tetrachloride, dimethyl sulfoxide (DMSO) and dimethylformamide (DMF). Suitable solvents include, but are not limited to, halogenated C 1 -C 3 Alcohol (trifluoromethanol, trifluoroethanol (TFE), hexafluoroisopropanol (HFIPA)). For example, the solvent can be a polar aprotic solvent, such as dichloromethane, N-methylpyrrolidone, tetrahydrofuran, ethyl acetate, acetone, methyl ethyl ketone, dimethylformamide (DMF), acetonitrile (AcCN), dimethyl sulfoxide (DMSO), etc. The solvent can also be a polar protic solvent, such as tert-butyl alcohol, n-propanol, isopropanol, ethanol, methanol, acetic acid, water, etc. The solvent can also be a non-polar solvent, such as hexane, pentane, petroleum ether, benzene, toluene, ether, methyl tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran, 1,2-dimethoxyethane and 1,4-dioxane, chloroform and carbon tetrachloride.

[0167] Two or more solvents can be used in a solvent mixture in any suitable ratio. 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 10: 1 to 1: 1, or 10: 1 to 5: 1, or 5: 1 to 1: 5, or 5: 1 to 1: 1, or 4: 1 to 1: 1, or 3: 1 to 1: 1, or 2: 1 to 1: 1. Other solvent ratios include about 10: 1, 9: 1, 8: 1, 7: 1, 6: 1, 5: 1, 4: 1, 3: 1, 2: 1, 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1: 6, 1: 7, 1: 8, 1: 9 or about 1: 10 (volume / volume or weight / weight).

[0168] The method for preparing the solid form of Compound I can be carried out under any suitable reaction conditions. For example, the method for preparing the crystalline form of Compound I can be carried out at any suitable temperature, such as but not limited to below room temperature, at room temperature or above room temperature. In some embodiments, the temperature may be from about -78°C to about 100°C, or from about 0°C to about 50°C, or from about 10°C to about 30°C. For example, the reaction mixture is at a temperature of about 20°C, or 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or about 100°C. The reaction mixture can also be at a temperature of about 20°C, 15°C, 10°C, 5°C, 0°C, -5°C, -10°C, -20°C, -30°C, -40°C, -50°C, -60°C, -70°C or about -78°C. In some embodiments, the temperature may be the reflux temperature of the specific solvent used in the method. In other embodiments, a crystalline form of Compound I can be heated to above about 100°C such that one crystalline form of Compound I forms a second crystalline form of Compound I.

[0169] The method for preparing a solid form of Compound I may include a variety of other steps. For example, the solvent may be evaporated, a seed crystal may be added to the mixture, the mixture may be heated and cooled once or repeatedly, etc. For example, the method may include heating the reaction mixture to a temperature of about 20°C, or 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or about 100°C. The method may also include cooling the reaction mixture to a temperature of about 20°C, 15°C, 10°C, 5°C, 0°C, -5°C, -10°C, -20°C, -30°C, -40°C, -50°C, -60°C, -70°C or about -78°C. The temperature of the reaction mixture may be changed at any suitable rate. For example, the temperature change rate may be about 0.1°C / min to about 10°C / min.

[0170] The method of preparing the crystalline form of Compound 1 can be carried out for any suitable time. For example, the time can be a few minutes, a few hours, or a few days. In some embodiments, the time can be a few hours, such as overnight. The method of preparing the crystalline form of Compound 1 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.

[0171] Crystallization can be induced by methods known in the art, such as by mechanical means, such as scraping or rubbing the contact surface of the reaction vessel with a glass rod. Optionally, a saturated or supersaturated solution can be seeded with seed crystals. The method of preparing a solid form of Compound 1 may also include crystallizing seed crystals of Compound 1.

[0172] The separation of the desired crystal form can be achieved by removing the solvent and precipitating the solvent from the crystal. Typically, this is done by known methods, such as filtering, suction filtration, decantation or centrifugation. Further separation can be achieved by removing any excess solvent from the crystal form by methods known to those skilled in the art (e.g., applying vacuum and / or by heating).

[0173] Crystalline Form I

[0174] Various solvents and combinations of solvents can be used to prepare crystalline Compound I Form I by a variety of methods. 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. Solvent combinations that can be used to prepare 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, solvent combinations may include ethanol and water, as well as 2-methyltetrahydrofuran and n-heptane. When two or more solvents are used in combination, they may be present in any suitable ratio as described above. In some embodiments, the solvent can be isopropanol:water (9:1), ethanol:n-heptane (1:2), tetrahydrofuran:n-heptane, acetone:water (9:1), methanol:water (9:1), 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 (1:1), tetrahydrofuran:n-heptane (1:2) or 2-methyltetrahydrofuran:n-heptane (1:3). In some embodiments, the solvent can 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).

[0175] In some embodiments, the present disclosure provides a method of preparing crystalline Compound 1, Form I of the present disclosure, comprising forming a mixture of Compound 1 of the present disclosure and a solvent under conditions suitable for preparing Form I. In some embodiments, Compound 1 is dissolved in the solvent. In some embodiments, the solvent can be a polar aprotic solvent. In some embodiments, the solvent can be ethyl acetate.

[0176] The method of preparing Compound 1, Form I may include various other steps. In some embodiments, the reaction mixture may 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 1, Form I further includes heating the mixture to dissolve Compound 1, and cooling the mixture. In some embodiments, the method of preparing Compound 1, Form I includes forming a mixture of Compound 1 and ethyl acetate, heating the mixture to dissolve Compound 1, and cooling the mixture to form Compound 1, Form I.

[0177] In some embodiments, the present disclosure provides a method of preparing crystalline Compound 1, Form I of the present disclosure, comprising forming a mixture of Compound 1 of the present disclosure and a solvent under conditions suitable for preparing Form I. In some embodiments, Compound 1 is dissolved in the solvent. In some embodiments, the solvent can be a polar protic solvent. In some embodiments, the solvent can be ethanol.

[0178] The method of preparing Compound 1, Form I may include various other steps. In some embodiments, the reaction mixture may be heated to a temperature of about 75°C. In some embodiments, the method further comprises cooling the reaction mixture to a temperature of about 0°C. In some embodiments, the method of preparing Compound 1, Form I further comprises heating the mixture to dissolve Compound 1, and cooling the mixture. In some embodiments, the method of preparing Compound 1, Form I comprises forming a mixture of Compound 1 and ethanol, heating the mixture to dissolve Compound 1, and cooling the mixture to a temperature of about 0°C, thereby forming Compound 1, Form I.

[0179] In some embodiments, the present disclosure provides a method for preparing a crystalline compound 1, Form I of the present disclosure, comprising forming a mixture of a compound 1 of the present disclosure and a first solvent, and adding a second solvent to the mixture under conditions suitable for preparing Form I. In some embodiments, compound 1 is dissolved in a first solvent (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 anti-solvent. In some embodiments, the second solvent may be water.

[0180] The mixture may include any suitable ratio of the first solvent to the second solvent. For example, the ratio of the first solvent to the second solvent may 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 10: 1 to 5: 1, or 5: 1 to 1: 5, or 5: 1 to 1: 1, or 4: 1 to 1: 1, or 3: 1 to 1: 1, or 2: 1 to 1: 1. Other solvent ratios include about 10: 1, 9: 1, 8: 1, 7: 1, 6: 1, 5: 1, 4: 1, 3: 1, 2: 1, 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1: 6, 1: 7, 1: 8, 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 to water is about 1:1 (weight / weight).

[0181] The method of preparing Compound 1, Form I may include various other steps. In some embodiments, the reaction mixture may be heated to a temperature of about 75°C. In some embodiments, the method further comprises cooling the reaction mixture to a temperature of about 22°C. In some embodiments, the method of preparing Compound 1, Form I further comprises heating the mixture to dissolve Compound 1, and cooling the mixture. In some embodiments, the method of preparing Compound 1, Form I comprises forming a mixture of Compound 1 and ethanol, heating the mixture to dissolve Compound 1, adding water to the mixture, and cooling the mixture to room temperature, thereby forming Compound 1, Form I.

[0182] Compound I HCl salt form I

[0183] Compound 1 HCl Salt Form I can be prepared by mixing Compound 1 Form I with hydrochloric acid in a solvent to form Compound 1 HCl Salt Form I. In some embodiments, the present invention provides a method for forming Compound 1 HCl Salt Form I, comprising forming a reaction mixture of Compound 1 Form I, hydrochloric acid, and a solvent, thereby preparing Compound 1 HCl Salt Form I. In some embodiments, the solvent may be a polar aprotic solvent. In some embodiments, the solvent may be methyl ethyl ketone.

[0184] The method may include various other steps. In some embodiments, the reaction mixture may be heated to a temperature of about 50° C. In some embodiments, the reaction mixture may be cooled to ambient temperature. In some embodiments, the reaction mixture may be cooled to a temperature of about 10° C. In some embodiments, the method may include multiple heating and cooling steps.

[0185] HCl salt form II

[0186] Compound I HCl salt crystal form II can be prepared from Compound I HCl salt crystal form I by exposing Compound I HCl salt crystal form I to an environment with a varying relative humidity. In some embodiments, the present disclosure provides a method for preparing Compound I HCl salt crystal form II, which is prepared by exposing Compound I HCl salt crystal form I to a low relative humidity atmosphere and increasing the relative humidity to form a high relative humidity atmosphere. Compound I HCl salt crystal form II. The low relative humidity atmosphere may be less than 50% relative humidity, including about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40% and 45% relative humidity. The high relative humidity atmosphere may be greater than 50% relative humidity, including about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% relative humidity. In some embodiments, the 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%.

[0187] tartaric acid

[0188] Compound 1 tartrate crystalline form can be prepared from Compound 1 crystalline form I by dissolving Compound 1 crystalline form I in a solvent having tartaric acid. In some embodiments, the present disclosure provides a method for preparing Compound 1 tartrate crystalline form, comprising forming a mixture of Compound 1 crystalline form I, tartaric acid, and a solvent under conditions suitable for preparing Compound 1 tartrate. In some embodiments, Compound 1 crystalline 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.

[0189] The method may include various other steps. In some embodiments, the reaction mixture may be heated to a temperature of about 50° C. In some embodiments, the reaction mixture may be cooled to ambient temperature. In some embodiments, the reaction mixture may be cooled to a temperature of about 10° C. In some embodiments, the method may include multiple heating and cooling steps.

[0190] Other steps of the method may 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.

[0191] Maleic acid

[0192] Crystalline Compound 1 Maleic Acid can be prepared from Compound 1 Crystalline Form I by dissolving Compound 1 Crystalline Form I in a solvent containing maleic acid. In some embodiments, the present disclosure provides a method for preparing crystalline Compound 1 maleic acid, comprising forming a mixture of Compound 1 Crystalline Form I, maleic acid, and a solvent under conditions suitable for preparing Compound 1 maleic acid. In some embodiments, Compound 1 Crystalline 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.

[0193] The method may include various other steps. In some embodiments, the reaction mixture may be heated to a temperature of about 50° C. In some embodiments, the reaction mixture may be cooled to ambient temperature. In some embodiments, the reaction mixture may be cooled to a temperature of about 10° C. In some embodiments, the method may include multiple heating and cooling steps.

[0194] Fumaric Acid

[0195] Compound 1 fumarate salt crystalline form can be prepared from Compound 1 crystalline form I by dissolving Compound 1 crystalline form I in a solvent containing fumaric acid. In some embodiments, the present disclosure provides a method for preparing Compound 1 fumarate salt crystalline form, comprising forming a mixture of Compound 1 crystalline form I, fumaric acid, and a solvent under conditions suitable for preparing Compound 1 fumarate. In some embodiments, Compound 1 crystalline 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 acetone.

[0196] The method may include various other steps. In some embodiments, the reaction mixture may be heated to a temperature of about 50° C. In some embodiments, the reaction mixture may be cooled to ambient temperature. In some embodiments, the reaction mixture may be cooled to a temperature of about 10° C. In some embodiments, the method may include multiple heating and cooling steps.

[0197] Methanesulfonic acid

[0198] Compound 1 mesylate salt crystalline form can be prepared from Compound 1 crystalline Form I by dissolving Compound 1 crystalline Form I in a solvent having methanesulfonic acid. In some embodiments, the present disclosure provides a method for preparing crystalline Compound 1 methanesulfonic acid, comprising forming a mixture of Compound 1 crystalline Form I, methanesulfonic acid, and a solvent under conditions suitable for preparing Compound 1 methanesulfonic acid. In some embodiments, Compound 1 crystalline 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.

[0199] The method may include various other steps. In some embodiments, the reaction mixture may be heated to a temperature of about 50° C. In some embodiments, the reaction mixture may be cooled to ambient temperature. In some embodiments, the reaction mixture may be cooled to a temperature of about 10° C. In some embodiments, the method may include multiple heating and cooling steps.

[0200] Amorphous Compound I

[0201] Amorphous Compound 1 can also be prepared by the methods of the present disclosure. For example, Compound 1 Form I can be dissolved in a solvent and freeze-dried to form amorphous Compound 1. In some embodiments, the present disclosure provides a method for preparing amorphous Compound 1, comprising forming a mixture of Compound 1 and a solvent under conditions suitable for preparing Form I. In some embodiments, Compound 1 is dissolved in a solvent.

[0202] In some embodiments, the solvent can be a polar protic solvent. In some embodiments, the solvent can be tert-butyl alcohol, n-propyl alcohol, isopropyl alcohol, ethanol or methanol. In some embodiments, the solvent can be tert-butyl alcohol.

[0203] 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, -40°C, or about -78°C. In some embodiments, the reaction mixture can be at a temperature of about -78°C.

[0204] V. Pharmaceutical Compositions

[0205] The solid form of Compound I provided herein can be administered in the form of a pharmaceutical composition. The present disclosure provides a pharmaceutical composition containing one or more solid forms of the Compound I as an active ingredient or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients, carriers (including inert solid diluents and fillers), diluents (including sterile aqueous solutions and various organic solvents), penetration enhancers, solubilizers and adjuvants. The pharmaceutical composition can be administered alone or in combination with other therapeutic agents (as shown in the combination therapy section below). Such compositions are prepared in a manner well known in the pharmaceutical field (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 & C.T. Rhodes, Eds).

[0206] The pharmaceutical composition can be administered in single or multiple doses by any of the accepted modes of administration for pharmaceutical agents with similar utilities, e.g., as described in those patents and patent applications incorporated herein by reference, including rectal, oral, intranasal, and transdermal routes, by intraarterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous oral, topically, as an inhalant, or via an impregnated or coated device, e.g., a stent, or, e.g., a cylindrical polymer inserted into an artery).

[0207] One mode of administration is parenteral administration, particularly administration by injection. The novel compositions of the present disclosure can be incorporated, and the form of administration by injection includes aqueous or oily suspensions or emulsions, with sesame oil, corn oil, cottonseed oil or peanut oil, and elixirs, mannitol, dextrose or sterile aqueous solutions and similar pharmaceutical carriers. Saline solutions are also commonly used for injection, but are less preferred in the context of the present disclosure. Ethanol, glycerol, propylene glycol, liquid polyethylene glycols, etc. (and suitable mixtures thereof), cyclodextrin derivatives and vegetable oils can also be used. Suitable fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining the desired particle size in the case of a dispersion, and by using a surfactant. The action of microorganisms can be prevented by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.

[0208] Sterile injectable solutions are prepared by incorporating the desired amount of a compound according to the present disclosure into a suitable solvent along with various other ingredients listed above, and then sterilizing by filtration if necessary. Typically, dispersions are prepared by incorporating various sterilized active ingredients into a sterile carrier containing a basic dispersion medium and other ingredients required from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, general preparation methods are vacuum drying and freeze drying techniques, which produce a powder of the active ingredient plus any additional required ingredients from a previously sterile filtered solution.

[0209] Oral administration is another route of administration for the compounds of the present invention. It can be administered by capsules or enteric coated tablets, etc. When preparing a pharmaceutical composition comprising at least one compound described herein, the active ingredient is usually diluted with an excipient and / or encapsulated in such a carrier, which can be in the form of a capsule, a sachet, paper or other container. When an excipient is used as a diluent, it can be in the form of a solid, semisolid or liquid material (as described above) as a vehicle, carrier or medium for the active ingredient. Therefore, the composition can be a tablet, a pill, a powder, a lozenge, a sachet, a cachet, an elixir, a suspension, an emulsion, a solution, a syrup, an aerosol (as a solid or in a liquid medium), an ointment, for example, containing up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injections and sterile packaged powders.

[0210] Some examples of suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, sterile water, syrup and methylcellulose. The formulation may additionally include: lubricants, such as talc, magnesium stearate and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methyl and propyl hydroxybenzoates; sweeteners; and flavoring agents.

[0211] The compositions of the present disclosure can be formulated by methods known in the art so as to provide rapid, sustained or delayed release of active ingredients after administration to the patient. 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 described in U.S. Patents No. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation used in the method of the present disclosure uses a transdermal delivery device ("patch"). 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 medicaments are well known in the art. See, for example, U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139. ​​Such patches can be constructed for continuous, pulsed or on-demand delivery of pharmaceutical agents.

[0212] In some embodiments, the composition is formulated into a unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human subjects and other mammals, each unit containing a predetermined amount of active substance. In some embodiments, the composition can be combined with a suitable pharmaceutical excipient (e.g., tablet, capsule, ampoule) to produce the desired therapeutic effect. The compound is usually administered in a pharmaceutically effective amount. In some embodiments, each dosage unit contains 1 mg to 2 g of the compound described herein, and for parenteral administration, in some embodiments, contains 0.1 to 700 mg of the compound described herein. However, it should be understood that the amount of the compound actually administered will usually be determined by a physician according to the relevant circumstances, including the condition to be treated, the selected route of administration, the actual compound administered and its relative activity, age, body weight and the response of individual patients, the severity of the patient's symptoms, etc.

[0213] To prepare solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of the disclosed compounds. When these preformulation compositions are referred to as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0214] Tablets or pills of the present disclosure can be coated or otherwise compounded to provide a dosage form with an advantage of prolonged action or protection from the acidic conditions of the stomach. For example, tablets or pills can comprise an inner dosage component and an outer dosage component, the latter being presented in the form of a film coating on the former. These two components can be separated by an enteric layer, which is used to resist the disintegration in the stomach and allows the inner component to enter the duodenum intact or delay release. Various materials can be used for such enteric layers or coatings, and such materials include a mixture of many polymeric acids and polymeric acids with materials such as shellac, cetyl alcohol and cellulose acetate.

[0215] Compositions for inhalation or insufflation include solutions and pharmaceutically acceptable suspensions, aqueous or organic solvents or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the composition is administered by oral or nasal respiratory route to obtain local or systemic effects. Compositions in preferably pharmaceutically acceptable solvents can be atomized by using an inert gas. Nebulized solutions can be inhaled directly from a nebulizing device, or the nebulizing device can be connected to a mask tent or an intermittent positive pressure breathing machine. In some embodiments, the composition can be administered orally or nasally from a device that delivers the preparation in an appropriate manner.

[0216] 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.

[0217] VI. How to use

[0218] The solid forms of Compound 1 described herein can be administered in single or multiple doses to a subject suffering from a viral infection, such as but not limited to hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV), by any acceptable mode of administration known to those skilled in the art and as detailed above.

[0219] As used herein, an "agonist" is a substance that stimulates its binding partner (usually a receptor). Stimulation is defined in the context of a specific assay, or may be apparent in the literature from the discussion herein, which is compared to factors or substances that are accepted as "agonists" or "antagonists" of a specific binding partner in substantially similar circumstances as understood by those skilled in the art. Stimulation can be defined relative to an increase in a specific effect or function induced by the interaction of an agonist or partial agonist with a binding partner, and may include allosteric effects.

[0220] As used herein, an "antagonist" is a substance that inhibits its binding partner (usually a receptor). Inhibition is defined in the context of a particular assay, or may be apparent in the literature from the discussion herein, which is compared to 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 relative to a reduction in a specific effect or function induced by the interaction of an antagonist with a binding partner, and may include allosteric effects.

[0221] 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 completely or fully agonistic or antagonistic, respectively. It should be recognized that for any substance or class of substances defined as an agonist, antagonist, or partial agonist, stimulation, and therefore inhibition, is essentially defined.

[0222] As used herein, "intrinsic activity" or "efficacy" 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 efficacy should be defined will depend on the context of the binding partner (e.g., receptor / ligand) complex and considerations of activity associated with a particular biological outcome. For example, in some cases, intrinsic activity may vary depending on the specific second messenger system involved. It will be apparent to one of ordinary skill in the art where these context-specific assessments are relevant, and how they are relevant in the context of the present disclosure.

[0223] As used herein, modulation of a receptor includes agonism, partial agonism, antagonism, partial antagonism, or inverse agonism of the receptor.

[0224] 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. The scope of the present disclosure is intended to encompass all of these characterizations.

[0225] In one embodiment, the method can be used to induce an immune response for multiple epitopes of viral infection in people. Any technique known to those skilled in the art for determining whether an immune response has occurred can be used to assess the induction of an immune response for viral infection. Suitable methods for detecting the immune response of the present disclosure include, in particular, detecting the reduction of viral load or antigen in subject serum, detecting IFN-γ secretory peptide-specific T cells, and detecting the increased levels of one or more liver enzymes such as alanine transferase (ALT) and aspartate transferase (AST). In one embodiment, the detection of IFN-γ secretory peptide-specific T cells is completed using ELISPOT determination. Another embodiment includes reducing the viral load associated with HBV infection, including the reduction measured by PCR testing.

[0226] In some embodiments, the present disclosure provides a method for treating viral infection, comprising administering a therapeutically effective amount of a crystalline form or pharmaceutical composition of Compound I of the present disclosure to a person in need thereof. In some embodiments, the present disclosure provides a crystalline form of Compound I for use in treating viral infection, comprising administering a therapeutically effective amount of a crystalline form or pharmaceutical composition of Compound I of the present disclosure. In some embodiments, the present disclosure provides the use of a crystalline form of Compound I for treating viral infection. In some embodiments, the present disclosure provides the use of a crystalline form of Compound I in the preparation of a medicament for treating viral infection.

[0227] In another aspect, the present invention provides methods for treating hepatitis B virus infection or hepatitis C virus infection, wherein each method comprises the step of 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. Typically, the human subject suffers from chronic hepatitis B infection or chronic hepatitis C infection, although treating humans with acute HBV or HCV infection is also within the scope of the present invention.

[0228] 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 in the preparation of a medicament for treating hepatitis B virus infection or hepatitis C virus infection.

[0229] 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 in the preparation of a medicament for treating hepatitis B virus infection.

[0230] Treatment according to the present disclosure generally results in stimulating an immune response against HBV or HCV in a person infected with HBV or HCV, and subsequently reducing the viral load of HBV or HCV in the infected person. Examples of immune responses include producing antibodies (e.g., IgG antibodies) that regulate immune system activity and / or producing cytokines, such as interferon. The immune system response may be a newly induced response, or may be to enhance an existing immune response. In particular, the immune system response may be seroconversion for one or more HBV or HCV antigens.

[0231] Viral load can be determined by measuring the amount of HBV DNA or HCV DNA present in the blood. For example, the quantification of serum HBV DNA can be measured using Roche COBAS Amplicor Monitor PCR (version 2.0; lower limit of quantification, 300 copies / mL [57IU / mL]) and Quantiplex bDNA (lower limit of quantification, 0.7MEq / mL; Bayer Diagnostics, formerly Chiron Diagnostics, Emeryville, CA). The amount of antibodies to antigens (e.g., hepatitis B surface antigen (HBsAG)) for specific HBV or HCV can be measured using techniques recognized in the art 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 Abbott AxSYM microparticle enzyme immunoassay system (Abbott Laboratories, North Chicago, IL).

[0232] Compound I can be administered by any useful route and mode, for example, by oral or parenteral (e.g., intravenous) administration. The therapeutically effective amount of Compound I is from about 0.00001 mg / kg body weight / day to about 10 mg / kg body weight / day, for example, from about 0.0001 mg / kg body weight / day to about 10 mg / kg body weight / day, or for example, from about 0.001 mg / kg body weight / day to about 1 mg / kg body weight / day, or for example, from about 0.01 mg / kg body weight / day to about 1 mg / kg body weight / day, or for example, from about 0.05 mg / kg body weight / day to about 0.5 mg / kg body weight / day, or for example, from about 0.3 μg to about 30 mg per day, or for example, from about 30 μg to about 300 mg per day.

[0233] The therapeutically effective amount of Compound I is also about 0.01 mg per dose to about 1000 mg per dose, such as about 0.01 mg per dose to about 100 mg per dose, or such as about 0.1 mg per dose to about 100 mg per dose, or such as about 1 mg per dose to about 100 mg per dose, or such as about 1 mg per dose to about 100 mg per dose. Other therapeutically effective amounts of Compound I are about 1 mg per dose, 1.5 mg per dose, 2 mg per dose, 2.5 mg per dose, 3 mg per dose, or 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 I 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. Single doses can be administered hourly, daily, or weekly. For example, a single dose can be administered once every 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours, or every 24 hours. A single dose can also be administered once every 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or every 7 days. A single dose can also be administered once every 1 week, 2 weeks, 3 weeks, or every 4 weeks. A single dose can also be administered once a month.

[0234] The frequency of administration of Compound I will be determined by the needs of the individual patient and may be, for example, once a day or twice a day or more. Compound I is administered continuously as long as necessary to treat HBV or HCV infection. For example, Compound I may be administered to a person infected with HBV or HCV for a period of 20 days to 180 days, or for example, a period of 20 days to 90 days, or for example, a period of 30 days to 60 days.

[0235] Dosing can be intermittent, with a period of several or more days in which the patient receives a daily dose of Compound I followed by a period of several or more days in which the patient does not receive a daily dose of Compound I. For example, a patient may receive a dose of Compound I every other day or three times a week. Again, by way of example, a patient may receive a dose of Compound I daily for a period of 1 to 14 days, followed by a period of 7 to 21 days in which the patient does not receive a dose of Compound I. This is followed by a period of time (e.g., 1 to 14 days) in which the patient again receives a daily dose of Compound I. Alternating cycles of administration of Compound I and subsequent non-administration of Compound I may be repeated as clinically necessary to treat the patient.

[0236] As described more fully herein, the crystalline form of Compound I can be administered to a person infected with hepatitis B virus or hepatitis C virus together with one or more additional therapeutic agents. The additional therapeutic agent can be administered to the infected patient. The additional additional therapeutic agent can be administered to the infected person simultaneously with the crystalline form of Compound I or before or after the 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 for 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 the use of a crystalline form of Compound I in the preparation of 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.

[0237] In another aspect, the present invention provides a method for improving symptoms associated with HBV infection or HCV infection, wherein the method comprises: administering a therapeutically effective amount of a 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 improve symptoms associated with HBV infection or HCV infection. These symptoms include the presence of HBV virus particles (or HCV virus particles) in the blood, liver inflammation, jaundice, muscle pain, weakness and fatigue.

[0238] In some embodiments, the present disclosure provides a crystalline form of Compound I for improving symptoms associated with HBV infection or HCV infection, wherein the method comprises administering a therapeutically effective amount of a 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 improve symptoms associated with HBV infection or HCV infection. In some embodiments, the present disclosure provides the use of a crystalline form of Compound I in the preparation of a medicament for improving symptoms associated with HBV infection or HCV infection, wherein the method comprises administering a therapeutically effective amount of a 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 improve symptoms associated with HBV infection or HCV infection.

[0239] In another aspect, the present disclosure provides a method for reducing the rate of progression of human hepatitis B virus infection or hepatitis C virus infection, wherein the method comprises administering a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof to a human subject infected with hepatitis B virus or hepatitis C virus, wherein the therapeutically effective amount is sufficient to reduce the rate of progression of hepatitis B virus infection or hepatitis C virus infection. The rate of progression of infection can be tracked by measuring the amount of HBV virus particles or HCV virus particles in the blood.

[0240] In another aspect, the present disclosure provides a method for reducing viral load associated with HBV infection or HCV infection, wherein the method comprises administering a therapeutically effective amount of Compound I 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.

[0241] On the other hand, the present disclosure provides a method of inducing or enhancing an immune response to hepatitis B virus or hepatitis C virus in a human body, wherein the method comprises administering a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof to a human, wherein a new immune response to hepatitis B virus or hepatitis C virus is induced in the human body, or a pre-existing immune response to hepatitis B virus or hepatitis C virus is enhanced in the human body. Seroconversion of HBV or HCV can be induced in humans. 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.

[0242] Inducing seroconversion against HCV or HBV in patients chronically infected with HCV or HBV is an unexpected property of Compound I. In clinical practice, Compound I is used alone or in combination with one or more other therapeutic agents to treat HBV patients or HCV patients until an immune response against HBV or HCV is induced or enhanced and the viral load of HBV or HCV is reduced. Thereafter, although the HBV or HCV virus may persist in the patient's body in a latent form, treatment with Compound I can be stopped, and the patient's own immune system is able to suppress further viral replication. In patients who are treated according to the present disclosure and have been treated with antiviral agents that inhibit HBV virus or HCV virus replication, there may be few or no detectable viral particles in the patient's body during the treatment with the antiviral agent. In these patients, seroconversion will be apparent when the antiviral agent is no longer administered to the patient and the viral load of HBV or HCV has not increased.

[0243] In the practice of the present disclosure, an immune response is induced against one or more antigens of HBV or HCV. For example, an immune response may 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 against a combination thereof. Again, for example, an immune response may be induced against HBV surface antigen (HBsAg) and other HBV-derived antigens (e.g., core polymerase or X protein).

[0244] Any technique known to those skilled in the art for determining whether an immune response has occurred can be used to assess the induction of an immune response against HCV or HBV. Suitable methods for detecting an immune response of the present disclosure include, inter alia, detecting a reduction in viral load in the serum of a subject, such as 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 antibodies or anti-HCV antibodies in the blood of a subject using a method such as ELISA.

[0245] In addition, the compounds of the present disclosure can be used to treat cancer or tumors (including dysplasia, such as uterine dysplasia). These include hematological malignancies, oral cancer (such as lips, tongue or pharynx), digestive organs (such as esophagus, stomach, small intestine, colon, large intestine or rectum), liver and bile duct, pancreas, respiratory system such as larynx or lung (small cell and non-small cell), bone, connective tissue, skin (such as melanoma), breast, reproductive organs (uterus, cervix, testicles, ovaries or prostate), urinary tract (such as bladder or kidney), brain and endocrine glands such as thyroid. In short, the compounds of the present disclosure are used to treat any tumor, including not only hematological malignancies, but also all kinds of solid tumors.

[0246] Hematological malignancies are broadly defined as proliferative diseases of blood cells and / or their progenitors, in which these cells proliferate in an uncontrolled manner. Anatomically, hematological malignancies are divided into two main groups: lymphomas—malignant masses of lymphocytes primarily but not exclusively in lymph nodes, and leukemias—tumors that usually originate from lymphocytes or myeloid cells, primarily affecting 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 different entities that can be distinguished clinically (e.g., aggressive lymphomas, indolent lymphomas), histologically (e.g., follicular lymphomas, mantle cell lymphomas), or based on the origin of the malignant cells (e.g., B lymphocytes, T lymphocytes). Leukemias and related malignancies include acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), and chronic lymphocytic leukemia (CLL). Other hematologic malignancies include plasma cell dyscrasias (including multiple myeloma) and myelodysplastic syndromes.

[0247] VII. Combination therapy

[0248] In certain embodiments, a method for treating or preventing an infectious disease, viral infection, hepatitis B infection, HIV infection, cancer, or hyperproliferative disease in a human suffering from or at risk of suffering from the disease is provided, the method comprising administering to the human 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., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents. In one embodiment, a method for treating an infectious disease, viral infection, hepatitis B infection, HIV infection, cancer, or hyperproliferative disease in a human suffering from or at risk of suffering from the disease is provided, the method comprising administering to the human 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., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents.

[0249] In certain embodiments, the present invention provides a method of 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 a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents suitable for treating viral infection. In some embodiments, the viral infection is hepatitis B infection. In some embodiments, the viral infection is HIV infection.

[0250] In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with one, two, three, four or more additional therapeutic agents. In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with two additional therapeutic agents. In other embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with three additional therapeutic agents. In further embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with four additional therapeutic agents. One, two, three, four or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents, and / or they may be selected from different classes of therapeutic agents.

[0251] Administration of combination therapy

[0252] In certain embodiments, the compounds disclosed herein are administered together with one or more additional therapeutic agents. The co-administration of compounds disclosed herein with one or more additional therapeutic agents generally refers to the simultaneous or sequential administration of compounds disclosed herein and one or more additional therapeutic agents, such that a therapeutically effective amount of compounds disclosed herein and one or more additional therapeutic agents are present in the subject. When administered sequentially, the combination can be administered twice or more.

[0253] 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.

[0254] In certain embodiments, the compounds disclosed herein can be combined with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents at any dose of the compound (e.g., 10 mg to 1000 mg of the compound).

[0255] Co-administration includes administering a unit dose of a compound disclosed herein before or after administering a unit dose of one or more additional therapeutic agents. Compounds disclosed herein can be administered within seconds, minutes, or hours of administering one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound disclosed herein is first administered, and then a unit dose of one or more additional therapeutic agents is administered within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is first administered, and then a unit dose of a compound disclosed herein is administered within seconds or minutes. In some embodiments, a unit dose of a compound disclosed herein is first administered, and then a unit dose of one or more additional therapeutic agents is administered after a few hours (e.g., 1-12 hours). In other embodiments, a unit dose of one or more additional therapeutic agents is first administered, and then a unit dose of a compound disclosed herein is administered after a few hours (e.g., 1-12 hours).

[0256] In certain embodiments, a compound disclosed herein is combined with one or more additional therapeutic agents in a single dosage form for simultaneous administration to a subject, for example, as a solid dosage form for oral administration.

[0257] In certain embodiments, the compounds described herein are formulated into tablets, which may optionally contain one or more other compounds for treating the disease being treated. In certain embodiments, the tablets may contain another active ingredient for treating viral diseases (e.g., hepatitis B virus or HIV).

[0258] In certain embodiments, such tablets are suitable for once-daily administration.

[0259] In one embodiment, a pharmaceutical composition is provided comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents and a pharmaceutically acceptable carrier, diluent, or excipient.

[0260] In one embodiment, a kit is provided comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents.

[0261] Viral combination therapy

[0262] The compounds described herein can be used or combined with one or more antiviral agents, including abacavir, acyclovir, adefovir, amantadine, amprenavir, arbidol, atazanavir, atropine, brivudine, cidofovir, combivir, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, fomvirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir, gardasil, ibacitabine, immunovir, iodoxuridine, Imiquimod, indinavir, inosine, integrase inhibitors, interferons, including type III interferons, type II interferons, type I interferons, lamivudine, lopinavir, loviride, MK-0518, maraviroc, morphine, nelfinavir, nevirapine, nexavir, nucleoside analogs, oseltamivir, penciclovir, peramivir, pleconaril, podophyllotoxin, protease inhibitors, reverse transcriptase inhibitors, ribavirin, rimantadine, ritonavir, saquinavir, stavudine, tenofovir, tenofovir disoproxil disoproxil), tipranavir, trifluridine, abacavir, trizivir, tromantine, Truvada, valacyclovir, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir or zidovudine, and combinations thereof.

[0263] In certain embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with 5-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate or tenofovir alafenamide. In certain embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are 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. In certain embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate or tenofovir alafenamide. In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. The compounds disclosed herein may be combined with the agents provided herein at any dose of the compound (e.g., 50 mg to 500 mg of the compound), as if each dose combination was specifically and individually listed.

[0264] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 100-400 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, compound disclosed herein or its pharmaceutically acceptable salt is combined with 300mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate or tenofovir disoproxil. In certain embodiments, compound disclosed herein or its pharmaceutically acceptable salt is combined with 250mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate or tenofovir disoproxil. In certain embodiments, compound disclosed herein or its pharmaceutically acceptable salt is combined with 150mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate or tenofovir disoproxil. Disclosed compound can be in any dosage (for example, 50mg to 500mg compound) of compound and pharmaceutical combination provided herein, as each dosage combination is specifically and individually listed.

[0265] HIV combination therapy

[0266] In certain embodiments, a method for treating or preventing HIV infection in a human or animal suffering from HIV infection or at risk of HIV infection is provided, comprising administering to a human or animal a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. In one embodiment, a method for treating HIV infection in a human or animal suffering from HIV infection or at risk of HIV infection is provided, comprising administering to a human or animal a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents in combination.

[0267] In certain embodiments, the present disclosure provides a method for treating 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.

[0268] In certain embodiments, the compounds disclosed herein are formulated into tablets, which may optionally contain one or more other compounds for treating HIV. In certain embodiments, the tablets may contain another active ingredient for treating HIV, such as HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.

[0269] In certain embodiments, such tablets are suitable for once-daily administration.

[0270] In the above embodiments, the additional therapeutic agent may be an anti-HIV agent. In some embodiments, the additional therapeutic agent is selected from HIV combination drugs, HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase. HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, immunomodulators, immunotherapeutics, antibody-drug conjugates, gene modifiers, gene editors (such as CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs), cell therapies (such as chimeric antigen receptor T cells, CAR-T and engineered T cell receptors, TCR-T), latency reversal agents, compounds targeting HIV capsid (including capsid inhibitors), immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, alpha-4 / beta-7 antagonists, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, 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 infection 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 ICAM-3 grabbing non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV 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 initiation complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines and other HIV therapeutic agents and combinations thereof.

[0271] In some embodiments, the additional therapeutic agent is selected from combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies and bispecific antibodies, and "antibody-like" therapeutic proteins, and combinations thereof.

[0272] HIV combination drugs

[0273] Examples of combination drugs include (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); ( rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); (tenofovir disoproxil fumarate and emtricitabine); (tenofovir alafenamide and emtricitabine); (tenofovir alafenamide, emtricitabine, and rilpivirine); (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir; (bitegvir, 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 and emtricitabine; tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine; tenofovir alafenamide hemifumarate, emtricitabine, cobicistat, and elvitegravir; (zidovudine and lamivudine; AZT+3TC), ( Abacavir sulfate and lamivudine; ABC+3TC); ( lopinavir and ritonavir); (dolutegravir, abacavir, and lamivudine); (abacavir sulfate, zidovudine and lamivudine; 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 fumarate; dolutegravir, lamivudine and tenofovir disoproxil fumarate Lutegravir + 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.

[0274] HIV protease inhibitors

[0275] Examples of HIV protease inhibitors include amprenavir, atazanavir, brenavir, 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.

[0276] HIV reverse transcriptase inhibitors

[0277] Examples of HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase include dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, nevirapine, rilpivirine, ACC-007, AIC-292, KM-023, PC-1005, and VM-1500.

[0278] Examples of HIV nucleoside or nucleotide inhibitors of reverse transcriptase include adefovir, adefovir dipivoxil, azithromycin, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, and VIDEX (didanosine, DDL), abacavir, abacavir sulfate, alovudine, arithiabine, censavudine, didanosine, efcitabine, festinavir, fosalvudine tidoxil, CMX-157, dapivirine, doravirine, etravirine, OCR-5753, tenofovir disoproxil orotate, fozivudine ester, lamivudine, phosphazid, stavudine, zalcitabine, zidovudine, GS-9131, GS-9148, MK-8504 and KP-1461.

[0279] HIV integrase inhibitors

[0280] Examples of HIV integrase inhibitors include elvitegravir, curcumin, curcumin derivatives, chicoric acid, chicoric acid derivatives, 3,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid derivatives, aurintricarboxylic acid, aurintricarboxylic acid derivatives, caffeic acid phenethyl ester, caffeic acid phenethyl ester derivatives, tyrosine phosphorylation inhibitors, tyrosine phosphorylation inhibitor derivatives, quercetin, quercetin derivatives, raltegravir, dolutegravir, JTK-351, bictegravir, AVX-15567, cabotegravir (long-acting injection), diketoquinoline-4-1 derivatives, integrase-LEDGF inhibitors, ledgins, M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbenedisulfonic acid, T-169, and cabotegravir.

[0281] Examples of HIV non-catalytic site or allosteric integrase inhibitors (NCINIs) include CX-05045, CX-05168, and CX-14442.

[0282] HIV entry inhibitors

[0283] Examples of HIV entry (fusion) inhibitors include cenicriviroc, CCR5 inhibitors, gp 41 inhibitors, CD4 attachment inhibitors, gp 120 inhibitors, and CXCR4 inhibitors.

[0284] Examples of CCR5 inhibitors include apraviroc, 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).

[0285] Examples of gp 41 inhibitors include albuvirtide, enfuvirtide, BMS-986197, enfuvirtide biobetter, enfuvirtide biosimilars, HIV-1 fusion inhibitor (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer, and sifuvirtide.

[0286] Examples of CD4 attachment inhibitors include ibalizumab and CADA analogs.

[0287] Examples of gp120 inhibitors include Radha-108 (receptol) 3B3-PE 38, BanLec, bentonite-based nanomedicines, fostemsavir tromethamine, IQP-0831, and BMS-663068.

[0288] Examples of CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide, and vMIP (Haimipu).

[0289] HIV maturation inhibitors

[0290] Examples of HIV maturation inhibitors include BMS-955176 and GSK-2838232.

[0291] Latency reversal agents

[0292] Examples of latency reversing agents 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 (arylidene hydroxamic acid, suberoyl, aniline, and hydroxamic acid), AM-0015, ALT-803, NIZ-985, NKTR-255, IL-15 modulating antibodies, JQ1, disulfiram, amphotericin B, and ubiquitin inhibitors such as ragozolane analogs and GSK-343.

[0293] Examples of HDAC inhibitors include romidepsin, vorinostat, and panobinostat.

[0294] Examples of PKC activators include indolactam, prostratin, ingenol B, and DAG-lactone.

[0295] Capsid inhibitors

[0296] 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 AVI-CAN1-15 series;

[0297] Immune-based therapies

[0298] 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 gamma; Hydroxyurea; mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF); ribavirin; rintatolimod, polymer polyethyleneimine (PEI); gepon; rintatolimod; IL-12; WF-10; VGV-1; MOR-22; BMS-936559; CYT-107, interleukin-15 / Fc fusion protein, normferon, peginterferon alpha-2a, peginterferon alpha-2b, recombinant interleukin-15, RPI-MN, GS-9620, STING modulators, RIG-I modulators, NOD2 modulators, and IR-103.

[0299] Examples of TLR8 modulators include motolimod, resquimod, 3M-051, 3M-052, MCT-465, IMO-4200, VTX-763, VTX-1463, and US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US20140350031 (Janssen), WO2014 / 023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira therapeutics), US20130251673 (Noviratherapeutics), U.S. Patent No. 9670205 (Gilead Sciences Inc.), US20160289229 (GileadSciences Inc.), U.S. Patent Application No. 15 / 692161 (Gilead Sciences Inc.), and U.S. Patent Application No. 15 / 692093 (Gilead Sciences Inc.).

[0300] Phosphatidylinositol 3-kinase (PI3K) inhibitors

[0301] Examples of PI3K inhibitors include idelalisib, alpelisib, buparlisib, CAI orotate, copanlisib, duvelisib, gedatolisib, neratinib, panulisib, perifosine, pictilisib, pilaralisib, puquitinib mesylate,rigosertib,rigosertib sodium,sonolisib,taselisib,AMG-319,AZD-8186,BAY-1082439,CLR-1401,CLR-457,CUDC-907,DS-7423,EN-3342,GSK-2126458,GSK-2269577,G SK-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.

[0302] Alpha-4 / beta-7 antagonists

[0303] Examples of integrin alpha-4 / beta-7 antagonists include PTG-100, TRK-170, abrilumab, etrolizumab, carotegrast methyl, and vedolizumab.

[0304] HIV antibodies, bispecific antibodies, and “antibody-like” therapeutic proteins

[0305] Examples of HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins include Fab derivatives, bnABs (broadly neutralizing HIV-1 antibodies), BMS-936559, TMB-360 and antibodies targeting HIV gp 120 or gp 41, antibody recruitment molecules targeting HIV, anti-CD 63 monoclonal antibodies, anti-GB virus C antibodies, anti-gp 120 / CD4, CCR5 bispecific antibodies, anti-Nef single domain antibodies, anti-Rev antibodies, camelid-derived anti-CD 18 antibodies, camelid-derived anti-ICAM-1 antibodies, DCVax-001, gp 140-targeting antibodies, gp 41-based HIV therapeutic antibodies, human recombinant mAbs (PGT-121), ibalizumab, Immuglo and MB-66.

[0306] Examples of those targeting HIV in this manner 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, 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.

[0307] Pharmacokinetic enhancers

[0308] Examples of pharmacokinetic enhancers include cobicistat and ritonavir.

[0309] HIV vaccine

[0310] Examples of HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, CD4-derived peptide vaccines, vaccine combinations, rgp 120 (AIDSVAX), ALVAC HIV (vCP1521) / AIDSVAX B / E (gp120) (RV144), monomeric gp 120 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, NAcGM3 / VSSP ISA-51, polyICLC adjuvant vaccine, TatiImmune, GTU-multiHIV (FIT-06), gp140[delta]V2.TV1+MF-59, rVSVIN-HIV-1 gag vaccine, SeV-gag vaccine, AT-20, DNK-4, Ad35GRIN / ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAVl-PG9DP, GOVX-B11, GOVX-B21, TVI-HIV-1, Ad-4 (Ad4-env evolutionary branch C+Ad4 -mGag), EN41-UGR7C, EN41-FPA2, PreVaxTat, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, DNA-Ad5gag / pol / nef / nev (HVTN505), MVATG and virus-like particle vaccines, such as pseudovirion vaccines, CombiVICHvac, LFN-p24B / C fusion vaccines, GTU-based DNA vaccines, HIV gag / pol / nef / env DNA vaccine, anti-Tat HIV vaccine, conjugated peptide vaccine, dendritic cell vaccine, gag-based DNA vaccine, GI-2010, gp41 HIV-1 vaccine, HIV vaccine (PIKA adjuvant), Ii-Key / MHC class II epitope hybrid peptide vaccine, ITV-2, ITV-3, ITV-4, LIPO-5, multi-clade Env vaccine, MVA vaccine, Pennvax-GP, pp71-deficient HCMV vector HIV gag vaccine, recombinant peptide vaccine (HIV infection), NCI, rgp160 HIV vaccine, RNA-active HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, therapeutic HIV vaccine, UBI HIV gp120, Vacc-4x + romidepsin, variant gp120 peptide vaccine, rAd5 gag-pol env A / B / C vaccine, DNA.HTI and MVA.HTI. .

[0311] Additional HIV therapeutics

[0312] Examples of additional HIV therapeutics include WO 2004 / 096286 (Gilead Sciences), WO 2006 / 015261 (Gilead Sciences), WO 2006 / 110157 (Gilead Sciences), WO 2012 / 003497 (Gilead Sciences), WO 2012 / 003498 (Gilead Sciences), WO 2012 / 145728(Gilead Sciences),WO2013 / 006738(Gilead Sciences),WO 2013 / 159064(Gilead Sciences),WO 2014 / 100323(Gilead Sciences),US 2013 / 0165489(University of Pennsylvania),US 2014 / 0221378(Japan Tobacco),US 2014 / 0221380(Japan Tobacco),WO Compounds disclosed in WO 2009 / 062285 (Boehringer Ingelheim), WO 2010 / 130034 (Boehringer Ingelheim), WO 2013 / 006792 (Pharma Resources), US 20140221356 (Gilead Sciences), US 20100143301 (Gilead Sciences) and WO 2013 / 091096 (Boehringer Ingelheim).

[0313] Examples of other drugs used to treat HIV include acemannan, alisporivir, BanLec, deferiprone, Gamimune, metenkefalin, naltrexone, Prolastin, REP 9, RPI-MN, VSSP, Hlviral, 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, IM O-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.

[0314] Gene therapy and cell therapy

[0315] Gene therapy and cell therapy include genetic modification to silence genes; genetic methods to directly kill infected cells; infusion of immune cells that are designed to replace most of the subject's own immune system to enhance the immune response to infected cells, or activate the subject's own immune system to kill infected cells, or find and kill infected cells; and genetically altering cellular activity to further change endogenous immune responsiveness to resist infection.

[0316] Examples of dendritic cell therapies include AGS-004.

[0317] Gene Editor

[0318] Examples of gene editing systems include the CRISPR / Cas9 system, the zinc finger nuclease system, the TALEN system, the homing endonuclease system, and the meganuclease system.

[0319] Examples of HIV-targeted CRISPR / Cas9 systems include EBT 101.

[0320] CAR-T cell therapy

[0321] CAR-T cell therapy includes an immune effector cell population engineered to express a chimeric antigen receptor (CAR), wherein the CAR comprises an HIV antigen binding domain. HIV antigens include HIV envelope proteins or portions thereof, gp120 or portions thereof, CD4 binding sites on gp120, CD4-induced binding sites on gp120, N-glycans on gp120, V2 of gp120, and membrane proximal regions on gp41. Immune effector cells are T cells or NK cells. In some embodiments, T cells are CD4+T cells, CD8+T cells, or a combination thereof.

[0322] Examples of HIV CAR-T include VC-CAR-T.

[0323] TCR-T cell therapy

[0324] TCR-T cell therapy involves T cells engineered to target HIV-derived peptides present on the surface of virus-infected cells.

[0325] Those skilled in the art will appreciate that the additional therapeutic agents listed above may be included in more than one of the categories listed above. The specific categories are not intended to limit the functionality of the compounds listed in these categories.

[0326] In a specific embodiment, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with a nucleoside or nucleotide inhibitor of HIV reverse transcriptase and a non-nucleoside inhibitor of HIV reverse transcriptase. In another specific embodiment, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with a nucleoside or nucleotide inhibitor of HIV reverse transcriptase and an HIV reverse transcriptase inhibitor. In another embodiment, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, a non-nucleoside inhibitor of HIV reverse transcriptase 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.

[0327] In a specific embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with one, two, three, four or more additional therapeutic agents selected from: (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); ( rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); (tenofovir disoproxil fumarate and emtricitabine); (tenofovir alafenamide and emtricitabine); (tenofovir alafenamide, emtricitabine, and rilpivirine); (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir; (Bitegravir, Emtricitabine, Tenofovir Alafenamide); Adefovir; Adefovir Dipivoxil; Cobicistat; Emtricitabine; Tenofovir; Tenofovir Disoproxil; Tenofovir Disoproxil Fumarate; Tenofovir Alafenamide; Tenofovir Alafenamide Hemifumarate; (dolutegravir, abacavir, and lamivudine); dolutegravir, abacavir sulfate, and lamivudine; raltegravir; raltegravir and lamivudine; maraviroc; enfuvirtide; ( lopinavir and ritonavir); (zidovudine and lamivudine; AZT+3TC); ( Abacavir sulfate and lamivudine; ABC+3TC); (abacavir sulfate, zidovudine and lamivudine; ABC+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 and efavirenz; etravirine; nelfamivir; nelfinavir mesylate; interferon; didanosine; stavudine ; indinavir; indinavir sulfate; tenofovir 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; phosphazid; lamivudine, nevirapine, and zidovudine; abacavir; and abacavir sulfate.

[0328] In a specific embodiment, 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.

[0329] In a specific embodiment, 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.

[0330] In a specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, and bictegravir, and a second additional therapeutic agent selected from emtricitabine and lamivudine.

[0331] In a specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, and bictegravir, and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine.

[0332] 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, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate or tenofovir alafenamide and 200 mg of emtricitabine. The compounds disclosed herein can be combined with the agents provided herein at any dose of the compound (e.g., 1 mg to 500 mg of the compound), as if each dose combination was specifically and individually listed.

[0333] In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 200-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate or tenofovir disoproxil, and 200 mg 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 tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate or tenofovir disoproxil and 200 mg emtricitabine. In certain embodiments, compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with 300 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate or tenofovir disoproxil and 200 mg of emtricitabine. Compounds disclosed herein can be combined with medicaments provided herein with any dose of compound (e.g., 1 mg to 500 mg compound), as if each dosage combination is specifically and individually listed.

[0334] HBV combination therapy

[0335] In certain embodiments, a method for treating or preventing HBV infection in a person suffering from infection or risk of infection is provided, comprising administering to a person a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three or one to four) other therapeutic agents. In one embodiment, a method for treating HBV infection in a person suffering from HBV infection or at risk of HBV infection is provided, the method comprising administering to a person a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three or one to four) other therapeutic agents.

[0336] In certain embodiments, the present disclosure provides a method 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., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents suitable for treating HBV infection.

[0337] The compounds described herein can be combined with one or more chemotherapeutic agents, immunomodulatory agents, immunotherapeutic agents, therapeutic antibodies, therapeutic vaccines, bispecific antibodies, and "antibody-like" therapeutic proteins (e.g. Fab derivatives), antibody-drug conjugates (ADCs), gene modifiers or gene editors (e.g., CRISPR Cas9, zinc finger nucleases, homing endonucleases, synthetic nucleases, TALENs), cell therapy agents such as CAR-T (chimeric antigen receptor T-cells) and TCR-T (engineered T cell receptor) agents, or any combination thereof, are used together or in combination.

[0338] In certain embodiments, the compounds described herein are formulated as tablets, which may optionally contain one or more additional compounds useful in treating HBV. In certain embodiments, the tablet may contain another active ingredient for treating HBV, such as 3-dioxygenase (IDO) inhibitors, apolipoprotein A1 regulators, 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 regulators, epigenetic modifiers, farnesoid X receptor agonists, HBsAg inhibitors, HBsAg secretion or assembly 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 assembly inhibitors, hepatitis B virus E antigen inhibitors, hepatitis B virus replication inhibitors, hepatitis virus structural protein inhibitors, HIV-1 reverse transcriptase inhibitors, hyaluronidase inhibitors, IAPs inhibitors, IL-2 agonists, IL-7 agonists, immunomodulators, indoleamine-2 inhibitors , ribonucleotide reductase inhibitors, interleukin-2 ligands, 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, Axl modulators, 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, SIRPα modulators, TIGIT modulators, Tim-4 modulators, Tyro modulators, Na+-taurocholate 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, RNA Enzyme inhibitors, RNA / DNA polymerase inhibitors, SLC10A1 gene inhibitors, SMAC mimetics, Src tyrosine kinase inhibitors, interferon gene (STING) agonist stimulators, NODI stimulators, T cell surface glycoprotein CD28 inhibitors, T cell surface glycoprotein CD8 regulators, thymosin agonists, thymosin α1 ligands, Tim-3 inhibitors, TLR-3 agonists, TLR-7 agonists, TLR-9 agonists, TLR9 gene stimulators, Toll-like receptor (TLR) regulators, viral ribonucleotide reductase inhibitors and combinations thereof.

[0339] Hepatitis B virus combination therapy

[0340] Examples of combination drugs used to treat HBV include (tenofovir disoproxil fumarate and emtricitabine); ABX-203, lamivudine, and PEG-IFN-α; ABX-203 adefovir and PEG-IFNα; and INO-1800 (INO-9112 and RG7944).

[0341] Other HBV drugs

[0342] Examples of other drugs used to treat HBV include α-hydroxytropinone, amdoxivir, β-hydroxycytidine, AL-034, CCC-0975, elvucitabine, ezetimibe, cyclosporin A, gentiopicroside, JNJ-56136379, nitazoxanide, birinapant, NJK14047, NOV-205 (molixan, BAM-205), oligotide, mi votilate, feron, GST-HG-131, levamisole, Ka Shu Ning, alloferon, WS-007, Y-101 (Ti Fen Tai), rSIFN-co, PEG-IIFNm, KW-3, BP-In ter-014, oleanolic acid, HepB-nRNA, cTP-5 (rTP-5), HSK-II-2, HEISCO-106-1, HEISCO-106, Hepbarna, IPB-0061A, Hepuyinfen, DasKl oster 0014-01, ISA-204, Jiangantai (Ganxikang), MIV-210, OB-A I-004, PF-06, picroside, DasKloster-0039, hepulantai, IMB-2613, TCM-800B, reduced glutathione, RO-6864018, RG-7834, UB-551, and ZH-2N, described in US20150210682, (Roche), US 2016 / 0122344(Roche)、WO2015173164、WO2016023877、US2015252057A(Roche)、WO16128335A1(Roche)、WO16120186A1(Roche)、US2016237090A(Roche) ), WO16107833A1(Roche), WO16107832A1(Roche), US2016176899A(Roche), WO16102438A1(Roche), WO16012470A1(Roche), US2016220586A(Roche), and Compounds in US2015031687A (Roche).

[0343] HBV vaccine

[0344] HBV vaccines include preventive and therapeutic vaccines. Examples of HBV preventive vaccines include Vaxelis, Hexaxim, Heplisav, Mosquirix, DTwP-HBV vaccine, Bio-Hep-B, D / T / P / HBV / M (LB VP-0101; LBVW-0101), DTwP-Hepb-Hib-IPV vaccine, Heberpenta L, DTwP-HepB-Hib, V-419, CVI-HBV-001, Tetrabhay, hepatitis B preventive vaccine (Advax Super D), Hepatrol-07, GSK-223192A, ENGERIX Recombinant Hepatitis B Vaccine (Intramuscular, Kangtai Biological Products), Recombinant Hepatitis B Vaccine (Intramuscular, Kangtai Biological Products), Recombinant Hepatitis B Surface Antigen Vaccine, Bimmugen, Euforavac, Eutravac, anrix-DTaP-IPV-Hep B, HBAI-20, Infanrix-DTaP-IPV-Hep B-Hib, Pentabio Vaksin DTP-HB-Hib, Comvac4, 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, Shannac-B, Hebsulin, Recombivax and DTaP-rHB-Hib Vaccine.

[0345] Examples of HBV therapeutic vaccines include HBsAG-HBIG complex, ARB-1598, Bio-Hep-B, NASVAC, abi-HB (intravenous), ABX-203, Tetrabhay, GX-110E, GS-4774, peptide vaccine (epsilonPA-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-adjuvant, HepB-v, RG7944 (INO-1800), recombinant VLP-based therapeutic vaccines (HBV infection, VLP Biotech), AdTG-17909, AdTG-17910, AdTG-18202, ChronVac-B, TG-1050 and Lm HBV.

[0346] HBV DNA polymerase inhibitors

[0347] Examples of HBV DNA polymerase inhibitors include adefovir Emtricitabine Tenofovir Disoproxil Fumarate Tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir dipivoxil, tenofovir dipivoxil fumarate, tenofovir octadecyloxyethyl ester, CMX-157, besifovir, entecavir Entecavir maleate, telbivudine filocilovir, pradefovir, clevudine, ribavirin, lamivudine Phosphorus azide, famciclovir, fusolin, metacavir, SNC-019754, FMCA, AGX-1009, AR-II-04-26, HIP-1302, tenofovir disoproxil aspartate, tenofovir disoproxil orotate, and HS-10234.

[0348] Immunomodulators

[0349] Examples of immunomodulators include rintatolimod, imidazolid 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, 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.

[0350] Toll-like receptor (TLR) modulators

[0351] TLR modulators include modulators of TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13. Examples of TLR3 modulators include rintatolimod, poly-ICLC, Apoxxim, IPH-33, MCT-465, MCT-475 and ND-1.1.

[0352] 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, telratolimod, SP-0509, TMX-30X, TMX-202, RG-7863, RG-7795, LHC-165, RG-7854, and compounds disclosed in US20100143301 (Gilead Sciences), US 20110098248 (Gilead Sciences), and US 20090047249 (Gilead Sciences).

[0353] Examples of TLR8 modulators include motomod, resiquimod, 3M-051, 3M-052, MCT-465, IMO-4200, VTX-763, VTX-1463, and US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US20140350031 (Janssen), WO2014 / 023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics), US20130251673 (Novira Therapeutics), U.S. Patent No. 9670205, US20160289229, U.S. Patent Application No. 15 / 692161 and U.S. Patent Application No. 15 / 692093.

[0354] 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), litenimod, and CYT-003-QBG10.

[0355] Examples of TLR7, TLR8, and TLR9 modulators include WO2017047769 (Teika Seiyaku), WO2015014815 (Janssen), WO2018045150 (Gilead Sciences Inc), WO2018045144 (Gilead Sciences Inc), WO2015162075 (Roche), WO2017034986 (University of Kansas), WO2018095426 (Jiangsu Hengrui Medicine Co Ltd), WO2016091698 (Roche), WO2016075661 (GlaxoSmithKline Biologicals), WO2016180743 (Roche), WO2018089695 (Dynavax Technologies), WO2016055553 (Roche), WO2015168279 (Novartis), WO2016107536 (Medshine Discovery), WO2018086593 (Livo(Shanghai)Pharmaceutical), WO2017106607 (Merck), WO2017061532 (Sumitomo Dainippon Pharma), WO2016023511 (ChiaTai Tianqing Pharmaceutical), WO2017076346 (Chia Tai Tianqing Pharmaceutical), WO2017046112 (Roche), WO2018078149 (Roche), WO2017040233 (3M Co), WO2016141092 (Gilead Sciences), WO2018049089 (Bristol Myers Squibb), WO2015057655 (Eisai Co Ltd), WO2017001307 (Roche), WO2018005586 (Bristol Myers Squibb), WO201704023 (3M Co), WO2017163264 (Council of Scientific and Industrial Research (India)), WO2018046460 (GlaxoSmithKlineBiologicals), WO2018047081 (Novartis), WO2016142250 (Roche), WO2015168269 (Novartis), WO201804163 (Roche), WO2018038877 (3M Co), WO2015057659 (Eisai Co) Ltd), WO2017202704 (Roche), WO2018026620 (Bristol Myers Squibb), WO2016029077 (Janus Biotherapeutics), WO201803143 (Merck), WO2016096778 (Roche), WO2017190669 (Shanghai De Novo Pharmatech), US09884866 (University of Minnesota), WO2017219931 (Sichuan KelunBiotech Biopharmaceutical), WO2018002319 (Janssen Sciences), WO2017216054 (Roche), WO2017202703 (Roche), WO2017184735 (IFM Therapeutics), WO2017184746 (IFM Therapeutics), WO2015088045 (Takeda Pharmaceutical), WO2017038909 (Takeda Pharmaceutical), WO2015095780 (University of Kansas), and WO2015023958 (University of Kansas).

[0356] Interferon alpha receptor ligand

[0357] Examples of interferon alpha receptor ligands include pegylated interferon alpha-2b (INTRON ), pegylated interferon α-2a Pegylated interferon α-1b, interferon α1b Veldona, Infradure, Roferon-A, YPEG-interferon α-2a (YPEG-rhIFNα-2a), P-1101, Algeron, Alfarona, Ingaron (interferon γ), rSIFN-co (interferon γ), pegylated interferon α-2b (YPEG-rhIFNα-2b), MOR-22, pegylated interferon α-2b Bioferon, Novaferon, Inmutag (Inferon), Interferon alpha-n 1 Interferon beta-1A Shaferon, interferon alpha-2b (Axxo), Alfaferone, interferon alpha-2b (BioGenericPharma), interferon-alpha 2 (CJ), Laferonum, VIPEG, BLAUFERON-A, BLAUFERON-B, Intermax Alpha, Realdiron, Lanstation, Pegaferon, PDferon-B, interferon alpha-2b (IFN interferon alpha-2b (Amega), interferon alpha-2b (Virchow), Luo pegylated interferon alpha-2b, rHSA-IFNα-2a (recombinant human serum albumin interferon alpha 2a fusion protein), rHSA-IFNα2b, recombinant human interferon alpha-(1b,2a,2b), pegylated interferon alpha-2b (Amega), pegylated interferon alpha-2a, Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alpha-2b (Changchun Institute of Biological Products), Anterferon, Shanferon, Layfferon, Shang Sheng Lei Tai, Interfen, SINOGEN, Fukangtai, Pegstat, rHSA-IFNα-2b, SFR-9216 and Interapo (Interapa).

[0358] Hyaluronidase inhibitors

[0359] Examples of hyaluronidase inhibitors include astodrimers.

[0360] Hepatitis B surface antigen (HBsAg) inhibitors

[0361] 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′.

[0362] Examples of HBsAg secretion inhibitors include BM601.

[0363] Cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitor

[0364] Examples of cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors include AGEN-2041, AGEN-1884, ipilumimab, belatacept, PSI-001, PRS-010, Probody mAbs, tremelimumab, and JHL-1155.

[0365] Cyclophilin inhibitors

[0366] 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 US 8513184, US 20140030221, US 20130344030, and US20130344029.

[0367] HBV viral entry inhibitors

[0368] Examples of HBV viral entry inhibitors include Myrcludex B.

[0369] Antisense oligonucleotides targeting viral mRNA

[0370] Examples of antisense oligonucleotides targeting viral mRNA include ISIS-HBVRx, IONIS-HBVRx, IONIS-GSK6-LRx, GSK-3389404, RG-6004.

[0371] Short interfering RNAs (siRNA) and ddRNAi

[0372] Examples of siRNA include TKM-HBV (TKM-HepB), ALN-HBV, SR-008, HepB-nRNA, and ARC-520, ARC-521, ARB-1740, ARB-1467.

[0373] Examples of DNA-directed RNA interference (ddRNAi) include BB-HB-331.

[0374] Endonuclease modulators

[0375] Examples of endonuclease modulators include PGN-514.

[0376] Ribonucleotide reductase inhibitors

[0377] Examples of ribonucleotide reductase inhibitors include Trimidox.

[0378] HBV E antigen inhibitors

[0379] Examples of HBV E antigen inhibitors include wogonin.

[0380] Covalently closed circular DNA (cccDNA) inhibitors

[0381] Examples of cccDNA inhibitors include BSBI-25 and CHR-101.

[0382] Farnesoid X receptor agonists

[0383] Examples of farnesoid x receptor agonists are EYP-001, GS-9674, EDP-305, MET-409, topiramate, AKN-083, RDX-023, BWD-100, LMB-763, INV-3, NTX-023-1, EP-024297, and GS-8670.

[0384] HBV antibodies

[0385] Examples of HBV antibodies targeting 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).

[0386] Examples of HBV antibodies (including monoclonal antibodies and polyclonal antibodies) include Zutectra, Shang Sheng GanDi, Uman Big (hepatitis B hyperimmune), Omri-Hep-B, Nabi-HB, Hepatect CP, HepaGam B, igantibe, Niuliva, CT-P24, hepatitis B immune globulin (intravenous, pH 4, HBV infection, Shanghai RAAS blood products) and Fovepta (BT-088).

[0387] Fully human monoclonal antibodies include HBC-34.

[0388] CCR2 chemokine antagonists

[0389] Examples of CCR2 chemokine antagonists include propamantium.

[0390] Thymosin agonists

[0391] Examples of thymosin agonists include thymalfasin, recombinant thymosin α1.

[0392] Cytokines

[0393] Examples of cytokines include recombinant IL-7, CYT-107, interleukin-2 (IL-2, Immunex), recombinant human interleukin-2, IL-15, IL-21, IL-24, and celmoleukin.

[0394] Nuclear protein regulator

[0395] Nucleoprotein regulators can be HBV core or capsid protein inhibitors. Examples of nucleoprotein regulators include GS-4882, AB-423, AT-130, GLS4, NVR-1221, NVR-3778, AL-3778, BAY 41-4109, thiazolidinone mesylate, ARB-168786, ARB-880, JNJ-379, RG-7907, HEC-72702, AB-506, ABI-H0731, JNJ-440, ABI-H2158 and DVR-23.

[0396] Examples of capsid inhibitors include US20140275167 (Novira Therapeutics), US20130251673 (Novira Therapeutics), US20140343032 (Roche), WO2014037480 (Roche), US20130267517 (Roche), WO2014131847 (Janssen), WO2014033176 (Janssen), WO2014033170 (Janssen), WO2014033167 (Janssen), WO2015 / 059212 (Janssen), WO2015118057 (Janssen), WO201511281 ( Janssen), WO2014184365 (Janssen), WO2014184350 (Janssen), WO2014161888 (Janssen), WO2013096744 (Novira), US20150225355 (Novira), US20140178337 (Novira), US20150315159 (Novira), US20150197533 (Novira), US20150274652 (Novira), US2015025932 4. (Novira), US20150132258 (Novira), US9181288 (Novira), WO2014184350 (Janssen), WO2013144129 (Roche), WO2017 198744 (Roche), US20170334882 (Novira), US20170334898 (Roche), WO2017202798 (Roche), WO2017214395 (Enanta), W O2018001944(Roche), W02018001952(Roche), WO2018005881(Novira), WO2018005883(Novira), WO2018011100(Roche) ), WO2018011160 (Roche), WO2018011160 (Roche) WO2018011163 (Roche), WO2018036941 (Roche), WO2018043747 (KyotoUniv), US20180065929 (Janssen), WO2016168619 (Indiana University), WO2016195982 (Pennsylvania State Foundation), WO2017001655 (Janssen), WO2017048950 (Assembly Biosciences), WO2017048954 (Assembly Biosciences), WO2017048962 (Assembly Biosciences), US20170121328 (Novira), and US20170121329 (Novira).

[0397] Examples of transcript inhibitors include compounds disclosed in WO2017013046 (Roche), WO2017016960 (Roche), WO2017017042 (Roche), WO2017017043 (Roche), WO2017061466 (Toyoma Chemicals), WO2016177655 (Roche), WO2016161268 (Enanta). WO2017001853 (RedexPharma), WO2017211791 (Roche), WO2017216685 (Novartis), WO2017216686 (Novartis), WO2018019297 (Ginkgo Pharmaceuticals), WO2018022282 (New Wave Pharmaceuticals), US20180030053 (Novartis), and WO2018045911 (Zhejiang Pharmaceuticals).

[0398] retinoic acid inducible gene 1 stimulator

[0399] 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.

[0400] NOD2 Stimulator

[0401] Examples of NOD2 stimulators include SB-9200.

[0402] Phosphatidylinositol 3-kinase (PI3K) inhibitors

[0403] Examples of PI3K inhibitors include edralisib, ACP-319, AZD-8186, AZD-8835, buparisib, CDZ-173, CLR-457, Pictilisib, Neratinib, Rigosertib, Rigosertib sodium, EN-3342, TGR-1202, Apelisib, Duvelisib, IPI-549, UCB-5857, Taselisib, XL-765, Gedatolisib, ME-401, VS-5584, Copanlisib, CAI Orotate, perifosine, RG-7666, GSK-2636771, DS-7423, panulisib, GSK-2269557, GSK-2126458, CUDC-907AMG-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.

[0404] Indoleamine-2,3-dioxygenase (IDO) pathway inhibitors

[0405] Examples of IDO inhibitors include epadostat (INCB24360), raminostat (4SC-201), indomod, F-001287, SN-35837, NLG-919, GDC-0919, GBV-1028, GBV-1012, NKTR-218, and compounds disclosed in US20100015178 (Incyte), US2016137652 (Flexus Biosciences, Inc.), WO2014073738 (Flexus Biosciences, Inc.), and WO2015188085 (Flexus Biosciences, Inc.).

[0406] PD-1 inhibitors

[0407] 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, JNJ-63723283, CA-170, Durvalumab, Atezolizumab, and MDX-400, JS-001, Camrelizu mab, Sintilimab, Sintilimab, Tislelizumab, BCD-100, BGB-A333, FNJ-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-LL / TGF-B bifunctional fusion protein), Genolimzumab, BMS-936559.

[0408] PD-L1 inhibitors

[0409] 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.

[0410] Examples of PD-1 inhibitors include WO2017112730 (Incyte Corp), WO2017087777 (Incyte Corp), WO2017017624, WO2014151634 (Bristol Myers Squibb Co), WO201317322 (Bristol Myers Squibb Co), WO2018119286 (Incyte Corp), WO2018119266 (Incyte Corp), WO2018119263 (Incyte Corp), WO2018119236 (Incyte Corp), WO2018119221 (Incyte Corp), WO2018118848 (Bristol Myers Squibb Co), WO20161266460 (Bristol Myers Squibb Co), WO2017087678 (Bristol Myers Squibb Co), WO2016149351 (Bristol Myers Squibb Co), WO2015033299 (Aurigene Discovery Technologies Ltd), WO2015179615 (Eisai Co Ltd; Eisai Research Institute), WO2017066227 (Bristol Myers Squibb Co), WO2016142886 (Aurigene Discovery Technologies Ltd), WO2016142852 (Aurigene Discovery Technologies Ltd), WO2016142835 (Aurigene Discovery Technologies Ltd; Individual), WO2016142833 (Aurigene Discovery Technologies Ltd), WO2018085750 (Bristol Myers Squibb Co), WO2015033303 (Aurigene Discovery Technologies Ltd), WO2017205464 (Incyte Corp), WO2016019232 (3M Co; Individual;Texas A&M UniversitySystem),WO2015160641(BristolMyers Squibb Co),WO2017079669(Incyte Corp),WO2015033301(Aurigene Discovery Technologies Ltd),WO2015034820(BristolMyersSquibb Co),WO2018073754(Aurigene Discovery Technologies Ltd),WO2016077518(BristolMyers Squibb Co),WO2016057624(BristolMyers Squibb Co),WO2018044783(Incyte Corp),WO2016100608(BristolMyers Squibb Co),WO2016100285(BristolMyersSquibb Co),WO2016039749(BristolMyers Squibb Co),WO2015019284(CambridgeEnterprise Ltd),WO2016142894(Aurigene Discovery Technologies Ltd),WO2015134605(BristolMyers Squibb Co),WO2018051255(Aurigene DiscoveryTechnologies Ltd),WO2018051254(Aurigene Discovery Technologies Ltd),WO2017222976(Incyte Corp),WO2017070089(Incyte Corp),WO2018044963(BristolMyersSquibb Co),WO2013144704(Aurigene Discovery Technologies Ltd),WO2018013789(Incyte Corp),WO2017176608(BristolMyers Squibb Co),WO2018009505(BristolMyersSquibb Co),WO2011161699(Aurigene Discovery Technologies Ltd),WO2015119944(Incyte Corp;Merck Sharp & Dohme Corp), WO2017192961 (Incyte Corp), WO2017106634 (Incyte Corp), WO2013132317 (Aurigene Discovery Technologies Ltd), WO2012168944 (Aurigene Discovery Technologies Ltd), WO2015036927 (Aurigene Discovery Technologies Ltd) Ltd), WO2015044900 (Aurigene Discovery Technologies Ltd), WO2018026971 (Arising International). ;

[0411] Recombinant Thymosin α1

[0412] Examples of recombinant thymosin alpha-1 include NL-004 and pegylated thymosin alpha-1.

[0413] Bruton's tyrosine kinase (BTK) inhibitors

[0414] 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, pembrolizumab, TAS-5315, TP-0158, TP-4207, HM-71224, KBP-7536, M-2951, TAK-020, AC-0025, and US20140330015 (Ono Pharmaceutical), US20130079327 (Ono Pharmaceutical). Pharmaceutical) and US20130217880 (Ono Pharmaceutical).

[0415] KDM inhibitors

[0416] Examples of KDM5 inhibitors include WO2016057924 (Genentech / Constellation Pharmaceuticals), US20140275092 (Genentech / Constellation Pharmaceuticals), US20140371195 (Epitherapeutics) and US20140371214(Epitherapeutics),US20160102096(Epitherapeutics),US20140194469(Quanticel),US20140171432 , US20140213591 (Quanticel), US20160039808 (Quanticel), US20140275084 (Quanticel), WO2014164708 (Quanticel).

[0417] Examples of KDM1 inhibitors include compounds disclosed in US 9186337 B2, GSK-2879552, and RG-6016.

[0418] STING agonists

[0419] Examples of STING agonists include SB-11285, AdVCA0848, STINGVAX, and 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), US 20170158724 (GlaxoSmithkline), WO 2017075477 (Aduro Biotech), US 20170044206 (Merck), WO 2014179760 (University of California), WO2018098203 (Janssen), WO2018118665 (Merck), WO2018118664 (Merck), WO2018100558 (Takeda), WO2018067423 (Merck), WO2018060323 (Boehringer).

[0420] Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

[0421] Examples of NNRTIs include compounds disclosed in WO 2018118826 (Merck), WO 2018080903 (Merck), WO 2018119013 (Merck), WO 2017100108 (Idenix), WO 2017027434 (Merck), WO 2017007701 (Merck), WO 2008005555 (Gilead).

[0422] HBV replication inhibitors

[0423] Examples of hepatitis B virus replication inhibitors include isothiafluxidine, IQP-HBV, RM-5038, and Xingantie.

[0424] Arginase inhibitors

[0425] Examples of arginase inhibitors include CB-1158, C-201, and resminostat.

[0426] Gene therapy and cell therapy

[0427] Gene therapy and cell therapy include genetic modification to silence genes; genetic methods to directly kill infected cells; infusions of immune cells designed to replace a large portion of the patient's own immune system to enhance the immune response to infected cells, or to activate the patient's own immune system to kill infected cells, or to find and kill infected cells; and genetic methods to alter cellular activity to further alter the endogenous immune responsiveness to infection.

[0428] Gene Editor

[0429] Examples of genome editing systems include CRISPR / Cas9 systems, zinc finger nuclease systems, TALEN systems, homing endonuclease systems, and meganuclease systems; for example, elimination of cccDNA by targeted cleavage, and alteration of one or more hepatitis B virus (HBV) viral genes. Alteration (e.g., knockout and / or knockdown) of PreC, C, X, PreSI, PreS2, S, P or SP gene refers to (1) reduction or elimination of PreC, C, X, PreSI, PreS2, S, P or SP gene expression, (2) interference with Precore, Core, X protein, long surface protein, middle surface protein, S protein (also known as HBs antigen and HBsAg), polymerase protein and / or hepatitis B splicing protein function (HBe, HBc, HBx, PreSI, PreS2, S, Pol and / or HBSP or (3) reduction or elimination of intracellular, serum and / or organ parenchymal levels of HBe, HBc, HBx, LHB, MHB, SHB, Pol and / or HBSP protein. Knockdown of one or more of PreC, C, X, PreSI, PreS2, S, P and / or SP genes is performed by targeting genes within HBV cccDNA and / or integrated HBV DNA.

[0430] CAR-T cell therapy

[0431] CAR T cell therapy includes a population of immune effector cells engineered to express a chimeric antigen receptor (CAR), wherein the CAR comprises an HBV antigen binding domain. 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.

[0432] TCR-T cell therapy

[0433] TCR T cell therapy includes T cells expressing HBV-specific T cell receptors. TCR-T cells are engineered to target HBV-derived peptides presented on the surface of virus-infected cells. In some embodiments, T cells express HBV surface antigen (HBsAg)-specific TCRs. Examples of TCR-T therapies for treating HBV include LTCR-H2-1.

[0434] In another specific embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with an HBV DNA polymerase inhibitor, one or two additional therapeutic agents selected from immunomodulators, TLR modulators, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, HBV therapeutic vaccines, HBV antibodies (including HBV antibodies and bispecific antibodies targeting hepatitis B virus surface antigens), and "antibody-like" therapeutic proteins (e.g. 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 NOD2 stimulators, and one or two additional therapeutic agents selected from HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting hepatitis B virus surface antigen, siRNA, miRNA gene therapy agents, sshRNA, KDM5 inhibitors and nucleoprotein regulators (HBV core or capsid protein regulators).

[0435] In another specific embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with an HBV DNA polymerase inhibitor and at least a second additional therapeutic agent selected from the group consisting of an immunomodulator, a TLR modulator, an HBsAg inhibitor, a HBV therapeutic vaccine, an HBV antibody, including an HBV antibody and a bispecific antibody targeting the surface antigen of the hepatitis B virus and an "antibody-like" therapeutic protein (e.g. 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 NOD2 stimulators.

[0436] In another specific embodiment, the 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: HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting hepatitis B virus surface antigen, siRNA, miRNA gene therapy agents, sshRNAs, KDM5 inhibitors and nucleoprotein modulators (HBV core or capsid protein inhibitors).

[0437] In a specific embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with compounds disclosed, for example, in U.S. Publication No. 2010 / 0143301, U.S. Publication No. 2011 / 0098248, U.S. Publication No. 2009 / 0047249, U.S. Pat. No. 8722054, U.S. Publication No. 2014 / 0045849 (Janssen), U.S. Publication No. 2014 / 0073642 (Janssen) , WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US Publication No. 2014 / 0350031 (Janssen), WO2014 / 023813 (Janssen), US Publication No. 2008 / 02341 (Janssen), US Publication No. 2010 / 0029585 (Ventirx Pharma), U.S. Publication No. 2011 / 0092485 (Ventirx Pharma), US2011 / 0118235 (Ventirx Pharm a), U.S. Publication No. 2012 / 0082658 (Ventirx Pharma), U.S. Publication No. 2012 / 0219615 (Ventirx Pharma), U.S. Publication No. 2011 / 0092485 (Ventirx Pharma), US2011 / 0118235 (Ventirx Pharma), U.S. Publication No. 2010 / 0029585 (Ventirx Pharma), U.S. Publication No. 2010 / 0029585 (Ventirx Pharma), U.S. Publication No. 2010 / 0029585 (Ventirx Pharma), U.S. Publication No. 2010 / 0029585 (Ventirx Pharma), Pharma), U.S. Publication No. 2014 / 0066432 (Ventirx Pharma), U.S. Publication No. 2014 / 0088085 (VentirxPharma), U.S. Publication No. 2014 / 0275167 (Novira Therapeutics), U.S. Publication No. 2013 / 0251673 (Novira Therapeutics), U.S. Patent No. 8513184 (Gilead Sciences), U.S. Publication No. 2013 / 0344030 (Gilead Sciences), U.S. Publication No. 2013 / 0344029 (Gilead Sciences), U.S. Publication No. 2014 / 0275167 (Novira Therapeutics), U.S. Publication No. 2013 / 0251673 (Novira Therapeutics), U.S. Patent No. 8513184 (Gilead Sciences), U.S. Publication No. 2013 / 0344030 (Gilead Sciences), U.S. Publication No. 2013 / 0344029 (Gilead Sciences), U.S. Publication No. 2013 / 0Therapeutics), U.S. Publication No. 2014 / 0343032 (Roche), WO2014037480 (Roche), U.S. Publication No. 2013 / 0267517 (Roche), WO2014131847 (Janssen), WO2014033176 (Janssen), WO2014033170 (Janssen), WO2014033167 (Janssen), WO2015 / 059212 (Janssen), WO2015118057 (Janssen), WO2015011281 (Janssen), WO2014184365 (Janssen), WO2014184350 (Janssen), WO201416 1888(Janssen)、WO2013096744(Novira)、US20150225355(Novira)、US20140178337(N ovira), US20150315159(Novira), US20150197533(Novira), US20150274652(Novira), US20150259324,(Novira), US20150132258(Novira), US9181288(Novira), WO20141843 50 (Janssen), WO2013144129 (Roche), US20100015178 (Incyte), US2016137652 (Flexus Biosciences, Inc.), WO2014073738 (Flexus Biosciences, Inc.), WO2015188085 (Flexus Biosciences, Inc.), U.S. Publication No. 2014 / 0330015 (Ono Pharmaceutical, Inc.), U.S. Publication No. 2013 / 0079327 (Ono Pharmaceutical), U.S. Publication No. 2013 / 0217880 (Ono Biosciences, Inc.), WO2016057924 (Genentech / Constellation Pharmaceuticals), US20140275092 (Genentech / ConstellationPharmaceuticals), US20140371195 (Epitherapeutics), WO2016057924 (Genentech / Constellation Pharmaceuticals), US20140371195 (Epitherapeutics), US20140371214 (Epitherapeutics). US20160102096 (Epitherapeutics), US20140194469 (Quanticel), US20140171432, US20140213591 (Quanticel), US20160039808 (Quanticel), US20140275084 (Quanticel), WO2014164708 (Quanticel), US9186337B2 (Oryzon Genomics), and other drugs for treating HBV, and combinations thereof.

[0438] Cancer combination therapy

[0439] In one embodiment, the compounds of the present disclosure may be used with other therapeutic approaches for cancer treatment. Preferably, combination therapy with: chemotherapy, hormones, antibodies, surgery and / or radiation therapy is contemplated.

[0440] In some embodiments, the further anti-cancer therapy is surgery and / or radiation therapy.

[0441] In some embodiments, the additional anti-cancer therapy is at least one additional cancer drug.

[0442] In some embodiments, a combination comprising a compound as described herein, or a pharmaceutically acceptable salt thereof, and at least one additional cancer drug is provided.

[0443] In some embodiments, provided is a combination comprising a compound as described herein, or a pharmaceutically acceptable salt thereof, and at least one additional cancer drug for use in treatment.

[0444] In some embodiments, there is provided use of a combination comprising a compound as described herein, or a pharmaceutically acceptable salt thereof, and at least one cancer drug in the preparation of a medicament for treating cancer.

[0445] Examples of other cancer drugs include intercalating substances, such as anthracyclines, doxorubicin, idarubicin, epirubicin, and daunorubicin; topoisomerase inhibitors, such as irinotecan, topotecan, camptothecin, lamelliposide D, etoposide, teniposide, mitoxantrone, amsacrine, ellipticine, and aurintricarboxylic acid; nitrosourea compounds, such as carmustine (BCNU), lomustine (CCNU), and streptozotocin; nitrogen mustards, such as cyclophosphamide, mechlorethamine, uramustine, bendamustine, melphalan, chlorambucil, mafosfamide, trofosfamide, and ifosfamide; alkyl sulfonates, such as busulfan and treoxavan; alkylating agents, such as procarbazine, dacarbazine, temozolomide, and thiotepa; platinum analogs, such as cisplatin, carboplatin, nedaplatin, oxaliplatin, satraplatin, and triplatin tetranitrate; microtubule disrupting drugs, Such as vinblastine, colcemid and nocodazole; antifolates such as methotrexate, aminopterin, dichloromethotrexate, pemetrexed, raltitrexed and pralatrexate; purine analogs such as azathioprine, mercaptopurine, thioguanine, fludarabine, fludarabine phosphate, pentostatin and cladribine; pyrimidine analogs such as 5-fluorouracil, floxuridine, cytarabine, 6-azauracil, gemcitabine; Steroids, such as pregnenolone, androgens, glucocorticoids, dexamethasone, prednisolone and prednisone; anticancer antibodies, such as monoclonal antibodies, for example, alemtuzumab, apolizumab, cetuximab, epratuzumab, galiximab, gemtuzumab, ipilimumab, labetuzumab, panitumumab, rituximab, trastuzumab, nimotuzumab, mapazumab, matuzumab, rhMab ICR62 and pertuzumab, radiolabeled antibodies and antibody-drug conjugates; anticancer peptides, such as radiolabeled peptides and peptide-drug conjugates; and taxanes and taxane analogs such as paclitaxel and docetaxel.

[0446] In certain embodiments, a method for treating or preventing a hyperproliferative disease or cancer in a human or animal having a hyperproliferative disease or cancer or having a risk of having a hyperproliferative disease or cancer is provided, comprising administering to the human or animal a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents in combination. In one embodiment, a method for treating a hyperproliferative disorder or cancer in a human is provided. The present invention provides a human or animal having a hyperproliferative disease or cancer or being at risk of having a 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, which is combined with a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof. A therapeutically effective amount of one or more (e.g., one, two, three, one or two or one to three) additional therapeutic agents.

[0447] 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, and a therapeutically effective amount of one or more additional therapeutic agents suitable for treating a hyperproliferative disease or cancer.

[0448] The compounds described herein can be combined with one or more chemotherapeutic agents, anti-cancer agents, anti-angiogenic agents, anti-fibrotic agents, immunotherapeutic agents, therapeutic antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins (e.g. Fab derivatives), antibody-drug conjugates (ADC), radiotherapeutics, antitumor agents, antiproliferative agents, oncolytic viruses, gene modifiers or editors (e.g., CRISPR / Cas9, zinc finger nucleases or synthetic nucleases, TALENs), CAR (chimeric antigen receptor) T cell immunotherapeutics, engineered T cell receptors (TCR-T) or any combination thereof. These therapeutic agents can be in the form of compounds, antibodies, polypeptides, or polynucleotides. In one embodiment, provided herein are products comprising a compound as described herein and an additional therapeutic agent, which are used as a combined preparation for simultaneous, separate, or sequential use in therapy.

[0449] The one or more therapeutic agents include, but are not limited to, inhibitors, agonists, antagonists, ligands, modulators, stimulators, blockers, activators or inhibitors of a gene, ligand, receptor, protein or factor. 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, A3), adenylate cyclase, ADP-ribosyl cyclase-1, adrenocorticotropic hormone receptor (ACTH), aeromonas, AKT1 gene, Alk-5 protein kinase, alkaline phosphatase, α1 adrenergic receptor, α2 adrenergic receptor, α-ketoglutarate dehydrogenase (KGDH), aminopeptidase N, AMP-activated protein kinase, anaplastic lymphoma kinase (ALK, such as ALK1), androgen receptor, angiopoietin (such as ligand-1, A2a, A3). ligand-2), angiotensinogen (AGT) gene, murine thymoma viral oncogene homolog 1 (AKT) protein kinase (such as Akt1, AKT2, AKT3), apolipoprotein AI (Apoa1) gene, apoptosis-inducing factor, apoptosis proteins (such as 1, 2), apoptosis signal-regulating kinase (ASK, such as ASK1), arginase (I), arginine deiminase, aromatase, asteroid homolog 1 (ASTE1) gene, ataxia telangiectasia and Rad 3-related (ATR) serine / threonine protein kinase, Aurora protein kinase (eg 1, 2), Axl tyrosine kinase receptor, baculovirus IAP repeat 5 (BIRC5) gene, Basigin, B cell lymphoma 2 (BCL2) gene, BCL2 binding component 3, BCL2 protein, BCL2L11 gene, BCR (breakpoint cluster region) protein and gene, beta adrenergic receptor, beta-catenin, B-lymphocyte antigen CD19, B-lymphocyte antigen CD20, B-lymphocyte adhesion molecule, B-lymphocyte stimulator ligand, bone morphogenetic protein-10 ligand, bone morphogenetic protein morphogenetic protein-9 ligand regulator, mouse short tail mutant phenotype protein, bradykinin receptor, B-Raf proto-oncogene (BRAF), Brc-Abl tyrosine kinase, bromodomain and extra-domain (BET) bromodomain-containing proteins (such as 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 (such as CB1, CB2), carbonic anhydrase, casein kinase (CK,Such as CKI, CKII), caspases (such as caspase-3, caspase-7, caspase-9), caspase 8 apoptosis-related cysteine ​​peptidase Casp8-FADD-like regulator, caspase recruitment domain protein-15, cathepsin G, CCR5 gene, CDK-activated kinase (CAK), checkpoint kinase (CHK1, CHK2), chemokine (CC motif) receptors (such as CCR2, CCR4, CCR5), chemokine (CXC motif) receptors CXCR4, CXCR1 and CXCR2), chemokine CC21 ligand, cholecystokinin CCK2 receptor, chorionic gonadotropin, c-Kit (tyrosine protein kinase Kit or CD117), claudin (such as 6, 18), cluster of differentiation (CD) such as CD4, CD27, CD29, CD30, CD33, CD37, CD40, CD40 ligand receptor, CD40 ligand, CD40Ig gene, CD44, CD45, CD47, CD49b, CD51, CD52, CD55, CD58, CD66e, CD70 gene, CD74, CD79, CD79b, CD79B gene, CD80, CD95, CD99, CD117, CD122, CDw123, CD134, CDw137, CD158a, CD158b1, CD158b2, CD223, CD276 antigen; clusterin (CLU) gene, clusterin, c-Met (hepatocyte growth factor receptor (HGFR )), complement C3, connective tissue growth factor, COP9 signaling subunit 5, CSF-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, CDK2-9), cyclooxygenases (such as 1, 2), 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 ligand (such as 3, 4), deoxyribonuclease, Dickkopf-1 ligand, dihydrofolate reductase (DHFR), dihydropyrimidine dehydrogenase, dipeptidyl peptidase IV, discoidin domain receptor (DDR,e.g. DDR1), DNA binding proteins (e.g. Hu-β), DNA-dependent protein kinases, DNA gyrase, DNA methyltransferase, DNA polymerase (e.g. α), DNA primase, dUTP pyrophosphatase, L-dopachrome tautomerase, echinoderm tubulin-like protein 4, EGFR tyrosine kinase receptor, elastase, elongation factor 1α2, elongation factor 2, endoglin, endonuclease, endoplasmic reticulum, endosialin, endostatin, endothelins (e.g. ET-A, ET-B), enhancer of zeste homolog 2 (EZH2), ephrin (EPH) tyrosine kinase (such as Epha3, Ephb4), ephrin B2 ligand, epidermal growth factor, epidermal growth factor receptor (EGFR), epidermal growth factor receptor (EGFR) gene, epithelial cell adhesion molecule (EpCAM), Erb-b2 (v-erb-b2 avian erythroblastic leukemia virus oncogene homolog 2) tyrosine kinase receptor, Erb-b3 tyrosine kinase receptor, Erb-b4 tyrosine kinase receptor, E-selectin, estradiol 17β dehydrogenase, estrogen receptor (such as α, β), estrogen-related receptors, eukaryotic translation initiation factor 5A (EIF5A) gene, exportin 1, extracellular signal-related kinases (such as 1, 2), extracellular signal-regulated kinases (ERK), factors (such as Xa, VIIa), farnesoid x receptor (FXR), Fas ligand, fatty acid synthase (FASN), ferritin, FGF-2 ligand, FGF-5 ligand, fibroblast growth factor (FGF, such as FGF1, FGF2, FGF4), fibronectin, Fms-related tyrosine kinase 3 (Flt3), Focal adhesion kinase (FAK, such as FAK2), folate hydrolase prostate-specific membrane antigen 1 (FOLH1), folate receptor (such as α), folate, folate transporter 1, FYN tyrosine kinase, paired basic amino acid cleaving enzyme (FURIN), β-glucuronidase, galactosyltransferase, galectin-3, ganglioside GD2, glucocorticoid, glucocorticoid-induced TNFR-related protein GITR receptor, glutamate carboxypeptidase II, glutaminase, glutathione S-transferase P, glycogen synthase kinase (GSK,3-β), phosphatidylinositol proteoglycan 3 (GPC3), gonadotropin-releasing hormone (GNRH), granulocyte macrophage colony-stimulating factor (GM-CSF) receptor, granulocyte colony-stimulating factor (GCSF) ligand, growth factor receptor binding protein 2 (GRB2), Grp78 (78kDa glucose-regulated protein) calcium-binding protein, molecular chaperone groEL2 gene, heat shock protein (such as 27, 70, 90α, β), heat shock protein gene, heat-stable enterotoxin receptor, Hedgehog protein, heparanase, hepatocyte growth factor, HERV-H LTR-associated protein 2, hexokinase, histamine H2 receptor, histone methyltransferase (DOT1L), histone deacetylase (HDAC, such as 1, 2, 3, 6, 10, 11), histone HI, histone H3, HLA class I antigen (A-2α), HLA Class II antigen, homeobox protein NANOG, HSPB1 gene, human leukocyte antigen (HLA), human papillomavirus (such as E6, E7) protein, -hyaluronic acid, hyaluronidase, hypoxia-inducible factor-1α (HIF1α), imprinted maternal expressed transcript (HI9) gene, mitogen-activated protein kinase 1 (MAP4K1), tyrosine protein kinase HCK, I-κ-B kinase (IKK, such as IKKbe), IL-1α, IL-1β, IL-12, IL-12 gene, IL-15, IL-17, IL-2 gene, IL-2 receptor α subunit, IL-2, IL-3 receptor, IL-4, IL-6, IL-7, IL-8, immunoglobulins (such as G, G1, G2, K, M), immunoglobulin Fc receptor, immunoglobulin γ Fc receptor (such as I, III, IIIA), indoleamine 2 ,3-dioxygenase (IDO, III, IIIA), such as IDO1), indoleamine pyrrole 2,3-dioxygenase 1 inhibitor, insulin receptor, insulin-like growth factor (such as 1, 2), integrin α-4 / β-1, integrin α-4 / β-7, integrin α-5 / β-1, integrin α-V / β-3, integrin α-V / β-5, integrin α-V / β-6, intercellular adhesion molecule 1 (ICAM-1), interferon (such as α, α2, β, γ), interferon-induced protein 2 (AIM2) absent in melanoma, type I interferon receptor, interleukin 1 ligand, interleukin 13 receptor α2, interleukin 2 ligand, interleukin-1 receptor associated kinase 4 (IRAK4), interleukin-2, interleukin-29 ligand, isocitrate dehydrogenase (such as Idh1, IDH2), Janus kinase (JAK,Such as JAK1, 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-associated protein-1, leukotriene A4 hydrolase, listeriolysin, L-selectin, luteinizing hormone receptor, lyase, lymphocyte activation gene 3 protein (LAG-3), lymphocyte antigen 75, lymphocyte function antigen-3 receptor, lymphocyte-specific protein tyrosine kinase (LCK), lymphocyte chemotactic protein, Lyn (Lck / Yes novel) tyrosine kinase, lysine demethylase (such as KDM1, KDM2, KDM4, KDM5, KDM6, A / B / C / D), lysophosphatidic acid-1 receptor, lysosomal associated membrane protein family (LAMP) gene, lysyl oxidase homolog 2, lysyl oxidase protein (LOX), lysyl oxidase-like protein (LOXL, such as LOXL2), hematopoietic progenitor cell kinase 1 (HPK1), hepatocyte growth factor receptor (MET) gene, macrophage colony stimulating factor (MCSF) ligand, macrophage migration inhibition fact, MAGEC1 gene, MAGEC2 gene, major vault protein, MAPK activated protein kinase (such as MK2), Mas-related G-protein coupled receptor, matrix metalloproteinase (MMP, such as MMP2, MMP9), Mcl-1 differentiation protein, Mdm2p53 binding protein, Mdm4 protein, Me lan-A (MART-1) melanoma antigen, melanocyte protein PMEL17, melanocyte stimulating hormone ligand, melanoma antigen family A3 (MAGEA3) gene, melanoma-associated antigens (such as 1, 2, 3, 6), membrane copper amine oxidase, mesothelin, MET tyrosine kinase, metabotropic glutamate receptor 1, metalloreductase STEAP1 (prostatic six-transmembrane epithelial antigen 1), mestatin, methionine aminopeptidase-2, methyltransferase, mitochondrial 3-ketoacyl CoA thiolase, mitogen-activated protein kinase (MAPK), mitogen-activated protein kinase (MEK, such as MEK1, mitogen-activated protein kinase (MEK), mitogen-activated protein kinase (MEK), mitogen-activated MEK2), mTOR (mechanical target of rapamycin (serine / threonine kinase), mTOR complex (such as 1, 2), mucin (such as 1, 5A, 16), mut T homolog (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, NFκB activated protein, NIMA-associated kinase 9 (NEK9), nitric oxide synthase, NK cell receptor, NK3 receptor, NKG2A / B activated NK receptor, norepinephrine transporter, Notch (such as Notch-2 receptor, Notch-3 receptor, Notch-4 receptor), nuclear erythroid 2-related factor 2, nuclear factor (NF)κB, nucleolin, nucleolar phosphatidylcholine, nucleolar phosphatidylcholine-anaplastic lymphoma kinase (NPM-ALK), 2-oxoglutarate dehydrogenase, 2, 5-oligoadenylate synthetase, O-methylguanine DNA methyltransferase, opioid receptor (eg, δ), 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, p38 MAP kinase, p53 tumor suppressor protein, parathyroid hormone ligand, peroxisome proliferator-activated receptor δ, γ), P-glycoprotein (eg, 1), phosphatase and tensin homolog (PTEN), phosphatidylinositol 3-kinase (PI3K), phosphoinositide-3 kinase (PI 3K, such as α, δ, γ), phosphorylase kinase (PK), PKN3 gene, placental growth factor, platelet-derived growth factor (PDGF, such as α, β), platelet-derived growth factor (PDGF, such as α, β), pleiotropic drug 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), preferentially expressed antigen in melanoma (PRAME) gene, prenyl binding protein (PrPB), possible transcription factor PML, progesterone receptor, programmed cell death 1 (PD-1), programmed cell death ligand 1 inhibitor (PD -L1), prosphingolipid activator protein (PSAP) gene, prostaglandin receptor (EP4), prostate specific antigen, prostatic acid phosphatase, proteasome, protein E7, protein farnesyl transferase, protein kinase (PK, such as A, B, C), protein tyrosine kinase, protein tyrosine phosphatase β, proto-oncogene serine / threonine protein kinase (PIM, such as PIM-1, PIM-2, 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-α-reductase, Raf protein kinase (such as 1,B), Raf1 gene, Ras gene, Ras GTPase, RET gene, RET tyrosine kinase receptor, retinoblastoma-associated protein, retinoic acid receptor (such as γ), retinoid X receptor, Rheb (brain-enriched Ras homolog) GTPase, Rho (Ras homolog)-related protein kinase 2, ribonuclease, ribonucleotide reductase (such as M2 subunit), ribosomal protein S6 kinase, RNA polymerase (such as I, II), Ron (Recepteur d'OrigineNantais) tyrosine kinase, ROS1 (ROS proto-oncogene 1, receptor tyrosine kinase) gene, ROS1 tyrosine kinase, Runt-related transcription factor 3, γ-secretase, S100 calcium-binding protein A9, Sarco endoplasmic calcium ATPase, second mitochondrial-derived caspase activator (SMAC) protein, secreted Frizzled-related protein-2, axon guidance factor-4D, serine protease, serine / threonine kinase (STK), serine / threonine protein kinase (TBK, such as TBK1), signal transduction and transcription (STAT, such as TK 1. For example, STAT-1, STAT-3, STAT-5), signaling lymphocyte activation molecule (SLAM) family member 7, prostate six-transmembrane epithelial antigen (STEAP) gene, SL cytokine ligand, smoothened (SMO) receptor, sodium iodide cotransporter, sodium phosphate cotransporter 2B, somatostatin receptors (such as 1, 2, 3, 4, 5), sonic hedgehog, Son ofsevenless (SOS), specificity protein 1 (Sp1) transcription factor, sphingomyelin synthase, sphingosine kinase (such as 1,2), sphingosine-1-phosphate receptor-1, spleen tyrosine kinase (SYK), Src gene, Src tyrosine kinase, STAT3 gene, steroid sulfatase, interferon gene (STING) receptor stimulator, interferon gene protein stimulator, stromal cell-derived factor 1 ligand, SUMO (small ubiquitin-like modifier), superoxide dismutase, survival protein, synapsin 3, syndecan-1, synuclein α, T cell surface glycoprotein CD28, TANK node TBK, TATA box binding protein-associated factor RNA polymerase I subunit B (TAF1B) gene, T cell CD3 glycoprotein ζ 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, tenascin, TGFβ2 ligand, thrombopoietin receptor, thymidine kinase, thymidine phosphorylase, thymidylate synthase, thymosin (such as α1), thyroid hormone receptor, thyroid stimulating hormone receptor, tissue factor, TNF-related apoptosis-inducing ligand,TNFR1-related death domain protein, TNF-related apoptosis-inducing ligand (TRAIL) receptor, TNFSF11 gene, TNFSF9 gene, Toll-like receptors (TLR, such as 1-13), topoisomerase (such as I, II, III), transcription factors, transferase, transferrin, transforming growth factor (TGF, such as β) kinase, transforming growth factor TGF-β receptor kinase, transglutaminase, translocation-related protein, transmembrane glycoprotein NMB, Trop-2 calcium signal transducer, trophoblast glycoprotein (TPBG) gene, trophoblast glycoprotein, tropomyosin receptor kinase (Trk) receptor (such as TrkA, TrkB, TrkC), tryptophan 5-hydroxylase, tubulin, tumor necrosis factor (TNF, such as α, β), 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, immunoglobulin-like tyrosine kinase and EGF-like domain (TIE) receptor, tyrosine protein kinase ABL1 inhibitor, ubiquitin, ubiquitin carboxyl hydrolase isozyme L5, ubiquitin thioesterase-14, ubiquitin conjugating enzyme E2I (UBE2I, UBC9), urease, urokinase 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.

[0450] Non-limiting examples of additional therapeutic agents can be categorized by their mechanism of action into, for example, the following groups:

[0451] -Antimetabolites / anticancer agents, such as the pyrimidine analogs floxuridine, capecitabine, cytarabine, CPX-351 (liposomal cytarabine, daunorubicin), and TAS-118;

[0452] -Purine analogs, folate antagonists (eg, pralatrexate), and related inhibitors;

[0453] - 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 and epipodophyllotoxins (etoposide, teniposide);

[0454] -DNA damaging agents such as actinomycin, amsacrine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide Actinomycin D, daunorubicin, doxorubicin, epirubicin, ifosfamide, melphalan, nitrogen mustard, mitomycin C, mitoxantrone, nitrosoureas, procarbazine, paclitaxel, taxotere, teniposide, etoposide, and triethylenephosphamide;

[0455] -DNA-hypomethylating agents, such as guadecitabine (SGI-110), ASTX727;

[0456] - Antibiotics, such as dactinomycin, daunorubicin, doxorubicin, idarubicin, anthracyclines, mitoxantrone, bleomycin, plicamycin (mithramycin);

[0457] - enzymes, such as L-asparaginase, which systemically metabolize L-asparagine and deprive cells that do not have the ability to synthesize their own asparagine;

[0458] - Antiplatelet agents;

[0459] - DNAi oligonucleotides targeting Bcl-2, such as PNT2258;

[0460] -Agents that activate or reactivate latent human immunodeficiency virus (HIV), such as panobinostat and romidepsin;

[0461] -Asparaginase stimulators, such as crisantaspase and GRASPA (ERY-001, ERY-ASP), pegylated caspase;

[0462] - pan-Trk, ROS1 and ALK inhibitors, such as entrectinib, TPX-0005;

[0463] - anaplastic lymphoma kinase (ALK) inhibitors, such as alectinib, ceritinib;

[0464] - Antiproliferative / antimitotic alkylating agents, such as the nitrogen mustard cyclophosphamide and analogs (melphalan, chlorambucil, hexamethylmelamine, thiotepa), alkyl nitrosoureas (carmustine) and analogs, streptozocin, and triazene (dacarbazine);

[0465] - Antiproliferative / antimitotic antimetabolites, such as folic acid analogs (methotrexate);

[0466] - Platinum coordination complexes (cisplatin, oloplatin, and carboplatin), procarbazine, hydroxyurea, mitotane, and aminoglutethimide;

[0467] - Hormones, hormone analogs (estrogens, tamoxifen, goserelin, bicalutamide, and nilutamide), and aromatase inhibitors (letrozole and anastrozole);

[0468] - Anticoagulants such as heparin, synthetic heparin salts and other thrombin inhibitors; fibrinolytics such as tissue plasminogen activator, streptokinase, urokinase, aspirin, dipyridamole, ticlopidine and clopidogrel;

[0469] - Anti-migration agents;

[0470] - Antisecretory agents (breveldin);

[0471] - Immunosuppressants such as tacrolimus, sirolimus, azathioprine, and mycophenolate mofetil; growth factor inhibitors and vascular endothelial growth factor inhibitors;

[0472] - Fibroblast growth factor inhibitors, such as FPA14;

[0473] - Anti-VEGFR antibodies, such as IMC-3C5, GNR-011, tanirumab;

[0474] - Anti-VEGF / DDL4 antibodies, such as ABT-165;

[0475] - Anti-cadherin antibodies, such as HKT-288;

[0476] - Anti-CD70 antibodies, such as AMG-172; Anti-leucine-rich repeat 15 (LRRC15) antibodies, such as ABBV-085. ARGX-110;

[0477] -Angiotensin receptor blockers, nitric oxide donors;

[0478] - antisense oligonucleotides, such as AEG35156, IONIS-KRAS-2.5Rx, EZN-3042, Rx-0201, IONIS-AR-2.5Rx, BP-100 (prexigebersen), IONIS-STAT3-2.5Rx;

[0479] -DNA interfering oligonucleotides, such as PNT2258, AZD-9150;

[0480] - Anti-ANG-2 antibodies, such as MEDI3617 and LY3127804; -

[0481] Anti-Ang-1 / ANG-2 antibodies, such as AMG-780;

[0482] - Anti-MET / EGFR antibodies, such as LY3164530;

[0483] - Anti-EGFR antibodies, such as ABT-414, AMG-595, nexitumomab, ABBV-221, mafodotin, depaxitumomab (ABT-414), tocilizumab, ABT-806, vicaribinib, moxifloxacin, RM-1929;

[0484] - Anti-CSFIR antibodies, such as emactuzumab, LY3022855, AMG-820, FPA-008 (cabiralizumab);

[0485] - Anti-CD40 antibodies, such as RG7876, SEA-CD40, APX-005M, ABBV-428;

[0486] - Anti-endoglin antibodies, such as TRC105 (catuximab);

[0487] - anti-CD45 antibodies, such as 131I-BC8 (lomab-B);

[0488] - Anti-HER3 antibodies, such as LJM716, GSK2849330;

[0489] - Anti-HER2 antibodies, such as margetuximab, MEDI4276, BAT-8001;

[0490] - Anti-HLA-DR antibodies, such as IMMU-114;

[0491] - Anti-IL-3 antibodies, such as JNJ-56022473;

[0492] - Anti-OX40 antibodies, such as MEDI6469, MEDI6383, MEDI0562 (tavolixizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368;

[0493] - Anti-EphA3 antibodies, such as KB-004;

[0494] - Anti-CD20 antibodies, such as obinutuzumab, IGN-002;

[0495] - anti-CD20 / CD3 antibodies, such as RG7828;

[0496] - Anti-CD37 antibodies, such as AGS67E, Otezoumab (TRU-016);

[0497] - anti-ENPP3 antibodies, for example AGS-16C3F;

[0498] - Anti-FGFR-3 antibodies, such as LY3076226, B-701;

[0499] - Anti-FGFR-2 antibodies, such as GAL-F2; anti-C5 antibodies, such as ALXN-1210;

[0500] - Anti-CD27 antibodies, such as varlilumab (CDX-1127);

[0501] - anti-Trop-2 antibodies, such as IMMU-132;

[0502] - Anti-NKG2A antibodies, such as monazumab;

[0503] -Anti-VISTA antibodies, such as HMBD-002;

[0504] - Anti-PVRIG antibodies, such as COM-701;

[0505] - Anti-EpCAM antibodies, such as VB4-845;

[0506] - Anti-BCMA antibodies, such as GSK-2857916

[0507] - Anti-CEA antibodies, such as RG-7813;

[0508] - Anti-cluster of differentiation 3 (CD3) antibodies, such as MGD015;

[0509] - Anti-folate receptor alpha antibodies, such as IMGN853;

[0510] -MCL-1 inhibitors, such as AMG-176, S-64315 and AZD-5991, 483-LM, A-1210477, UMI-77, JKY-5-037;

[0511] -epha2 inhibitors, such as MM-310;

[0512] - Anti-LAG-3 antibodies, such as relatlimab (ONO-4482), LAG-525, MK-4280, REGN-3767;

[0513] -raf kinase / VEGFR inhibitors, such as RAF-265;

[0514] - Polycomb protein (EED) inhibitors, such as MAK683;

[0515] - Anti-fibroblast activation protein (FAP) / IL-2R antibodies, such as RG7461;

[0516] - Anti-fibroblast activation protein (FAP) / TRAIL-R2 antibodies, such as RG7386;

[0517] - anti-fucosyl-GM1 antibodies, such as BMS-986012;

[0518] -p38 MAP kinase inhibitors, such as ramelteonide;

[0519] -PRMT1 inhibitors, such as MS203;

[0520] - Sphingosine kinase 2 (SK2) inhibitors, such as opaganib;

[0521] - FLT3-ITD inhibitors, such as BCI-332;

[0522] - erythroid 2-related factor 2 stimulators, such as omaveloxolone (RTA-408);

[0523] -Tropomyosin receptor kinase (TRK) inhibitors, such as LOXO-195, ONO-7579

[0524] - Anti-ICOS antibodies, such as JTX-2011, GSK3359609;

[0525] - Anti-DR5 (TRAIL2) antibodies, such as DS-8273;

[0526] - Anti-GD2 antibodies, such as APN-301;

[0527] - Anti-interleukin-17 (IL-17) antibodies, such as CJM-112;

[0528] - Anti-carbonic anhydrase IX antibodies, such as TX-250;

[0529] - Anti-CD38-attenuating factors, such as TAK573;

[0530] - Anti-mucin 1 antibodies, such as galactosidase;

[0531] - Mucin 1 inhibitors, such as GO-203-2C;

[0532] - MARCKS protein inhibitors, such as BIO-11006;

[0533] -Folic acid antagonists, such as arfolitixorin;

[0534] -Galectin-3 inhibitors, such as GR-MD-02;

[0535] -Phosphopeptide 68 inhibitors, such as RX-5902;

[0536] -CD95 / TNF modulators, such as ofranergene obadenovec;

[0537] -PI3K / Akt / mTOR inhibitors, such as ABTL-0812;

[0538] - Pan-PIM kinase inhibitors, such as INCB-053914;

[0539] -IL-12 gene stimulators, such as EGEN-001, tavokinogene telseplasmid

[0540] - Heat shock protein HSP90 inhibitors, such as TAS-116 and PEN-866;

[0541] -VEGF / HGF antagonists, such as MP-0250;

[0542] -SYK tyrosine kinase / FLT3 tyrosine kinase inhibitors, such as TAK-659;

[0543] -SYK tyrosine kinase / JAK tyrosine kinase inhibitors, such as ASN-002;

[0544] - FLT3 tyrosine kinase inhibitors, such as FF-10101;

[0545] - FLT3 tyrosine kinase agonists, such as CDX-301;

[0546] - FLT3 / MEK1 inhibitors, such as E-6201;

[0547] - IL-24 antagonists, such as AD-IL24;

[0548] -RIG-I agonists, such as RGT-100;

[0549] -Aerolysin stimulators, such as acrolysin;

[0550] - P-glycoprotein 1 inhibitors, such as HM-30181A;

[0551] - CSF-1 antagonists, such as ARRY-382, BLZ-945;

[0552] - Anti-mesothelin antibodies, such as SEL-403;

[0553] -Thymidine kinase stimulators, such as aglatimagene besadenovec;

[0554] - Polo-like kinase 1 inhibitors, such as PCM-075;

[0555] - TLR-7 agonists, such as TMX-101 (imiquimod);

[0556] -NEDD8 inhibitors, such as pevonedistat (MLN-4924), TAS-4464;

[0557] - Pleiotropic pathway modulators, such as avadomide (CC-122);

[0558] -FOXII inhibitors, such as thiostrepton;

[0559] - Anti-Muc1 antibodies, such as Mab-AR-20.5;

[0560] - Anti-CD38 antibodies, such as isatuximab, MOR-202;

[0561] -UBA1 inhibitors, such as TAK-243;

[0562] -Src tyrosine kinase inhibitors, such as VAL-201;

[0563] - VDAC / HK inhibitors, such as VDA-1102;

[0564] -BRAF / PI3K inhibitors, such as ASN-003;

[0565] -EIF4α inhibitors, such as rofitinib, eFT226;

[0566] -TP53 gene stimulators, such as ad-p53;

[0567] -PD-L1 / EGFR inhibitors, such as GNS-1480;

[0568] - Retinoic acid receptor alpha (RARα) inhibitors, such as SY-1425;

[0569] - SIRT3 inhibitors, such as YC8-02;

[0570] - Stromal cell-derived factor-1 ligand inhibitors, such as olaptesed pegol (NOX-A12);

[0571] -IL-4 receptor modulators, such as MDNA-55;

[0572] - Arginase-I stimulators, such as polyethylene glycol arginase;

[0573] - Topoisomerase I inhibitors / hypoxia-inducible factor-1α inhibitors, such as PEG-SN38 (firtecan pegol);

[0574] -Hypoxia-inducible factor-1α inhibitors, such as PT-2977, PT-2385;

[0575] -CD122 agonists, such as NKTR-214;

[0576] - p53 tumor suppressor protein stimulators, such as kevetrin;

[0577] - Mdm4 / Mdm2p53 binding protein inhibitors, such as ALRN-6924;

[0578] - Kinesin spindle protein (KSP) inhibitors, such as filansib (ARRY-520);

[0579] -CD80-fc fusion protein inhibitors, such as FPT-155;

[0580] -Menin and mixed lineage leukemia (MLL) inhibitors, such as KO-539;

[0581] - Liver X receptor agonists, such as RGX-104;

[0582] - IL-10 agonists, such as AM-0010;

[0583] -EGFR / ErbB-2 inhibitors, such as valcitinib;

[0584] -VEGFR / PDGFR inhibitors, such as voronib;

[0585] - IRAK4 inhibitors, such as CA-4948;

[0586] - Anti-TLR-2 antibodies, such as OPN-305;

[0587] - Calmodulin modulators, such as CBP-501;

[0588] - glucocorticoid receptor antagonists, such as relacorilant (CORT-125134);

[0589] Second mitochondrial-derived activator of caspase (SMAC) protein inhibitors, such as BI-891065;

[0590] - Lactoferrin modulators, such as LTX-315;

[0591] -Kit tyrosine kinase / PDGF receptor alpha antagonists, such as DCC-2618;

[0592] - KIT inhibitors, such as PLX-9486;

[0593] - Exportin 1 inhibitors, such as eltanexor;

[0594] -EGFR / ErbB2 / Ephb4 inhibitors, such as tefatinib;

[0595] - Anti-CD33 antibodies, such as IMGN-779;

[0596] - Anti-KMA antibodies, such as MDX-1097;

[0597] - Anti-TIM-3 antibodies, such as TSR-022, LY-3321367, MBG-453;

[0598] - Anti-CD55 antibodies, such as PAT-SC1;

[0599] - Anti-PSMA antibodies, such as ATL-101;

[0600] Anti-CD100 antibodies, such as VX-15;

[0601] - Anti-EphA3 antibodies, such as fibatuzumab;

[0602] - Anti-ErbB antibodies, such as CDX-3379, HLX-02, seribantumab;

[0603] - Anti-APRIL antibodies, such as BION-1301;

[0604] - Anti-TIGIT antibodies, such as BMS-986207, RG-6058;

[0605] - CHST15 gene inhibitors, such as STNM-01;

[0606] -RAS inhibitors, such as Neo-100;

[0607] -Somatostatin receptor antagonists, such as OPS-201;

[0608] -CEBPA gene stimulators, such as MTL-501;

[0609] -DKK3 gene modulators, such as MTG-201;

[0610] - p70s6k inhibitors, such as MSC2363318A;

[0611] -Methionine aminopeptidase 2 (MetAP2) inhibitors, such as M8891 and APL-1202;

[0612] -Arginine N-methyltransferase 5 inhibitors, such as GSK-3326595;

[0613] - Anti-programmed cell death protein 1 (anti-PD-1) antibodies, such as nivolumab ( BMS-936558, MDX-1106), pembrolizumab ( MK-3477, SCH-900475, lambrolizumab, CAS Reg. No. 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, genolimz umab (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, BAT-1306, and anti-programmed death ligand 1 (PD-L1) antibodies, such as BMS-936559, atezolizumab (MPDL3280A), durvalumab (MEDI4736), avelumab, CK-301, (MSB0010718C), MEDI0680, CX-072, CBT-502, PDRs-001 042 (dostarlimab), JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155, KN-035, IBI-308, FAZ-053, and MDX1105-01;

[0614] -PD-L1 / VISTA antagonists, such as CA-170;

[0615] - anti-PD-L1 / TGFb antibodies, such as M7824;

[0616] - Anti-transferrin antibodies, such as CX-2029;

[0617] - Anti-IL-8 (interleukin-8) antibodies, such as HuMax-Inflam;

[0618] - ATM (ataxia telangiectasia) inhibitors, such as AZD0156;

[0619] - CHK1 inhibitors, such as GDC-0575, LY2606368 (prexasertib), SRA737, RG7741 (Chk1 / 2);

[0620] -CXCR4 antagonists, such as BL-8040, LY2510924, brixafor (TG-0054), X4P-002, X4P-001-10;

[0621] -EXH2 inhibitors, such as GSK2816126;

[0622] -HER2 inhibitors, such as neratinib and tucatinib (ONT-380);

[0623] -KDM1 inhibitors, such as ORY-1001, IMG-7289, INCB-59872, GSK-2879552;

[0624] -CXCR2 antagonists, such as AZD-5069;

[0625] -GM-CSF antibodies, such as lenzilumab;

[0626] - DNA-dependent protein kinase inhibitors, such as MSC2490484A (nedisertib), VX-984, AsiDNA (DT-01);

[0627] - Protein kinase C (PKC) inhibitors, such as LXS-196, sotrastuzumab;

[0628] -Selective estrogen receptor downregulators (SERDs), such as fulvestrant RG6046, RG6047, enastrant (RAD-1901), and AZD9496;

[0629] - Selective estrogen receptor covalent antagonists (SERCAs), such as H3B-6545;

[0630] - Selective androgen receptor modulators (SARMs), such as GTX-024, daroglutide;

[0631] - Transforming growth factor-β (TGF-β) kinase antagonists, such as galunisertib; anti-transforming growth factor-β (TGF-β) antibodies, such as LY3022859, NIS793, XOMA 089;

[0632] - 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), APV0436 (CD123 / CD3), flotetuzumab (CD123 / CD3), REGN-1979 (CD20 / CD3), MCLA-117 (CD3 / CLEC AMG-420(BCMA / CD3), BI-836880(VEFG / ANG2), JNJ-63709178(CD123 / CD3), MGD-007(CD3 / gpA33), MGD-009(CD3 / B7H3);

[0633] - Mutant-selective EGFR inhibitors, such as PF-06747775, EGF816 (nazartinib), ASP8273, ACEA-0010, BI-1482694;

[0634] - 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;

[0635] - anti-delta-like ligand 3 (DDL3) antibodies, such as tecillin-rovacinumab; anti-clusterin antibodies, such as AB-16B5;

[0636] - anti-ephrin-A4 (EFNA4) antibodies, such as PF-06647263;

[0637] - Anti-RANKL antibodies, such as denosumab;

[0638] - Anti-mesothelin antibodies, such as BMS-986148, anti-MSLN-MMAE;

[0639] - Anti-sodium phosphate cotransporter 2B (NaP2B) antibodies, such as rifazumab;

[0640] - anti-c-Met antibodies, such as ABBV-399;

[0641] - Adenosine A2A receptor antagonists, such as CPI-444, AZD-4635, preladenant, PBF-509;

[0642] -α-ketoglutarate dehydrogenase (KGDH) inhibitors, such as CPI-613;

[0643] -XPO1 inhibitors, such as selinexor (KPT-330);

[0644] - Isocitrate dehydrogenase 2 (IDH2) inhibitors, such as ensidinib (AG-221);

[0645] - IDH1 inhibitors, such as AG-120 and AG-881 (IDH1 and IDH2), IDH-305, BAY-1436032;

[0646] - Interleukin-3 receptor (IL-3R) modulators, such as SL-401;

[0647] - Arginine deiminase stimulators, such as pegargiminase (ADI-PEG-20);

[0648] - Antibody-drug conjugates, such as MLN0264 (anti-GCC, guanylate cyclase C), T-DM1 (trastuzumab emtansine, Kadcycla), milatuzumab-doxorubicin (hCD74-DOX), brentuximab vedotin, DCDT2980S, palatuzumab vedotin, SGN-CD70A, SGN-CD19A, ozogamicin intuzumab, emtansine rofutuzumab, SAR3419, govitecan ivacuzumab, vedotin fifutuzumab (ASG-22ME), ASG-15ME, DS-8201 (trastuzumab deruxtecan), 225Ac-lintuzumab, U3-1402, 177Lu-tetraxetan-tetuloma, vedotin tetuzumab

[0649] -claudin-18 inhibitors, such as claudiximab;

[0650] -β-catenin inhibitors, such as CWP-291;

[0651] - Anti-CD73 antibodies, such as MEDI-9447 (oleclumab), CPX-006, IPH-53, BMS-986179;

[0652] -CD73 antagonists, such as AB-680, PSB-12379, PSB-12441, PSB-12425;

[0653] -CD39 / CD73 antagonists, such as PBF-1662;

[0654] - Chemokine receptor 2 (CCR) inhibitors, such as PF-04136309, CCX-872, BMS-813160 (CCR2 / CCR5);

[0655] -Thymidylate synthase inhibitors, such as ONX-0801;

[0656] - ALK / Ros1 inhibitors, such as lorlatinib;

[0657] - Tankyrase inhibitors, such as G007-LK;

[0658] - Mdm2p53 binding protein inhibitors, such as CMG-097, HDM-201;

[0659] -c-PIM inhibitors, such as PIM447;

[0660] -BRAF inhibitors, such as dabrafenib, vemurafenib, connefenib (LGX818), PLX8394;

[0661] - Sphingosine kinase-2 (SK2) inhibitors, such as (ABC294640);

[0662] - Cell cycle inhibitors such as selumetinib (MEK1 / 2) and sapacitabine;

[0663] - AKT inhibitors such as MK-2206, etanercept, afarezetib, AZD5363 and ARQ-092, capisertib, triciribine;

[0664] - Anti-CTLA-4 (cytotoxic T-lymphocyte protein-4) inhibitors, such as tremelimumab, AGEN-1884, BMS-986218;

[0665] -c-MET inhibitors, such as AMG-337, savolitinib, tepotinib (ARQ-197), capmatinib and tepotinib, ABT-700, AG213, AMG-208, JNJ-38877618 (OMO-1), merestinib, HQP-8361;

[0666] -c-Met / VEGFR inhibitors, such as BMS-817378 and TAS-115;

[0667] -c-Met / RON inhibitors, such as BMS-777607;

[0668] -BRAF / EGFR inhibitors, such as BGB-283;

[0669] -BCR / ABL inhibitors, such as rebastinib and asciminib;

[0670] - MNK1 / MNK2 inhibitors, such as eFT-508;

[0671] - mTOR inhibitors / cytochrome P450 3A4 stimulators, such as TYME-88;

[0672] -Lysine-specific demethylase-1 (LSD1) inhibitors, such as CC-90011;

[0673] - Pan-Raf inhibitors, such as LY3009120, LXH254, TAK-580;

[0674] -Raf / MEK inhibitors, such as RG7304;

[0675] -CSF1R / KIT and FLT3 inhibitors, such as pecitinib (PLX3397);

[0676] -Kinase inhibitors, such as vandetanib;

[0677] - E-selectin antagonists, such as GMI-1271;

[0678] - Differentiation-inducing agents, such as retinoic acid;

[0679] - Epidermal growth factor receptor (EGFR) inhibitors, such as osimertinib (AZD-9291);

[0680] - Topoisomerase inhibitors such as doxorubicin, daunorubicin, actinomycin D, eniposide, epirubicin, etoposide, idarubicin, irinotecan, mitoxantrone, picroquine, sobuzosine, topotecan, irinotecan, MM-398 (liposomal irinotecan), vosaroxin, and GPX-150, doxorubicin, AR-67, mavitinib, AST-2818, avitinib (ACEA-0010), and irofluvan (MGI-114);

[0681] -Corticosteroids, such as cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisone, prednisolone;

[0682] - Growth factor signaling kinase inhibitors;

[0683] - Nucleoside analogs, such as DFP-10917;

[0684] -Axl inhibitors, such as BGB-324 (becitinib), SLC-0211;

[0685] -BET inhibitors, such as INCB-054329, INCB057643, TEN-010, AZD-5153, ABT-767, BMS-986158, CC-90010, GSK525762 (molibresib), NHWD-870, ODM-207, GSK-2820151, GSK-1210151A, ZBC246, ZBC260, ZEN3694, FT-1101, RG-6146, CC-90010, mivebresib, BI-89499, PLX-2853, PLX-51107, CPI-0610, GS-5829;

[0686] -PARP inhibitors, such as olaparib, rucaparib, veliparib, talazoparib, ABT-767, BGB-290;

[0687] -Proteasome inhibitors, such as ixazomib, carfilzomib Malizumab;

[0688] -Glutaminase inhibitors, such as CB-839;

[0689] - vaccines, such as peptide vaccines TG-01 (RAS), GALE-301, GALE-302, nelipep imut-s, SurVaxM, DSP-7888, TPIV-200, PVX-410, VXL-100, DPX-E7, ISA-101, 6MHP, OSE-2101, galinpepimut-S, SVN53-67 / M57-KLH, IMU-131; bacterial vector vaccines, such as CRS-207 / GVAX, axalimogene filolisbac (ADXS11-001); adenovirus vector vaccines, such as nadofar agene) firadenovec; autologous Gp96 vaccine; dendritic cell vaccines, such as CVactm, stapuldencel-T, eltrapuldencel-T, SL-701, BSK01TM, rocapuldencel-T (AGS-003), DCVAC, CVactm, stapuldencel-T, eltrap uldencel-T, SL-701, BSK 01 TM, ADXS31-142; oncolytic vaccines, such as talimogene laherparepvec, pexastimogenedevacirepvec, GL-ONC1, MG1-MA3, parvovirus H-1, ProstAtak, enadenotucirev, MG1MA3, ASN-002 (TG-1042); therapeutic vaccines, such as CVAC-301, CMP-001, PF-06753512, VBI-1901, TG-4010, ProscaVax TM ; Tumor cell vaccines, such as (IND-14205), Oncoquest-L vaccine; live attenuated recombinant serotype 1 poliovirus vaccines, such as PVS-RIPO; adaloxacin simolenin; MEDI-0457; DPV-001, a tumor-derived autophagosome-enriched cancer vaccine; RNA vaccines, such as CV-9209, LV-305; DNA vaccines, such as MEDI-0457, MVI-816, INO-5401; modified vaccinia virus Ankara vaccine expressing p53, such as MVA-p53; DPX-Survivac; BriaVax TM ;GI-6301;GI-6207;GI-4000;

[0690] - anti-DLL4 (delta-like ligand 4) antibodies, for example demcizumab;

[0691] STAT-3 inhibitors, such as napabucasin (BBI-608);

[0692] - ATPase p97 inhibitors, such as CB-5083;

[0693] -Smoothened (SMO) receptor inhibitors, such as (sonidegi, formerly known as LDE-225), LEQ506, vismodegib (GDC-0449), BMS-833923, glasgib (PF-04449913), LY2940680, and itraconazole;

[0694] - Interferon alpha ligand modulators, such as interferon alpha-2b, interferon alpha-2A biosimilar (Biogenomics), Ropeg interferon 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, Inter2a), interferon alpha-2b follow-on biologic (Biosidus-Bioferon, Citopheron, Ganapar, Beijing Kawin Technology-Kaferon), Alfalon, pegylated interferon alpha-1b, pegylated interferon alpha-2b follow-on biologic (Amega), recombinant human interferon α-1b, recombinant human interferon α-2A, recombinant human interferon veltuzumab-IFNα2b conjugate, Dynavax (SD-101), and interferon α-n1 (Humoferon, SM-10500, Sumiferon);

[0695] -Interferon gamma ligand modulators, such as interferon gamma (OH-6000, Ogamma 100)

[0696] -IL-6 receptor modulators, such as tocilizumab, cetuximab, AS-101 (CB-06-02, IVX-Q-101);

[0697] -Telomerase modulators, such as tertomotide (GV-1001, HR-2802, Riavax) and imetelstat (GRN-163, JNJ-63935937);

[0698] -DNA methyltransferase inhibitors, such as temozolomide (CCRG-81045), decitabine, guadecitabine (S-110, SGI-110), KRX-0402, RX-3117, RRx-001, and azacitidine;

[0699] -DNA gyrase inhibitors, such as pisetron and sobuzosane;

[0700] -Bcl-2 family protein inhibitors, such as ABT-263, enetoclax (ABT-199), ABT-737, and AT-101;

[0701] -Notch inhibitors, such as LY3039478 (Crigosistat), Taretumomab (anti-Notch2 / 3), BMS-906024;

[0702] - Anti-myostatin inhibitors, such as landogrozumab;

[0703] - Hyaluronidase stimulators, such as PEGPH-20;

[0704] -Wnt pathway inhibitors, such as SM-04755, PRI-724, WNT-974;

[0705] -γ-secretase inhibitors, such as PF-03084014, MK-0752, RO-4929097;

[0706] -Grb-2 (growth factor receptor binding protein-2) inhibitors, such as BP1001;

[0707] -TRAIL pathway inducing compounds, such as ONC201, ABBV-621;

[0708] - Focal adhesion kinase inhibitors, such as VS-4718, nifedipine, GSK2256098;

[0709] -hedgehog inhibitors, such as saridegib, sonidegib (LDE225), glaucomagib, and vismodegib;

[0710] - Aurora kinase inhibitors, such as alisertib (MLN-8237) and AZD-2811, AMG-900, barasertib, ENMD-2076;

[0711] - HSPB1 modulators (heat shock protein 27, HSP27), such as brivudine, apatorsen;

[0712] -ATR inhibitors, such as BAY-937, AZD6738, AZD6783, VX-803, VX-970 (berzosertib), and VX-970;

[0713] - mTOR inhibitors, such as sapacetib and viscetib (AZD2014), ME-344;

[0714] -mTOR / PI3K inhibitors, such as gedatolisib, GSK2141795, omipalisib, RG6114;

[0715] -Hsp90 inhibitors, such as AUY922, Onapib (AT13387), SNX-2112, SNX5422;

[0716] - Mouse double minute (mdm2) oncogene inhibitors, such as DS-3032b, RG7775, AMG-232, HDM201, and idarucizumab (RG7388);

[0717] -CD137 agonists, such as ushelumab, utolumab (PF-05082566);

[0718] -STING agonists, such as ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291;

[0719] - FGFR inhibitors, such as FGF-401, INCB-054828, BAY-1163877, AZD4547, JNJ-42756493, LY2874455, Debio-1347;

[0720] - Fatty acid synthase (FASN) inhibitors, such as TVB-2640;

[0721] - Anti-KIR monoclonal antibodies, such as lirilumab (IPH-2102), IPH-4102;

[0722] - Antigen CD19 inhibitors, such as MOR208, MEDI-551, AFM-11, inebilizumab;

[0723] -CD44 binders, such as A6;

[0724] - Protein phosphatase 2A (PP2A) inhibitors, such as LB-100;

[0725] -CYP17 inhibitors, such as seviterol (VT-464), ASN-001, ODM-204, CFG920, abiraterone acetate;

[0726] -RXR agonists, such as IRX4204;

[0727] -hedgehog / smoothened (hh / Smo) antagonists, such as taragib, patigib;

[0728] - Complement C3 modulators, such as Imprime PGG;

[0729] -IL-15 agonists, such as ALT-803, NKTR-255, and hetIL-15;

[0730] - EZH2 (enhancer of zeste homolog 2) inhibitors, such as tazemetostat, CPI-1205, GSK-2816126;

[0731] - Oncolytic viruses, such as pelareorep, CG-0070, MV-NIS therapy, HSV-1716, DS-1647, VCN-01, ONCOS-102, TBI-1401, tasadenoturev (DNX-2401), vocimagene amiretrorepvec, RP-1, CVA21, Celyvir, LOAd-703, OBP-301;

[0732] -DOT1L (histone methyltransferase) inhibitors, such as binostat (EPZ-5676);

[0733] -Toxins, such as cholera toxin, ricin, Pseudomonas exotoxin, Bordetella pertussis adenylate cyclase toxin, diphtheria toxin, and caspase activators;

[0734] -DNA plasmid, such as BC-819;

[0735] -PLK inhibitors of PLK 1, 2, and 3, such as volasertib (PLK1);

[0736] -WEE1 inhibitors, such as AZD1775 (adavothioine);

[0737] - Rho kinase (ROCK) inhibitors, such as AT13148, KD025;

[0738] -ERK inhibitors, such as GDC-0994, LY3214996, MK-8353;

[0739] IAP inhibitors, such as ASTX660, Debio-1143, birinapant, APG-1387, and LCL-161;

[0740] - RNA polymerase inhibitors, such as lurbinectedin (PM-1183), CX-5461; tubulin inhibitors, such as PM-184, BAL-101553 (lisabulin) and OX1-4503, flurapacin (AC-0001), plinabulin;

[0741] -Toll-like receptor 4 (TL4) agonists, such as G100, GSK1795091, and PEPA-10;

[0742] - Elongation factor 1α2 inhibitors, such as Prilidexin; CD95 inhibitors, such as APG-101, APO-010, anacept;

[0743] -WT1 inhibitors, such as DSP-7888;

[0744] - Splicing factor 3B subunit 1 (SF3B1) inhibitors, such as H3B-8800;

[0745] - PDGFRα / KIT mutant-specific inhibitors, such as BLU-285;

[0746] - SHP-2 inhibitors, such as TN0155 (SHP-099), RMC-4550; and

[0747] - Retinoid Z receptor gamma (RORg) agonists, such as LYC-55716.

[0748] In some embodiments, provided herein are methods for treating or preventing a hyperproliferative disease or cancer in a human or animal suffering from or at risk of suffering from a 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 or solvate thereof, a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents selected from the group consisting of an apoptosis signal-regulating kinase (ASK) inhibitor; a Bruton's tyrosine kinase (BTK) inhibitor; a cluster of differentiation 47 (CD47) inhibitor; a cyclin-dependent kinase (CDK) inhibitor. Inhibitors; discoidin domain receptor (DDR) inhibitors; histone deacetylase (HDAC) inhibitors; indoleamine-pyrrole-2,3-dioxygenase (Ido1) inhibitors; Janus kinase (JAK) inhibitors; lysyl oxidase-like protein (LOXL) inhibitors; matrix metalloproteinase (MMP) inhibitors; mitogen-activated protein kinase (MEK) inhibitors; phosphatidylinositol 3-kinase (PI3K) inhibitors; spleen tyrosine kinase (SYK) inhibitors; Toll-like receptor 8 (TLR8) inhibitors; Toll-like receptor 9 (TLR9) inhibitors; tyrosine kinase inhibitors (TKIs) and any combination thereof, or pharmaceutically acceptable salts thereof. Non-limiting examples include:

[0749] - 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);

[0750] - Bruton's tyrosine kinase (BTK) inhibitors: Examples of BTK inhibitors include, but are not limited to, (S)-6-amino-9-(1-(but-2-ynyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one, acalabrutinib (ACP-196), BGB-3111, CB988, HM71224, ibrutinib, M-2951 (evobrutinib), M7583, telatinib (ONO-4059), PRN-1008, spebrutinib (CC-292), TAK-020, vecabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, TAS-5315;

[0751] - Cluster of differentiation 47 (CD47) inhibitors: Examples of CD47 inhibitors include, but are not limited to, anti-CD47 mAbs (Vx-1004), anti-human CD47 mAbs (CNTO-7108), CC-90002, CC-90002-ST-001, humanized anti-CD47 antibody (Hu5F9-G4), NI-1701, NI-1801, RCT-1938, and TTI-621;

[0752] - 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, milciclib, trilaciclib and TG-02;

[0753] -Discoid 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 WO 2014 / 047624 (Gilead Sciences), US 2009-0142345 (Takeda Pharmaceutical), US 2011-0287011 (Oncomed Pharmaceuticals), WO 2013 / 027802 (Chugai Pharmaceutical), and WO 2013 / 034933 (Imperial Innovations);

[0754] - 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, givinostat, mocetinostat, panobinostat, pracinostat, quisinostat (JNJ-26481585), ricolinostat, ricolinostat, SHP-141, valproic acid (VAL-001), vorinostat, tinostamustine, remetinostat, entinostat;

[0755] - Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors: Examples of IDO 1 inhibitors include, but are not limited to, BLV-0801, icadolstat, 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;

[0756] -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, filatinib, filgotinib (GLPG0634), gandutinib (LY2784544), INCB039110 (itatinib), lestaurtinib, mometinib (CYT0387), NS-018, pacultinib (SB1518), peftinib (ASP015K), ruxolitinib, tofacitinib (formerly known as tasotinib), INCB052793 and XL019;

[0757] -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, antibodies described in WO 2009 / 017833 (Arresto Biosciences). Examples of LOXL2 inhibitors include, but are not limited to, antibodies described in WO 2009 / 017833 (Arresto Biosciences), WO 2009 / 035791 (Arresto Biosciences), and WO 2009 / 017833 (Arresto Biosciences), WO 2011 / 097513 (Gilead Biologics).

[0758] - Matrix metalloproteinase (MMR) inhibitors: MMP inhibitors include inhibitors of MMP1 to 10. Examples of MMP9 inhibitors include, but are not limited to, marimastat (BB-2516), cipemastat (Ro 32-3555), GS-5745 (andecaliximab), and those described in WO2012 / 027721 (Gilead Biologics);

[0759] -Mitogen-activated protein kinase (MEK) inhibitors: MEK inhibitors include antroquinonol, binimetinib, cobimetinib (GDC-0973, XL-518), MT-144, selumetinib, sorafenib, trametinib (GSK1120212), urosetinib + trametinib, PD-0325901, pimacetinib, LTT462, AS703988, CC-90003, and rifatinib;

[0760] -Phosphatidylinositol 3-kinase (PI3K) inhibitors: PI3K inhibitors include RI3Kg, PI3Kδ, RI3Kb, RI3Kα and / or pan-PI3K inhibitors. Examples of PI3K inhibitors include, but are not limited to, ACP-319, AEZA-129, AMG-319, AS252424, AZD8186, BAY 10824391, BEZ235, buparlisib (BKM120), BYL719 (alpelisib), CH5132799, copanlisib (BAY 80-6946), duvelisib, GDC-0032, GDC-0077, GDC-0941, GDC-0980, GSK2636771, GSK2269557, idelalisib INCB50465, IPI-145, IPI-443, IPI-549, KAR4141, LY294002, IPI-443, IPI-549, KAR4141, LY294002.

[0761] 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 WO 2005 / 113556 (ICOS), WO 2013 / 052699 (Gilead Calistoga), WO 2013 / 116562 (Gilead Calistoga), WO 2014 / 100765 (Gilead Calistoga), WO Compounds described in 2014 / 100767 (Gilead Calistoga) and WO 2014 / 201409 (Gilead Sciences);

[0762] - Spleen tyrosine kinase (SYK) inhibitors: including but 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-QAB 205AA, R112, R343, tamatinib (R406), and those described in US8450321 (Gilead Connecticut) and US2015 / 0175616;

[0763] - 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, motomod, resiquimod, VTX-1463, and VTX-763;

[0764] - Toll-like receptor 9 (TLR9) inhibitors: Examples of TLR9 inhibitors include, but are not limited to, AST-008, IMO-2055, IMO-2125, rifetimod, ritilimod, MGN-1601, and PUL-042; and

[0765] -Tyrosine kinase inhibitors (TKIs) TKIs can target receptors for epidermal growth factor receptors (EGFRs), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF). Examples of TKIs include, but are not limited to, afatinib, ARQ-087 (derazantinib), asp5878, AZD3759, AZD4547, bosutinib, brigatinib, cabozantinib, cediranib, crenolanib, dacomitinib, dasatinib, dovitinib, E-6201, erdafitinib, erlotinib, gefitinib, gitinib (ASP-2215), FP-103 9. HM61713, icotinib, imatinib, KX2-391 (Src), lapatinib, lestautinib, lenvatinib, midostaurin, nintedanib, ODM-203, osimertinib (AZD-9291), ponatinib, poziotinib, quizartinib, radotinib, rociletinib, surufatinib (HMPL-012), sunitinib, tivoanib and TH-4000, MEDI-575 (anti-PDGFR antibody).

[0766] As used herein, the term "chemotherapeutic agent" or "chemotherapeutic agent" (or "chemotherapy" in the case of treatment with a chemotherapeutic agent) is intended to include any non-protein (i.e., non-peptide) compound that can be used to treat cancer. Examples of chemotherapeutic agents include, but are not limited to: alkylating agents such as thiotepa and cyclophosphamide Alkyl sulfonates such as busulfan, improsulfan and piposulfan, aziridines such as benzodepa, carboquinone, metodepa and uredepa; ethyleneimines and methylmelamines, including hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimemyllomelamine; annona lactones, especially bratacin and bratacinone; camptothecins, including the synthetic analogue topotecan; bryostatin, callystatin; CC-1065, including its synthetic analogues adolesin, carzelesin and biszelesin; cryptophycin, especially cryptophycin 1 (cryptophycin 1) and cryptophycin 8; Aplysia caudatum; Duocarcin, including its synthetic analogs KW-2189 and CBI-TMI; Acanthopanax; 5-azacytidine; Pancratistatin; Sarcodictyin; Spongistatin; Nitrogen mustards, such as chlorambucil, naphthyl mustard, cyclophosphamide, glufosfamide, evofosfamide, bendamustine, estramustine, ifosfamide, dichloromethyl diethylamine, oxazolidinone hydrochloride, melphalan, new nitrogen mustard, phenylephrine, prednimustine, trofosfamide and uracil nitrogen mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine and ranimustine; antibiotics such as enediyne antibiotics (e.g., calicheamicins, especially calicheamicin gamma II and calicheamicin phiI), dynemicins (including dynemicin A), bisphosphonates (e.g. clodronate), esperamicin, neocarcinogen and related chromoprotein enediyne antibiotic chromophores, aclarubicin, dactinomycin, authramycin, azaserine, bleomycin, actinomycin, karanomycin, carminomycin, carmophilin, chromomycin, actinomycin D, daunorubicin, detoxibacin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolidone- doxorubicin and deoxydoxorubicin); antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as methotrexate, methotrexate, pteropterin, and trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiabine, and thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as calutosterone, drostanolone propionate, cyclothiocarb, melastosane, and testolactone;Antiadreners, such as aminoglutethimide, mitotane, and trilostane; folic acid supplements, such as folinic acid; radiotherapeutic agents, such as radium-223; trichothecenes, especially T-2 toxin, verracurin A, roridin A, and anguidine; taxanes, such as paclitaxel; Albumin-bound taxanes, docetaxel Cabazitaxel, BIND-014, tesetaxel; platinum analogs such as cisplatin and carboplatin, NC-6004 nanoplatin; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; hestrabucil; bisantrene; edatrexate; difoamide; colchicine; diazocone; elformthine; elliptonium acetate; epothilones; etoglucagon; gallium nitrate; hydroxyurea; lentinan; leucovorin; lonidamine; maytansine alkaloids such as maytansine and ansamitocin; mitoxantrone guanidine; mitoxantrone; mopidamole; nitracrine; pentostatin; phenammet; pirarubicin; losoxantrone; fluoropyrimidine; folinic acid; podophyllic acid; 2-ethylhydrazide; procarbazine; polysaccharide-K (PSK); razoxane; rhizoxin; sizofran; spirogermanamine; tenidronic acid; trabectedin, triazoquinone; 2,2',2"-trifluorotriethylamine; ethyl carbamate; vindesine; dacarbazine; mannomustine; dibromomannitol; dibromodulanol; pipobroman; cytosine; arabinoside ("Ara-C"); cyclophosphamide; thiopeta; chlorambucil; gemcitabine 6-thioguanine; mercaptopurine; methotrexate; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbine Mitoxantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; 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 foregoing.

[0767] Also included in the definition of "chemotherapeutic agent" are anti-hormonal agents, such as antiestrogens and selective estrogen receptor modulators (SERMs), aromatase inhibitors, antiandrogens, and pharmaceutically acceptable salts, acids or derivatives of any of the foregoing, which act to modulate or inhibit the effects of hormones on tumors.

[0768] Antihormonal agents

[0769] Examples of antiestrogens and SERMs include, for example, tamoxifen (including NOLVADEX TM), raloxifene, droloxifene, 4-hydroxytamoxifen, troloxifen, raloxifene, raloxifene, raloxifene, raloxifene, raloxifene, raloxifene, raloxifene, raloxifene, raloxifene, raloxifene, raloxifene, raloxifene, raloxifene, raloxifene, raloxifene, raloxifene, LY117018, onapristone and toremifene (F ).

[0770] Aromatase inhibitors regulate estrogen production in the adrenal glands. Examples include 4(5)-imidazole, aminoglutethimide, megestrol acetate Exemestane, formestane, fadrozole, vorozole Letrozole and anastrozole (A ).

[0771] Examples of antiandrogens include apalutamide, abiraterone, enzalutamide, flutamide, galeterone, nilutamide, bicalutamide, leuprolide, goserelin, ODM-201, APC-100, ODM-204.

[0772] Examples of progesterone receptor antagonists include onapristone.

[0773] Anti-angiogenic agents

[0774] Anti-angiogenic agents include, but are not limited to, retinoids and their derivatives, 2-methoxyestradiol, Regorafenib, nikupanib, suramin, squalamine, tissue inhibitor of metalloproteinase-1, tissue inhibitor of metalloproteinase-1, tissue inhibitor of endostatin-1, tissue inhibitor of endostatin-1, tissue inhibitor of endostatin-1, tissue inhibitor of endostatin-1, tissue inhibitor of endostatin-1, tissue inhibitor of endostatin-1, tissue inhibitor of endostatin-1, metalloproteinase-2 of endostatin-1, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, cartilage-derived inhibitor, paclitaxel (nab-paclitaxel), platelet factor 4, protamine sulfate (clupeine), sulfated chitin derivatives (prepared from crab shells), sulfated chitin derivatives (prepared from queen bee shells), sulfated polysaccharide peptidoglycan complex (sp-pg), staurosporine, matrix metabolism regulators, including Proline analogs such as 1-azetidine-2-carboxylic acid (LACA), cis-hydroxyproline, d,I-3,4-dehydroproline, thioproline, α,α'-bipyridine, β-aminopropionitrile fumarate, 4-propyl-5-(4-pyridyl)-2(3h)-oxazolone, methotrexate, mitoxantrone, heparin, interferon, 2-macroglobulin-serum, chicken metalloproteinase-3 inhibitor (ChIMP-3) , chymotrypsin inhibitors, β-cyclodextrin tetradecan sulfate, ipramycin, fumagillin, gold sodium thiomalate, D-penicillamine, β-1-anticollagenase-serum, α-2-antiplasmin, bisantrene, lobenzalide disodium, n-2-carboxyphenyl-4-chloroanthronic acid "CCA", thalidomide, angiostatic steroids, carboxyaminoimidazoles, metalloproteinase inhibitors such as BB-94, S100A9 inhibitors such as tasquinimod. Other anti-angiogenic agents include antibodies, preferably monoclonal antibodies against these angiogenic growth factors: β-FGF, α-FGF, FGF-5, VEGF isoforms, VEGF-C, HGF / SF and Ang-1 / Ang-2.

[0775] Antifibrotic agents

[0776] Antifibrotic agents include, but are not limited to, compounds such as β-aminopropionitrile (BAPN), and compounds disclosed in US 4965288, which relate to lysyl oxidase inhibitors and their use in treating diseases and conditions associated with abnormal collagen deposition, and compounds disclosed in US 4997854, which relate to compounds that inhibit LOX to treat various pathological fibrotic states, which are incorporated herein by reference. Other exemplary inhibitors are described in US 4943593, which relate to compounds such as 2-isobutyl-3-fluoro-, chloro- or bromo-allylamine, US 5021456, US 5059714, US 5120764, US 5182297, US 5252608, which relate to 2-(1-naphthyloxymethyl)-3-fluoroallylamine, and US 2004-0248871, which are incorporated herein by reference.

[0777] Exemplary anti-fibrotic agents also include primary amines that react with the carbonyl group of the active site of lysyl oxidase, more specifically, those that produce products stabilized by resonance after binding to the carbonyl group, such as the following structures: lower primary amines: ethyleneamines, hydrazine, phenylhydrazine and their derivatives; semicarbazide and urea derivatives; aminonitriles such as BAPN or 2-nitroethylamine; unsaturated or saturated halogenated amines such as 2-bromo-ethylamine, 2-chloroethylamine, 2-trifluoroethylamine, 3-bromopropylamine and p-halobenzylamine; and selenohomocysteine ​​lactones.

[0778] Other anti-fibrotic agents are copper chelators that penetrate or impermeate cells. Exemplary compounds include indirect inhibitors that block the aldehyde derivatives derived from the oxidative deamination of lysyl and hydroxylysyl residues by lysyl oxidase. Examples include thiolamines, particularly D-penicillamine and its analogs, such as 2-amino-5-mercapto-5-methylhexanoic acid, D-2-amino-3-methyl-3-((2-acetamidoethyl) dithio) butyric acid, P-2-amino-3-methyl-3-((2-aminoethyl) dithio) butyric acid, 4-((β-1-dimethyl-2-amino-2-carboxyethyl) dithio) butane sodium sulfate, 2-acetamidoethyl-2-acetamidoethanethiol sodium sulfate and 4-mercaptobutanesulfinate sodium trihydrate.

[0779] Immunotherapeutic agents

[0780] 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, amatuximab, anatumomab, acetumomab, bavituximab, bevacizumab, bivatuzumab, blinatumomab, brentuximab, cantuzumab, catumaxomab, CC49, cetuximab, cetuximab, cilivacumab, cilotuzumab, cilotuximab, bavituximab, bavituximab, bevacizumab, bivatuzumab, blinatumomab, brentuximab, cantuzumab, catumaxomab, CC49, cetuximab, cetuximab, cilivacumab, cilotuximab, cilotuximab, bavit ... ab, conatumumab, dacetuzumab, dalotuzumab, daratumumab, demostatumab, dinutuximab, drotuzumab, durituzumab, dusilumab, elotuzumab, elotuzumab, emibetuzumab, ensituximab, ertumaxomab, etaracizumab, farletuzumab, ficlatuzumab, figitumumab, flanvotumab, futuximab, ganitumab, gemtuzumab, girentuximab, glilimumab, ibritumomab tiuxetan, igovomab, igatuzumab, intuximab, ituzumab, intuzumab, ipilimumab ( MDX-010, BMS-734016, and MDX-101), eletumumab, labetuzumab, lexatumumab, lintuzumab, lauvotuzumab, rucamumab, mapatumumab, matuzumab, milatuzumab, mirituzumab, mitumomab, mogazumab, mosetuzumab, natuzumab, nanatumumab, nexituzumab, nimotuzumab, noficitozumab, OBI-833, obinutuzumab, okalaizumab, ofatumumab, olatumumab, onatumumab, obinutuzumab, orgovotumab, panitumumab, pasatuzumab, pertuzumab, pertuzumab, piwtuzumab, pertuzumab, rexuzumab, randuzumab, ramucirumab Rituximab, rituximab, robatumumab, samazumab, samatumomab, cilotuzumab, silotuximab, solizumab, sintuzumab, tacadizumab, talimumab, tenatumomab, teprotumumab, tigatuzumab, tositumomab, trastuzumab, tucotuzumab, ublituximab, veltuzumab, vorsetuzumab, votumumab, zalutumumab and 3F8. Tuliximab can be used to treat indolent B-cell cancers, including marginal zone lymphoma, WM, CLL and small lymphocytic lymphoma. The combination of rituximab and a chemotherapeutic agent is particularly effective.

[0781] Exemplary therapeutic antibodies can be further labeled with radioactive isotope particles such as indium-111, yttrium-90 (90Y-clivatuzumab) or iodine-131 or a combination thereof.

[0782] Tumor gene therapy and cell therapy

[0783] Cancer gene therapy and cell therapy include inserting normal genes into cancer cells to replace mutated or altered genes; genetic modifications to silence mutated genes; genetic methods to directly kill cancer cells; including infusions of immune cells that are designed to replace most of the subject's own immune system to enhance the immune response to cancer cells, or activate the subject's own immune system (T cells or natural killer cells) to kill cancer cells, or find and kill cancer cells; genetic methods that alter cell activity to further alter the endogenous immune response against cancer.

[0784] Gene Editor

[0785] Examples of genome editing systems include the CRISPR / Cas9 system, the zinc finger nuclease system, the TALEN system, the homing endonuclease system, and the meganuclease system.

[0786] CAR-T cell therapy and TCR-T cell therapy

[0787] CAR-T cell therapy includes a population of immune effector cells engineered to express a chimeric antigen receptor (CAR), wherein the CAR comprises a tumor antigen binding domain. Immune effector cells are T cells or NK cells. TCR-T cell therapy includes TCR-T cells engineered to target tumor-derived peptides present on the surface of tumor cells. The cells can be autologous or allogeneic.

[0788] In some embodiments, the CAR comprises an antigen binding domain, an antigen binding domain, and an antigen binding domain.

[0789] transmembrane domain and intracellular signaling domain.

[0790] In some embodiments, the intracellular domain comprises a primary signaling domain, a costimulatory domain, or both a primary signaling domain and a costimulatory domain.

[0791] In some embodiments, the primary signaling domain comprises a functional signaling domain of one or more proteins selected from the group consisting of CD3ζ, CD3γ, CD3δ, CD3ε, common FcRγ (FCERIG), FcRβ (Fc EpsilonRlb), CD79a, CD79b, FcγRIIa, DAP10, and DAP12.

[0792] In some embodiments, the co-stimulatory domain comprises a functional domain of one or more proteins selected from the group consisting of CD27, CD28, 4-1BB (CD137), OX40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds to CD83, CDS, ICAM-1, GITR, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRFI), CD160, CD19, CD4, CD8alpha, CD8beta, IL2Rbeta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD 1 ld, ITGAE, CD103, ITGAL, CD 1la,LFA-1,ITGAM,CD1 lb,ITGAX,CD1 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),PSGL 1, 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.

[0793] In some embodiments, the transmembrane domain comprises a transmembrane domain of a protein selected from the group consisting of: α, β, or ζ chain of a T cell receptor, CD28, CD3ε, 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, IL2Rβ, IL2Rγ, IL7R u, ITGA1, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD1ld, ITGAE, CD103, ITGAL, CD1 la, LFA-1, ITGAM, CD1 lb, ITGAX, CD1 lc, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, TNFR2, DNAM1(CD226), SLAMF4(CD244, 2B4), CD84, CD96(Tactile), CEACAM1, CRTAM, Ly9(CD229), CD160(BY55), PSG L1, CD100(SEMA4D), SLAMF6(NTB-A, Ly108), SLAM(SLAMF1, CD150, IPO-3), BLAME(SLAMF8), SELPLG(CD162), LTBR, ​​PAG / Cbp, NKp44, NKp30, NKp46, NKG2D, and NKG2C.

[0794] In some embodiments, the antigen binding domain binds a tumor antigen.

[0795] In some embodiments, the tumor antigen is selected from the group consisting of: CD19; CD123; CD22; CD30; CD171; CS-1 (also known as CD2 subset 1, CRACC, SLAMF7, CD319 and 19A24); C-type lectin-like molecule-1 (CLL-1 or CLECLI); CD33; epidermal growth factor receptor variant III (EGFRvIII); 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 (GalNAcu-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); testisin or PRSS21; vascular endothelial growth factor receptor 2 (VEGFR2); Lewis (Y) antigen; CD24; platelet-derived growth factor receptor beta (PDGFR-β); stage-specific embryonic antigen-4 (SSEA-4); CD20; delta-like 3 (DLL3); folate receptor alpha; receptor tyrosine-protein kinase, ERBB2 (Her2 / neu) ; Mucin 1, cell surface associated (MUC1); Epidermal growth factor receptor (EGFR); Neural cell adhesion molecule (NCAM); Prostatic enzyme; 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 (Macropain) subunit, beta type, 9 (LMP2); Glycoprotein 100 (gp1 00); oncogene fusion protein composed of breakpoint cluster region (BCR) and Abelson murine leukemia virus oncogene homolog 1 (Abl) (bcr-abl); tyrosinase; ephrin type A receptor 2 (EphA2); fucosyl GM1; sialyl Lewis adhesion molecule (sLe); ganglioside GM3 (aNeuSAc(2-3)BdGalβ(1-4)BdGlcβ(1-1)Cer); transglutaminase 5 (TGS5); high molecular weight melanoma associated antigen (HMWMAA);O-acetyl-GD2 ganglioside (OAcGD2); folate receptor beta; tumor endothelial marker 1 (TEM1 / CD248); tumor endothelial marker 7-related (TEM7R); six transmembrane epithelial antigen of the prostate I (STEAP1); claudin 6 (CLDN6); thyroid stimulating hormone receptor (TSHR); G protein-coupled receptor class C group 5 member D (GPRCSD); chromosome X open reading frame 61 (CXORF61); CD97; CD179a; anaplastic lymphoma kinase (ALK); polysialic acid; placenta-specific 1 (PLAC1); hexasaccharide portion of globoH glycoceramide (globoH); breast differentiation antigen (NY-BR-1); uroplakin 2 (UPK2); hepatitis A virus cellular receptor 1 (HAVCR1); adrenergic receptor beta 3 (ADRB3); pan-nexin 3 (PANX3); G protein-coupled receptor 20 (GPR20); lymphocyte antigen 6 complex, locus K9 (LY6K); olfactory receptor 51E2 (ORS1E2); TCR gamma alternate 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 (Tie 2); melanoma cancer testis antigen-1 (MADCT-1); melanoma cancer testis antigen-2 (MAD-CT-2); Fos-related antigen 1; tumor protein p53 (p53); p53 mutant; prostein; survivin; telomerase; prostate cancer tumor antigen-1 (PCTA-1 or galectin 8), melanoma antigen recognized by T cells 1 (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 -acetylglucosaminyltransferase V (NA17); paired box protein Pax-3 (PAX3); androgen receptor; v-myc avian myelocytomatosis viral oncogene neuroblastoma-derived homolog (MYCN); Ras homolog family member C (RhoC); tyrosinase-related protein 2 (TRP-2); cytochrome P4501B1 (CYP1B1); CCCTC-binding factor (zinc finger protein)-like (brother of BORIS or imprinted site regulator), squamous cell carcinoma antigen recognized by T cells 3 (SART3); paired box protein PAX-5 (PAX5); acrosinogen binding protein sp32 (OY-TES1);Lymphocyte-specific protein tyrosine kinase (LCK); kinase anchoring protein 4 (AKAP-4); synovial sarcoma, breakpoint X 2 (SSX2); receptor for advanced glycation end products (RAGE-1); renal ubiquitin 1 (RUI); renal ubiquitin 2 (RU2); legumin; human papillomavirus E6 (HPV E6); human papillomavirus E7 (HPV E7); intestinal carboxylesterase; mutant heat shock protein 70-2 (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); mucin-like hormone receptor-like 2 containing an EGF-like module (EMR2); lymphocyte antigen 75 (LY75); glypican-3 (GPC3); Fc receptor-like 5 (FCRL5); and immunoglobulin lambda-like polypeptide 1 (IGLL1). ;

[0796] In some embodiments, the tumor antigen is selected from 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, CD 54, CD56, CD66a-d, CD74, CD8, CD80, CD92, CE7, CS-1, CSPG4, ED-B fibronectin, EGFR, EGFRvIII, EGP-2, EGP-4, EPHa2, ErbB2, ErbB3, ErbB2HM1.24, HMW-MAA, Her2, Her2 / neu, IGF-1R, IL-11Rα, IL-13R-α2, IL-2, IL-22R-α, IL-6, IL-6R, Ia, I1, Ll-CAM, LL-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-R1 (DR4), TRAIL-R2 (DR5), VEGF, VEGFR2, WT-1, G protein-coupled receptor, alpha-fetoprotein (AFP), angiogenic factors, exogenous cognate binding molecules (ExoCBM), oncogene products, 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, activin, melanoma-associated antigen, mesothelin, mouse double minute homolog (MDM2), mucin 16 (MUC16), mutated p53, mutated ras, necrosis antigen, carcinoembryonic antigen, ROR2, progesterone receptor, prostate specific antigen, tEGFR, tenascin, β2-microglobulin, Fc receptor-like 5 (FcRL5).

[0797] Non-limiting examples of cell therapy include Algenpantucel-L, Sipuleucel-T, (BPX-501)rivogenlecleucel US9089520, WO2016100236, AU-105, ACTR-087, activated allogeneic natural killer cells CNDO-109-AANK, MG-4101, AU-101, BPX-601, FATE-NK 100, LFU-835 hematopoietic stem cells, Imilecleucel-T, baltaleucel-T, PNK-007, UCARTCSl, 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 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, CSG-005.

[0798] In some embodiments, tumor targeting antigens include: alpha-fetoprotein, such as ET-1402, and AFP-TCR; anthrax toxin receptor 1, such as anti-TEM8 CAR T cell therapy; B cell maturation antigen (BCMA), such as 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, such as KITE-796; B7 homolog 6, such as CAR-NKp30 and C AR-B7H6; B lymphocyte antigen CD19, such as TBI-1501, CTL-119huCART-19T cells, JCAR-015, US7446190, JCAR-014, JCAR-017 (WO2016196388, WO2016033570, WO2015157386), axicatalin ciloperidol (KTE-C19), US7741465, US6319494, UCART-19, EBV-CTL, T tisagenlecleucel-T (CTL019), WO2012079000, WO2017049166, T cells expressing CD19CAR-CD28-CD3ζ-EGFRt, CD19 / 4-1BBL armored CAR T cell therapy, C-CAR-011, CIK-CAR.CD19, CD19CAR-28-ζT cells, pCAR-019, MatchCART, DSCAR-01, IM19CAR-T; B lymphocyte antigen CD20, such as ATTCK-20; B lymphocyte adhesion, such as UC ART-22, JCAR-018, WO2016090190; NY-ESO-1, such as GSK-3377794, TBI-1301; carbonic anhydrase, such as DC-Ad-GMCAIX; caspase 9 suicide gene, such as caspase DLI, BPX-501; CCR5, such as SB-728; CDw123, such as MB-102, UCART-123; CD20m, such as CBM-C20.1; CD4, such as ICG-122; CD30, such as CART30 (CBM-C30.1); CD33, such as CIK-CAR.CD33; CD38, such as T-007, UCART-38; CD40 ligand, such as BPX-201; CEACAM protein 4 modulator, such as MG7-CART; claudin 6, such as CSG-002; EBV targeting, such as CMD-003; EGFR, such as autologous 4H11-28z / fIL-12 / EFGRt T cells; endonucleases, such as PGN-514, PGN-201; Epstein-Barr virus-specific T lymphocytes , such as TT-10; Erbb2, such as CST-102, CIDeCAR; ganglioside (GD2), such as 4SCAR-GD2; glutamate carboxypeptidase II, such as CIK-CAR.PSMA, CART-PSMA-TGFβRDN, P-PSMA-101; phosphatidylinositol proteoglycan-3 (GPC3), such as TT-16, GLYCAR; hemoglobin, such as PGN-236; hepatocyte growth factor receptor, such as anti-cMet RNA CAR T; human papillomavirus E7 protein, such as KITE-439; immunoglobulin gamma Fc receptor III, such as ACTR087; IL-12, such as DC-RTS-IL-12; IL-12 agonist / mucin 16, such as JCAR-020; IL-13α2, such as MB-101; IL-2, such as CST-101; K-Ras GTPase, such as anti-KRas GUV mTCR cell therapy; neural cell adhesion molecule LICAM (CD171), such as JCAR-023; latent membrane protein 1 / latent membrane protein 2, such as Ad5F35-LMPDL-2-transduced autologous dendritic cells; melanoma associated antigen 10, such as MAGE-A10C796T MAGE-A10 TCR; melanoma associated antigen 3 / melanoma associated antigen 6 (MAGE A3 / A6), such as KITE-718; mesothelin, such as CSG-MESO, TC-210; NKG2D, such as NKR-2; Ntrkrl tyrosine kinase receptor, such as JCAR-024; T cell receptor, such as BPX-701, IMCGP100; T lymphocyte, such as TT-12; tumor infiltrating lymphocyte, such as LN-144, LN-145; and nephroblastoma protein, such as JTCR-016, WT1-CTL. .

[0799] Combination therapy for lymphoma or leukemia

[0800] In some embodiments, the additional therapeutic agent is suitable for treating lymphoma or leukemia. These agents include aldesleukin, avosidic acid, amifostine trihydrate, aminocamptothecin, anti-oncogene A10, anti-oncogene AS2-1, anti-thymocyte globulin, arsenic trioxide, Bcl-2 family protein inhibitor ABT-263, βalethine, BMS-345541, bortezomib, Bortezomib ( PS-341), bryostatin 1, Dingshufan, campath-1H, carboplatin, carfilzomib 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, dolastin 10, doxorubicin, doxorubicin hydrochloride, DT-PACE (dexamethasone, cyclophosphamide, cyclophosphamide, cyclophosphamide, cyclophosphamide, epoetin alfa, etoposide, everolimus (RAD001), FCM (fludarabine, cyclophosphamide, and mitoxantrone), FCR (fludarabine, cyclophosphamide, and rituximab), fenretinide, filgrastim, flavopiridol, fludarabine, and FR7), hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, and cytarabine), ICE (ifosfamide, carboplatin, and etoposide), ifosfamide, irinotecan hydrochloride, interferon alfa-2b, ixabepilone, lenalidomide (R CC-5013), lymphokine-activated killer cells, MCP (mitoxantrone, chlorambucil, and prednisolone), melphalan, mesna, methotrexate, mitoxantrone hydrochloride, motexafm gadolinium, mycophenolate mofetil, nelarabine, obakla (GX15-070), oblimersen, octreotide acetate, omega-3 fatty acids, Omr-IgG-am (WNIG, Omrix), oxaliplatin, paclitaxel, palbociclib (PD0332991), pegylated filgrastim, pegylated liposomal doxorubicin hydrochloride, perifosin, prednisolone, prednisone, recombinant flt3 ligand, recombinant human thrombopoietin, recombinant interferon alpha, recombinant interleukin-11, recombinant white blood cell interleukin-12, rituximab, R-CHOP (rituximab and CHOP), R-CVP (rituximab and CVP), R-FCM (rituximab and FCM), R-ICE (rituximab and ICE), and R-MCP (rituximab and MCP), R-roscovitine (seliciclib, CYC202), sargramostim, sildenafil citrate, simvastatin, sirolimus, tacrolimus styrene sulfone, tansirolimus, temsirolimus (CCl-779), thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tipifarnib, vincristine, vincristine sulfate, vinorelbine ditartrate, SAHA (suberyl, anilide, and hydroxamic acid), vemurafenib Venetoclax (ABT-199).

[0801] An improved approach is radioimmunotherapy, in which monoclonal antibodies are combined 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 Yttrium-90 Ibritumomab Tiuxetan and with CHOP.

[0802] The above therapies may be supplemented with or combined with stem cell transplantation or therapy. Therapeutic procedures 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, bone marrow ablation with stem cell support, ex vivo processed peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzymatic technology, low LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery, radiation therapy, and non-myeloablative allogeneic hematopoietic stem cell transplantation.

[0803] Combination therapy for non-Hodgkin lymphoma

[0804] In some embodiments, additional therapeutic agents are suitable for treating non-Hodgkin lymphoma (NHL), especially those of B cell origin, including monoclonal antibodies, standard chemotherapy methods (e.g., CHOP, CVP, FCM, MCP, etc.), radioimmunotherapy, and combinations thereof, especially the integration of antibody therapy with chemotherapy.

[0805] Examples of unconjugated monoclonal antibodies used to treat NHL / B-cell cancers include rituximab, alemtuzumab, human or humanized anti-CD20 antibodies, lumiliximab, anti-TNF-related apoptosis-inducing ligand (anti-Trat1), bevacizumab, galiximab, epratuzumab, SGN-40, and anti-CD-74.

[0806] Examples of experimental antibody agents for treating NHL / B-cell cancers include ofatumumab, HA 20, PR0131921, alemtuzumab, galiximab, SGN-40, CHIR-12.12, epratuzumab, ruximab, apolizumab, milatuzumab, and bevacizumab.

[0807] Examples of standard chemotherapy regimens for NHL / B-cell cancers include CHOP, FCM, CVP, MCP, R-CHOP, R-FCM, R-CVP, and R-MCP.

[0808] Examples of radioimmunotherapy for NHL / B-cell cancers include yttrium-90 ibritumomab tiuxetan and iodine-131 tositumomab

[0809] Combination therapy for mantle cell lymphoma

[0810] In some embodiments, the additional therapeutic agent is suitable for treating mantle cell lymphoma (MCL), which includes combined chemotherapy, such as CHOP, hyperCVAD and FCM. These regimens can also be supplemented with the monoclonal antibody rituximab to form the combination therapy R-CHOP, hyperCVAD-R and R-FCM. Any of the above therapies can be combined with stem cell transplantation or ICE to treat MCL.

[0811] Other examples of therapeutic agents suitable for treating MCL include:

[0812] - Immunotherapies, such as monoclonal antibodies (such as rituximab) and cancer vaccines, such as GTOP-99, which are based on the genetic makeup of an individual subject’s tumor;

[0813] -Radioimmunotherapy, in which monoclonal antibodies are combined with radioisotope particles, such as iodine-131 tositumomab Yttrium-90 Ibritumomab Tiuxetan and Sequential treatment with CHOP;

[0814] -Autologous stem cell transplantation combined with high-dose chemotherapy, administration of proteasome inhibitors such as bortezomib ( or PS-341), or administration of antiangiogenic agents such as thalidomide, particularly in combination with rituximab;

[0815] - Drugs that cause degradation of the Bcl-2 protein and increase the sensitivity of cancer cells to chemotherapy, such as oblimersen, in combination with other chemotherapeutic agents;

[0816] - mTOR inhibitors, which can lead to inhibition of cell growth or even cell death. Non-limiting examples are sirolimus, temsirolimus ( CCI-779), CC-115, CC-223, SF-1126, PQR-309 (bimiralisib), voxtalisib, GSK-2126458, and temsirolimus combinations with other chemotherapeutic agents;

[0817] - Other agents, such as flavonoids, palbociclib (PD0332991), R-roscovitine (selicicilib, CYC202), styryl sulfones, obaclava (GX15-070), TRAIL, anti-TRAIL death receptor DR4 and DR5 antibodies, temsirolimus ( CCI-779), everolimus (RAD001), BMS-345541, curcumin, SAHA, thalidomide, lenalidomide ( CC-5013) and geldanamycin (17-AAG).

[0818] Combination therapy for Waldenstrom's macroglobulinemia

[0819] In some embodiments, additional therapeutic agents are useful for treating Waldenstrom's macroglobulinemia (WM) and include aldesleukin, alemtuzumab, avosidix, amifostine trihydrate, aminocamptothecin, antioplaston A10, antioplaston AS2-1, antithymocyte globulin, arsenic trioxide, autologous human tumor-derived HSPPC-96, Bcl-2 family protein inhibitor ABT-263, beta-alexin, bortezomib Bryostatin 1, busulfan, campath-1H, carboplatin, carmustine, caspofungin acetate, CC-5103, cisplatin, clofarabine, cyclophosphamide, cyclosporine, cytarabine, denileukin, dexamethasone, docetaxel, Aplysia 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, CTL-019), monoclonal antibody CD20, motexafm gadolinium, mycophenolate mofetil, nelarabine, oblimersen, octreotide acetate, omega-3 fatty acids, oxaliplatin, paclitaxel, pegylated liposomal doxorubicin hydrochloride, pentostatin, perifosine, prednisone, recombinant flt3 ligand, recombinant human thrombopoietin, recombinant interferon α, recombinant interleukin-11, recombinant interleukin-12, rituximab, sargramostim, sildenafil citrate Simvastatin, sirolimus, tacrolimus, tansimab, thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tipifarnib, tositumomab, veltuzumab, vincristine sulfate, vinorelbine ditartrate, vorinostat, WT1126-134 peptide vaccine, WT-1 analog peptide vaccine, yttrium-90 ibritumomab tiuxetan, yttrium-90 humanized epratuzumab, and any combination thereof.

[0820] Other examples of therapeutic approaches for treating 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, bone marrow ablation with stem cell support, ex vivo processed peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzymatic techniques, low-LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery, radiation therapy, and non-myeloablative allogeneic hematopoietic stem cell transplantation.

[0821] Combination therapy for diffuse large B-cell lymphoma

[0822] In some embodiments, additional therapeutic agents are useful for treating diffuse large B-cell lymphoma (DLBCL) and include cyclophosphamide, doxorubicin, vincristine, prednisone, anti-CD20 monoclonal antibodies, etoposide, bleomycin, many of the agents listed in WM, and any combination thereof, such as ICE and R-ICE.

[0823] Combination therapy for chronic lymphocytic leukemia

[0824] In some embodiments, additional therapeutic agents are useful for treating chronic lymphocytic leukemia (CLL) and include 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.

[0825] Combination therapy for myelofibrosis

[0826] In some embodiments, additional therapeutic agents are suitable for treating myelofibrosis and include hedgehog inhibitors, histone deacetylase (HDAC) inhibitors, and tyrosine kinase inhibitors. Non-limiting examples of hedgehog inhibitors are saridegib and vismodegib.

[0827] Examples of HDAC inhibitors include, but are not limited to, pracinostat and panobinostat.

[0828] Non-limiting examples of tyrosine kinase inhibitors are lestaurtinib, bosutinib, imatinib, gilteritinib, radotinib, and cabozantinib.

[0829] Combination therapy for hyperproliferative diseases

[0830] 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.

[0831] Combination therapy for bladder cancer

[0832] In some embodiments, the additional therapeutic agent is suitable for treating bladder cancer and includes atezolizumab, carboplatin, cisplatin, docetaxel, doxorubicin, fluorouracil (5-FU), gemcitabine, edoxamide, interferon alpha-2b, methotrexate, mitomycin, nab-paclitaxel, paclitaxel, pemetrexed, thiotepa, vinblastine, and any combination thereof.

[0833] Combination therapy for breast cancer

[0834] 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.

[0835] Combination therapy for triple-negative breast cancer

[0836] In some embodiments, the additional therapeutic agents are suitable for treating triple-negative breast cancer and include cyclophosphamide, docetaxel, doxorubicin, epirubicin, fluorouracil, paclitaxel, and combinations thereof.

[0837] Combination therapy for colorectal cancer

[0838] 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.

[0839] Combination therapy for castration-resistant prostate cancer

[0840] 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.

[0841] Combined treatment for esophageal and esophagogastric junction cancer

[0842] In some embodiments, the additional therapeutic agent is suitable for treating esophageal and esophagogastric junction cancer and includes capecitabine, carboplatin, cisplatin, docetaxel, epirubicin, fluoropyrimidines, fluorouracil, irinotecan, leucovorin, oxaliplatin, paclitaxel, ramucirumab, trastuzumab, and any combination thereof.

[0843] Gastric cancer combination therapy

[0844] In some embodiments, the additional therapeutic agent is suitable for treating gastric cancer and includes capecitabine, carboplatin, cisplatin, docetaxel, epirubicin, carboplatin, fluoropyrimidine, fluorouracil, irinotecan, leucovorin, mitomycin, oxaliplatin, paclitaxel, ramucirumab, trastuzumab, and any combination thereof.

[0845] Combination therapy for head and neck cancer

[0846] 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.

[0847] Combination therapy for hepatobiliary cancer

[0848] In some embodiments, the additional therapeutic agent is suitable for treating hepatobiliary cancer and includes capecitabine, cisplatin, fluoropyrimidine, 5-fluorouracil, gemcitabine, oxaliplatin, sorafenib, and any combination thereof.

[0849] Combination therapy for hepatocellular carcinoma

[0850] In some embodiments, the additional therapeutic agent is suitable for treating hepatocellular carcinoma and includes capecitabine, doxorubicin, gemcitabine, sorafenib, and any combination thereof.

[0851] Combination therapy for non-small cell lung cancer

[0852] In some embodiments, the additional therapeutic agent is suitable for treating non-small cell lung cancer (NSCLC) and includes afatinib, albumin-bound paclitaxel, alectinib, bevacizumab, 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.

[0853] Combination therapy for small cell lung cancer

[0854] In some embodiments, the additional therapeutic agent is useful 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

[0855] Combination therapy for melanoma

[0856] In some embodiments, the additional therapeutic agent is suitable for treating melanoma and includes albumin-bound paclitaxel, carboplatin, cisplatin, cobimetinib, dabrafenib, dacarbazine, IL-2, imatinib, interferon alpha-2b, ipilimumab, nitrosoureas, nivolumab, paclitaxel, pembrolizumab, ipilimumab, temozolomide, trametinib, vemurafenib, vinblastine, and any combination thereof.

[0857] Combination therapy for ovarian cancer

[0858] 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, capecitabine, carboplatin, cisplatin, cyclophosphamide, pazopanib, pemetrexed, tamoxifen, topotecan, vinorelbine, and any combination thereof.

[0859] Combination therapy for pancreatic cancer

[0860] In some embodiments, the additional therapeutic agent is suitable for treating pancreatic cancer and includes 5-fluorouracil, albumin-bound paclitaxel, capecitabine, cisplatin, docetaxel, erlotinib, a fluoropyrimidine, gemcitabine, irinotecan, leucovorin, oxaliplatin, paclitaxel, and any combination thereof.

[0861] Combination therapy for renal cell carcinoma

[0862] In some embodiments, additional therapeutic agents are suitable.

[0863] These include axitinib, bevacizumab, cabozantinib, erlotinib, everolimus, lenvatinib, nivolumab, pazopanib, sorafenib, sunitinib, temsirolimus, and any combination thereof.

[0864] VIII. Kit

[0865] The present disclosure provides a kit comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof. The kit may further comprise instructions for use, for example, for treating viral infections. The instructions for use are typically written instructions, although electronic storage media (e.g., disks or optical disks) comprising instructions are also acceptable.

[0866] The present disclosure also provides a drug kit, which includes one or more containers, and the container includes a compound of the present disclosure or a pharmaceutically acceptable salt thereof. Optionally, associated with such a container may be a notice in the form prescribed by a government agency that manages the manufacture, use or sale of the drug, which reflects the approval of the agency for manufacture, use or sale for human administration. Each component (if there is more than one component) can be packaged in a separate container, or some components can be combined in a container when cross-reactivity and shelf life allow. The kit can be a unit dosage form, bulk (e.g., multi-dose packaging) or subunit dosage. The kit can also include a plurality of unit doses of compounds and instructions for use, and is packaged in an amount sufficient to be stored and used in a pharmacy (e.g., a hospital pharmacy and a compounding pharmacy).

[0867] Also provided are articles of manufacture comprising a unit dose of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, in suitable packaging for use in the methods described herein. Suitable packaging is known in the art and includes, for example, vials, containers, ampoules, bottles, cans, flexible packaging, etc. The articles of manufacture may be further sterilized and / or sealed. Example

[0868] The abbreviations used herein have the following respective meanings:

[0869]

[0870]

[0871]

[0872] Solid forms (polymorphs, solvates and hydrates) of Compound I were characterized by the following various methods.

[0873] XRPD patterns were collected using a PANalytical X'Pert PRO MPD diffractometer, using an incident beam of Cu Kα radiation produced by a long focus source and a nickel filter. The diffractometer was configured using a symmetric Bragg-Brentano geometry. Prior to analysis, a silicon sample (NIST SRM 640e) was analyzed to verify that the position of the observed Si 111 peak was consistent with the NIST certified position. A specimen of the sample was prepared as a thin circular layer centered on a silicon zero background substrate. An anti-scatter slit (SS) was used to minimize the background generated by air. Soller slits for the incident and diffracted beams were used to minimize broadening caused by axial divergence. Diffraction patterns were collected using a scanning position sensitive detector (X'Celerator) located 240 mm from the sample and data collector software v.2.2b.

[0874] Differential Scanning Calorimetry (DSC) data were collected using TA Instruments 2920 and Q 2000 differential scanning calorimeters. Temperature calibration was performed using NIST traceable indium metal. The sample was placed in a T zero aluminum DSC pan, covered with a lid and crimped. The weight was then accurately recorded. A weighed aluminum pan configured as a sample pan was placed on the reference side of the cell. The sample was heated from -30°C to 250°C at 10°C / min.

[0875] Thermogravimetric analysis (TGA) data were collected using a TA Instruments Discovery Thermogravimetric Analyzer. Nickel and Alumel TM Temperature calibration was performed. Each sample was placed in an aluminum pan and inserted into a TG furnace. The furnace was heated under a nitrogen purge. The samples were heated from ambient temperature to 350°C at 10°C / min.

[0876] 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. Adsorption and desorption data were collected over a range of 5% to 95% RH in 10% RH increments under a nitrogen purge. The equilibrium standard for the analysis was less than 0.0100% weight change in 5 minutes with a maximum equilibrium time of 3 hours. The weight percentages reported in the data sections are related to the total sample mass introduced prior to equilibrium at 5% relative humidity as measured on the instrument.

[0877] Example 1: Preparation of Compound I

[0878]

[0879] Compound A (2.69kg, 6.07 moles, 1.0 equivalents) was added to a 50-L jacketed reactor purged with nitrogen. Dichloromethane (10.13L, 13.44kg) was then added. Stirring was set to 175rpm and the contents were stirred until a solution was observed. The feed rate of trifluoroacetic acid (4.53L, 6.75kg) ensured that the internal temperature did not exceed 35°C (about 30 minutes). After the addition of trifluoroacetic acid, the jacket was set to 46°C (to maintain a gentle reflux). The contents were stirred at this temperature for 3h, and the jacket was then set to 15°C. Once the internal temperature reached 20°C, ethanol (denatured from n-heptane) (8.56L, 6.75kg) was added and the contents were stirred at 20°C for 14 hours. After this period of time, the heterogeneous contents were filtered through a benchtop polyfilter into a 100-L jacketed reactor flushed with nitrogen.

[0880] Dichloromethane (5.21L, 6.91kg) was added to the 50-L reactor, and the solution was rinsed through the filter into the 100-L reactor. Water (15.5L, 15.5kg) and ethyl acetate (19.0L, 17.0kg) were then added to the 100-L reactor. Stirring was set to 175rpm 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 water layer was discharged. Water (18.4L, 18.4kg) was added to the reactor, and stirring was set to 200rpm. 30% w / w NaOH (8.61kg) was added and the contents were stirred for 30 minutes. At 30°C (the jacket was set at 40°C). Ethyl acetate (45.0L, 40.4kg) was then injected and the jacket was set to 55°C. Once the internal temperature reached 45°C, the contents were stirred at 200rpm for 30 minutes. After this period of time, stirring was stopped, the phases were separated and the aqueous layer was drained. A 4.5% w / w aqueous sodium bicarbonate solution (prepared from 605 g of sodium bicarbonate and 12.8 kg of water) was added and the contents were stirred at 200 RPM for 30 minutes at an internal temperature of 45°C. After this period of time, stirring was stopped and the layers were separated. The aqueous layer was drained 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, a 4.5% w / w aqueous sodium bicarbonate solution (prepared from 605 g of sodium bicarbonate and 12.8 kg of water) was added and the contents were stirred (200 rpm) at 45°C for 30 minutes. Stirring was then stopped, the phases were separated and the aqueous layer was drained. A 4.5% w / w aqueous sodium bicarbonate solution (prepared from 605 g of sodium bicarbonate and 12.8 kg of water). The contents were stirred (200 rpm) at 45°C for 30 minutes. Agitation was then stopped, the phases were allowed to separate and the aqueous layer was drained. Water (13.6 L, 13.6 kg) was added and the contents were stirred (150 rpm) at 45°C for 30 minutes. After this time, agitation was stopped, the phases were allowed to separate and the aqueous layer was drained.

[0881] Alternatively, compound A (proportional factor, 1.0 part) is added to a nitrogen-flushed reaction vessel. Dichloromethane (2.5 parts) is then added. The contents are stirred until a uniform solution is observed. The rate of loading of trifluoroacetic acid (2.0 parts) should ensure that the internal temperature does not exceed 35°C (about 30 minutes). After the addition of trifluoroacetic acid, the jacket is set to maintain the internal temperature at about 30°C. The contents are stirred at this temperature for about 10 hours, and then the jacket is set to 22°C. Once the internal temperature reaches 22°C, ethanol (2.0 parts) is added and the contents are stirred at 22°C for 14 hours. After this period of time, the contents are filtered. The filter is rinsed with ethanol (2.0 parts) and the contents are distilled to about 3L / kg. The contents are cooled to 22°C, and ethanol (1 part) and water (1 part) are added to the contents. A 50% wt / wt aqueous sodium hydroxide solution (about 0.7 parts) is added thereto until a pH of 12-14 is reached. The internal temperature of the contents is adjusted to 22°C, and water (3.0 parts) is added within 30 minutes. The contents were cooled to about 0°C over 2 hours and maintained at this temperature for 2 hours. The slurry was filtered and the filter cake was rinsed with water and ethanol (2 parts) in a 1:1 weight / weight ratio. The contents were dried at 45°C until constant weight was reached. Compound I (Form I) was discharged and packaged.

[0882] Example 2 Crystalline Form I (ethyl acetate)

[0883] The reactor was configured for vacuum distillation, with the jacket set to 70°C and the agitation set to 150RPM. The solvent was removed by vacuum distillation to about 30L. The jacket was set to 35°C and the reactor was backfilled with nitrogen. Ethyl acetate (45L, 40.4kg) was added and the reactor was heated to 70°C, the agitation was set to 150rpm and the pressure was reduced. The solvent was removed by vacuum distillation to about 30L. The jacket was set to 35°C and the reactor was backfilled with nitrogen. The ethyl acetate distillation sequence was repeated 5X. The distillation was about 15%. The final volume of the five distillations after adding 45L of ethyl acetate to each sequence was about 30L. The contents were sampled to determine the water content (target <0.5% H 2 O). After passing the water content standard, the jacket was heated to 70°C, the stirring was set to 150 rpm, and the pressure was reduced and the distillation continued to about 22 L. The jacket was set to 35°C and the reactor was backfilled with nitrogen. Ethyl acetate (15 L, 13.5 kg) was added and the contents were finely filtered through a 1.0 μm filter into the crystallizer. The jacket on the crystallizer was set to 70°C and the stirring was set to 150 rpm. The pressure of the vessel was reduced and the distillation continued to about 18 L. After reaching this target volume, the crystallizer was backfilled with nitrogen and the jacket was set to 87°C. Ethyl acetate (9.5 L, 8.5 kg) was added and the contents were stirred until a uniform solution was observed. After all solids were dissolved, cooling from 85°C to 20°C over 8 h was begun.

[0884] The solids were filtered and the wet cake was washed with ethyl acetate (6.1 L, 5.5 kg). The jacket on the filter was set to 46 °C and the contents were dried under reduced pressure under a stream of nitrogen for 24 hours. Compound I (Form I) was isolated in good purity (99.6% assay, 99.7% AN).

[0885] Optionally, compound I (1.2kg, 4.0mol) is added to a 50-L jacketed reactor, followed by ethyl acetate (25L, 22kg). The jacket on the reactor is set to 87°C, and stirring is set to 150rpm. The contents are stirred until a solution is observed. After all solids are dissolved, cooling from 85°C to 20°C begins within 8h. The solid is filtered and the wet cake is washed with ethyl acetate (6.1L, 5.5kg). The jacket on the filter is set to 46°C, and the contents are dried under reduced pressure for 24 hours under a stream of nitrogen. Compound I Form I is isolated.

[0886] Form I is a non-solvated phase. Its XRPD pattern is shown in Figure 1 middle.

[0887] Table 1 Crystal data and data collection parameters of Compound I Form I

[0888]

[0889] Table 2 Peak list of Form I

[0890]

[0891] DSC curve Figure 2 As shown in Figure 2, an endothermic transition is shown at about 164°C. The TGA curve is shown in Figure 2 Figure 3 The dynamic vapor sorption curve is shown in Figure 4 The data showed that the crystalline form absorbed about 0.89% water at 25°C up to 95% RH. The material was found to have no change in crystalline form after the experiment.

[0892] Single crystal data for Form I were collected and are summarized in Table 1. Crystals were prepared by dissolving Form I in tetrahydrofuran. The solution was filtered through a 0.2 mm nylon filter into an Erlenmeyer flask. Water was added at a 4 / 1 (v / v) tetrahydrofuran / water ratio. The flask was covered with perforated aluminum foil and the solution was evaporated to dryness under ambient conditions. The tetragonal unit cell parameters and calculated volumes are: (α=β=γ=90°), The molecular weight of the asymmetric unit in the crystal structure of Compound I Form I is 293.35 g mol -1 , Z = 4, the calculated density is 1.269 g cm -3 The space group is determined to be P41 (No. 76).

[0893] Example 3 Crystalline Form I (Ethanol)

[0894] Compound I (1 part, scale factor) was added to an inert reaction vessel, followed by anhydrous ethanol (12 parts). The contents were heated until all solids were dissolved (about 75°C). Once all solids were dissolved, the internal temperature was adjusted to about 65°C and the contents were finely filtered. The filter was rinsed with ethanol (1 part). The contents were distilled to about 8L / kg. The internal temperature was adjusted to 75°C and any solids were dissolved. The contents were cooled to 0°C over 8h and maintained at this temperature for another 6h. After this period of time, the contents were filtered and the filter cake was washed with cold (about 0°C) anhydrous ethanol (2 parts) and the filter cake was dried at 45°C until constant weight was reached. Compound I (Form I) was discharged and packaged.

[0895] Example 4 Crystalline Form I (ethanol / water)

[0896] Compound I (1 part, proportional factor) was added to an inert reaction vessel, followed by anhydrous ethanol (12 parts). The contents were heated until all solids were dissolved (about 75°C). Once all solids were dissolved, the internal temperature was adjusted to about 65°C and the contents were finely filtered. The filter was rinsed with ethanol (1 part). The contents were distilled to about 7L / kg. The internal temperature was adjusted to 75°C and any solids were dissolved. Water (5 parts) was added to the solution within 1 hour. The contents were cooled to 22°C over 3 hours and kept at this temperature for another 2 hours. After this amount of time, the slurry was filtered and the filter cake was rinsed with water and ethanol (2 parts) in a 1:1 wt / wt ratio. The contents were dried at 45°C until constant. Ant weight was obtained. Compound I (Form I) was discharged and packaged.

[0897] Example 5 HCl salt, Form I

[0898] In Avantium Crystal In a multi-reactor system, Compound I Form I (35.18 mg), about 1 molar equivalent of hydrochloric acid (96 μL, 1.25 M EtOH solution) and methyl ethyl ketone (300 ml) were heated to about 50 ° C. After about 15 minutes, the reactor system was closed to quickly cool to ambient temperature. After reaching ambient temperature, the sample was reheated to about 50 ° C for about 4 hours and then cooled to about 10 ° C at 0.1 ° C / min. The solid was collected by vacuum filtration and analyzed.

[0899] In another experiment, Compound I (43.8 mg) and approximately 1 molar equivalent of hydrochloric acid (120 μL, 1.25 M in EtOH) were dissolved in methyl ethyl ketone (500 μl) at ambient temperature. After the addition of hydrochloric acid, the solution turned pink, but then turned yellow after mixing. The vial was capped with perforated aluminum foil and the solution was evaporated. After drying, a gel was obtained and grinding with ethyl acetate and then ether was attempted. Some precipitation was observed after the addition of ether, and the mixture was seeded with crystallized HCl salt Form I. After stirring for 1 day at ambient temperature, the solid was isolated by vacuum filtration and analyzed.

[0900] Compound I HCl Form I is a...

Claims

1. Crystalline form of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (Compound I): Features The X-ray powder diffraction (XRPD) pattern includes five or more peaks located at 10.9°, 11.5°, 13.2°, 14.7°, 15.5°, 21.4°, 21.9°, 23.2° or 24.9° 2θ (±0.2° 2θ), Form I.

2. The crystal form according to claim 1, characterized in that The XRPD pattern included peaks at 10.9°, 13.2°, 14.7°, 15.5°, 21.4°, and 21.9° 2Θ (± 0.2° 2Θ).

3. The crystalline form of claim 1, wherein the XRPD pattern comprises peaks at 10.9°, 11.5°, 13.2°, 14.7°, 23.2°, and 24.9° 2θ (±0.2° 2θ).

4. The crystalline form of claim 1, wherein the XRPD pattern comprises peaks at 11.5°, 15.5°, 21.4°, 21.9°, 23.2°, and 24.9° 2θ (±0.2° 2θ).

5. The crystal form according to claim 1, characterized in that The XRPD pattern included 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).

6. The crystal form according to claim 1, characterized in that The unit cell with the following dimensions was determined by single crystal X-ray crystallography: α=90°; β=90°; γ=90°.

7. The crystal form according to claim 1, characterized in that The XRPD pattern is substantially as shown in Figure 1.

8. The crystal form according to claim 1, characterized in that The differential scanning calorimetry (DSC) thermogram had an endotherm onset at about 164°C.

9. The crystal form according to claim 1, characterized in that The DSC thermogram is essentially as shown in Figure 2.

10. Crystalline form of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol tartrate: Features The XRPD pattern includes five or more peaks located at 6.3°, 9.9°, 12.5°, 17.7°, 18.3°, 19.2°, 23.4°, 25.7°, or 28.1° 2θ (±0.2° 2θ), Compound 1 tartrate salt.

11. The crystal form according to claim 10, characterized in that The XRPD pattern included peaks at 6.3°, 9.9°, 12.5°, 17.7°, 18.3°, and 23.4° 2Θ (± 0.2° 2Θ).

12. The crystalline form of claim 10, wherein the XRPD pattern comprises peaks at 9.9°, 12.5°, 17.7°, 19.2°, 25.7°, and 28.1° 2θ (±0.2° 2θ).

13. The crystalline form of claim 10, wherein the XRPD pattern comprises peaks at 6.3°, 18.3°, 19.2°, 23.4°, 25.7°, and 28.1° 2θ (±0.2° 2θ).

14. The crystal form according to claim 10, characterized in that The XRPD pattern included 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).

15. The crystal form according to claim 10, characterized in that The XRPD pattern is substantially as shown in Figure 13.

16. The crystal form according to claim 10, characterized in that The differential scanning calorimetry (DSC) thermogram had an endotherm onset at about 157°C.

17. The crystal form according to claim 10, characterized in that The DSC thermogram is essentially as shown in Figure 14.

18. Crystalline form of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol maleate: Characterized by an XRPD pattern including five or more peaks located at 7.3°, 8.4°, 8.8°, 13.9°, 15.6°, 17.7°, 20.7°, 24.7°, or 27.4° 2θ (±0.2° 2θ), Compound I maleate salt.

19. The crystal form according to claim 18, characterized in that The XRPD pattern included peaks at 7.3°, 13.9°, 15.6°, 17.7°, 24.7°, and 27.4° 2Θ (± 0.2° 2Θ).

20. The crystalline form of claim 18, wherein the XRPD pattern comprises peaks at 8.4°, 8.8°, 13.9°, 15.6°, 20.7°, and 27.4° 2θ (±0.2° 2θ).

21. The crystalline form of claim 18, wherein the XRPD pattern comprises a peak at 7.3°, 8.4°, 8.8°, 17.7°, 20.7°, or 24.7° 2θ (±0.2° 2θ).

22. The crystalline form of claim 18, characterized in that The XRPD pattern included 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).

23. The crystalline form of claim 18, characterized in that The XRPD pattern is substantially as shown in Figure 17.

24. The crystalline form of claim 18, characterized in that The differential scanning calorimetry (DSC) thermogram had an endotherm onset at about 143°C.

25. The crystalline form of claim 18, characterized in that The DSC thermogram is essentially as shown in Figure 18.

26. Crystalline form of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol fumarate: Features The XRPD pattern includes five or more peaks located at 6.7°, 8.3°, 10.1°, 12.6°, 16.1°, 18.5°, 20.6°, 25.2°, or 27.6° 2θ (± 0.2° 2θ), Compound 1 fumarate salt.

27. The crystalline form of claim 26, characterized in that The XRPD pattern included peaks at 6.7°, 8.3° 18.5°, 20.6°, 25.2° and 27.6° 2Θ (± 0.2° 2Θ).

28. The crystalline form of claim 26, wherein the XRPD pattern comprises peaks at 10.1°, 12.6°, 16.1°, 18.5°, 20.6°, and 27.6° 2θ (±0.2° 2θ).

29. The crystalline form of claim 26, wherein the XRPD pattern comprises peaks at 6.7°, 8.3°, 10.1°, 12.6°, 16.1°, and 25.2° 2θ (±0.2° 2θ).

30. The crystalline form of claim 26, characterized in that The XRPD pattern included 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).

31. The crystalline form of claim 26, characterized in that The XRPD pattern is substantially as shown in Figure 21.

32. The crystalline form of claim 26, characterized in that The differential scanning calorimetry (DSC) thermogram had an endotherm onset at about 70°C.

33. The crystalline form of claim 32, wherein the DSC thermogram has a second endotherm with an onset at about 167°C.

34. The crystalline form of claim 26, characterized in that The DSC thermogram is essentially as shown in Figure 22.

35. A pharmaceutical composition comprising the crystalline form of any one of claims 1, 10, 18 or 26 and one or more pharmaceutically acceptable excipients.

36. The pharmaceutical composition of claim 35, wherein the crystalline form is Form I.

37. The pharmaceutical composition of claim 35, wherein the crystalline form is a tartrate salt.

38. The pharmaceutical composition of claim 35, wherein the crystalline form is a maleate salt.

39. The pharmaceutical composition of claim 35, wherein the crystalline form is a fumarate salt.

40. Use of the crystalline form described in any one of claims 1, 10, 18 and 26 or the pharmaceutical composition described in claim 35 in the preparation of a medicament for treating or preventing HBV infection.

41. The use of claim 40, further comprising administering a therapeutically effective amount of one or more additional therapeutic agents.

42. The use of claim 41, wherein the one or more additional therapeutic agents are administered simultaneously with the crystalline form or the pharmaceutical composition.

43. The use of claim 41, wherein the one or more additional therapeutic agents are selected from: HBV combination drugs, HBV vaccines, HBV DNA polymerase inhibitors, immunomodulators, toll-like receptor (TLR) modulators, interferon α receptor ligands, hyaluronidase inhibitors, hepatitis B surface antigen (HBsAg) inhibitors, cytotoxic T lymphocyte-associated protein 4 (ipi4) inhibitors, cyclophilin inhibitors, HBV viral entry inhibitors, antisense oligonucleotides targeting viral mRNA, short interfering RNA (siRNA) and ddRNAi endonuclease modulators, ribonucleotide reductase inhibitors, HBV E antigen inhibitors, covalently closed circular DNA (cccDNA) inhibitors, farnesoid X receptor agonists, HBV antibodies, CCR2 chemokine antagonists, thymosin agonists, cytokines, nuclear protein regulators, retinoic acid-inducible gene 1 stimulators, NOD2 stimulators, phosphatidylinositol 3-kinase (PI3K) inhibitors, indoleamine-2,3-dioxygenase (IDO) pathway inhibitors, PD-1 inhibitors, PD-L1 inhibitors, recombinant thymosin alpha-1 agonists, Bruton's tyrosine kinase (BTK) inhibitors, KDM inhibitors, HBV replication inhibitors, arginase inhibitors and other HBV drugs.

44. The use of claim 41, wherein the one or more additional therapeutic agents are selected from: adefovir Tenofovir disoproxil fumarate + emtricitabine Tenofovir Disoproxil Fumarate Entecavir Lamivudine Tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine Emtricitabine Pegylated interferon alfa-2b Interferon α1b Interferon alfa-2b Pegylated interferon alfa-2a Interferon α-n1 Ribavirin, interferon beta-1a Bioferon, Ingaron, Inmutag (Inferon), Algeron, Roferon-A, Oligotide, Zutectra, Shaferon, interferon alfa-2b (Axxo), Alfaferone, interferon alfa-2b, Feron, interferon-alpha 2 (CJ), Bevac, Laferonum, Vipeg, Blauferon-B, Blauferon-A, Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-B, alfainterferona 2b, Kalferon, Pegnano, Feronsure, PegiHep, Optipeg A, Realfa 2B, Reliferon, peginterferon alfa-2b, Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alpha-2b, Anterferon, Shanferon, MOR-22, interleukin-2 (IL-2), recombinant human interleukin-2 (Shenzhen Neptunus), Layfferon, Ka ShuNing, Shang Sheng Lei Tai, Intefen, Sinogen, Fukangtai, Alloferon, and Simu-interleukin.

45. The use of claim 41, wherein the one or more additional therapeutic agents are selected from the group consisting of entecavir, adefovir, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine, and lamivudine.

46. ​​The use according to claim 41, wherein the one or more additional therapeutic agents are selected from tenofovir alafenamide, tenofovir alafenamide fumarate and tenofovir alafenamide hemifumarate.

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