Solid forms of TOLL-like receptor modulators

Abstract

The present disclosure provides solid 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 the benefit of U.S. Provisional Application No. 62 / 835,359, filed April 17, 2019, the entire contents of which are hereby incorporated 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, and pharmaceutical compositions that, among other things, 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 an important role in pathogen recognition and innate immune activation. Toll-like receptor 8 (TLR-8) is primarily expressed by myeloid immune cells, and activation of this receptor stimulates a broad immune response. TLR-8 agonists activate myeloid dendritic cells, monocytes, monocyte-derived dendritic cells, and Kupffer cells, leading to the production of proinflammatory cytokines and chemokines such as interleukin-18 (IL-18), interleukin-12 (IL-12), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ). Such agonists also promote the production of co-stimulatory molecules such as CD8 + The expression of NK cells, major histocompatibility complex molecules (MAIT, NK cells) and chemokine receptors was increased.

[0005] Together, activation of these innate and adaptive immune responses induces immune responses and provides therapeutic benefits in a variety of conditions involving autoimmunity, inflammation, allergies, asthma, transplant rejection, graft-versus-host disease (GvHD), infection, cancer, and immunodeficiency. For example, in 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 their potential for treating a variety of diseases, there remains a need for novel modulators of toll-like receptors, such as TLR-8. Potent and selective modulators of TLR-8 with reduced potential for off-target propensity are particularly desired. 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-olgentisic acid:

[0008]

[0009] Characterized in that the X-ray powder diffraction (XRPD) pattern includes three or more peaks at 4.4°, 8.7°, 12.9°, 14.9°, 17.3°, 19.5°, 24.8°, 25.7° or 26.3° 2θ (±0.2° 2θ), i.e., Compound I gentisic acid.

[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 hippuric acid:

[0011]

[0012] Characterized in that the XRPD pattern includes three or more peaks at 2.9°, 5.0°, 7.6°, 10.4°, 12.6°, 17.6°, 19.0°, 25.2° or 28.5° 2θ (±0.2° 2θ), i.e., Compound I hippuric acid.

[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-olphosphonic acid:

[0014]

[0015] Characterized by an XRPD pattern comprising three or more peaks at 3.7°, 6.1°, 7.1°, 12.1°, 14.2°, 21.6°, 24.0°, 27.4° or 28.2° 2θ (±0.2° 2θ), i.e., phosphate Form I.

[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-olphosphonic acid:

[0017]

[0018] Characterized by an XRPD pattern comprising three or more peaks at 5.4°, 6.3°, 15.8°, 18.1°, 18.9°, 20.6°, 24.1°, 26.7° or 27.4° 2θ (±0.2° 2θ), i.e., phosphate Form II.

[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 succinic acid:

[0020]

[0021] Characterized in that the XRPD pattern includes three or more peaks at 4.6°, 6.8°, 9.3°, 13.2°, 17.5°, 18.7°, 19.0°, 25.7° or 27.0° 2θ (±0.2° 2θ), i.e., Compound I succinic 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 ethanedisulfonic acid:

[0023]

[0024] Characterized in that the XRPD pattern includes three or more peaks at 4.4°, 7.9°, 8.7°, 13.0°, 16.6°, 20.6°, 21.1°, 22.1° or 26.0° 2θ (±0.2° 2θ), i.e., Compound I ethanedisulfonic acid Form I.

[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 ethanedisulfonic acid:

[0026]

[0027] Characterized in that the XRPD pattern includes three or more peaks at 4.5°, 5.6°, 8.4°, 12.9°, 13.4°, 16.6°, 17.9°, 18.3° or 22.2° 2θ (±0.2° 2θ), i.e., Compound I ethanedisulfonic acid Form II. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 The XRPD pattern of Compound 1 Form I is shown.

[0029] Figure 2 The XRPD pattern of Compound 1 gentisic acid is shown.

[0030] Figure 3 The DSC thermogram of Compound I gentisic acid is shown.

[0031] Figure 4 The TGA curve of Compound I gentisic acid is shown.

[0032] Figure 5 The DVS curve of Compound I gentisic acid is shown.

[0033] Figure 6 The XRPD pattern of Compound 1 hippuric acid is shown.

[0034] Figure 7 The DSC thermogram of Compound I hippuric acid is shown.

[0035] Figure 8 The TGA curve of Compound I hippuric acid is shown.

[0036] Fig. 9 The DVS curve of Compound I hippuric acid is shown.

[0037] Fig.10 The XRPD pattern of Compound 1 Phosphate Form I is shown.

[0038] Fig.11 The DSC thermogram of Compound 1 Phosphate Form I is shown.

[0039] Fig.12 The TGA curve of Compound 1 Phosphate Form I is shown.

[0040] Fig.13 The XRPD pattern of Compound Phosphate Form II is shown.

[0041] Fig.14 Shown is the DSC thermogram of Compound I Phosphate Form II.

[0042] Fig.15 The TGA curve of Compound I Phosphate Form II is shown.

[0043] Fig.16 The XRPD pattern of Compound 1 succinic acid is shown.

[0044] Fig.17 The DSC thermogram of Compound I succinic acid is shown.

[0045] Fig.18 The TGA curve of Compound I succinic acid is shown.

[0046] Fig.19The DVS curve of Compound I succinic acid is shown.

[0047] Fig. 20 Shown is the XRPD pattern of Compound 1 ethanedisulfonic acid Form I.

[0048] Fig.21 Shown is the XRPD pattern of Compound 1 ethanedisulfonic acid Form II. DETAILED DESCRIPTION

[0049] I. Overview

[0050] The present disclosure arises from the surprising discovery of a solid form of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (Compound I):

[0051]

[0052] And their salts, solvates or co-crystals. Compound I can adopt multiple crystalline forms, including but not limited to crystalline Compound I gentisic acid, crystalline Compound I hippuric acid, crystalline Compound I phosphate Form I, crystalline Compound I phosphate Form II, crystalline Compound I succinic acid, crystalline Compound I ethanedisulfonic acid Form I, and crystalline Compound I ethanedisulfonic acid Form II. Compound I can form a mixture of two or more crystalline forms, or form a single crystalline form that is substantially free of other crystalline forms.

[0053] An 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.

[0054] II. Definitions

[0055] 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.

[0056] "Hydrate" refers to a complex formed by mixing Compound I and water. The term includes stoichiometric hydrates as well as non-stoichiometric hydrates.

[0057] "Solvate" refers to a complex formed by mixing Compound I and a solvent.

[0058] "Desolvated" refers to a form of Compound 1 that is a solvate as described herein and from which solvent molecules have been partially or completely removed. Desolvation techniques for preparing a desolvated form include, but are not limited to, exposing a Compound 1 form (solvate) to a vacuum, subjecting a solvate to elevated temperatures, exposing a 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 solvent molecules are present in stoichiometric or non-stoichiometric amounts.

[0059] "Alcohol" refers to a solvent having a hydroxyl group. Representative alcohols can have any suitable number of carbon atoms, such as C1-C6, and any suitable number of hydroxyl groups, such as 1-3. Exemplary alcohols include, but are not limited to, methanol, ethanol, n-propanol, isopropanol, and the like.

[0060] A "therapeutically effective amount" refers to an amount sufficient to effect such treatment when administered to a mammal in need of treatment, as defined below. The therapeutically effective amount will vary depending on the subject being treated, 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.

[0061] "Substantially free of other crystalline forms of Compound I" refers to a crystalline form of Compound I that contains less than 10% of other crystalline forms of Compound I. For example, substantially free may refer to 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 refers to a crystalline form of Compound I that contains less than 5% of other crystalline forms of Compound I. Preferably, substantially free refers to a crystalline form of Compound I that contains less than 1% of other crystalline forms of Compound I.

[0062] III. Solid Form of Compound I

[0063] The present disclosure provides solid forms of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (Compound I; see U.S. Pat. No. 9,670,205), including crystalline forms and salts, solvates or co-crystal forms. In some embodiments, the present disclosure provides a crystalline form of Compound I having the following structure:

[0064]

[0065] and their salts, solvates or co-crystals.

[0066] Compound I may adopt a variety of crystalline forms, including, but not limited to, crystalline Compound I gentisic acid, crystalline Compound I hippuric acid, crystalline Compound I phosphate Form I, crystalline Compound I phosphate Form II, crystalline Compound I succinic acid, crystalline Compound I ethanedisulfonic acid Form I, and crystalline Compound I ethanedisulfonic acid Form II. 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.

[0067] In some embodiments, the present disclosure provides a compound selected from the group consisting of: (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol gentisic acid; (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol hippuric acid; (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol phosphate Form I; (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol phosphate Form I; (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol ethanedisulfonic acid Form I; and (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol ethanedisulfonic acid Form II.

[0068] Form I

[0069] 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):

[0070]

[0071] Characterized by an X-ray powder diffraction (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 having the following dimensions as determined by single crystal X-ray diffraction techniques: α = 90°; β = 90°; and γ = 90°. In some embodiments, Form I is characterized by an XRPD pattern substantially as Figure 1 shown.

[0072] Gentisic acid

[0073] 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 gentisate, wherein the crystalline form is a gentisate 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 gentisic acid co-crystal. 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 gentisic acid:

[0074]

[0075] Characterized in that the X-ray powder diffraction (XRPD) pattern includes three or more peaks at 4.4°, 8.7°, 12.9°, 14.9°, 17.3°, 19.5°, 24.8°, 25.7° or 26.3° 2θ (±0.2° 2θ), i.e., Compound I gentisic acid.

[0076] In some embodiments, Compound 1 gentisic acid is characterized by an XRPD pattern comprising four or more peaks at 4.4°, 8.7°, 12.9°, 14.9°, 17.3°, 19.5°, 24.8°, 25.7°, or 26.3° 2θ (±0.2° 2θ). In some embodiments, Compound 1 gentisic acid is characterized by an XRPD pattern comprising five or more peaks at 4.4°, 8.7°, 12.9°, 14.9°, 17.3°, 19.5°, 24.8°, 25.7°, or 26.3° 2θ (±0.2° 2θ). In some embodiments, Compound 1 gentisic acid is characterized by an XRPD pattern comprising six or more peaks at 4.4°, 8.7°, 12.9°, 14.9°, 17.3°, 19.5°, 24.8°, 25.7°, or 26.3° 2θ (±0.2° 2θ). In some embodiments, Compound 1 gentisic acid is characterized by an XRPD pattern comprising seven or more peaks at 4.4°, 8.7°, 12.9°, 14.9°, 17.3°, 19.5°, 24.8°, 25.7°, or 26.3° 2θ (±0.2° 2θ). In some embodiments, Compound 1 gentisic acid is characterized by an XRPD pattern comprising eight or more peaks at 4.4°, 8.7°, 12.9°, 14.9°, 17.3°, 19.5°, 24.8°, 25.7°, or 26.3° 2θ (±0.2° 2θ).

[0077] In some embodiments, Compound I gentisic acid is characterized in that the XRPD pattern includes peaks at 4.4°, 8.7°, and 14.9° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern also includes one or more additional peaks at 12.9°, 17.3°, 19.5°, 24.8°, 25.7°, or 26.3° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern also includes two or more additional peaks at 12.9°, 17.3°, 19.5°, 24.8°, 25.7°, or 26.3° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern also includes three or more additional peaks at 12.9°, 17.3°, 19.5°, 24.8°, 25.7°, or 26.3° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern further comprises four or more additional peaks at 12.9°, 17.3°, 19.5°, 24.8°, 25.7°, or 26.3° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern further comprises five or more additional peaks at 12.9°, 17.3°, 19.5°, 24.8°, 25.7°, or 26.3° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern further comprises additional peaks at 12.9°, 17.3°, 19.5°, 24.8°, 25.7°, and 26.3° 2θ (± 0.2° 2θ).

[0078] In some embodiments, Compound I gentisic acid is characterized in that the XRPD pattern includes peaks at 12.9°, 24.8°, and 25.7° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern also includes one or more additional peaks at 4.4°, 8.7°, 14.9°, 17.3°, 19.5°, or 26.3° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern also includes two or more additional peaks at 4.4°, 8.7°, 14.9°, 24.8°, or 26.3° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern also includes three or more additional peaks at 4.4°, 8.7°, 14.9°, 24.8°, or 26.3° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern further comprises four or more additional peaks at 4.4°, 8.7°, 14.9°, 24.8°, or 26.3° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern further comprises five or more additional peaks at 4.4°, 8.7°, 14.9°, 24.8°, or 26.3° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern further comprises additional peaks at 4.4°, 8.7°, 14.9°, 24.8°, and 26.3° 2θ (± 0.2° 2θ).

[0079] In some embodiments, Compound I gentisic acid is characterized by an XRPD pattern including three or more peaks at 4.4°, 8.7°, 12.9°, 14.9°, 24.8°, or 25.7° 2θ (± 0.2° 2θ). In some embodiments, Compound I gentisic acid is characterized by an XRPD pattern including four or more peaks at 4.4°, 8.7°, 12.9°, 14.9°, 24.8°, or 25.7° 2θ (± 0.2° 2θ). In some embodiments, Compound I gentisic acid is characterized by an XRPD pattern including five or more peaks at 4.4°, 8.7°, 12.9°, 14.9°, 24.8°, or 25.7° 2θ (± 0.2° 2θ). In some embodiments, Compound 1 gentisic acid is characterized by an XRPD pattern including peaks at 4.4°, 8.7°, 12.9°, 14.9°, 24.8°, and 25.7° 2θ (±0.2° 2θ).

[0080] In some embodiments, Compound I gentisic acid is characterized by an XRPD pattern including peaks at 4.4°, 8.7°, 12.9°, 14.9°, 17.3°, 19.5°, 24.8°, 25.7°, and 26.3° 2θ (±0.2° 2θ). In some embodiments, Compound I gentisic acid is characterized by an XRPD pattern substantially as Figure 2In some embodiments, Compound I gentisic acid is characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset temperature of about 178°C. In some embodiments, Compound I gentisic acid is characterized by a DSC thermogram substantially as Figure 3 shown.

[0081] In some embodiments, Compound I gentisic acid is characterized by: (a) an XRPD pattern comprising peaks at 4.4°, 8.7°, 12.9°, 14.9°, 17.3°, 19.5°, 24.8°, 25.7°, and 26.3° 2θ (±0.2° 2θ); and (b) a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset temperature of about 178°C. In some embodiments, Compound I gentisic acid is characterized by: (a) an XRPD pattern substantially as Figure 2 As shown; and (b) the DSC thermogram is substantially as Figure 3 shown.

[0082] In some embodiments, Compound 1 gentisic acid is substantially free of Compound 1 Form I.

[0083] Hippuric acid

[0084] 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 hippurate, wherein the crystalline form is hippurate. 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 hippuric acid co-crystal. 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 hippurate:

[0085]

[0086] Characterized in that the XRPD pattern includes three or more peaks at 2.9°, 5.0°, 7.6°, 10.4°, 12.6°, 17.6°, 19.0°, 25.2° or 28.5° 2θ (±0.2° 2θ), i.e., Compound I hippuric acid.

[0087] In some embodiments, Compound 1 hippuric acid is characterized by an XRPD pattern comprising four or more peaks at 2.9°, 5.0°, 7.6°, 10.4°, 12.6°, 17.6°, 19.0°, 25.2°, or 28.5° 2θ (±0.2° 2θ). In some embodiments, Compound 1 hippuric acid is characterized by an XRPD pattern comprising five or more peaks at 2.9°, 5.0°, 7.6°, 10.4°, 12.6°, 17.6°, 19.0°, 25.2°, or 28.5° 2θ (±0.2° 2θ). In some embodiments, Compound 1 hippuric acid is characterized by an XRPD pattern comprising six or more peaks at 2.9°, 5.0°, 7.6°, 10.4°, 12.6°, 17.6°, 19.0°, 25.2°, or 28.5° 2θ (± 0.2° 2θ). In some embodiments, Compound 1 hippuric acid is characterized by an XRPD pattern comprising seven or more peaks at 2.9°, 5.0°, 7.6°, 10.4°, 12.6°, 17.6°, 19.0°, 25.2°, or 28.5° 2θ (± 0.2° 2θ). In some embodiments, Compound 1 hippuric acid is characterized by an XRPD pattern comprising eight or more peaks at 2.9°, 5.0°, 7.6°, 10.4°, 12.6°, 17.6°, 19.0°, 25.2°, or 28.5° 2θ (±0.2° 2θ).

[0088] In some embodiments, Compound I hippuric acid is characterized in that the XRPD pattern includes peaks at 5.0°, 12.6°, and 25.2°2θ (±0.2°2θ). In some embodiments, the XRPD pattern also includes one or more additional peaks at 2.9°, 7.6°, 10.4°, 17.6°, 19.0°, or 28.5°2θ (±0.2°2θ). In some embodiments, the XRPD pattern also includes two or more additional peaks at 2.9°, 7.6°, 10.4°, 17.6°, 19.0°, or 28.5°2θ (±0.2°2θ). In some embodiments, the XRPD pattern also includes three or more additional peaks at 2.9°, 7.6°, 10.4°, 17.6°, 19.0°, or 28.5°2θ (±0.2°2θ). In some embodiments, the XRPD pattern further comprises four or more additional peaks at 2.9°, 7.6°, 10.4°, 17.6°, 19.0°, or 28.5° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern further comprises five or more additional peaks at 2.9°, 7.6°, 10.4°, 17.6°, 19.0°, or 28.5° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern further comprises additional peaks at 2.9°, 7.6°, 10.4°, 17.6°, 19.0°, and 28.5° 2θ (± 0.2° 2θ).

[0089] In some embodiments, Compound I hippuric acid is characterized in that the XRPD pattern includes peaks at 2.9°, 7.6°, and 19.0° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern also includes one or more additional peaks at 5.0°, 10.4°, 12.6°, 17.6°, 25.2°, or 28.5° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern also includes two or more additional peaks at 5.0°, 10.4°, 12.6°, 17.6°, 25.2°, or 28.5° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern also includes three or more additional peaks at 5.0°, 10.4°, 12.6°, 17.6°, 25.2°, or 28.5° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern further comprises four or more additional peaks at 5.0°, 10.4°, 12.6°, 17.6°, 25.2°, or 28.5° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern further comprises five or more additional peaks at 5.0°, 10.4°, 12.6°, 17.6°, 25.2°, or 28.5° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern further comprises additional peaks at 5.0°, 10.4°, 12.6°, 17.6°, 25.2°, and 28.5° 2θ (± 0.2° 2θ).

[0090] In some embodiments, Compound I hippuric acid is characterized by an XRPD pattern including peaks at 2.9°, 5.0°, 7.6°, 10.4°, 12.6°, 19.0°, 17.6°, 25.2°, and 28.5° 2θ (±0.2° 2θ). In some embodiments, Compound I hippuric acid is characterized by an XRPD pattern substantially as Figure 6 In some embodiments, Compound I hippuric acid is characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset temperature of about 127°C. In some embodiments, Compound I hippuric acid is characterized by a DSC thermogram substantially as shown in Figure 7 shown.

[0091] In some embodiments, Compound I hippuric acid is characterized by: (a) an XRPD pattern comprising peaks at 2.9°, 5.0°, 7.6°, 10.4°, 12.6°, 19.0°, 17.6°, 25.2°, and 28.5° 2θ (±0.2° 2θ); and (b) a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset temperature of about 127°C. In some embodiments, Compound I hippuric acid is characterized by: (a) an XRPD pattern substantially as Figure 6 As shown; and (b) the DSC thermogram is substantially as Figure 7 shown.

[0092] In some embodiments, Compound 1 hippuric acid is substantially free of Compound 1 Form I.

[0093] Phosphate Form I

[0094] 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 phosphonate, wherein the crystalline form is phosphate 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, wherein the crystalline form is a Compound 1 Phosphate Form I co-crystal. 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 phosphoric acid:

[0095]

[0096] Characterized by an XRPD pattern comprising three or more peaks at 3.7°, 6.1°, 7.1°, 12.1°, 14.2°, 21.6°, 24.0°, 27.4° or 28.2° 2θ (±0.2° 2θ), i.e., phosphate Form I.

[0097] In some embodiments, the phosphate salt form I is characterized in that the XRPD pattern includes four or more peaks at 3.7°, 6.1°, 7.1°, 12.1°, 14.2°, 21.6°, 24.0°, 27.4°, or 28.2° 2θ (± 0.2° 2θ). In some embodiments, the phosphate salt form I is characterized in that the XRPD pattern includes five or more peaks at 3.7°, 6.1°, 7.1°, 12.1°, 14.2°, 21.6°, 24.0°, 27.4°, or 28.2° 2θ (± 0.2° 2θ). In some embodiments, the phosphate salt form I is characterized in that the XRPD pattern includes six or more peaks at 3.7°, 6.1°, 7.1°, 12.1°, 14.2°, 21.6°, 24.0°, 27.4°, or 28.2° 2θ (± 0.2° 2θ). In some embodiments, the phosphate salt Form I is characterized by an XRPD pattern comprising seven or more peaks at 3.7°, 6.1°, 7.1°, 12.1°, 14.2°, 21.6°, 24.0°, 27.4°, or 28.2° 2θ (± 0.2° 2θ). In some embodiments, the phosphate salt Form I is characterized by an XRPD pattern comprising eight or more peaks at 3.7°, 6.1°, 7.1°, 12.1°, 14.2°, 21.6°, 24.0°, 27.4°, or 28.2° 2θ (± 0.2° 2θ).

[0098] In some embodiments, the phosphate form I is characterized in that the XRPD pattern includes peaks at 3.7 °, 6.1 °, and 7.1 ° 2θ (± 0.2 ° 2θ). In some embodiments, the XRPD pattern also includes one or more additional peaks at 12.1 °, 14.2 °, 21.6 °, 24.0 °, 27.4 °, or 28.2 ° 2θ (± 0.2 ° 2θ). In some embodiments, the XRPD pattern also includes two or more additional peaks at 12.1 °, 14.2 °, 21.6 °, 24.0 °, 27.4 °, or 28.2 ° 2θ (± 0.2 ° 2θ). In some embodiments, the XRPD pattern also includes three or more additional peaks at 12.1 °, 14.2 °, 21.6 °, 24.0 °, 27.4 °, or 28.2 ° 2θ (± 0.2 ° 2θ). In some embodiments, the XRPD pattern further comprises four or more additional peaks at 12.1°, 14.2°, 21.6°, 24.0°, 27.4°, or 28.2° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern further comprises five or more additional peaks at 12.1°, 14.2°, 21.6°, 24.0°, 27.4°, or 28.2° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern further comprises additional peaks at 12.1°, 14.2°, 21.6°, 24.0°, 27.4°, and 28.2° 2θ (± 0.2° 2θ).

[0099] In some embodiments, the phosphate form I is characterized in that the XRPD pattern includes peaks at 14.2 °, 27.4 °, and 28.2 ° 2θ (± 0.2 ° 2θ). In some embodiments, the XRPD pattern also includes one or more additional peaks at 3.7 °, 6.1 °, 7.1 °, 12.1 °, 21.6 °, or 24.0 ° 2θ (± 0.2 ° 2θ). In some embodiments, the XRPD pattern also includes two or more additional peaks at 3.7 °, 6.1 °, 7.1 °, 12.1 °, 21.6 °, or 24.0 ° 2θ (± 0.2 ° 2θ). In some embodiments, the XRPD pattern also includes three or more additional peaks at 3.7 °, 6.1 °, 7.1 °, 12.1 °, 21.6 °, or 24.0 ° 2θ (± 0.2 ° 2θ). In some embodiments, the XRPD pattern further comprises four or more additional peaks at 3.7°, 6.1°, 7.1°, 12.1°, 21.6°, or 24.0° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern further comprises five or more additional peaks at 3.7°, 6.1°, 7.1°, 12.1°, 21.6°, or 24.0° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern further comprises additional peaks at 3.7°, 6.1°, 7.1°, 12.1°, 21.6°, and 24.0° 2θ (± 0.2° 2θ).

[0100] In some embodiments, the phosphate salt form I is characterized in that the XRPD pattern includes three or more peaks at 3.7°, 6.1°, 7.1°, 14.2°, 27.4°, or 28.2° 2θ (± 0.2° 2θ). In some embodiments, the phosphate salt form I is characterized in that the XRPD pattern includes four or more peaks at 3.7°, 6.1°, 7.1°, 14.2°, 27.4°, or 28.2° 2θ (± 0.2° 2θ). In some embodiments, the phosphate salt form I is characterized in that the XRPD pattern includes five or more peaks at 3.7°, 6.1°, 7.1°, 14.2°, 27.4°, or 28.2° 2θ (± 0.2° 2θ). In some embodiments, phosphate salt Form I is characterized by an XRPD pattern including peaks at 3.7°, 6.1°, 7.1°, 14.2°, 27.4°, and 28.2° 2Θ (± 0.2° 2Θ).

[0101] In some embodiments, the phosphate salt Form I is characterized by an XRPD pattern comprising peaks at 3.7°, 6.1°, 7.1°, 12.1°, 14.2°, 21.6°, 24.0°, 27.4°, and 28.2° 2θ (±0.2° 2θ). In some embodiments, the phosphate salt Form I is characterized by an XRPD pattern substantially as Fig.10In some embodiments, the phosphate salt form I is characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset temperature of about 43°C. In some embodiments, the DSC thermogram has a second endotherm with an onset temperature of about 118°C. In some embodiments, the DSC thermogram has a third endotherm with an onset temperature of about 202°C. In some embodiments, the phosphate salt form I is characterized by a differential scanning calorimetry (DSC) thermogram having endotherms with onset temperatures of about 43°C, about 118°C, and about 202°C. In some embodiments, the phosphate salt form I is characterized by a DSC thermogram substantially as Fig.11 shown.

[0102] In some embodiments, the phosphate salt Form I is characterized by: (a) an XRPD pattern comprising peaks at 3.7°, 6.1°, 7.1°, 12.1°, 14.2°, 21.6°, 24.0°, 27.4°, and 28.2° 2θ (±0.2° 2θ); and (b) a differential scanning calorimetry (DSC) thermogram having endotherms with onset temperatures of about 43° C., about 118° C., and about 202° C. In some embodiments, the phosphate salt Form I is characterized by: (a) an XRPD pattern substantially as Fig.10 As shown; and (b) the DSC thermogram is substantially as Fig.11 shown.

[0103] In some embodiments, Compound 1 Phosphate Form I is substantially free of Compound 1 Form I.

[0104] Phosphate Form II

[0105] 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 phosphate, wherein the crystalline form is phosphate 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, wherein the crystalline form is a Compound I phosphate Form II co-crystal. 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 phosphate:

[0106]

[0107] Characterized by an XRPD pattern comprising three or more peaks at 5.4°, 6.3°, 15.8°, 18.1°, 18.9°, 20.6°, 24.1°, 26.7° or 27.4° 2θ (±0.2° 2θ), i.e., phosphate Form II.

[0108] In some embodiments, the phosphate salt Form II is characterized by an XRPD pattern comprising four or more peaks at 5.4°, 6.3°, 15.8°, 18.1°, 18.9°, 20.6°, 24.1°, 26.7°, or 27.4° 2θ (± 0.2° 2θ). In some embodiments, the phosphate salt Form II is characterized by an XRPD pattern comprising five or more peaks at 5.4°, 6.3°, 15.8°, 18.1°, 18.9°, 20.6°, 24.1°, 26.7°, or 27.4° 2θ (± 0.2° 2θ). In some embodiments, the phosphate salt Form II is characterized by an XRPD pattern comprising six or more peaks at 5.4°, 6.3°, 15.8°, 18.1°, 18.9°, 20.6°, 24.1°, 26.7°, or 27.4° 2θ (± 0.2° 2θ). In some embodiments, the phosphate salt Form II is characterized by an XRPD pattern comprising seven or more peaks at 5.4°, 6.3°, 15.8°, 18.1°, 18.9°, 20.6°, 24.1°, 26.7°, or 27.4° 2θ (± 0.2° 2θ). In some embodiments, phosphate Form II is characterized by an XRPD pattern comprising eight or more peaks at 5.4°, 6.3°, 15.8°, 18.1°, 18.9°, 20.6°, 24.1°, 26.7°, or 27.4° 2θ (±0.2° 2θ).

[0109] In some embodiments, the phosphate form II is characterized in that the XRPD pattern includes peaks at 5.4 °, 6.3 °, and 26.7 ° 2θ (± 0.2 ° 2θ). In some embodiments, the XRPD pattern also includes one or more additional peaks at 15.8 °, 18.1 °, 18.9 °, 20.6 °, 24.1 °, or 27.4 ° 2θ (± 0.2 ° 2θ). In some embodiments, the XRPD pattern also includes two or more additional peaks at 15.8 °, 18.1 °, 18.9 °, 20.6 °, 24.1 °, or 27.4 ° 2θ (± 0.2 ° 2θ). In some embodiments, the XRPD pattern also includes three or more additional peaks at 15.8 °, 18.1 °, 18.9 °, 20.6 °, 24.1 °, or 27.4 ° 2θ (± 0.2 ° 2θ). In some embodiments, the XRPD pattern further comprises four or more additional peaks at 15.8°, 18.1°, 18.9°, 20.6°, 24.1°, or 27.4° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern further comprises five or more additional peaks at 15.8°, 18.1°, 18.9°, 20.6°, 24.1°, or 27.4° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern further comprises additional peaks at 15.8°, 18.1°, 18.9°, 20.6°, 24.1°, and 27.4° 2θ (± 0.2° 2θ).

[0110] In some embodiments, the phosphate form II is characterized in that the XRPD pattern includes peaks at 15.8 °, 18.1 °, and 18.9 ° 2θ (± 0.2 ° 2θ). In some embodiments, the XRPD pattern also includes one or more additional peaks at 5.4 °, 6.3 °, 20.6 °, 24.1 °, 26.7 °, or 27.4 ° 2θ (± 0.2 ° 2θ). In some embodiments, the XRPD pattern also includes two or more additional peaks at 5.4 °, 6.3 °, 20.6 °, 24.1 °, 26.7 °, or 27.4 ° 2θ (± 0.2 ° 2θ). In some embodiments, the XRPD pattern also includes three or more additional peaks at 5.4 °, 6.3 °, 20.6 °, 24.1 °, 26.7 °, or 27.4 ° 2θ (± 0.2 ° 2θ). In some embodiments, the XRPD pattern further comprises four or more additional peaks at 5.4°, 6.3°, 20.6°, 24.1°, 26.7°, or 27.4° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern further comprises five or more additional peaks at 5.4°, 6.3°, 20.6°, 24.1°, 26.7°, or 27.4° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern further comprises additional peaks at 5.4°, 6.3°, 20.6°, 24.1°, 26.7°, and 27.4° 2θ (± 0.2° 2θ).

[0111] In some embodiments, the phosphate form II is characterized in that the XRPD pattern includes three or more peaks at 5.4°, 6.3°, 15.8°, 18.1°, 18.9°, or 26.7° 2θ (± 0.2° 2θ). In some embodiments, the phosphate form II is characterized in that the XRPD pattern includes four or more peaks at 5.4°, 6.3°, 15.8°, 18.1°, 18.9°, or 26.7° 2θ (± 0.2° 2θ). In some embodiments, the phosphate form II is characterized in that the XRPD pattern includes five or more peaks at 5.4°, 6.3°, 15.8°, 18.1°, 18.9°, or 26.7° 2θ (± 0.2° 2θ). In some embodiments, phosphate salt Form II is characterized by an XRPD pattern including peaks at 5.4°, 6.3°, 15.8°, 18.1°, 18.9°, and 26.7° 2Θ (± 0.2° 2Θ).

[0112] In some embodiments, the phosphate salt Form II is characterized by an XRPD pattern comprising peaks at 5.4°, 6.3°, 15.8°, 18.1°, 18.9°, 20.6°, 24.1°, 26.7°, and 27.4° 2θ (± 0.2° 2θ). In some embodiments, the phosphate salt Form II is characterized by an XRPD pattern substantially as Fig.13 In some embodiments, the phosphate salt form II is characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset temperature of about 42°C. In some embodiments, the DSC thermogram has a second endotherm with an onset temperature of about 95°C. In some embodiments, the phosphate salt form II is characterized by a differential scanning calorimetry (DSC) thermogram having endotherms with onset temperatures of about 42°C and about 95°C. In some embodiments, the phosphate salt form II is characterized by a DSC thermogram substantially as Fig.14 shown.

[0113] In some embodiments, the phosphate salt Form II is characterized by: (a) an XRPD pattern comprising peaks at 5.4°, 6.3°, 15.8°, 18.1°, 18.9°, 20.6°, 24.1°, 26.7°, and 27.4° 2θ (±0.2° 2θ); and (b) a differential scanning calorimetry (DSC) thermogram having endotherms with onset temperatures of about 42° C. and about 95° C. In some embodiments, the phosphate salt Form II is characterized by: (a) an XRPD pattern substantially as Fig.13 As shown; and (b) the DSC thermogram is substantially as Fig.14 shown.

[0114] In some embodiments, Compound 1 Phosphate Form II is substantially free of Compound 1 Form I.

[0115] Succinic acid

[0116] 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 succinate, wherein the crystalline form is a succinate 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 succinic acid co-crystal. 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 succinic acid:

[0117]

[0118] Characterized in that the XRPD pattern includes three or more peaks at 4.6°, 6.8°, 9.3°, 13.2°, 17.5°, 18.7°, 19.0°, 25.7° or 27.0° 2θ (±0.2° 2θ), i.e., Compound I succinic acid.

[0119] In some embodiments, Compound 1 succinic acid is characterized by an XRPD pattern comprising four or more peaks at 4.6°, 6.8°, 9.3°, 13.2°, 17.5°, 18.7°, 19.0°, 25.7°, or 27.0° 2θ (±0.2° 2θ). In some embodiments, Compound 1 succinic acid is characterized by an XRPD pattern comprising five or more peaks at 4.6°, 6.8°, 9.3°, 13.2°, 17.5°, 18.7°, 19.0°, 25.7°, or 27.0° 2θ (±0.2° 2θ). In some embodiments, Compound 1 succinic acid is characterized by an XRPD pattern comprising six or more peaks at 4.6°, 6.8°, 9.3°, 13.2°, 17.5°, 18.7°, 19.0°, 25.7°, or 27.0° 2θ (±0.2° 2θ). In some embodiments, Compound 1 succinic acid is characterized by an XRPD pattern comprising seven or more peaks at 4.6°, 6.8°, 9.3°, 13.2°, 17.5°, 18.7°, 19.0°, 25.7°, or 27.0° 2θ (±0.2° 2θ). In some embodiments, Compound 1 succinic acid is characterized by an XRPD pattern comprising eight or more peaks at 4.6°, 6.8°, 9.3°, 13.2°, 17.5°, 18.7°, 19.0°, 25.7°, or 27.0° 2θ (±0.2° 2θ).

[0120] In some embodiments, Compound 1 succinic acid is characterized in that the XRPD pattern includes peaks at 4.6°, 6.8°, and 9.3° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern also includes one or more additional peaks at 13.2°, 17.5°, 18.7°, 19.0°, 25.7°, or 27.0° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern also includes two or more additional peaks at 13.2°, 17.5°, 18.7°, 19.0°, 25.7°, or 27.0° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern also includes three or more additional peaks at 13.2°, 17.5°, 18.7°, 19.0°, 25.7°, or 27.0° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern further comprises four or more additional peaks at 13.2°, 17.5°, 18.7°, 19.0°, 25.7°, or 27.0° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern further comprises five or more additional peaks at 13.2°, 17.5°, 18.7°, 19.0°, 25.7°, or 27.0° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern further comprises additional peaks at 13.2°, 17.5°, 18.7°, 19.0°, 25.7°, and 27.0° 2θ (± 0.2° 2θ).

[0121] In some embodiments, Compound 1 succinic acid is characterized in that the XRPD pattern includes peaks at 18.7°, 19.0°, and 25.7° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern also includes one or more additional peaks at 4.6°, 6.8°, 9.3°, 13.2°, 17.5°, or 27.0° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern also includes two or more additional peaks at 4.6°, 6.8°, 9.3°, 13.2°, 17.5°, or 27.0° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern also includes three or more additional peaks at 4.6°, 6.8°, 9.3°, 13.2°, 17.5°, or 27.0° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern further comprises four or more additional peaks at 4.6°, 6.8°, 9.3°, 13.2°, 17.5°, or 27.0° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern further comprises five or more additional peaks at 4.6°, 6.8°, 9.3°, 13.2°, 17.5°, or 27.0° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern further comprises additional peaks at 4.6°, 6.8°, 9.3°, 13.2°, 17.5°, and 27.0° 2θ (± 0.2° 2θ).

[0122] In some embodiments, Compound 1 succinic acid is characterized by an XRPD pattern including three or more peaks at 4.6°, 6.8°, 9.3°, 18.7°, 19.0°, or 25.7° 2θ (± 0.2° 2θ). In some embodiments, Compound 1 succinic acid is characterized by an XRPD pattern including four or more peaks at 4.6°, 6.8°, 9.3°, 18.7°, 19.0°, or 25.7° 2θ (± 0.2° 2θ). In some embodiments, Compound 1 succinic acid is characterized by an XRPD pattern including five or more peaks at 4.6°, 6.8°, 9.3°, 18.7°, 19.0°, or 25.7° 2θ (± 0.2° 2θ). In some embodiments, Compound 1 succinic acid is characterized by an XRPD pattern including peaks at 4.6°, 6.8°, 9.3°, 18.7°, 19.0°, and 25.7° 2θ (±0.2° 2θ).

[0123] In some embodiments, Compound 1 succinic acid is characterized by an XRPD pattern including peaks at 4.6°, 6.8°, 9.3°, 13.2°, 17.5°, 18.7°, 19.0°, 25.7°, and 27.0° 2θ (±0.2° 2θ). In some embodiments, Compound 1 succinic acid is characterized by an XRPD pattern substantially as Fig.16 In some embodiments, Compound I succinic acid is characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset temperature of about 96°C. In some embodiments, the DSC thermogram has a second endotherm with an onset temperature of about 115°C. In some embodiments, Compound I succinic acid is characterized by a differential scanning calorimetry (DSC) thermogram having endotherms with onset temperatures of about 96°C and about 115°C. In some embodiments, Compound I succinic acid is characterized by a DSC thermogram substantially as shown. Fig.17 shown.

[0124] In some embodiments, Compound I succinic acid is characterized by: (a) an XRPD pattern comprising peaks at 4.6°, 6.8°, 9.3°, 13.2°, 17.5°, 18.7°, 19.0°, 25.7°, and 27.0° 2θ (±0.2° 2θ); and (b) a differential scanning calorimetry (DSC) thermogram having endotherms with onset temperatures of about 96°C and about 115°C. In some embodiments, Compound I succinic acid is characterized by: (a) an XRPD pattern substantially as Fig.16 As shown; and (b) the DSC thermogram is substantially as Fig.17 shown.

[0125] In some embodiments, Compound 1 succinate is substantially free of Compound 1 Form I.

[0126] Ethylenedisulfonic acid form I

[0127] 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 edisylate, wherein the crystalline form is edisylate 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, wherein the crystalline form is Compound 1 edisylate Form I co-crystal. 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 edisylate:

[0128]

[0129] Characterized in that the XRPD pattern includes three or more peaks at 4.4°, 7.9°, 8.7°, 13.0°, 16.6°, 20.6°, 21.1°, 22.1° or 26.0° 2θ (±0.2° 2θ), i.e., Compound I ethanedisulfonic acid Form I.

[0130] In some embodiments, Compound 1 edisylate Form I is characterized by an XRPD pattern comprising four or more peaks at 4.4°, 7.9°, 8.7°, 13.0°, 16.6°, 20.6°, 21.1°, 22.1°, or 26.0° 2θ (±0.2° 2θ). In some embodiments, Compound 1 edisylate Form I is characterized by an XRPD pattern comprising five or more peaks at 4.4°, 7.9°, 8.7°, 13.0°, 16.6°, 20.6°, 21.1°, 22.1°, or 26.0° 2θ (±0.2° 2θ). In some embodiments, Compound 1 edisylate Form I is characterized by an XRPD pattern comprising six or more peaks at 4.4°, 7.9°, 8.7°, 13.0°, 16.6°, 20.6°, 21.1°, 22.1°, or 26.0° 2θ (±0.2° 2θ). In some embodiments, Compound 1 edisylate Form I is characterized by an XRPD pattern comprising seven or more peaks at 4.4°, 7.9°, 8.7°, 13.0°, 16.6°, 20.6°, 21.1°, 22.1°, or 26.0° 2θ (±0.2° 2θ). In some embodiments, Compound 1 edisylate Form I is characterized by an XRPD pattern comprising eight or more peaks at 4.4°, 7.9°, 8.7°, 13.0°, 16.6°, 20.6°, 21.1°, 22.1°, or 26.0° 2θ (±0.2° 2θ).

[0131] In some embodiments, Compound I edisulphonic acid Form I is characterized in that the XRPD pattern includes peaks at 4.4°, 8.7°, and 22.1° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern also includes one or more additional peaks at 7.9°, 13.0°, 16.6°, 20.6°, 21.1°, or 26.0° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern also includes two or more additional peaks at 7.9°, 13.0°, 16.6°, 20.6°, 21.1°, or 26.0° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern also includes three or more additional peaks at 7.9°, 13.0°, 16.6°, 20.6°, 21.1°, or 26.0° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern further comprises four or more additional peaks at 7.9°, 13.0°, 16.6°, 20.6°, 21.1°, or 26.0° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern further comprises five or more additional peaks at 7.9°, 13.0°, 16.6°, 20.6°, 21.1°, or 26.0° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern further comprises additional peaks at 7.9°, 13.0°, 16.6°, 20.6°, 21.1°, and 26.0° 2θ (± 0.2° 2θ).

[0132] In some embodiments, Compound I edisulphonic acid Form I is characterized in that the XRPD pattern includes peaks at 7.9°, 13.0°, and 21.1° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern also includes one or more additional peaks at 4.4°, 8.7°, 16.6°, 20.6°, 22.1°, or 26.0° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern also includes two or more additional peaks at 4.4°, 8.7°, 16.6°, 20.6°, 22.1°, or 26.0° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern also includes three or more additional peaks at 4.4°, 8.7°, 16.6°, 20.6°, 22.1°, or 26.0° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern further comprises four or more additional peaks at 4.4°, 8.7°, 16.6°, 20.6°, 22.1°, or 26.0° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern further comprises five or more additional peaks at 4.4°, 8.7°, 16.6°, 20.6°, 22.1°, or 26.0° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern further comprises additional peaks at 4.4°, 8.7°, 16.6°, 20.6°, 22.1°, and 26.0° 2θ (± 0.2° 2θ).

[0133] In some embodiments, Compound 1 edisylate Form I is characterized by an XRPD pattern comprising three or more peaks at 4.4°, 7.9°, 8.7°, 13.0°, 21.1°, or 22.1° 2θ (± 0.2° 2θ). In some embodiments, Compound 1 edisylate Form I is characterized by an XRPD pattern comprising four or more peaks at 4.4°, 7.9°, 8.7°, 13.0°, 21.1°, or 22.1° 2θ (± 0.2° 2θ). In some embodiments, Compound 1 edisylate Form I is characterized by an XRPD pattern comprising five or more peaks at 4.4°, 7.9°, 8.7°, 13.0°, 21.1°, or 22.1° 2θ (± 0.2° 2θ). In some embodiments, Compound 1 edisylate Form I is characterized by an XRPD pattern including peaks at 4.4°, 7.9°, 8.7°, 13.0°, 21.1°, and 22.1° 2θ (±0.2° 2θ).

[0134] In some embodiments, Compound 1 edisylate Form I is characterized by an XRPD pattern comprising peaks at 4.4°, 7.9°, 8.7°, 13.0°, 16.6°, 20.6°, 21.1°, 22.1°, and 26.0° 2θ (±0.2° 2θ). In some embodiments, Compound 1 edisylate Form I is characterized by an XRPD pattern substantially as Fig. 20 shown.

[0135] In some embodiments, Compound 1 ethanesulfonic acid Form I is substantially free of Compound 1 Form I.

[0136] Ethylenedisulfonic acid form II

[0137] 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 edisulphonate, wherein the crystalline form is edisulphonate 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, wherein the crystalline form is Compound I edisulphonic acid Form II co-crystal. 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 edisulphonic acid:

[0138]

[0139] Characterized in that the XRPD pattern includes three or more peaks at 4.5°, 5.6°, 8.4°, 12.9°, 13.4°, 16.6°, 17.9°, 18.3° or 22.2° 2θ (±0.2° 2θ), i.e., Compound I ethanedisulfonic acid Form II.

[0140] In some embodiments, Compound 1 edisylate Form II is characterized by an XRPD pattern comprising four or more peaks at 4.5°, 5.6°, 8.4°, 12.9°, 13.4°, 16.6°, 17.9°, 18.3°, or 22.2° 2θ (±0.2° 2θ). In some embodiments, Compound 1 edisylate Form II is characterized by an XRPD pattern comprising five or more peaks at 4.5°, 5.6°, 8.4°, 12.9°, 13.4°, 16.6°, 17.9°, 18.3°, or 22.2° 2θ (±0.2° 2θ). In some embodiments, Compound 1 edisylate Form II is characterized by an XRPD pattern comprising six or more peaks at 4.5°, 5.6°, 8.4°, 12.9°, 13.4°, 16.6°, 17.9°, 18.3°, or 22.2° 2θ (±0.2° 2θ). In some embodiments, Compound 1 edisylate Form II is characterized by an XRPD pattern comprising seven or more peaks at 4.5°, 5.6°, 8.4°, 12.9°, 13.4°, 16.6°, 17.9°, 18.3°, or 22.2° 2θ (±0.2° 2θ). In some embodiments, Compound 1 edisylate Form II is characterized by an XRPD pattern comprising eight or more peaks at 4.5°, 5.6°, 8.4°, 12.9°, 13.4°, 16.6°, 17.9°, 18.3°, or 22.2° 2θ (±0.2° 2θ).

[0141] In some embodiments, Compound I edisulphonic acid Form II is characterized in that the XRPD pattern includes peaks at 4.5°, 8.4°, and 22.2° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern also includes one or more additional peaks at 5.6°, 12.9°, 13.4°, 16.6°, 17.9°, or 18.3° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern also includes two or more additional peaks at 5.6°, 12.9°, 13.4°, 16.6°, 17.9°, or 18.3° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern also includes three or more additional peaks at 5.6°, 12.9°, 13.4°, 16.6°, 17.9°, or 18.3° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern further comprises four or more additional peaks at 5.6°, 12.9°, 13.4°, 16.6°, 17.9°, or 18.3° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern further comprises five or more additional peaks at 5.6°, 12.9°, 13.4°, 16.6°, 17.9°, or 18.3° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern further comprises additional peaks at 5.6°, 12.9°, 13.4°, 16.6°, 17.9°, and 18.3° 2θ (± 0.2° 2θ).

[0142] In some embodiments, Compound I edisulphonic acid Form II is characterized in that the XRPD pattern includes peaks at 12.9°, 13.4°, and 16.6° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern also includes one or more additional peaks at 4.5°, 5.6°, 8.4°, 17.9°, 18.3°, or 22.2° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern also includes two or more additional peaks at 4.5°, 5.6°, 8.4°, 17.9°, 18.3°, or 22.2° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern also includes three or more additional peaks at 4.5°, 5.6°, 8.4°, 17.9°, 18.3°, or 22.2° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern further comprises four or more additional peaks at 4.5°, 5.6°, 8.4°, 17.9°, 18.3°, or 22.2° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern further comprises five or more additional peaks at 4.5°, 5.6°, 8.4°, 17.9°, 18.3°, or 22.2° 2θ (± 0.2° 2θ). In some embodiments, the XRPD pattern further comprises additional peaks at 4.5°, 5.6°, 8.4°, 17.9°, 18.3°, and 22.2° 2θ (± 0.2° 2θ).

[0143] In some embodiments, Compound I ethanedisulfonic acid Form II is characterized by an XRPD pattern comprising three or more peaks at 4.5°, 8.4°, 12.9°, 13.4°, 16.6°, or 22.2° 2θ (± 0.2° 2θ). In some embodiments, Compound I ethanedisulfonic acid Form II is characterized by an XRPD pattern comprising four or more peaks at 4.5°, 8.4°, 12.9°, 13.4°, 16.6°, or 22.2° 2θ (± 0.2° 2θ). In some embodiments, Compound I ethanedisulfonic acid Form II is characterized by an XRPD pattern comprising five or more peaks at 4.5°, 8.4°, 12.9°, 13.4°, 16.6°, or 22.2° 2θ (± 0.2° 2θ). In some embodiments, Compound 1 edisylate Form II is characterized by an XRPD pattern including peaks at 4.5°, 8.4°, 12.9°, 13.4°, 16.6°, and 22.2° 2θ (±0.2° 2θ).

[0144] In some embodiments, Compound I edisylate Form II is characterized by an XRPD pattern comprising peaks at 4.5°, 5.6°, 8.4°, 12.9°, 13.4°, 16.6°, 17.9°, 18.3°, and 22.2° 2θ (±0.2° 2θ). In some embodiments, Compound I edisylate Form II is characterized by an XRPD pattern substantially as Fig.21 shown.

[0145] In some embodiments, Compound 1 edisylate Form II is substantially free of Compound 1 Form I.

[0146] IV. Methods for Preparing Solid Forms of Compound I

[0147] 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 two-solvent system by dissolving Compound 1 in a solvent and then adding an anti-solvent to the mixture to allow Compound 1 to crystallize.

[0148] The solvent can be any solvent suitable for forming a solution. Generally, the solvent can be a polar solvent, and the polar solvent is a protic solvent in some embodiments. Other suitable solvents include non-polar solvents. Suitable solvents include but are not limited to water, alkanes (such as heptane, hexane and cyclohexane), petroleum ether, C1-C3 alcohol (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, alkanones (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 1,4-dioxane), aromatic compounds (such as benzene and toluene), halogenated solvents (such as methylene chloride, chloroform and carbon tetrachloride, dimethyl sulfoxide (DMSO) and dimethylformamide (DMF)). Suitable solvents also include, but are not limited to, halogenated C1-C3 alcohols (trifluoromethanol, trifluoroethanol (TFE), hexafluoroisopropanol (HFIPA)). For example, the solvent 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, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran, 1,2-dimethoxyethane and 1,4-dioxane, chloroform and carbon tetrachloride.

[0149] Two or more solvents can be used in the 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 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).

[0150] 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, equal to 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 temperature of the reaction mixture is about 20°C, or 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or about 100°C. The temperature of the reaction mixture may also be about 20°C, 15, 10, 5, 0, -5, -10, -20, -30, -40, -50, -60, -70 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, the crystalline form of Compound I may be heated to above about 100°C such that one crystalline form of Compound I forms a second crystalline form of Compound I.

[0151] The method for preparing a solid form of Compound I may include a number of other steps. For example, the solvent may be evaporated, seed crystals 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, 10, 5, 0, -5, -10, -20, -30, -40, -50, -60, -70, or about -78°C. The temperature of the reaction mixture may change at any suitable rate. For example, the rate of temperature change may be about 0.1°C / min to about 10°C / min.

[0152] The method of preparing the crystalline form of Compound 1 can be carried out for any suitable time. For example, the time can be several minutes, several hours, or several days. In some embodiments, the time can be several hours, 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, equal to about atmospheric pressure, or above atmospheric pressure.

[0153] Crystallization can be induced by methods known in the art, for example by mechanical means, such as scraping or rubbing the contact surface of the reaction vessel with, for example, 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 can also include crystallizing seed crystals of Compound 1.

[0154] Isolation of the desired crystalline form can be achieved by removing the solvent and precipitation solvent from the crystals. Generally, this is performed by known methods, such as filtering, suction filtration, decanting or centrifuging. Further separation can be achieved by removing any excess solvent from the crystalline form by methods known to those skilled in the art (e.g., applying vacuum and / or by heating).

[0155] Form I

[0156] Crystalline Compound 1 Form I can be prepared by a variety of methods. In some embodiments, the present disclosure provides methods for 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 a solvent.

[0157] In some embodiments, the solvent can be ethyl acetate.

[0158] The method of preparing Compound 1 Form I may include a number of additional 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.

[0159] Gentisic acid

[0160] Crystalline Compound 1 gentisic acid can be prepared from Compound 1 Form I by dissolving Compound 1 Form I and gentisic acid in a solvent. In some embodiments, the present disclosure provides a method for preparing crystalline Compound 1 gentisic acid, comprising forming a mixture of Compound 1 Form I, gentisic acid, and a solvent under conditions suitable for preparing Compound 1 gentisic acid. In some embodiments, Compound 1 Form I is dissolved in a solvent. In some embodiments, the solvent can be a polar aprotic solvent. In some embodiments, the solvent can be acetonitrile.

[0161] The method may include multiple 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.

[0162] Hippuric acid

[0163] Crystalline Compound 1 hippuric acid can be prepared from Compound 1 Form I by dissolving Compound 1 Form I and hippuric acid in a solvent. In some embodiments, the present disclosure provides a method for preparing crystalline Compound 1 hippuric acid, comprising forming a mixture of Compound 1 Form I, hippuric acid, and a solvent under conditions suitable for preparing Compound 1 hippuric acid. In some embodiments, Compound 1 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.

[0164] The method may include multiple 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.

[0165] Phosphate Form I

[0166] Crystalline Compound 1 Phosphate Form I can be prepared from Compound 1 Form I by dissolving Compound 1 Form I and phosphoric acid in a solvent. In some embodiments, the present disclosure provides methods of preparing crystalline Compound 1 Phosphate, comprising forming a mixture of Compound 1 Form I, phosphoric acid, and a solvent under conditions suitable for preparing Form I. In some embodiments, Compound 1 Form I is dissolved in a solvent. In some embodiments, the solvent can be a polar aprotic solvent. In some embodiments, the solvent can be acetone.

[0167] The method may include a number of additional steps. In some embodiments, the reaction mixture may be triturated with a solvent mixture of acetonitrile and isopropanol.

[0168] Phosphate Form II

[0169] Crystalline Compound I Phosphate Form II can be prepared from Compound I Form I by dissolving Compound I Form I and phosphoric acid in a solvent. In some embodiments, the present disclosure provides a method for preparing crystalline Compound I Form II, comprising forming a mixture of Compound I Form I, phosphoric acid, and a solvent under conditions suitable for preparing Compound I Phosphate Form II. In some embodiments, Compound I Form I is dissolved in a solvent. In some embodiments, the solvent may be a polar protic solvent. In some embodiments, the solvent may be tert-butyl alcohol, n-propyl alcohol, isopropyl alcohol, ethanol, or methanol. In some embodiments, the solvent may be isopropyl alcohol.

[0170] The method for preparing Compound I Phosphate Form II may include a number of additional steps. For example, the reaction mixture may be ground with a solvent mixture of acetonitrile and isopropanol. The method may also include slurrying Compound I Phosphate Form I in diethyl ether and adding seed crystals of Compound I Phosphate Form I.

[0171] Succinic acid

[0172] Crystalline Compound 1 succinic acid can be prepared from Compound 1 Form I by dissolving Compound 1 Form I and succinic acid in a solvent. In some embodiments, the present disclosure provides a method for preparing crystalline Compound 1 succinic acid, comprising forming a mixture of Compound 1 Form I, succinic acid, and a solvent under conditions suitable for preparing Compound 1 succinic acid. In some embodiments, Compound 1 Form I is dissolved in a solvent. 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 isopropyl alcohol.

[0173] The method may include multiple other steps. In some embodiments, the reaction mixture may be heated to a temperature of about 60° 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 5° C. In some embodiments, the method may include multiple heating and cooling steps.

[0174] Ethylenedisulfonic acid form I

[0175] Crystalline Compound 1 edisulphonic acid Form I can be prepared from Compound 1 Form I by dissolving Compound 1 Form I and edisulphonic acid in a solvent. In some embodiments, the present disclosure provides a method for preparing crystalline Compound 1 edisulphonic acid, comprising forming a mixture of Compound 1 Form I, edisulphonic acid, and a solvent under conditions suitable for preparing Compound 1 edisulphonic acid Form I. In some embodiments, Compound 1 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.

[0176] The method may include multiple 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.

[0177] Ethylenedisulfonic acid form II

[0178] Crystalline Compound 1 edisylate Form II can be prepared by slurrying Compound 1 edisylate Form I in a solvent. In some embodiments, the present disclosure provides a method for preparing crystalline Compound 1 edisylate Form II, comprising forming a mixture of Compound 1 edisylate Form I and a solvent under conditions suitable for preparing Compound 1 edisylate Form II. In some embodiments, the solvent can be dichloromethane.

[0179] Alternatively, crystalline Compound I edisulphonic acid Form I can be prepared from Compound I Form I by dissolving Compound I Form I and edisulphonic acid in a solvent. In some embodiments, the present disclosure provides a method for preparing crystalline Compound I edisulphonic acid Form II, comprising forming a mixture of Compound I Form I of the present disclosure, edisulphonic acid, and a solvent under conditions suitable for preparing Compound I edisulphonic acid Form II. In some embodiments, Compound I edisulphonic acid Form II is dissolved in a solvent. In some embodiments, the solvent may be a polar aprotic solvent. In some embodiments, the solvent may be acetone.

[0180] The method may include a number of further steps. In some embodiments, the reaction mixture may be heated to a temperature of about 60°C. In some embodiments, the reaction mixture may be cooled to a temperature of about 20°C.

[0181] V. Pharmaceutical Compositions

[0182] The solid form of Compound I provided herein can be applied in the form of a pharmaceutical composition. The present disclosure provides a pharmaceutical composition, which comprises one or more of the solid forms of Compound I or its pharmaceutically acceptable salt or ester as an active ingredient 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 applied alone or in combination with other therapeutic agents (as shown in the combined treatment 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 edition (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd edition (GS Banker & C.T. Rhodes ed.)).

[0183] The pharmaceutical compositions can be administered in single or multiple doses by any of the accepted modes of administration for pharmaceutical agents having similar utilities, e.g., as described in those patents and patent applications incorporated by reference, including rectal, oral, intranasal, and transdermal routes, by intra-arterial, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous oral, topical injection inhalation, or via an impregnated or coated device such as a stent or an arterial inserted cylindrical polymer.

[0184] One mode of administration is parenteral, especially by injection. The form in which the novel composition of the present disclosure can be incorporated for administration by injection includes aqueous or oil suspensions or emulsions, with sesame oil, corn oil, cottonseed oil or peanut oil, as well as elixirs, mannitol, dextrose or sterile aqueous solutions and similar pharmaceutical solvents. 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 their suitable mixtures), 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.).

[0185] Sterile injectable solutions are prepared by incorporating the desired amount of a compound according to the present disclosure into a suitable solvent together with various other ingredients as enumerated above, followed by sterilization by filtration as required. Generally, dispersions are prepared by incorporating various sterilized active ingredients into a sterile vehicle containing a basic dispersion medium and other desired ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, general preparation methods are vacuum drying and freeze drying techniques that produce a powder of the active ingredient plus any additional desired ingredients from a previously sterile filtered solution.

[0186] Oral administration is another way to administer the compounds according to the present disclosure. Administration can be carried out via capsules or enteric coated tablets, etc. In the preparation of 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 above), which acts as a solvent, carrier or medium for the active ingredient. Therefore, the composition can be in the form of 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 containing, for example, up to 10% by weight of an active compound, a soft gelatin capsule and a hard gelatin capsule, a sterile injectable solution and a sterile packaged powder.

[0187] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup and methylcellulose. The formulation may additionally contain: lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methyl benzoate and propyl hydroxybenzoate; sweeteners; and flavoring agents.

[0188] The compositions of the present disclosure can be formulated so as to provide a rapid, sustained or delayed release of the active ingredient after being administered to the patient by using procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patents Nos. 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 a controlled amount of continuous or discontinuous infusion of the compounds of the present disclosure. The construction and use of transdermal patches for delivering medicaments are well known in the art. See, for example, U.S. Patents Nos. 5,023,252, 4,992,445 and 5,001,139. ​​Such patches can be constructed for continuous, pulsatile or on-demand delivery of medicaments.

[0189] In some embodiments, the composition is formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as single doses for human subjects and other mammals, each unit containing a predetermined amount of active substances associated with suitable pharmaceutical excipients (e.g., tablets, capsules, ampoules), which are calculated 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 mg 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 the 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, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[0190] To prepare solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogenous mixture of a compound of the present disclosure. When these preformulation compositions are referred to as homogenous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0191] Tablets or pills of the present disclosure can be coated or otherwise mixed to provide a dosage form with the advantage of prolonged action or to protect against 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 the form of the envelope on the former. These two components can be separated by an enteric layer, which is used to resist 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 multiple polymeric acids and polymeric acids with materials such as shellac, cetyl alcohol and cellulose acetate.

[0192] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the composition is administered by oral or nasal respiratory route to achieve local or systemic effects. Compositions in preferably pharmaceutically acceptable solvents may be atomized by the use of an inert gas. Nebulized solutions may be inhaled directly from a nebulizing device, or the nebulizing device may be attached to a mask tent or intermittent positive pressure breathing machine. In some embodiments, solution, suspension or powder compositions may be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0193] 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 as described above, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or hydrate thereof.

[0194] VI. How to use

[0195] 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.

[0196] As used herein, an "agonist" is a substance that stimulates its binding partner (usually a receptor). Stimulation is defined in the context of a particular assay, or may be apparent from the literature discussed herein, which is compared to factors or substances that are accepted as "agonists" or "antagonists" of a particular binding partner in substantially similar circumstances 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.

[0197] 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 from the literature discussed herein, which is compared to factors or substances that are accepted as "agonists" or "antagonists" of a particular binding partner in 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.

[0198] As used herein, a "partial agonist" or "partial antagonist" is a substance that provides insufficient or incomplete agonism or antagonism, respectively, of a level of stimulation or inhibition to its binding partner. It should be understood that for any substance or class of substances defined as an agonist, antagonist or partial agonist, stimulation and therefore inhibition are inherently defined.

[0199] As used herein, "intrinsic activity" or "efficacy" refers to some measure of the biological effect 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 such context-specific assessments are relevant and how they may be relevant in the context of the present disclosure.

[0200] As used herein, modulation of a receptor includes agonism, partial agonism, antagonism, partial antagonism, or inverse agonism of the receptor.

[0201] 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 such characterizations.

[0202] In one embodiment, the method can be used for inducing immune responses in human body for multiple epitopes of viral infection.Any technique known to those skilled in the art for determining whether immune response has occurred can be used to assess the induction of immune response for viral infection.Among other things, suitable methods for detecting immune response of the present disclosure also include detecting the reduction of viral load or antigen in subject serum, detecting IFN-γ secretory peptide-specific T cells, and detecting the elevated 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 assay.Another embodiment includes reducing the viral load associated with HBV infection, including the reduction measured by PCR test.

[0203] In some embodiments, the present disclosure provides a method of treating a viral infection, comprising administering a therapeutically effective amount of a crystalline form of Compound I or a pharmaceutical composition of the present disclosure to a person in need thereof. In some embodiments, the present disclosure provides a crystalline form of Compound I for use in treating a viral infection, comprising administering a therapeutically effective amount of a crystalline form of Compound I or a pharmaceutical composition of the present disclosure. In some embodiments, the present disclosure provides the use of a crystalline form of Compound I for treating a viral infection. In some embodiments, the present disclosure provides the use of a crystalline form of Compound I in the manufacture of a medicament for treating a viral infection.

[0204] In another aspect, the present disclosure provides methods for treating hepatitis B virus infection or hepatitis C virus infection, wherein each of the methods 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 1. Typically, the human subject suffers from chronic hepatitis B infection or chronic hepatitis C infection, but treating humans acutely infected with HBV or HCV is within the scope of the present disclosure.

[0205] In some embodiments, the present disclosure provides a crystalline form of Compound 1 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 1 in the manufacture of a medicament for treating hepatitis B virus infection or hepatitis C virus infection.

[0206] In some embodiments, the present disclosure provides a crystalline form of Compound 1 for use in treating hepatitis B virus infection. In some embodiments, the present disclosure provides a use of a crystalline form of Compound 1 in the manufacture of a medicament for treating hepatitis B virus infection.

[0207] Treatment according to the present disclosure generally produces stimulation of an immune response to HBV or HCV, respectively, in people infected with HBV or HCV, and subsequently produces a reduction in the viral load of HBV or HCV in infected people. Examples of immune responses include the production of antibodies (e.g., IgG antibodies) and / or the production of cytokines (such as interferons) that regulate the activity of the immune system. The immune system response can be a newly induced response, or it can be an enhancement of an existing immune response. Specifically, the immune system response can be seroconversion for one or more HBV or HCV antigens.

[0208] Viral load can be determined by measuring the amount of HBV DNA or HCV DNA present in the blood. For example, serum HBV DNA can be quantified using Roche COBAS Amplicor Monitor PCR assay (version 2.0; the lower limit of quantification is 300 copies / mL [57IU / mL]) and Quantiplex bDNA assay (the lower limit of quantification is 0.7MEq / mL; Bayer Diagnostics, formerly known as Chiron Diagnostics, Emeryville, CA). The amount of antibodies against specific HBV or HCV antigens (e.g., hepatitis B surface antigen (HBsAG)) 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 against specific HBV or HCV antigens can be measured using Abbott AxSYM microparticle enzyme immunoassay system (Abbott Laboratories, North Chicago, IL).

[0209] Compound I can be administered by any available route and means, such as 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, such as from about 0.0001 mg / kg body weight / day to about 10 mg / kg body weight / day, or such as from about 0.001 mg / kg body weight / day to about 1 mg / kg body weight / day, or such as from about 0.01 mg / kg body weight / day to about 1 mg / kg body weight / day, or such as from about 0.05 mg / kg body weight / day to about 0.5 mg / kg body weight / day, or such as from about 0.3 μg to about 30 mg / day, or such as from about 30 μg to about 300 μg / day.

[0210] The therapeutically effective amount of Compound I is also about 0.01 mg / dose to about 1000 mg / dose, such as about 0.01 mg / dose to about 100 mg / dose, or such as about 0.1 mg / dose to about 100 mg / dose, or such as about 1 mg / dose to about 100 mg / dose, or such as about 1 mg / dose to about 100 mg / dose. Other therapeutically effective amounts of Compound I are about 1 mg / dose, 1.5 mg / dose, 2 mg / dose, 2.5 mg / dose, 3 mg / dose or 3.5 mg / 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 / dose. Other therapeutically effective amounts of Compound I are about 100 mg / dose, or about 125, 150, 175, 200, 225, 250, 275, 300, 350, 400, 450, or about 500 mg / dose. A single dose can be administered hourly, daily, or weekly. For example, a single dose can be administered once every 1, 2, 3, 4, 6, 8, 12, 16 hours, or once every 24 hours. A single dose can also be administered once every 1, 2, 3, 4, 5, 6 days, or once every 7 days. A single dose can also be administered once every 1, 2, 3 weeks, or once every 4 weeks. A single dose can also be administered once a month.

[0211] The dosage frequency of Compound I will be determined by the needs of the individual patient and can be, for example, once a day or twice a day or more. Administration of Compound I is continued as long as required for the treatment of HBV or HCV infection. For example, Compound I can 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.

[0212] Administration may 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, followed by a subsequent period (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 followed by no administration of Compound I may be repeated as clinically necessary to treat the patient.

[0213] As described more fully herein, the crystalline form of Compound 1 can be administered to a human infected with hepatitis B virus or hepatitis C virus together with one or more additional therapeutic agents. The additional therapeutic agent can be administered to the infected human simultaneously with the crystalline form of Compound 1 or before or after the administration of the crystalline form of Compound 1. In some embodiments, the present disclosure provides a crystalline form of Compound 1 for use in a method of treating or preventing hepatitis B virus infection, wherein the crystalline form of Compound 1 is administered simultaneously, separately, or sequentially with one or more additional therapeutic agents for treating hepatitis B virus infection. In some embodiments, the present disclosure provides a use of a crystalline form of Compound 1 in the manufacture of a medicament for treating hepatitis B virus infection, wherein the crystalline form of Compound 1 is administered simultaneously, separately, or sequentially with one or more additional therapeutic agents for treating hepatitis B virus infection.

[0214] In another aspect, the present disclosure 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. Such symptoms include the presence of HBV virus particles (or HCV virus particles) in the blood, liver inflammation, jaundice, muscle pain, weakness and fatigue.

[0215] In some embodiments, the present disclosure provides a crystalline form of Compound I for use in improving symptoms associated with HBV infection or HCV infection, wherein the method comprises administering a therapeutically effective amount of the crystalline form of Compound I to a human subject infected with hepatitis B virus or hepatitis C virus, wherein the therapeutically effective amount is sufficient to 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 manufacture of a medicament for improving symptoms associated with HBV infection or HCV infection, wherein the method comprises administering a therapeutically effective amount of the crystalline form of Compound I to a human subject infected with hepatitis B virus or hepatitis C virus, wherein the therapeutically effective amount is sufficient to improve symptoms associated with HBV infection or HCV infection.

[0216] In another aspect, the present disclosure provides a method for reducing the progression rate of hepatitis B virus infection or hepatitis C virus infection in humans, wherein the method comprises administering a therapeutically effective amount of Compound 1 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 progression rate of hepatitis B virus infection or hepatitis C virus infection. The progression rate of infection can be tracked by measuring the amount of HBV virus particles or HCV virus particles in the blood.

[0217] 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 1 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.

[0218] On the other hand, the present disclosure provides a method for 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 the human body. 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.

[0219] Inducing seroconversion against HCV or HBV in patients chronically infected with any of these viruses is an unexpected property of Compound I. In clinical practice, HBV patients or HCV patients are treated with Compound I alone or in combination with one or more other therapeutic agents 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 exist in a latent form in the patient's body, treatment with Compound I can be stopped, and the patient's own immune system is able to suppress further viral replication. In patients who have been treated according to the present disclosure and have received treatment with an antiviral agent that inhibits HBV virus or HCV virus replication, there may be few or no detectable viral particles in the patient's body during 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 does not increase.

[0220] In the practice of the present disclosure, an immune response is induced for one or more antigens of HBV or HCV. For example, an immune response may be induced for HBV surface antigen (HBsAg) or for a smaller form of HBV surface antigen (smaller S antigen) or for a medium form of HBV surface antigen (medium S antigen) or for a combination thereof. Again by way of example, an immune response may be induced for HBV surface antigen (HBsAg) and also for antigens from other HBV sources (such as core polymerase or x-protein).

[0221] The induction of an immune response to HCV or HBV can be assessed using any technique known to those skilled in the art for determining whether an immune response has occurred. Suitable methods for detecting an immune response of the present disclosure include, among other things, 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.

[0222] 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 (e.g., lip cancer, tongue cancer, or pharyngeal cancer), digestive organs (e.g., 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 (e.g., melanoma), breast, reproductive organs (uterus, cervix, testicles, ovaries, or prostate), urinary tract (e.g., bladder or kidney), brain, and endocrine glands such as thyroid. In general, the compounds of the present disclosure are used to treat any neoplasm, including not only hematological malignancies, but also all types of solid tumors.

[0223] Hematological malignancies are broadly defined as proliferative disorders of blood cells and / or their progenitors in which these cells proliferate in an uncontrolled manner. Anatomically, hematological malignancies are divided into two major categories: lymphomas—malignant masses of lymphoid cells, primarily but not exclusively in the lymph nodes; and leukemias—neoplasms, usually derived from lymphoid 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 encompasses several distinct entities that can be distinguished clinically (e.g., aggressive lymphoma, indolent lymphoma), histologically (e.g., follicular lymphoma, mantle cell lymphoma), or based on the origin of the malignant cell (e.g., B lymphocytes, T lymphocytes). Leukemias and related malignancies include acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), and chronic lymphocytic leukemia (CLL). Other hematological malignancies include plasma cell dyscrasias (including multiple myeloma) and myelodysplastic syndromes.

[0224] VII. Combination therapy

[0225] In certain embodiments, methods for treating or preventing an infectious disease, a viral infection, a hepatitis B infection, an HIV infection, a cancer, or a hyperproliferative disease in a person at risk of the disease are provided, comprising administering to the person 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, methods for treating an infectious disease, a viral infection, a hepatitis B infection, an HIV infection, a cancer, or a hyperproliferative disease in a person at risk of the disease are provided, comprising administering to the person 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.

[0226] In certain embodiments, the present disclosure provides a method for treating a viral infection, comprising administering a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof to a subject in need 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 a viral infection. In some embodiments, the viral infection is a hepatitis B infection. In some embodiments, the viral infection is an HIV infection.

[0227] 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. The 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.

[0228] Administration of combination therapy

[0229] In certain embodiments, the compounds disclosed herein are administered together with one or more additional therapeutic agents. Co-administration of compounds disclosed herein with one or more additional therapeutic agents generally refers to the simultaneous or sequential administration of the compounds disclosed herein and the one or more additional therapeutic agents, such that a therapeutically effective amount of the compounds disclosed herein and the one or more additional therapeutic agents are both present in the subject. When administered sequentially, the combination may be administered in two or more administrations.

[0230] Co-administration of a compound disclosed herein and 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.

[0231] In certain embodiments, the compounds as disclosed herein may 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).

[0232] 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 may 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).

[0233] 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.

[0234] In certain embodiments, the compounds as described herein are formulated into tablets, which may optionally contain one or more other compounds useful 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).

[0235] In certain embodiments, such tablets are suitable for once-daily administration.

[0236] In one embodiment, a pharmaceutical composition is provided that comprises 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.

[0237] 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, one to three, or one to four) additional therapeutic agents.

[0238] Viral combination therapy

[0239] The compounds described herein can be used or combined with one or more of the following antiviral agents: abacavir, acyclovir, adefovir, amantadine, amprenavir, arbidol, atazanavir, atripla, brivudine, cidofovir, compivir, edouridine, efavirenz, emtricitabine, enfuvirtide, entecavir, fomvirsen, fosamprenavir, foscarnet, fosfoethol sodium, 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, morpholino, nelfinavir, nevirapine, nexavir, nucleoside analogs, oseltamivir, penciclovir, peramivir, pranarib, podophyllotoxin, protease inhibitors, reverse transcriptase inhibitors, ribavirin, rimantadine, ritonavir, saquinavir, stavudine, tenofovir, tenofovir disoproxil, tipranavir, trifluridine, trizivir, tromantine, truvada, valganciclovir, vicrovir, cytarabine, viramidine, zalcitabine, zanamivir, zidovudine, and combinations thereof.

[0240] In certain embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with 5-30 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 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 pharmaceutically acceptable salts thereof 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 combination of doses were specifically and individually listed.

[0241] 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, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 300mg tenofovir disoproxil fumarate, hemi-tenofovir disoproxil fumarate or tenofovir disoproxil. In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 250mg tenofovir disoproxil fumarate, hemi-tenofovir disoproxil fumarate or tenofovir disoproxil. In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 150mg tenofovir disoproxil fumarate, hemi-tenofovir disoproxil fumarate or tenofovir disoproxil. The disclosed compound can be combined with a pharmaceutical agent provided herein with a compound (e.g., a compound of 50mg to 500mg) of any dosage, as specifically and individually listing each combination of dosage.

[0242] HIV combination therapy

[0243] In certain embodiments, methods for treating or preventing HIV infection in a human or animal at risk of infection are provided, comprising administering to the human or animal a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, in combination with 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, methods for treating HIV infection in a human or animal at risk of infection are provided, comprising administering to the human or animal a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.

[0244] In certain embodiments, the present disclosure provides methods 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.

[0245] In certain embodiments, the compounds disclosed herein are formulated into tablets, which may optionally contain one or more other compounds useful for treating HIV. In certain embodiments, the tablets may contain another active ingredient useful for treating HIV, such as HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.

[0246] In certain embodiments, such tablets are suitable for once-daily administration.

[0247] In the above embodiments, the additional therapeutic agent can be an anti-HIV agent. In some embodiments, the additional therapeutic agent is selected from the group consisting of HIV combination drugs, HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of 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, TALEN), cell therapies (such as chimeric antigen receptor T cells CAR-T and engineered T cell receptors TCR-T), latency reversal agents, compounds targeting HIV capsids (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, defensin modulators, CDK-9 inhibitors, dendritic ICAM-3 grab non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H regulators, 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.

[0248] In some embodiments, the additional therapeutic agent is selected from the group consisting of: combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic 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.

[0249] HIV combination drugs

[0250] 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; TDF+FTC); (tenofovir alafenamide and emtricitabine); (tenofovir alafenamide, emtricitabine, and rilpivirine); (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); (bictegravir, emtricitabine, tenofovir alafenamide); darunavir, tenofovir alafenamide hemifumarate, emtricitabine and cobicistat; efavirenz, lamivudine and tenofovir disoproxil fumarate; lamivudine and tenofovir disoproxil fumarate; tenofovir and lamivudine; tenofovir alafenamide and emtricitabine; tenofovir alafenamide hemifumarate and emtricitabine; tenofovir alafenamide hemifumarate, emtricitabine and rilpivirine; tenofovir alafenamide 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 Vacc-4x and romidepsin; and APH-0812.

[0251] HIV protease inhibitors

[0252] Examples of HIV protease inhibitors include amprenavir, atazanavir, brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, tipranavir, DG-17, TMB-657 (PPL-100), T-169, BL-008, and TMC-310911.

[0253] HIV reverse transcriptase inhibitors

[0254] 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.

[0255] 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, aritibine, sinavudine, didanosine, efavirenz, festinavir, fosalvudinetidoxil, CMX-157, dapivirine, doravirine, etravirine, OCR-5753, tenofovir disoproxil orotate, fosalvudinetidoxil, lamivudine, phosphazid, stavudine, zalcitabine, zidovudine, GS-9131, GS-9148, MK-8504 and KP-1461.

[0256] HIV integrase inhibitors

[0257] Examples of HIV integrase inhibitors include elvitegravir, curcumin, a derivative of curcumin, chicoric acid, a derivative of chicoric acid, 3,5-dicaffeoylquinic acid, a derivative of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, a derivative of aurintricarboxylic acid, caffeic acid phenethyl ester, a derivative of caffeic acid phenethyl ester, a tyrosine kinase inhibitor, a derivative of a tyrosine kinase inhibitor, quercetin, a derivative of quercetin, raltegravir, dolutegravir, JTK-351, bictegravir, AVX-155 67. Cabotegravir (long-acting injectable form), 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, distilbenesulphonic acid, T-169 and cabotegravir.

[0258] Examples of HIV non-catalytic site or allosteric integrase inhibitors (NCINIs) include CX-05045, CX-05168, and CX-14442.

[0259] HIV entry inhibitors

[0260] Examples of HIV entry (fusion) inhibitors include cenikvir, CCR5 inhibitors, gp41 inhibitors, CD4 attachment inhibitors, gpl20 inhibitors, and CXCR4 inhibitors.

[0261] Examples of CCR5 inhibitors include apraviroc, vicoviroc, maraviroc, cenikviroc, PRO-140, adatasvir (RAP-101), nifaviroc (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptide C25P, TD-0680, and vMIP (Haimipu).

[0262] Examples of gp41 inhibitors include abavirtide, enfuvirtide, BMS-986197, enfuvirtide biobetter, enfuvirtide biosimilar, HIV-1 fusion inhibitor (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer, and sifuvirtide.

[0263] Examples of CD4 attachment inhibitors include ibalizumab and CADA analogs.

[0264] Examples of gp120 inhibitors include Radha-108 (acceptor alcohol) 3B3-PE38, BanLec, bentonite-based nanomedicine, forsteravir tromethamine, IQP-0831, and BMS-663068.

[0265] Examples of CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide, and vMIP (Haimipu).

[0266] HIV maturation inhibitors

[0267] Examples of HIV maturation inhibitors include BMS-955176 and GSK-2838232.

[0268] Latency reversal agents

[0269] 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 (suberylanilide hydroxamic acid or suberoyl, anilide and hydroxamic acid), AM-0015, ALT-803, NIZ-985, NKTR-255, IL-15 modulating antibodies, JQ1, disulfiram, amphotericin B and ubiquitin inhibitors (such as ragozola analogs) and GSK-343.

[0270] Examples of HDAC inhibitors include romidipine, vorinostat, and panobinostat.

[0271] Examples of PKC activators include indole lactams, tyrosine kinase inhibitors, ingenol B, and DAG-lactone.

[0272] Capsid inhibitors

[0273] 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.

[0274] Immune-based therapies

[0275] 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; prilocaine (hydroxychloroquine); prilocaine (aldesleukin, IL-2); interferon alpha; interferon alpha-2b; interferon alpha-n3; pegylated interferon alpha; stem cell transplants. Interferon gamma; hydroxyurea; mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF); ribavirin; retamod, polymer polyethyleneimine (PEI); gepon; retamod; IL-12; WF-10; VGV-1; MOR-22; BMS-936559; CYT-107, interleukin-15 / Fc fusion protein, noferon, pegylated interferon alpha-2a, pegylated interferon alpha-2b, recombinant interleukin-15, RPI-MN, GS-9620, STING modulators, RIG-I modulators, NOD2 modulators and IR-103.

[0276] 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 (Noviratherapeutics), US Patent No. 9670205 (Gilead Sciences Inc.), US20160289229 (Gilead Sciences Inc.), US Patent Application No. 15 / 692161 (Gilead Sciences Inc.), and US Patent Application No. 15 / 692093 (Gilead Sciences Inc.)

[0277] Phosphatidylinositol 3-kinase (PI3K) inhibitors

[0278] Examples of PI3K inhibitors include idelalisib, alpelisib, buparlisib, CAI orotate, copanlisib, duvelisib, gedatolisib, neratinib, panulisib, perifosine, pictilisib, pilaralisib, puroquintinib mesylate, regoratinib, regoratinib sodium, sonolisib, taselisib , AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, DS-7423, EN-3342, GSK-2126458, GSK-2269577, GSK-2636771, INCB-040093, LY -3023414, MLN-1117, PQR-309, RG-7666, RP-6530, RV-1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857, VS-5584, XL-765 and ZSTK-474.

[0279] Alpha-4 / beta-7 antagonists

[0280] Examples of integrin α-4 / β-7 antagonists include PTG-100, TRK-170, alirocumab, edrolizumab, carotegrast methyl, and vedolizumab.

[0281] HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins

[0282] Examples of HIV antibodies, bispecific antibodies, and “antibody-like” therapeutic proteins include Fab derivatives, bnAB (broadly neutralizing HIV-1 antibodies), BMS-936559, TMB-360 and those targeting HIV gp120 or gp41, antibody recruitment molecules targeting HIV, anti-CD63 monoclonal antibodies, anti-GB virus C antibodies, anti-GP120 / CD4, CCR5 bispecific antibodies, anti-nef single domain antibodies, anti-Rev antibodies, camelid-derived anti-CD18 antibodies, camelid-derived anti-ICAM-1 antibodies, DCVax-001, gp140-targeting antibodies, gp41-based HIV therapeutic antibodies, human recombinant mAb (PGT-121), ibalizumab, Immuglo and MB-66.

[0283] Examples of those antibodies that target HIV in this manner include bavicumab, 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.

[0284] Pharmacokinetic enhancers

[0285] Examples of pharmacokinetic enhancers include cobicistat and ritonavir.

[0286] HIV vaccine

[0287] Examples of HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, CD4-derived peptide vaccines, vaccine combinations, rgp120 (AIDSVAX), ALVAC HIV (vCP1521) / AIDSVAX B / E (gp120) (RV144), monomeric gp120 HIV-1 subtype C vaccine, Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), Vacc-4X, Vacc-C5, VAC-3S, multi-stage DNA recombinant adenovirus-5 (rAd5), Pennvax-G, Pennvax-GP, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3 / VSSP ISA-51, polyICLC adjuvanted vaccine, TatImmune, GTU-multiHIV (FIT-06), gp140 [delta] V2.TV1 + MF-59, rVSVIN HIV-1 gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin / ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV1-PG9DP, GOVX-B11, GOVX-B21, TVI-HIV-1, Ad-4 (Ad4-env Clade C+Ad4-mGag), EN41-UGR7C, EN41-FPA2, PreVaxTat, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, DNA-Ad5 gag / pol / nef / nev(HVTN505), MVATG-17401, ETV-01, CDX-1401, rcAD26.MOS1.HIV-Env, Ad26.Mod.HIV vaccine, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, IHV-001 and virus-like particle vaccines (such as pseudovirus vaccines), CombiVICHvac, LFn-p24 B / C fusion vaccine, GTU-based DNA vaccine, 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), I i-key / MHC Class II epitope hybrid peptide vaccine, ITV-2, ITV-3, ITV-4, LIPO-5, multi-stage Env vaccine, MVA vaccine, Pennvax-GP, pp71-deficient HCMV vector HIV gag vaccine, recombinant peptide vaccine (HIV infection), NCI, rgp160 HIV vaccine, RNActive HIV vaccine, SCB-703, TatOyi 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. .

[0288] Additional HIV therapeutics

[0289] Examples of additional HIV therapeutics include WO 2004 / 096286 (Gilead Sciences), WO 2006 / 015261 (Gilead Sciences), WO 2006 / 110157 (Gilead Sciences), WO 2012 / 003497 (GileadSciences), 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).

[0290] Examples of other drugs used to treat HIV include acetomorphan, alisporivir, BanLec, deferiprone, Gamimune, mitoflavin, naltrexone, alpha 1-proteinase inhibitor (Prolastin), REP 9, RPI-MN, VSSP, H1 virus, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, AAV-eCD4-Ig gene therapy, MazF gene therapy, BlockAide, ABX-464, AG-1105, APH-0812, BIT-225, CYT-107, HGTV-43, HPH-116, HS-10234, IMO -3100, IND-02, MK-1376, MK-8507, MK-8591, NOV-205, PA-1050040 (PA-040), PGN-007, SCY-635, SB -9200, SCB-719, TR-452, TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, Immuglo and VIR-576.

[0291] Gene therapy and cell therapy

[0292] Gene therapy and cell therapy include genetic modifications that silence genes; genetic methods that directly kill infected cells; infusions of immune cells that are designed to replace a large portion of the subject's own immune system to enhance the immune response to infected cells, or to activate the subject's own immune system to kill infected cells, or to find and kill infected cells; genetic methods that alter cellular activity to further alter the endogenous immune response to the infection.

[0293] Examples of dendritic cell therapies include AGS-004.

[0294] Gene Editor

[0295] 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.

[0296] Examples of HIV-targeting CRISPR / Cas9 systems include EBT101.

[0297] CAR-T cell therapy

[0298] CAR-T cell therapy includes a population of immune effector cells 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 combinations thereof.

[0299] Examples of HIV CAR-T include VC-CAR-T.

[0300] TCR-T cell therapy

[0301] TCR-T cell therapy involves T cells engineered to target HIV-derived peptides present on the surface of virally infected cells.

[0302] It will be appreciated by those skilled in the art 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 those compounds listed in those categories.

[0303] In one specific embodiment, the compound disclosed herein or its pharmaceutically acceptable salt is combined with HIV nucleoside or nucleotide inhibitors of reverse transcriptase and HIV non-nucleoside inhibitors of reverse transcriptase. In another specific embodiment, the compound disclosed herein or its pharmaceutically acceptable salt is combined with HIV nucleoside or nucleotide inhibitors of reverse transcriptase and HIV protease inhibitory compounds. In another embodiment, the compound disclosed herein or its pharmaceutically acceptable salt is combined with HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV non-nucleoside inhibitors of reverse transcriptase and pharmacokinetic enhancers. In certain embodiments, the compound disclosed herein or its pharmaceutically acceptable salt is combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor and a pharmacokinetic enhancer. In another embodiment, the compound disclosed herein or its pharmaceutically acceptable salt is combined with two HIV nucleoside or nucleotide inhibitors of reverse transcriptase.

[0304] 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; TDF+FTC); (tenofovir alafenamide and emtricitabine); (tenofovir alafenamide, emtricitabine, and rilpivirine); (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); (Bictegravir, Emtricitabine, Tenofovir Alafenamide); Adefovir; Adefovir Dipivoxil; Cobicistat; Emtricitabine; Tenofovir; Tenofovir Disoproxil; Tenofovir Disoproxil Fumarate; Tenofovir Alafenamide; Tenofovir Hemifumarate; (dulutegravir, 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; α1-proteinase inhibitor; fosamprenavir; fosamprenavir calcium efavirenz; etravirine; nelfinavir; nelfinavir mesylate; interferon; dida Noxin; stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (receptor alcohol); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine and tenofovir disoproxil fumarate; phosphinothricin; lamivudine, nevirapine and zidovudine; abacavir; and abacavir sulfate.

[0305] In a specific embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, or bictegravir.

[0306] 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.

[0307] In a specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, and bictegravir and a second additional therapeutic agent selected from the group consisting of emtricitabine and lamivudine.

[0308] In a specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, and bictegravir, and wherein the second additional therapeutic agent is emtricitabine.

[0309] In certain embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with 5-30 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 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, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate or tenofovir alafenamide and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. A compound as disclosed herein may be combined with an agent provided herein at any dose of the compound (e.g., 1 mg to 500 mg of the compound), as if each combination of doses is specifically and individually listed.

[0310] In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 200-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate or tenofovir disoproxil and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 200-250, 200-300, 200-350, 250-350, 250-400, 350-400, 300-400 or 250-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate or tenofovir disoproxil and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 300 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate or tenofovir disoproxil and 200 mg of emtricitabine. A compound as disclosed herein can be combined with a pharmaceutical agent provided herein in any dose of a compound (e.g., 1 mg to 500 mg of a compound), as specifically and individually listed for each combination of doses.

[0311] HBV combination therapy

[0312] In certain embodiments, a method for treating or preventing an infection in a person suffering from HBV infection or at risk of the infection is provided, comprising administering to the person 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 infection in a person suffering from HBV infection or at risk of the infection is provided, comprising administering to the person 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.

[0313] In certain embodiments, the present disclosure provides a method for treating HBV infection, which comprises administering a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof to a patient in need 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.

[0314] The compounds described herein can be used or combined with one or more of the following: chemotherapeutic agents, immunomodulatory agents, immunotherapeutic agents, therapeutic antibodies, therapeutic vaccines, bispecific antibodies, and "antibody-like" therapeutic proteins (such as Fab derivatives), antibody-drug conjugates (ADCs), gene modifiers or gene editors (such as CRISPR Cas9, zinc finger nucleases, homing endonucleases, synthetic nucleases, TALENs), cell therapies such as CAR-T (chimeric antigen receptor T cells) and TCR-T (engineered T cell receptor) agents, or any combination thereof.

[0315] In certain embodiments, the compounds described herein are formulated into tablets, which may optionally contain one or more other compounds useful for treating HBV. In certain embodiments, the tablets may contain another active ingredient for treating HBV, such as 3-dioxygenase (IDO) inhibitors, apolipoprotein A1 regulators, arginase inhibitors, B and T attenuation factor 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, IAP 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, Ax l regulators, B7-H3 regulators, B7-H4 regulators, CD160 regulators, CD161 regulators, CD27 regulators, CD47 regulators, CD70 regulators, GITR regulators, HEVEM regulators, ICOS regulators, Mer regulators, NKG2A regulators, NKG2D regulators, OX40 regulators, SIRPα regulators, TIGIT regulators, Tim-4 regulators, Tyro regulators, Na+-taurocholate cotransporting polypeptide (NTCP) inhibitors, natural killer cell receptor 2B4 inhibitors, NOD2 gene stimulators, nuclear protein inhibitors, nuclear protein regulators, PD-1 inhibitors, PD-L1 inhibitors, peptidyl prolyl isomerase inhibitors, phosphatidylinositol-3 kinase (PI3K) inhibitors, retinoic acid-inducible gene 1 stimulators, reverse transcriptase inhibitors, ribonuclease inhibitors, RNA DNA polymerase inhibitors, SLC10A1 gene inhibitors, SMAC mimetics, Src tyrosine kinase inhibitors, stimulators of interferon genes (STING) agonists, stimulators of NOD1, T cell surface glycoprotein CD28 inhibitors, T cell surface glycoprotein CD8 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.

[0316] HBV combination drugs

[0317] 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).

[0318] Other HBV drugs

[0319] Examples of other drugs used to treat HBV include α-hydroxytropolone, amdosovir, β-hydroxycytidine, AL-034, CCC-0975, efcitabine, ezetimibe, cyclosporine A, gentioside (gentiopicroside), JNJ-56136379, nitazoxanide, birenapam, NJK14047, NOV-205 (molixan, BAM-205), oligonucleotides, mivotifen, feron, GST-HG-131, levamisole, Ka Shu Ning, alloferon, WS-007, Y-101 (Ti Fen Tai), rSIFN-co, PEG-IIFNm, KW-3, BP-Inter-014, oleanolic acid, HepB-nRNA, cTP-5 (rTP-5), HSK-II-2, HEISCO-106-1, HEISCO-106, Hepbarna, IPB-006IA, Hepuyinfen, DasKloster 0014-01, ISA-204, Jiangantai (Ganxikang), MIV-210, OB-AI-004, PF-06, picroside, DasKloster-0039, hepulantai, IMB-2613, TCM-800B, reduced glutathione, RO-6864018, RG-7834, UB-551 and ZH-2N, and US20150210682 (Roche), US Compounds disclosed in 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 US2015031687A (Roche).

[0320] HBV vaccine

[0321] HBV vaccines include both preventive vaccines and therapeutic vaccines. Examples of HBV preventive vaccines include Vaxelis, Hexaxim, Heplisav, Mosquirix, DTwP-HBV vaccine, Bio-Hep-B, D / T / P / HBV / M (LBVP-0101; LBVW-0101), DTwP-Hepb-Hib-IPV vaccine, Heberpenta L, DTwP-HepB-Hib, V-419, CVI-HBV-001, Tetrabhay, Hepatitis B preventive vaccine (Advax Super D), Hepatrol-07, GSK-223192A, ENGERIX Recombinant Hepatitis B Vaccine (intramuscular injection, Kangtai Biological Products), Recombinant Hepatitis B Vaccine (Hansenual polymorpha yeast, intramuscular injection, Hualan Biological Engineering), Recombinant Hepatitis B Surface Antigen Vaccine, Bimmugen, Euforavac, Eutravac, anrix-DTaP-IPV-Hep B, HBAI-20, Infanrix-DTaP-IPV-Hep B-Hib, PentabioVaksin DTP-HB-Hib, Comvac 4, Twinrix, Euvax-B, Tritanrix HB, Infanrix Hep B, Comvax, DTP-Hib-HBV Vaccine, DTP-HBV Vaccine, Yi Tai, Heberbiovac HB, Trivac HB, GerVax, DTwP-Hep B-Hib vaccine, Bilive, Hepavax-Gene, SUPERVAX, Comvac5, Shanvac-B, Hebsulin, Recombivax HB, Revac B mcf, Revac B+, Fendrix, DTwP-HepB-Hib, DNA-001, Shan5, Shan6, rhHBsAG vaccine, HBI pentavalent vaccine, LBVD, Infanrix HeXa and DTaP-rHB-Hib vaccine.

[0322] 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 adjuvanted vaccine, HepB-v, RG7944 (INO-1800), recombinant VLP-based therapeutic vaccines (HBV infection, VLP Biotech), AdTG-17909, AdTG-17910AdTG-18202, ChronVac-B, TG-1050 and Lm HBV.

[0323] HBV DNA polymerase inhibitors

[0324] Examples of HBV DNA polymerase inhibitors include adefovir Emtricitabine Tenofovir Disoproxil Fumarate Tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir octadecyloxyethyl ester, CMX-157, besifovir, entecavir Entecavir Maleate, Telbivudine Feloxivir, pradefovir, clavudine, 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.

[0325] Immunomodulators

[0326] Examples of immunomodulators include retasimide, imidol hydrochloride, ingaron, dermaVir, hydroxychloroquine, prilocaine, 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.

[0327] Toll-like receptor (TLR) modulators

[0328] TLR modulators include modulators of TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13. Examples of TLR3 modulators include retamod, polyICLC, Apoxxim, IPH-33, MCT-465, MCT-475 and ND-1.1.

[0329] 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, teramod, SP-0509, TMX-30X, TMX-202, RG-7863, RG-7795, LHC-165, RG-7854, and compounds disclosed in US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences), and US20090047249 (Gilead Sciences).

[0330] 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. Application No. 9670205, US20160289229, U.S. Patent Application No. 15 / 692161 and U.S. Patent Application No. 15 / 692093.

[0331] 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.

[0332] 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).

[0333] Interferon alpha receptor ligand

[0334] Examples of interferon alpha receptor ligands include interferon alpha-2b Pegylated interferon Pegylated interferon α-1b, interferon Veldona, Infradure, Roferon-A, YPEG-interferon α-2a (YPEG-rhIFNα-2a), P-1101, Algeron, Alfarona, Ingaron (interferon gamma), rSIFN-co (recombinant super compound interferon), Ypeg interferon α-2b (YPEG-rhIFNα-2b), MOR-22, pegylated interferon α-2b Bioferon, Novaferon, Inmutag (Inferon), Interferon α-n1 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, Lanstion, Pegaferon, PDferon-B, interferon alpha-2b (IFN, LaboratoriosBioprofarma), alpha interferon a 2b, Kalferon, Pegnano, Feronsure, PegiHep, interferon alpha 2b (Zydus-Cadila), interferon alpha 2a, Optipeg A, Realfa 2B, Reliferon, interferon alpha-2b (Amega), interferon alpha-2b (Virchow), ropeg 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, INTEFEN, SINOGEN, Fukangtai, Pegstat, rHSA-IFNα-2b, SFR-9216 and Interapo (Interapa).

[0335] Hyaluronidase inhibitors

[0336] Examples of hyaluronidase inhibitors include astodrimers.

[0337] Hepatitis B surface antigen (HBsAg) inhibitors

[0338] 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, REP-006 and REP-9AC′.

[0339] Examples of HBsAg secretion inhibitors include BM601.

[0340] Cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitor

[0341] Examples of cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors include AGEN-2041, AGEN-1884, ipilumimab, belatacept, PSI-001, PRS-010, Probody monoclonal antibody, tremelimumab, and JHL-1155.

[0342] Cyclophilin inhibitors

[0343] 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 US8513184 (Gilead Sciences), US20140030221 (Gilead Sciences), US20130344030 (Gilead Sciences), and US20130344029 (Gilead Sciences).

[0344] HBV viral entry inhibitors

[0345] Examples of HBV viral entry inhibitors include Myrcludex B.

[0346] Antisense oligonucleotides targeting viral mRNA

[0347] Examples of antisense oligonucleotides targeting viral mRNA include ISIS-HBVRx, IONIS-HBVRx, IONIS-GSK6-LRx, GSK-3389404, RG-6004.

[0348] Short interfering RNA (siRNA) and ddRNAi

[0349] Examples of siRNA include TKM-HBV (TKM-HepB), ALN-HBV, SR-008, HepB-nRNA, and ARC-520, ARC-521, ARB-1740, ARB-1467.

[0350] Examples of DNA-directed RNA interference (ddRNAi) include BB-HB-331.

[0351] Endonuclease modulators

[0352] Examples of endonuclease modulators include PGN-514.

[0353] Ribonucleotide reductase inhibitors

[0354] Examples of ribonucleotide reductase inhibitors include Trimidox.

[0355] HBV E antigen inhibitors

[0356] Examples of HBV E antigen inhibitors include wogonin.

[0357] Covalently closed circular DNA (cccDNA) inhibitors

[0358] Examples of cccDNA inhibitors include BSBI-25 and CHR-101.

[0359] Farnesoid X receptor agonists

[0360] Examples of farnesoid x receptor agonists are such as EYP-001, GS-9674, EDP-305, MET-409, Tropifexor, AKN-083, RDX-023, BWD-100, LMB-763, INV-3, NTX-023-1, EP-024297, and GS-8670.

[0361] HBV antibodies

[0362] Examples of HBV antibodies that target the surface antigen of the hepatitis B virus include GC-1102, XTL-17, XTL-19, KN-003, IV Hepabulin SN, and Fully Human Monoclonal Antibody Therapy (Hepatitis B Virus Infection, HumabsBioMed).

[0363] Examples of HBV antibodies (including monoclonal antibodies and polyclonal antibodies) include Zutectra, Shangsheng Gandi, UmanBig (hepatitis B hyperimmune), Omri-Hep-B, Nabi-HB, Hepatect CP, HepaGam B, Igantibe, Niuliva, CT-P24, hepatitis B immune globulin (intravenous, pH4, HBV infection, Shanghai RAAS blood products) and Fovepta (BT-088).

[0364] Fully human monoclonal antibodies include HBC-34.

[0365] CCR2 chemokine antagonists

[0366] Examples of CCR2 chemokine antagonists include propagermanium.

[0367] Thymosin agonists

[0368] Examples of thymosin agonists include thymalfasin, recombinant thymosin α1 (GeneScience).

[0369] Cytokines

[0370] Examples of cytokines include recombinant IL-7, CYT-107, interleukin-2 (IL-2, Immunex), recombinant human interleukin-2 (Shenzhen Neptunus), IL-15, IL-21, IL-24, and simu-leukin.

[0371] Nuclear protein regulator

[0372] Nucleoprotein modulators can be HBV core protein or capsid protein inhibitors. Examples of nucleoprotein modulators include GS-4882, AB-423, AT-130, GLS4, NVR-1221, NVR-3778, AL-3778, BAY 41-4109, meficycline mesylate, ARB-168786, ARB-880, JNJ-379, RG-7907, HEC-72702, AB-506, ABI-H0731, JNJ-440, ABI-H2158, and DVR-23.

[0373] Examples of capsid inhibitors include compounds disclosed in the following patents: US20140275167 (Novira Therapeutics), US20130251673 (Novira Therapeutics), US20140343032 (Roche), WO2014037480 (Roche), US20130267517 (Roche), WO2014131847 (Janssen), WO2014033176 (Janssen), WO2014033170 (Janss en), WO2014033167(Janssen), WO2015 / 059212(Janssen), WO2015118057(Janssen), WO2015011281(Janssen), WO2014184365(Janssen), WO2014184350(Janssen), WO 2014161888(Janssen), WO2013096744(Novira), US20150225355(Novira), US20140178337(Novira), US20150315159(Novira), US20150197533(Novira), US2015027 US 20170334882(Novira)、US 20170334898(Roche), WO2017202798(Roche), WO2017214395(Enanta), WO2018001944(Roche), WO2018001952(Roche), WO2018005881(Novira), WO2018005 883 (Novira), WO2018011100 (Roche), WO2018011160 (Roche), WO2018011162 (Roche), WO2018011163 (Roche), WO2018036941 (Roche), WO2018043747 (Kyoto Univ), US20180065929 (Janssen), WO2016168619 (Indiana University), WO2016195982 (The PennState Foundation), WO2017001655 (Janssen), WO2017048950 (Assembly Biosciences), WO2017048954 (Assembly Biosciences), WO2017048962 (Assembly Biosciences), US20170121328 (Novira), US20170121329 (Novira).

[0374] Examples of transcript inhibitors include compounds disclosed in WO2017013046 (Roche), WO2017016960 (Roche), WO2017017042 (Roche), WO2017017043 (Roche), WO2017061466 (Toyoma chemicals), WO2016177655 (Roche), WO2016161268 (Enanta), WO2017001853 (Redex Pharma), WO2017211791 (Roche), WO2017216685 (Novartis), WO2017216686 (Novartis), WO2018019297 (Ginkgo Pharma), WO2018022282 (Newave Pharma), US20180030053 (Novartis), WO2018045911 (Zhejiang Pharma).

[0375] retinoic acid inducible gene 1 stimulator

[0376] 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.

[0377] NOD2 Stimulator

[0378] Examples of stimulators of NOD2 include SB-9200.

[0379] Phosphatidylinositol 3-kinase (PI3K) inhibitors

[0380] Examples of PI3K inhibitors include idelixib, ACP-319, AZD-8186, AZD-8835, bupariciib, CDZ-173, CLR-457, idarucizumab, neratinib, regoratinib, regoratinib sodium, EN-3342, TGR-1202, abolicibub, duvelixibub, IPI-549, UCB-5857, taselixibub, XL-765, gadalixibub, ME-401, VS-5584, copanlixibub, orotate CAI, perifosine, RG-7666, GSK-2636771, DS-7423, panulicibub, GSK -2269557, GSK-2126458, CUDC-907, PQR-309, INCB-40093, pilalisibu, BAY-1082439, puroquitinib mesylate, SAR-245409, AMG-319, RP-6530, ZSTK-474, MLN-1117, SF-1126, RV-1729, sonolisibu, LY-3023414, SAR-260301, TAK-117, HMPL-689, tenalisib, voxtalisib, and CLR-1401.

[0381] Indoleamine-2,3-dioxygenase (IDO) pathway inhibitors

[0382] Examples of IDO inhibitors include icaridostat (INCB24360), resminostat (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.).

[0383] PD-1 inhibitors

[0384] Examples of PD-1 inhibitors include cemiplizumab, 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, carrelizumab, sintilimab, tislelizumab, BCD-100, BGB-A333, and sirolimus. JNJ-63723283, GLS-010 (WBP-3055), CX-072, AGEN-2034, GNS-1480 (epidermal growth factor receptor antagonist; programmed cell death ligand 1 inhibitor), CS-1001, M-7824 (PD-L1 / TGF-β bifunctional fusion protein), Genolizumab, BMS-936559.

[0385] PD-L1 inhibitors

[0386] 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.

[0387] Examples of PD-1 inhibitors include compounds disclosed in the following patents: 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 (BristolMyers Squibb Co), WO2016142886 (Aurigene Discovery Technologies Ltd), WO2016142852 (Aurigene Discovery Technologies Ltd), WO2016142835 (AurigeneDiscovery Technologies Ltd; Individual), WO2016142833 (Aurigene DiscoveryTechnologies Ltd), WO2018085750 (Bristol Myers Squibb Co), WO2015033303 (AurigeneDiscovery Technologies Ltd), WO2017205464 (Incyte Corp), WO2016019232 (3M Co; Individual;Texas A&M University System)、WO2015160641(Bristol Myers SquibbCo)、WO2017079669(Incyte Corp)、WO2015033301(Aurigene Discovery TechnologiesLtd)、WO2015034820(Bristol Myers Squibb Co)、WO2018073754(Aurigene DiscoveryTechnologies Ltd)、WO2016077518(Bristol Myers Squibb Co)、WO2016057624(BristolMyers Squibb Co)、WO2018044783(Incyte Corp)、WO2016100608(Bristol Myers SquibbCo)、WO2016100285(Bristol Myers Squibb Co)、WO2016039749(Bristol Myers SquibbCo)、WO2015019284(Cambridge Enterprise Ltd)、WO2016142894(Aurigene DiscoveryTechnologies Ltd)、WO2015134605(Bristol Myers Squibb Co)、WO2018051255(AurigeneDiscovery Technologies Ltd)、WO2018051254(Aurigene Discovery TechnologiesLtd)、WO2017222976(Incyte Corp)、WO2017070089(Incyte Corp)、WO2018044963(BristolMyers Squibb Co)、WO2013144704(Aurigene Discovery Technologies Ltd)、WO2018013789(Incyte Corp)、WO2017176608(Bristol Myers Squibb Co)、WO2018009505(Bristol Myers Squibb 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). ;

[0388] Recombinant Thymosin Alpha-1

[0389] Examples of recombinant thymosin alpha-1 include NL-004 and pegylated thymosin alpha-1.

[0390] Bruton's tyrosine kinase (BTK) inhibitors

[0391] 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, sipetinib, 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).

[0392] KDM inhibitors

[0393] Examples of KDM5 inhibitors include compounds disclosed in WO2016057924 (Genentech / Constellation Pharmaceuticals), US20140275092 (Genentech / Constellation Pharmaceuticals), US20140371195 (Epitherapeutics) and US20140371214 (Epitherapeutics), US20160102096 (Epitherapeutics), US20140194469 (Quanticel), US20140171432, US20140213591 (Quanticel), US20160039808 (Quanticel), US20140275084 (Quanticel), and WO2014164708 (Quanticel).

[0394] Examples of KDM1 inhibitors include compounds disclosed in US9186337B2 (Oryzon Genomics), GSK-2879552, and RG-6016.

[0395] STING agonists

[0396] Examples of STING agonists include SB-11285, AdVCA0848, STINGVAX, and compounds disclosed in WO 2018065360 ("Biolog Life Science Institute Forschungslabor und Biochemica-Vertrieb GmbH, Germany), WO 2018009466 (Aduro Biotech), WO 2017186711 (InvivoGen), WO 2017161349 (Immune Sensor), WO 2017106740 (Aduro Biotech), US 20170158724 (Glaxo Smithkline), WO 2017075477 (Aduro Biotech), US 20170044206 (Merck), WO 2014179760 (University of California), WO2018098203 (Janssen), WO2018118665 (Merck), WO2018118664 (Merck), WO2018100558 (Takeda), WO2018067423 (Merck), WO2018060323 (Boehringer).

[0397] Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

[0398] Examples of NNRTIs include compounds disclosed in WO2018118826 (Merck), WO2018080903 (Merck), WO2018119013 (Merck), WO2017100108 (Idenix), WO2017027434 (Merck), WO2017007701 (Merck), and WO2008005555 (Gilead).

[0399] HBV replication inhibitors

[0400] Examples of hepatitis B virus replication inhibitors include isothiafluxidine, IQP-HBV, RM-5038, and Xingantie.

[0401] Arginase inhibitors

[0402] Examples of arginase inhibitors include CB-1158, C-201, and Resminostat.

[0403] Gene therapy and cell therapy

[0404] Gene therapy and cell therapy include genetic modifications that silence genes; genetic approaches that directly kill infected cells; infusions of immune cells designed to replace a large portion of the patient's own immune system to boost 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 approaches that alter cellular activity to further alter the endogenous immune response to infection.

[0405] Gene Editor

[0406] Examples of genome editing systems include CRISPR / Cas9 systems, zinc finger nuclease systems, TALEN systems, homing endonuclease systems, and meganuclease systems; for example, cccDNA elimination via targeted cleavage and alteration of one or more of hepatitis B virus (HBV) viral genes. Alteration (e.g., knockout and / or knockdown) of PreC, C, X, PreSI, PreS2, S, P or SP genes refers to (1) reduction or elimination of PreC, C, X, PreSI, PreS2, S, P or SP gene expression, (2) interference with pre-core, core, X protein, long surface protein, intermediate surface protein, S protein (also known as HBs antigen and HBsAg), polymerase protein and / or hepatitis B splicing protein function (HBe, HBc, HBx, PreS1, PreS2, S, Pol and / or HBSP, or (3) reduction or elimination of intracellular, serum and / or intraparenchymal levels of HBe, HBc, HBx, LHB, MHB, SHB, Pol and / or HBSP proteins. Knockdown of one or more of the PreC, C, X, PreSI, PreS2, S, P and / or SP genes is performed by targeting these genes within HBVcccDNA and / or integrated HBV DNA.

[0407] CAR-T cell therapy

[0408] 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.

[0409] TCR-T cell therapy

[0410] TCR T cell therapy includes T cells expressing HBV-specific T cell receptors. TCR-T cells are engineered to target HBV-derived peptides present 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 HBV treatment include LTCR-H2-1.

[0411] In another specific embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with an HBV DNA polymerase inhibitor, one or more additional therapeutic agents selected from the group consisting of an immunomodulator, a TLR modulator, an HBsAg inhibitor, an HBsAg secretion or assembly inhibitor, an HBV therapeutic vaccine, an HBV antibody (including an HBV antibody targeting a surface antigen of the hepatitis B virus), and a bispecific antibody and an "antibody-like" therapeutic protein (such as 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 more additional therapeutic agents selected from the group consisting of: HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting the surface antigen of hepatitis B virus, siRNA, miRNA gene therapy agents, sshRNA, KDM5 inhibitors and nucleoprotein modulators (HBV core protein or capsid protein modulators).

[0412] In another specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HBV DNA polymerase inhibitor and at least a second additional therapeutic agent selected from the group consisting of an immunomodulator, a TLR modulator, an HBsAg inhibitor, an HBV therapeutic vaccine, an HBV antibody (including an HBV antibody targeting a surface antigen of the hepatitis B virus), and a bispecific antibody and an "antibody-like" therapeutic protein (such as Fab derivatives or TCR-like antibodies), cyclophilin inhibitors, stimulators of retinoic acid-inducible gene 1, stimulators of RIG-I-like receptors, PD-1 inhibitors, PD-L1 inhibitors, arginase inhibitors, PI3K inhibitors, IDO inhibitors and stimulators of NOD2.

[0413] 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 the group consisting of: HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting the surface antigen of hepatitis B virus, siRNA, miRNA gene therapy agents, sshRNA, KDM5 inhibitors, and nucleoprotein modulators (HBV core protein or capsid protein modulators).

[0414] In a specific embodiment, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with compounds such as those disclosed in the following patents and other drugs for treating HBV, and combinations thereof: U.S. Publication No. 2010 / 0143301 (Gilead Sciences), U.S. Publication No. 2011 / 0098248 (Gilead Sciences), U.S. Publication No. 2009 / 0047249 (Gilead Sciences), U.S. Patent No. 8722054 (Gilead Sciences), Sciences), US Publication No. 2014 / 0045849 (Janssen), US 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 / 0234251 (ArrayBiopharma), US Publication No. 2008 / 0306050 (Array Biopharma), US Publication No. 2010 / 0029585 (Ventirx Pharma), US Publication No. 2011 / 0092485 (Ventirx Pharma), US2011 / 0118235 (Ventirx Pharma), U.S. Publication No. 2012 / 0082658 (Ventirx Pharma), U.S. Publication No. 2012 / 0219615 (Ventirx Pharma), U.S. Publication No. 2014 / 0066432 (Ventirx Pharma), U.S. Publication No. 2014 / 0088085 (Ventirx Pharma), 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. 2014 / 0030221 (Gilead Sciences), U.S. Publication No. 2013 / 0344030 (GileadSciences), U.S. Publication No. 2013 / 0344029 (Gilead Sciences), US20140275167 (Novira Therapeutics), US20130251673 (NoviraTherapeutics), 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), WO2014161888 (Janssen), WO2015 13096744(Novira)、US20150225355(Novira)、US20140178337(Novira)、US20150315159(No vira), US20150197533 (Novira), US20150274652 (Novira), US20150259324 (Novira), US201 50132258(Novira)、US9181288(Novira)、WO2014184350(Janssen)、WO2013144129(Roche)、 US20100015178 (Incyte), US2016137652 (Flexus Biosciences, Inc.), WO2014073738 (Flexus Biosciences, Inc.), WO2015188085 (Flexus Biosciences, Inc.), US Publication No. 2014 / 0330015 (Ono Pharmaceutical), US Publication No. 2013 / 0079327 (Ono Pharmaceutical), US Publication No. 2013 / 0217880 (Ono pharmaceutical), WO2016057924 (Genentech / Constellation Pharmaceuticals), US20140275092 (Genentech / Constellation Pharmaceuticals),Pharmaceuticals), US20140371195 (Epitherapeutics) and US20140371214 (Epitherapeutics), US20160102096 (Epitherapeutics), US20140194469 (Quanticel), US2 0140171432, US20140213591 (Quanticel), US20160039808 (Quanticel), US20140275084 (Quanticel), WO2014164708 (Quanticel), US9186337B2 (OryzonGenomics).

[0415] Cancer combination therapy

[0416] In one embodiment, the compounds of the present disclosure may be used together with other therapeutic approaches for the treatment of cancer. Preferably, combination therapy with chemotherapy, hormones, antibodies, surgery and / or radiation therapy is contemplated.

[0417] In some embodiments, the additional anti-cancer therapy is surgery and / or radiation therapy.

[0418] In some embodiments, the additional anti-cancer therapy is at least one additional cancer drug.

[0419] 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.

[0420] In some embodiments, provided are combinations comprising a compound as described herein, or a pharmaceutically acceptable salt thereof, and at least one additional cancer drug for use in treatment.

[0421] In some embodiments, there is provided the use of a combination comprising a compound as described herein, or a pharmaceutically acceptable salt thereof, and at least one cancer drug in the manufacture of a medicament for treating cancer.

[0422] Examples of additional 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 aurin tricarboxylic acid; nitrosourea compounds such as carmustine (BCNU), lomustine (CCNU), and streptozotocin; nitrogen mustards such as cyclophosphamide, dimethoate, and succinate; chlorethylmethylamine, uramustine, bendamustine, melphalan, chlorambucil, mafosfamide, trofosfamide, and ifosfamide; alkyl sulfonates such as busulfan and threosulfan; 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 progestins, 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, mapatumumab, matuzumab, rhMabICR62 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.

[0423] In certain embodiments, methods for treating or preventing a hyperproliferative disorder or cancer in a human or animal having or at risk of a hyperproliferative disorder or cancer are provided, comprising administering to the human or animal a therapeutically effective amount of a compound as disclosed herein, or 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. In one embodiment, methods for treating a hyperproliferative disorder or cancer in a human or animal having or at risk of a hyperproliferative disorder or cancer are provided, comprising administering to the human or animal a therapeutically effective amount of a compound as disclosed herein, or 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.

[0424] In certain embodiments, the present disclosure provides methods for treating a hyperproliferative disorder or cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents suitable for treating the hyperproliferative disorder or cancer.

[0425] The compounds described herein can be used or combined with one or more of the following: chemotherapeutic agents, anti-cancer agents, anti-angiogenic agents, anti-fibrotic agents, immunotherapeutic agents, therapeutic antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins (such as Fab derivatives), antibody-drug conjugates (ADC), radiotherapeutics, antitumor agents, antiproliferative agents, oncolytic viruses, gene modifiers or editors (such as CRISPR / Cas9, zinc finger nucleases or synthetic nucleases, TALEN), 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, a product is provided herein, comprising a compound as described herein and an additional therapeutic agent, as a combined preparation used simultaneously, separately, or sequentially in treatment.

[0426] The one or more therapeutic agents include, but are not limited to, inhibitors, agonists, antagonists, ligands, modulators, stimulators, blockers, activators or inhibitors of genes, ligands, receptors, proteins or factors. Non-limiting examples of additional therapeutic agents include: Epstein murine leukemia virus 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 bacteriolysin, AKT1 gene, Alk-5 protein kinase, alkaline phosphatase, α1 adrenal receptor, α2 adrenal receptor, α-ketoglutarate dehydrogenase (KGDH), aminopeptidase N, AMP activity , anaplastic lymphoma kinase (ALK, such as ALK1), androgen receptor, angiopoietin (such as ligand-1, 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 protein (such as 1, 2), apoptosis signal regulating kinase (ASK, such as ASK1), arginase (I), arginine deiminase, aromatase, steroid homolog 1 (ASTE1) gene, ataxia telangiectasia and Rad3-related (A TR) serine / threonine protein kinase, Aurora protein kinase (such as 1, 2), Axl tyrosine kinase receptor, baculovirus IAP repeat-containing 5 (BIRC5) gene, Basigin, B cell lymphoma 2 (BCL2) gene, Bcl2 binding component 3, Bcl2 protein, BCL2L11 gene, BCR (breakpoint cluster region) protein and gene, beta adrenal 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-9 ligand regulator Regulators, Brachyury proteins, Bradykinin receptors, 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 kinases (such as CHK1, CHK2), chemokine (CC motif) receptors (such as CCR2, CCR4, CCR5), chemokine (CXC motif) receptors (such as CXCR4, CXCR1 and CXCR2), chemokine CC21 ligand, cholecystokinin CCK2 receptor, chorionic gonadotropin, c-Kit (tyrosine-protein kinase Kit or CD117), occludens (such as 6, 18), clusters of differentiation (CD) (such as CD4, CD27, CD29, CD30, CD33, CD37, CD40, CD40 ligand receptor, CD40 ligand, CD40LG gene, CD44, CD45, CD47, CD49b , CD51, CD52, CD55, CD58, CD66e, CD70 gene, CD74, 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 body 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 P45011B2, cytochrome P450 17, cytochrome P450 17A1, cytochrome P450 2D6, cytochrome P4503A4, cytochrome P450 reductase, cytokine signaling-1, cytokine signaling-3, cytochrome 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,such as DDR1), DNA binding proteins (such as HU-β), DNA dependent protein kinases, DNA gyrase, DNA methyltransferase, DNA polymerase (such as α), DNA primase, dUTP pyrophosphatase, L-dopa acid tautomerase, echinoderm tubulin 4, EGFR tyrosine kinase receptor, elastase, elongation factor 1 α2, elongation factor 2, endoglin, endonuclease, endoplasmin, endosialin, endostatin, endothelin (such as ET-A, ET-B), enhancer of zeste homolog 2 (EZ H2), 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 mitogen (Epigen), 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 deoxy Hydrogenase, estrogen receptor (such as α, β), estrogen-related receptor, eukaryotic translation initiation factor 5A (EIF5A) gene, exportin 1, extracellular signal-related kinase (such as 1, 2), extracellular signal-regulated kinase (ERK), factor (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 alkaline amino acid lyase (FURIN), β-glucuronidase, galactosyltransferase, galectin-3, ganglioside GD2, glucocorticoids, glucocorticoid-induced TNFR-related protein GITR receptor, glutamate carboxypeptidase II, glutaminase, glutathione S-transferase P, glycogen synthase kinase (GSK,such as 3-β), acetylin 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 (78 kDa 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 H1, 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 maternally expressed transcript (H19) 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, 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 melanoma missing factor 2 (AIM2), interferon type I 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, lysase, lymphocyte activation gene 3 protein (LAG-3), lymphocyte antigen 75, lymphocyte function antigen-3 receptor, lymphocyte-specific protein tyrosine kinase (LCK), lymphocyte chemokine, 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 kinase 1 (HPK1), hepatocyte growth factor receptor (MET) gene, macrophage colony stimulating factor (MCSF) ligand, macrophage migration inhibitory factor, 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, Mdm2 p53 binding protein, Mdm4 protein, melanin-A (MART-1) melanoma antigen, melanocyte protein Pmel 17, 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 (six transmembrane epithelial antigen of the prostate 1), metastasis inhibitor, methionine aminopeptidase-2, methyltransferase, mitochondrial 3 ketoacyl CoA thiolase, mitogen activated protein kinase (MAPK), mitogen activated protein kinase (MEK, such as MEK1, MEK2), mTOR (mechanistic target of rapamycin (serine / threonine kinase), mTOR complex (such as 1, 2), mucin (such as 1, 5A, 16), mutT 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 activating protein, NIMA-associated kinase 9 (NEK9), nitric oxide synthase, NK cell receptor, NK3 receptor, NKG2 AB 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 (such as delta), ornithine decarboxylase, orotate phosphoribosyltransferase, orphan nuclear hormone receptor NR4A1, osteocalcin, osteoclast differentiation factor, osteopontin, OX-40 (tumor necrosis factor receptor superfamily member 4T NFRSF4 or CD134) receptor, P3 protein, p38 kinase, p38MAP kinase, p53 tumor suppressor protein, parathyroid hormone ligand, peroxisome proliferator-activated receptor (PPAR, such as α, δ, γ), P-glycoprotein (such as 1), phosphatase and tensin homolog (PTEN), phosphatidylinositol 3-kinase (PI3K), phosphoinositide-3 kinase (PI3K, 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), multi-directional 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), melanoma preferentially expressed antigen (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), prosaposin (PSAP) gene, prostanoid 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 (Ras homolog abundant in brain) GTPase, Rho (Ras homolog) associated protein kinase 2, ribonuclease, ribonucleotide reductase (such as M2 subunit), ribosomal protein S6 kinase, RNA polymerase (such as I, II), Ron (Recepteur d'Origine Nantais) 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 activator of caspase (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 STAT-1, STAT-3, STAT-5), signaling lymphocyte activation molecule (SLAM) family member 7, six transmembrane epithelial antigens of the prostate (STEAP) gene, SL cytokine ligand, smoothened (SMO) receptor, sodium iodide co-transporter, sodium phosphate co-transporter 2B, somatostatin receptors (such as 1, 2, 3, 4, 5), sonic hedgehog protein, Son of sevenless (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, stimulator of interferon genes (STING) receptor, stimulator of interferon genes protein, stromal cell-derived factor 1 ligand, SUMO (small ubiquitin-like modifier), superoxide dismutase, survivin protein , synaptophysin 3, syndecan-1, synuclein α, T cell surface glycoprotein CD28, tank binding kinase (TBK), TATA box binding protein-associated factor RNA polymerase I subunit B (TAF1B) gene, T cell CD3 glycoprotein 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 (T ERT) 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 (TLRs such as 1-13), topoisomerases (such as I, I I, III), transcription factors, transferases, transferrin, transforming growth factor (TGF, such as β) kinase, transforming growth factor TGF-β receptor kinase, transglutaminase, translocation-associated protein, transmembrane glycoprotein NMB, Trop-2 calcium signal transducer, trophoblast cell glycoprotein (TPBG) gene, trophoblast cell 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, tyrosine kinase with immunoglobulin-like and EGF-like domains (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, uterus Globin, capsaicin (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.

[0427] Non-limiting examples of additional therapeutic agents can be categorized according to their mechanism of action into, for example, the following groups:

[0428] -Antimetabolites / anticancer agents such as the pyrimidine analogs floxuridine, capecitabine, cytarabine, CPX-351 (liposomal cytarabine, daunorubicin), and TAS-118;

[0429] -Purine analogs, folate antagonists (such as pralatrexate) and related inhibitors;

[0430] - 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);

[0431] -DNA damaging agents such as actinomycin, amsacrine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide Dactinomycin, daunorubicin, doxorubicin, epirubicin, ifosfamide, melphalan, nitrogen mustard (merchlorethamine), mitomycin C, mitoxantrone, nitrosoureas, procarbazine, tacrolimus, taxotere, teniposide, etoposide, and triethylenethiophosphoramide;

[0432] - DNA-methylating agents, such as guadecitabine (SGI-110), ASTX727;

[0433] - Antibiotics such as dactinomycin, daunorubicin, doxorubicin, idarubicin, anthracyclines, mitoxantrone, bleomycin, plicamycin (mithramycin);

[0434] - enzymes, such as L-asparaginase, which systemically metabolize L-asparagine and inactivate cells that do not have the ability to synthesize their own asparagine;

[0435] - Antiplatelet agents;

[0436] - DNAi oligonucleotides targeting Bcl-2, such as PNT2258;

[0437] -Agents that activate or reactivate latent human immunodeficiency virus (HIV), such as panobinostat and romidepsin;

[0438] -Asparaginase stimulators, such as crisantaspase and GRASPA (ERY-001, ERY-ASP), calaspargase pegol;

[0439] - pan-Trk, ROS1 and ALK inhibitors, such as entrectinib, TPX-0005;

[0440] - anaplastic lymphoma kinase (ALK) inhibitors, such as alectinib, ceritinib;

[0441] - Antiproliferative / antimitotic alkylating agents, such as the nitrogen mustard cyclophosphamide and analogs (melphalan, chlorambucil, hexamethonium, thiotepa), alkylnitrosoureas (carmustine) and analogs, streptozotocin, and triazenes (dacarbazine);

[0442] - Antiproliferative / antimitotic antimetabolites, such as folic acid analogs (methotrexate);

[0443] - Platinum coordination complexes (cisplatin, oxaliplatin and carboplatin), procarbazine, hydroxyurea, mitotane and aminoglutethimide;

[0444] - Hormones, hormone analogs (estrogens, tamoxifen, goserelin, bicalutamide, and nilutamide), and aromatase inhibitors (letrozole and anastrozole);

[0445] - anticoagulants, such as heparin, synthetic heparin salts and other inhibitors of thrombin;

[0446] - Fibrinolytic agents, such as tissue plasminogen activator, streptokinase, urokinase, aspirin, dipyridamole, ticlopidine and clopidogrel;

[0447] - Anti-migration agents;

[0448] - Antisecretory agents (breveldin);

[0449] - immunosuppressants such as tacrolimus, sirolimus, azathioprine and mycophenolate; - growth factor inhibitors and vascular endothelial growth factor inhibitors;

[0450] - Fibroblast growth factor inhibitors, such as FPA14;

[0451] - anti-VEGFR antibodies, such as IMC-3C5, GNR-011, tanibirumab;

[0452] - anti-VEGF / DDL4 antibodies, such as ABT-165;

[0453] - anti-cadherin antibodies, such as HKT-288;

[0454] -Anti-CD70 antibodies, such as AMG-172; anti-leucine-rich repeat-containing 15 (LRRC15) antibodies, such as ABBV-085. ARGX-110;

[0455] -Angiotensin receptor blockers, nitric oxide donors;

[0456] - antisense oligonucleotides, such as AEG35156, IONIS-KRAS-2.5Rx, EZN-3042, RX-0201, IONIS-AR-2.5Rx, BP-100 (prexigebersen), IONIS-STAT3-2.5Rx;

[0457] -DNA interfering oligonucleotides, such as PNT2258, AZD-9150;

[0458] - anti-ANG-2 antibodies, such as MEDI3617 and LY3127804;

[0459] - anti-ANG-1 / ANG-2 antibodies, such as AMG-780;

[0460] - anti-MET / EGFR antibodies, such as LY3164530;

[0461] - anti-EGFR antibodies, such as ABT-414, AMG-595, necitumumab, ABBV-221, depatuxizumab, modotuximab, ABT-414, tomozuotuximab, ABT-806, Vectibix, modotuximab, RM-1929;

[0462] - anti-CSF1R antibodies, such as emactuzumab, LY3022855, AMG-820, FPA-008 (cabiralizumab);

[0463] - anti-CD40 antibodies, such as RG7876, SEA-CD40, APX-005M, ABBV-428;

[0464] - anti-endoglin antibodies, such as TRC105 (carotuximab);

[0465] - anti-CD45 antibodies, such as 131I-BC8 (lomab-B);

[0466] - Anti-HER3 antibodies, such as LJM716, GSK2849330;

[0467] - anti-HER2 antibodies, such as margetuximab, MEDI4276, BAT-8001;

[0468] - anti-HLA-DR antibodies, such as IMMU-114;

[0469] - anti-IL-3 antibodies, such as JNJ-56022473;

[0470] - anti-OX40 antibodies such as MEDI6469, MEDI6383, MEDI0562 (tavolixizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368;

[0471] - anti-EphA3 antibodies, such as KB-004;

[0472] - Anti-CD20 antibodies, such as atezolizumab, IGN-002;

[0473] - anti-CD20 / CD3 antibodies, such as RG7828;

[0474] - anti-CD37 antibodies, such as AGS67E, oleotuzumab (TRU-016);

[0475] - anti-ENPP3 antibodies, such as AGS-16C3F;

[0476] - anti-FGFR-3 antibodies, such as LY3076226, B-701;

[0477] - anti-FGFR-2 antibodies, such as GAL-F2;

[0478] - anti-C5 antibodies, such as ALXN-1210;

[0479] - anti-CD27 antibodies, such as varilumab (CDX-1127);

[0480] - anti-TROP-2 antibodies, such as IMMU-132;

[0481] - anti-NKG2a antibodies, such as monalizumab;

[0482] -Anti-VISTA antibodies, such as HMBD-002;

[0483] - anti-PVRIG antibodies, such as COM-701;

[0484] - anti-EpCAM antibodies, such as VB4-845;

[0485] - anti-BCMA antibodies, such as GSK-2857916;

[0486] - anti-CEA antibodies, such as RG-7813;

[0487] - anti-cluster of differentiation 3 (CD3) antibodies, such as MGD015;

[0488] - anti-folate receptor alpha antibodies, such as IMGN853;

[0489] - MCL-1 inhibitors such as AMG-176, S-64315 and AZD-5991, 483-LM, A-1210477, UMI-77, JKY-5-037;

[0490] -epha2 inhibitors, such as MM-310;

[0491] - Anti-LAG-3 antibodies, such as relalizumab (ONO-4482), LAG-525, MK-4280, REGN-3767;

[0492] -raf kinase / VEGFR inhibitors, such as RAF-265;

[0493] - Polycomb (EED) inhibitors, such as MAK683;

[0494] - anti-fibroblast activation protein (FAP) / IL-2R antibodies, such as RG7461;

[0495] - anti-fibroblast activation protein (FAP) / TRAIL-R2 antibodies, such as RG7386;

[0496] - anti-Fucosyl-GM1 antibodies, such as BMS-986012;

[0497] - p38 MAP kinase inhibitors, such as lenimetinib;

[0498] -PRMT1 inhibitors, such as MS203;

[0499] - Sphingosine kinase 2 (SK2) inhibitors, such as opaganib;

[0500] - FLT3-ITD inhibitors, such as BCI-332;

[0501] - Erythroid 2-related factor 2 stimulators, such as omasorolone (RTA-408);

[0502] - Tropomyosin receptor kinase (TRK) inhibitors, such as LOXO-195, ONO-7579;

[0503] - Anti-ICOS antibodies, such as JTX-2011, GSK3359609;

[0504] - anti-DR5 (TRAIL2) antibodies, such as DS-8273;

[0505] - anti-GD2 antibodies, such as APN-301;

[0506] - anti-interleukin-17 (IL-17) antibodies, such as CJM-112;

[0507] - anti-carbonic anhydrase IX antibodies, such as TX-250;

[0508] - anti-CD38 attenukine, such as TAK573;

[0509] - anti-mucin 1 antibodies, such as gatipotuzumab;

[0510] - Mucin 1 inhibitors, such as GO-203-2C;

[0511] - MARCKS protein inhibitors, such as BIO-11006;

[0512] - Folate antagonists, such as arfolitixorin;

[0513] - galectin-3 inhibitors, such as GR-MD-02;

[0514] -Phosphopeptide 68 inhibitors, such as RX-5902;

[0515] -CD95 / TNF modulators, such as ofranergene obadenovec;

[0516] -PI3K / Akt / mTOR inhibitors, such as ABTL-0812;

[0517] - pan-PIM kinase inhibitors, such as INCB-053914;

[0518] - IL-12 gene stimulators, such as EGEN-001, tavokinogene telseplasmid;

[0519] - Heat shock protein HSP90 inhibitors, such as TAS-116, PEN-866;

[0520] - VEGF / HGF antagonists, such as MP-0250;

[0521] -SYK tyrosine kinase / FLT3 tyrosine kinase inhibitors, such as TAK-659;

[0522] -SYK tyrosine kinase / JAK tyrosine kinase inhibitors, such as ASN-002;

[0523] - FLT3 tyrosine kinase inhibitors, such as FF-10101;

[0524] - FLT3 tyrosine kinase agonists, such as CDX-301;

[0525] - FLT3 / MEK1 inhibitors, such as E-6201;

[0526] - IL-24 antagonists, such as AD-IL24;

[0527] - RIG-I agonists, such as RGT-100;

[0528] - Aeromonas lysin stimulators, such as topsalysin;

[0529] - P-glycoprotein 1 inhibitors, such as HM-30181A;

[0530] - CSF-1 antagonists, such as ARRY-382, BLZ-945;

[0531] - anti-mesothelin antibodies, such as SEL-403;

[0532] - thymidine kinase stimulators, such as aglatimagene besadenovec;

[0533] - Polo-like kinase 1 inhibitors, such as PCM-075;

[0534] - TLR-7 agonists, such as TMX-101 (imiquimod);

[0535] -NEDD8 inhibitors, such as pevonedistat (MLN-4924), TAS-4464;

[0536] - Multidirectional pathway modulators, such as avadomide (CC-122);

[0537] -FoxM1 inhibitors, such as thiostrepton;

[0538] - anti-MUC1 antibodies, such as Mab-AR-20.5;

[0539] - anti-CD38 antibodies, such as isatuximab, MOR-202;

[0540] -UBA1 inhibitors, such as TAK-243;

[0541] - Src tyrosine kinase inhibitors, such as VAL-201;

[0542] - VDAC / HK inhibitors, such as VDA-1102;

[0543] -BRAF / PI3K inhibitors, such as ASN-003;

[0544] - Elf4a inhibitors, such as rohinitib, eFT226;

[0545] -TP53 gene stimulators, such as ad-p53;

[0546] -PD-L1 / EGFR inhibitors, such as GNS-1480;

[0547] - Retinoic acid receptor alpha (RARα) inhibitors, such as SY-1425;

[0548] - SIRT3 inhibitors, such as YC8-02;

[0549] - Stromal cell-derived factor 1 ligand inhibitors, such as olaptesed pegol (NOX-A12);

[0550] - IL-4 receptor modulators, such as MDNA-55;

[0551] - Arginase-I stimulators, such as pegzilarginase;

[0552] - Topoisomerase I inhibitors / hypoxia-inducible factor-1α inhibitors, such as PEG-SN38 (firtecanpegol);

[0553] - Hypoxia-inducible factor-1α inhibitors, such as PT-2977, PT-2385;

[0554] -CD122 agonists, such as NKTR-214;

[0555] - p53 tumor suppressor protein stimulators, such as kevetrin;

[0556] - Mdm4 / Mdm2 p53 binding protein inhibitors, such as ALRN-6924;

[0557] - Kinesin (KSP) inhibitors, such as filanisib (ARRY-520);

[0558] -CD80-fc fusion protein inhibitors, such as FPT-155;

[0559] -Menin and mixed lineage leukemia (MLL) inhibitors, such as KO-539;

[0560] - liver x receptor agonists, such as RGX-104;

[0561] - IL-10 agonists, such as AM-0010;

[0562] - EGFR / ErbB-2 inhibitors, such as varlitinib;

[0563] - VEGFR / PDGFR inhibitors, such as vorolanib;

[0564] - IRAK4 inhibitors, such as CA-4948;

[0565] - anti-TLR-2 antibodies, such as OPN-305;

[0566] - Calmodulin modulators, such as CBP-501;

[0567] - glucocorticoid receptor antagonists, such as relacorilant (CORT-125134);

[0568] - Second mitochondrial-derived activator of caspase (SMAC) protein inhibitors, such as BI-891065;

[0569] - Lactoferrin modulators, such as LTX-315;

[0570] -Kit tyrosine kinase / PDGF receptor alpha antagonists, such as DCC-2618;

[0571] - KIT inhibitors, such as PLX-9486;

[0572] - exportin 1 inhibitors, such as eltanexor;

[0573] - EGFR / ErbB2 / Ephb4 inhibitors, such as tesevatinib;

[0574] - anti-CD33 antibodies, such as IMGN-779;

[0575] - anti-KMA antibodies, such as MDX-1097;

[0576] - Anti-TIM-3 antibodies, such as TSR-022, LY-3321367, MBG-453;

[0577] - anti-CD55 antibodies, such as PAT-SC1;

[0578] - anti-PSMA antibodies, such as ATL-101;

[0579] - anti-CD100 antibodies, such as VX-15;

[0580] - anti-EPHA3 antibodies, such as fibatuzumab;

[0581] - Anti-Erbb antibodies, such as CDX-3379, HLX-02, seribantumab;

[0582] - anti-APRIL antibodies, such as BION-1301;

[0583] - Anti-Tigit antibodies, such as BMS-986207, RG-6058;

[0584] - CHST15 gene inhibitors, such as STNM-01;

[0585] -RAS inhibitors, such as NEO-100;

[0586] - somatostatin receptor antagonists, such as OPS-201;

[0587] -CEBPA gene stimulators, such as MTL-501;

[0588] -DKK3 gene modulators, such as MTG-201;

[0589] - p70s6k inhibitors, such as MSC2363318A;

[0590] - Methionine aminopeptidase 2 (MetAP2) inhibitors, such as M8891, APL-1202;

[0591] - arginine N-methyltransferase 5 inhibitors, such as GSK-3326595;

[0592] - 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 (cemiprilimab), AGEN-2034, JS-001, JNJ-63723283, genol monoclonal antibody (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, BAT-1306, and anti-programmed death ligand 1 (anti-PD-L1) antibodies, such as BMS-936559, atezolizumab (MPDL3280A), durvalumab (MEDI4736), avelumab, CK-301 (MSB0010718C), MEDI0680, CX-072, CBT-502, PDR-001 (spartalizumab), TSR-042 (dostarlimab), JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155, KN-035, IBI-308, FAZ-053, and MDX1105-01);

[0593] -PD-L1 / VISTA antagonists, such as CA-170;

[0594] -Anti-PD-L1 / TGFβ antibodies, such as M7824;

[0595] - Anti-transferrin antibodies, such as CX-2029;

[0596] - anti-IL-8 (interleukin-8) antibodies, such as HuMax-Inflam;

[0597] - ATM (ataxia telangiectasia) inhibitors, such as AZD0156;

[0598] - CHK1 inhibitors, such as GDC-0575, LY2606368 (prexasertib), SRA737, RG7741 (CHK1 / 2);

[0599] - CXCR4 antagonists, such as BL-8040, LY2510924, burixafor (TG-0054), X4P-002, X4P-001-IO;

[0600] - EXH2 inhibitors, such as GSK2816126;

[0601] -HER2 inhibitors, such as neratinib, tucatinib (ONT-380);

[0602] - KDM1 inhibitors such as ORY-1001, IMG-7289, INCB-59872, GSK-2879552;

[0603] - CXCR2 antagonists, such as AZD-5069;

[0604] -GM-CSF antibodies, such as lenzilumab;

[0605] - DNA-dependent protein kinase inhibitors, such as MSC2490484A (nedisertib), VX-984, AsiDNA (DT-01);

[0606] - Protein kinase C (PKC) inhibitors, such as LXS-196, sotrastaurin;

[0607] -Selective estrogen receptor downregulators (SERDs), such as fulvestrant RG6046, RG6047, elacestrant (RAD-1901), and AZD9496;

[0608] - Selective estrogen receptor covalent antagonists (SERCAs), such as H3B-6545;

[0609] - Selective androgen receptor modulators (SARMs), such as GTX-024, darolutamide;

[0610] - Transforming growth factor-β (TGF-β) kinase antagonists, such as galunisertib;

[0611] - anti-transforming growth factor-β (TGF-β) antibodies, such as LY3022859, NIS793, XOMA089;

[0612] - Bispecific antibodies, such as MM-141 (IGF-1 / ErbB3), MM-111 (Erb2 / Erb3), JNJ-64052781 (CD19 / CD3), PRS-343 (CD-137 / HER2), AFM26 (BCMA / CD16A), JNJ-61186372 (EGFR / cMET), AMG-211 (CEA / CD3), RG7802 (CEA / CD3), ERY-974 (CD3 / GPC3), vancizumab (angiopoietin / VEGF), PF-06671008 (cadherin / CD3), AFM-13 (CD16 / CD30), APVO436 (CD123 / CD3), flotozumab (flotuzumab) tuzumab) (CD123 / CD3), REGN-1979 (CD20 / CD3), MCLA-117 (CD3 / CLEC12A), MCLA-128 (HER2 / HER3), JNJ-0819, JNJ-7564 (CD3 / heme), AMG-757 (DLL3-CD3), MGD-013 (PD-1 / LA G-3), AK-104(CTLA-4 / PD-1), AMG-330(CD33 / CD3), AMG-420(BCMA / CD3), BI-836880( VEFG / ANG2), JNJ-63709178(CD123 / CD3), MGD-007(CD3 / gpA33), MGD-009(CD3 / B7H3);

[0613] - Mutant-selective EGFR inhibitors such as PF-06747775, EGF816 (nazartinib), ASP8273, ACEA-0010, BI-1482694;

[0614] - 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;

[0615] - anti-delta-like protein ligand 3 (DDL3) antibodies, such as rovalpituzumabtesirine;

[0616] - anti-clusterin antibodies, such as AB-16B5;

[0617] - anti-Ephrin-A4 (EFNA4) antibodies, such as PF-06647263;

[0618] - anti-RANKL antibodies, such as denosumab;

[0619] - anti-mesothelin antibodies, such as BMS-986148, anti-MSLN-MMAE;

[0620] - Anti-sodium phosphate co-transporter 2B (NaP2B) antibodies, such as lifastuzumab;

[0621] - anti-c-Met antibodies, such as ABBV-399;

[0622] - adenosine A2A receptor antagonists, such as CPI-444, AZD-4635, preladenant, PBF-509;

[0623] -α-ketoglutarate dehydrogenase (KGDH) inhibitors, such as CPI-613;

[0624] - XPO1 inhibitors, such as selinexor (KPT-330);

[0625] - isocitrate dehydrogenase 2 (IDH2) inhibitors, such as enasidenib (AG-221);

[0626] - IDH1 inhibitors such as AG-120 and AG-881 (IDH1 and IDH2), IDH-305, BAY-1436032;

[0627] - interleukin-3 receptor (IL-3R) modulators, such as SL-401;

[0628] - arginine deiminase stimulators, such as pegargiminase (ADI-PEG-20);

[0629] - Antibody-drug conjugates, such as MLN0264 (anti-GCC, guanylate cyclase C), T-DM1 (trastuzumab emtansine, Kadcycla), milatuzumab-doxorubicin (hCD74-DOX), brentuximab vedotin, DCDT2980S, polatuzumab vedotin, SGN-CD70A, SGN-CD19A, inotuzumab ozogamicin, lorvotuzumab emtansine, mertansine), SAR3419, isactuzumab govitecan, enfortumab vedotin (ASG-22ME), ASG-15ME, DS-8201 (trastuzumab deruxtecan), 225Ac-lintuzumab, U3-1402, 177Lu-tetraxetan-tetuloma, tisotumab vedotin, anetumab ravtansine, CX-2009, SAR-566658, W-0101, polatuzumab vedotin, ABBV-085;

[0630] - Occludin-18 inhibitors, such as claudiximab;

[0631] -β-catenin inhibitors, such as CWP-291;

[0632] -Anti-CD73 antibodies, such as MEDI-9447 (oleclumab), CPX-006, IPH-53, BMS-986179;

[0633] -CD73 antagonists, such as AB-680, PSB-12379, PSB-12441, PSB-12425;

[0634] -CD39 / CD73 antagonists, such as PBF-1662;

[0635] - Chemokine receptor 2 (CCR) inhibitors such as PF-04136309, CCX-872, BMS-813160 (CCR2 / CCR5);

[0636] - thymidylate synthase inhibitors, such as ONX-0801;

[0637] -ALK / ROS1 inhibitors, such as lorlatinib;

[0638] - Tankyrase inhibitors, such as G007-LK;

[0639] - Mdm2 p53 binding protein inhibitors, such as CMG-097, HDM-201;

[0640] - c-PIM inhibitors, such as PIM447;

[0641] -BRAF inhibitors such as dabrafenib, vemurafenib, encofenib (LGX818), PLX8394;

[0642] - Sphingosine kinase-2 (SK2) inhibitors, such as (ABC294640);

[0643] - Cell cycle inhibitors, such as selumetinib (MEK1 / 2) and sapacitabine;

[0644] - AKT inhibitors such as MK-2206, ipatasertib, afuresertib, AZD5363 and ARQ-092, capivasertib, triciribine;

[0645] - anti-CTLA-4 (cytotoxic T-lymphocyte protein-4) inhibitors such as tesimumab, AGEN-1884, BMS-986218;

[0646] -c-MET inhibitors such as AMG-337, savolitinib, tivantinib (ARQ-197), capmatinib and tepotinib, ABT-700, AG213, AMG-208, JNJ-38877618 (OMO-1), merestinib, HQP-8361;

[0647] -c-Met / VEGFR inhibitors, such as BMS-817378, TAS-115;

[0648] -c-Met / RON inhibitors, such as BMS-777607;

[0649] -BRAF / EGFR inhibitors, such as BGB-283;

[0650] - bcr / abl inhibitors, such as rebastinib, asciminib;

[0651] - MNK1 / MNK2 inhibitors, such as eFT-508;

[0652] - mTOR inhibitors / cytochrome P450 3A4 stimulators, such as TYME-88;

[0653] - lysine-specific demethylase-1 (LSD1) inhibitors, such as CC-90011;

[0654] - Pan-RAF inhibitors, such as LY3009120, LXH254, TAK-580;

[0655] - Raf / MEK inhibitors, such as RG7304;

[0656] - CSF1R / KIT and FLT3 inhibitors, such as pexidartinib (PLX3397);

[0657] - kinase inhibitors, such as vandetanib;

[0658] - E-selectin antagonists, such as GMI-1271;

[0659] - Differentiation inducing agents, such as retinoic acid;

[0660] - epidermal growth factor receptor (EGFR) inhibitors, such as osimertinib (AZD-9291);

[0661] - Topoisomerase inhibitors such as doxorubicin, daunorubicin, dactinomycin, eniposide, epirubicin, etoposide, idarubicin, irinotecan, mitoxantrone, pisantrone, sobuzoxane, topotecan, irinotecan, MM-398 (liposomal irinotecan), vosarosin and GPX-150, adoxirubicin, AR-67, mavelertinib, AST-2818, avitinib (ACEA-0010), ilofofofen (MGI-114);

[0662] -Corticosteroids such as cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisone, prednisolone;

[0663] - Growth factor signaling kinase inhibitors;

[0664] - Nucleoside analogs, such as DFP-10917;

[0665] - Axl inhibitors such as BGB-324 (bemcentinib), SLC-0211;

[0666] - 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-894999, PLX-2853, PLX-51107, CPI-0610, GS-5829;

[0667] - PARP inhibitors such as olaparib, rucaparib, veliparib, talazoparib, ABT-767, BGB-290;

[0668] -Proteasome inhibitors, such as ixazomib, carfilzomib Marizomib;

[0669] - glutaminase inhibitors, such as CB-839;

[0670] - vaccines, such as peptide vaccines TG-01 (RAS), GALE-301, GALE-302, nelipepimut-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, axalimogenefilolisbac (ADXS11-001); adenovirus vector vaccines, such as nadofaragene firadenovec; autologous Gp96 vaccines; dendritic cell vaccines, such as CVactm, stapuldencel-T, eltrapuldencel-T, SL-701, BSK01TM, rocapuldencel-T (AGS-003), DCVAC, CVac tm ,stapuldencel-T,eltrapuldencel-T,SL-701,BSK01 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 vaccine, such as PVS-RIPO; Adagloxad simolenin; MEDI-0457; DPV-001 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;

[0671] - anti-DLL4 (delta-like ligand 4) antibodies, such as demcizumab;

[0672] - STAT-3 inhibitors, such as napabucasin (BBI-608);

[0673] - ATPase p97 inhibitors, such as CB-5083;

[0674] - Smoothened (SMO) receptor inhibitors such as (sonidegib, formerly known as LDE-225), LEQ506, vismodegib (GDC-0449), BMS-833923, glasdegib (PF-04449913), LY2940680, and itraconazole;

[0675] - Interferon alpha ligand modulators, such as interferon alpha-2b, interferon alpha-2a biosimilars (Biogenomics), ropeg interferon alpha-2b (AOP-2014, P-1101, PEGIFN alpha-2b), Multiferon (Alfanative, Viragen), interferon alpha 1b, Roferon-A (Canferon, Ro-25-3036), interferon alpha-2a follow-up biologics (Biosidus) (Inmutag, Inter 2A), interferon alpha-2b follow-up biologics (Biosidus-Bioferon, Citopheron, Ganapar, Beijing Kawin Technology–Kaferon), Alfaferone, pegylated interferon alpha-1b, pegylated interferon alpha-2b follow-on biologic (Amega), recombinant human interferon alpha-1b, recombinant human interferon alpha-2a, recombinant human interferon alpha-2b, veltuzumab-IFNα2b conjugate, Dynavax (SD-101), and interferon alpha-n1 (Humoferon, SM-10500, Sumiferon);

[0676] - interferon gamma ligand modulators, such as interferon gamma (OH-6000, Oγ100);

[0677] - IL-6 receptor modulators, such as tocilizumab, siltuximab, AS-101 (CB-06-02, IVX-Q-101);

[0678] - Telomerase modulators, such as tertomotide (GV-1001, HR-2802, Riavax) and imetelstat (GRN-163, JNJ-63935937);

[0679] - DNA methyltransferase inhibitors such as temozolomide (CCRG-81045), decitabine, guacitabine (S-110, SGI-110), KRX-0402, RX-3117, RRx-001, and azacitidine;

[0680] -DNA gyrase inhibitors, such as pisantron and sobuzoxan;

[0681] - Bcl-2 family protein inhibitors, such as ABT-263, venetoclax (ABT-199), ABT-737, and AT-101;

[0682] - Notch inhibitors such as LY3039478 (crenigacestat), tarextumab (anti-Notch2 / 3), BMS-906024;

[0683] - anti-myostatin inhibitors, such as landogrozumab;

[0684] - hyaluronidase stimulators, such as PEGPH-20;

[0685] -Wnt pathway inhibitors such as SM-04755, PRI-724, WNT-974;

[0686] -γ-secretase inhibitors such as PF-03084014, MK-0752, RO-4929097;

[0687] - Grb-2 (growth factor receptor binding protein-2) inhibitors, such as BP1001;

[0688] -TRAIL pathway inducing compounds, such as ONC201, ABBV-621;

[0689] - Focal adhesion kinase inhibitors such as VS-4718, defactinib, GSK2256098;

[0690] - Hedgehog inhibitors, such as saridegib, songib (LDE225), gradigib, and vismogib;

[0691] - Aurora kinase inhibitors such as alisertib (MLN-8237) and AZD-2811, AMG-900, barasertib, ENMD-2076;

[0692] - HSPB1 modulators (heat shock protein 27, HSP27), such as brivudine, apatorsen;

[0693] -ATR inhibitors such as BAY-937, AZD6738, AZD6783, VX-803, VX-970 (berzosertib) and VX-970;

[0694] - mTOR inhibitors such as sapanisertib and vistusertib (AZD2014), ME-344;

[0695] - mTOR / PI3K inhibitors such as gadalisib, GSK2141795, omipalisib, RG6114;

[0696] - Hsp90 inhibitors such as AUY922, onalespib (AT13387), SNX-2112, SNX5422;

[0697] - mouse double minute (mdm2) oncogene inhibitors, such as DS-3032b, RG7775, AMG-232, HDM201 and idasanutlin (RG7388);

[0698] - CD137 agonists, such as urelumab, utomilumab (PF-05082566);

[0699] - STING agonists, such as ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291;

[0700] - FGFR inhibitors such as FGF-401, INCB-054828, BAY-1163877, AZD4547, JNJ-42756493, LY2874455, Debio-1347;

[0701] - fatty acid synthase (FASN) inhibitors, such as TVB-2640;

[0702] - anti-KIR monoclonal antibodies, such as lirilumab (IPH-2102), IPH-4102;

[0703] - Antigen CD19 inhibitors, such as MOR208, MEDI-551, AFM-11, inebilizumab;

[0704] -CD44 binding agents, such as A6;

[0705] - Protein phosphatase 2A (PP2A) inhibitors, such as LB-100;

[0706] -CYP17 inhibitors such as seviteronel (VT-464), ASN-001, ODM-204, CFG920, abiraterone acetate;

[0707] -RXR agonists, such as IRX4204;

[0708] - Hedgehog / Smoothened (hh / Smo) antagonists, such as taladegib, patidegib;

[0709] - Complement C3 modulators, such as Imprime PGG;

[0710] - IL-15 agonists, such as ALT-803, NKTR-255, and hetIL-15;

[0711] - EZH2 (enhancer of zeste homolog 2) inhibitors, such as tazemetostat, CPI-1205, GSK-2816126;

[0712] - 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;

[0713] - DOT1L (histone methyltransferase) inhibitors, such as pinostat (EPZ-5676);

[0714] - toxins, such as cholera toxin, ricin, Pseudomonas exotoxin, Bordetella pertussis adenylate cyclase toxin, diphtheria toxin and caspase activators;

[0715] - DNA plasmids, such as BC-819;

[0716] - PLK inhibitors of PLK1, 2 and 3, such as volasertib (PLK1);

[0717] -WEE1 inhibitors, such as AZD1775 (adavosertib);

[0718] - Rho kinase (ROCK) inhibitors, such as AT13148, KD025;

[0719] -ERK inhibitors such as GDC-0994, LY3214996, MK-8353;

[0720] - IAP inhibitors such as ASTX660, debio-1143, birinapant, APG-1387, LCL-161;

[0721] - RNA polymerase inhibitors such as lurbinectedin (PM-1183), CX-5461;

[0722] - microtubulin inhibitors, such as PM-184, BAL-101553 (lisavanbulin) and OXI-4503, fluorapacin (AC-0001), plinabulin;

[0723] - Toll-like receptor 4 (TL4) agonists, such as G100, GSK1795091 and PEPA-10;

[0724] - elongation factor 1α2 inhibitors, such as plitidepsin;

[0725] -CD95 inhibitors, such as APG-101, APO-010, asunercept;

[0726] -WT1 inhibitors, such as DSP-7888;

[0727] - Splicing factor 3B subunit 1 (SF3B1) inhibitors, such as H3B-8800;

[0728] - PDGFRα / KIT mutation-specific inhibitors, such as BLU-285;

[0729] - SHP-2 inhibitors, such as TNO155 (SHP-099), RMC-4550; and

[0730] - Retinoid Z receptor gamma (RORγ) agonists, such as LYC-55716.

[0731] In some embodiments, provided herein are methods for treating or preventing a hyperproliferative disorder or cancer in a human or animal having or at risk of a hyperproliferative disorder or cancer, comprising administering to the human or animal a therapeutically effective amount of a compound as disclosed herein, or 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; a discoidin-dependent kinase (CDK) inhibitor. 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 (TKI), and any combination thereof or pharmaceutically acceptable salts thereof. Non-limiting examples include:

[0732] - 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);

[0733] - 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, tirabrutinib (ONO-4059), PRN-1008, sepretinib (CC-292), TAK-020, vecabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, TAS-5315;

[0734] - Cluster of differentiation 47 (CD47) inhibitors: Examples of CD47 inhibitors include, but are not limited to, anti-CD47 mAb (Vx-1004), anti-human CD47 mAb (CNTO-7108), CC-90002, CC-90002-ST-001, humanized anti-CD47 antibody (Hu5F9-G4), NI-1701, NI-1801, RCT-1938, and TTI-621;

[0735] - Cyclin-dependent kinase (CDK) inhibitors: CDK inhibitors include inhibitors of CDK1, 2, 3, 4, 6, 7 and 9, such as abemaciclib, avocidib (HMR-1275, flavopiridol), AT-7519, dinaciclib, ibrance, FLX-925, LEE001, palbociclib, ribociclib, regoratinib, selinexor, UCN-01, SY1365, CT-7001, SY-1365, G1T38, mirciclib, tremaciclib and TG-02;

[0736] -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);

[0737] - 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), resminostat, ricolinostat, SHP-141, valproic acid (VAL-001), vorinostat, tinostamustine, remetinostat, entinostat;

[0738] - Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors: Examples of IDO1 inhibitors include, but are not limited to, BLV-0801, icadolstat, F-001287, GBV-1012, GBV-1028, GDC-0919, indomod, 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;

[0739] -Janus kinase (JAK) inhibitors: JAK inhibitors inhibit JAK1, JAK2 and / or JAK3. Examples of JAK inhibitors include, but are not limited to, AT9283, AZD1480, baricitinib, BMS-911543, fedratinib, filgotinib (GLPG0634), gandotinib (LY2784544), INCB039110 (itacitinib), lestaurtinib, momelotinib (CYT0387), NS-018, pacritinib (SB1518), peficitinib (ASP015K), ruxolitinib, tofacitinib (formerly known as tasocitinib), INCB052793, and XL019;

[0740] - 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 2011 / 097513 (Gilead Biologics);

[0741] - Matrix metalloproteinase (MMP) 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 WO 2012 / 027721 (Gilead Biologics);

[0742] -Mitogen-activated protein kinase (MEK) inhibitors: MEK inhibitors include antroquinol, binimetinib, cobimetinib (GDC-0973, XL-518), MT-144, selumetinib (AZD6244), sorafenib, trametinib (GSK1120212), uprosertib + trametinib, PD-0325901, pimasertib, LTT462, AS703988, CC-90003, and refametinib;

[0743] -Phosphatidylinositol 3-kinase (PI3K) inhibitors: PI3K inhibitors include inhibitors of PI3Kγ, PI3Kδ, PI3Kβ, PI3Kα and / or pan-PI3K. Examples of PI3K inhibitors include, but are not limited to, ACP-319, AEZA-129, AMG-319, AS252424, AZD8186, BAY 10824391, BEZ235, Bupalixib (BKM120), BYL719 (Abolixib), CH5132799, Copanlixib (BAY 80-6946), Duvelixib, GDC-0032, GDC-0077, GDC-0941, GDC-0980, GSK2636771, GSK2269557, Edelicib INCB50465, IPI-145, IPI-443, IPI-549, KAR4141, LY294002, LY3023414, MLN1117, OXY111A, PA799, PX-866, RG7604, regoratinib, RP5090, RP6530, SRX3177, taselixib, 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 Compounds described in WO 2013 / 116562 (Gilead Calistoga), WO 2014 / 100765 (Gilead Calistoga), WO 2014 / 100767 (Gilead Calistoga) and WO 2014 / 201409 (Gilead Sciences);

[0744] - Spleen tyrosine kinase (SYK) inhibitors: Examples of SYK inhibitors include, but are not limited to, 6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine, BAY-61-3606, cerdulatinib (PRT-062607), entospletinib, fostamatinib (R788), HMPL-523, NVP-QAB 205AA, R112, R343, tamatinib (R406), and those described in US 8450321 (Gilead Connecticut) and those described in US2015 / 0175616;

[0745] - 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;

[0746] - Toll-like receptor 9 (TLR9) inhibitors: Examples of TLR9 inhibitors include, but are not limited to, AST-008, IMO-2055, IMO-2125, lefitolimod, lefitolimod, MGN-1601, and PUL-042; and

[0747] -Tyrosine kinase inhibitors (TKIs): TKIs can target the epidermal growth factor receptor (EGFR) as well as receptors for 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, clenonib, dacomitinib, dasatinib, dovitinib, E-6201, erdafitinib, erlotinib, gefitinib, gilteritinib (ASP-2215), FP-1039, HM61713, icotinib, imatinib, KX2-391 (Src), lapatinib, lestaurine, lenvatinib, midostaurin, nintedanib, ODM-203, osimertinib (AZD-9291), ponatinib, poziotinib, quizartinib, radotinib, rociletinib, surufatinib (HMPL-012), sunitinib, tivanib and TH-4000, MEDI-575 (anti-PDGFR antibody).

[0748] As used herein, the term "chemotherapeutic agent" or "chemotherapeutic agent" (or "chemotherapy" in the case of treatment with a chemotherapeutic agent) is intended to encompass any non-proteinaceous (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, for example benzdepa, carboquinone, metodepa and uredepa; ethyleneimines and methylmelamines, including hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trihydroxymethylmelamine; lactones, especially bratacin and bratacinone; camptothecins, including the synthetic analogue topotecan; bryostatin, callystatin; CC-1065, including its synthetic analogues adolesin, carzelesin and biszelesin; nostoc, especially nostoc 1 and nostoc 8; caudatelin; duocarmycins, including the synthetic analogues KW-2189 and CBI-T MI; eleutherobin; 5-azacytidine; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, naphthyl mustard, cyclophosphamide, glufosfamide, ivophosphamide, bendamustine, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and remustine mustin; antibiotics such as enediyne antibiotics (e.g., calicheamicins, especially calicheamicin gamma II and calicheamicin phi II), danimycins (including danimycin A), bisphosphonates (such as clodronate), espammycins, neostatin chromophores and related chromogenic protein enediyne antibiotic chromophores, aclarubicin, actinomycin, authramycin, azaserine, bleomycin, actinomycin, carabicin, carrninomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detopicin, 6-diazo-5- -oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolo-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, mexilomycin, mitomycin (such as mitomycin C), mycophenolic acid, nogamycin, olivemycin, peplomycin, porfiromycin, puromycin, quinamycin, rhodorubicin, streptomycin, streptozotocin, tuberculocidin, ubenimex, zoloft and daunorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as norpterin, methotrexate, pteropterin and trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiabendazole and thioguanine;Pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as calosterone, drostanolone propionate, cyclothiocarb, melastosane, and testolactone; antiadrenal agents such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as folinic acid; radiotherapeutic agents such as radium-223; trichothecenes, especially T-2 toxin, eusporin A, baculosporin A, and serpentin; taxanes such as paclitaxel; nab-paclitaxel, docetaxel Cabazitaxel, BIND-014, tesetaxel; platinum analogs such as cisplatin and carboplatin, NC-6004 nanoplatin; acetoglucuronide; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; hestrabucil; bisantrene; edatrexate; defofamine; demecilcin; diazocine; elformthine; elliptinium acetate acetate; epothilones; etoglucid; gallium nitrate; hydroxyurea; lentinan; leucovorin; lonidamine; maytansinoids, such as maytansine and ansamitocin; mitoguanidine; mitoxantrone; mopidarol; diamine nitrazolium; pentostatin; phenamet; pirarubicin; losoxantrone; fluoropyrimidines; folinic acid; podophyllotoxin; 2-ethylhydrazide; procarbazine; polysaccharide-K (PSK); razor ; rhizoxin; sizolan; spirogermanamine; tricUorotriemylamine; urethane; vindesine; dacarbazine; mannomustine; dibromomannitol; dibromodulanol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiopeta; chlorambucil; gemcitabine 6-thioguanine; mercaptopurine; methotrexate; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbine Novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeoloda; 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.

[0749] Also included within 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 are used to modulate or inhibit the effects of hormones on tumors.

[0750] Antihormonal agents

[0751] Examples of antiestrogens and SERMs include, for example, tamoxifen (including NOLVADEX TM ), raloxifene, droloxifene, 4-hydroxytamoxifen, troloxifene, comoxifen, LY117018, onapristone, and toremifene

[0752] Aromatase inhibitors regulate estrogen production in the adrenal glands. Examples include 4(5)-imidazole, aminoglutethimide, megestrol acetate Exemestane, formestane, fadrozole, vorozole Letrozole and anastrozole

[0753] Examples of antiandrogens include apalutamide, abiraterone, enzalutamide, flutamide, galactron, nilutamide, bicalutamide, leuprolide, goserelin, ODM-201, APC-100, ODM-204.

[0754] Examples of progesterone receptor antagonists include onapristone.

[0755] Anti-angiogenic agents

[0756] Anti-angiogenic agents include, but are not limited to, retinoids and their derivatives, 2-methoxyestradiol, regorafenib, nicuparib, suramin, squalamine, tissue inhibitor of metalloproteinase-1, tissue inhibitor of metalloproteinase-2, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, cartilage-derived inhibitor, paclitaxel (nab-paclitaxel), platelet factor 4, protamine sulfate (herring protamine), sulfated chitin derivatives (prepared from queen crab shells), sulfated polysaccharide peptidoglycan complex (sp-pg), staurosporine, matrix metabolism regulators (including proline analogs such as l-azetidine-2-carboxylic acid (LACA), cis-hydroxyproline, d,I-3,4-dehydroproline, thioproline), α,α'-bipyridyl, fumarate acid β-aminopropionitrile, 4-propyl-5-(4-pyridinyl)-2(3h)-oxazolone, methotrexate, mitoxantrone, heparin, interferon, 2-macroglobulin-serum, chicken inhibitor of metalloproteinase-3 (ChIMP-3), chymosin inhibitor, β-cyclodextrin tetradeoxyphosphate, epothilone, fumagillin, gold sodium thiomalate, d-penicillamine, β-1-anticollagenase-serum, α-2-antithrombin, bisantrene, lobenzarit disodium, n-2-carboxyphenyl-4-chloroanthranilic acid disodium or "CCA", thalidomide, antiangiogenic steroids, carboxyaminoimidazoles, metalloproteinase inhibitors such as BB-94, inhibitors of S100A9 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).

[0757] Antifibrotic agents

[0758] Antifibrotic agents include, but are not limited to, compounds such as β-aminopropionitrile (BAPN), and compounds disclosed in US 4965288 (involving inhibitors of lysyl oxidase and their use in treating diseases and conditions associated with abnormal collagen deposition) and US 4997854 (involving compounds that inhibit LOX to treat various pathological fibrotic states) (these patents are incorporated herein by reference). Additional exemplary inhibitors are described in US 4943593 (involving compounds such as 2-isobutyl-3-fluoro-, chloro- or bromo-allylamine), US 5021456, US 5059714, US 5120764, US 5182297, US 5252608 (involving 2-(1-naphthyloxymethyl)-3-fluoroallylamine) and US 2004-0248871 (these patents are incorporated herein by reference).

[0759] Exemplary anti-fibrotic agents also include primary amines that react with the carbonyl group of the active site of lysyl oxidase, and more specifically, those that produce products stabilized by resonance upon binding to the carbonyl group, such as the following primary amines: emylenemamine, hydrazine, phenylhydrazine, and their derivatives; semicarbazide and urea derivatives; aminonitriles, such as BAPN or 2-nitroethylamine; unsaturated or saturated halogenated amines, such as 2-bromoethylamine, 2-chloroethylamine, 2-trifluoroethylamine, 3-bromopropylamine, and p-halobenzylamine; and selenohomocysteine ​​lactones.

[0760] Other anti-fibrotic agents are copper chelators that infiltrate or do not infiltrate cells. Exemplary compounds include indirect inhibitors of aldehyde derivatives that block oxidation deamination of lysyl and hydroxylysyl residues by lysyl oxidase. Examples include thiolamines, especially 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-((p-1-dimethyl-2-amino-2-carboxyethyl) dithio)butane sulfonate sodium, 2-acetamidoethyl-2-acetamidoethanethiol sulfate and 4-mercaptobutanesulfinate sodium trihydrate.

[0761] Immunotherapeutic agents

[0762] Immunotherapeutic agents include, but are not limited to, therapeutic antibodies suitable for treating a subject.Some examples of therapeutic antibodies include abagovomab, ABP-980, adecatumumab, afutuzumab, alemtuzumab, altumomab, amatuximab, anatumomab, arcitumomab, bavituximab, bectumomab, bevacizumab, bivatuzumab, blinatumomab blinatumomab, brentuximab, cantuzumab, catumaxomab, CC49, cetuximab, citatuzumab, cixutumumab, clivatuzumab, conatumumab, dacetuzumab, dalotuzumab, daratumumab, detumomab, dinutuximab, drozitumab, duligotumab, dusigitumab, ecoromeximab, elotuzumab, emibetuzumab, ensituximab, ertumaxomab, etaracizumab, farletuzumab, ficlatuzumab, figitumumab umab), flanvotumab, futuximab, ganitumab, gemtuzumab, girentuximab, glembatumumab, ibritumomab, igovomab, imgatuzumab, indatuximab, inotuzumab, intetumumab, ipilimumab (. MDX-010, BMS-734016, and MDX-101), iratumumab, labetuzumab, lexatumumab, lintuzumab, lorvotuzumab, lucatumumab, mapatumumab, matuzumab, milatuzumab, minretumomab, mitumomab, mogamulizumab, moxetumomab, naptumomab, narnatumab, necitumumab, nimotuzumab, nofetumomab nofetumomab, OBI-833, obinutuzumab, ocaratuzumab, ofatumumab, olaratumab, onartuzumab, oportuzumab, oregovomab, panitumumab, parsatuzumab, pasudotox, patritumab, pemtumomab, pertuzumab, pintumomab, pritumumab, racotumomab, radretumab, ramucirumab Rilotumumab, rituximab, robatumumab, samalizumab, satumomab, sibrotuzumab, siltuximab, solitomab, simtuzumab, tacatuzumab, tapitumomab, tenatumomab Rituximab is used to treat indolent B-cell cancers, including marginal zone lymphoma, WM, CLL, and small lymphocytic lymphoma. The combination of rituximab and chemotherapeutic agents is particularly effective.

[0763] The exemplified therapeutic antibodies may be further labeled or combined with radioactive isotope particles such as indium-111, yttrium-90 (90Y-clituzumab), or iodine-131.

[0764] Cancer gene therapy and cell therapy

[0765] Cancer gene therapy and cell therapy include inserting a normal gene into a cancer cell to replace a mutated or altered gene; genetic modifications that silence mutated genes; genetic methods that directly kill cancer cells; infusions of immune cells designed to replace a large portion of the subject's own immune system to boost the immune response to cancer cells, or to activate the subject's own immune system (T cells or natural killer cells) to kill cancer cells, or to seek out and kill cancer cells; and genetic methods that alter cell activity to further alter the endogenous immune response to the cancer.

[0766] Gene Editor

[0767] 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.

[0768] CAR-T cell therapy and TCR-T cell therapy

[0769] 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.

[0770] In some embodiments, the CAR comprises an antigen binding domain, a transmembrane domain, and an intracellular signaling domain.

[0771] In some embodiments, the intracellular domain comprises a primary signaling domain, a costimulatory domain, or both a primary signaling domain and a costimulatory domain.

[0772] 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 (FcεRlb), CD79a, CD79b, FcγRIIa, DAP10, and DAP12.

[0773] 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-I), 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, CD8α, CD8β, IL2Rβ, IL2Rγ, IL7Rα, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD 11d, 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.

[0774] 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, CD1 ld, 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.

[0775] In some embodiments, the antigen binding domain binds a tumor antigen.

[0776] In some embodiments, the tumor antigen is selected from the group consisting of: CD19; CD123; CD22; CD30; CD171; CS-1 (also known as CD2 subunit 1, CRACC, SLAMF7, CD319 and 19A24); C-type lectin-like molecule-1 (CLL-1 or CLECLI); CD33; epidermal growth factor receptor variant III (EGFRvlll); ganglioside G2 (GD2); ganglioside GD3 (aNeuSAc(2-8)aNeuSAc(2-3)bDGaip(1-4)bDGIcp(1-1)Cer); TNF receptor family member B cell maturation (BCMA); Tn antigen ((Tn Ag) or (GaINAcu-Ser / Thr)); prostate-specific membrane antigen (PSMA); receptor tyrosine kinase-like orphan receptor 1 (RORI); Fms-like tyrosine kinase 3 (FLT3); tumor-associated glycoprotein 72 (TAG72); CD38; CD44v6; carcinoembryonic antigen (CEA); epithelial cell adhesion molecule (EPCAM); B7H3 (CD276); KIT (CD117); interleukin-13 receptor subunit alpha-2 (IL-13Ra2 or CD213A2); Mesothelin; interleukin 11 receptor alpha (IL-11Ra); prostate stem cell antigen (PSCA); proteinase serine 21 (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) ; cell surface associated mucin 1 (MUC1); epidermal growth factor receptor (EGFR); neural cell adhesion molecule (NCAM); prostatic enzyme; prostatic acid phosphatase (PAP); mutated elongation factor 2 (ELF2M); ephrin B2; fibroblast activation protein alpha (FAP); insulin-like growth factor 1 receptor (IGF-I receptor), carbonic anhydrase IX (CAIX); proteasome (Prosome, Macropain) subunit, beta type, 9 (LMP2); glycoprotein 100 (gp 100); oncogene fusion protein composed of breakpoint cluster region (BCR) and Epstein 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)bDGalp(1-4)bDGlcp(1-1)Cer); transglutaminase 5 (TGS5); high molecular weight melanoma associated antigen (HMWMAA);o-acetyl-GD2 ganglioside (OAcGD2); folate receptor beta; tumor endothelial marker 1 (TEM1 / CD248); tumor endothelial marker 7-related (TEM7R); six transmembrane epithelial antigen of the prostate 1 (STEAP1); occludin 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); adrenal receptor beta 3 (ADRB3); pan-nexin 3 (PANX3); G protein-coupled receptor 20 (GPR20); lymphocyte antigen 6 complex, locus K9 (LY6K); olfactory receptor 51E2 (ORS IE2); TCR gamma alternate reading frame protein (TARP); Wilms tumor protein (WT1); cancer / testis antigen 1 (NY-ESO-1); cancer / testis antigen 2 (LAGE-la); 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 testis cancer antigen-1 (MADCT-1); melanoma testis cancer antigen-2 (MAD-CT-2); Fos-related antigen 1; tumor protein p53 (p53); p53 mutant; prostaglandin (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 breakpoints; 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; cyclin B1; v-myc avian myelocytic tumor viral oncogene neuroblastoma-derived homolog (MYCN); Ras homolog family member C (RhoC); tyrosinase-related protein 2 (TRP-2); cytochrome P450 1B1 (CYP IBI); CCCTC-binding factor (zinc finger protein)-like (brother of BORIS or imprinted site regulator), squamous cell carcinoma antigen recognized by T cells 3 (SART3); paired box protein Pax-5 (PAX5);pre-acrosin binding protein sp32 (OY-TESI); 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-I); 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). ;

[0777] 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, CD54, CD56, CD66a-d, CD74, CD8, CD80, CD92, CE7, CS-1 、CSPG4、ED-B fibronectin、EGFR、EGFRvIII、EGP-2、EGP-4、EPHa2、ErbB2、ErbB3、ErbB4、FBP、GD2、GD3、HER1-HER2 combination、HER2-HER3 combination、HERV-K、HIV-1 envelope glycoprotein gp120、HIV-1 envelope glycoprotein gp41、HLA-DR、HM1.24、HMW-MAA、Her2、Her2 / neu、IGF-1R、IL-11Rα、IL-13R-α2、IL-2、IL-22R-α、IL-6、IL-6R、Ia、Ii、L1-CAM、L1-cell adhesion molecule、Lewis Y、Ll-CAM、MAGE A3, MAGE-A1, MART-1, MUC1, NKG2C ligand, NKG2D ligand, NYESO-1, OEPHa2, PIGF, PSCA, PSMA, ROR1, T101, TAC, TAG72, TIM-3, TRAIL-R1, TRAIL-Rl (DR4), TRAIL-R2 (DR5), VEGF, VEGFR2, WT-I, G protein-coupled receptor, α-fetoprotein (AFP), angiogenic factors, exogenous cognate binding molecules (ExoCBM), oncogene products, antifolate receptor, c-Met, Carcinoembryonic antigen (CEA), cyclin (D1), ephrin B2, epithelial tumor antigen, estrogen receptor, fetal acetylcholine receptor, folate binding protein, gp100, hepatitis B surface antigen, kappa chain, kappa light chain, kdr, lambda chain, actin, melanoma associated antigen, mesothelin, mouse double minute 2 homolog (MDM2), mucin 16 (MUC16), mutant p53, mutant ras, necrosis antigen, carcinoembryonic antigen, ROR2, progesterone receptor, prostate specific antigen, tEGFR, tenascin, P2-Microgiobuiin, Fc receptor-like 5 (FcRL5).

[0778] 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-NK100, LFU-835 hematopoietic stem cells, Imilecleucel-T, baltaleucel-T, PNK-007, UCARTCS1, ET-1504, ET-1501, ET-1502, ET-190, CD19-ARTEMIS, ProHema, FT-1050 treated bone marrow stem cell therapy, CD4CARNK-92 cells, CryoStim, AlloStim, lentiviral transduced huCART-meso cells, CART-22 cells, EGFRt / 19-28z / 4-1BBL CAR T cells, autologous 4H11-28z / fIL-12 / EFGRt T cells, CCR5-SBC-728-HSPCs, 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.

[0779] 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 CAR-B7H6; B-lymphocyte antigen CD19, such as TBI-1501, CTL-119huCART-19T cells, JCAR-015US7446190, JCAR-014, JCAR-017 (WO2016196388, WO2016033570, WO2015157386), axicabtagene ciloleucel (KTE-C19), US7741465, US6319494, UCART-19, EBV-CTL, Ttisagenlecleucel-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, IM19 CAR-T; B-lymphocyte antigen CD20, such as ATTCK-20; B-lymphocyte cell adhesion, such as UCART-22, JCAR-018WO2016090190; NY-ESO-1, such as GSK-3377794, TBI-1301; carbonic anhydrase, such as DC-Ad-GMCAIX; caspase 9 suicide gene, such as CaspaCIDeDLI, 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; Occludin 6, such as CSG-002; EBV targeted, 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; acetylin-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 G12V mTCR cell therapy; neural cell adhesion molecule L1 L1CAM (CD171), such as JCAR-023; latent membrane protein 1 / latent membrane protein 2, such as autologous dendritic cells transduced with Ad5f35-LMPd1-2; 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; Ntrkr1 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 Wilms tumor protein, such as JTCR-016, WT1-CTL. .

[0780] Combination therapy for lymphoma or leukemia

[0781] In some embodiments, the additional therapeutic agent is suitable for treating lymphoma or leukemia. These agents include aldesleukin, alvocidib, amifostine trihydrate, aminocamptothecin, antineoplastic A10, antineoplastic AS2-1, antithymocyte globulin, arsenic trioxide, Bcl-2 family protein inhibitor ABT-263, beta alethine, BMS-345541, bortezomib, Bortezomib ( PS-341), bryostatin 1, bulsulfan, 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, Aplysia 10, doxorubicin, doxorubicin hydrochloride, DT-PACE (dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide and etoposide), enzastaurin, epoetin alfa, etoposide, everolimus (RAD001), FCM (fludarabine, cyclophosphamide and mitoxantrone), FCR (fludarabine, cyclophosphamide and rituximab), fenretinide, Filgrastim, flavopiridol, fludarabine, FR (fludarabine and rituximab), geldanamycin (17-AAG), hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, and cytarabine), ICE (ifosfamide, carboplatin, and etoposide), ifosfamide, irinotecan hydrochloride, interferon α-2b, ixabepilone, lenalidomide ( CC-5013), lymphokine-activated killer cells, MCP (mitoxantrone, chlorambucil, and prednisolone), melphalan, mesna, methotrexate, mitoxantrone hydrochloride, motexafin gadolinium, mycophenolate mofetil, nelarabine, obatoclax (GX15-070), oblimersen, octreotide acetate, omega-3 fatty acids, Omr-IgG-am (WNIG, Omrix), oxaliplatin, paclitaxel, palbociclib (PD0332991), ethylenediaminetetracycline, ethylenediaminetetracycline liposomal doxorubicin hydrochloride, perifosine, prednisolone, prednisone, recombinant flt3 ligand, recombinant human thrombopoietin, recombinant interferon alpha, recombinant interleukin-11, recombinant interleukin-12, rituximab, R-CHOP (rituximab and CHOP), R-CVP (rituximab and CVP), R-FCM (rituximab and FCM), R-ICE (rituximab and ICE), and R-MCP (rituximab and MCP), R-roscovitine (seliciclib, CYC202), sargramostim, sildenafil citrate, simvastatin, sirolimus, styryl sulfone, tacrolimus, tanespimycin, temsirolimus (CCl-779), thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tipifarnib, vincristine, vincristine sulfate, vinorelbine bitartrate, SAHA (suberoylanilide hydroxamic acid or suberoyl, anilide and hydroxamic acid), vemurafenib Venetoclax (ABT-199).

[0782] 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 therapy include, but are not limited to, iodine-131, simumab, and monoclonal antibodies. Yttrium-90 Ibritumomab tiuxetan and with CHOP.

[0783] The above therapies may be supplemented 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, whole 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.

[0784] Combination therapy for non-Hodgkin lymphoma

[0785] 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.

[0786] Examples of unconjugated monoclonal antibodies used to treat NHL / B-cell cancers include rituximab, alemtuzumab, human or humanized anti-CD20 antibodies, ruximab, anti-TNF-related apoptosis-inducing ligand (anti-TRAIL), bevacizumab, galiximab, epratuzumab, SGN-40, and anti-CD74.

[0787] Examples of experimental antibody agents used to treat NHL / B cell cancers include ofatumumab, ha20, PRO131921, alemtuzumab, galiximab, SGN-40, CHIR-12.12, epratuzumab, ruximab, apolizumab, milatuzumab, and bevacizumab.

[0788] Examples of standard regimens for NHL / B cell cancer chemotherapy include CHOP, FCM, CVP, MCP, R-CHOP, R-FCM, R-CVP, and R-MCP.

[0789] Examples of radioimmunotherapy for NHL / B-cell cancers include yttrium-90 tiuxetan and iodine-131 simumab monoclonal antibody

[0790] Combination therapy for mantle cell lymphoma

[0791] In some embodiments, additional therapeutic agents are suitable for treating mantle cell lymphoma (MCL), which include combination chemotherapy such as CHOP, hyperCVAD and FCM. These regimens can also be supplemented with the monoclonal antibody rituximab to form the combination therapies R-CHOP, hyperCVAD-R and R-FCM. Any of the above therapies can be combined with stem cell transplantation or ICE to treat MCL.

[0792] Other examples of therapeutic agents suitable for treating MCL include:

[0793] - Immunotherapies based on the genetic makeup of an individual subject's tumor, such as monoclonal antibodies (e.g., rituximab) and cancer vaccines (such as GTOP-99);

[0794] - Radioimmunotherapy, in which monoclonal antibodies are combined with radioisotope particles (such as iodine-131 simumab) in sequential treatment with CHOP Yttrium-90 Ibritumomab tiuxetan and combination;

[0795] - Autologous stem cell transplantation combined with high-dose chemotherapy, administration of a proteasome inhibitor such as bortezomib ( or PS-341), or administration of anti-angiogenic agents such as thalidomide, especially in combination with rituximab;

[0796] - Combinations of drugs that cause degradation of the Bcl-2 protein and increase the sensitivity of cancer cells to chemotherapy such as oblimersen with other chemotherapeutic agents;

[0797] - 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), votocib, GSK-2126458, and temsirolimus or other combinations of chemotherapeutic agents;

[0798] - Other agents such as flavopiridol, palbociclib (PD0332991), roscovitine (celicilib, CYC202), styryl sulfone, obaclava (GX15-070), TRAIL, anti-TRAIL death receptor DR4 and DR5 antibodies, temsirolimus ( CCl-779), everolimus (RAD001), BMS-345541, curcumin, SAHA, thalidomide, lenalidomide ( CC-5013) and geldanamycin (17-AAG).

[0799] Combination therapy for Waldenstrom's macroglobulinemia

[0800] In some embodiments, the additional therapeutic agent is suitable for treating Waldenstrom's macroglobulinemia (WM), which includes aldesleukin, alemtuzumab, avosidide, amifostine trihydrate, aminocamptothecin, antineoplastic A10, antineoplastic 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, Campas-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 simumab monoclonal antibody, irinotecan hydrochloride, ixabepilone, lymphokine-activated killer cells, mefa len, mesna, methotrexate, mitoxantrone hydrochloride, monoclonal antibody CD19 (such as tisagenlecleucel-T, CART-19, CTL-019), monoclonal antibody CD20, motexafin gadolinium, mycophenolate mofetil, nelarabine, oblimersen, octreotide acetate, omega-3 fatty acids, oxaliplatin, paclitaxel, ethylene glycol filgrastim, ethylene glycol liposomal doxorubicin hydrochloride, pentostatin, perifosine, prednisone, recombinant flt3 ligand, recombinant human thrombopoietin, recombinant interferon alpha, recombinant interleukin-11, recombinant interleukin-12, rituximab, sargramostim, sildenafil citrate Simvastatin, sirolimus, tacrolimus, tansimab, thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tipifarnib, citumomab, veltuzumab, vincristine sulfate, vinorelbine bitartrate, vorinostat, WT1 126-134 peptide vaccine, WT-1 analog peptide vaccine, yttrium-90 ibritumomab tiuxetan, yttrium-90 humanized epratuzumab, and any combination thereof.

[0801] Other examples of therapeutic procedures used to treat WM include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, whole 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.

[0802] Combination therapy for diffuse large B-cell lymphoma

[0803] In some embodiments, additional therapeutic agents are suitable 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 for WM, and any combination thereof, such as ICE and R-ICE.

[0804] Combination therapy for chronic lymphocytic leukemia

[0805] In some embodiments, the additional therapeutic agents are suitable 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.

[0806] Combination therapy for myelofibrosis

[0807] 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 saridajit and vismogib.

[0808] Examples of HDAC inhibitors include, but are not limited to, pracinostat and panobinostat.

[0809] Non-limiting examples of tyrosine kinase inhibitors are lestaurtinib, bosutinib, imatinib, gilteritinib, radotinib, and cabozantinib.

[0810] Combination therapy for hyperproliferative diseases

[0811] In some embodiments, the additional therapeutic agent is suitable for treating a hyperproliferative disease and includes gemcitabine, nab-paclitaxel, and gemcitabine / nab-paclitaxel and a JAK inhibitor and / or a PI3Kδ inhibitor.

[0812] Combination therapy for bladder cancer

[0813] In some embodiments, the additional therapeutic agent is suitable for treating bladder cancer and includes atezolizumab, carboplatin, cisplatin, docetaxel, doxorubicin, fluorouracil (5-FU), gemcitabine, idosfamide, interferon alpha-2b, methotrexate, mitomycin, nab-paclitaxel, paclitaxel, pemetrexed, thiotepa, vinblastine, and any combination thereof.

[0814] Combination therapy for breast cancer

[0815] In some embodiments, the additional therapeutic agent is suitable for treating breast cancer and includes nab-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.

[0816] Combination therapy for triple-negative breast cancer

[0817] In some embodiments, the additional therapeutic agent is suitable for treating triple-negative breast cancer and includes cyclophosphamide, docetaxel, doxorubicin, epirubicin, fluorouracil, paclitaxel, and combinations thereof.

[0818] Combination therapy for colorectal cancer

[0819] In some embodiments, the additional therapeutic agent is suitable for treating colorectal cancer and includes bevacizumab, capecitabine, cetuximab, fluorouracil, irinotecan, leucovorin, oxaliplatin, panitumumab, zifr-aflibercept, and any combination thereof.

[0820] Combination therapy for castration-resistant prostate cancer

[0821] In some embodiments, the additional therapeutic agent is suitable for treating castration-resistant prostate cancer and includes abiraterone, cabazitaxel, docetaxel, enzalutamide, prednisone, siprucel-T, and any combination thereof.

[0822] Combination therapy for esophageal and esophagogastric junction cancer

[0823] 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.

[0824] Combination therapy for gastric cancer

[0825] In some embodiments, the additional therapeutic agent is suitable for treating gastric cancer and includes capecitabine, carboplatin, cisplatin, docetaxel, epirubicin, fluoropyrimidine, fluorouracil, irinotecan, leucovorin, mitomycin, oxaliplatin, paclitaxel, ramucirumab, trastuzumab, and any combination thereof.

[0826] Combination therapy for head and neck cancer

[0827] 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.

[0828] Combination therapy for hepatobiliary carcinoma

[0829] In some embodiments, the additional therapeutic agent is suitable for treating hepatobiliary duct cancer and includes capecitabine, cisplatin, fluoropyrimidines, 5-fluorouracil, gemcitabine, oxaliplatin, sorafenib, and any combination thereof.

[0830] Combination therapy for hepatocellular carcinoma

[0831] In some embodiments, the additional therapeutic agent is suitable for treating hepatocellular carcinoma and includes capecitabine, doxorubicin, gemcitabine, sorafenib, and any combination thereof.

[0832] Combination therapy for non-small cell lung cancer

[0833] In some embodiments, the additional therapeutic agent is suitable for treating non-small cell lung cancer (NSCLC) and includes afatinib, nab-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.

[0834] Combination therapy for small cell lung cancer

[0835] In some embodiments, the additional therapeutic agent is suitable for treating small cell lung cancer (SCLC) and includes bendamustine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, etoposide, gemcitabine, ipilimumab, irinotecan, nivolumab, paclitaxel, temozolomide, topotecan, vincristine, vinorelbine, and any combination thereof.

[0836] Combination therapy for melanoma

[0837] In some embodiments, the additional therapeutic agent is suitable for treating melanoma and includes nab-paclitaxel, carboplatin, cisplatin, cobimetinib, dabrafenib, dacarbazine, IL-2, imatinib, interferon alpha-2b, ipilimumab, nitrosourea, nivolumab, paclitaxel, pembrolizumab, ipilimumab, temozolomide, trametinib, vemurafenib, vinblastine, and any combination thereof.

[0838] Combination therapy for ovarian cancer

[0839] In some embodiments, the additional therapeutic agent is suitable for treating ovarian cancer and includes 5-fluorouracil, nab-paclitaxel, altretamine, anastrozole, bevacizumab, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, etoposide, exemestane, gemcitabine, ifosfamide, irinotecan, letrozole, leuprolide acetate, liposomal doxorubicin, megestrol acetate, melphalan, olaparib, oxaliplatin, paclitaxel, pazopanib, pemetrexed, tamoxifen, topotecan, vinorelbine, and any combination thereof.

[0840] Combination therapy for pancreatic cancer

[0841] In some embodiments, the additional therapeutic agent is suitable for treating pancreatic cancer and includes 5-fluorouracil, nab-paclitaxel, capecitabine, cisplatin, docetaxel, erlotinib, a fluoropyrimidine, gemcitabine, irinotecan, leucovorin, oxaliplatin, paclitaxel, and any combination thereof.

[0842] Combination therapy for renal cell carcinoma

[0843] In some embodiments, the additional therapeutic agent is suitable for treating renal cell carcinoma and includes axitinib, bevacizumab, cabozantinib, erlotinib, everolimus, lenvatinib, nivolumab, pazopanib, sorafenib, sunitinib, temsirolimus, and any combination thereof.

[0844] VIII. Kit

[0845] The present disclosure provides a kit comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof. The kit may also include instructions for use, such as for treating viral infections. The instructions are typically written instructions, but electronic storage media (e.g., disks or optical disks) containing the instructions are also acceptable.

[0846] The present disclosure also provides a drug kit, which includes one or more containers, which contain compounds of the present disclosure or pharmaceutically acceptable salts thereof. Optionally associated with such containers may be a notification 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 that allows cross-reactivity and shelf life. The kit can be a unit dosage form, batch packaging (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 can be packaged in an amount sufficient to be stored and used in a pharmacy (e.g., a hospital pharmacy and a compounding pharmacy).

[0847] Also provided are articles comprising a unit dose of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in a suitable package for use in the methods described herein. Suitable packaging is known in the art and includes, for example, vials, containers, ampoules, bottles, jars, flexible packaging, etc. The articles may be further sterilized and / or sealed.

[0848] IX. Examples

[0849] The abbreviations used herein have the following corresponding meanings:

[0850]

[0851]

[0852] Solid forms (polymorphs, solvates and hydrates) of Compound 1 were characterized by various of the following methods.

[0853] XRPD patterns were collected using an incident beam of Cu Kα radiation using a PANalytical X'Pert PRO MPD diffractometer, which was produced using a long fine focus source and a nickel filter. A symmetrical Bragg-Brentano geometry was used to construct the diffractometer. Before analysis, a silicon specimen (NIST SRM 640e) was analyzed to verify that the observed position of the Si 111 peak was consistent with the NIST certified position. The specimen of the sample was prepared as a circular thin layer centered on a silicon zero background substrate. The background generated by air was minimized using an anti-scattering slit (SS). The broadening from axial divergence was minimized using the soller slit of the incident beam and the diffracted beam. Diffraction patterns were collected using a scanning position sensitive detector (X'Celerator) located at 240 mm from the sample and data collector software v.2.2b.

[0854] Differential Scanning Calorimetry (DSC) data were collected using a TA Instruments 2920 and Q2000 Differential Scanning Calorimeter. Temperature calibration was performed using NIST traceable indium metal. The sample was placed in a T zero aluminum DSC pan, covered with a cover 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 unit. The sample was heated from -30°C to 250°C at a rate of 10°C / min.

[0855] Thermogravimetric analysis (TGA) data were collected using a TA Instruments Discovery Thermogravimetric Analyzer. Nickel and Alumel TM Temperature correction 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 a rate of 10°C / min.

[0856] Moisture adsorption / desorption data were collected on a VTI SGA-100 vapor sorption analyzer. NaCl and PVP were used as calibration standards. The samples were not dried prior to analysis. Adsorption and desorption data were collected in the range of 5% to 95% RH at 10% RH increments under a nitrogen purge. The equilibrium standard for analysis was a weight change of less than 0.0100% in 5 minutes, with a maximum equilibrium time of 3 hours. The weight percentages reported in the data section are relative to the total sample mass introduced before equilibrium at 5% RH, as measured on the instrument.

[0857] Example 1: Preparation of Compound I

[0858]

[0859] Compound A (2.69kg, 6.07mol, 1.0 equivalent) was added to a 50L jacketed reactor purged with nitrogen. Dichloromethane (10.13L, 13.44kg) was added afterwards. Stirring was set to 175RPM, and the contents were stirred until a solution was observed. Trifluoroacetic acid (4.53L, 6.75kg) was added at a rate such 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 gentle reflux). The contents were stirred at this temperature for 3 hours, and the jacket was then set to 15°C. Once the internal temperature reached 20°C, ethanol (denatured by n-heptane) (8.56L, 6.75kg) was added, and the contents were stirred at 20°C for 14 hours. After this amount of time, the heterogeneous contents were filtered into a 100L jacketed reactor purged with nitrogen through a benchtop multi-filter.

[0860] Dichloromethane (5.21L, 6.91kg) was loaded into a 50L reactor, and the solution was rinsed into a 100L reactor through a filter. Water (15.5L, 15.5kg) and ethyl acetate (19.0L, 17.0kg) were then added to the 100L reactor. Agitation was set to 175RPM, and the jacket was set to 87°C. The contents were heated to reflux for 30 minutes. After this amount of time, the jacket was set to 20°C. The water layer was discharged. Water (18.4L.18.4kg) was added to the reactor, and agitation was set to 200RPM. 30% w / w NaOH (8.61kg) was added, and the contents were stirred at 30°C for 30 minutes (the jacket was set to 40°C). Ethyl acetate (45.0L, 40.4kg) was then loaded, 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 amount of time, stirring was stopped and the phases were separated, and the aqueous layer was discharged. A 4.5% w / w aqueous sodium bicarbonate solution (prepared by 605g sodium bicarbonate and 12.8kg water) was added, and the contents were stirred at 200RPM for 30 minutes at an internal temperature of 45°C. After this amount of time, stirring was stopped and the layers were separated. The aqueous layer was discharged, and the jacket was set to 20°C. The contents were aged at this temperature and 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 by 605g sodium bicarbonate and 12.8kg water) was added, and the contents were stirred (200RPM) at 45°C for 30 minutes. Stirring was then stopped, the phases were separated, and the aqueous layer was discharged. A 4.5% w / w aqueous sodium bicarbonate solution (prepared by 605g sodium bicarbonate and 12.8kg water). The contents were stirred (200RPM) 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 amount of time, agitation was stopped and the phases were allowed to separate, and the aqueous layer was drained.

[0861] Example 2: Form I

[0862] The reactor was configured for vacuum distillation, and the jacket was set to 70°C and the stirring was set to 150RPM. The solvent was removed via vacuum distillation to approximately 30L. The jacket was set to 35°C and the reactor was backfilled with nitrogen. Ethyl acetate (45L, 40.4kg) was loaded and the reactor was heated to 70°C, the stirring was set to 150RPM and the pressure was reduced. The solvent was removed via vacuum distillation to approximately 30L. The jacket was set to 35°C and the reactor was backfilled with nitrogen. The ethyl acetate distillation sequence was repeated 5 times as described. After adding 45L of ethyl acetate in each sequence, the final volume of the five distillations was approximately 30L. The contents were sampled for water content determination (target <0.5% H2O). After passing the water content standard, the jacket was heated to 70°C, the stirring was set to 150RPM and the pressure was reduced, and distillation continued to approximately 22L. 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 a 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 distillation continued to about 18 L. Once the target volume was reached, 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, a cooling slope of cooling from 85 ° C to 20 ° C was started in 8 hours.

[0863] 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 with a nitrogen purge for 24 hours. (Form I) Compound I was isolated in good purity (99.6% assay, 99.7% AN).

[0864] Optionally, compound I (1.2kg, 4.0mol) is added to a 50L 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, a cooling slope of 85°C to 20°C is started over 8 hours. The solids are 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 nitrogen venting. Compound I is isolated.

[0865] Form I is the unsolvated phase. Its XRPD pattern is Figure 1 Shown in.

[0866] Table 1: Crystallographic Data and Data Collection Parameters for Compound 1 Form I

[0867]

[0868]

[0869] Table 2: Peak list of Form I

[0870]

[0871]

[0872] Example 3: Gentisic acid

[0873] Compound I Form I (37.01 mg), approximately one molar equivalent of gentisic acid (18.1 mg), and acetonitrile (300 μl) were mixed in an Avantium The reactor system was heated to 50°C. After approximately 15 minutes, the reactor system was closed to rapidly cool to ambient temperature. After reaching ambient temperature, the sample was reheated to approximately 50°C for approximately 4 hours and then cooled to approximately 10°C at 0.1°C / min. The solid was collected by vacuum filtration, added to dichloromethane (0.5 ml), and stirred at ambient temperature. After approximately 5 hours, the solid was collected by vacuum filtration and analyzed.

[0874] XRPD pattern of compound I gentisic acid Figure 2 Shown in.

[0875] Table 3: Peak list of gentisic acid

[0876]

[0877] DSC curve Figure 3 The TGA curve shows an endothermic transition at about 178 °C. Figure 4 The dynamic vapor sorption curve is shown in Figure 5 , and the data indicate that the form absorbs about 1.1% water up to 95% RH at 25° C. The material was found not to change form after the experiment.

[0878] Example 4: Hippuric acid

[0879] Compound I Form I (40.09 mg), approximately one molar equivalent of hippuric acid (24.5 mg) and acetone (300 μl) were mixed in an Avantium The multi-reactor system was heated to about 50°C. After approximately 15 minutes, the reactor system was closed to rapidly 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.

[0880] XRPD pattern of compound I hippuric acid Figure 6 Shown in.

[0881] Table 4: Peak table of hippuric acid

[0882]

[0883] DSC curve Figure 7 The TGA curve shows an endothermic transition at about 127 °C. Figure 8 The dynamic vapor sorption curve is shown in Fig. 9 , and the data indicate that the form absorbs about 0.68% water up to 95% RH at 25° C. The material was found not to change form after the experiment.

[0884] Example 5: Phosphate Form I

[0885] Compound I phosphonate Form I was isolated by dissolving Compound I Form I (39.14 mg) and 2 molar equivalents of phosphoric acid (18 μl, 85% aqueous solution) in acetone (300 μl). The reaction gave a gel which was ground with a variety of solvents including ethyl acetate, diethyl ether and a final mixture of acetonitrile and isopropanol (67 / 33 v / v, 300 μl). A solid was obtained after stirring at ambient temperature for about 5 days in an acetonitrile / isopropanol mixture. The solid was collected by vacuum filtration and the wet cake was washed with isopropanol (100 μl).

[0886] The XRPD pattern of Compound I Phosphate Form I is Fig.10 Shown in.

[0887] Table 5: Peak list of phosphate form I

[0888]

[0889] DSC curve Fig.11 The TGA curve is shown in Figure 2 and shows several endothermic transitions at about 43°C, 118°C and 202°C. Fig.12 , and indicates that this phase is solvated. This form was not further characterized.

[0890] Example 6: Phosphate Form II

[0891] Compound I phosphate material II was isolated by cooling Compound I Form I (53.00 mg) and 1 molar equivalent of phosphoric acid (13 μl, 85% aqueous solution) in isopropanol (500 μl). Note that a purple discoloration was observed when phosphoric acid was added to a mixture of Compound I and isopropanol, but became clear upon mixing. The reaction gave a gel, which was ground with a variety of solvents including acetonitrile, diethyl ether, and acetonitrile / isopropanol (67 / 33 v / v). The solid was crystallized by slurrying the gel in diethyl ether (1 ml) and adding seeds of Compound I phosphate Form I. The solid was isolated by vacuum filtration after stirring for about 3 days.

[0892] XRPD pattern of Compound I Phosphate Form II Fig.13 Shown in.

[0893] Table 6: Peak list of phosphate form II

[0894]

[0895]

[0896] DSC curve Fig.14 The TGA curve shows two endothermic transitions at about 42°C and 95°C. Fig.15 , and indicates that this phase is solvated. This form was not further characterized.

[0897] Example 7: Succinic acid

[0898] In a Mettler-Toledo EasyMax synthesis workstation, Compound 1 Form I (35.7 mg) and approximately half a molar equivalent of succinic acid (7.54 mg) were dissolved in isopropanol (0.5 ml) at approximately 60° C. The solution was cooled to approximately 5° C. over approximately 9 hours. The solid was collected by vacuum filtration, air dried for approximately 10 minutes, and analyzed.

[0899] Compound I succinic acid XRPD pattern Fig.16 Shown in.

[0900] Table 7: Peak list of succinic acid

[0901]

[0902]

[0903] DSC curve Fig.17 The TGA curve shows two endothermic transitions at about 96°C and 115°C. Fig.18 The dynamic vapor sorption curve is shown in Fig.19 , and the data indicate that the form absorbs about 1.2% water up to 95% RH at 25° C. The material was found not to change form after the experiment.

[0904] Example 8: Ethylenedisulfonic Acid Form I

[0905] Ethylenedisulfonic acid Form I was isolated from a cooling experiment in acetone. In one experiment, Compound I Form I (34.19 mg), approximately one molar equivalent of 1,2-ethanedisulfonic acid hydrate (27.3 mg) and acetone (300 μl) were mixed in an Avantium The multi-reactor system was heated to about 50°C. After approximately 15 minutes, the reactor system was closed to rapidly 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.

[0906] Compound I ethanedisulfonic acid form I XRPD pattern Fig. 20 Shown in.

[0907] Table 8: Peak list of ethanedisulfonic acid form I

[0908]

[0909]

[0910] Example 9: Ethylenedisulfonic Acid Form II

[0911] Compound I ethanedisulfonic acid Form II was isolated by slurrying Form I in dichloromethane. Compound I oxalate Form II was also isolated from a cooling experiment in acetone. The procedure involved dissolving Compound I Form I (32.10 mg) in acetone (800 μl) at approximately 60 °C in a Mettler-Toledo EasyMax reactor. 1,2-ethanesulfonic acid hydrate (1.1 molar equivalents, 26.05 mg) was added to the solution to give a dark purple solution. The solution was cooled to approximately 20 °C in approximately 6.5 hours.

[0912] XRPD pattern of Compound I ethanedisulfonic acid form II Fig.21 Shown in.

[0913] Table 9: Peak list of ethanedisulfonic acid form II

[0914]

[0915]

[0916] Although the foregoing disclosure has been described in considerable detail by way of illustration and example for the purpose of clear understanding, it will be appreciated by those skilled in the art that certain changes and modifications may be implemented within the scope of the appended claims. In addition, to the extent not inconsistent with this specification, each reference (including all U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications mentioned in this specification) is incorporated herein by reference in its entirety. In the event of a conflict between the present application and the references provided herein, the present application shall prevail.

Claims

1. A crystalline form of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol gentisic acid: It is characterized in that The X-ray powder diffraction (XRPD) pattern includes five or more peaks at 4.4°, 8.7°, 12.9°, 14.9°, 17.3°, 19.5°, 24.8°, 25.7°, or 26.3° 2θ (±0.2° 2θ), ie, Compound I gentisic acid.

2. The crystalline form according to claim 1, characterized in that The XRPD pattern included peaks at 4.4°, 8.7°, 12.9°, 14.9°, 24.8°, and 25.7° 2Θ (± 0.2° 2Θ).

3. The crystalline form of claim 1, wherein the XRPD pattern comprises 12.9°, Peaks at 17.3°, 19.5°, 24.8°, 25.7°, and 26.3° 2θ (± 0.2° 2θ).

4. The crystalline form of claim 1, wherein the XRPD pattern comprises 4.4°, Peaks at 8.7°, 14.9°, 17.3°, 19.5°, and 26.3° 2θ (± 0.2° 2θ).

5. The crystalline form according to claim 1, characterized in that The XRPD pattern included peaks at 4.4°, 8.7°, 12.9°, 14.9°, 17.3°, 19.5°, 24.8°, 25.7°, and 26.3° 2Θ (± 0.2° 2Θ).

6. The crystalline form according to claim 1, characterized in that The XRPD pattern is essentially as shown in Figure 2.

7. The crystalline form according to claim 1, characterized in that The differential scanning calorimetry (DSC) thermogram had an endotherm with an onset temperature of about 178°C.

8. The crystalline form according to claim 1, characterized in that The DSC thermogram is essentially as shown in Figure 3.

9. A crystalline form of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol hippuric acid: It is characterized in that The XRPD pattern included five or more peaks at 2.9°, 5.0°, 7.6°, 10.4°, 12.6°, 17.6°, 19.0°, 25.2°, or 28.5° 2Θ (±0.2° 2Θ), ie, Compound 1 hippuric acid.

10. The crystalline form according to claim 9, characterized in that The XRPD pattern included peaks at 2.9°, 5.0°, 7.6°, 12.6°, 19.0°, and 25.2° 2Θ (± 0.2° 2Θ).

11. The crystalline form of claim 9, wherein the XRPD pattern comprises 2.9°, Peaks at 7.6°, 10.4°, 17.6°, 19.0°, and 28.5° 2θ (± 0.2° 2θ).

12. The crystalline form of claim 9, wherein the XRPD pattern comprises 5.0°, Peaks at 10.4°, 12.6°, 17.6°, 25.2°, and 28.5° 2θ (± 0.2° 2θ).

13. The crystalline form according to claim 9, characterized in that The XRPD pattern included peaks at 2.9°, 5.0°, 7.6°, 10.4°, 12.6°, 19.0°, 17.6°, 25.2°, and 28.5° 2Θ (± 0.2° 2Θ).

14. The crystalline form according to claim 9, characterized in that The XRPD pattern is substantially as shown in FIG6 .

15. The crystalline form according to claim 9, characterized in that The differential scanning calorimetry (DSC) thermogram had an endotherm with an onset temperature of about 127°C.

16. The crystalline form of claim 9, wherein The DSC thermogram is essentially as shown in FIG7 .

17. A crystalline form of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol succinic acid: It is characterized in that The XRPD pattern included five or more peaks at 4.6°, 6.8°, 9.3°, 13.2°, 17.5°, 18.7°, 19.0°, 25.7°, or 27.0° 2Θ (± 0.2° 2Θ), ie, Compound 1 succinic acid.

18. The crystalline form according to claim 17, characterized in that The XRPD pattern included peaks at 4.6°, 6.8°, 9.3°, 18.7°, 19.0°, and 25.7° 2Θ (± 0.2° 2Θ).

19. The crystalline form of claim 17, wherein the XRPD pattern comprises peaks at 13.2°, 17.5°, 18.7°, 19.0°, 25.7°, and 27.0° 2θ (±0.2° 2θ).

20. The crystalline form of claim 17, wherein the XRPD pattern comprises peaks at 4.6°, 6.8°, 9.3°, 13.2°, 17.5°, and 27.0° 2θ (± 0.2° 2θ).

21. The crystalline form of claim 17, wherein The XRPD pattern included peaks at 4.6°, 6.8°, 9.3°, 13.2°, 17.5°, 18.7°, 19.0°, 25.7°, and 27.0° 2Θ (± 0.2° 2Θ).

22. The crystalline form of claim 17, wherein The XRPD pattern is substantially as shown in FIG16 .

23. The crystalline form of claim 17, wherein The differential scanning calorimetry (DSC) thermogram had an endotherm with an onset temperature of about 96°C.

24. The crystalline form of claim 23, wherein the DSC thermogram has a second endotherm with an onset temperature of about 115°C.

25. The crystalline form of claim 17, wherein The DSC thermogram is essentially as shown in FIG17 .

26. A pharmaceutical composition comprising the crystalline form according to any one of claims 1 to 25 and one or more pharmaceutically acceptable excipients.

27. The pharmaceutical composition of claim 26, wherein the crystalline form is gentisate.

28. The pharmaceutical composition of claim 26, wherein the crystalline form is hippurate.

29. The pharmaceutical composition of claim 26, wherein the crystalline form is a succinate salt.

30. The crystalline form according to any one of claims 1 to 25 or the pharmaceutical composition according to any one of claims 26 to 29 for use in a method of treating or preventing HBV infection.

31. The crystalline form or pharmaceutical composition for use according to claim 30, wherein the method comprises administering a therapeutically effective amount of one or more additional therapeutic agents.

32. The crystalline form or the pharmaceutical composition for use according to claim 31, wherein the one or more additional therapeutic agents are administered simultaneously with the crystalline form or the pharmaceutical composition.

33. A crystalline form or a pharmaceutical composition for use according to claim 31 or 32, wherein the one or more additional therapeutic agents are selected from the group consisting of: HBV combination drugs, HBV vaccines, HBV DNA polymerase inhibitors, immunomodulators, toll-like receptor (TLR) modulators, interferon alpha 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.

34. The crystalline form or pharmaceutical composition for use according to claim 31 or 32, wherein the one or more additional therapeutic agents are selected from the group consisting of: adefovir Tenofovir disoproxil fumarate + emtricitabine Tenofovir Disoproxil Fumarate Entecavir Lamivudine Tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine Emtricitabine Peginterferon 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 alpha-2b (Axxo), Alfaferone, Interferon alpha-2b, Feron, Interferon-alpha 2 (CJ), Bevac, Laferonum, Vipeg, Blauferon-B, Blauferon-A, Intermax alpha, Realdiron, Lanstion, Pegaferon, PDferon-B, alpha interferon a 2b, Kalferon, Pegnano, Feronsure, PegiHep, Optipeg A, Realfa 2B, Reliferon, Pegylated interferon alpha-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 Shu Ning, Shangsheng Leitai, Intefen, Sinogen, Fukangtai, Alloferon, and Simoleukin.

35. The crystalline form or pharmaceutical composition for use according to claim 31 or 32, 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 fumarate, tenofovir alafenamide hemifumarate, telbivudine and lamivudine.

36. The crystalline form or pharmaceutical composition for use according to claim 31 or 32, wherein the one or more additional therapeutic agents are selected from the group consisting of tenofovir alafenamide, tenofovir alafenamide fumarate and tenofovir alafenamide hemifumarate.

37. Use of a crystalline form according to any one of claims 1 to 25 or a pharmaceutical composition according to any one of claims 26 to 29 in the manufacture of a medicament for the treatment or prevention of HBV infection.

38. The use of claim 37, further comprising administering a therapeutically effective amount of one or more additional therapeutic agents.

39. The use according to claim 38, wherein the one or more additional therapeutic agents are administered simultaneously with the crystalline form or the pharmaceutical composition.

40. The use according to claim 38 or 39, wherein the one or more additional therapeutic agents are selected from the group consisting of: HBV combination drugs, HBV vaccines, HBV DNA polymerase inhibitors, immunomodulators, toll-like receptor (TLR) modulators, interferon alpha 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.

41. The use according to claim 38 or 39, wherein the one or more additional therapeutic agents are selected from the group consisting of: adefovir Tenofovir disoproxil fumarate + emtricitabine Tenofovir Disoproxil Fumarate Entecavir Lamivudine Tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine Emtricitabine Peginterferon 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 alpha-2b (Axxo), Alfaferone, Interferon alpha-2b, Feron, Interferon-alpha 2 (CJ), Bevac, Laferonum, Vipeg, Blauferon-B, Blauferon-A, Intermax alpha, Realdiron, Lanstion, Pegaferon, PDferon-B, alpha interferon a 2b, Kalferon, Pegnano, Feronsure, PegiHep, Optipeg A, Realfa 2B, Reliferon, Pegylated interferon alpha-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 Shu Ning, Shangsheng Leitai, Intefen, Sinogen, Fukangtai, Alloferon, and Simoleukin.

42. The use according to claim 38 or 39, 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 fumarate, tenofovir alafenamide hemifumarate, telbivudine and lamivudine.

43. The use according to claim 38 or 39, wherein the one or more additional therapeutic agents are selected from the group consisting of tenofovir alafenamide, tenofovir alafenamide fumarate and tenofovir alafenamide hemifumarate.

44. The crystalline form according to any one of claims 1 to 25 or the pharmaceutical composition according to any one of claims 26 to 29 for use in medical therapy.

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