Use of amiloride and derivatives to treat adverse events due to the use of antibody drug conjugates

Abstract

Disclosed herein are methods for treating and preventing adverse events, including ocular surface disorders, induced by antibody-drug conjugates (ADCs) using compounds of Formula (I) or a pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, racemates or isotopes thereof, wherein the groups R1, R2 and R3 are defined herein. Also disclosed herein are methods for treating cancer using a combination of an ADC and a compound of Formula (I).

Description

USE OF AMILORIDE AND DERIVATIVES TO TREAT ADVERSE EVENTS DUE TO THE USE OF ANTIBODY DRUG CONJUGATESSTATEMENT OF GOVERNMENT INTEREST

[0001] This invention was made with government support under Grant Numbers K08 EY033859, K12 EY031372 and R01 EY036139, awarded by the National Institutes of Health / National Eye Institute. The government has certain rights in the invention.BACKGROUND

[0002] Antibody-drug conjugates (ADCs)-induced adverse events, such as ocular toxicity, have become prevalent as the ADCs are increasingly popular and effective for targeted cancer therapy. An ADC is composed of a monoclonal antibody (mAb) fused to a highly potent cytotoxic payload by a chemical linker. There are currently 11 FDA-approved ADCs on the market with over 150 in the clinical trial pipeline.

[0003] Despite the designed selectivity of ADCs, off-target adverse events still occur. For example, about 40% of ADCs cause ocular disorders, including corneal or conjunctival toxicity, with >20% of FDA-approved ADCs including an FDA black box warning for ocular toxicity. Over 50,000 patients are at risk for ADC-induced corneal toxicity in the U.S. currently with that number increasing annually. In particular, ADC-induced corneal toxicity is clinically relevant due to its ability to interrupt ADC therapy, and is responsible for up to 50% of ADC dose delays, 25% of ADC dose reductions, and 5% of ADC discontinuations. Current preventative therapies for ADC-induced corneal toxicity (e.g., topical steroids, vasoconstrictors, lubrication) have limited efficacy with no FDA-approved therapy existing for ADC-induced corneal toxicity.

[0004] One proposed mechanism of ADC-induced adverse events, including but not limited to ocular surface disorders (e.g., corneal toxicity), thrombocytopenia, and peripheral neuropathy, is macropinocytosis — a form of non-specific endocytosis known as “cell drinking,” which facilitates the internalization of ADCs or the deconjugated cytotoxic payload. (Reference 1).

[0005] The mechanism of macropinocytosis is poorly understood and may vary depending on the cell types. Several classes of compounds, namely, (i) actin polymerization inhibitors (Reference 2), (ii) PI3K blockers (Reference 3) and (iii) inhibitors of sodium / hydrogen exchangers (NHEs) appeared to inhibit macropinocytosis in certain cell types, e.g., cancer cells, dendritic cells and macrophages (Reference 4). Lin et al. screened 640 FDA-approved compounds for their ability to inhibit macropinocytosis, and the primary screen identified 14 compounds that can inhibit > 95% of macropinocytotic solute internalization at ~10 pM concentration. (Reference 5). A secondary screening revealed seven compounds having diverse structural variation(flubendazole, terfenadine, itraconazole, phenoxybenzamine, vinblastine, auranofin and impramine) that exhibited moderate to good potency and selectivity for inhibition of macropinocytosis. (Reference 2, Table 1).

[0006] A need exists to discover therapeutic agents and methods for treating ADC-induced adverse events, including ocular surface disorders such as corneal toxicity.BRIEF SUMMARY

[0007] Provided herein are methods for treating ADC-induced adverse events, particularly due to cell internalization of the ADC by macropinocytosis. Examples of the adverse events include, without limitation, ocular and corneal toxicity, hematological toxicity, and neurotoxicity. Thus, certain embodiments provide methods for treating ADC-induced adverse effects by macropinocytosis inhibitors, including for example, inhibitors of Na+ / H+ exchanger subtype 1 (NHE1).

[0008] More specifically, various embodiments provide methods for treating an ADC- induced adverse event, including an ocular surface disorder, by macropinocytosis inhibitors, including but not limited to, inhibitors of Na+ / H+ exchanger subtype 1 (NHE1). In various embodiments, the macropinocytosis inhibitors are applied topically to the ocular surface. In other embodiments, the macropinocytosis inhibitors are administered systemically.

[0009] In preferred embodiments, the macropinocytosis inhibitors include amiloride or a derivative thereof, represented by Formula (I). In particular, the ocular surface disorder is ADC- induced corneal toxicity or conjunctival toxicity. Also provided are methods for treating cancer using ADCs in conjunction with one or more compounds of Formula (I).

[0010] One specific embodiment provides a method for treating an ADC-induced ocular surface disorder such as corneal toxicity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I):or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, racemate or isotope thereof, wherein: R1is selected from the group consisting of -OH, -NH2, -SH, -F, -Cl, -Br, -CO2H, -CONH2, -OC(O)NH2, -NH-C(0)NH2, -NHC(O)2H, -S(O)2H, -SO2NH2, -NHSO2H,-NHNH2, -ONH2, -CN, -NHSO2H and -NHOH; and R2and R3are each independently selectedfrom the group consisting of H, alkyl, haloalkyl, heterocycloalkyl and aryl, or R2and R3together with the nitrogen to which they are connected form a substituted or unsubstituted heterocycloalkyl, provided that the compound of Formula (I) is not 5-(N-ethyl-N-isopropyl)-amiloride.

[0011] Another embodiment relates to a method for treating a cancer in a subject in need thereof, the method comprising (a) administering to the subject a therapeutically effective amount of antibody drug conjugate (ADC); and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I):or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, racemate or isotope thereof, wherein: R1is selected from the group consisting of -OH, -NH2, -SH, -F, -Cl, -Br, - CO2H, -CONH2, -OC(O)NH2, -NH-C(O)NH2, -NHC(O)2H, -S(O)2H, -SO2NH2,NHSO2H, -NHNH2, -ONH2, -CN, -NHSO2H and -NHOH; and R2and R3are each independently selected from the group consisting of H, alkyl, haloalkyl, heterocycloalkyl and aryl, or R2and R3together with the nitrogen to which they are connected form a heterocycloalkyl, provided that the compound of Formula (I) is not 5-(N-ethyl-N-isopropyl)-amiloride.BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0012] Figure 1 summarizes experimental results for a study measuring 6-day cell viability of human corneal epithelial cells (HCECs) that are treated with an ADC (belantamab mafodotin), amiloride, and a control medium.

[0013] Figure 2 summarizes experimental results for a study measuring 4-hour cell viability of human corneal epithelial cells (HCECs) that are treated with an ADC (belantamab mafodotin), a combination of the ADC (belantamab mafodotin) and 5-(N-ethyl-N-isopropyl)- amiloride (EIP A), and a control medium.

[0014] Figures 3A and 3B summarize experimental results for a study measuring internalization of an ADC (belantamab mafodotin) into human corneal epithelial cells (HCECs) that are treated with the ADC (belantamab mafodotin), a combination of the ADC (belantamab mafodotin) and 5-(N-ethyl-N-isopropyl)-amiloride (EIP A), a combination of the ADC (belantamab mafodotin) and amiloride, and a control medium.

[0015] Figures 3C and 3D show the IgG fluorescence intensity of the HCECs tested in the experimental results of Figures 3 A and 3B.

[0016] Figures 4A and 4B summarize experimental results for studies measuring the macropinocytosis index (number of macropinosomes per cell) of human corneal epithelial cells (HCECs) that are treated with an ADC (belantamab mafodotin), a combination of the ADC (belantamab mafodotin) and 5-(N-ethyl-N-isopropyl)-amiloride (EIP A), a combination of the ADC (belantamab mafodotin) and amiloride, and a dextran-only control medium.

[0017] Figures 4C and 4D show cellular images of the HCECs tested in Figures 4A and 4B.

[0018] Figure 4E summarizes the TMR-dextran intensities for the cellular images of the HCECs in Figure 4D.

[0019] Figure 5A summarizes experimental results for a study measuring internalization of Elahere® (mirvetuximab soravtansine) into human corneal epithelial cells (HCECs) that are treated with Elahere®, a combination of Elahere® and 5-(N-ethyl-N-isopropyl)-amiloride (EIP A), a combination of Elahere® and amiloride, and a control medium.

[0020] Figure 5B shows the IgG fluorescence intensity of the HCECs tested in the experimental results of Figure 5 A.

[0021] Figure 6A summarize experimental results for a study measuring the macropinocytosis index of human corneal epithelial cells (HCECs) that are treated with Elahere® (mirvetuximab soravtansine), a combination of Elahere® and 5-(N-ethyl-N-isopropyl)-amiloride (EIP A), a combination of Elahere® and amiloride, and a dextran-only control medium.

[0022] Figure 6B shows cellular images of the HCECs tested in Figure 6A.

[0023] Figure 6C summarizes the TMR-dextran intensities for the cellular images of the HCECs in Figure 6B.

[0024] Figure 7A shows cellular images of human pluripotent stem cell-derived sensory neurons (nociceptors) subject to Elahere® (mirvetuximab soravtansine) internalization visualized by co-localization (yellow) of anti-human IgG (H+L) green immunofluorescent staining and TUJ 1 P3-tubulin red immunofluorescent staining (neuron).

[0025] Figure 7B summarizes experimental results for a study in which human pluripotent stem cell-derived sensory neurons (nociceptors) are treated with Elahere® (mirvetuximab soravtansine), a combination of Elahere® with 0.2% DMSO, a combination of Elahere® and 5- (N-ethyl-N-isopropyl)-amiloride (EIP A), and a combination of Elahere® and amiloride.DETAILED DESCRIPTION

[0026] As used herein the terms “ADC” and “antibody-drug conjugate” are equivalent and refer to any compounds composed of an antibody covalently linked to a biologically active payload or cytotoxic drug. In some embodiments the antibody is a monoclonal antibody that binds to specific proteins or receptors expressed on certain types of cells, including cancer cells. The linked drug enters the targeted cells and kills them without harming other cells. In some embodiments the ADCs described herein are used to treat cancer.

[0027] “ADC-induced adverse events” refer to Grades 1-4 treatment-related adverse events, including adverse hematologic events (thrombocytopenia, febrile neutropenia, lymphopenia, anemia, etc.), gastrointestinal effects, ocular toxicities, peripheral neuropathy, fatigue, hepatic dysfunction, and the like. In particular, the ADC-induced adverse events according to the present disclosure are thrombocytopenia, peripheral neuropathy and ocular surface disorder. Without wishing to be bound by theory, the underlying cause of the ADC- induced adverse events according to the present disclosure include macropinocytosis, which facilitates the internalization of ADCs or the deconjugated cytotoxic payload.

[0028] Ocular surface disorder,” as used herein, refer to conditions that affect and damage the surface layers of the eyes, include cornea and conjunctiva. The conditions are induced or caused by one or more ADCs used for treating a disease (e.g., cancer). Symptoms of the ocular surface disorder includes, for example, corneal epithelial atrophy, corneal pseudomicrocysts, punctate erosion, eye pain, blurry vision, mononuclear cell infiltration, dry eye, and the like.

[0029] The terms “micrograms” or “pg” when referencing the weight of an active agent refers to micrograms of the free base form of the active agent regardless of whether the active agent is present in the form of the free base or the pharmaceutically acceptable salt. For example, 5 micrograms of a pharmaceutically acceptable salt of a compound of Formula (I) means that there is 5 micrograms of the free base form of the compound of Formula (I).

[0030] The terms “nanomoles” or “nM” or “nmoles” when referencing the unit of measurement of an active agent refers to nanomoles of the free base form of the active agent regardless of whether the active agent is present in the form of the free base or the pharmaceutically acceptable salt. For example, 5 nanomoles of a pharmaceutically acceptable salt of a compound of Formula (I) means that there is 5 nanomoles of the free base form of the compound of Formula (I).

[0031] “NHE1” refers to Na+ / H+ exchanger (NHE) subtype 1. NHE is a sodium-proton pump involved in water transport in cells. In some embodiments, the macropinocytosis inhibitors are NHEl inhibitors.

[0032] “Subject” and “subject in need thereof’ refer to a patient suffering from or prone to a disorder or disease, including one or symptoms of ADC-induced ocular surface disorder (e.g., corneal toxicity), as well as the underlying disease (e.g., cancer) being treated by an ADC.

[0033] The terms “treating,” or “treatment” refer to any indicia of success in the treatment or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; or improving a patient’s physical well-being. The treatment of symptoms can be based on objective or subjective parameters, including the results of a physical examination. The term “treating” includes prevention of an injury, pathology, condition, or disease. “Treating” in reference to treating a symptom of ADC-induced ocular surface disorder, including corneal toxicity, refers to, for example, reducing corneal epithelial atrophy, reducing corneal pseudomicrocysts, reducing punctate erosion, reducing eye pain, reducing blurry vision, and / or reducing mononuclear cell infiltration.

[0034] A “therapeutically effective amount” is an amount of the active agent sufficient to accomplish a stated purpose, e.g., achieve the effect for which it is administered (i.e., reducing corneal pseudomicrocysts) in a patient. A “therapeutically effective amount” is an amount of the active agent sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). In embodiments, the “therapeutically effective amount” is the amount described herein.

[0035] As discussed in detail herein, the compound of Formula (I) or a composition comprising the same may be administered once or as frequently as the symptoms occur.

[0036] The active agents and compositions described herein can be used in combination with one or more other drugs known to be useful in treating ADC-induced corneal toxicity. The active agents and compositions described herein can be used with adjunctive agents that may not be effective alone, but may contribute to the efficacy of the active agent. Thus, the active agents described herein may be co-administered with one or more other drugs that are useful to treat ADC-induced corneal toxicity in patients. Exemplary drugs used to treat ADC-induced corneal toxicity include vasoconstricting agents, epithelial sodium channel inhibitors, lymphocytefunction-associated antigen- 1 antagonists, anti-inflammatory agents, cholinergic agonists, steroids, antibiotics, and the like. Steroids that may be used in combination with compounds of the present disclosure include, for example, prednisolone phosphate, prednisolone acetate, fluoromethoIone acetate, dexamethasone, and the like.

[0037] By “co-administer” it is meant that active agent or compositions described herein are administered at the same time, prior to (e.g., minutes or hours), or after (e.g., minutes or hours) the administration of one or more additional therapies. The active agents described herein can be administered alone or can be co-administered to the patient. Co-administration is meant to include simultaneous or sequential administration of the active agent individually or in combination. Thus, the preparations can also be combined, when desired, with other active substances.

[0038] Co-administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second pharmaceutical compound (e.g., anti-dry eye agents). Also contemplated herein, are embodiments, where co-administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of another pharmaceutical compound. Co-administration includes administering the active agent and other pharmaceutical compound simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. Co-administration can be accomplished by coformulation, z.e., preparing a single pharmaceutical composition including both the active agent and the other pharmaceutical compound. In other embodiments, the active agent and other pharmaceutical compound can be formulated separately.

[0039] “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by a patient and can be included in the compositions described herein. In particular, the pharmaceutically acceptable excipient or carrier is suitable for ophthalmic uses, including topical or ocular surface administration. Exemplary pharmaceutically acceptable excipients include stabilizers, cosolvents, and the like. Other non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with other pharmaceutically acceptable excipients such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and / or aromatic substances and the like.

[0040] A “stabilizer” refers to a pharmaceutically acceptable excipient that maintains the properties of the active agents described herein and / or that delays or prevents physical or chemical degradation of the active agents described herein. Exemplary stabilizers include microcrystalline cellulose, carboxymethyl cellulose, hydromellose, dextran, and the like.

[0041] Co-solvent” refers to pharmaceutically acceptable excipients that can increase, maintain, or prolong the solubility of the active agents. Exemplary co-solvents include sorbitol, glycerol, propylene glycol, polyethylene glycol, polyvinyl alcohol, polysorbate, and the like.

[0042] The compound of Formula (I) may be administered systemically or topically. “Topically administering” means topical application of the compounds or compositions described herein to one or both eyes of a patient. In embodiments, the topical administration is topical administration to the cornea of the eye. The active agents and compositions described herein can be delivered topically as a liquid formulation, e.g., as eye drops. In embodiments, the topical liquid formulation is a solution. In embodiments, the topical liquid formulation is an aqueous solution. In embodiments, the topical liquid formulation is a suspension. In embodiments, the topical liquid formulation is an emulsion. In embodiments, the topical liquid formulation is an ointment.

[0043] In other embodiments, the compound of Formula (I) or composition comprising the same may be delivered through an implantable device in the eyes, including fluid-eluting contact lens. The implantable device includes a reservoir containing the pharmaceutical composition described herein and may further include means that allows the active agent to elute onto the ocular surface in a sustained manner. See, e.g., U.S. 2020 / 0409177.

[0044] “Systemic administering” refers to delivering a drug into the circulatory system (e.g., blood). Examples include oral and intravenous administration. Preferably, the circulating serum macropinocytosis inhibitors of the present disclosure target specific tissue types, such as the corneal or conjunctival tissues.Methods of Treatment

[0045] In various embodiments, disclosed herein are methods for treating ADC-induced adverse events, including ocular surface disorder, by administering one or more macropinocytosis inhibitors, including but not limited to, NHE1 inhibitors. In various embodiments, the macropinocytosis inhibitors are applied topically to the ocular surface. In other embodiments, the macropinocytosis inhibitors are administered systemically with targeted action in various tissues, including ocular tissues such as corneal or conjunctival tissues.

[0046] One specific embodiment relates to a method for treating an ocular surface disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I):or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, racemate or isotope thereof, wherein:

[0047] R1is selected from the group consisting of -OH, -NH2, -SH, -F, -Cl, -Br, -CO2H, -CONH2, -OC(O)NH2, -NH-C(O)NH2, -NHC(O)2H, -S(O)2H, -SO2NH2, -NHSO2H, -NHNH2, -ONH2, -CN, -NHSO2H and -NHOH; and

[0048] R2and R3are each independently selected from the group consisting of H, alkyl, haloalkyl, heterocycloalkyl and aryl, or R2and R3together with the nitrogen to which they are connected form a substituted or unsubstituted heterocycloalkyl, provided that the compound of Formula (I) is not 5-(N-ethyl-N-isopropyl)-amiloride.

[0049] In more specific embodiments, the ocular surface disorder is ADC-induced corneal toxicity.

[0050] In even more specific embodiments, treating ADC-induced corneal toxicity comprises reducing corneal epithelial atrophy, reducing corneal pseudomicrocysts, reducing punctate erosion, reducing eye pain, reducing blurry vision, and / or reducing mononuclear cell infiltration.

[0051] In more specific embodiments, the ocular surface disorder is dry-eye disease.

[0052] Another embodiment relates to a method for treating a cancer in a subject in need thereof, the method comprising (a) administering to the subject a therapeutically effective amount of antibody drug conjugate (ADC), and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I):or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, racemate or isotope thereof, wherein:

[0053] R1is selected from the group consisting of -OH, -NH2, -SH, -F, -Cl, -Br, -CO2H, -CONH2, -OC(O)NH2, -NH-C(0)NH2, -NHC(O)2H, -S(O)2H, -SO2NH2, -NHSO2H, -NHNH2, -ONH2, -CN, -NHSO2H and -NHOH; and

[0054] R2and R3are each independently selected from the group consisting of H, alkyl, haloalkyl, heterocycloalkyl and aryl, or R2and R3together with the nitrogen to which they are connected form a heterocycloalkyl, provided that the compound of Formula (I) is not 5-(N-ethyl- N-isopropyl)-amiloride.

[0055] In various embodiments, the ADC may be any compound composed of an antibody covalently linked to a biologically active payload (e.g., a cytotoxic drug) targeting antigenexpressing cells (e.g., tumor cells). In some specific embodiments the ADC that induces corneal toxicity, or the ADC that is used to treat cancer, is selected from belantamab mafodotin, mirvetuximab soravtasine, trastuzumab emtansine, tisotumab vedotin, enfortumab vedotin, datopotamab deruxtecan, patritumab deruxtecan, trastuzumab deruxtecan, telisotuzumab vedotin, disitamab vedotin, polatuzumab vedotin, brentuximab vedotin, cetuximab sarotalocan, loncastuximab tesirine, inotuzumab ozogamicin, gemtuzumab ozogamicin, sacituzumab govitecan, anvatabart opadotin, datopotamab deruxtecan, trastuzumab envedotin, and the like.

[0056] In some embodiments the cancer that is treated by methods disclosed herein may include, for example, adrenocortical carcinoma, astrocytoma, childhood cerebellar or cerebral, basal-cell carcinoma, bone tumor, osteosarcoma / malignant fibrous histiocytoma, a brain cancer, a brain tumor (such as cerebellar astrocytoma, malignant glioma, ependymoma, medulloblastoma, visual pathway and hypothalamic glioma, and the like), brainstem glioma, a breast cancer (such as triple negative breast cancer, HER2-positive breast cancer, and the like), bronchial adenomas / carcinoids, cerebellar astrocytoma, cervical cancer, cholangiocarcinoma, chronic myeloproliferative disorders, colon cancer, cutaneous endometrial cancer, ependymoma, esophageal cancer, an eye cancer (such as intraocular melanoma, retinoblastoma, and the like), gallbladder cancer, gastric cancer, glioma, a head and neck cancer (such as head and neck squamous cell carcinoma, and the like), heart cancer, hepatocellular (liver) cancer, hypopharyngeal cancer, islet cell carcinoma (endocrine pancreas), kidney cancer (renal cell cancer), laryngeal cancer, leukemia (e.g., acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia, chronic myelogenous leukemia and hairy cell leukemia), lip and oral cavity cancer, lung cancer (e.g., non-small cell and small cell), a lymphoma(e.g., anaplastic large cell lymphoma, B-cell lymphoma, AIDS-related lymphoma, Burkitt’s lymphoma, cutaneous T-Cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, etc.), macroglobulinemia, a melanoma (such as cutaneous melanoma, and the like), Merkel cell cancer, mesothelioma, multiple myeloma, multiple myeloma / plasma cell neoplasm, a mycosis fungoide, a myelodysplastic syndrome, a myelodysplastic / myeloproliferative disease, a myeloproliferative disorder, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, oligodendroglioma, oropharyngeal cancer, osteosarcoma / malignant fibrous histiocytoma of bone, ovarian cancer, pancreatic cancer, parathyroid cancer, pharyngeal cancer, pheochromocytoma, pituitary adenoma, plasma cell neoplasia, pleuropulmonary blastoma, prostate cancer, rectal cancer, a renal cell carcinoma (such as kidney cancer, and the like), a renal pelvis and ureter transitional cell cancer, salivary gland cancer, a sarcoma (such as chondrosarcoma, kaposi sarcoma, liposarcoma, malignant fibrous histiocytoma of bone / osteosarcoma, rhabdomyosarcoma, soft tissue sarcoma, and the like), Ewing family of tumors, Sezary syndrome, skin cancer (nonmelanoma), skin carcinoma, small intestine cancer, squamous cell carcinoma, squamous neck cancer with occult primary (metastatic), stomach cancer, testicular cancer, throat cancer, thymoma and thymic carcinoma, thymoma, thyroid cancer, thyroid cancer, urothelial cancer, uterine cancer, vaginal cancer, Waldenstrom macroglobulinemia, Wilms tumor, and the like, or any combination thereof.

[0057] In some embodiments the cancer that is treated by methods disclosed herein is selected from the group consisting of an acute lymphoblastic leukemia, an acute myeloid leukemia, an anaplastic large cell lymphoma, a B-cell lymphoma, a Hodgkin lymphoma, a multiple myeloma, a cervical cancer, an HER2-positive breast cancer, a lung cancer, an ovarian cancer, a triplenegative breast cancer, and a urothelial cancer.

[0058] In some embodiments the compound of Formula (I) is defined such that R1is selected from the group consisting of -OH, -NH2, -SH, -F, -Cl, -Br, and -CN. In certain specific embodiments R1is -OH. In certain specific embodiments R1is -NH2. In certain specific embodiments R1is -SH. In certain specific embodiments R1is -F. In certain specific embodiments R1is -Cl. In certain specific embodiments R1is -Br. In certain specific embodiments R1is -CN.

[0059] In some embodiments the compound of Formula (I) is defined such that R2and R3are each independently H or Ci-Ce alkyl, or R2and R3together form a 3- to 8-membered heterocycloalkyl. In certain specific embodiments R2and R3are each H. In certain specific embodiments R2is H and R3is Ci-Ce alkyl. In certain specific embodiments R2is Ci-Ce alkyl and R3is H. In certain specific embodiments R2and R3are each independently Ci-Ce alkyl. In certainspecific embodiments R2and R3together with the nitrogen to which they are connected form a 3- to 8-membered heterocycloalkyl. In certain specific embodiments R2and R3together with the nitrogen to which they are connected form a 3 -membered heterocycloalkyl. In certain specific embodiments R2and R3together with the nitrogen to which they are connected form a 4-membered heterocycloalkyl. In certain specific embodiments R2and R3together with the nitrogen to which they are connected form a 5-membered heterocycloalkyl. In certain specific embodiments R2and R3together with the nitrogen to which they are connected form a 6-membered heterocycloalkyl. In certain specific embodiments R2and R3together with the nitrogen to which they are connected form a 7-membered heterocycloalkyl. In certain specific embodiments R2and R3together with the nitrogen to which they are connected form an 8-membered heterocycloalkyl.

[0060] In some embodiments the compound of Formula (I) is defined such that R1is selected from the group consisting of -OH, -NH2, -SH, -F, -Cl, -Br, and -CN; and R2and R3are each independently H or Ci-Ce alkyl, or R2and R3together form a 3- to 8-membered heterocycloalkyl.

[0061] In some embodiments the compound of Formula (I) is defined such that R1is selected from the group consisting of -OH, -NH2, -SH, -F, -Cl, -Br, and -CN. In certain specific embodiments R1is -OH. In certain specific embodiments R1is -NH2. In certain specific embodiments R1is -SH. In certain specific embodiments R1is -F. In certain specific embodiments R1is -Cl. In certain specific embodiments R1is -Br. In certain specific embodiments R1is -OH, -NH2, -SH, -F, -Cl, -Br, and -CN.

[0062] In certain specific embodiments R1is -OH, and R2and R3together form a 3- to 8- membered heterocycloalkyl. In certain specific embodiments R1is -NH2, and R2and R3together form a 3- to 8-membered heterocycloalkyl. In certain specific embodiments R1is -SH, and R2and R3together form a 3- to 8-membered heterocycloalkyl. In certain specific embodiments R1is -F, and R2and R3together form a 3- to 8-membered heterocycloalkyl. In certain specific embodiments R1is -Cl, and R2and R3together form a 3- to 8-membered heterocycloalkyl. In certain specific embodiments R1is -Br, and R2and R3together form a 3-to 8-membered heterocycloalkyl. In certain specific embodiments R1is -CN, and R2and R3together form a 3- to 8-membered heterocycloalkyl.

[0063] In certain specific embodiments R1is selected from the group consisting of -OH, R2is H, and R3is H. In certain specific embodiments R1is -NH2, R2is H, and R3is H. In certain specific embodiments R1is -SH, R2is H, and R3is H. In certain specific embodiments R1is -F,R2is H, and R3is H. In certain specific embodiments R1is -Cl, R2is H, and R3is H. In certain specific embodiments R1is -Br, R2is H, and R3is H.

[0064] In some embodiments the compound of Formula (I) is defined such that R1is selected from the group consisting of -OH, -NH2, -SH, -F, -Cl, -Br, and -CN; R2is H; and R3is selected from the group consisting of H or Ci-Ce alkyl.

[0065] In certain specific embodiments R1is selected from the group consisting of -OH, R2is H, and R3is Ci-Ce alkyl. In certain specific embodiments R1is selected from the group consisting of -NH2, R2is H, and R3is Ci-Ce alkyl. In certain specific embodiments R1is -SH, R2is H, and R3is Ci-Ce alkyl. In certain specific embodiments R1is -F, R2is H, and R3is Ci-Ce alkyl. In certain specific embodiments R1is -Cl, R2is H, and R3is Ci-Ce alkyl. In certain specific embodiments R1is -Br, R2is H, and R3is Ci-Ce alkyl. In certain specific embodiments R1is -CN, R2is H, and R3is Ci-Ce alkyl.

[0066] In some embodiments the compound of Formula (I) is selected from:or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or isotope thereof, wherein: Ring s X| - N XA represents: ' 'a; X is CH2 or O, a is an integer from 0 to 3; and b is an integer from 2 to 3.

[0067] In certain specific embodiments the compound of Formula (I) is amiloride, which has the following structure:or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or isotope thereof.

[0068] In certain specific embodiments the compound of Formula (I) is:or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or isotope thereof.

[0069] In specific embodiments, the compound of Formula (I) excludes EIPA.

[0070] In certain specific embodiments the compound of Formula (I) isor a pharmaceutically acceptable salt, solvate, hydrate, tautomer or isotope thereof, wherein: Ring s XA represents: ' 'a; X is CH2 or O, a is an integer from 0 to 3; and b is an integer from 2 to 3. In certain specific embodiments X is CH2. In certain specific embodiments X is O. In certain specific embodiments a is 0 and b is 2. In certain specific embodiments a is 0 and b is 3. In certain specific embodiments a is 1 and b is 2. In certain specific embodiments a is 1 and b is 3. In certain specific embodiments a is 2 and b is 2. In certain specific embodiments a is 2 and b is 3. In certain specific embodiments a is 3 and b is 2. In certain specific embodiments a is 3 and b is 3. In certain specific embodiments X is CH2, a is 0, and b is 2. In certain specific embodiments X is CH2, a is 0, and b is 3. In certain specific embodiments X is CH2, a is 1, and b is 2. In certain specific embodiments X is CH2, a is 1, and b is 3. In certain specific embodiments X is CH2, a is 2, and b is 2. In certain specific embodiments X is CH2, a is 2, and b is 3. In certain specific embodiments X is CH2, a is 3, and b is 2. In certain specific embodiments X is CH2, a is 3, and b is 3. In certain specific embodiments X is O, a is 0, and b is 2. In certain specific embodiments X is O, a is 0, and b is 3. In certain specific embodiments X is O, a is 1, and b is 2. In certain specific embodiments X is O, a is 1, and b is 3. In certain specific embodiments X is O, a is 2, and b is 2. In certain specific embodiments X is O, a is 2, and b is 3. In certain specific embodiments X is O, a is 3, and b is 2. In certain specific embodiments X is O, a is 3, and b is 3.

[0071] In more specific embodiments, the compound of Formula (I) is systemically administered to the subject, e.g., by oral administration. In more specific embodiments, thecompound of Formula (I) is administered topically to the eye of the subject. In more specific embodiments, the compound of Formula (I) is topically administered to the eye of the subject. In some embodiments the compound of Formula (I) is administered to the cornea of the subject. In other embodiments the compound of Formula (I) is administered to the conjunctiva of the subject.

[0072] In some embodiments the compound of Formula (I) is administered to the subject in the form of a solution or dispersion having a concentration ranging from about 1% (m / v) (z.e., ~1 gram per 100 mL) to about 10% (m / v) (i.e., ~10 grams per 100 mL). For example, in some embodiments the compound of Formula (I) is administered to the subject in the form of a solution or dispersion having a concentration ranging from about 1.0% (m / v) to about 1.5% (m / v), or from about 1.5% (m / v) to about 2.0% (m / v), or from about 2.0% (m / v) to about 2.5% (m / v), or from about 2.5% (m / v) to about 3.0% (m / v), or from about 3.0% (m / v) to about 3.5% (m / v), or from about 3.5% (m / v) to about 4.0% (m / v), or from about 4.0% (m / v) to about 4.5% (m / v), or from about 4.5% (m / v) to about 5.0% (m / v), or from about 5.0% (m / v) to about 5.5% (m / v), or from about 5.5% (m / v) to about 6.0% (m / v), or from about 6.0% (m / v) to about 6.5% (m / v), or from about 6.5% (m / v) to about 7.0% (m / v), or from about 7.0% (m / v) to about 7.5% (m / v), or from about 7.5% (m / v) to about 8.0% (m / v), or from about 8.0% (m / v) to about 8.5% (m / v), or from about 8.5% (m / v) to about 9.0% (m / v), or from about 9.0% (m / v) to about 9.5% (m / v), or from about 9.5% (m / v) to about 10.0% (m / v). In a specific embodiment, the concentration is 4%. In some embodiments the compound of Formula (I) is administered to the subject in the form of an aqueous solution or aqueous dispersion; in other embodiments the compound of Formula (I) is administered to the subject in the form of a non-aqueous solution or non-aqueous dispersion.

[0073] In some embodiments the compound of Formula (I) is administered to the subject in the form of a solution or dispersion having a concentration ranging from about 40 pM to 500 pM. In more specific embodiments, the concentration ranges from 50 pM to 100 pM, 100 pM to150 pM, 150 pM to 200 pM, 200 pM to 250 pM, 250 pM to 300 pM, 300 pM to 350 pM, 350 pM to 400 pM, 400 pM to 450 pM, or 450 pM to 500 pM. In a specific embodiment, the concentration is 175 pM.

[0074] In some embodiments the compound of Formula (I) is administered to the subject at a dosage ranging from about 2 nanomoles to about 200 nanomoles.

[0075] In some embodiments the therapeutically effective amount of the compound of Formula (I) provides a concentration of about 100 nM to about 1,000 mM of the compound of Formula (I) in the eye of the subject after a period of about 1-3 hours following administration.

[0076] In some embodiments the therapeutically effective amount of the compound of Formula (I) provides a concentration of about 100 nM to about 500 nM, or about 500 nM to about 1 pM, or about 1 pM to about 50 pM, or about 50 pM to about 100 pM, or about 100 pM to about 150 pM, or about 150 pM to about 200 pM, or about 200 pM to about 250 pM, or about 250 pM to about 300 pM, or about 300 pM to about 350 pM, or about 350 pM to about 400 pM, or about 400 pM to about 450 pM, or about 450 pM to about 500 pM, or about 500 pM to about 550 pM, or about 550 pM to about 600 pM, or about 600 pM to about 650 pM, or about 650 pM to about 700 pM, or about 700 pM to about 750 pM, or about 750 pM to about 800 pM, or about 800 pM to about 850 pM, or about 850 pM to about 900 pM, or about 900 pM to about 950 pM, or about 950 pM to about 1,000 pM, of the compound of Formula (I) in the eye of the subject after a period of about 1-3 hours following administration.

[0077] In certain specific embodiments the pharmaceutically acceptable salt is selected from the group consisting of a hydrochloric acid salt, hydrobromic acid salt, nitric acid salt, carbonic acid salt, monohydrogencarbonic acid salt, phosphoric acid salt, monohydrogenphosphoric acid salt, dihydrogenphosphoric acid salt, sulfuric acid salt, monohydrogensulfuric acid salt, hydriodic acid salt, phosphorous acid salt, acetic acid salt, propionic acid salt, isobutyric acid salt, maleic acid salt, malonic acid salt, benzoic acid salt, succinic acid salt, suberic acid salt, fumaric acid salt, lactic acid salt, mandelic acid salt, phthalic acid salt, benzenesulfonic acid salt, p-tolylsulfonic acid salt, citric acid salt, tartaric acid salt, oxalic acid salt, and methanesulfonic acid salt.

[0078] In some embodiments at least one additional therapeutic agent is co-administered with the compound of Formula (I) in an amount effective to enhance the therapeutic effects of the compound of Formula (I). In some embodiments the at least one additional therapeutical agent is selected from the group consisting of a vasoconstricting agent, epithelial sodium channel inhibitor, a lymphocyte function-associated antigen- 1 antagonist, an anti-inflammatory agent, a cholinergic agonist, a steroid, an antibiotic, and any combination thereof. In some embodiments at least one steroid is co-administered with the compound of Formula (I). In some embodiments at least one steroid such as, for example, prednisolone phosphate, prednisolone acetate, fluoromethoIone acetate, dexamethasone, and the like, is co-administered with the compound of Formula (I).

[0079] In some embodiments, a pharmaceutical composition comprising the compound of Formula (I) is systemically administered to the subject. In more specific embodiments, a pharmaceutical composition comprising the compound of Formula (I) is administered to the eye of the subject. In more specific embodiments, a pharmaceutical composition comprising thecompound of Formula (I) is topically administered to the eye of the subject. In some embodiments, a pharmaceutical composition comprising the compound of Formula (I) is administered to the cornea or conjunctiva of the subject.

[0080] In some embodiments the pharmaceutical composition is a liquid pharmaceutical composition. In some embodiments the liquid pharmaceutical composition is a solution, a suspension, an emulsion, or an ointment. In some embodiments the liquid pharmaceutical composition is an aqueous solution. In some embodiments the liquid pharmaceutical composition is a suspension; and the compound of Formula (I) is micronized. In some embodiments the pharmaceutical composition further comprises a pharmaceutically acceptable excipient. In some embodiments the pharmaceutically acceptable excipient is a stabilizer, a co-solvent, or a combination thereof.

[0081] In some embodiments the compound of Formula (I), or a pharmaceutical composition thereof, is administered once per day. In some embodiments the compound of Formula (I), or a pharmaceutical composition thereof, is administered twice per day. In some embodiments the compound of Formula (I), or a pharmaceutical composition thereof, is administered for about 14 days. In some embodiments the compound of Formula (I), or a pharmaceutical composition thereof, is administered for about one month. In some embodiments the compound of Formula (I), or a pharmaceutical composition thereof, is administered for more than one month. In some embodiments the compound of Formula (I), or a pharmaceutical composition thereof, is administered for at least one year. In some embodiments the compound of Formula (I), or a pharmaceutical composition thereof, is administered for more than one year. In some embodiments the compound of Formula (I), or a pharmaceutical composition thereof, is administered indefinitely.

[0082] In some embodiments the pharmaceutical composition comprises a therapeutically effective amount of a compound of Formula (I), wherein the therapeutically effective amount of the compound of Formula (I) is about 1 microgram or more. In some embodiments the therapeutically effective amount of the compound of Formula (I) is from about 1 microgram to about 200 micrograms. In some embodiments the therapeutically effective amount of the compound of Formula (I) is from about 1 microgram to about 100 micrograms. In some embodiments the therapeutically effective amount of the compound of Formula (I) is from about 1 microgram to about 75 micrograms. In some embodiments the therapeutically effective amount of the compound of Formula (I) is from about 1 microgram to about 50 micrograms. In some embodiments the therapeutically effective amount of the active agent is from about 1 microgramto about 35 micrograms. In some embodiments the therapeutically effective amount of the compound of Formula (I) is from about 1 microgram to about 20 micrograms. In some embodiments the therapeutically effective amount of the compound of Formula (I) is from about 1 microgram to about 15 micrograms. In some embodiments the therapeutically effective amount of the compound of Formula (I) is from about 1 microgram to about 12 micrograms. In some embodiments the therapeutically effective amount of the compound of Formula (I) is from about 1 microgram to about 10 micrograms.

[0083] In some embodiments the pharmaceutical composition comprises a therapeutically effective amount of the compound of Formula (I), wherein the therapeutically effective amount is about 2 nanomoles or more. In some embodiments the therapeutically effective amount of the compound of Formula (I) is from about 2 nanomoles to about 100 nanomoles. In some embodiments the therapeutically effective amount of the compound of Formula (I) is from about 5 nanomoles to about 80 nanomoles. In some embodiments the therapeutically effective amount of the compound of Formula (I) is from about 5 nanomoles to about 60 nanomoles. In some embodiments the therapeutically effective amount of the compound of Formula (I) is from about 5 nanomoles to about 50 nanomoles. In some embodiments the therapeutically effective amount of the compound of Formula (I) is from about 5 nanomoles to about 40 nanomoles. In some embodiments the therapeutically effective amount of the compound of Formula (I) is from about 5 nanomoles to about 30 nanomoles. In some embodiments the therapeutically effective amount of the compound of Formula (I) is from about 5 nanomoles to about 20 nanomoles. In some embodiments the therapeutically effective amount of the compound of Formula (I) is about 10 nanomoles.

[0084] In some embodiments the therapeutically effective amount provides a concentration of the compound of Formula (I) in an amount of about 100 pM or more in the tear fluid of the eye about 1 hour to about 12 hours after administration. In some embodiments the therapeutically effective amount provides a concentration of the compound of Formula (I) in an amount of (i) about 200 pM or more in the tear fluid of the eye about 30 minutes to about 3 hours after administration, or (ii) about 100 pM or more in the tear fluid of the eye about 4 hours to about to about 12 hours after administration, or (iii) both (i) and (ii). In some embodiments the therapeutically effective amount provides a concentration of the compound of Formula (I) in an amount of (i) about 100 pM to about 200 pM about 1 hour to about 3 hours after administration, or (ii) about 50 pM to about 150 pM about 4 hours to about 8 hours after administration, or (iii) both (i) and (ii). In some embodiments the therapeutically effective amount provides aconcentration of the compound of Formula (I) in an amount of (i) about 150 pM to about 200 pM about 1 hour to about 3 hours after administration, or (ii) about 100 pM to about 150 pM about 4 hours to about 8 hours after administration, or (iii) both (i) and (ii). In some embodiments the therapeutically effective amount provides a concentration of the compound of Formula (I) in an amount of (i) about 150 pM to about 250 pM about 1 hour to about 3 hours after administration, or (ii) about 50 pM to about 200 pM about 5 hours to about 7 hours after administration, or (iii) both (i) and (ii). In some embodiments the therapeutically effective amount provides a concentration of the compound of Formula (I) in an amount of (i) about 200 pM to about 300 pM about 1 hour to about 3 hours after administration, or (ii) about 100 pM to about 200 pM about 5 hours to about 7 hours after administration, or (iii) both (i) and (ii). In some embodiments the therapeutically effective amount provides a concentration of the compound of Formula (I) in an amount of (i) about 175 pM about 2 hours after administration, or (ii) about 50 pM about 6 hours after administration, or (iii) both (i) and (ii).

[0085] Any eye dropper known in the art can be used to topically administer the compounds and compositions described herein. In embodiments, the eye dropper has a volume sufficient to house from about 1 drop to about 50 drops of the pharmaceutical compositions described herein. In embodiments, the eye dropper has a volume sufficient to house from about 1 drop to about 25 drops of the pharmaceutical compositions described herein. In embodiments, the eye dropper has a volume sufficient to house from about 1 drop to about 20 drops of the pharmaceutical compositions described herein. In embodiments, the eye dropper has a volume sufficient to house from about 1 drop to about 15 drops of the pharmaceutical compositions described herein. In embodiments, the eye dropper has a volume sufficient to house from about 1 drop to about 10 drops of the pharmaceutical compositions described herein. In embodiments, the eye dropper has a volume sufficient to house 1 to 5 drops of the composition. In embodiments, the eye dropper has a volume sufficient to house 1 to 4 drops of the composition. In embodiments, the eye dropper has a volume sufficient to house 1 to 3 drops of the composition. In embodiments, the eye dropper has a volume sufficient to house 1 or 2 drops of the composition.

[0086] A “drop” will be a volume of the pharmaceutical composition described herein that can provide a therapeutically effective amount of the compounds described herein when administered at the doses (e.g., 1 microgram or more; 5 nanomoles or more) and dosing regimen (e.g., one or twice per day) described herein. In embodiments, a drop has a volume from about 10 pL to about 100 pL. In embodiments, a drop has a volume from about 20 pL to about 90 pL. In embodiments, a drop has a volume from about 30 pL to about 80 pL. In embodiments, a drop hasa volume from about 40 pL to about 70 pL. In embodiments, a drop has a volume from about 50 pL to about 85 pL. In embodiments, a drop has a volume from about 30 pL to about 65 pL. In embodiments, a drop has a volume from about 40 pL to about 60 pL. In embodiments, a drop has a volume from about 55 pL to about 65 pL.

[0087] The disclosure provides kits comprising the eye droppers described herein. The kit can contain any number of eye droppers that can conveniently be used by the patient for administration of the compositions described herein. Generally, the kit will contain an amount of eye droppers to meet the frequency of the dosing regimen. In embodiments, the kit will contain one eye dropper that can be re-used for the duration of the treatment regimen. In embodiments, the kit will contain seven eye droppers, sufficient to provide single use eye droppers for one week of treatment. In embodiments, the kit will contain fourteen eye droppers. In embodiments, the kit will contain twenty-eight eye droppers. In embodiments, the kit will contain fifty-six eye droppers.

[0088] The disclosure provides kits comprising an eye dropper container which comprises a topical pharmaceutical composition comprising the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, racemate or isotope thereof. The kit can contain any number of eye droppers and any number of containers housing the pharmaceutical compositions that can conveniently be used by the patient for administration of the compositions described herein. Generally, the kit will contain an amount of eye droppers and containers to meet the frequency of the dosing regimen. In embodiments, the kit will comprise one eye dropper and one container, where the container comprises one dose of the composition. In embodiments, the kit will comprise two eye droppers and one container; wherein the container comprises two doses of the composition. In embodiments, the kit will comprise two eye droppers and two containers; wherein each container comprises one dose of the composition. In embodiments, the kit will comprise seven eye droppers and seven containers; wherein each container comprises one dose of the composition. In embodiments, the kit will comprise fourteen eye droppers and seven containers; wherein each container comprises two doses of the composition. In embodiments, the kit will comprise fourteen eye droppers and fourteen containers; wherein each container comprises one dose of the composition.

[0089] In some embodiments the compound of Formula (I) is administered orally such that the therapeutically effective amount provides an oral dose ranging from about 1 mg / day to about 100 mg / day. In some embodiments the oral dose ranges from about 1 mg / day to about 5 mg / day, or from about 5 mg / day to about 10 mg / day, or from about 10 mg / day to about 15 mg / day, or from about 15 mg / day to about 20 mg / day, or from about 20 mg / day to about 25 mg / day, or from about25 mg / day to about 30 mg / day, or from about 30 mg / day to about 35 mg / day, or from about 35 mg / day to about 40 mg / day, or from about 40 mg / day to about 45 mg / day, or from about 45 mg / day to about 50 mg / day, or from about 50 mg / day to about 55 mg / day, or from about 55 mg / day to about 60 mg / day, or from about 60 mg / day to about 65 mg / day, or from about 65 mg / day to about 70 mg / day, or from about 75 mg / day to about 80 mg / day, or from about 80 mg / day to about 85 mg / day, or from about 85 mg / day to about 90 mg / day, or from about 90 mg / day to about 95 mg / day, or from about 95 mg / day to about 100 mg / day.

[0090] In some embodiments the compound of Formula (I) is administered orally in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup) — such that the unit dose ranges from about 1 mg / dose to about 10 mg / dose. In some embodiments the unit dose ranges from about 1 mg / dose to about 2 mg / dose, or from about 2 mg / dose to about 3 mg / dose, or from about 3 mg / dose to about 4 mg / dose, or from about 4 mg / dose to about 5 mg / dose, or from about 5 mg / dose to about 6 mg / dose, or from about 6 mg / dose to about 7 mg / dose, or from about 7 mg / dose to about 8 mg / dose, or from about 8 mg / dose to about 9 mg / dose, or from about 9 mg / dose to about 10 mg / dose.

[0091] The compounds described herein can be made by processes known to those skilled in the art of synthetic organic chemistry.

[0092] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0093] The term “Cx-y” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain. For example, the term “Ci-ealkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from 1 to 6 carbons. The term “-Cx-y alkylene-” refers to a substituted or unsubstituted alkylene chain with from x to y carbons in the alkylene chain. For example -Ci -ealkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted.

[0094] “Alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight (z.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include mono-, di- and multivalent radicals, having the number of carbon atoms designated (z.e., Ci-Cio means one to ten carbons). Alkyl is an uncyclized chain. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl,(cyclohexyl)methyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2- isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3- butynyl, and the higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-O-).

[0095] In embodiments, “alkyl” refers to and includes linear or branched univalent hydrocarbon structures and combination thereof, which may be fully saturated, mono- or polyunsaturated, having the number of carbon atoms designated (z.e., Ci-Cio means one to ten carbons). Particular alkyl groups are those having 1 to 20 carbon atoms (a “C1-C20 alkyl”). More particular alkyl groups are those having 1 to 8 carbon atoms (a “Ci-Cs alkyl”), 3 to 8 carbon atoms (a “C3-C8 alkyl”), 1 to 6 carbon atoms (a “Ci-Ce alkyl”), 1 to 5 carbon atoms (a “C1-C5 alkyl”), or 1 to 4 carbon atoms (a “C1-C4 alkyl”), or 1 to 3 carbon atoms (a “C1-C3 alkyl”), or 1 to 2 carbon atoms (a “C1-C2 alkyl”). Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2- propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. Examples of saturated C1-C4 alkyl include methyl (CH3), ethyl (C2H5), propyl (C3H7) and butyl (C4H9). Examples of saturated Ci-Ce alkyl include methyl (CH3), ethyl (C2H5), propyl (C3H7), butyl (C4H9), pentyl (C5H11) and hexyl (CeHn). An alkyl group may be substituted (z.e., one or more hydrogen atoms are replaced with univalent or divalent radicals) with one more substituents, such as radicals described herein, for example, fluoro, chloro, bromo, iodo, hydroxyl, alkoxy, thio, amino, acylamino, alkoxycarbonylamido, carboxyl, acyl, alkoxycarbonyl, sulfonyl, cycloalkyl, aryl, heterocyclyl and heteroaryl, and other functional groups known in the art. A “perfluoroalkyl” refers to an alkyl group where every hydrogen atom is replaced with a fluorine atom. Examples of saturated Ci-Ce perfluroalkyl include trifluoromethyl (CF3), pentafluoroethyl (C2F5), heptafluoropropyl (C3F7), nonafluorobutyl (C4F9), undecafluoropentyl (C5F11) and tridecafluorohexyl (C6F13).

[0096] “Heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., selected from the group consisting of O, N, P,Si, and S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quatemized. The heteroatom(s) (e.g., O, N, P, S, B, As, and Si) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Heteroalkyl is an uncyclized chain. Examples include, but are not limited to: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, - CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-0-CH3, -Si(CH3)3, - CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -0-CH3, -0-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. Heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', -NR'R", -OR', -SR', and / or -SO2R'. Where “heteroalkyl” is recited, followed by recitations of specific heteroalkyl groups, such as - NR'R" or the like, it will be understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R" or the like.

[0097] “Alkoxy” means an alkyl radical attached through an oxygen linking atom, represented by -O alkyl, wherein alkyl is as defined above. For example, “Cl-6 alkoxy” includes methoxy, ethoxy, propoxy, butoxy, pentoxy, isopentoxy, isopropoxy, and hexoxy. “Haloalkoxy” is a haloalkyl group which is attached to another moiety via an oxygen atom such as, e.g., but are not limited to -OCHCF2 or -OCF3.

[0098] “Cycloalkyl” and “heterocycloalkyl,” by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl,” respectively. Cycloalkyl and heteroalkyl are not aromatic. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1 -cyclohexenyl, 3 -cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, l-(l,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2- piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3- yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. A “cycloalkylene” and a “heterocycloalkylene,” alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively.

[0099] “Halo” or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as“haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo(Ci-C4)alkyl” includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3 -bromopropyl, and the like.

[0100] The term “heteroaryl” refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. Thus, the term “heteroaryl” includes fused ring heteroaryl groups (z.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring). A 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a 6,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom.

[0101] Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazoyl benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1 -naphthyl, 2-naphthyl, 4-biphenyl, 1 -pyrrolyl, 2-pyrrolyl, 3 -pyrrolyl, 3- pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5- oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3- furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5- benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1 -isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. An “arylene” and a “heteroarylene,” alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. A heteroaryl group substituent may be a -O- bonded to a ring heteroatom nitrogen.

[0102] The term “oxo,” as used herein, means an oxygen that is double bonded to a carbon atom. The term “oxo” can be depicted as “=O ”

[0103] Each of the above terms (e.g., “alkyl,” “haloalkyl,” “heterocycloalkyl,” and “aryl”) includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

[0104] As used herein, the terms “heteroatom” or “ring heteroatom” are meant to include, oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), Boron (B), Arsenic (As), and silicon (Si).

[0105] A “substituent” or “substituent group” or the term “substituted” (e.g., “substituted” alkyl, “substituted” heterocycloalkyl, “substituted” heteroaryl) as used herein, means a group selected from the following moi eties: (A) oxo, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2CI, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2,-NHC=(O)NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, substituted with at least one substituent selected from: (i) oxo, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2CI,-SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O) NH2, -NHSO2H, - NHC= (O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, substituted with at least one substituent selected from: (a) oxo, halogen, -CF3, -CN, - OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2CI, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, substituted with at least one substituent selected from: oxo, halogen, -CF3, -CN, -OH, -NH2, -COOH, - CONH2, -NO2, -SH, -SO2CI, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,NHC=(O)NHNH2, -NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, -OCF3, - OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, and unsubstituted heteroaryl.

[0106] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2- and -N= is equivalent to =N-.

[0107] The term “pharmaceutically acceptable” refers an agent that has been approved for human consumption and is generally non-toxic. For example, the term “pharmaceutically acceptable salt” refers to nontoxic inorganic or organic acid and / or base addition salts (see, e.g., Lit et al., Salt Selection for Basic Drugs, Int. J. Pharm., 33, 201-217, 1986) (incorporated by reference herein).

[0108] Salt” generally refers to an organic compound, such as a carboxylic acid or an amine, in ionic form, in combination with a counter ion. For example, salts formed between acids in their anionic form and cations are referred to as “acid addition salts.” Conversely, salts formed between bases in the cationic form and anions are referred to as “base addition salts.”

[0109] The term “pharmaceutically acceptable salt” is meant to include salts of the active agents that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the active agents described herein. When the active agents contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such active agents with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When the active agents contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such active agents with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 1977, 66, 1-19).

[0110] Pharmaceutically acceptable base addition salts of compounds of the disclosure include, for example, metallic salts including alkali metal, alkaline earth metal, and transition metal salts such as, for example, calcium, magnesium, potassium, sodium, and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N'dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-m ethylglucamine), and procaine.

[0111] Pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, aromatic aliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, hippuric, malonic, oxalic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, panthothenic, trifluoromethanesulfonic, 2-hydroxy-ethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, phydroxybutyric, salicylic, galactaric, and galacturonic acid.

[0112] Although pharmaceutically unacceptable salts are not generally useful as medicaments, such salts may be useful, for example as intermediates in the synthesis of compounds of structure (I), for example in their purification by recrystallization.

[0113] The neutral forms of the active agents are regenerated by contacting the salt with a base or acid and isolating the parent active agent in the conventional manner. The parent form of the active agent differs from the various salt forms in certain physical properties, such as solubility in polar solvents and the like.

[0114] As used herein, the term “pharmaceutical composition” refers to a composition containing one or more of the compounds described herein, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, formulated with a pharmaceutically acceptable carrier, which can also include other additives, and manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); for administration to a pediatric subject (e.g., solution, syrup, suspension, elixir, powder for reconstitution as suspension or solution, dispersible / effervescent tablet, chewable tablet, lollipop, freezer pops, troches, oral thin strips, orally disintegrating tablet, orally disintegrating strip, and sprinkle oral powder or granules); or in any other formulation described herein. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippencott Williams& Wilkins (2005) and in The United States Pharmacopeia: The National Formulary (USP 36 NF31), published in 2013.

[0115] The term “tautomer,” as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another. It will be apparent to one skilled in the art that certain active agents may exist in tautomeric forms, all such tautomeric forms of the active agents being within the scope of the disclosure. A “tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented throughout this disclosure, in some embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0116] The symbol “ — ” denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula.

[0117] A “hydrate” is a compound that exists in combination with water molecules. The combination can include water in stoichiometric quantities, such as a monohydrate or a dihydrate, or can include water in random amounts. As the term is used herein a “hydrate” refers to a solid form; that is, a compound in a water solution, while it may be hydrated, is not a hydrate as the term is used herein.

[0118] “Isomer” is used herein to encompass all chiral, diastereomeric or racemic forms of a structure (also referred to as a stereoisomer, as opposed to a structural or positional isomer),unless a particular stereochemistry or isomeric form is specifically indicated. Such compounds can be enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions, at any degree of enrichment. Both racemic and diastereomeric mixtures, as well as the individual optical isomers can be synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these are all within the scope of certain embodiments of the disclosure. The isomers resulting from the presence of a chiral center comprise a pair of nonsuperimposable-isomers that are called “enantiomers.” Single enantiomers of a pure compound are optically active (z.e., they are capable of rotating the plane of plane polarized light and designated R or S).

[0119] “Isotope” refers to atoms with the same number of protons but a different number of neutrons, and an isotope of a compound of structure (I) includes any such compound wherein one or more atoms are replaced by an isotope of that atom. For example, carbon 12, the most common form of carbon, has six protons and six neutrons, whereas carbon 13 has six protons and seven neutrons, and carbon 14 has six protons and eight neutrons. Hydrogen has two stable isotopes, deuterium (one proton and one neutron) and tritium (one proton and two neutrons). While fluorine has a number of isotopes, fluorine- 19 is longest-lived. Thus, an isotope of a compound having the structure of structure (I) includes, but not limited to, compounds of structure (I) wherein one or more carbon 12 atoms are replaced by carbon-13 and / or carbon-14 atoms, wherein one or more hydrogen atoms are replaced with deuterium and / or tritium, and / or wherein one or more fluorine atoms are replaced by fluorine- 19.

[0120] A “solvate” is similar to a hydrate except that a solvent other that water is present. For example, methanol or ethanol can form an “alcoholate,” which can again be stoichiometric or non-stoichiometric. As the term is used herein a “solvate” refers to a solid form; that is, a compound in a solvent solution, while it may be solvated, is not a solvate as the term is used herein.

[0121] Certain active agents described herein possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the disclosure. The disclosure includes active agents in racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the active agents described herein contain olefinic bonds or other centers of geometric asymmetry,and unless specified otherwise, it is intended that the active agents include both E and Z geometric isomers.

[0122] The terms “racemate” and “racemic mixture” refer to an equal mixture of two enantiomers. A racemate is labeled “(±)” because it is not optically active (z.e., will not rotate plane-polarized light in either direction since its constituent enantiomers cancel each other out). Compounds are sometime noted herein with an asterisk (*) adjacent to a tertiary or quaternary carbon to indicate optically active isomers, which may be purified from the respective racemate and / or synthesized by appropriate chiral synthesis.

[0123] “Substantially enantiomerically or diastereomerically” pure means a level of enantiomeric or diastereomeric enrichment of one enantiomer with respect to the other enantiomer or diastereomer of at least about 80%, and more specifically in excess of 80%, 85%, 90%, 95%, 98%, 99%, 99.5% or 99.9%.

[0124] “Isolated optical isomer” means a compound which has been substantially purified from the corresponding optical isomer(s) of the same formula. For example, the isolated isomer may be at least about 80%, at least 80% or at least 85% pure by weight. In other embodiments, the isolated isomer is at least 90% pure or at least 98% pure, or at least 99% pure by weight.

[0125] The term “amiloride” refers the compound shown below.

[0126] The term “EIPA” means 5-(N-ethyl-N-isopropyl)-amiloride and refers to the compound shown below.

[0127] Description of the active agents is limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give active agents which are not inherently unstable and / or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions. For example, a heterocycloalkyl orheteroaryl is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable active agents.

[0128] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. It is to be understood that the detailed description is exemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. In this application, the use of “or” means “and / or” unless stated otherwise. Furthermore, use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting.

[0129] The phrase “at least one” or “at least one of’ when followed by a list of items or elements refers to an open-ended set of one or more of the elements in the list, which may, but does not necessarily, include more than one of the elements.

[0130] As used herein, ranges and amounts can be expressed as “about” a particular value or range. About also includes the exact amount. Hence “about lOOpL” means “about lOOpL” and also “lOOpL.” In some embodiments, about means within 5% of the value. Hence, “about 100 pL” means 95-105 pL. In some embodiments, about means within 4% of the value. In some embodiments, about means within 3% of the value. In some embodiments, about means within 2% of the value. In some embodiments, about means within 1% of the value. Generally, the term “about” includes an amount that would be expected to be within experimental error.

[0131] Where values are described as ranges, it will be understood that such disclosure includes the disclosure of all possible sub-ranges within such ranges, as well as specific numerical values that fall within such ranges irrespective of whether a specific numerical value or specific sub-range is expressly stated.EXAMPLES

[0132] The following examples are for purposes of illustration and are not intended to limit the spirit or scope of the disclosure or claims.EXAMPLE 1COMPARING CELLULAR TOXICITY OF BELANTAMAB MAFODOTIN ANDAMILORIDE TOWARDS IMMORTALIZED HCECS

[0133] Immortalized human corneal epithelial cells (HCECs) provided by Dr. James Jester (UC Irvine) were plated in 96-well plates at 30,000 cells per well density. Cells were incubated with calcium-free Keratinocyte-SFM culture medium (Thermo Fisher Scientific; Waltham, MA) for 2 days until 70-80% confluence, and then treated with amiloride hydrochloride (100 pM, Sigma-Aldrich; St. Louis, MO) or belantamab mafodotin (100 nM, MedChemExpress USA; Monmouth Junction, NJ) for six days without changing the culture medium. Cell viability was quantified using the alamarBlue assay (Thermo Fisher Scientific). As shown in Figure 1, after 6 days treatment, amiloride showed no cell toxicity but treatment with belantamab mafodotin significantly reduced cell viability compared to the medium only group, ns p > 0.05, **** p < 0.0001. Long-term exposure (6 days) of amiloride is non-toxic to immortalized HCECs.EXAMPLE 2COMPARING CELLULAR TOXICITY OF BELANTAMAB MAFODOTIN AND EIPA / BELANTAMAB COMBINATIONS TOWARDS IMMORTALIZED HCECS

[0134] Immortalized HCECs were plated in 96-well plates and cultured with calcium-free Keratinocyte-SFM culture medium for 2 days until 70-80% confluence. On day 3, HCECs were pre-treated with 5-(N-ethyl-N-isopropyl) amiloride (EIPA, MedChemExpress USA) at concentrations ranging from 25-100 pM for 30 minutes and then co-treated with belantamab mafodotin (75 nM) for another 3.5 hours. Cell viability was quantified using the alamarBlue assay and compared with the vehicle control (DMSO), belantamab mafodotin only, and medium only groups, nsp > 0.05, *** p < 0.001, **** p < 0.0001. As shown in Figure 2, short term exposure (4 hours) of EIPA induces dose-dependent toxicity to immortalized HCECs.EXAMPLE 3COMPARING CELLULAR TOXICITY OF BELANTAMAB MAFODOTIN, EIPA / BELANTAMAB AND AMILORIDE / BELANTAMAB COMBINATIONS TOWARDS IMMORTALIZED HCECS

[0135] Primary HCECs were isolated from healthy donor corneal tissue provided by Sierra Donor Services Eye Bank (Sacramento, CA) and digested with Dispase II enzyme (15 mg / mL, Thermo Fisher Scientific) at 4°C overnight. HCECs were cultured in corneal epithelial cell basal medium supplemented with corneal epithelial cell growth kit (ATCC; Manassas, VA) for 2 weeksin a T25 flask until 70-80% confluence, then HCECs were plated in 96-well plates for another 7 days.

[0136] To study the effect of EIPA and amiloride on belantamab mafodotin internalization, HCECs were pre-treated with EIPA (100 pM) or amiloride (100 pM) for 30 minutes and then cotreated with belantamab mafodotin (75 nM) for another 3.5 hours. After the 4 hours treatment, HCECs were rinsed once and washed 3 times with PBS, then fixed with 37% formaldehyde (Sigma-Aldrich) for 20 minutes. After repeating the wash protocol, HCECs were incubated with block solution (pH 7.4, PBS, 5% normal goat serum, 0.1% Triton-X-100) at room temperature for 30 minutes.

[0137] Cell surface-bound and internalized cytosolic belantamab mafodotin was visualized by incubating cells with goat anti-human IgG (H+L) cross-adsorbed secondary antibody, Alexa Fluor 488 (Thermo Fisher Scientific) at 1 :500 concentration overnight at 4°C. After repeating the wash protocol, Fluoroshield mounting medium with DAPI (Abeam; Cambridge, UK) was added in each well and the plate was stored at 4°C until imaging. The 96- well plate was imaged using the Opera Phenix Plus High-Content Screening System (Revvity; Waltham, USA).

[0138] As shown in Figures 3 A and 3B, pre-treatment with amiloride significantly reduces internalization of belantamab mafodotin in primary HCECs. *** p < 0.001, **** p < 0.0001. Figures 3C and 3D depict the IgG fluorescence intensity of the HCECs tested in the experimental results of Figures 3 A and 3B respectively. The representative images show cell-surface bound and internalized cytosolic belantamab mafodotin. Pre-treatment of EIPA (100 pM) or amiloride (100 pM) significantly reduced belantamab mafodotin internalization (less green fluorescent signal).EXAMPLE 4COMPARING MACROPINOCYTOSIS OF IMMORTALIZED HCECS WHEN EXPOSED TO BELANTAMAB MAFODOTIN, EIPA / BELANTAMAB MAFODOTIN AND AMILORIDE / BELANTAMAB MAFODOTIN COMBINATIONS TOWARDS IMMORTALIZED HCECS

[0139] Immortalized HCECs were plated in 96-well plates and incubated with calcium- free Keratinocyte-SFM culture medium for 2 days.

[0140] The immortalized HCECs were then pre-treated with EIPA (50 pM) or amiloride (100 pM) for 30 minutes, and then co-treated with belantamab mafodotin (75 nM) for another 3.5 hours. As shown in Figures 4A and 4C, pre-treatment with both amiloride and EIPA significantly reduced macropinocytosis in immortalized HCECs. *** p < 0.001, **** p < 0.0001.

[0141] Figures 4B and 4D show the results for a corresponding study where the immortalized HCECs were pre-treated with EIPA (100 pM) or amiloride (100 pM) for 30 minutes and then co-treated with belantamab mafodotin (75 nM) for another 3.5 hours.

[0142] Macropinosomes were visualized using fluorescently tagged high molecular weight (70 kDa) TMR-dextran (Life Technologies), a large (70 kDA) red fluorescent molecule that can only enter cells via macropinocytosis rather than by other endocytic pathways. The HCEC nuclei were visualized with DAPI (blue signal), and representative images from the in vitro macropinocytosis assay using immortalized HCECs were obtained, see Figures 4C and 4D. Figure 4E shows the TMR-dextran intensities for the images in Figure 4D.

[0143] Using ImageJ, a minimum threshold of 90 (on a dark background) was applied to all of the threshold images related to Figures 4A and 4C, and the macropinosomes were isolated using a size filter (diameter range 0.2-5 pm). The threshold images in Figure 4C were converted into binary images with macropinosomes in black on a white background (left, “Binary Image” in Figure 4C). In the binary image, the TMR-dextran positive macropinosomes (middle, “Macropinosomes” in Figure 4C) were highlighted and the macropinocytosis index in Figure 4 A was calculated as the number of macropinosomes per number of cells (right, “Cell Counts” in Figure 4C).

[0144] Pretreatment for 30 minutes with EIPA (100 pM) or amiloride (100 pM) significantly reduces ADC-induced macropinocytosis, as evidenced by the lower macropinocytosis index in Figure 4B and the reduced red fluorescent signal in Figure 4D. The macropinocytosis index in Figure 4B was calculated as the number of macropinosomes per number of cells in Figure 4D. As illustrated in Figures 4B, 4D and 4E, there was no effect on ADC internalization or ADC-induced macropinocytosis by pre-treatment with DMSO 0.2% (negative control).EXAMPLE 5COMPARING CELLULAR TOXICITY OF ELAHERE®, EIPA / ELAHERE®AND AMILORIDE / ELAHERE® COMBINATIONS TOWARDS IMMORTALIZED HCECS

[0145] Primary HCECs were isolated from healthy donor corneal tissue provided by Sierra Donor Services Eye Bank (Sacramento, CA) and digested with Dispase II enzyme (15 mg / mL, Thermo Fisher Scientific) at 4°C overnight. HCECs were cultured in corneal epithelial cell basal medium supplemented with corneal epithelial cell growth kit (ATCC; Manassas, VA) for 2 weeks in a T25 flask until 70-80% confluence, then HCECs were plated in 96-well plates for another 7 days.

[0146] To study the effect of EIPA and amiloride on Elahere® (mirvetuximab soravtansine) internalization, HCECs were pre-treated with EIPA (100 pM) or amiloride (100 pM) for 30 minutes and then co-treated with Elahere® (75 nM) for another 3.5 hours. After the 4 hours treatment, HCECs were rinsed once and washed 3 times with PBS, then fixed with 37% formaldehyde (Sigma-Aldrich) for 20 minutes. After repeating the wash protocol, the HCECs were incubated with block solution (pH 7.4, PBS, 5% normal goat serum, 0.1% Triton-X-100) at room temperature for 30 minutes.

[0147] Cell surface-bound and internalized cytosolic Elahere® was visualized by incubating cells with goat anti-human IgG (H+L) cross-adsorbed secondary antibody, Alexa Fluor 488 (Thermo Fisher Scientific) at 1 :500 concentration overnight at 4°C. After repeating the wash protocol, Fluoroshield mounting medium with DAPI (Abeam; Cambridge, UK) was added in each well and the plate was stored at 4°C until imaging. The 96-well plate was imaged using the Opera Phenix Plus High-Content Screening System (Revvity; Waltham, USA).

[0148] As shown in Figures 5 A and 5B, pre-treatment with amiloride significantly reduces internalization of Elahere® in primary HCECs. *** p < 0.001, **** p < 0.0001. The representative images in Figure 5B show cell-surface bound and internalized cytosolic Elahere®. Pre-treatment of EIPA (100 pM) or amiloride (100 pM) significantly reduced Elahere® internalization (less green fluorescent signal).EXAMPLE 6COMPARING MACROPINOCYTOSIS OF IMMORTALIZED HCECS WHEN EXPOSED TOELAHERE®, EIPA / ELAHERE® AND AMILORIDE / ELAHERE® COMBINATIONS TOWARDS IMMORTALIZED HCECS

[0149] Immortalized HCECs were plated in 96-well plates and incubated with calcium- free Keratinocyte-SFM culture medium for 2 days. The immortalized HCECs were then pretreated with EIPA (100 pM) or amiloride (100 pM) for 30 minutes and were then co-treated with Elahere® (mirvetuximab soravtansine) (75 nM) for another 3.5 hours. As shown in Figures 6A and 6B, pre-treatment with both amiloride and EIPA significantly reduced macropinocytosis in immortalized HCECs. *** p < 0.001, **** p < 0.0001.

[0150] Macropinosomes were visualized using fluorescently tagged high molecular weight (70 kDa) TMR-dextran (Life Technologies), a large (70 kDA) red fluorescent molecule that can only enter cells via macropinocytosis rather than by other endocytic pathways. The HCEC nuclei were visualized with DAPI (blue signal), and representative images from the in vitromacropinocytosis assay using immortalized HCECs were obtained, see Figure 6B. Figure 6C shows the TMR-dextran intensities for the images in Figure 6B.

[0151] Pretreatment for 30 minutes with EIPA (100 pM) or amiloride (100 pM) significantly reduces Elahere®-induced macropinocytosis, as evidenced by the lower macropinocytosis index in Figure 6A and the reduced red fluorescent signal in Figure 6B. The macropinocytosis index in Figure 6A was calculated as the number of macropinosomes per number of cells in Figure 6B. As illustrated in Figures 6A-6C, there was no effect on ADC internalization or Elahere®-induced macropinocytosis by pre-treatment with DMSO 0.2% (negative control).EXAMPLE 7MIRVETUXIMAB SORAVTANSINE INTERNALIZATION INTO HUMANPLURIPOTENT STEM CELL-DERIVED SENSORY NEURONS

[0152] Elahere® (mirvetuximab soravtansine) internalization into RealDRG™ cryopreserved human pluripotent stem cell-derived sensory neurons (nociceptors) was visualized by co-localization (yellow) of anti-human IgG (H+L) green immunofluorescent staining (ADC) and TUJ1 P3-tubulin red immunofluorescent staining (neuron) 3.5 hours after Elahere® addition in vitro. As illustrated in Figures 7A & 7B, pre-treatment for 30 minutes with EIPA or amiloride significantly reduced Elahere® internalization (less yellow co-localization). *** p < 0.001. There was no effect on Elahere® internalization by pre-treatment with DMSO 2% (negative control).EMBODIMENTS

[0153] Embodiment [1] relates to a method for treating an ADC-induced adverse event, such as ocular surface disorder, (2) thrombocytopenia or (3) peripheral neuropathy, in a subject in need thereof, the method comprising administering to an eye of the subject a therapeutically effective amount of a compound of Formula (I):or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, racemate or isotope thereof, wherein: R1is selected from the group consisting of -OH, -NH2, -SH, -F, -Cl, -Br, -CO2H, -CONH2, -OC(O)NH2, -NH-C(O)NH2, -NHC(O)2H, -S(O)2H, -SO2NH2, -NHSO2H, -NHNH2, - ONH2, -CN, -NHSO2H and -NHOH; and R2and R3are each independently selected from the group consisting of H, alkyl, haloalkyl, heterocycloalkyl and aryl, or R2and R3together form asubstituted or unsubstituted heterocycloalkyl, provided that the compound of Formula (I) is not 5- (N-ethyl-N-isopropyl)-amiloride.

[0154] Embodiment [2] relates to a method for treating a cancer in a subject in need thereof, the method comprising: (a) administering to the subject a therapeutically effective amount of antibody drug conjugate (ADC); and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I):or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, racemate or isotope thereof, wherein: R1is selected from the group consisting of -OH, -NH2, -SH, -F, -Cl, -Br, -CO2H, -CONH2, -OC(O)NH2, -NH-C(O)NH2, -NHC(O)2H, -S(O)2H, -SO2NH2, -NHSO2H,-NHNH2, -ONH2, -CN, -NHSO2H and -NHOH; and R2and R3are each independently selected from the group consisting of H, alkyl, haloalkyl, heterocycloalkyl and aryl, or R2and R3together form a heterocycloalkyl, provided that the compound of Formula (I) is not 5-(N-ethyl-N- isopropylj-amiloride.

[0155] Embodiment [3] relates to Embodiment [1], Embodiment [2], or a combination thereof, wherein ADC is selected from the group consisting of belantamab mafodotin, mirvetuximab soravtasine, trastuzumab emtansine, tisotumab vedotin, enfortumab vedotin, datopotamab deruxtecan, patritumab deruxtecan, trastuzumab deruxtecan, telisotuzumab vedotin, disitamab vedotin, polatuzumab vedotin, brentuximab vedotin, cetuximab sarotalocan, loncastuximab tesirine, inotuzumab ozogamicin, gemtuzumab ozogamicin, sacituzumab govitecan, anvatabart opadotin, datopotamab deruxtecan, trastuzumab envedotin, and the like.

[0156] Embodiment [4] relates to Embodiment [2], Embodiment [3], or a combination thereof, wherein the cancer is selected from the group consisting of adrenocortical carcinoma, astrocytoma, childhood cerebellar or cerebral, basal-cell carcinoma, bone tumor, osteosarcoma / malignant fibrous histiocytoma, a brain cancer, a brain tumor (such as cerebellar astrocytoma, malignant glioma, ependymoma, medulloblastoma, visual pathway and hypothalamic glioma, and the like), brainstem glioma, a breast cancer (such as triple negative breast cancer, HER2-positive breast cancer, and the like), bronchial adenomas / carcinoids, cerebellar astrocytoma, cervical cancer, cholangiocarcinoma, chronic myeloproliferative disorders, colon cancer, cutaneous endometrial cancer, ependymoma, esophageal cancer, an eyecancer (such as intraocular melanoma, retinoblastoma, and the like), gallbladder cancer, gastric cancer, glioma, a head and neck cancer (such as head and neck squamous cell carcinoma, and the like), heart cancer, hepatocellular (liver) cancer, hypopharyngeal cancer, islet cell carcinoma (endocrine pancreas), kidney cancer (renal cell cancer), laryngeal cancer, leukemia (e.g., acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia, chronic myelogenous leukemia and hairy cell leukemia), lip and oral cavity cancer, lung cancer (e.g., non-small cell and small cell), a lymphoma (e.g., anaplastic large cell lymphoma, B-cell lymphoma, AIDS-related lymphoma, Burkitt’s lymphoma, cutaneous T-Cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, etc.), macroglobulinemia, a melanoma (such as cutaneous melanoma, and the like), Merkel cell cancer, mesothelioma, multiple myeloma, multiple myeloma / plasma cell neoplasm, a mycosis fungoide, a myelodysplastic syndrome, a myelodysplastic / myeloproliferative disease, a myeloproliferative disorder, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, oligodendroglioma, oropharyngeal cancer, osteosarcoma / malignant fibrous histiocytoma of bone, ovarian cancer, pancreatic cancer, parathyroid cancer, pharyngeal cancer, pheochromocytoma, pituitary adenoma, plasma cell neoplasia, pleuropulmonary blastoma, prostate cancer, rectal cancer, a renal cell carcinoma (such as kidney cancer, and the like), a renal pelvis and ureter transitional cell cancer, salivary gland cancer, a sarcoma (such as chondrosarcoma, kaposi sarcoma, liposarcoma, malignant fibrous histiocytoma of bone / osteosarcoma, rhabdomyosarcoma, soft tissue sarcoma, and the like), Ewing family of tumors, Sezary syndrome, skin cancer (non-melanoma), skin carcinoma, small intestine cancer, squamous cell carcinoma, squamous neck cancer with occult primary (metastatic), stomach cancer, testicular cancer, throat cancer, thymoma and thymic carcinoma, thymoma, thyroid cancer, thyroid cancer, urothelial cancer, uterine cancer, vaginal cancer, Waldenstrom macroglobulinemia, Wilms tumor, and the like, and any combination thereof.

[0157] Embodiment [5] relates to Embodiments [l]-[4], or any combination thereof, wherein: R1is selected from the group consisting of -OH, -NH2, -SH, -F, -Cl, -Br, and -CN; and R2and R3are each independently H or Ci-Ce alkyl, or R2and R3together form a 3- to 8- membered heterocycloalkyl.

[0158] Embodiment [6] relates to Embodiments [l]-[5], or any combination thereof, wherein: R1is selected from the group consisting of -OH, -NH2, -SH, -F, -Cl, -Br, and -CN; and R2and R3together form a 3- to 8-membered heterocycloalkyl.

[0159] Embodiment [7] relates to Embodiments [l]-[6], or any combination thereof, wherein: R1is selected from the group consisting of -OH, -NH2, -SH, -F, -Cl, -Br, and -CN; and R2is H; and R3is selected from the group consisting of H or Ci-Ce alkyl.

[0160] Embodiment [8] relates to Embodiments [l]-[7], or any combination thereof, wherein the compound of Formula (I) is selected from the group consisting of:or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or isotope thereof, wherein: RingA represents:integer from 0 to 3; and b is an integer from 2 to 3.

[0161] Embodiment [9] relates to Embodiments [l]-[8], or any combination thereof, wherein the compound of Formula (I) is:or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or isotope thereof.

[0162] Embodiment

[0010] relates to Embodiments [l]-[9], or any combination thereof, wherein the compound of Formula (I) excludes EIPA.

[0163] Embodiment

[0011] relates to Embodiments [l]-

[0010] , or any combination thereof, wherein the compound of Formula (I) is systemically administered to the subject.

[0164] Embodiment

[0012] relates to Embodiments [1]-

[0011] , or any combination thereof, wherein the compound of Formula (I) is administered to the eye of the subject.

[0165] Embodiment

[0013] relates to Embodiments [1]-

[0012] , or any combination thereof, wherein the compound of Formula (I) is topically administered to the eye of the subject.

[0166] Embodiment

[0014] relates to Embodiments [1]-

[0013] , or any combination thereof, wherein the compound of Formula (I) is applied to the cornea of the subject.

[0167] Embodiment

[0015] relates to Embodiments [1]-

[0014] , or any combination thereof, wherein the method comprises administering from about 2 nanomoles to about 200 nanomoles of the compounds of Formula (I) the eye of the subject.

[0168] Embodiment

[0016] relates to Embodiments [1]-

[0015] , or any combination thereof, the therapeutically effective amount of the compound of Formula (I) provides a concentration of about 100 nM to about 1,000 nM of the compound of Formula (I) in the eye of the subject after a period of about 1-3 hours following administration.

[0169] Embodiment

[0017] relates to Embodiments [1]-

[0016] , or any combination thereof, wherein a pharmaceutically acceptable salt of the compound of Formula (I) is administered to the eye of the subject.

[0170] Embodiment

[0018] relates to Embodiments [1]-

[0017] , or any combination thereof, wherein the compound of Formula (I) is administered orally to the subject such that the therapeutically effective amount provides an oral dose ranging from about 1 mg / day to about 100 mg / day.

[0171] Embodiment

[0019] relates to Embodiments [1]-

[0018] , or any combination thereof, wherein a pharmaceutically acceptable salt of the compound of Formula (I) is administered orally to the subject.

[0172] Embodiment

[0020] relates to Embodiments [1]-

[0019] , or any combination thereof, wherein the pharmaceutically acceptable salt is a hydrochloride salt.

[0173] Embodiment

[0021] relates to Embodiments [l]-

[0020] , or any combination thereof, wherein the method further comprises co-administering at least one additional therapeutic agent in an amount effective to enhance the therapeutic effects of the compound of Formula (I).

[0174] Embodiment

[0022] relates to Embodiments [1]-

[0021] , or any combination thereof, wherein the method further comprises co-administering at least one additional therapeutic agent in an amount effective to enhance the therapeutic effects of the compound of Formula (I), wherein the at least one additional therapeutical agent comprises a vasoconstricting agent, an epithelial sodium channel inhibitor, a lymphocyte function-associated antigen-1 antagonist, an antiinflammatory agent, a cholinergic agonist, a steroid, an antibiotic, or any combination thereof.

[0175] Embodiment

[0023] relates to Embodiments [l]-

[0022] , or any combination thereof, wherein the method further comprises co-administering at least one additional therapeutic agent in an amount effective to enhance the therapeutic effects of the compound of Formula (I), whereinthe at least one additional therapeutical agent comprises a steroid selected from the group consisting of prednisolone phosphate, prednisolone acetate, fluoromethoIone acetate and dexamethasone.REFERENCES

[0176] Ref. 1 : Zhao et al. “Modulation of macropinocytosis-medidated internatlization decreases ocular toxicity of antibody-drug conjugates,” Cancer Research (2018), 78(8), 2115- 2126.

[0177] Ref. 2: Aleksandrowicz et al. “Ebola virus enters host cells by macropinocytosis and clathrin-mediated endocytosis,” J. Infect. Dis. (2011), 204 (Suppl 3), S957-S967.

[0178] Ref. 3: Araki et al. “A role for phosphoinositide 3 -kinase in the completion of macropinocytosis and phagocytosis by macrophages,” J. Cell. Biol. (1996), 135, 1249-1260.

[0179] Ref. 4: Koivusalo et al. “Amiloride inhibits macropinocytosis by lowering submembranous pH and preventing Rael and Cdc42 signaling,” J. Cell. BioL, (2010), 188, 547- 563.

[0180] Ref. 5: Lin et al., “Identification of novel macropinocytosis inhibitors using a rational screen of Food and Drug Administration-approved drugs,” British Journal of Pharmacology (2018), 175, 3640-3655.

[0181] This application claims the benefit of priority to U.S. Provisional Application Nos. 63 / 671,607 filed July 15, 2024, and 63 / 695,752, filed September 17, 2024, the entirety of both is incorporated by reference herein.

[0182] These and other changes can be made to the embodiments in light of the abovedetailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.

Claims

CLAIMS1. A method for treating an ADC-induced adverse event in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of one or more macropinocytosis inhibitors.

2. A method for treating a cancer in a subject in need thereof, the method comprising:(a) administering to the subject a therapeutically effective amount of antibody drug conjugate (ADC); and(b) administering to the subject a therapeutically effective amount of a compound of one or more macropinocytosis inhibitors.

3. The method of claim 1 or claim 2 wherein the macropinocytosis inhibitors include NHE1 inhibitors.

4. A method for treating (1) an ADC-induced ocular surface disorder, (2) thrombocytopenia or (3) peripheral neuropathy in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I):or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, racemate or isotope thereof, wherein:R1is selected from the group consisting of -OH, -NH2, -SH, -F, -Cl, -Br, -CO2H, -CONH2, -OC(O)NH2, -NH-C(O)NH2, -NHC(O)2H, -S(O)2H, -SO2NH2, -NHSO2H, -NHNH2, -ONH2, -CN, -NHSO2H and -NHOH; andR2and R3are each independently selected from the group consisting of H, alkyl, haloalkyl, heterocycloalkyl and aryl, or R2and R3together with the nitrogen to which they are connected form a substituted or unsubstituted heterocycloalkyl,with the proviso that the compound is not 5-(N-ethyl-N-isopropyl)-amiloride.

5. A method for treating a cancer in a subject in need thereof, the method comprising:(a) administering to the subject a therapeutically effective amount of antibody drug conjugate (ADC); and(b) administering to the subject a therapeutically effective amount of a compound of Formula (I):or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, racemate or isotope thereof, wherein:R1is selected from the group consisting of -OH, -NH2, -SH, -F, -Cl, -Br, -CO2H, -CONH2, -OC(O)NH2, -NH-C(O)NH2, -NHC(O)2H, -S(O)2H, -SO2NH2, -NHSO2H, -NHNH2, -ONH2, -CN, -NHSO2H and -NHOH; andR2and R3are each independently selected from the group consisting of H, alkyl, haloalkyl, heterocycloalkyl and aryl, or R2and R3together with the nitrogen to which they are connected form a heterocycloalkyl, with the proviso that the compound is not 5-(N-ethyl-N- isopropylj-amiloride.

6. The method of any one of the preceding claims, wherein the ADC comprises belantamab mafodotin, mirvetuximab soravtasine, trastuzumab emtansine, tisotumab vedotin, enfortumab vedotin, datopotamab deruxtecan, patritumab deruxtecan, trastuzumab deruxtecan, telisotuzumab vedotin, disitamab vedotin, polatuzumab vedotin, brentuximab vedotin, cetuximab sarotalocan, loncastuximab tesirine, inotuzumab ozogamicin, gemtuzumab ozogamicin, sacituzumab govitecan, anvatabart opadotin, datopotamab deruxtecan, trastuzumab envedotin, and the like, or any combination.

7. The method of claim 2, 5 or 6, wherein the cancer is selected from the group consisting of adrenocortical carcinoma, astrocytoma, childhood cerebellar or cerebral, basal-cellcarcinoma, bone tumor, osteosarcoma / malignant fibrous histiocytoma, a brain cancer, a brain tumor (such as cerebellar astrocytoma, malignant glioma, ependymoma, medulloblastoma, visual pathway and hypothalamic glioma, and the like), brainstem glioma, a breast cancer (such as triple negative breast cancer, HER2 -positive breast cancer, and the like), bronchial adenomas / carcinoids, cerebellar astrocytoma, cervical cancer, cholangiocarcinoma, chronic myeloproliferative disorders, colon cancer, cutaneous endometrial cancer, ependymoma, esophageal cancer, an eye cancer (such as intraocular melanoma, retinoblastoma, and the like), gallbladder cancer, gastric cancer, glioma, a head and neck cancer (such as head and neck squamous cell carcinoma, and the like), heart cancer, hepatocellular (liver) cancer, hypopharyngeal cancer, islet cell carcinoma (endocrine pancreas), kidney cancer (renal cell cancer), laryngeal cancer, leukemia (e.g., acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia, chronic myelogenous leukemia and hairy cell leukemia), lip and oral cavity cancer, lung cancer (e.g., non-small cell and small cell), a lymphoma (e.g., anaplastic large cell lymphoma, B-cell lymphoma, AIDS-related lymphoma, Burkitt’s lymphoma, cutaneous T-Cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, etc.), macroglobulinemia, a melanoma (such as cutaneous melanoma, and the like), Merkel cell cancer, mesothelioma, multiple myeloma, multiple myeloma / plasma cell neoplasm, a mycosis fungoide, a myelodysplastic syndrome, a myelodysplastic / myeloproliferative disease, a myeloproliferative disorder, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, oligodendroglioma, oropharyngeal cancer, osteosarcoma / malignant fibrous histiocytoma of bone, ovarian cancer, pancreatic cancer, parathyroid cancer, pharyngeal cancer, pheochromocytoma, pituitary adenoma, plasma cell neoplasia, pleuropulmonary blastoma, prostate cancer, rectal cancer, a renal cell carcinoma (such as kidney cancer, and the like), a renal pelvis and ureter transitional cell cancer, salivary gland cancer, a sarcoma (such as chondrosarcoma, kaposi sarcoma, liposarcoma, malignant fibrous histiocytoma of bone / osteosarcoma, rhabdomyosarcoma, soft tissue sarcoma, and the like), Ewing family of tumors, Sezary syndrome, skin cancer (non-melanoma), skin carcinoma, small intestine cancer, squamous cell carcinoma, squamous neck cancer with occult primary (metastatic), stomach cancer, testicular cancer, throat cancer, thymoma and thymic carcinoma, thymoma, thyroid cancer, thyroid cancer, urothelial cancer, uterine cancer, vaginal cancer, Waldenstrom macroglobulinemia, Wilms tumor, and the like, or any combination thereof.

8. The method of any one of claims 4-7, wherein: R1is selected from the group consisting of -OH, -NH2, -SH, -F, -Cl, -Br, and -CN; and R2and R3are each independently H or Ci-Ce alkyl, or R2and R3together form a 3- to 8-membered heterocycloalkyl.

9. The method of any one of claims 4-7, wherein: R1is selected from the group consisting of -OH, -NH2, -SH, -F, -Cl, -Br, and -CN; and R2and R3together form a 3- to 8- membered heterocycloalkyl.

10. The method of any one of claims 4-7, wherein: R1is selected from the group consisting of -OH, -NH2, -SH, -F, -Cl, -Br, and -CN; R2is H; and R3is selected from the group consisting of H or Ci-Ce alkyl.

11. The method of any one of claims 4-7, wherein the compound of Formula (I) is selected from the group consisting of:or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or isotope thereof, wherein:Ring A represents:X is CH2or O, a is an integer from 0 to 3; and b is an integer from 2 to 3.

12. The method of any one of claims 4-7, wherein the compound of Formula (I) is:or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or isotope thereof.

13. The method of any one of the preceding claims, wherein the one or more macropinocytosis inhibitors or the compound of Formula (I) are systemically administered to the subject.

14. The method of any one of claims 1-12, wherein the one or more macropinocytosis inhibitors or the compound of Formula (I) are administered to an eye of the subject.

15. The method of any one of claims 1-12, wherein the one or more macropinocytosis inhibitors or the compound of Formula (I) are topically administered to the eye of the subject.

16. The method of any one of claims 1-12, wherein the one or more macropinocytosis inhibitors or the compound of Formula (I) are administered to the cornea or conjunctiva of the subject.

17. The method of any one of claims 1-16, comprising administering from about 2 nanomoles to about 200 nanomoles of the one or more macropinocytosis inhibitors or the compounds of Formula (I) to the eye of the subject.

18. The method of any one of claims 1-17, wherein the therapeutically effective amount of the one or more macropinocytosis inhibitors or the compound of Formula (I) provides a concentration of about 100 nM to about 1,000 mM of the compound of Formula (I) in the eye of the subject after a period of about 1-3 hours following administration.

19. The method of any one of claims 1-18, wherein a pharmaceutically acceptable salt of the compound of Formula (I) is administered to the eye of the subject.

20. The method of claim 19, wherein the pharmaceutically acceptable salt is a hydrochloride salt.

21. The method of any one of the preceding claims, further comprising coadministering at least one additional therapeutic agent in an amount effective to enhance the therapeutic effects of the one or more macropinocytosis inhibitors or the compound of Formula (I).

22. The method of claim 21, wherein the at least one additional therapeutical agent comprises a vasoconstricting agent, an epithelial sodium channel inhibitor, a lymphocyte function-associated antigen-1 antagonist, an anti-inflammatory agent, a cholinergic agonist, a steroid, an antibiotic, or any combination thereof.

23. The method of claim 22, wherein the at least one additional therapeutical agent comprises a steroid selected from the group consisting of prednisolone phosphate, prednisolone acetate, fluoromethoIone acetate and dexamethasone.

Images