Combination therapies comprising IKZF2 degrader compounds

Abstract

Provided are combination use of compounds that mediate IKZF2 degradation with a second therapeutic agent or second therapy in the treatment of diseases or disorders involving IKZF2.

Description

COMBINATION THERAPIES COMPRISING IKZF2 DEGRADER COMPOUNDSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. § 119(e) of United States Provisional Application No. 63 / 718,448, filed November 8, 2024, which is hereby incorporated by reference in its entirety.BACKGROUND

[0002] Regulatory T-cells (Tregs) are a specialized population of CD4+ T-cells that maintain normal immune tolerance and homeostasis; however, in the tumor microenvironment (TME), Tregs are potent immunosuppressive cells that promote tumor immune evasion and reduced clinical response to CPI. The transcription factor IKAROS Family Zinc Finger 2 (IKZF2) (which encodes the protein Helios) is a marker of highly suppressive Tregs and is required to maintain a stable, suppressive Treg cell phenotype in the inflammatory TME. Depletion of IKZF2 reprograms suppressive Tregs into effector-like T-cells leading to anti-tumor immunity, but targeting transcription factors has been challenging due to the lack of defined structures and binding pockets. Protein degradation using the endogenous Ubiquitin Proteasome System (UPS) has enabled accessing undruggable proteins, such as IKZF2, through chemically induced proximity that promotes degradation.

[0003] Immune checkpoint inhibitors (CPI) have significant advantages in cancer treatment. Tumor cells evade immuno surveillance and progress through different mechanisms, including activation of immune checkpoint pathways that suppress antitumor immune responses. CPIs reinvigorate antitumor immune responses by interrupting co-inhibitory signaling pathways and promote immune-mediated elimination of tumor cells. Nevertheless, responses are limited to patient subsets, thereby necessitating additional treatment strategies.

[0004] A combination of the CPIs and compounds that promote degradation of IKZF2 in the Tregs would be a promising therapeutic method in cancer treatment.SUMMARY

[0005] The present disclosure provides herein a method of treating or preventing a disease or disorder mediated, at least in part by, IKZF2 in a subject in need thereof, comprising administering an effective amount of compound in combination with an effective amount of second therapeutic agent or second therapy, wherein the compound is:(i) Compound I having the structure:or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof; or(ii) Compound II having the structure:or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof.

[0006] In certain embodiments, the disease or disorder is cancer or non-cancerous disease or disorder mediated at least in part by IKZF2.

[0007] In certain embodiments, the cancer is non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), micro satellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, gastrointestinal stromal tumor (GIST), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), skin cutaneous melanoma (SKCM), kidney renal clear cell carcinoma (KIRC), lung adenocarcinoma (LU AD), head and neck squamous cell carcinoma (HNSCC), breast invasive carcinoma (BRCA), human papillomavirus (HPV)+ cervical cancer, or human papillomavirus (HPV)+ head and neck SCC (Oropharyngeal cancer).

[0008] In certain embodiments, the non-cancerous disease or disorder is inflammatory diseases, autoimmune diseases, neurodegenerative diseases, heart diseases, viral diseases, chronic and acute kidney diseases or injuries, metabolic diseases, or allergic and genetic diseases.

[0009] In certain embodiments, the second therapy comprises a standard of care treatment, a cell therapy, a radiation therapy, surgery, or any combination thereof.

[0010] In certain embodiments, the second therapeutic agent is an immune checkpoint modulator. Depending on the type of the checkpoint protein, its activation or inhibitor can improve the cancer treatment efficacy, which is readily understood in the art.

[0011] In certain embodiments, the immune checkpoint modulator binds one or more molecules selected from PD-1, PD-L1, CTLA-4, LAG-3, TIGIT, TIM3, BTLA, HVEM, VISTA, B7-H3, B7-H4, A2aR-Adenosine, (stimulatory) CD27 / CD70, CD28, 4-1BB (CD137), OX-40 / OX40L, CD40 / CD40L, ICOS, ICOSL, GITR / GITRL, ILT-2, ILT-4, HHLA2, butyrophilins, STimulator of INterferon Genes (STING), SIRPa, and CD47. For instance, the modulator can be an inhibitor of PD-1, PD-L1, CTLA-4, LAG-3, TIGIT, TIM3, BTLA, HVEM, VISTA, B7-H3, B7- H4, A2aR-Adenosine, (stimulatory) CD27 / CD70, CD28, 4-1BB (CD137), OX-40 / OX40L, CD40 / CD40L, ICOS, ICOSL, GITR / GITRL, ILT-2, ILT-4, HHLA2, butyrophilins, STimulator of INterferon Genes (STING), SIRPa, or CD47.

[0012] In certain embodiments, the immune checkpoint modulator is PD-1 antagonist.

[0013] In certain embodiments, the immune checkpoint modulator is an anti-PD-1 antibody.

[0014] In certain embodiments, the anti-PD-1 antibody is pembrolizumab, nivolumab, pidilizumab, cemiplimab, retifanlimab, toripalimab, dostarlimab, sintilimab, tislelizumab, ivonescimab, MEDI-0680, REGN2810, PF-06801591, BGB-A317, BGB-108, INCSHR1210, TSR-042, AMP 514 or AMP-224.

[0015] In certain embodiments, the anti-PD-1 antibody is pembrolizumab. In certain embodiments, the anti-PD-1 antibody is atezolizumab.

[0016] In certain embodiments, the compound is administered prior to, concurrently or after the administration of second therapeutic agent.

[0017] In certain embodiments, the compound is administered in a single dose.

[0018] In certain embodiments, the compound is administered in multiple doses. In certain embodiments, the compound is administered to the subject every 1, 2, 3, 4, 5, 6, 7, 14, or 21 days, or one month, two months, three months, four months, or six months.

[0019] In certain embodiments, the second therapeutic agent is administered in a single dose.

[0020] In certain embodiments, the second therapeutic agent is administered in multiple doses. In certain embodiments, the second therapeutic agent is administered to the subject every 1, 2, 3, 4, 5, 6, 7, 14, or 21 days, or one month, two months, three months, four months, or six months.

[0021] In certain embodiments, the second therapeutic agent is administered to the subject about 1 hour, 3 hours, 6 hours, 12 hours, 18 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 2 months, 3 months, 4 months, or 6 months after the administration of the compound.

[0022] In certain embodiments, the compound is administered to the subject about 1 hour, 3 hours, 6 hours, 12 hours, 18 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 2 months, 3 months, 4 months, or 6 months after the administration of the second therapeutic agent.

[0023] In certain embodiments, the compound is administered to the subject intradermally, intramuscularly, intraperitoneally, intravenously, subcutaneously, intranasally, epidurally, or orally.

[0024] In certain embodiments, the second therapeutic agent is administered to the subject intradermally, intramuscularly, intraperitoneally, intravenously, subcutaneously, intranasally, epidurally, or orally.

[0025] In certain embodiments, the compound and the second therapeutic agent are administered in different routes.BRIEF DESCRIPTION OF THE DRAWINGS

[0026] FIG. 1 illustrates in vivo tumor growth inhibition of the combination of Compound I and anti-PD-1 antibody pembrolizumab in a humanized MDA-MB-231 TNBC xenograft mouse model.

[0027] FIG. 2 illustrates in vivo tumor growth inhibition of the combination of Compound I and anti-PD-1 antibody pembrolizumab in a Syngeneic B16 melanoma mouse model.

[0028] FIG. 3 shows that the combination of Compound I and pembrolizumab statistically significantly increased the percentage of IL-2+FoxP3+Treg cells in the tumor tissues over each agent alone.DETAILED DESCRIPTIONDefinitions

[0029] Before describing the disclosure in detail, it is to be understood that this disclosure is not limited to particular compositions or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. As used in this specification and the appended claims, the singular forms “a”, “an” and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to “a molecule” optionally includes a combination of two or more such molecules, and the like.

[0030] The term “about” as used herein refers to the usual error range for the respective value readily known to the skilled person in this technical field. Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value orparameter per se. In case of doubt, or should there be no art recognized common understanding regarding the error range for a certain value or parameter, “about” means ± 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% of this value or parameter.

[0031] The term “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. Thus, reference to “the compound” includes a plurality of such compounds, and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art.

[0032] As used herein, an “antibody” refers to a polypeptide or a polypeptide complex that specifically recognizes and binds to an antigen. An antibody can be a whole antibody and any antigen binding fragment or a single chain thereof. Thus the term “antibody” includes any protein or peptide containing molecule that comprises at least a portion of an immunoglobulin molecule having biological activity of binding to the antigen. Examples of such include, but are not limited to a complementarity determining region (CDR) of a heavy or light chain or a ligand binding portion thereof, a heavy chain or light chain variable region, a heavy chain or light chain constant region, a framework (FR) region, or any portion thereof, or at least one portion of a binding protein.

[0033] By “specifically binds” or “has specificity to,” it is generally meant that an antibody binds to an epitope via its antigen-binding domain, and that the binding entails some complementarity between the antigen-binding domain and the epitope. According to this definition, an antibody is said to “specifically bind” to an epitope when it binds to that epitope, via its antigen-binding domain more readily than it would bind to a random, unrelated epitope. The term “specificity” is used herein to qualify the relative affinity by which a certain antibody binds to a certain epitope. For example, antibody “A” may be deemed to have a higher specificity for a given epitope than antibody “B,” or antibody “A” may be said to bind to epitope “C” with a higher specificity than it has for related epitope “D.”

[0034] As used herein, the terms “treat” or “treatment” refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as the progression of cancer. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (z.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival ascompared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.

[0035] As used herein, the term “modulating” or “modulate” refers to an effect of altering a biological activity, especially a biological activity associated with a particular biomolecule such as IKZF2 activity. For example, an agonist or antagonist of a particular biomolecule modulates the activity or change the expression levels of the IKZF2 by either increasing (e.g. agonist, activator), or decreasing (e.g. antagonist, inhibitor) the activity, of the biomolecule. Such activity is typically indicated in terms of an inhibitory or degradation concentration (IC50, DC50) or effective concentration (EC50) of the compound for an inhibitor or activator, respectively. In certain embodiments of the present disclosure, the modulation of IKZF2 activity can be increase IKZF2 activity. In certain embodiments, the modulation can be decrease IKZF2 activity, eliminate or deplete IKZF2 activity or protein levels.

[0036] The terms “effective amount,” “pharmaceutically effective amount,” and “therapeutically effective amount” refer to an amount that may be effective to elicit the desired biological or medical response, including the amount of a compound or a polypeptide that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The effective amount will vary depending on the compound or the polypeptide, the disease and its severity and the age, weight, etc., of the subject to be treated. The effective amount can include a range of amounts. A pharmaceutically effective amount includes amounts of an agent which are effective when combined with other agents.

[0037] By “subject” or “individual” or “animal” or “patient” or “mammal,” is meant any subject, particularly a mammalian subject, for whom diagnosis, prognosis, or therapy is desired. Mammalian subjects include humans, domestic animals, farm animals, and zoo, sport, or pet animals such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, cows, and so on.

[0038] As used herein, phrases such as “to a patient in need of treatment” or “a subject in need of treatment” includes subjects, such as mammalian subjects, that would benefit from administration of an antibody or composition of the present disclosure used, e.g., for detection, for a diagnostic procedure and / or for treatment.Compounds that Mediate IKZF2 Degradation

[0039] The compounds provided herein useful for cancer therapy is a molecular glue designed to promote a novel interaction between IKZF2 and the E3 ubiquitin ligase substrate receptor, cereblon, leading to potent and selective degradation of IKZF2. The compounds are capable of selectively depleting IKZF2 protein levels without degrading other cereblon neo-substrates.

[0040] In certain embodiments, provided herein is a compound which binds to and modulates cereblon, and in some instances, degrades IKZF2. The degradation of IKZF2 results in reprogramming of Tregs, which increase Treg’s production of effector- like cytokines.

[0041] In certain embodiments, the compound provided herein includes Compound I and Compound II.

[0042] The compound 3-(l-oxo-5-(((lS,2S)-2-(3-phenylazetidin-l- yl)cyclohexyl)oxy)isoindolin-2-yl)piperidine-2, 6-dione designated herein as Compound I, has the following formula:

[0043] The compound (S)-3-(l-oxo-5-(((lS,2S)-2-(3-phenylazetidin-l- yl)cyclohexyl)oxy)isoindolin-2-yl)piperidine-2, 6-dione designated herein as Compound II, has the following formula:

[0044] Compound I and Compound II bind to and modulate cereblon. It is contemplated that the stereocenter at the 3-position of the piperidine-2, 6-dione of Compound I may epimerize in vivo. The synthesis and method of use thereof is described in PCT International Application Publication No. WO2023 / 283425, which is incorporated by reference in its entirety. Unless otherwise specified, reference to Compound I (CAS Registry number 2892065-49-3) and Compound II (2892065-45-9) is intended to encompass the compound per se, or a salt, such as a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, prodrug, co-crystal, solvate, and / or hydrate thereof.

[0045] The term “co-crystal” refers to a molecular complex of a compound disclosed herein and one or more non-ionized co-crystal formers connected via non-covalent interactions. In some embodiments, the co-crystals disclosed herein may include a non-ionized form of Compound I (e.g., Compound I free form) and one or more non-ionized co-crystal formers, where nonionized Compound I and the co-crystal former(s) are connected through non-covalent interactions. In some embodiments, co-crystals disclosed herein may include an ionized form of Compound I (e.g., a salt of Compound I) and one or more non-ionized co-crystals formers, where ionized Compound I and the co-crystal former(s) are connected through non-covalent interactions. Co-crystals may additionally be present in anhydrous, solvated or hydrated forms. In certain instances, co-crystals may have improved properties as compared to the parent form (i.e., the free molecule, zwitterion, etc.) or a salt of the parent compound. Improved properties can be increased solubility, increased dissolution, increased bioavailability, increased dose response, decreased hygroscopicity, increased stability, a crystalline form of a normally amorphous compound, a crystalline form of a difficult to salt or unsaltable compound, decreased form diversity, more desired morphology, and the like. Methods for making and characterizing co-crystals are known to those of skill in the art.

[0046] The term “co-crystal former” or “co-former” refers to one or more pharmaceutically acceptable bases or pharmaceutically acceptable acids disclosed herein in association with Compound I, or any other compound disclosed herein. Such bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. Such acids include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, maleic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, gluconic acid, glutamic acid, salicylic acid, stearic acid, and the like.

[0047] The term “solvate” refers to a complex formed by combination of solvent molecules with molecules or ions of the solute. The solvent can be an organic compound, an inorganic compound, or a mixture of both. As used herein, the term “solvate” includes a “hydrate” (i.e., a complex formed by combination of water molecules with molecules or ions of the solute), hemihydrate, channel hydrate, etc. Some examples of solvents include, but are not limited to, acetonitrile, methanol, N,N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, dimethylsulfoxide, and water. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure.

[0048] A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. Thepresent disclosure contemplates various stereoisomers, or mixtures thereof, and includes “enantiomers,” which refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another.

[0049] “Diastereomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0050] The term “tautomer” refers to structurally distinct isomers that interconvert by tautomerization. Tautomerization is a form of isomerization and includes prototropic or protonshift tautomerization, which is considered a subset of acid-base chemistry. Prototropic tautomerization or proton- shift tautomerization involves the migration of a proton accompanied by changes in bond order, often the interchange of a single bond with an adjacent double bond. Where tautomerization is possible (e.g. in solution), a chemical equilibrium of tautomers can be reached.Compositions

[0051] The present disclosure also provides pharmaceutical compositions. Such compositions include a pharmaceutically effective amount of a compound provided herein, and a pharmaceutically acceptable carrier. In some embodiments, the composition further includes a pharmaceutically effective amount of immune checkpoint modulator as provided herein.

[0052] The term “pharmaceutically acceptable” component is one that is suitable for use with humans and / or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit / risk ratio. Further, a “pharmaceutically acceptable carrier” will generally be a non-toxic solid, semisolid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.

[0053] The term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents such as acetates, citrates or phosphates. Antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelatingagents such as ethylenediaminetetraacetic acid; and agents for the adjustment of tonicity such as sodium chloride or dextrose are also envisioned.

[0054] Depending on the intended mode of administration, the disclosed compounds or compositions can be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides. Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences by E. W. Martin, incorporated herein by reference. Such compositions will contain a therapeutically effective amount of the antigen-binding polypeptide, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulation should suit the mode of administration. The parental preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

[0055] Illustrative pharmaceutical compositions are tablets and gelatin capsules comprising a compound of the disclosure and a pharmaceutically acceptable carrier, such as a) a diluent, e.g., purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, com oil, olive oil, sunflower oil, safflower oil, fish oils, such as EPA or DHA, or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and / or glycine; b) a lubricant, e.g., silica, talcum, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and / or polyethylene glycol; for tablets also; c) a binder, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, com sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, waxes, and / or polyvinylpyrrolidone, if desired; d) a disintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthan gum, algic acid or its sodium salt, or effervescent mixtures; e) absorbent, colorant, flavorant and sweetener; f) an emulsifier or dispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 90, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E TGPS or other acceptable emulsifier; and / or g) an agent that enhances absorption of the compound such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400, PEG200.

[0056] Liquid, particularly injectable, compositions can, for example, be prepared by dissolution, dispersion, etc. For example, the disclosed compound is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form an injectable isotonic solution or suspension. Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the disclosed compounds.

[0057] The disclosed compounds can be also formulated as a suppository that can be prepared from fatty emulsions or suspensions; using poly alkylene glycols such as propylene glycol, as the carrier.

[0058] The disclosed compounds can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, containing cholesterol, stearylamine or phosphatidylcholines.

[0059] In some embodiments, a film of lipid components is hydrated with an aqueous solution of drug to a form lipid layer encapsulating the drug, as described in U.S. Pat. No. 5,262,564, which is hereby incorporated by reference in its entirety.

[0060] Disclosed compounds can also be delivered by the use of monoclonal antibodies as individual carriers to which the disclosed compounds are coupled. The disclosed compounds can also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the disclosed compounds can be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, poly dihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels. In one embodiment, disclosed compounds are not covalently bound to a polymer, e.g., a polycarboxylic acid polymer, or a polyacrylate.

[0061] Parental injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection.

[0062] Pharmaceutical dosage forms of a compound of this disclosure may be manufactured by any of the methods well-known in the art, such as, for example, by conventional mixing, sieving, dissolving, melting, granulating, dragee-making, tableting, suspending, extruding, spray-drying, levigating, emulsifying, (nano- / micro-) encapsulating, entrapping, orlyophilization processes. As noted above, the compositions of this disclosure can include one or more physiologically acceptable inactive ingredients that facilitate processing of active molecules into preparations for pharmaceutical use.

[0063] In certain embodiments, the compositions are comprised of a compound of this disclosure in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the claimed compounds. Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.

[0064] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semi-solid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. In some embodiments, liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.

[0065] Compressed gases may be used to disperse a compound of this disclosure in an aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc. Other suitable pharmaceutical excipients and their formulations are described in Remington’s Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).

[0066] The compositions of this disclosure may, if desired, be presented in a pack or dispenser device containing one or more unit dosage forms containing the active ingredient. Such a pack or device may, for example, comprise metal or plastic foil, such as a blister pack, or glass, and rubber stoppers such as in vials. The pack or dispenser device may be accompanied by instructions for administration. Compositions comprising a compound of this disclosure that can be formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0067] The amount of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound of this disclosure based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. In one embodiment, the compound is present at a level of about 1-80 wt %. Representative pharmaceutical formulations are described below.

[0068] The compounds of the present disclosure is administered to a subject at various dosing amounts for a single dose. For example, from 0.1 mg to 2000 mg, from 0.1 mg to 1500 mg,from 0.1 mg to 1000 mg, from 0.1 mg to 900 mg, from 0.1 mg to 800 mg, from 0.1 mg to 700 mg, from 0.1 mg to 600 mg, from 0.1 mg to 500 mg, from 0.1 mg to 400 mg, from 0.1 mg to 300 mg, from 0.1 mg to 200 mg, from 0.1 mg to 100 mg, from 0.1 mg to 90 mg, from 0.1 mg to 80 mg, from 0.1 mg to 70 mg, from 0.1 mg to 60 mg, from 0.1 mg to 50 mg, from 0.1 mg to 40 mg, from 0.1 mg to 30 mg, from 0.1 mg to 20 mg, from 0.1 mg to 10 mg, from 0.1 mg to 9 mg, from 0.1 mg to 8 mg, from 0.1 mg to 7 mg, from 0.1 mg to 6 mg, from 0.1 mg to 5 mg, from 0.1 mg to 4 mg, from 0.1 mg to 3 mg, from 0.1 mg to 2 mg, from 0.1 mg to 1 mg, from 1 mg to 2000 mg, from 5 mg to 2000 mg, from 10 mg to 2000 mg, from 20 mg to 2000 mg, from 30 mg to 2000 mg, from 40 mg to 2000 mg, from 50 mg to 2000 mg, from 60 mg to 2000 mg, from 70 mg to 2000 mg, from 80 mg to 2000 mg, from 90 mg to 2000 mg, from 100 mg to 2000 mg, from 150 mg to 2000 mg, from 200 mg to 2000 mg, from 250 mg to 2000 mg, from 300 mg to 2000 mg, from 350 mg to 2000 mg, from 400 mg to 2000 mg, from 450 mg to 2000 mg, from 500 mg to 2000 mg, from 550 mg to 2000 mg, from 600 mg to 2000 mg, from 650 mg to 2000 mg, from 700 mg to 2000 mg, from 750 mg to 2000 mg, from 800 mg to 2000 mg, from 850 mg to 2000 mg, from 900 mg to 2000 mg, from 950 mg to 2000 mg, from 1000 mg to 2000 mg, from 1500 mg to 2000 mg, from 5 mg to 1500 mg, from 5 mg to 1000 mg, from 5 mg to 900 mg, from 10 mg to 1000 mg, from 10 mg to 900 mg, from 10 mg to 800 mg, from 10 mg to 700 mg, from 10 mg to 600 mg, from 10 mg to 500 mg, from 10 mg to 400 mg, from 10 mg to 300 mg, from 10 mg to 200 mg, from 10 mg to 100 mg, from 10 mg to 90 mg, from 10 mg to 80 mg, from 10 mg to 70 mg, from 10 mg to 60 mg, from 10 mg to 50 mg, from 10 mg to 40 mg, from 10 mg to 30 mg, from 10 mg to 20 mg, from 50 mg to 1000 mg, from 50 mg to 900 mg, from 50 mg to 800 mg, from 50 mg to 700 mg, from 50 mg to 600 mg, from 50 mg to 500 mg, from 50 mg to 400 mg, from 50 mg to 300 mg, from 50 mg to 200 mg, from 50 mg to 100 mg, from 50 mg to 90 mg, from 50 mg to 80 mg, from 50 mg to 70 mg, from 50 mg to 60 mg.

[0069] In certain embodiments, the dosing amount is less than 0.1 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 20mg, 30 mg, 40mg, 50mg, 60 mg, 70mg, 80 mg, 90mg, lOOmg, 150mg, 200 mg, 250mg, 300 mg, 350mg, 400mg, 450 mg, 500mg, 550 mg, 600mg, 650mg, 700mg, 750 mg, 800mg, 850 mg, 900mg, 950mg, lOOOmg, 1200mg, 1500mg, or 2000mg.

[0070] In certain embodiments, dosing amounts of the compounds of the present disclosure is from 0.1 mg / kg to 200 mg / kg, from 0.1 mg / kg to 100 mg / kg, from 0.1 mg / kg to 90 mg / kg, from 0.1 mg / kg to 80 mg / kg, from 0.1 mg / kg to 70 mg / kg, from 0.1 mg / kg to 60 mg / kg, from 0.1 mg / kg to 50 mg / kg, from 0.1 mg / kg to 40 mg / kg, from 0.1 mg / kg to 30 mg / kg, from 0.1 mg / kg to 20 mg / kg, from 0.1 mg / kg to 10 mg / kg, from 0.1 mg / kg to 9 mg / kg, from 0.1 mg / kg to 8 mg / kg, from 0.1 mg / kg to 7 mg / kg, from 0.1 mg / kg to 6 mg / kg, from 0.1 mg / kg to 5 mg / kg,from 0.1 mg / kg to 4 mg / kg, from 0.1 mg / kg to 3 mg / kg, from 0.1 mg / kg to 2 mg / kg, from 0.1 mg / kg to 1 mg / kg, from 1 mg / kg to 200 mg / kg, from 5 mg / kg to 200 mg / kg, from 10 mg / kg to 200 mg / kg, from 20 mg / kg to 200 mg / kg, from 30 mg / kg to 200 mg / kg, from 40 mg / kg to 200 mg / kg, from 50 mg / kg to 200 mg / kg, from 60 mg / kg to 200 mg / kg, from 70 mg / kg to 200 mg / kg, from 80 mg / kg to 200 mg / kg, from 90 mg / kg to 200 mg / kg, from 100 mg / kg to 200 mg / kg, from 150 mg / kg to 200 mg / kg, from 5 mg / kg to 150 mg / kg, from 5 mg / kg to 100 mg / kg, from 5 mg / kg to 90 mg / kg, from 10 mg / kg to 100 mg / kg, from 10 mg / kg to 90 mg / kg, from 10 mg / kg to 80 mg / kg, from 10 mg / kg to 70 mg / kg, from 10 mg / kg to 60 mg / kg, from 10 mg / kg to 50 mg / kg, from 10 mg / kg to 40 mg / kg, from 10 mg / kg to 30 mg / kg, from 10 mg / kg to 20 mg / kg, from 10 mg / kg to 15 mg / kg.

[0071] In certain embodiments, the dosing amount of the compounds of the present disclosure is equivalent or less than about 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 15 mg / kg, 20mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40mg / kg, 45mg / kg, 50mg / kg, 55mg / kg, 60 mg / kg, 65mg / kg, 70mg / kg, 75mg / kg, 80 mg / kg, 85mg / kg, 90mg / kg, 95mg / kg, lOOmg / kg, 150mg / kg, 180mg / kg, or 200 mg / kg.Combination Treatments

[0072] In one aspect, the present disclosure is directed to methods of treating diseases or disorders involving IKZF2, that entails administration of a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in combination with a second therapeutic agent or a second therapy to a subject in need thereof. Combination use of the compound or the composition provided herein and a second therapeutic agent may bring significant benefit.

[0073] In some embodiments, combination therapy may be given to a subject who has received prior therapy, such as chemotherapy, radioimmunotherapy, surgical therapy, immunotherapy, radiation therapy, targeted therapy or any combination thereof.

[0074] The diseases or disorders that may be amenable to treatment with compounds of the present disclosure involve IKZF2 or otherwise functionally abnormal IKZF2 activity relative to a non-pathological state. A “disease” is generally regarded as a state of health of a subject wherein the subject cannot maintain homeostasis, and wherein if the disease is not ameliorated then the subject’s health continues to deteriorate. In contrast, a “disorder” in a subject is a state of health in which the subject is able to maintain homeostasis, but in which the subject’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the subject’s state of health.

[0075] The terms “in combination” and “concurrently” in this context mean that the agents are co-administered, which includes substantially contemporaneous administration, by way of the same or separate dosage forms, and by the same or different modes of administration, or sequentially, e.g., as part of the same treatment regimen, or by way of successive treatment regimens. Therefore, if given sequentially, at the onset of administration of the second agent, the first of the two agents is in some cases still detectable at effective concentrations at the site of treatment. The sequence and time interval may be determined such that they can act together (e.g., synergistically to provide an increased benefit than if they were administered otherwise). For example, the agents may be administered at the same time or sequentially in any order at different points in time; however, if not administered at the same time, they may be administered sufficiently close in time so as to provide the desired therapeutic effect, which may be in a synergistic fashion. Therefore, the terms are not limited to the administration of the active agents at exactly the same time.

[0076] The second therapeutic agent can be any other anti-tumor agents, anti-allergic agents, anti-nausea agents (or anti-emetics), pain relievers, cytoprotective agents, and combinations thereof.

[0077] In certain embodiments, the compound or the composition is administered in a single dose.

[0078] In certain embodiments, the compound or the composition is administered in multiple doses (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 10, 15, 20, or more doses). In certain embodiments, the compound or the composition is administered to the subject in a frequency of once every 1, 2, 3, 4, 5, 6, 7, 14, or 21 days, or one month, two months, three months, four months, or six months.

[0079] In certain embodiments, the second therapeutic agent is administered in a single dose.

[0080] In certain embodiments, the second therapeutic agent is administered in multiple doses (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 10, 15, 20, or more doses). In certain embodiments, the second therapeutic agent is administered to the subject in a frequency of once every 1, 2, 3, 4, 5, 6, 7, 14, or 21 days, or one month, two months, three months, four months, or six months.

[0081] In certain embodiments, the compound or the composition, and the second therapeutic agent are administered to the subject concurrently. In certain embodiments, the combined administration use separate formulations or a single pharmaceutical formulation.

[0082] In certain embodiments, the compound or the composition, and the second therapeutic agent are administered to the subject separately. The consecutive administration in either order, wherein preferably there is a time period while both (or all) of the compounds or the composition, and the second therapeutic agents simultaneously exert their biological activities.In certain embodiments, the compound or the composition, and the second therapeutic agent are administered at an interval of about 5 min, 10 min, 15 min, 30 min, 1 hour, 3 hours, 6 hours, 12 hours, 18 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, or 6 months.

[0083] In some embodiments, the compound of the present invention and the additional therapeutic agent (e.g., an anti-cancer therapeutic) are cyclically administered. By way of example in the context of cancer treatment, cycling therapy involves the administration of one anti-tumor therapeutic for a period of time, followed by the administration of a second antitumor therapeutic for a period of time and repeating this sequential administration, i.e., the cycle, in order to reduce the development of resistance to one or both of the anticancer therapeutics, to avoid or reduce the side effects of one or both of the anti-tumor therapeutics, and / or to improve the efficacy of the therapies. In one example, cycling therapy involves the administration of a first anti-tumor therapeutic for a period of time, followed by the administration of a second anti-tumor therapeutic for a period of time, optionally, followed by the administration of a third anti-tumor therapeutic for a period of time and so forth, and repeating this sequential administration, i.e., the cycle in order to reduce the development of resistance to one of the anti-tumor therapeutics, to avoid or reduce the side effects of one of the anti-tumor therapeutics, and / or to improve the efficacy of the anti-tumor therapeutics.

[0084] In certain embodiments, the second therapeutic agent is an immune checkpoint modulator.

[0085] In such embodiments, the compound or the composition provided herein may be administered prior to, concurrently with, or after the administration of immune checkpoint modulator.

[0086] In such embodiments, an immune checkpoint modulator may be administered to the subject 5 min, 10 min, 15 min, 30 min, 1 hour, 3 hours, 6 hours, 12 hours, 18 hours, one day, one week, two weeks, three weeks, four weeks, five weeks, or six weeks after the administration of the compound or the composition provided herein.

[0087] In such embodiments, the compound or the composition provided herein may be administered to the subject 5 min, 10 min, 15 min, 30 min, 1 hour, 3 hours, 6 hours, 12 hours, 18 hours, one day, one week, two weeks, three weeks, four weeks, five weeks, or six weeks after the administration of immune checkpoint modulator.

[0088] Methods of administration of the compounds or the compositions provided herein or immune checkpoint modulator include but are not limited to parenteral, transdermal, vaginal, buccal, rectal, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal,epidural, oral routes and topical administration. The compounds or compositions or immune checkpoint modulator may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Thus, pharmaceutical compositions containing the compounds or immune checkpoint modulator of the present disclosure may be administered orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, ointments, drops or transdermal patch), buccally, or as an oral or nasal spray.

[0089] The term “parenteral” as used herein refers to modes of administration which include intravenous (both bolus and infusion), intramuscular, intraperitoneal, intrasternal, subcutaneous and intra-articular injection and infusion.

[0090] Administration can be systemic or local. In addition, it may be desirable to introduce the compounds or the composition of the disclosure into the central nervous system by any suitable route, including intraventricular and intrathecal injection; intraventricular injection may be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir. Pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosolizing agent.

[0091] It may be desirable to administer the compounds or the composition of the disclosure locally to the area in need of treatment; this may be achieved by, for example, and not by way of limitation, local infusion during surgery, topical application, e.g., in conjunction, with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers. Preferably, when administering a protein, including an antibody, of the disclosure, care must be taken to use materials to which the protein does not absorb.

[0092] Administration routes of the compounds or the composition provided herein can be the same or different from the immune checkpoint modulator.

[0093] In certain embodiments, the compounds or the composition provided herein is administered to the subject orally.

[0094] In certain embodiments, the immune checkpoint modulator is administered to the subject intravenously.

[0095] In certain embodiments, the second therapeutic agent of the present disclosure is administered to a subject at various dosing amounts for a single dose. For example, from 0.1 mg to 2000 mg, from 0.1 mg to 1500 mg, from 0.1 mg to 1000 mg, from 0.1 mg to 900 mg, from0.1 mg to 800 mg, from 0.1 mg to 700 mg, from 0.1 mg to 600 mg, from 0.1 mg to 500 mg, from 0.1 mg to 400 mg, from 0.1 mg to 300 mg, from 0.1 mg to 200 mg, from 0.1 mg to 100 mg, from 0.1 mg to 90 mg, from 0.1 mg to 80 mg, from 0.1 mg to 70 mg, from 0.1 mg to 60 mg, from 0.1 mg to 50 mg, from 0.1 mg to 40 mg, from 0.1 mg to 30 mg, from 0.1 mg to 20 mg, from 0.1 mg to 10 mg, from 0.1 mg to 9 mg, from 0.1 mg to 8 mg, from 0.1 mg to 7 mg, from 0.1 mg to 6 mg, from 0.1 mg to 5 mg, from 0.1 mg to 4 mg, from 0.1 mg to 3 mg, from 0.1 mg to 2 mg, from 0.1 mg to 1 mg, from 1 mg to 2000 mg, from 5 mg to 2000 mg, from 10 mg to 2000 mg, from 20 mg to 2000 mg, from 30 mg to 2000 mg, from 40 mg to 2000 mg, from 50 mg to 2000 mg, from 60 mg to 2000 mg, from 70 mg to 2000 mg, from 80 mg to 2000 mg, from 90 mg to 2000 mg, from 100 mg to 2000 mg, from 150 mg to 2000 mg, from 200 mg to 2000 mg, from 250 mg to 2000 mg, from 300 mg to 2000 mg, from 350 mg to 2000 mg, from 400 mg to 2000 mg, from 450 mg to 2000 mg, from 500 mg to 2000 mg, from 550 mg to 2000 mg, from 600 mg to 2000 mg, from 650 mg to 2000 mg, from 700 mg to 2000 mg, from 750 mg to 2000 mg, from 800 mg to 2000 mg, from 850 mg to 2000 mg, from 900 mg to 2000 mg, from 950 mg to 2000 mg, from 1000 mg to 2000 mg, from 1500 mg to 2000 mg, from 5 mg to 1500 mg, from 5 mg to 1000 mg, from 5 mg to 900 mg, from 10 mg to 1000 mg, from 10 mg to 900 mg, from 10 mg to 800 mg, from 10 mg to 700 mg, from 10 mg to 600 mg, from 10 mg to 500 mg, from 10 mg to 400 mg, from 10 mg to 300 mg, from 10 mg to 200 mg, from 10 mg to 100 mg, from 10 mg to 90 mg, from 10 mg to 80 mg, from 10 mg to 70 mg, from 10 mg to 60 mg, from 10 mg to 50 mg, from 10 mg to 40 mg, from 10 mg to 30 mg, from 10 mg to 20 mg, from 50 mg to 1000 mg, from 50 mg to 900 mg, from 50 mg to 800 mg, from 50 mg to 700 mg, from 50 mg to 600 mg, from 50 mg to 500 mg, from 50 mg to 400 mg, from 50 mg to 300 mg, from 50 mg to 200 mg, from 50 mg to 100 mg, from 50 mg to 90 mg, from 50 mg to 80 mg, from 50 mg to 70 mg, from 50 mg to 60 mg.

[0096] In certain embodiments, the dosing amount of the second therapeutic agent of the present disclosure is equivalent or less than 0.1 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 20mg, 30 mg, 40mg, 50mg, 60 mg, 70mg, 80 mg, 90mg, lOOmg, 150mg, 200 mg, 250mg, 300 mg, 350mg, 400mg, 450 mg, 500mg, 550 mg, 600mg, 650mg, 700mg, 750 mg, 800mg, 850 mg, 900mg, 950mg, lOOOmg, 1200mg, 1500mg, or 2000mg.

[0097] In certain embodiments, dosing amounts of the second therapeutic agent of the present disclosure is from 0.1 mg / kg to 200 mg / kg, from 0.1 mg / kg to 100 mg / kg, from 0.1 mg / kg to 90 mg / kg, from 0.1 mg / kg to 80 mg / kg, from 0.1 mg / kg to 70 mg / kg, from 0.1 mg / kg to 60 mg / kg, from 0.1 mg / kg to 50 mg / kg, from 0.1 mg / kg to 40 mg / kg, from 0.1 mg / kg to 30 mg / kg, from 0.1 mg / kg to 20 mg / kg, from 0.1 mg / kg to 10 mg / kg, from 0.1 mg / kg to 9 mg / kg, from 0.1mg / kg to 8 mg / kg, from 0.1 mg / kg to 7 mg / kg, from 0.1 mg / kg to 6 mg / kg, from 0.1 mg / kg to 5 mg / kg, from 0.1 mg / kg to 4 mg / kg, from 0.1 mg / kg to 3 mg / kg, from 0.1 mg / kg to 2 mg / kg, from 0.1 mg / kg to 1 mg / kg, from 1 mg / kg to 200 mg / kg, from 5 mg / kg to 200 mg / kg, from 10 mg / kg to 200 mg / kg, from 20 mg / kg to 200 mg / kg, from 30 mg / kg to 200 mg / kg, from 40 mg / kg to 200 mg / kg, from 50 mg / kg to 200 mg / kg, from 60 mg / kg to 200 mg / kg, from 70 mg / kg to 200 mg / kg, from 80 mg / kg to 200 mg / kg, from 90 mg / kg to 200 mg / kg, from 100 mg / kg to 200 mg / kg, from 150 mg / kg to 200 mg / kg, from 5 mg / kg to 150 mg / kg, from 5 mg / kg to 100 mg / kg, from 5 mg / kg to 90 mg / kg, from 10 mg / kg to 100 mg / kg, from 10 mg / kg to 90 mg / kg, from 10 mg / kg to 80 mg / kg, from 10 mg / kg to 70 mg / kg, from 10 mg / kg to 60 mg / kg, from 10 mg / kg to 50 mg / kg, from 10 mg / kg to 40 mg / kg, from 10 mg / kg to 30 mg / kg, from 10 mg / kg to 20 mg / kg, from 10 mg / kg to 15 mg / kg.

[0098] In certain embodiments, the dosing amount of the second therapeutic agent of the present disclosure is equivalent or less than about 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 15 mg / kg, 20mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40mg / kg, 45mg / kg, 50mg / kg, 55mg / kg, 60 mg / kg, 65mg / kg, 70mg / kg, 75mg / kg, 80 mg / kg, 85mg / kg, 90mg / kg, 95mg / kg, lOOmg / kg, 150mg / kg, 180mg / kg, or 200 mg / kg.Additional therapeutic agents or therapies

[0099] One or more second therapeutic agents or second treatment regimens can be used in combination with the compounds or the composition provided herein. The second therapeutic agents includes for example, a chemical compound, peptide, antibody, antibody fragment or nucleic acid, which is therapeutically active or enhances the therapeutic activity when administered to a subject in combination with a compound or composition of the present disclosure.

[0100] The second treatment regimens include a standard of care treatment (e.g., for cancers or infectious disorders), a cell therapy (e.g., a CAR-T therapy), a radiation therapy, surgery, or any other therapeutic agent or modality, or any combinations thereof. A “standard of care treatment” is a treatment process, including a drug or combination of drugs, radiation therapy (RT), surgery or other medical intervention that is recognized by medical practitioners as appropriate, accepted, and / or widely used for a certain type of patient, disease or clinical circumstance. Standard of care therapies for different types of cancer are well known by persons of skill in the art. For example, the National Comprehensive Cancer Network (NCCN), an alliance of 21 major cancer centers in the USA, publishes the NCCN Clinical Practice Guidelines in Oncology(NCCN GUIDELINES®) that provide detailed up-to-date information on the standard of care treatments for a wide variety of cancers (see NCCN GUIDELINES®, 2013).

[0101] Representative examples of additional anti-tumor agents include, chemotherapeutic s (e.g., mitotic inhibitors, angiogenesis inhibitors, anti-hormones, autophagy inhibitors, alkylating agents, intercalating antibiotics, growth factor inhibitors, anti-androgens, signal transduction pathway inhibitors, anti-microtubule agents, platinum coordination complexes, HD AC inhibitors, proteasome inhibitors, and topoisomerase inhibitors), immunomodulators, therapeutic antibodies (e.g., mono-specific and bispecific antibodies), a vaccine (e.g., a therapeutic cancer vaccine).

[0102] One or more chemotherapeutic agents can be used in combination with the compounds of the present disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for treating a disease, e.g., cancer, wherein said chemotherapeutic agents include, but are not limited to, anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection (Busulfex®), capecitabine (Xeloda®), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposome injection (DepoCyt®), dacarbazine (DTIC-Dome®), dactinomycin (Actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine®), daunorubicin citrate liposome injection (DaunoXome®), dexamethasone, docetaxel (Taxotere®), doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®), 5-fluorouracil (Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, Gemcitabine (difluorodeoxycitidine), hydroxyurea (Hydrea®), Idarubicin (Idamycin®), ifosfamide (IFEX®), irinotecan (Camptosar®), L-asparaginase (ELSPAR®), leucovorin calcium, melphalan (Alkeran®), 6-mercaptopurine (Purinethol®), methotrexate (Folex®), mitoxantrone (Novantrone®), mylotarg, paclitaxel (Taxol®), phoenix (Yttrium90 / MX-DTPA), pentostatin, polifeprosan 20 with carmustine implant (Gliadel®), tamoxifen citrate (Nolvadex®), teniposide (Vumon®), 6- thioguanine, thiotepa, tirapazamine (Tirazone®), topotecan hydrochloride for injection (Hycamptin®), vinblastine (Velban®), vincristine (Oncovin®), vinorelbine (Navelbine®), epirubicin (Ellence®), oxaliplatin (Eloxatin®), exemestane (Aromasin®), letrozole (Femara®), and fulvestrant (Faslodex®).

[0103] In certain embodiments, the second therapeutic agents include tyrosine kinase inhibitors, including but not limited to, EGFR inhibitors, Her2 inhibitors, Her3 inhibitors, IGFR inhibitors, c-MET inhibitors and Met inhibitors. Examples of the tyrosine kinase inhibitors include, but arenot limited to, erlotinib hydrochloride (Tarceva®); linifanib (N-[4-(3-amino-lH-indazol-4- yl)phenyl]-N'-(2-fhioro-5-methylphenyl)urea, also known as ABT 869, available from Genentech); sunitinib malate (Sutent®); bosutinib (4-[(2,4-dichloro- 5-methoxyphenyl)amino]- 6-methoxy-7-[3-(4-methylpiperazin-l-yl)propoxy]quinoline-3-carbonitrile, also known as SKI- 606, and described in US Patent No. 6,780,996); dasatinib (Sprycel®); pazopanib (Votrient®); sorafenib (Nexavar®); zactima (ZD6474); and imatinib or imatinib mesylate (Gilvec® and Gleevec®).

[0104] Epidermal growth factor receptor (EGFR) inhibitors include but are not limited to, erlotinib hydrochloride (Tarceva®), gefitinib (Iressa®); N-[4-[(3-Chloro-4- fhiorophenyl)amino]-7-[[(3"S")- tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2- butenamide, Tovok®); vandetanib (Caprelsa®); lapatinib (Tykerb®); (3R,4R)-4-amino-l-((4- ((3-methoxyphenyl)amino)pyrrolo[2,l- f][l,2,4]triazin-5-yl)methyl)piperidin-3-ol (BMS690514); canertinib dihydrochloride (CI-1033); 6-[4-[(4- Ethyl-1- piperazinyl)methyl] phenyl] -N- [( 1R)- 1 -phenylethyl] -7H-pyrrolo[2,3-d]pyrimidin-4-amine (AEE788, CAS 497839-62-0); Mubritinib (TAK165); pelitinib (EKB569); afatinib (Gilotrif®); neratinib (HKI- 272) ; N- [4- [ [ 1 - [ (3 -fluorophenyl)methyl] - 1 H-indazol- 5 -yl] amino] - 5 - methylpyrrolo[2,l- f][l,2,4]triazin-6-yl]-carbamic acid, (3S)-3-morpholinylmethyl ester (BMS599626); XL647 (CAS 781613-23-8); and 4-[4-[[(lR)-l-phenylethyl]amino]-7H- pyrrolo[2,3- d]pyrimidin-6-yl] -phenol (PKI166, CAS187724-61-4). EGFR antibodies include but are not limited to, cetuximab (Erbitux®); panitumumab (Vectibix®); matuzumab (EMD- 72000); nimotuzumab (hR3); zalutumumab; TheraCIM h-R3; MDX0447 (CAS 339151-96-1); and ch806 (mAb-806, CAS 946414-09-1).

[0105] HER2 antagonists include anti-HER2 antibodies and HER2 inhibitors. For example, anti-HER2 antibodies, such as trastuzumab, pertuzumab, margetuximab, or HT-19, or with other anti-HER2 conjugates, e.g., ado- trastuzumab emtansine (also known as Kadcyla®, or T-DM1). Other HER2 inhibitors include but are not limited to, neratinib (HKI-272, (2E)-N-[4-[[3-chloro- 4- [(pyridin-2-yl)methoxy] phenyl] amino] -3 -cyano-7-ethoxyquinolin-6-yl] -4- (dimethylamino)but-2-enamide, and described PCT Publication No. WO05 / 028443); lapatinib or lapatinib ditosylate (Tykerb®); (3R,4R)- 4-amino-l-((4-((3- methoxyphenyl)amino)pyrrolo[2,l-f][l,2,4]triazin-5-yl)methyl)piperidin-3-ol (BMS690514); (2E)-N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6- quinazolinyl]-4-(dimethylamino)-2-butenamide (BIBW-2992, CAS 850140-72-6); N-[4-[[l-[(3- Fluorophenyljmethyl] - 1 H-indazol-5-yl] amino]-5-methylpyrrolo[2, 1 -f] [ 1 ,2,4]triazin-6-yl] -carbamic acid, (3S)-3-morpholinylmethyl ester (BMS 599626, CAS 714971-09-2); canertinib dihydrochloride (PD183805 or CI-1033); and XL647 (CAS 781613-23-8).

[0106] HER3 inhibitors include but are not limited to, LJM716, MM-121, AMG-888, RG7116, REGN- 1400, AV-203, MP-RM-1, MM-111, and MEHD-7945A.

[0107] C-MET inhibitors include but are not limited to, capmatinib (INC280), JNJ-3887605, AMG 337, LY2801653, MSC2156119J, crizotinib, tivantinib, or golvatinib.

[0108] MET inhibitors include but are not limited to, Cabozantinib (XL184, CAS 849217-68-1); foretinib (GSK1363089, formerly XL880, CAS 849217-64-7); tivantinib (ARQ197, CAS 1000873-98-2); l-(2-hydroxy-2-methylpropyl)-N-(5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl)- 5-methyl-3-oxo-2-phenyl-2,3- dihydro- lH-pyrazole-4-carboxamide (AMG 458); cryzotinib (Xalkori®, PF-02341066); (3Z)-5-(2,3-dihydro-lH-indol-l-ylsulfonyl)-3-({3,5-dimethyl-4-[(4- methylpiperazin-l-yl)carbonyl]-lH-pyrrol-2- yl] methylene)- l,3-dihydro-2H-indol-2-one (SU11271); (3Z)-N-(3-chlorophenyl)-3-({3,5-dimethyl-4-[(4- methylpiperazin-l-yl)carbonyl]- lH-pyrrol-2-yl}methylene)-N-methyl-2-oxoindoline-5-sulfonamide (SU 11274); (3Z)-N-(3- chlorophenyl)-3-{[3,5-dimethyl-4-(3-morpholin-4-ylpropyl)-lH-pyrrol-2- yl]methylene}-N- methyl-2-oxoindoline-5-sulfonamide (SU11606); 6- [difluoro [6- (1 -methyl- lH-pyrazol-4- yl)- l,2,4-triazolo[4,3-b]pyridazin-3-yl]methyl]-quinoline (JNJ38877605, CAS 943540-75-8); 2-[4- [l-(quinolin-6-ylmethyl)-lH-[l,2,3]triazolo[4,5-b]pyrazin-6-yl]-lH-pyrazol-l-yl]ethanol (PF04217903, CAS 956905-27-4); N-((2R)-l,4-dioxan-2-ylmethyl)-N-methyl-N'-[3-(l-methyl- lH-pyrazol-4-yl)-5-oxo- 5H-benzo[4,5]cyclohepta[l,2-b]pyridin-7-yl]sulfamide (MK2461, CAS 917879-39-1); 6-[[6-(l-methyl-lH-pyrazol-4-yl)-l,2,4-triazolo[4,3-b]pyridazin 3-yl]thio]- quinoline (SGX523, CAS 1022150-57-7); and (3Z)-5-[[(2,6-dichlorophenyl)methyl]sulfonyl]-3- [[3,5-dimethyl-4-[[(2R)-2-(l-pyrrolidinylmethyl)-l- pyrrolidinyl]carbonyl]-lH-pyrrol-2- yl]methylene]-l,3-dihydro-2H-indol-2-one (PHA665752, CAS 477575-56-7).

[0109] IGFR inhibitors include but are not limited to, BMS-754807, XL-228, OSI-906, GSK0904529A, A-928605, AXL1717, KW-2450, MK0646, AMG479, IMCA12, MEDI-573, and BI836845.

[0110] In certain embodiments, the second therapeutic agents include proliferation signaling pathway inhibitors, including but not limited to, MEK inhibitors, BRAF inhibitors, PI3K / Akt inhibitors, SHP2 inhibitors, and also mTOR inhibitors, and CDK inhibitors.

[0111] For example, mitogen-activated protein kinase (MEK) inhibitors include but are not limited to, XL-518 (also known as GDC-0973, Cas No. 1029872-29-4, available from ACC Corp.); 2-[(2-chloro-4- iodophenyl)amino]-N-(cyclopropylmethoxy)-3,4-difluoro-benzamide (also known as CI-1040 or PD184352 and described in PCT Publication No. W02000035436);N-[(2R)-2,3-dihydroxypropoxy]-3,4- difluoro-2-[(2-fluoro-4-iodophenyl)amino]- benzamide (also known as PD0325901 and described in PCT Publication No. W02002006213); 2,3- Bis[amino[(2-aminophenyl)thio]methylene]-butanedinitrile (also known as U0126 and described in US Patent No. 2,779,780); N-[3,4-difhioro-2-[(2-fhioro-4- iodophenyl)amino]-6- methoxyphenyl]-l-[(2R)-2,3-dihydroxypropyl]- cyclopropanesulfonamide (also known as RDEA1 19 or BAY869766 and described in PCT Publication No. W02007014011); (3S,4R,5Z,8S,9S,llE)-14-(Ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9, 19-tetrahydro- 1H-2- benzoxacyclotetradecine-l,7(8H)-dione] (also known as E6201 and described in PCT Publication No. W02003076424); 2’-amino-3’-methoxyflavone (also known as PD98059 available from Biaffin GmbH & Co., KG, Germany); Vemurafenib (PLX-4032, CAS 918504- 65-1); (R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8- methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (TAK-733, CAS 1035555-63-5); pimasertib (AS-703026, CAS 1204531-26-9); and trametinib dimethyl sulfoxide (GSK- 1120212, CAS 1204531-25-80).

[0112] BRAF inhibitors include, but are not limited to, vemurafenib (or Zelboraf®), GDC-0879, PLX- 4720 (available from Symansis), dabrafenib (or GSK2118436), LGX 818, CEP-32496, UI-152, RAF 265, regorafenib (BAY 73-4506), CCT239065, or sorafenib (or sorafenib Tosylate, or Nexavar®), or ipilimumab (or MDX-010, MDX-101, or Yervoy).

[0113] Phosphoinositide 3-kinase (PI3K) inhibitors include, but are not limited to, 4-[2-(lH- Indazol-4-yl)- 6- [ [4- (methylsulfonyl)piperazin- 1 -yl]methyl] thieno [3 ,2-d] pyrimidin-4- yl]morpholine (also known as GDC0941, RG7321, GNE0941, pictrelisib, or pictilisib; and described in PCT Publication Nos. WO 09 / 036082 and WO 09 / 055730); tozasertib (VX680 or MK-0457, CAS 639089-54-6); (5Z)-5-[[4-(4-pyridinyl)-6-quinolinyl]methylene]-2,4- thiazolidinedione (GSK1059615, CAS 958852-01-2); (lE,4S,4aR,5R,6aS,9aR)-5-(Acetyloxy)-1-[(di-2-propenylamino)methylene]-4,4a,5,6,6a,8,9,9a- octahydro- ll-hydroxy-4- (methoxymethyl)-4a,6a-dimethylcyclopenta[5,6]naphtho[l,2-c]pyran- 2,7,10(lH)-trione (PX866, CAS 502632-66-8); 8-phenyl-2-(morpholin-4-yl)-chromen-4-one (LY294002, CAS 154447-36-6); (S)-Nl-(4-methyl-5-(2-(l,l,l-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2- yl)pyrrolidine-l,2-dicarboxamide (also known as BYL719 or Alpelisib); 2-(4-(2-(l-isopropyl-3-methyl- lH-l,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepin-9-yl)-lH- pyrazol-l-yl)-2-methylpropanamide (also known as GDC0032, RG7604, or taselisib).

[0114] MTOR inhibitors include but are not limited to, Temsirolimus (Torisel®); ridaforolimus (formally known as deferolimus, (lR,2R,4S)-4-[(2R)-2 [(lR,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28Z,30S,32S,35R)-l,18-dihydroxy-19,30-dimethoxy- 15,17,21,23, 29,35-hexamethyl-2,3,10,14,20-pentaoxo-l l,36-dioxa-4- azatricyclo[30.3.1.04,9] hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl dimethylphosphinate, also known as AP23573 and MK8669, and described in PCT Publication No. WO 03 / 064383); everolimus (Afinitor® or RAD001); Rapamycin (AY22989, Sirolimus®); simapimod (CAS 164301-51-3); (5-{2,4-Bis[(3S)-3- methylmorpholin-4-yl]pyrido[2,3- d]pyrimidin-7-yl}-2-methoxyphenyl)methanol (AZD8055); 2-amino- 8-[trans-4-(2- hydroxyethoxy)cyclohexyl]-6-(6-methoxy-3-pyridinyl)-4-methyl-pyrido[2,3-d]pyrimidin- 7(8H)-one (PF04691502, CAS 1013101-36-4); and N2-[l,4-dioxo-4-[[4-(4-oxo-8-phenyl-4H-l- benzopyran-2-yl)morpholinium-4-yl]methoxy]butyl]-L-arginylglycyl-L-A-aspartylL-serine- (SF1126, CAS 936487-67-1).

[0115] CDK inhibitors include but are not limited to, palbociclib (also known as PD-0332991, Ibrance®, 6-scetyl-8-cyclopentyl-5-methyl-2-{ [5-(l-piperazinyl)-2-pyridinyl]amino]pyrido[2,3- d]pyrimidin- 7(8H)-one).

[0116] In certain embodiments, the second therapeutic agents include proapoptotics, including but not limited to, IAP inhibitors, BCL2 inhibitors, MCL1 inhibitors, TRAIL agents, CHK inhibitors.

[0117] IAP inhibitors include but are not limited to, LCL161, GDC-0917, AEG-35156, AT406, and TL32711. Other examples of IAP inhibitors include but are not limited to those disclosed in W004 / 005284, WO 04 / 007529, W005 / 097791, WO 05 / 069894, WO 05 / 069888, WO 05 / 094818, US2006 / 0014700, US2006 / 0025347, WO 06 / 069063, WO 06 / 010118, WO 06 / 017295, and WO08 / 134679, all of which are incorporated herein by reference.

[0118] BCL-2 inhibitors include but are not limited to, venetoclax, 4-[4-[[2-(4-Chlorophenyl)- 5 ,5-dimethyl- 1 - cyclohexen- 1 -yl]methyl] - 1 -piperazinyl] -N- [ [4- [ [( 1 R)-3- (4-morpholinyl)- 1 - [(phenylthio)methyl]propyl]amino]-3-[(trifhioromethyl)sulfonyl]phenyl]sulfonyl]benzamide (also known as ABT-263 and described in PCT Publication No. WO 09 / 155386); tetrocarcin A; antimycin; gossypol ((-)BL-193); obatoclax; ethyl-2-amino-6-cyclopentyl-4-(l-cyano-2-ethoxy- 2-oxoethyl)-4H-chromone-3- carboxylate (HA14-1); oblimersen (G3139, Genasense®); Bak BH3 peptide; (-)-gossypol acetic acid (AT-101); 4-[4-[(4'-Chloro[l,l'-biphenyl]-2-yl)methyl]-l- piperazinyl]-N-[[4-[[(lR)-3-(dimethylamino)-l- [(phenylthio)methyl]propyl]amino]-3- nitrophenyl] sulfonyl] -benzamide (ABT-737, CAS 852808-04-9); and navitoclax (ABT-263, CAS 923564-51-6).

[0119] Proapoptotic receptor agonists (PARAs) including DR4 (TRAILR1) and DR5 (TRAILR2), including but are not limited to, dulanermin (AMG-951, RhApo2L / TRAIL); mapatumumab (HRS-ETR1, CAS 658052-09-6); lexatumumab (HGS-ETR2, CAS 845816-02-6); apomab (Apomab®); conatumumab (AMG655, CAS 896731-82-1); and tigatuzumab(CS1008, CAS 946415-34-5). Checkpoint Kinase (CHK) inhibitors include but are not limited to, 7-hydroxystaurosporine (UCN- 01); 6-bromo-3-(l-methyl-lH-pyrazol-4-yl)-5- (3R)-3-piperidinylpyrazolo[l,5-a]pyrimidin-7-amine (SCH900776, CAS 891494-63-6); 5-(3- fluorophenyl)-3-ureidothiophene-2-carboxylic acid N-[(S)- piperidin-3-yl] amide (AZD7762, CAS 860352-01-8); 4-[((3S)-l-azabicyclo[2.2.2]oct-3-yl)amino]-3-(lH- benzimidazol-2-yl)-6- chloroquinolin-2(lH)-one (CHIR 124, CAS 405168-58-3); 7 -Aminodactinomycin (7-AAD), isogranulatimide, debromohymenialdisine; N-[5-bromo-4-methyl-2-[(2S)-2- morpholinylmethoxy]-phenyl]-N'-(5-methyl-2-pyrazinyl)urea (LY2603618, CAS 911222-45-2); sulforaphane (CAS 4478-93-7, 4-methylsulfinylbutyl isothiocyanate); 9,10,11,12-tetrahydro- 9,12- epoxy-lH-diindolo[l,2,3-fg:3',2',r-kl]pyrrolo[3,4-i][l,6]benzodiazocine-l,3(2H)-dione (SB-218078, CAS 135897-06-2); and TAT-S216A, and CBP501 ((d-Bpa)sws(d-Phe-F5)(d- Cha)rrrqrr).

[0120] In certain embodiments, the second therapeutic agents include cytokines. Cytokines include but not limited to, interferon, IL-2, IL-15, IL-7, or IL21.

[0121] In certain embodiments, the second therapeutic agents include toll like receptors (TLRs), such as, TLR7, TLR8, TLR9.

[0122] In certain embodiments, the second therapeutic agents include a transforming growth factor beta (also known as TGF-P TGFp, TGF p, or TGF-beta). Examples of the TGFP include XOMA 089 or fresolimumab (CAS Registry Number: 948564-73-6).

[0123] In certain embodiments, the second therapeutic agents include interleukin- 1 beta (IL- lb) inhibitors, such as canakinumab, gevokizumab, anakinra, or rilonacept.

[0124] In certain embodiments, the second therapeutic agents include MDM2 inhibitors, such as HDM201 ((S)-5-(5-chloro-l-methyl-2-oxo-l,2- dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4- dimethoxypyrimidin-5-yl)-l-isopropyl-5,6- dihydropyrrolo[3,4-d]imidazol-4(lH)-one) or CGM097 ((S)-l-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-(methyl(((lr,4S)-4-(4-methyl- 3-oxopiperazin-l-yl)cyclohexyl)methyl)amino)phenyl)-l,2-dihydroisoquinolin-3(4H)-one).

[0125] In certain embodiments, the second therapeutic agents include angiogenesis inhibitors, such as bevacizumab (A vastin®), axitinib (Inlyta®); brivanib alaninate (BMS-582664, (S)-(®- l-(4-(4-fluoro-2- methyl- lH-indol-5-yloxy)-5-methylpyrrolo[2,l-f] [1,2, 4]triazin-6- yloxy)propan-2-yl)2-aminopropanoate); sorafenib (Nexavar®); pazopanib (Votrient®); sunitinib malate (Sutent®); cediranib (AZD2171, CAS 288383-20-1); vargatef (BIBF1120, CAS 928326- 83-4); foretinib (GSK1363089); telatinib (BAY57- 9352, CAS 332012-40-5); apatinib (YN968D1, CAS 811803-05-1); imatinib (Gleevec®); ponatinib (AP24534, CAS 943319-70-8);tivozanib (AV951, CAS 475108-18-0); regorafenib (BAY73-4506, CAS 755037-03-7); vatalanib dihydrochloride (PTK787, CAS 212141-51-0); brivanib (BMS-540215, CAS 649735- 46-6); vandetanib (Caprelsa® or AZD6474); motesanib diphosphate (AMG706, CAS 857876- 30- 3, N-(2,3-dihydro-3,3-dimethyl-lH-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3- pyridinecarboxamide, described in PCT Publication No. WO 02 / 066470); dovitinib dilactic acid (TKI258, CAS 852433-84-2); linfanib (ABT869, CAS 796967-16-3); cabozantinib (XL184, CAS 849217-68-1); lestaurtinib (CAS 111358-88-4); N-[5-[[[5-(l,l-dimethylethyl)-2- oxazolyl]methyl]thio]-2-thiazolyl]-4- piperidinecarboxamide (BMS38703, CAS 345627-80-7); (3R,4R)-4-amino-l-((4-((3- methoxyphenyl)amino)pyrrolo[2,l-f][l,2,4]triazin-5- yl)methyl)piperidin-3-ol (BMS690514); N-(3,4- dichloro-2-fluorophenyl)-6-methoxy-7- [[(3aa,5b,6aa)-octahydro-2-methylcyclopenta[c]pyrrol-5- yl]methoxy]- 4-quinazolinamine (XL647, CAS 781613-23-8); 4-Methyl-3-[[l-methyl-6-(3-pyridinyl)-lH- pyrazolo[3,4- d]pyrirnidin-4-yl]amino]-N-[3-(trifluoromethyl)phenyl]-benzamide (BHG712, CAS 940310- 85- 0); or aflibercept (Eylea®).

[0126] In certain embodiments, the second therapeutic agents include heat shock protein inhibitors, such as tanespimycin (17-allylamino-17-demethoxygeldanamycin, also known as KOS-953 and 17-AAG, available from SIGMA, and described in US4,261,989); retaspimycin (IPI504), ganetespib (STA-9090); [6-chloro-9-(4-methoxy-3,5-dimethylpyridin-2-ylmethyl)-9H- purin-2-yl] amine (BIIB021 or CNF2024, CAS 848695-25-0); trans-4-[[2-(aminocarbonyl)-5- [4,5,6,7-tetrahydro-6,6-dimethyl-4-oxo-3- (trifluoromethyl)-lH-indazol-l- yl] phenyl] amino] cyclohexyl glycine ester (SNX5422 or PF04929113, CAS 908115-27-5); 5- [2,4-Dihydroxy-5-(l-methylethyl)phenyl]-N-ethyl-4-[4-(4- morpholinylmethyl)phenyl]- 3- isoxazolecarboxamide (AUY922, CAS 747412-49-3); or 17- dimethylaminoethylamino- 17- demethoxygeldanamycin (17-DMAG).

[0127] In certain embodiments, the second therapeutic agents include HD AC inhibitors or other epigenetic modifiers. Exemplary HD AC inhibitors include, but not limited to, voninostat (Zolinza®); romidepsin (Istodax®); treichostatin A (TSA); oxamflatin; vorinostat (Zolinza®, suberoylanilide hydroxamic acid); pyroxamide (syberoyl-3-aminopyridineamide hydroxamic acid); trapoxin A (RF-1023A); trapoxin B (RF-10238); cyclo[(aS,2S)-a-amino-h-oxo-2- oxiraneoctanoyl-O-methyl-D-tyrosyl-L-isoleucyl-L-prolyl] (Cyl- 1); cyclo[(aS,2S)-a-amino-h- oxo-2-oxiraneoctanoyl-0-methyl-D-tyrosyl-L-isoleucyl-(2S)-2- piperidinecarbonyl] (Cyl-2); Cyclic[L-alanyl-D-alanyl-(2S)-h-oxo-L-a-aminooxiraneoctanoyl-D-prolyl] (HC-toxin); cyclo[(aS,2S)-a-amino-h-oxo-2-oxiraneoctanoyl-D-phenylalanyl-L-leucyl-(2S)-2- piperidinecarbonyl] (WF-3161); chlamydocin ((S)-Cyclic(2-methylalanyl-L-phenylalanyl-D-prolyl-h- oxo-L-a-aminooxiraneoctanoyl); apicidin (cyclo(8-oxo-L-2-aminodecanoyl-l- methoxy-L-tryptophyl-L- isoleucyl-D-2-piperidinecarbonyl); romidepsin (Istodax®, FR- 901228); 4-phenylbutyrate; spirucho statin A; mylproin (valproic acid); entinostat (MS-275, N- (2-aminophenyl)-4-[N-(pyridine-3-yl- methoxycarbonyl)-amino-methyl]-benzamide); depudecin (4,5:8,9-dianhydro-l,2,6,7,l l-pentadeoxy- D- threo-D-ido-undeca-l,6-dienitol); 4- (acetylamino)-N-(2-aminophenyl)-benzamide (also known as CI- 994); Nl-(2-aminophenyl)- N8 -phenyl- octanediamide (also known as BML-210); 4-(dimethylamino)-N- (7- (hydroxyamino)-7-oxoheptyl)benzamide (also known as M344); (E)-3-(4-(((2-(lH-indol-3- yl)ethyl)(2- hydroxyethyl)amino)-methyl)phenyl)-N-hydroxyacrylamide; panobinostat (Farydak®); mocetinostat, and belinostat (also known as PXD101, Beleodaq®, or (2E)-N- hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop- 2-enamide), or chidamide (also known as CS055 or HB 1-8000, (E)-N-(2-amino-5-fluorophenyl)-4-((3- (pyridin-3- yl)acrylamido)methyl)benzamide). Other epigenetic modifiers include but not limited to inhibitors of EZH2 (enhancer of zeste homolog 2), EED (embryonic ectoderm development), or LSD1 (lysine-specific histone demethylase 1A or KDM1A).

[0128] In certain embodiments, the second therapeutic agents include immunomodulators, for example, one or more of an activator of a costimulatory molecule or an inhibitor of an immune checkpoint molecule. The modulator of the costimulatory molecule (e.g., an antibody or antigenbinding fragment thereof, or a soluble fusion) binds 0X40, CD2, CD27, CDS, ICAM-1, LFA-1 (CDl la / CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83 ligand.

[0129] In certain embodiments, the second treatment regimens include cell therapy, such as chimeric antigen receptor (CAR) therapy, which utilizes immune effector cells, e.g., T cells. Two classes of cancer associated antigens (“tumor associated antigens” or “TAA”) that can be targeted by the CARs of the present disclosure: (1) cancer associated antigens that are expressed on the surface of cancer cells; and (2) cancer associated antigens that itself is intracellular, however, a fragment of such antigen (peptide) is presented on the surface of the cancer cells by MHC (major histocompatibility complex).

[0130] In some embodiments, the tumor antigen is chosen from one or more of: CD19; CD123; CD22; CD30; CD171; CS-1 (also referred to as CD2 subset 1, CRACC, SLAMF7, CD319, and 19A24); C-type lectin-like molecule-1 (CLL-1 or CLECL1); CD33; epidermal growth factor receptor variant III (EGFRvIII); ganglioside G2 (GD2); ganglioside GD3 (aNeu5Ac(2- 8)aNeu5Ac(2-3)bDGalp(l- 4)bDGlcp(l-l)Cer); TNF receptor family member B cell maturation (BCMA); Tn antigen ((Tn Ag) or (GalNAca-Ser / Thr)); prostate-specific membrane antigen(PSMA); Receptor tyrosine kinase-like orphan receptor 1 (R0R1); Fms-Like Tyrosine Kinase 3 (FLT3); Tumor-associated glycoprotein 72 (TAG72); CD38; CD44v6; Carcinoembryonic antigen (CEA); Epithelial cell adhesion molecule (EPCAM); B7H3 (CD276); KIT (CD117); Interleukin- 13 receptor subunit alpha-2 (IL-13Ra2 or CD213A2); Mesothelin; Interleukin 11 receptor alpha (IL-l lRa); prostate stem cell antigen (PSCA); Protease Serine 21 (Testisin or PRSS21); vascular endothelial growth factor receptor 2 (VEGFR2); Lewis(Y) antigen; CD24; Platelet- derived growth factor receptor beta (PDGFR-beta); Stage-specific embryonic antigen-4 (SSEA-4); CD20; Folate receptor alpha; Receptor tyrosine-protein kinase ERBB2 (Her2 / neu); Mucin 1, cell surface associated (MUC1); epidermal growth factor receptor (EGFR); neural cell adhesion molecule (NCAM); Prostase; prostatic acid phosphatase (PAP); elongation factor 2 mutated (ELF2M); Ephrin B2; fibroblast activation protein alpha (FAP); insulin-like growth factor 1 receptor (IGF-I receptor), carbonic anhydrase IX (CAIX); Proteasome (Prosome, Macropain) Subunit, Beta Type, 9 (LMP2); glycoprotein 100 (gplOO); oncogene fusion protein consisting of breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Abl) (bcr-abl); tyrosinase; ephrin type-A receptor 2 (EphA2); Fucosyl GM1; sialyl Lewis adhesion molecule (sLe); ganglioside GM3 (aNeu5Ac(2-3)bDGalp(l-4)bDGlcp(l-l)Cer); transglutaminase 5 (TGS5); high molecular weight-melanoma- associated antigen (HMWMAA); o-acetyl- GD2 ganglioside (OAcGD2); Folate receptor beta; tumor endothelial marker 1 (TEM1 / CD248); tumor endothelial marker 7-related (TEM7R); claudin 6 (CLDN6); thyroid stimulating hormone receptor (TSHR); G protein-coupled receptor class C group 5, member D (GPRC5D); chromosome X open reading frame 61 (CXORF61); CD97; CD179a; anaplastic lymphoma kinase (ALK); Polysialic acid; placenta- specific 1 (PLAC1); hexasaccharide portion of globoH glycoceramide (GloboH); mammary gland differentiation antigen (NY-BR-1); uroplakin 2 (UPK2); Hepatitis A virus cellular receptor 1 (HAVCR1); adrenoceptor beta 3 (ADRB3); pannexin 3 (PANX3); G protein-coupled receptor 20 (GPR20); lymphocyte antigen 6 complex, locus K 9 (LY6K); Olfactory receptor 51 E2 (OR51E2); TCR Gamma Alternate Reading Frame Protein (TARP); Wilms tumor protein (WT1); Cancer / testis antigen 1 (NY- ESO-1); Cancer / testis antigen 2 (LAGE-la); Melanoma- associated antigen 1 (MAGE-A1); ETS translocation-variant gene 6, located on chromosome 12p (ETV6-AML); sperm protein 17 (SPA17); X Antigen Family, Member 1A (XAGE1); angiopoietin-binding cell surface receptor 2 (Tie 2); melanoma cancer testis antigen-1 (MAD-CT-1); melanoma cancer testis antigen-2 (MAD-CT-2); Fos-related antigen 1; tumor protein p53 (p53); p53 mutant; protein; surviving; telomerase; prostate carcinoma tumor antigen- 1 (PCTA-1 or Galectin 8), melanoma antigen recognized by T cells 1 (MelanA or MARTI); Rat sarcoma (Ras) mutant; human Telomerasereverse transcriptase (hTERT); sarcoma translocation breakpoints; melanoma inhibitor of apoptosis (ML- IAP); ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene); N-Acetyl glucosaminyl- transferase V (NA17); paired box protein Pax-3 (PAX3); Androgen receptor; Cyclin Bl; v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN); Ras Homolog Family Member C (RhoC); Tyrosinase-related protein 2 (TRP-2); Cytochrome P450 1B1 (CYP1B1); CCCTC- Binding Factor (Zinc Finger Protein)- Like (BORIS or Brother of the Regulator of Imprinted Sites), Squamous Cell Carcinoma Antigen Recognized By T Cells 3 (SART3); Paired box protein Pax-5 (PAX5); proacrosin binding protein sp32 (OY-TES1); lymphocyte- specific protein tyrosine kinase (LCK); A kinase anchor protein 4 (AKAP-4); synovial sarcoma, X breakpoint 2 (SSX2); Receptor for Advanced Glycation Endproducts (RAGE-1); renal ubiquitous 1 (RU1); renal ubiquitous 2 (RU2); legumain; human papilloma virus E6 (HPV E6); human papilloma virus E7 (HPV E7); intestinal carboxyl esterase; heat shock protein 70-2 mutated (mut hsp70-2); CD79a; CD79b; CD72; Leukocyte-associated immunoglobulin-like receptor 1 (LAIR1); Fc fragment of IgA receptor (FCAR or CD89); Leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2); CD300 molecule-like family member f (CD300LF); C-type lectin domain family 12 member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); EGF-like module- containing mucinlike hormone receptor-like 2 (EMR2); lymphocyte antigen 75 (LY75); Glypican-3 (GPC3); Fc receptor-like 5 (FCRL5); and immunoglobulin lambda-like polypeptide 1 (IGLL1).

[0131] In certain embodiments, the CARs target a tumor- supporting antigen present on a stromal cell (such as bone marrow stromal cell antigen 2 (BST2), fibroblast activation protein (FAP) and tenascin) or a myeloid-derived suppressor cell (MDSC), such as CD33, CDl lb, C14, CD15, and CD66b.Immune Checkpoint modulators

[0132] Immune checkpoints are a type of immunosuppressive molecules expressed on immune cells, which can regulate the degree of immune activation and avoid autoimmune responses. Immune checkpoint modulators can specifically activate immune cells by targeting immune checkpoints, thereby modulating the binding of the checkpoint proteins with their partner proteins and allowing the T cells to kill cancer cells. The immune checkpoints proteins or their ligands are targets for the immune checkpoint modulators.

[0133] It is discovered herein that the compound or the composition provided herein including the compound synergistically inhibited tumor growth with an immune checkpoint modulator, such as anti-PD-1 antibody, for example pembrolizumab. Accordingly, one embodiment of the present disclosure provides a method for treating cancer in a patient in need thereof, whichentails administering to the patient a compound in combination with an immune checkpoint modulator. The compound binds to and modulates cereblon activity, and mediates degradation of IKZF2.

[0134] In certain embodiments, the immune checkpoint modulator binds one or more molecules selected from PD-1, PD-L1, CTLA-4, LAG-3, TIGIT, TIM3, BTLA, HVEM, VISTA, B7-H3, B7-H4, A2aR-Adenosine, (stimulatory) CD27 / CD70, CD28, 4-1BB (CD137), OX-40 / OX40L, CD40 / CD40L, ICOS, ICOSL, GITR / GITRL, ILT-2, ILT-4, HHLA2, butyrophilins, STimulator of INterferon Genes (STING), SIRPa, and CD47. For instance, the modulator can be an inhibitor of PD-1, PD-L1, CTLA-4, LAG-3, TIGIT, TIM3, BTLA, HVEM, VISTA, B7-H3, B7- H4, A2aR-Adenosine, (stimulatory) CD27 / CD70, CD28, 4-1BB (CD137), OX-40 / OX40L, CD40 / CD40L, ICOS, ICOSL, GITR / GITRL, ILT-2, ILT-4, HHLA2, butyrophilins, STimulator of INterferon Genes (STING), SIRPa, or CD47.

[0135] In certain embodiments, the immune checkpoint modulators are PD-1 or PD-L1 (PD- 1 / PD-L1) antagonists. In certain embodiments, the immune checkpoint modulators are PD-1 antagonists. For example, an agent that binds to and antagonizes PD-1. Such agents can be, for example, a peptide that binds PD-1. In certain embodiments, the PD-1 antagonist can be an antibody that selectively binds PD-1. In certain embodiments, the antagonist is (i) an antisense molecule directed against PD-1, (ii) an adnectin directed against PD-1, (iii) a single stranded or double stranded RNAi inhibitor of PD-1, and / or (iv) a small molecule inhibitor of PD-1.

[0136] In certain embodiments, the antibody that selectively binds PD-1 includes pembrolizumab, nivolumab, pidilizumab, cemiplimab, retifanlimab, toripalimab, dostarlimab, sintilimab, tislelizumab, MEDI-0680, REGN2810, PF-06801591, BGB-A317, BGB-108, INCSHR1210, TSR-042, AMP-224 or AMP 514. Other anti-PDl antibodies are disclosed in, WO 2015 / 112800, WO 2016 / 092419, WO 2015 / 085847, WO 2014 / 179664, WO 2014 / 194302, WO 2014 / 209804, WO 2015 / 200119, US 8,735,553, US 7,488,802, US 8,927,697, US 8,993,731, and US 9,102,727, US 8,609,089, US 2010028330, and US 20120114649, incorporated by reference in their entirety.

[0137] In certain embodiments, the immune checkpoint modulators are PD-L1 antagonists. For example, an agent that binds to and antagonizes PD-L1. Such agents can be, for example, a peptide that binds PD-L1. In certain embodiments, the PD-L1 antagonist can be an antibody that selectively binds PD-L1. In certain embodiments, the antagonist is (i) an antisense molecule directed against PD-L1, (ii) an adnectin directed against PD-L1, (iii) a single stranded or double stranded RNAi inhibitor of PD-L1, and / or (iv) a small molecule inhibitor of PD-L1.

[0138] In certain embodiments, the antibody that selectively binds PD-L1 includes BMS- 936559 / MDX-l 105, MPDL3280A / RG7446 / atezolizumab, MSB0010718C / avelumab, MEDI4736 / durvalumab or YW243.55.S70. Further known anti-PD-Ll antibodies include those described, e.g., in WO 2015 / 181342, WO 2014 / 100079, WO 2016 / 000619, WO 2014 / 022758, WO 2014 / 055897, WO 2015 / 061668, WO 2013 / 079174, WO 2012 / 145493, WO 2015 / 112805, WO 2015 / 109124, WO 2015 / 195163, US 8,168,179, US 8,552,154, US 8,460,927, and US 9,175,082, incorporated by reference in their entirety.

[0139] In certain embodiments, the immune checkpoint modulators are CTLA-4 antagonists.For example, an agent that binds to and antagonizes CTLA-4. Such agents can be, for example, a peptide that binds CTLA-4. In certain embodiments, the CTLA-4 antagonist can be an antibody that selectively binds CTLA-4. In certain embodiments, the antibody that selectively binds CTLA-4 includes ipilimumab or tremelimumab. In certain embodiments, the antagonist is (i) an antisense molecule directed against CD80, CD86, and / or CTLA-4, (ii) an adnectin directed against CD80, CD86, and / or CTLA-4, (iii) a single stranded or double stranded RNAi inhibitor of CD80, CD86, and / or CTLA-4, and / or (iv) a small molecule inhibitor of CD80, CD86, and / or CTLA-4.

[0140] In certain embodiments, the immune checkpoint modulators are VISTA antagonists. For example, an agent that binds to and antagonizes VISTA. Such agents can be, for example, a peptide that binds VISTA. In certain embodiments, the VISTA antagonist can be an antibody that selectively binds VISTA. In certain embodiments, the antibody that selectively binds VISTA includes CL8993, HMBD-002, and KVA12123. In certain embodiments, the antagonist is (i) an antisense molecule directed against VISTA , (ii) an adnectin directed against VISTA, (iii) a single stranded or double stranded RNAi inhibitor of VISTA, and / or (iv) a small molecule inhibitor of VISTA.

[0141] In certain embodiments, the immune checkpoint modulators are LAG-3 antagonists. For example, an agent that binds to and antagonizes LAG-3. Such agents can be, for example, a peptide that binds LAG-3, such as IMP321. In certain embodiments, the LAG-3 antagonist can be an antibody that selectively binds LAG-3In certain embodiments, the antagonist is (i) an antisense molecule directed against LAG-3, (ii) an adnectin directed against LAG-3, (iii) a single stranded or double stranded RNAi inhibitor of LAG-3, and / or (iv) a small molecule inhibitor of LAG-3.

[0142] In certain embodiments, the antibody that selectively binds LAG-3 includes relatlimab, BMS-986016, REGN3767, MK-4280, LAG525, TSR-033, Sym022, GSK2831781, INCAGN02385, IMP321, MGD013, FS118, RO7247669, EMB-02, XmAb841 and IBI323.Further known anti-LAG-3 antibodies include those described, e.g., in WO 2008 / 132601, WO 2010 / 019570, WO 2014 / 140180, WO 2015 / 116539, WO 2015 / 200119, WO 2016 / 028672, US 9,244,059, US 9,505,839, incorporated by reference in their entirety.

[0143] In certain embodiments, the immune checkpoint modulators are TIM1 antagonists. For example, an agent that binds to and antagonizes TIM1. Such agents can be, for example, a peptide that binds TIM1. In certain embodiments, the TIM1 antagonist can be an antibody that selectively binds TIM1. In certain embodiments, the antagonist is (i) an antisense molecule directed against TIM1, (ii) an adnectin directed against TIM1, (iii) a single stranded or double stranded RNAi inhibitor of TIM1, and / or (iv) a small molecule inhibitor of TIM1.

[0144] In certain embodiments, the immune checkpoint modulators are TIM3 antagonists. For example, an agent that binds to and antagonizes TIM3. Such agents can be, for example, a peptide that binds TIM3. In certain embodiments, the TIM3 antagonist can be an antibody that selectively binds TIM3. In certain embodiments, the antagonist is (i) an antisense molecule directed against TIM3, (ii) an adnectin directed against TIM3, (iii) a single stranded or double stranded RNAi inhibitor of TIM3, and / or (iv) a small molecule inhibitor of TIM3.

[0145] In certain embodiments, the immune checkpoint modulators are TIM4 antagonists. For example, an agent that binds to and antagonizes TIM4. Such agents can be, for example, a peptide that binds TIM4. In certain embodiments, the TIM4 antagonist can be an antibody that selectively binds TIM4. In certain embodiments, the antagonist is (i) an antisense molecule directed against TIM4, (ii) an adnectin directed against TIM4, (iii) a single stranded or double stranded RNAi inhibitor of TIM4, and / or (iv) a small molecule inhibitor of TIM4.

[0146] In certain embodiments, the immune checkpoint modulators are CD47 antagonists. For example, an agent that binds to and antagonizes CD47. Such agents can be, for example, a peptide that binds CD47. In certain embodiments, the CD47 antagonist can be an antibody that selectively binds CD47. In certain embodiments, the antagonist is (i) an antisense molecule directed against CD47, (ii) an adnectin directed against CD47, (iii) a single stranded or double stranded RNAi inhibitor of CD47, and / or (iv) a small molecule inhibitor of CD47.

[0147] In certain embodiments, the antibody that selectively binds CD47 includes TSR-022, CC-90002, GenSci-059, IMC-002, Lemzoparlimab, Letaplimab, Ligufalimab, Magrolimab, MIL-95, SHR-1603, ZL-1201, BAT-7104, HX-009, IBL322, IMM-0306, JMT-601, SG-12473, TG-1801, XL- 114, Evorpacept, IMM-01, TTI-621, TTL622, and RRx-001. Further known anti- TIM-3 antibodies include those described, e.g., in WO 2016 / 111947, WO 2016 / 071448, WO 2016 / 144803, US 8,552,156, US 8,841,418, and US 9,163,087, incorporated by reference in their entirety.

[0148] In certain embodiments, the immune checkpoint modulators are SIRPa antagonists. For example, an agent that binds to and antagonizes SIRPa. Such agents can be, for example, a peptide that binds SIRPa. In certain embodiments, the SIRPa antagonist can be an antibody that selectively binds SIRPa. In certain embodiments, the antibody that selectively binds SIRPa includes HEFLB, 1H9, SIRPAB-l l / BMS-986351, BR105, hAB21, CC-95251, and CC-90002. In certain embodiments, the antagonist is (i) an antisense molecule directed against SIRP, (ii) an adnectin directed against SIRPa, (iii) a single stranded or double stranded RNAi inhibitor of SIRPa, and / or (iv) a small molecule inhibitor of SIRPa.

[0149] In certain embodiments, the immune checkpoint modulators are B7H2 antagonists. For example, an agent that binds to and antagonizes B7H2. Such agents can be, for example, a peptide that binds B7H2. In certain embodiments, the B7H2 antagonist can be an antibody that selectively binds B7H2. In certain embodiments, the antibody that selectively binds B7H2 includes IBBN0979, and MGC018. In certain embodiments, the antagonist is (i) an antisense molecule directed against B7H2, (ii) an adnectin directed against B7H2, (iii) a single stranded or double stranded RNAi inhibitor of B7H2, and / or (iv) a small molecule inhibitor of B7H2.

[0150] In certain embodiments, the immune checkpoint modulators are B7H3 antagonists. For example, an agent that binds to and antagonizes B7H3. Such agents can be, for example, a peptide that binds B7H3. In certain embodiments, the B7H3 antagonist can be an antibody that selectively binds B7H3. In certain embodiments, the antibody that selectively binds B7H3 includes IBBN0979, and MGC018. In certain embodiments, the antagonist is (i) an antisense molecule directed against B7H3, (ii) an adnectin directed against B7H3, (iii) a single stranded or double stranded RNAi inhibitor of B7H3, and / or (iv) a small molecule inhibitor of B7H3.

[0151] In certain embodiments, the immune checkpoint modulators are B7-CD28-like molecule agonists. For example, an agent that binds to and agonizes B7-CD28-like molecule. Such agents can be, for example, a peptide that binds B7-CD28-like molecule. In certain embodiments, the B7-CD28-like molecule agonist can be an antibody that selectively binds B7-CD28-like molecule. In certain embodiments, the agonist is (i) an mRNA encoding B7-CD28; and / or (iv) a small molecule agonist of B7-CD28-like molecule.

[0152] In certain embodiments, the immune checkpoint modulators are 4- IBB agonists. For example, an agent that binds to and agonizes 4- IBB. Such agents can be, for example, a peptide that binds 4-1BB. In certain embodiments, the 4-1BB agonist can be an antibody that selectively binds 4-1BB. In certain embodiments, the agonist is (i) an mRNA encoding 4-1BB, and / or (ii) a small molecule agonist of 4- IBB.

[0153] In certain embodiments, the immune checkpoint modulators are OX-40 agonists. For example, an agent that binds to and agonizes OX-40 or OX40L. Such agents can be, for example, a peptide that binds OX-40. In certain embodiments, the OX-40 agonist can be an antibody that selectively binds OX-40. In certain embodiments, the antibody that selectively binds OX-40 includes INCAGN01949, rocatinlimab / KHK4083, IBI101, GBR830, and MED 16469. In certain embodiments, the agonist is (i) an mRNA encoding OX-40, and / or (ii) a small molecule agonist of OX-40.

[0154] In certain embodiments, the immune checkpoint modulators are CD40 agonists. For example, an agent that binds to and agonizes CD40. Such agents can be, for example, a peptide that binds CD40. In certain embodiments, the CD40 agonist can be an agonist antibody that selectively binds CD40. In certain embodiments, the agonist is (i) an mRNA encoding CD40, and / or (ii) a small molecule agonist of CD40.

[0155] In certain embodiments, the immune checkpoint modulators are B7H3 antagonists. For example, an agent that binds to and antagonizes B7H4. Such agents can be, for example, a peptide that binds B7H4. In certain embodiments, the B7H4 antagonist can be an antibody that selectively binds B7H4. In certain embodiments, the antagonist is (i) an antisense molecule directed against B7H4, (ii) an adnectin directed against B7H4, (iii) a single stranded or double stranded RNAi inhibitor of B7H4, and / or (iv) a small molecule inhibitor of B7H4.

[0156] In certain embodiments, the immune checkpoint modulators are CD27 agonists. For example, an agent that binds to and agonizes CD27. Such agents can be, for example, a peptide that binds CD27. In certain embodiments, the CD27 agonist can be an agonist antibody that selectively binds CD27. In certain embodiments, the agonist is (i) an mRNA encoding CD27, and / or (ii) a small molecule agonist of CD27.

[0157] In certain embodiments, the immune checkpoint modulators are CD48 antagonists. For example, an agent that binds to and antagonizes CD48. Such agents can be, for example, a peptide that binds CD48. In certain embodiments, the CD48 antagonist can be an antibody that selectively binds CD48. In certain embodiments, the antagonist is (i) an antisense molecule directed against CD48, (ii) an adnectin directed against CD48, (iii) a single stranded or double stranded RNAi inhibitor of CD48, and / or (iv) a small molecule inhibitor of CD48.

[0158] In certain embodiments, the immune checkpoint modulators are CD 160 antagonists. For example, an agent that binds to and antagonizes CD 160. Such agents can be, for example, a peptide that binds CD160. In certain embodiments, the CD160 antagonist can be an antibody that selectively binds CD160. In certain embodiments, the antagonist is (i) an antisensemolecule directed against CD 160, (ii) an adnectin directed against CD 160, (iii) a single stranded or double stranded RNAi inhibitor of CD 160, and / or (iv) a small molecule inhibitor of CD 160.

[0159] In certain embodiments, the immune checkpoint modulators are gp49B antagonists. For example, an agent that binds to and antagonizes gp49B. Such agents can be, for example, a peptide that binds gp49B. In certain embodiments, the gp49B antagonist can be an antibody that selectively binds gp49B. In certain embodiments, the antagonist is (i) an antisense molecule directed against gp49B, (ii) an adnectin directed against gp49B, (iii) a single stranded or double stranded RNAi inhibitor of gp49B, and / or (iv) a small molecule inhibitor of gp49B.

[0160] In certain embodiments, the immune checkpoint modulators are 2B4 antagonists. For example, an agent that binds to and antagonizes 2B4. Such agents can be, for example, a peptide that binds 2B4. In certain embodiments, the 2B4 antagonist can be an antibody that selectively binds 2B4. In certain embodiments, the antagonist is (i) an antisense molecule directed against 2B4, (ii) an adnectin directed against 2B4, (iii) a single stranded or double stranded RNAi inhibitor of 2B4, and / or (iv) a small molecule inhibitor of 2B4.

[0161] In certain embodiments, the immune checkpoint modulators are CD244 antagonists. For example, an agent that binds to and antagonizes CD244. Such agents can be, for example, a peptide that binds CD244. In certain embodiments, the CD244 antagonist can be an antibody that selectively binds CD244. In certain embodiments, the antagonist is (i) an antisense molecule directed against CD244, (ii) an adnectin directed against CD244, (iii) a single stranded or double stranded RNAi inhibitor of CD244, and / or (iv) a small molecule inhibitor of CD244.

[0162] In certain embodiments, the immune checkpoint modulators are B7.1 antagonists. For example, an agent that binds to and antagonizes B7.1. Such agents can be, for example, a peptide that binds B7.1. In certain embodiments, the B7.1 antagonist can be an antibody that selectively binds B7.1. In certain embodiments, the antagonist is (i) an antisense molecule directed against B7.1, (ii) an adnectin directed against B7.1, (iii) a single stranded or double stranded RNAi inhibitor of B7.1, and / or (iv) a small molecule inhibitor of B7.1.

[0163] In certain embodiments, the immune checkpoint modulators are B7.2 antagonists. For example, an agent that binds to and antagonizes B7.2. Such agents can be, for example, a peptide that binds B7.2. In certain embodiments, the B7.2 antagonist can be an antibody that selectively binds B7.2. In certain embodiments, the antagonist is (i) an antisense molecule directed against B7.2, (ii) an adnectin directed against B7.2, (iii) a single stranded or double stranded RNAi inhibitor of B7.2, and / or (iv) a small molecule inhibitor of B7.2.

[0164] In certain embodiments, the immune checkpoint modulators are ILT-2 antagonists. For example, an agent that binds to and antagonizes ILT-2. Such agents can be, for example, apeptide that binds ILT-2. In certain embodiments, the ILT-2 antagonist can be an antibody that selectively binds ILT-2. In certain embodiments, the antagonist is (i) an antisense molecule directed against ILT-2, (ii) an adnectin directed against ILT-2, (iii) a single stranded or double stranded RNAi inhibitor of ILT-2, and / or (iv) a small molecule inhibitor of ILT-2.

[0165] In certain embodiments, the immune checkpoint modulators are ILT-4 antagonists. For example, an agent that binds to and antagonizes ILT-4. Such agents can be, for example, a peptide that binds ILT-4. In certain embodiments, the ILT-4 antagonist can be an antibody that selectively binds ILT-4. In certain embodiments, the antagonist is (i) an antisense molecule directed against ILT-4, (ii) an adnectin directed against ILT-4, (iii) a single stranded or double stranded RNAi inhibitor of ILT-4, and / or (iv) a small molecule inhibitor of ILT-4.

[0166] In certain embodiments, the immune checkpoint modulators are butyrophilins antagonists. For example, an agent that binds to and antagonizes butyrophilins. Such agents can be, for example, a peptide that binds butyrophilins. In certain embodiments, the butyrophilins antagonist can be an antibody that selectively binds butyrophilins. In certain embodiments, the antagonist is (i) an antisense molecule directed against butyrophilins, (ii) an adnectin directed against butyrophilins, (iii) a single stranded or double stranded RNAi inhibitor of butyrophilins, and / or (iv) a small molecule inhibitor of butyrophilins.

[0167] In certain embodiments, the immune checkpoint modulators are STING agonists. For example, an agent that binds to and agonizes STING. Such agents can be, for example, a peptide that binds STING. In certain embodiments, the STING agonist can be an agonist antibody that selectively binds STING. In certain embodiments, the agonist is (i) an mRNA encoding STING, and / or (ii) a small molecule agonist of STING.

[0168] In certain embodiments, the immune checkpoint modulators are CEACAM antagonists. For example, an agent that binds to and antagonizes CEACAM (CEACAM- 1, CEACAM-3 or CEACAM-5). Such agents can be, for example, a peptide that binds CEACAM (CEACAM- 1, CEACAM-3 or CEACAM-5). In certain embodiments, the CEACAM antagonist can be an antibody that selectively binds CEACAM (CEACAM- 1, CEACAM-3 or CEACAM-5). In certain embodiments, the antagonist is (i) an antisense molecule directed against CEACAM (CEACAM- 1, CEACAM-3 or CEACAM-5), (ii) an adnectin directed against CEACAM (CEACAM- 1, CEACAM-3 or CEACAM-5), (iii) a single stranded or double stranded RNAi inhibitor of CEACAM (CEACAM- 1, CEACAM-3 or CEACAM-5), and / or (iv) a small molecule inhibitor of CEACAM (CEACAM- 1, CEACAM-3 or CEACAM-5).

[0169] In certain embodiments, the immune checkpoint modulators are TIGIT antagonists. For example, an agent that binds to and antagonizes TIGIT. Such agents can be, for example, apeptide that binds TIGIT. In certain embodiments, the TIGIT antagonist can be an antibody that selectively binds TIGIT. In certain embodiments, the antagonist is (i) an antisense molecule directed against TIGIT, (ii) an adnectin directed against TIGIT, (iii) a single stranded or double stranded RNAi inhibitor of TIGIT, and / or (iv) a small molecule inhibitor of TIGIT.

[0170] In certain embodiments, the immune checkpoint modulators are ICOS agonists. For example, an agent that binds to and agonizes ICOS. Such agents can be, for example, a peptide that binds ICOS. In certain embodiments, the ICOS agonist can be an agonist antibody that selectively binds ICOS. In certain embodiments, the agonist is (i) an mRNA encoding ICOS, and / or (ii) a small molecule agonist of ICOS.

[0171] In certain embodiments, the immune checkpoint modulators are GITR agonists. For example, an agent that binds to and agonizes GITR. Such agents can be, for example, a peptide that binds GITR. In certain embodiments, the GITR agonist can be an agonist antibody that selectively binds GITR. In certain embodiments, the agonist is (i) an mRNA encoding GITR, and / or (ii) a small molecule agonist of GITR.

[0172] In certain embodiments, the immune checkpoint modulators are BTLA antagonists. For example, an agent that binds to and antagonizes BTLA. Such agents can be, for example, a peptide that binds BTLA. In certain embodiments, the BTLA antagonist can be an antibody that selectively binds BTLA. In certain embodiments, the antagonist is (i) an antisense molecule directed against BTLA, (ii) an adnectin directed against BTLA, (iii) a single stranded or double stranded RNAi inhibitor of BTLA, and / or (iv) a small molecule inhibitor of BTLA.

[0173] In certain embodiments, the immune checkpoint modulators are HEVM antagonists. For example, an agent that binds to and antagonizes HEVM. Such agents can be, for example, a peptide that binds HEVM. In certain embodiments, the HEVM antagonist can be an antibody that selectively binds HEVM. In certain embodiments, the antagonist is (i) an antisense molecule directed against HEVM, (ii) an adnectin directed against HEVM, (iii) a single stranded or double stranded RNAi inhibitor of HEVM, and / or (iv) a small molecule inhibitor of HEVM.

[0174] In certain embodiments, the immune checkpoint modulators are KIR antagonists. For example, an agent that binds to and antagonizes KIR. Such agents can be, for example, a peptide that binds KIR. In certain embodiments, the KIR antagonist can be an antibody that selectively binds KIR. In certain embodiments, the antagonist is (i) an antisense molecule directed against KIR, (ii) an adnectin directed against KIR, (iii) a single stranded or double stranded RNAi inhibitor of KIR, and / or (iv) a small molecule inhibitor of KIR.

[0175] In certain embodiments, the immune checkpoint modulators are IDO1 antagonists. For example, an agent that binds to and antagonizes IDOL Such agents can be, for example, apeptide that binds IDOl. In certain embodiments, the IDO1 antagonist can be an antibody that selectively binds IDOl, such as Indoximod (also known as NLG-8189), a-Cyclohexyl-5H- imidazo[5,l- a]isoindole-5-ethanol (also known as NLG919), or (4E)-4-[(3-Chloro-4- fluoroanilino)- nitrosomethylidene]- 1, 2, 5-oxadiazol-3-amine (also known as INCB024360). In certain embodiments, the antagonist is (i) an antisense molecule directed against IDOl, (ii) an adnectin directed against IDOl, (iii) a single stranded or double stranded RNAi inhibitor of IDOl, and / or (iv) a small molecule inhibitor of IDOl.

[0176] In certain embodiments, the immune checkpoint modulators are A2aR- Adenosine antagonists. For example, an agent that binds to and antagonizes A2aR- Adenosine. Such agents can be, for example, a peptide that binds A2aR- Adenosine. In certain embodiments, the A2aR- Adenosine antagonist can be an antibody that selectively binds A2aR- Adenosine. In certain embodiments, the antagonist is (i) an antisense molecule directed against A2aR-Adenosine, (ii) an adnectin directed against A2aR- Adenosine, (iii) a single stranded or double stranded RNAi inhibitor of A2aR- Adenosine, and / or (iv) a small molecule inhibitor of A2aR- Adenosine. Cancers and Non-Cancerous Diseases

[0177] Patients that can be suitably treated by the instantly disclosed methods include those having a cancer, such as carcinomas (solid tumors including both primary and metastatic tumors), sarcomas, melanomas, and hematological cancers (cancers affecting blood including lymphocytes, bone marrow and / or lymph nodes) such as leukemia, lymphoma and multiple myeloma. Adult tumors / cancers and pediatric tumors / cancers are included. The cancers may be vascularized, or not yet substantially vascularized, or non- vascularized tumors.

[0178] Representative examples of cancers includes adrenocortical carcinoma, AIDS-related cancers (e.g., Kaposi's and AIDS-related lymphoma), appendix cancer, childhood cancers (e.g., childhood cerebellar astrocytoma, childhood cerebral astrocytoma), basal cell carcinoma, skin cancer (non-melanoma), biliary cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, bladder cancer, urinary bladder cancer, brain cancer (e.g., gliomas and glioblastomas such as brain stem glioma, gestational trophoblastic tumor glioma, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodeimal tumors, visual pathway and hypothalamic glioma), breast cancer, bronchial adenomas / carcinoids, carcinoid tumor, nervous system cancer (e.g., central nervous system cancer, central nervous system lymphoma), cervical cancer, chronic myeloproliferative disorders, colorectal cancer (e.g., colon cancer, rectal cancer), polycythemia vera, lymphoid neoplasm, mycosis fungoids, Sezary Syndrome, endometrial cancer, esophageal cancer, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eyecancer, intraocular melanoma, retinoblastoma, gallbladder cancer, gastrointestinal cancer (e.g., stomach cancer, small intestine cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST)), germ cell tumor, ovarian germ cell tumor, head and neck cancer, Hodgkin's lymphoma, leukemia, lymphoma, multiple myeloma, hepatocellular carcinoma, hypopharyngeal cancer, intraocular melanoma, ocular cancer, islet cell tumors (endocrine pancreas), renal cancer (e.g., Wilm's Tumor, clear cell renal cell carcinoma), liver cancer, lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), Waldenstrom's macroglobulinema, melanoma, intraocular (eye) melanoma, merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer with occult primary, multiple endocrine neoplasia (MEN), myelodysplastic syndromes, essential thrombocythemia, myelodysplastic / myeloproliferative diseases, nasopharyngeal cancer, neuroblastoma, oral cancer (e.g., mouth cancer, lip cancer, oral cavity cancer, tongue cancer, oropharyngeal cancer, throat cancer, laryngeal cancer), ovarian cancer (e.g., ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor), pancreatic cancer, islet cell pancreatic cancer, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineoblastoma, pituitary tumor, plasma cell neoplasm, pleuropulmonary blastoma, prostate cancer, retinoblastoma rhabdomyosarcoma, salivary gland cancer, uterine cancer (e.g., endometrial uterine cancer, uterine sarcoma, uterine corpus cancer), squamous cell carcinoma, testicular cancer, thymoma, thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter and other urinary organs, urethral cancer, gestational trophoblastic tumor, vaginal cancer and vulvar cancer.

[0179] In some embodiments, the cancer is mediated at least in part by IKZF2. IKZF2 has been shown to be a biomarker of highly suppressive Treg cells and is critical for maintaining the anergic and suppressive phenotype in the tumor microenvironment. Genetic depletion or degradation of IKZF2 in Treg cells results in both loss of suppressive activity and conversion of Tregs into T effector cells, leading to enhanced anti-tumor immunity.

[0180] In some embodiments, the cancer types mediated at least in part by IKZF2 include non- small cell lung cancer (NSCEC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, gastrointestinal stromal tumor (GIST), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), melanoma, skin cutaneous melanoma (SKCM), kidney renal clear cell carcinoma (KIRC), lung adenocarcinoma (FUAD), head and neck squamous cell carcinoma (HNSCC), breast invasive carcinoma (BRCA), human papillomavirus (HPV)+ cervical cancer, or human papillomavirus (HPV)+ head and neck SCC (Oropharyngeal cancer).

[0181] In some embodiments, the tumor types that are mediated by IKZF2 and responsive to the combination of the compounds provided herein and the immune checkpoint modulators are selected according to predictive gene signatures.

[0182] In some embodiments, patients that can be suitably treated by the instantly disclosed methods have non-cancerous diseases or disorders. Those non-cancerous diseases or disorders are also mediated by IKZF2. Exemplary types of non-cancerous (e.g., cell proliferative) diseases or disorders that may be amenable to treatment with the compounds of the present invention include inflammatory diseases and conditions, autoimmune diseases, neurodegenerative diseases, heart diseases, viral diseases, chronic and acute kidney diseases or injuries, metabolic diseases, and allergic and genetic diseases.

[0183] Representative examples of specific non-cancerous diseases and disorders include rheumatoid arthritis, alopecia areata, lymphoproliferative conditions, autoimmune hematological disorders (e.g. hemolytic anemia, aplastic anemia, anhidrotic ectodermal dysplasia, pure red cell anemia and idiopathic thrombocytopenia), cholecystitis, acromegaly, rheumatoid spondylitis, osteoarthritis, gout, scleroderma, sepsis, septic shock, dacryoadenitis, cryopyrin associated periodic syndrome (CAPS), endotoxic shock, endometritis, gram-negative sepsis, keratoconjunctivitis sicca, toxic shock syndrome, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease, chronic pulmonary inflammation, chronic graft rejection, hidradenitis suppurativa, inflammatory bowel disease, Crohn's disease, Behcet's syndrome, systemic lupus erythematosus, glomerulonephritis, multiple sclerosis, juvenile-onset diabetes, autoimmune uveoretinitis, autoimmune vasculitis, thyroiditis, Addison's disease, lichen planus, appendicitis, bullous pemphigus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, myasthenia gravis, immunoglobulin A nephropathy, Hashimoto's disease, Sjogren's syndrome, vitiligo, Wegener granulomatosis, granulomatous orchitis, autoimmune oophoritis, sarcoidosis, rheumatic carditis, ankylosing spondylitis, Grave's disease, autoimmune thrombocytopenic purpura, psoriasis, psoriatic arthritis, eczema, dermatitis herpetiformis, ulcerative colitis, pancreatic fibrosis, hepatitis, hepatic fibrosis, CD 14 mediated sepsis, nonCD 14 mediated sepsis, acute and chronic renal disease, irritable bowel syndrome, pyresis, restenosis, cervicitis, stroke and ischemic injury, neural trauma, acute and chronic pain, allergic rhinitis, allergic conjunctivitis, chronic heart failure, congestive heart failure, acute coronary syndrome, cachexia, malaria, leprosy, leishmaniasis, Lyme disease, Reiter's syndrome, acute synovitis, muscle degeneration, bursitis, tendonitis, tenosynovitis, herniated, ruptured, or prolapsed intervertebral disk syndrome, osteopetrosis, rhinosinusitis, thrombosis, silicosis, pulmonary sarcosis, bone resorption diseases, such as osteoporosis, fibromyalgia, AIDS andother viral diseases such as Herpes Zoster, Herpes Simplex I or II, influenza virus and cytomegalovirus, diabetes Type I and II, obesity, insulin resistance and diabetic retinopathy, 22ql l.2 deletion syndrome, Angelman syndrome, Canavan disease, celiac disease, Charcot- Marie-Tooth disease, color blindness, Cri du chat, Down syndrome, cystic fibrosis, Duchenne muscular dystrophy, haemophilia, Klinefleter's syndrome, neurofibromatosis, phenylketonuria, Prader-Willi syndrome, sickle cell disease, Tay-Sachs disease, Turner syndrome, urea cycle disorders, thalassemia, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, uveitis, polymyositis, proctitis, interstitial lung fibrosis, dermatomyositis, atherosclerosis, arteriosclerosis, amyotrophic lateral sclerosis, asociality, varicosis, vaginitis, depression, and Sudden Infant Death Syndrome.Embodiments

[0184] Embodiment 1. A method of treating or preventing a disease or disorder involving IKZF2 in a subject in need thereof, comprising administering to the subject an effective amount of a compound in combination with an effective amount of a second therapeutic agent or a second therapy, wherein the compound is:(i) Compound I having the structure:or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof; or (ii) Compound II having the structure:or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof.

[0185] Embodiment 2. The method of embodiment 1, wherein the disease or disorder is cancer or non-cancerous disease or disorder mediated at least in part by IKZF2.

[0186] Embodiment 3. The method of embodiment 2, wherein the cancer is non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), micro satellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, gastrointestinal stromal tumor (GIST), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), skin cutaneous melanoma (SKCM), kidney renal clear cell carcinoma (KIRC), lung adenocarcinoma (LU AD), head and neck squamous cell carcinoma (HNSCC), breast invasive carcinoma (BRCA), human papillomavirus (HPV)+ cervical cancer, or human papillomavirus (HPV)+ head and neck SCC (Oropharyngeal cancer).

[0187] Embodiment 4. The method of embodiment 1, wherein the second therapy is a standard of care treatment, a cell therapy, a radiation therapy, a surgery, or any combination thereof.

[0188] Embodiment 5. The method of embodiment 1, wherein the second therapeutic agent is an immune checkpoint modulator.

[0189] Embodiment 6. The method of embodiment 5, wherein the immune checkpoint modulator binds to one or more molecules selected from PD-1, PD-L1, CTLA-4, LAG-3, TIGIT, TIM3, BTLA, HVEM, VISTA, B7-H3, B7-H4, A2aR-Adenosine, (stimulatory) CD27 / CD70, CD28, 4-1BB (CD137), OX-40 / OX40L, CD40 / CD40L, ICOS, ICOSL, GITR / GITRL, ILT-2, ILT-4, HHLA2, butyrophilins, STimulator of INterferon Genes (STING), SIRPa, and CD47.

[0190] Embodiment 7. The method of embodiment 5, wherein the immune checkpoint modulator is a PD-1 antagonist.

[0191] Embodiment 8. The method of embodiment 7, wherein the immune checkpoint modulator is an anti-PD- 1 antibody.

[0192] Embodiment 9. The method of embodiment 8, wherein the anti-PD- 1 antibody is pembrolizumab, nivolumab, pidilizumab, cemiplimab, retifanlimab, toripalimab, dostarlimab, sintilimab, tislelizumab, RMP1-14, MEDI-0680, REGN2810, PF-06801591, BGB-A317, BGB- 108, INCSHR1210, TSR-042, AMP 514, or AMP-224.

[0193] Embodiment 10. The method of embodiment 9, wherein the anti-PD- 1 antibody is pembrolizumab.

[0194] Embodiment 11. The method of embodiment 1, wherein the compound is administered prior to, concurrently or after the administration of the second therapeutic agent.

[0195] Embodiment 12. The method of any preceding embodiment, wherein the compound is administered in a single dose.

[0196] Embodiment 13. The method of any one of embodiments 1-11, wherein the compound is administered in multiple doses.

[0197] Embodiment 14. The method of embodiment 13, wherein the compound is administered to the subject every 1, 2, 3, 4, 5, 6, 7, 14, or 21 days, or one month, two months, three months, four months, or six months.

[0198] Embodiment 15. The method of any preceding embodiment, wherein the second therapeutic agent is administered in a single dose.

[0199] Embodiment 16. The method of any one of embodiments 1-14, wherein the second therapeutic agent is administered in multiple doses.

[0200] Embodiment 17. The method of embodiment 16, wherein the second therapeutic agent is administered to the subject every 1, 2, 3, 4, 5, 6, 7, 14, or 21 days, or one month, two months, three months, four months, or six months.

[0201] Embodiment 18. The method of any one of embodiments 1-17, wherein the second therapeutic agent is administered to the subject about 1 hour, 3 hours, 6 hours, 12 hours, 18 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 2 months, 3 months, 4 months, or 6 months after the administration of the compound.

[0202] Embodiment 19. The method of any one of embodiments 1-17, wherein the compound is administered to the subject about 1 hour, 3 hours, 6 hours, 12 hours, 18 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 2 months, 3 months, 4 months, or 6 months after the administration of the second therapeutic agent.

[0203] Embodiment 20. The method of any preceding embodiment, wherein the compound is administered to the subject intradermally, intramuscularly, intraperitoneally, intravenously, subcutaneously, intranasally, epidurally, or orally.

[0204] Embodiment 21. The method of any preceding embodiment, wherein the second therapeutic agent is administered to the subject intradermally, intramuscularly, intraperitoneally, intravenously, subcutaneously, intranasally, epidurally, or orally.

[0205] Embodiment 22. The method of embodiment 20 or 21, wherein the compound and the second therapeutic agent are administered in different routes.

[0206] Embodiment 23. The method of embodiment 2, wherein the non-cancerous disease or disorder is inflammatory diseases, autoimmune diseases, neurodegenerative diseases, heartdiseases, viral diseases, chronic and acute kidney diseases or injuries, metabolic diseases, or allergic and genetic diseases.

[0207] Embodiment 24. A method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound in combination with an effective amount of a PD-1 / PD-L1 antagonist, wherein the compound is Compound I having the structure:or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof.

[0208] Embodiment 25. The method of embodiment 24, wherein the cancer is mediated at least in part by IKZF2.

[0209] Embodiment 26. The method of embodiment 25, wherein the cancer is non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, gastrointestinal stromal tumor (GIST), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), skin cutaneous melanoma (SKCM), kidney renal clear cell carcinoma (KIRC), lung adenocarcinoma (LU AD), head and neck squamous cell carcinoma (HNSCC), breast invasive carcinoma (BRCA), human papillomavirus (HPV)+ cervical cancer, or human papillomavirus (HPV)+ head and neck SCC (Oropharyngeal cancer).

[0210] Embodiment 27. The method of any one of embodiments 24-26, wherein a PD-1 / PD-L1 antagonist is an anti-PD- 1 antibody.

[0211] Embodiment 28. The method of embodiment 27, wherein the anti-PD- 1 antibody is pembrolizumab, nivolumab, pidilizumab, cemiplimab, retifanlimab, toripalimab, dostarlimab, sintilimab, tislelizumab, RMP1-14, MEDI-0680, REGN2810, PF-06801591, BGB-A317, BGB- 108, INCSHR1210, TSR-042, AMP 514, or AMP-224.

[0212] Embodiment 29. The method of embodiment 27, wherein the anti-PD- 1 antibody is pembrolizumab.EXAMPLESExample 1. Compound I enhances immune checkpoint inhibitor efficacy in vivo

[0213] Compound I was co-administered with anti-PD-1 antibodies in tumor models. It is contemplated that, the stereocenter at the 3-position of the piperidine-2, 6-dione of Compound I may epimerize in vivo.1. Humanized MDA-MB-231 TNBC xenograft mouse model

[0214] All animal studies were carried out in accordance with the guidelines established by the Institutional Animal Care and Use Committee at Explora BioLabs. Exponentially growing MDA-MB-231 human breast cancer cells were harvested (>90% viability) and implanted subcutaneously in the right flank region of each NOD.SCID mouse with 7 million cells in 0.1 mL of FBS un- supplemented DMEM and an equal volume (1:1) ratio of Matrigel (BD Biosciences) for tumor development. Human PBMCs were freshly isolated from whole blood and were adoptively transferred into tumor bearing mice via intravenous tail vein injection between 1-7 days before treatment initiation. When the mean tumor size reached approximately 105 mm3, the mice were randomized and size-matched into vehicle and treatment groups (10 animals / group). Tumor size was measured in length and width with a caliper twice a week. The tumor volume was calculated by the formula L x Wx W / 2 according to NCI standards. Body weights were collected prior to study start and twice a week during the study. Compound I was dissolved in 0.5% Methylcellulose (4000 cp) and 0.2% Tween80 in water at concentration of 20 mg / ml resulting in a suspension. Pembrolizumab was prepared freshly by diluting to desired concentration with PBS. Statistical analysis of difference in tumor volume among the groups were conducted on the data obtained at the last day of treatment and subsequently evaluated using the one-way ANOVA, no matching and corrected for multiple comparisons using Dunnett's t-test (equal variance assumed). All data were analyzed using GraphPad Prism, where p < 0.05 was considered as statistically significant.

[0215] Compound I (1 mg / kg, PO, QD) was co-administered with anti-PD-1 antibody pembrolizumab (1 mg / kg, IP, Q5D) in the humanized MDA-MB-231 TNBC xenograft mouse model. The tumor volume has been measured at day 0, 4, 8, 12, 14 and 17 after treatment initiation. The tumor volume change between different treatment groups (Control group (“Vehicle”), single agent groups of Compound I (“Comp. I Img / kg PO QD”) and pembrolizumab (“Pembro 1 mg / kg IP Q5D”), respectively, and Combo group (“Comp. I + Pembro”)) were shown in FIG. 1. The Combo group showed prominent growth inhibition to thetumor volume at day 17 as compared with Compound I treatment group or pembrolizumab treatment group.2. Syngeneic B16 melanoma mouse model

[0216] Exponentially growing B16F10 murine melanoma cells were harvested (>95% viability) and implanted subcutaneously in the right flank region of each CRBNI391VC57BL mouse with 0.1 million cells in 0.1 mF of FBS un-supplemented DMEM for tumor development. When the mean tumor size reached approximately 60 mm3, day 8 post implantation, the mice were randomized and size-matched into vehicle and treatment groups (10 animals / group). Tumor size was measured in length and width with a caliper three times per week. The tumor volume was calculated by the formula Lx Wx W / 2 according to NCI standards. Body weights were collected prior to study start and three times a week during the study. Compound I was dissolved in 0.5% Methylcellulose (4000 cp) and 0.2% Tween80 in water at concentration of 20 mg / ml resulting in a suspension. Anti-PD-1 (RMP1-14) was prepared fresh by diluting to desired concentration with PBS. Statistical analysis of difference in tumor volume among the groups were conducted on the data obtained at the last day of treatment and subsequently evaluated using the one-way ANOVA, no matching and corrected for multiple comparisons using Dunnett's t-test (equal variance assumed). All data were analyzed using GraphPad Prism, where p < 0.05 was considered as statistically significant.

[0217] Vehicle (“Veh”), Compound I (100 mg / kg) (“Comp. I”), and RMP1-14 (100 mg / kg) (“aPD-1”), respectively were administered to each corresponding group of the Syngeneic B16 melanoma mouse model. Compound I was also co-administered with an anti-PD-1 antibody (RMP1-14, BIW) in the Syngeneic B16 melanoma mouse model. The tumor volume change between different treatment groups (Control group (“Veh”), single agent groups of Compound I (“Comp. I”) and RMP1-14 (“aPDl”), respectively, and Combo group (“Combo”)) were shown in FIG. 2. The Combo group also showed significant growth inhibition to the tumor volume (FIG. 2) as compared with Compound I treatment group or anti-PD-1 treatment group.3. Combination of Compound I and PD-1 Inhibitor Resulted in Synergistic Inhibition of Tumor Growth in vivo

[0218] In this example, humanized MDA-MB-231 TNBC xenograft model using hPBMCs adoptively transferred into immune incompetent mice were treated with vehicle (“Veh”), Compound I (PO, QD 5mg / kg) (“Comp. I”), pembrolizumab (5mg / kg) (“aPD-1”) or a combination of Compound I and pembrolizumab (“Combo”), for 14 days. Treatment with each of Compound I and pembrolizumab resulted in significant tumor growth inhibition.

[0219] The amounts of various Tregs were measured in the tumor tissues, and the results are shown in FIG. 3. While the treatment with both Compound I and pembrolizumab individually increased the percentage of IL-2+FoxP3+Tregs (%IL-2+FoxP3+Treg, panel on the right), their combination resulted in statistically significantly higher %IL-2+FoxP3+Treg in the tumor, underscoring the synergism of these two agents.Methods

[0220] Spleen and tumor tissue were collected / harvested from all mice in each group. Tumor tissue was cut into small pieces between 3-4 mm3, placed into gentleMACS™ C Tubes and incubated for 40 minutes at 37°C in a gentleMACS™ Octo Dissociator. The lysate was filtered by adding 20 mL of DMEM into gentleMACS™ C Tube, gently shaking, then filtered through a MACS Smartstrainer. Samples were centrifuged and supernatant was discarded. Cell pellets were resuspended in 30 mL of DMEM medium, 10 mL of Ficoll was added to the bottom of tube, then centrifuged for 20 min at 1025g at room temperature. Tumor infiltrating lymphocytes were collected, transferred to a clean tube, washed twice with DMEM medium and resuspended in DMEM complete.

[0221] Spleen tissue was cut into small pieces between 3-4 mm3and ground with the flat end of a syringe in 5 mL of DMEM on a 100 mm culture dish. Cells were passed through a cell strainer into a 50 mL tube. The cell culture dish was rinsed with 10 mL of DMEM twice and all cells were combined. The cell suspension was spun down and the cell pellet resuspended in 5 mL of DMEM / 10% FBS / lxBME.

[0222] In vitro culture (cytokine stimulation). 200 pL aliquots of TILs were added into 96-well U-bottom plates. Samples were spun down and washed once in PBS then again in RPML1640 (+10% FBS+2-Mercaptoethanol). Samples spun down once again and resuspended in 200 pL of RPML1640 (+10%FBS+2-Mercaptoethanol) containing PMA / Ionomycin / Brefeldin A. Cells were incubated at 37‘ C for 4 hours. After 4 hours, cells were spun down, resuspended in 100 pL PBS, and transferred to 96-well V-bottom plates.

[0223] FACS staining. Samples were incubated with live / dead dye for 10 minutes, spun down and supernatant removed. Mouse Fc block was added and incubated for 15 minutes, spun down, and supernatant removed. 80 pL of extracellular antibody master mix (containing conjugated) was added, samples were spun down and supernatant removed. Cells were washed twice with FACS buffer and resuspended in 100 pL ebio Fix / Perm solution, incubated at RT in the dark for 30-60 minutes, centrifuged and rinsed with IX perm / wash buffer. The cells were resuspended in 100 pL staining antibodies and incubated in the dark at RT for 30 minutes. Cells were rinsedwith 2X perm / wash buffer, resuspended in 200 pL FACS buffer and analyzed by flow cytometry.* * *

[0224] The present disclosure is not to be limited in scope by the specific embodiments described which are intended as single illustrations of individual aspects of the disclosure, and any compositions or methods which are functionally equivalent are within the scope of this disclosure. It will be apparent to those skilled in the art that various modifications and variations can be made in the methods and compositions of the present disclosure without departing from the spirit or scope of the disclosure. Thus, it is intended that the present disclosure cover the modifications and variations of this disclosure provided they come within the scope of the appended claims and their equivalents.

[0225] All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

Claims

CLAIMSWhat is claimed is:

1. A method of treating or preventing a disease or disorder involving IKZF2 in a subject in need thereof, comprising administering to the subject an effective amount of a compound in combination with an effective amount of a second therapeutic agent or a second therapy, wherein the compound is:(i) Compound I having the structure:or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof; or(ii) Compound II having the structure:or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof.

2. The method of claim 1, wherein the disease or disorder is cancer or non-cancerous disease or disorder mediated at least in part by IKZF2.

3. The method of claim 2, wherein the cancer is non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), micro satellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, gastrointestinal stromal tumor (GIST), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), skin cutaneous melanoma (SKCM), kidney renal clear cell carcinoma (KIRC), lung adenocarcinoma (LU AD), head and neck squamous cell carcinoma (HNSCC), breast invasive carcinoma (BRCA), human papillomavirus (HPV)+ cervical cancer, or human papillomavirus (HPV)+ head and neck SCC (Oropharyngeal cancer).

4. The method of claim 1, wherein the second therapy is a standard of care treatment, a cell therapy, a radiation therapy, a surgery, or any combination thereof.

5. The method of claim 1, wherein the second therapeutic agent is an immune checkpoint modulator.

6. The method of claim 5, wherein the immune checkpoint modulator binds to one or more molecules selected from PD-1, PD-L1, CTLA-4, LAG-3, TIGIT, TIM3, BTLA, HVEM, VISTA, B7-H3, B7-H4, A2aR-Adenosine, (stimulatory) CD27 / CD70, CD28, 4-1BB (CD137), OX-40 / OX40L, CD40 / CD40L, ICOS, ICOSL, GITR / GITRL, ILT-2, ILT-4, HHLA2, butyrophilins, STimulator of INterferon Genes (STING), SIRPa, and CD47.

7. The method of claim 5, wherein the immune checkpoint modulator is a PD-1 antagonist.

8. The method of claim 7, wherein the immune checkpoint modulator is an anti-PD-1 antibody.

9. The method of claim 8, wherein the anti-PD-1 antibody is pembrolizumab, nivolumab, pidilizumab, cemiplimab, retifanlimab, toripalimab, dostarlimab, sintilimab, tislelizumab, RMP1-14, MEDI-0680, REGN2810, PF-06801591, BGB-A317, BGB-108, INCSHR1210, TSR-042, AMP 514, or AMP-224.

10. The method of claim 9, wherein the anti-PD-1 antibody is pembrolizumab.

11. The method of claim 1, wherein the compound is administered prior to, concurrently or after the administration of the second therapeutic agent.

12. The method of any preceding claim, wherein the compound is administered in a single dose.

13. The method of any one of claims 1-11, wherein the compound is administered in multiple doses.

14. The method of claim 13, wherein the compound is administered to the subject every 1, 2, 3, 4, 5, 6, 7, 14, or 21 days, or one month, two months, three months, four months, or six months.

15. The method of any preceding claim, wherein the second therapeutic agent is administered in a single dose.

16. The method of any one of claims 1-14, wherein the second therapeutic agent is administered in multiple doses.

17. The method of claim 16, wherein the second therapeutic agent is administered to the subject every 1, 2, 3, 4, 5, 6, 7, 14, or 21 days, or one month, two months, three months, four months, or six months.

18. The method of any one of claims 1-17, wherein the second therapeutic agent is administered to the subject about 1 hour, 3 hours, 6 hours, 12 hours, 18 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 2 months, 3 months, 4 months, or 6 months after the administration of the compound.

19. The method of any one of claims 1-17, wherein the compound is administered to the subject about 1 hour, 3 hours, 6 hours, 12 hours, 18 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 2 months, 3 months, 4 months, or 6 months after the administration of the second therapeutic agent.

20. The method of any preceding claim, wherein the compound is administered to the subject intradermally, intramuscularly, intraperitoneally, intravenously, subcutaneously, intranasally, epidurally, or orally.

21. The method of any preceding claim, wherein the second therapeutic agent is administered to the subject intradermally, intramuscularly, intraperitoneally, intravenously, subcutaneously, intranasally, epidurally, or orally.

22. The method of claim 20 or 21, wherein the compound and the second therapeutic agent are administered in different routes.

23. The method of claim 2, wherein the non-cancerous disease or disorder is inflammatory diseases, autoimmune diseases, neurodegenerative diseases, heart diseases, viral diseases, chronic and acute kidney diseases or injuries, metabolic diseases, or allergic and genetic diseases.

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