Cancer Treatment Methods

Abstract

The present invention relates to a method for treating solid cancers and hematological malignancies using MDM2 degraders. Mouse double minute 2 (MDM2) oncoprotein is a key E3 ubiquitin ligase that degrades tumor suppressor p53. Reversible small molecule inhibitors (SMIs) of MDM2 / p53 interaction have been developed to stabilize p53 and induce apoptosis in wild-type p53 tumors. However, MDM2 SMIs induce a p53 / MDM2 feedback loop, resulting in upregulation of MDM2 protein levels and inhibition of p53 pathway, thus dramatically limiting their biological activity and clinical application.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 265,474, filed December 15, 2021, U.S. Provisional Application No. 63 / 375,820, filed September 15, 2022, and U.S. Provisional Application No. 63 / 384,043, filed November 16, 2022, each of which is incorporated by reference in its entirety herein.

[0002] TECHNICAL FIELD OF THEINVENTION The present invention relates to methods of treating solid cancers and hematological malignancies using MDM2 degraders. [Background technology]

[0003] 2. Background of the Invention Mouse double minute 2 (MDM2) oncoprotein is a key E3 ubiquitin ligase that degrades the tumor suppressor p53. Reversible small molecule inhibitors (SMIs) of MDM2 / p53 interaction have been developed to stabilize p53 and induce apoptosis in wild-type p53 tumors. However, MDM2 SMIs induce a p53 / MDM2 feedback loop, resulting in upregulation of MDM2 protein levels and p53 pathway inhibition, thus dramatically limiting their biological activity and clinical application. MDM2-targeted protein degradation is expected to suppress the upregulation of p53-dependent MDM2 protein feedback and thus result in superior responses compared to MDM2 SMIs.

[0004] There is a need to develop dosing and schedules for MDM2 degrading agents to improve the efficacy of MDM2 SMI and other therapies and to provide single agent activity in solid tumors and hematological malignancies. Summary of the Invention [Means for solving the problem]

[0005] Certain MDM2 degraders have been found to be suitable for enteral and parental administration in patients to treat solid cancers and hematological malignancies. Accordingly, in one aspect, the present invention provides a method of treating a solid cancer or hematological malignancy in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of an MDM2 degrading agent, or a pharma- ceutically acceptable salt thereof, wherein the MDM2 degrading agent is (3'R,4'S,5'R)-6''-chloro-4'-(3-chloro-2-fluorophenyl)-N-((1R,4R)-4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-1-carbonyl)cyclohexyl)-2''-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indoline]-5'-carboxamide (Compound A); (3'R,4'S,5'R)-6''-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-N-((6S)-6-((5-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)pentyl)carbamoyl)tetrahydro-2H-pyran-3-yl)-4,4-dimethyl-2''-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indoline]-5'-carboxamide (compound B), (3'R ,4'S,5'R)-6''-chloro-4'-(3-chloro-2-fluorophenyl)-N-((1r,4R)-4-((2-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)cyclohexyl)-1'-methyl-2''-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indoline]-5'-carboxamide (compound C); (3'R,4'S,5'R)-6''-chloro-4'-(3-chloro-2-fluorophenyl)-N-(4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-1-carbonyl)phenyl)-2''-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indoline]-5'-carboxamide (compound D), or (3'R,4'S,5'R)-6''-chloro-4'-(3-chloro-2-fluorophenyl)-N-((1r,4R)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidine-1-carbonyl)cyclohexyl)-2''-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indoline]-5'-carboxamide (Compound E).

[0006] In one embodiment, the MDM2 degrading agent or pharma- ceutically acceptable salt thereof is administered to the patient at a dose of up to about 0.5 mg / kg, up to about 0.65 mg / kg, or up to about 0.8 mg / kg. In some examples, the MDM2 degrading agent or pharma- ceutically acceptable salt thereof is administered at a dose of about 0.3 mg / kg to about 0.6 mg / kg or about 0.5 mg / kg to about 0.8 mg / kg. In another embodiment, the MDM2 degrading agent or pharma- ceutically acceptable salt thereof is administered to the patient at a dose of up to about 35 mg, up to about 40 mg, up to about 50 mg, or up to about 100 mg. In some examples, the MDM2 degrading agent or pharma- ceutically acceptable salt thereof is administered at a dose of about 10 mg to about 100 mg, 10 mg to about 40 mg, or about 20 mg to about 50 mg. In further embodiments, the MDM2 degrading agent or pharma- ceutically acceptable salt thereof is administered at a dose of up to 5 mg / m 2 , up to 15mg / m 2 , or up to 30 mg / m 2 In some examples, the MDM2 degrading agent or a pharma- ceutical acceptable salt thereof is administered to the patient at a dose of about 1 mg / m 2 ~about 10mg / m 2 or about 5 mg / m 2 ~about 15mg / m2 is administered at a dose of

[0007] In one embodiment, the MDM2 degrading agent or a pharma- ceutically acceptable salt thereof is orally administered to the patient. Oral administration of the MDM2 degrading agent to the patient can include the MDM2 degrading agent in a solution, suspension, emulsion, tablet, pill, capsule, powder, or sustained release formulation. In another embodiment, the MDM2 degrading agent or a pharma- ceutically acceptable salt thereof is intravenously administered to the patient. Intravenous administration of the MDM2 degrading agent to the patient can include the MDM2 degrading agent in a sterile injectable solution.

[0008] In one embodiment, the MDM2 degrading agent or a pharma- ceutically acceptable salt thereof is administered to a patient once per week (QW) or once every two weeks (Q2W) or once every three weeks (Q3W).

[0009] Also provided herein are pharmaceutical compositions comprising an MDM2 degrading agent or a pharma- ceutically acceptable salt thereof and one or more pharma- ceutically acceptable excipients or carriers. In some embodiments, the one or more pharma- ceutically acceptable excipients or carriers comprise one or more diluents, preservatives, binders, lubricants, disintegrants, swelling agents, fillers, or stabilizers. In other embodiments, the one or more pharma- ceutically acceptable excipients or carriers comprise one or more buffers, surfactants, dispersants, emulsifiers, or viscosity adjusters.

[0010] In a further aspect, the solid cancer or hematological malignancy is selected from acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), large granular lymphocytic leukemia (LGL-L), B-cell prolymphocytic leukemia, acute myeloid leukemia (AML), Burkitt's lymphoma / leukemia, primary effusion lymphoma, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), diffuse large B-cell lymphoma (DLBCL), aggressive B-cell diffuse large B-cell lymphoma (ABC DLBCL), intravascular large B-cell lymphoma, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, uveal melanoma, or myelodysplastic syndrome (MDS). In some embodiments, the patient receiving the MDM2 degrading agent or a pharmacologic acceptable salt thereof to treat a solid cancer or hematological malignancy has undergone at least one prior therapy. In some embodiments, the solid cancer or hematological malignancy is refractory. In some embodiments, the patient is a human.

[0011] These and other aspects of the present disclosure will become apparent upon reference to the following detailed description, to which end various references are set forth herein which describe in more detail certain background information and procedural steps, each of which is incorporated herein by reference in its entirety. [Brief description of the drawings]

[0012] [Figure 1] FIG. 1 shows that compound A degrades MDM2 at 0.4 nm, unlike SMIs such as DS-3032.

[0013] [Diagram 2] FIG. 2 shows that Compound A, unlike SMIs such as DS-3032, potently stabilizes p53.

[0014] [Diagram 3]FIG. 3 shows that compound A is superior to SMIs such as DS-3032 for killing cancer cells.

[0015] [Figure 4] FIG. 4 shows that short-term exposure to Compound A is sufficient to commit cells to apoptosis, unlike SMIs such as DS-3032.

[0016] [Diagram 5] FIG. 5 shows a schematic diagram of the washout experiment performed with RS4;11 cells.

[0017] [Figure 6] FIG. 6 shows that a single dose of Compound A achieves durable tumor regression in an RS4;11 mouse xenograft model (A) and that MDM2 degradation with 1 mg / kg Compound A results in a dose-dependent increase in p53, p21 and PUMA.

[0018] [Figure 7A] Figures 7A and 7B show that Compound A (1 mg / kg, Q3W) achieves tumor regression in the CTG-2227 AML patient-derived xenograft (PDX) model and partial responses in the CTG-2240 and CTG-2700 AML PDX models. [Figure 7B] Figures 7A and 7B show that Compound A (1 mg / kg, Q3W) achieves tumor regression in the CTG-2227 AML patient-derived xenograft (PDX) model and partial responses in the CTG-2240 and CTG-2700 AML PDX models.

[0019] [Figure 8A] Figures 8A and 8B show the benefit of combining Compound A with venetoclax and midostaurin in MOLM-13 cell lines. [Figure 8B] Figures 8A and 8B show the benefit of combining Compound A with venetoclax and midostaurin in MOLM-13 cell lines.

[0020] [Figure 9] FIG. 9 shows significant combination benefit of Compound A with standard of care in an AML in vivo model.

[0021] [Figure 10] FIG. 10 shows that Compound A is active across multiple heme indications in vitro, with AML, T-cell lymphoma, mantle cell lymphoma, and DLBCL being the most sensitive.

[0022] [Figure 11] Figure 11 shows that Compound A is highly active in p53WT ABC subtype DLBCL. Compound A was highly active in the OCI-LY10 p53WT ABC subtype DLBCL xenograft model (A) but not in the TMD8 p53MUT ABC subtype DLBCL xenograft model (B). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] Detailed Description of Specific Embodiments 1. General Description of Certain Embodiments of the Invention: The MDM2 degraders provided herein are highly potent heterobifunctional small molecule therapeutics that target MDM2 to mediate selective degradation of MDM2 protein. The provided MDM2 degraders show superior activity in wild-type p53 cell lines and xenograft models compared to SMI of MDM2. For example, in acute lymphoblastic leukemia (ALL) cell line RS4;11, compound A can overcome p53-dependent upregulation of MDM2 protein levels as seen for reversible SMI. A short 2-hour exposure of compound A can stabilize p53 more potently than SMI. Furthermore, washout experiments in these cells showed that pulse doses of compound A can result in apoptosis mediated through p53 target genes. The superior MDM2 / p53 pathway inhibition and induction of apoptosis by compound A translates into more than 200-fold stronger cell growth inhibition compared to SMI across a range of solid and hematological tumor cell lines. In some embodiments, provided herein is treatment of adult patients with solid cancer or hematological malignancies who have received at least one prior therapy. The MDM2 degrading agents of the present invention are provided by oral and intravenous administration at the doses and schedules described herein.

[0024] In the following disclosure, specific details are described to provide a thorough understanding of the various embodiments. However, those skilled in the art will understand that the methods and uses described herein may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context requires otherwise, throughout the specification and the following claims, the word "comprise" and variations thereof, such as "comprises" and "comprising," should be interpreted in an open and inclusive sense, i.e., "including, but not limited to." Additionally, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0025] References throughout this specification to "one embodiment" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment. Thus, appearances of the phrase "in one embodiment" or "in an embodiment" in various places throughout this specification do not necessarily all refer to the same embodiment. Moreover, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, 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. Also, it should be noted that the term "or" is generally used in its sense including "and / or" unless the content clearly dictates otherwise.

[0026] 2.Definition: As used in this specification and the appended claims, unless specified to the contrary, the following terms and abbreviations have the following meanings.

[0027] As used herein, the term "about" refers to within 20% of a given value. In some embodiments, the term "about" refers to within 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of a given value.

[0028] As used herein, the term "compound A" refers to (3'R,4'S,5'R)-6"-chloro-4'-(3-chloro-2-fluorophenyl)-N-((1R,4R)-4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-1-carbonyl)cyclohexyl)-2"-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-indoline]-5'-carboxamide, having the formula: [ka] In some embodiments, Compound A or a pharma- ceutically acceptable salt thereof is in an amorphous form.In some embodiments, Compound A or a pharma- ceutically acceptable salt thereof is in a crystalline form.

[0029] As used herein, the term "compound B" refers to (3'R,4'S,5'R)-6"-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-N-((6S)-6-((5-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)pentyl)carbamoyl)tetrahydro-2H-pyran-3-yl)-4,4-dimethyl-2"-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indoline]-5'-carboxamide, having the formula: [ka] In some embodiments, Compound B or a pharma- ceutically acceptable salt thereof is in an amorphous form.In some embodiments, Compound B or a pharma- ceutically acceptable salt thereof is in a crystalline form.

[0030] As used herein, the term "compound C" refers to (3'R,4'S,5'R)-6"-chloro-4'-(3-chloro-2-fluorophenyl)-N-((1r,4R)-4-((2-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)cyclohexyl)-1'-methyl-2"-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-indoline]-5'-carboxamide, having the formula: [ka] In some embodiments, Compound C or a pharma- ceutically acceptable salt thereof is in an amorphous form. In some embodiments, Compound C or a pharma- ceutically acceptable salt thereof is in a crystalline form.

[0031] As used herein, the term "compound D" refers to (3'R,4'S,5'R)-6"-chloro-4'-(3-chloro-2-fluorophenyl)-N-(4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-1-carbonyl)phenyl)-2"-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-indoline]-5'-carboxamide, having the formula: [ka] In some embodiments, Compound D or a pharma- ceutically acceptable salt thereof is in an amorphous form.In some embodiments, Compound D or a pharma- ceutically acceptable salt thereof is in a crystalline form.

[0032] As used herein, the term "compound E" refers to (3'R,4'S,5'R)-6"-chloro-4'-(3-chloro-2-fluorophenyl)-N-((1r,4R)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidine-1-carbonyl)cyclohexyl)-2"-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indoline]-5'-carboxamide, having the formula: [ka] In some embodiments, Compound E or a pharma- ceutically acceptable salt thereof is in an amorphous form.In some embodiments, Compound E or a pharma- ceutically acceptable salt thereof is in a crystalline form.

[0033] As used herein, the term "inhibitor" is defined as a compound that binds to and / or inhibits MDM2 protein with measurable affinity. In certain embodiments, an inhibitor has an IC of less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM. 50 and / or has a binding constant.

[0034] As used herein, the term "MDM2 degrading agent" refers to an agent that degrades MDM2 protein. Various MDM2 degrading agents have been previously described, for example, in WO2021 / 188948, the contents of which are incorporated herein by reference in their entirety. In certain embodiments, the MDM2 degrading agent has a DC concentration of less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM. 50 In certain embodiments, the MDM2 degrading agent is compound A, B, C, D or E disclosed herein.

[0035] The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human.

[0036] As used herein, the term "mg / kg" or "mpk" refers to milligrams of drug (e.g., Compound A) per kilogram of body weight of the subject taking the drug.

[0037] As used herein, the term "pharmaceutical acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., within the scope of sound medical judgment, and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describe pharmaceutical acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic acids, inorganic bases, organic acids, and organic bases. Examples of pharma- ceutically acceptable, non-toxic acid addition salts are salts of amino groups formed with inorganic acids (e.g., hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric) or organic acids (e.g., acetic, oxalic, maleic, tartaric, citric, succinic, or malonic acids), or by using other methods used in the art, such as ion exchange. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and the like. Examples of suitable salts include phosphate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.

[0038] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharma-ceutically acceptable salts include non-toxic ammonium, quaternary ammonium and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates and arylsulfonates.

[0039] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure, such as the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, structures of the invention in which hydrogen is replaced by deuterium or tritium, or in which carbon is replaced by tautomeric isomers of the invention. 13 C or 14 Compounds having the invention in which C is replaced with an enriched carbon are within the scope of the invention. Such compounds are useful, for example, as analytical tools according to the invention, as probes in biological assays, or as therapeutic agents.

[0040] The term "pharmaceutically acceptable additive or carrier" refers to a non-toxic additive or carrier that does not destroy the pharmacological activity of the compound that it is formulated with.The pharmaceutically acceptable additive or carrier that can be used in the composition of the present invention includes, but is not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, saturated vegetable fatty acids, partial glyceride mixtures of water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0041] The term "therapeutically effective amount" as used herein refers to an amount of an MDM2 degrading agent sufficient to treat a described disease, disorder, or condition, or to have a desired described effect on a subject's disease, disorder, or condition, or one or more mechanisms underlying the disease, disorder, or condition. In certain embodiments, when Compound A is administered for the treatment of a solid cancer or hematological malignancy, a therapeutically effective amount refers to an amount of Compound A that, upon administration to a subject, exhibits a detectable therapeutic effect in the subject that treats or ameliorates the subject's solid cancer or hematological malignancy, or results in partial to complete tumor regression.

[0042] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset, or inhibiting the progression of a disease or disorder or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., taking into account a history of the symptoms and / or taking into account genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, e.g., to prevent or delay recurrence.

[0043] 3. Description of Exemplary Embodiments: According to one aspect, the invention provides a method of treating a solid cancer or hematological malignancy in a patient in need thereof, comprising administering a therapeutically effective amount of an MDM2 degrading agent (e.g., Compound A, B, C, D or E) or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering up to 50 mg of an MDM2 degrading agent (e.g., Compound A, B, C, D or E) or a pharmaceutically acceptable salt thereof in a single dose or in divided doses.

[0044] Pharmaceutically acceptable compositions According to one embodiment, the present invention provides a composition comprising an MDM2 degrading agent of the present invention (e.g., compound A, B, C, D or E) or a pharma- ceutically acceptable derivative thereof and a pharma- ceutically acceptable excipient or carrier. The amount of MDM2 degrading agent in the composition of the present invention is such that it is effective to measurably degrade and / or inhibit MDM2 protein or a variant thereof in a patient. In certain embodiments, the composition of the present invention is formulated for administration to a patient in need of such a composition. In some embodiments, the composition of the present invention is formulated for oral administration to a patient. In some embodiments, the composition of the present invention is formulated for intravenous administration to a patient.

[0045] Most preferably, the pharma- ceutically acceptable compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharma- ceutically acceptable compositions of this invention are administered without food. In other embodiments, the pharma- ceutically acceptable compositions of this invention are administered with food.

[0046] The amount of the compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending on the host treated, the particular mode of administration. Preferably, the compositions provided should be formulated so that a dosage of between 0.01-100 mg of compound per kg of body weight per day can be administered to a patient receiving these compositions.

[0047] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the particular compound used, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, as well as the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the invention in the composition will also depend on the particular MDM2 degrading agent in the composition.

[0048] composition The dosage forms disclosed herein include a pharma- ceutically acceptable salt of the MDM2 degrading agent (e.g., Compound A, B, C, D, or E). In some embodiments, the dosage forms can be formulated for enteral or parenteral administration. The MDM2 degrading agent can be combined with one or more pharma- ceutically acceptable carriers that are deemed safe and effective to form a unit dosage form as described herein, and can be administered to an individual without causing undesirable biological side effects or undesirable interactions.

[0049] These dosage forms can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained release formulations and the like.

[0050] In a preferred embodiment, the dosage form is in the form of a solution comprising an MDM2 degrading agent (e.g., compound A, B, C, D or E). The dosage form is administered to a subject in need thereof for a period of time effective to ameliorate the patient's condition (e.g., a solid cancer or hematological malignancy).

[0051] Additives and Carriers 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, etc. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.

[0052] Suitable pharmaceutical excipients include starch, glucose, sucrose, gelatin, lactose, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, glycerol, propylene, glycol, water, ethanol, etc. The pharmaceutical composition may also contain wetting agents or emulsifying agents or suspending agents / diluents, or pH buffering agents, or agents to modify or maintain the release rate of the disclosed salts, all of which are further disclosed herein.

[0053] Administration and Dosage As described herein, the MDM2 degrading agents provided herein are administered by parenteral and enteral routes. In some embodiments, the MDM2 degrading agents (e.g., Compound A, B, C, D, or E) or a pharma- ceutically acceptable salt thereof are administered intravenously. In some embodiments, the MDM2 degrading agents (e.g., Compound A, B, C, D, or E) or a pharma-ceutically acceptable salt thereof are administered by IV injection. In some embodiments, the MDM2 degrading agents (e.g., Compound A, B, C, D, or E) or a pharma-ceutically acceptable salt thereof are administered by IV infusion.

[0054] As described herein, the MDM2 degrading agent (e.g., Compound A, B, C, D, or E) or a pharma- ceutically acceptable salt thereof is administered enterally. In some embodiments, the MDM2 degrading agent (e.g., Compound A, B, C, D, or E) or a pharma- ceutically acceptable salt thereof is administered in amorphous form (e.g., pressed into a pill or capsule). In some embodiments, the MDM2 degrading agent (e.g., Compound A, B, C, D, or E) or a pharma- ceutically acceptable salt thereof is administered as a lyophilized powder.

[0055] In some embodiments, the methods of the invention comprise orally administering to a patient a pharmaceutical composition comprising an MDM2 degrading agent. In some embodiments, the pharmaceutical composition is a solid pharmaceutical composition. In some embodiments, the solid pharmaceutical composition is a powder. In some embodiments, the pharmaceutical composition is a lyophilized powder. In some embodiments, the solid pharmaceutical composition is a granule. In some embodiments, the solid pharmaceutical composition of the invention is a tablet. In some embodiments, the solid pharmaceutical composition is a capsule. In some embodiments, the solid pharmaceutical composition is a pill. In some embodiments, the solid pharmaceutical composition is a suspension. In some embodiments, the solid pharmaceutical composition is an emulsion. In some embodiments, the solid pharmaceutical composition is a solution.

[0056] In some embodiments, the methods and uses described herein, such as, for example, methods or uses in treating a solid cancer or hematological malignancy in a patient in need thereof, are accomplished by administering (e.g., orally or intravenously) a therapeutically effective amount of an MDM2 degrading agent (e.g., Compound A, B, C, D or E), for example, up to 100 mg of an MDM2 degrading agent, in a single dosage unit or in multiple dosage units. In some embodiments, the methods include administering about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, The dosage form may include a single dosage unit or multiple dosage units ranging from about 1 to about 100 mg per dosage form, such as about 1 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, or about 100 mg, administered (e.g., orally or intravenously). For example, an enteric coated tablet or liquid formulation may include 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg per dosage form of an MDM2 degrader (e.g., Compound A, B, C, D, or E) or a pharma- ceutically acceptable salt thereof.

[0057] In some embodiments, the MDM2 degrading agent (e.g., Compound A, B, C, D, or E) or a pharma- ceutically acceptable salt thereof is administered intravenously to a patient at a dose of up to 5 mg. In some embodiments, the MDM2 degrading agent (e.g., Compound A, B, C, D, or E) or a pharma- ceutically acceptable salt thereof is administered intravenously to a patient at a dose of up to 10 mg. In some embodiments, the MDM2 degrading agent (e.g., Compound A, B, C, D, or E) or a pharma- ceutically acceptable salt thereof is administered intravenously to a patient at a dose of up to 15 mg. In some embodiments, the MDM2 degrading agent (e.g., Compound A, B, C, D, or E) or a pharma- ceutically acceptable salt thereof is administered intravenously to a patient at a dose of up to 20 mg. In some embodiments, the MDM2 degrading agent (e.g., Compound A, B, C, D, or E) or a pharma- ceutically acceptable salt thereof is administered intravenously to a patient at a dose of up to 25 mg. In some embodiments, the MDM2 degrading agent (e.g., Compound A, B, C, D, or E) or a pharma- ceutically acceptable salt thereof is administered intravenously to a patient at a dose of up to 30 mg. In some embodiments, the MDM2 degrading agent (e.g., Compound A, B, C, D, or E) or a pharma- ceutically acceptable salt thereof is administered intravenously to a patient at a dose of up to 35 mg. In some embodiments, the MDM2 degrading agent (e.g., Compound A, B, C, D, or E) or a pharma- ceutically acceptable salt thereof is administered intravenously to a patient at a dose of up to 40 mg. In some embodiments, the MDM2 degrading agent (e.g., Compound A, B, C, D, or E) or a pharma- ceutically acceptable salt thereof is administered intravenously to a patient at a dose of up to 45 mg. In some embodiments, the MDM2 degrading agent (e.g., Compound A, B, C, D, or E) or a pharma- ceutically acceptable salt thereof is administered intravenously to a patient at a dose of up to 50 mg. In some embodiments, the MDM2 degrading agent (e.g., Compound A, B, C, D, or E) or a pharma- ceutically acceptable salt thereof is administered intravenously to a patient at a dose of about 10 mg to about 40 mg. In some embodiments, the MDM2 degrading agent (e.g., Compound A, B, C, D, or E) or a pharma- ceutically acceptable salt thereof is administered intravenously to a patient at a dose of about 20 mg to about 50 mg, e.g., about 30 mg, 35 mg, or 40 mg.In some embodiments, the MDM2 degrading agent (eg, compound A, B, C, D or E) or a pharma- ceutically acceptable salt thereof is administered intravenously to a patient at a dose of about 35 mg.

[0058] In some embodiments, pharmaceutical compositions are provided that include 5 mg to about 50 mg of an MDM2 degrading agent (e.g., Compound A, B, C, D, or E) or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients or carriers. In some embodiments, pharmaceutical compositions are provided that include 25 mg to about 45 mg of an MDM2 degrading agent (e.g., Compound A, B, C, D, or E) or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients or carriers.

[0059] In some embodiments, the MDM2 degrading agent (e.g., Compound A, B, C, D, or E) or a pharma- ceutically acceptable salt thereof, or pharmaceutical composition thereof is administered to mice at a dose of up to about 10 mg / kg for intravenous administration. Thus, in some embodiments, the MDM2 degrading agent (e.g., Compound A, B, C, D, or E) or a pharma- ceutically acceptable salt thereof, or pharmaceutical composition thereof is administered to mice at a dose of up to about 30 mg / m 2 In some embodiments, the MDM2 degrading agent (e.g., compound A, B, C, D, or E) or a pharma- ceutically acceptable salt thereof, or pharmaceutical composition thereof, is administered intravenously to a patient at a dose of up to about 25 mg / m 2 , or up to about 20 mg / m 2 , or up to about 15 mg / m 2 In some embodiments, the MDM2 degrading agent (e.g., compound A, B, C, D, or E) or a pharma- ceutically acceptable salt thereof, or pharmaceutical composition thereof, is administered intravenously to a patient at a dose of about 1 mg / m 2 ~about 5mg / m 2 , or about 3 mg / m 2 ~about 8mg / m 2 , or about 5 mg / m 2 ~about 10mg / m 2 , or about 7 mg / m 2 ~about 12mg / m 2 , or about 10 mg / m2 ~about 15mg / m 2 , or about 12 mg / m 2 ~about 7mg / m 2 , or about 15 mg / m 2 ~about 20mg / m 2 , or about 17 mg / m 2 ~about 22mg / m 2 , or about 20 mg / m 2 ~about 25mg / m 2 , or about 22 mg / m 2 ~about 27mg / m 2 In some embodiments, the MDM2 degrading agent (e.g., compound A, B, C, D, or E) or a pharma- ceutically acceptable salt thereof, or pharmaceutical composition thereof, is administered intravenously to a patient at a dose of about 30 mg / m 2 , about 27mg / m 2 , about 20mg / m 2 , about 17mg / m 2 , about 15mg / m 2 , about 12mg / m 2 , about 10mg / m 2 , about 7mg / m 2 , about 5mg / m 2 , about 3mg / m 2 , or about 1 mg / m 2 is administered intravenously to the patient at a dose of

[0060] In some embodiments, the MDM2 degrading agent (e.g., Compound A, B, C, D, or E) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered to the mouse at a dose of up to about 10 mg / kg for intravenous administration. Thus, in some embodiments, the MDM2 degrading agent (e.g., Compound A, B, C, D, or E) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof is orally administered to the patient at a dose of up to about 0.8 mg / kg. In some embodiments, the MDM2 degrading agent (e.g., Compound A, B, C, D, or E) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof is orally administered to the patient at a dose of up to about 0.6 mg / kg, or up to about 0.3 mg / kg, or up to about 0.1 mg / kg. In some embodiments, the MDM2 degrader (e.g., compound A, B, C, D, or E) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, is orally administered to a patient at a dose of about 0.01 mg / kg to about 0.05 mg / kg, or about 0.03 mg / kg to about 0.08 mg / kg, or about 0.05 mg / kg to about 0.1 mg / kg, or about 0.07 mg / kg to about 0.12 mg / kg, or about 0.1 mg / kg to about 0.15 mg / kg, or about 0.12 mg / kg to about 0.17 mg / kg. In some embodiments, the MDM2 degrading agent (e.g., compound A, B, C, D or E) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, is orally administered to a patient at a dose of about 1 mg / kg, about 0.8 mg / kg, about 0.5 mg / kg, about 0.3 mg / kg, about 0.1 mg / kg, about 0.08 mg / kg, or about 0.06 mg / kg.

[0061] Dosing schedule As provided in view of the preclinical data described herein, the MDM2 degrading agent (e.g., Compound A, B, C, D, or E) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered to a patient at an appropriate dosing schedule to provide the desired tumor reductive effect with minimal side effects. In some embodiments, the MDM2 degrading agent (e.g., Compound A, B, C, D, or E) or a pharmaceutical composition thereof is administered to a patient once every 1, 2, 3, 4, 5, 6, 7, 14, or 21 days. In some embodiments, the MDM2 degrading agent (e.g., Compound A, B, C, D, or E) or a pharmaceutical composition thereof is administered to a patient daily (QD). In some embodiments, the MDM2 degrading agent (e.g., Compound A, B, C, D, or E) or a pharmaceutical composition thereof is administered to a patient twice weekly (BW). In some embodiments, the MDM2 degrading agent (e.g., Compound A, B, C, D, or E) or a pharmaceutical composition thereof is administered to a patient weekly (QW). In some embodiments, the MDM2 degrading agent (e.g., Compound A, B, C, D, or E) or a pharmaceutical composition thereof is administered to a patient every two weeks (Q2W). In some embodiments, the MDM2 degrading agent (e.g., Compound A, B, C, D, or E) or a pharmaceutical composition thereof is administered to a patient every three weeks (Q3W).

[0062] In some embodiments, the IV infusion of the pharmaceutical composition of the present invention lasts for about 5-30 minutes. In some embodiments, the IV infusion of the pharmaceutical composition of the present invention lasts for about 30-90 minutes. In some embodiments, the IV infusion of the pharmaceutical composition of the present invention lasts for about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 minutes. In some embodiments, the IV infusion of the pharmaceutical composition of the present invention lasts for about 2, 2.5, 3, 3.5, or 4 hours.

[0063] In some embodiments, the pharmaceutical compositions of the present invention have a dosage of about 0.1 mg / m 2 ~about 30mg / m 2 In some embodiments, the pharmaceutical compositions of the present invention are administered intravenously at a dose of about 1 mg / m 2 ~about 10mg / m2 is administered weekly at a dose of

[0064] Formulation of pharmaceutical compositions Administration of the MDM2 degrading agents of the invention may be by any suitable means that results in a concentration of drug that, in combination with other components, can improve the patient's condition (e.g., solid cancer or hematological malignancy).

[0065] While it is possible for the active ingredients of the combination to be administered as pure chemicals, it is preferable to present them as pharmaceutical compositions, also referred to in this context as pharmaceutical formulations. Possible compositions include those suitable for oral, rectal, topical (including transdermal, buccal and sublingual) or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.

[0066] More commonly, these pharmaceutical formulations are prescribed to patients in a "patient pack" that contains a number of dosage units for use during separate treatment periods, usually in a blister pack, or other means for administering metered unit doses. Patient packs have the advantage over conventional prescriptions, in which a pharmacist divides a patient's supply of medicine from a bulk supply, in that the patient always has access to the package insert contained in the patient pack, which is usually lacking in conventional prescriptions. The inclusion of a package insert has been shown to improve patient compliance with the physician's instructions. Thus, the present invention further includes a pharmaceutical formulation, as previously described herein, in combination with a suitable packaging material for said formulation. In such patient packs, the intended use of the formulation for combination treatment can be inferred by instructions, facilities, provision, indications and / or other means that aid in the most appropriate use of the formulation for treatment. Such means make the patient pack particularly suitable and adapted for use in treatment with the combination of the present invention.

[0067] The drug may be contained in any suitable amount in any suitable carrier material and may be present in an amount of 1-99% by weight of the total weight of the composition. The composition may be provided in a dosage form suitable for oral, parenteral (e.g., intravenous, intramuscular), rectal, dermal, nasal, vaginal, inhalant, dermal (patch) or ocular administration routes. Thus, the composition may be in the form of, for example, a tablet, capsule, pill, powder, granule, suspension, emulsion, solution, gel including hydrogel, paste, ointment, cream, plaster, drench, osmotic delivery device, suppository, enema, injection, implant, spray or aerosol.

[0068] Pharmaceutical compositions may be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy (20th ed.), ed. A. R. Gennaro, Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York).

[0069] Pharmaceutical compositions according to the present invention may be formulated to release the active drug substantially immediately upon administration, or at any predetermined time or period after administration.

[0070] Controlled release formulations include: (i) formulations that produce a substantially constant concentration of drug in the body over an extended period of time; (ii) formulations that produce a substantially constant concentration of drug in the body over an extended period of time after a predetermined lag time; (iii) formulations that maintain drug action over a predetermined period of time by maintaining a relatively constant effective drug level in the body while simultaneously minimizing undesirable side effects associated with fluctuations in the plasma levels of the active drug substance; (iv) formulations that localize drug action, for example, by spatially placing a controlled release composition adjacent to or within an affected tissue or organ; and (v) formulations that target drug action by using carriers or chemical derivatives to deliver the drug to a specific target cell type.

[0071] Administration of drugs in the form of controlled release formulations is beneficial because the combined drugs (i) have a narrow therapeutic index (i.e., the difference between the plasma concentration that produces adverse side effects or toxic reactions and the plasma concentration that produces the therapeutic effect is small; in general, the therapeutic index, TI, is the median lethal dose (LD 50 ) versus median effective dose (ED 50 ) ratio); (ii) a narrow absorption window in the gastrointestinal tract; or (iii) a very short biological half-life such that frequent dosing throughout the day is required to maintain plasma levels at therapeutic levels.

[0072] In order to obtain controlled release, in which the release rate exceeds the metabolism rate of the drug in question, any of several strategies can be pursued.Controlled release can be obtained by appropriate selection of various formulation parameters and ingredients, including, for example, various types of controlled release compositions and coatings.Therefore, the drug is formulated with suitable additives into a pharmaceutical composition that releases the drug in a controlled manner when administered (single or multiple unit tablet or capsule composition, oil solution, suspension, emulsion, microcapsule, microsphere, nanoparticle, patch, and liposome).

[0073] Parenteral Compositions The pharmaceutical compositions can also be administered parenterally by injection, infusion or implantation (intravenous, intramuscular, subcutaneous, etc.) in dosage forms, formulations containing conventional non-toxic pharma- ceutically acceptable carriers and adjuvants, or via suitable delivery devices or implants. The formulation and preparation of such compositions are well known to those skilled in the art of pharmaceutical formulations.

[0074] Compositions for parenteral use can be provided in unit dosage form (e.g., in single dose ampoules) or in vials that contain several doses and can add suitable preservatives (see below).Typically, such compositions can be prepared as injectable preparations, for example, solution or suspension; solid forms that are suitable for use in preparing solution or suspension by adding reconstitution medium before injection; emulsions, such as water-in-oil (w / o) emulsions, oil-in-water (o / w) emulsions, and their microemulsions, liposomes, or emulsomes.

[0075] The components of the composition can be mixed separately or together in unit dosage form, for example, as a dry lyophilized powder (which can be reconstituted before use in a carrier such as saline) or a concentrated solution in a sealed container such as an ampoule or sachet indicating the amount of active agent.When the composition is administered by injection, the composition can be dispensed in an infusion bottle containing sterile pharmaceutical grade water or saline.When the composition is administered by injection, an ampoule of sterile water or saline can be provided so that the components can be mixed before injection.

[0076] The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, one or more polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), oils such as vegetable oils (e.g., peanut oil, corn oil, sesame oil, and the like), and combinations thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and / or by the use of surfactants. In many cases, it is preferable to include an isotonic agent, for example, sugar or sodium chloride.

[0077] Solutions and dispersions of the active compounds as a free acid or free base or a pharmacologically acceptable salt thereof can be prepared in water or another solvent or dispersion medium suitably mixed with one or more pharma- ceutically acceptable additives including, but not limited to, buffers, surfactants, dispersing agents, emulsifying agents, viscosity modifiers, and combinations thereof.

[0078] Suitable surfactants can be anionic, cationic, amphoteric or nonionic surface active agents. Suitable anionic surfactants include, but are not limited to, those containing carboxylate, sulfonate and sulfate ions. Examples of anionic surfactants include sodium, potassium, ammonium long chain alkyl sulfonates and alkylaryl sulfonates such as sodium dodecylbenzene sulfonate; sodium dialkyl sulfosuccinates, such as sodium dodecylbenzene sulfonate; sodium dialkyl sulfosuccinates, such as sodium bis-(2-ethylthiol)-sulfosuccinate; and alkyl sulfates, such as sodium lauryl sulfate. Cationic surfactants include, but are not limited to, quaternary ammonium compounds, such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene and coconut amine. Examples of nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acylate, sucrose acylate, PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbate, polyoxyethylene octylphenyl ether, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, Poloxamer® 401, stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallow amide. Examples of amphoteric surfactants include sodium N-dodecyl-beta, -alanine, sodium N-lauryl β-iminodipropionate, myristamphoacetate, lauryl betaine, and lauryl sulfobetaine. The formulation may contain a preservative to prevent the growth of microorganisms. Suitable preservatives include, but are not limited to, parabens, chlorobutanol, phenol, sorbic acid, and thimerosal. The formulation may also contain an antioxidant to prevent the degradation of the active agent.

[0079] In some embodiments, parenteral compositions (e.g., for intravenous administration) are packaged in a solution comprising a sterile isotonic aqueous buffer. In some embodiments, the parenteral composition is buffered to a pH of 3-8 for parenteral administration upon reconstitution. Suitable buffers include, but are not limited to, phosphate buffers, acetate buffers, and citrate buffers.

[0080] In some embodiments, the buffering agent is in an amount to adjust the pH of the pharmaceutical composition of the invention to about 3 to 8. In some embodiments, the buffering agent is added in an amount of about 0.1 to 5 mg per mg of the MDM2 degrading agent (e.g., compound A, B, C, D or E) or a pharma- ceutically acceptable equivalent thereof.

[0081] In some embodiments, the liquid pharmaceutical composition of the present invention has a pH of about 3-8.

[0082] Water soluble polymers are often used in formulations for parenteral administration. Suitable water soluble polymers include, but are not limited to, polyvinylpyrrolidone, dextran, carboxymethylcellulose, and polyethylene glycol.

[0083] In some embodiments, the parenteral composition may include a solubilizing agent. In some embodiments, the solubilizing agent is a cyclodextrin. Cyclodextrins include members of a family of cyclic oligosaccharides composed of five or more α-D-glucopyranoside units linked between the 1- and 4-positions, as is known for amylose, a fragment of starch. In some embodiments, the cyclodextrin is an α-cyclodextrin, a β-cyclodextrin, and / or a γ-cyclodextrin. In certain embodiments, the cyclodextrin is a β-cyclodextrin, such as hydroxypropyl-β-cyclodextrin (HP-β-CD). In some embodiments, the incorporation of a β-cyclodextrin (e.g., HPβCD) in the intravenous composition of the present invention improves the dissolution of the MDM2 degrading agent (e.g., compound A, B, C, D, or E) to provide a clear, homogenous solution for injection. In some embodiments, the amount of cyclodextrin (e.g., HPβCD) added to parenteral compositions of the invention (e.g., for intravenous administration) may comprise from about 1% to about 50% w / w or w / v, such as about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, or 49% w / w or w / v. In certain embodiments, the amount of cyclodextrin (eg, HPβCD) is about 20% w / w or w / v.

[0084] In some embodiments, the MDM2 degrading agent (e.g., compound A, B, C, D, or E) or a pharma- ceutically acceptable salt thereof is at a concentration of about 0.01 to about 0.5 mg / mL, e.g., about 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.40, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.50, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.60, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.70, 0.71, 0.72, 0.73, 0.74, 0.7 In certain embodiments, the MDM2 degrading agent (e.g., compound A, B, C, D, or E) or a pharma- ceutically acceptable salt thereof is added to the parenteral composition of the invention (e.g., for intravenous administration) in an amount of up to about 0.1 mg / mL.

[0085] The sterile injectable solution of the present invention can be prepared by incorporating the required amount of active compound into a suitable solvent or dispersion medium, optionally with one or more of the additives listed above, followed by sterilization by filtration.Generally, dispersion is prepared by incorporating various sterilized active ingredients into a sterile vehicle containing a basic dispersion medium and other necessary ingredients from those listed above.In the case of sterile powder for preparing sterile injectable solution, the preferred preparation method is vacuum drying and freeze-drying technology, which obtains a powder of active ingredient and any additional desired ingredient from its solution that has been previously sterilized and filtered.Powder can be prepared so that the particles are inherently porous, which can increase the dissolution of the particles.The method of producing porous particles is well known in the art.

[0086] In some embodiments, the parenteral formulations described herein can be formulated for controlled release, including immediate release, delayed release, extended release, pulsatile release, and combinations thereof.

[0087] In some embodiments, the present invention provides liquid pharmaceutical compositions prepared by dissolving a solid pharmaceutical composition of the present invention in water. In some embodiments, the present invention provides liquid pharmaceutical compositions prepared by dissolving a solid pharmaceutical composition of the present invention in an injectable medium (e.g., saline or 5% dextrose). In some embodiments, the present invention provides liquid pharmaceutical compositions prepared by reconstituting a solid pharmaceutical composition of the present invention in water, followed by dilution with saline or 5% dextrose. In some embodiments, the liquid pharmaceutical composition is diluted into a saline or 5% dextrose IV bag for IV administration. In some embodiments, the liquid pharmaceutical composition in the saline or 5% dextrose IV bag is stored at room temperature (about 20-25° C.) for up to about 4 hours prior to IV administration. In some embodiments, the liquid pharmaceutical composition in the saline or 5% dextrose IV bag is stored under refrigerated (about 2-8° C.) conditions for up to about 20 hours prior to IV administration. In some embodiments, the liquid pharmaceutical composition in saline or 5% dextrose IV bags is stored under refrigerated (about 2-8° C.) conditions for up to about 20 hours, followed by storage at room temperature (about 20-25° C.) for up to about 4 hours prior to IV administration.

[0088] Uses of the Compounds and Pharmaceutically Acceptable Compositions The compounds and compositions described herein are generally useful for degrading and / or inhibiting MDM2 protein activity.

[0089] In some embodiments, the present invention provides MDM2 degraders that regulate targeted ubiquitination and degradation of MDM2 protein. The compounds provided are degraders and / or inhibitors of MDM2 protein and are therefore useful for treating one or more disorders associated with the activity of MDM2 protein. Thus, in certain embodiments, the present invention provides a method for treating a disorder mediated by MDM2, comprising administering a compound of the present invention or a pharma- ceutically acceptable composition thereof to a patient in need thereof.

[0090] As used herein, the term "MDM2-mediated" disorder, disease, and / or condition means any disease or other deleterious condition in which the MDM2 protein or a variant thereof is known to play a role. Accordingly, another embodiment of the present invention relates to treating or reducing the severity of one or more diseases in which the MDM2 protein or a variant thereof is known to play a role.

[0091] In some embodiments, the invention provides methods of treating one or more disorders, diseases and / or conditions, wherein the disorder, disease or condition is cancer, a neurodegenerative disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a genetic disorder, a hormone-related disease, a metabolic disorder, a condition associated with organ transplantation, an immunodeficiency disorder, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, a liver disease, a pathological immune condition involving T cell activation, a cardiovascular disorder, or a CNS disorder.

[0092] In some embodiments, the cancer is selected from the group consisting of adrenal gland cancer, lobular carcinoma, acoustic neuroma, acral lentigo melanoma, acral hidradenoma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenoid odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasms, adrenal cortical carcinoma, adult T-cell leukemia / lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastic fibroma ameloblastic fibroma, anaplastic large cell lymphoma, anaplastic thyroid carcinoma, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, astrocytoma, rhabdoid tumor (e.g., atypical teratoid rhabdoid tumor), B-cell Chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, B-cell lymphoma, basal cell carcinoma, cholangiocarcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, myelofibrosis, Brenner's tumor, Brown's tumor, Burkitt's lymphoma, breast cancer, brain cancer, carcinoma, intraepithelial carcinoma, carcinosarcoma, cartilage tumor, cementoma, myelosarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus papilloma, clear cell sarcoma of the kidney, craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer, colorectal cancer, Dego's disease, desmoplastic small round cell tumor, diffuse large B-cell lymphoma, dysembryoplastic neuroepithelial tumor neuroepithelial tumor, dysgerminoma, embryonal carcinoma, endocrine neoplasm, endodermal sinus tumor, enteropathy-associated T-cell lymphoma, esophageal cancer, fetal in utero, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, gangliocytoma, gastrointestinal cancer, germ cell tumor, gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumor of bone, glial tumor, glioblastoma multiforme, glioma, gliomatosis cerebri, glucagonoma, gonadoblastoma, granulosa cell tumor, hemispheric ovarian tumor, gallbladder cancer, gastric cancer, hairy cell leukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma, hematologic malignancies, hepatoblastoma, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna, lethal midline carcinomacarcinoma), leukemia, Leydig cell tumor, liposarcoma, lung cancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non-small cell lung cancer, MALT lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, malignant triton tumor tumor), mantle cell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, medullary breast carcinoma, medullary thyroid carcinoma, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma, mesothelioma, metastatic urothelial carcinoma, mixed Müllerian tumor, mucinous tumor, multiple myeloma, muscle tissue neoplasm, mycosis fungoides, myxoid liposarcoma, myxoma, myxosarcoma, nasopharyngeal carcinoma, schwannoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, ocular cancer, oligoastrocytoma, oligodendroglioma, oncocytoma, optic nerve sheath meningioma, optic nerve tumor, oral cancer, osteosarcoma, ovarian cancer, Pancoast tumor, papillary thyroid cancer, paraganglioma, pineoblastoma, pineocytoma, pituitary cell tumor, pituitary adenoma, pituitary tumor, plasmacytoma polyembryoma, precursor T-lymphoblastic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, primary peritoneal cancer, prostate cancer, pancreatic cancer, pharyngeal cancer, peritoneal pseudomyxoma, renal cell carcinoma, medullary renal carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter's transformation, rectal cancer, sarcoma, Ewing's sarcoma, schwannoma, seminoma, Sertoli cell tumor, sex cord-gonadal stromal tumor, signet ring cell carcinoma, skin cancer, Merkel cell carcinoma, small blue round cell tumor, small cell carcinoma, soft tissue sarcoma, somatostatinoma, smoky wart, spinal tumor, splenic marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma, Sezary's disease, small intestine cancer, squamous cell carcinoma, gastric cancer, T-cell lymphoma, testicular cancer, thecoma thyroid cancer cancer), transitional cell carcinoma, pharyngeal cancer, urachal cancer, genitourinary cancer, urothelial carcinoma, uveal melanoma, uterine cancer, verrucous carcinoma, visual pathway GH-producing pituitary adenoma, vulvar cancer, vaginal cancer, Waldenstrom's macroglobulinemia, Warthin's tumor, and Wilms' tumor.

[0093] MDM2 hyperactivity can inhibit wild-type p53 function due to the amplification / overexpression or mutational inactivation of ARF locus, leading to the development of a wide variety of cancers.In some embodiments, the MDM2 hyperactivity that can be treated according to the method of the present invention is human cancer.In some embodiments, the human cancer that can be treated according to the method of the present invention is selected from solid cancer or hematological malignancy.In some embodiments, the wild-type p53 cancer is mesothelioma, melanoma, DLBCL, prostate cancer, cholangiocarcinoma, cervical cancer, AML, renal cell carcinoma, uveal melanoma, thyroid cancer, liposarcoma, HCC, or breast cancer.

[0094] In some embodiments, solid cancers include solid tumors that have abnormal tissue masses that may not contain cysts or liquid areas. Solid tumors can be benign or malignant. In some embodiments, examples of solid tumors include sarcomas, carcinomas, and lymphomas. In some embodiments, the solid cancer is carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumor, ovary, colon, rectum, prostate, pancreas, lung, vagina, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastoma, neuroblastoma, gastrointestinal cancer such as colon cancer or colorectal adenoma, neck and head tumor, epidermal hyperproliferation, prostatic hyperplasia, neoplasm, epithelial neoplasm, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer such as Hodgkin and non-Hodgkin, breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, IL-1-driven disorder, MyD88-driven disorder, or smoldering indolent multiple myeloma. In some embodiments, the solid tumor is refractory (e.g., treatment-resistant). In some embodiments, the hematological malignancy is a cancer affecting the blood, bone marrow and lymph nodes. In some embodiments, hematological malignancies include leukemias, lymphomas, and myelomas, such as acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), large granular lymphocytic leukemia (LGL-L), B-cell prolymphocytic leukemia, acute myeloid leukemia (AML), Burkitt's lymphoma / leukemia, primary effusion lymphoma, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), diffuse large B-cell lymphoma (DLBCL), aggressive B-cell diffuse large B-cell lymphoma (ABC DLBCL), intravascular large B-cell lymphoma, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, uveal melanoma, or myelodysplastic syndromes (MDS). In some embodiments, the hematological malignancy is refractory (eg, resistant to treatment).

[0095] In some embodiments, the AML is caused by a mutation or fusion of a protein (e.g., KMT2A or MLL). In some embodiments, the AML is a mutant or fusion protein AML, such as IDH1, DNMT3A, NPM1, ASXL1, FLT3-ITD, KMT2A-MLLT3, MLL-MLLT3, or MLL-AF9.

[0096] In some embodiments, the present disclosure provides methods of treating benign proliferative disorders, including, but not limited to, benign soft tissue tumors, bone tumors, brain and spinal cord tumors, eyelid and orbital tumors, granulomas, lipomas, meningiomas, multiple endocrine neoplasms, nasal polyps, pituitary tumors, prolactinomas, pseudotumor cerebri, seborrheic keratosis, gastric polyps, thyroid nodules, pancreatic cystic neoplasms, hemangiomas, vocal cord nodules, polyps and cysts, Castleman's disease, chronic pilonidal disease, dermatofibroma, sebaceous cyst, pyogenic granuloma, and juvenile polyposis syndrome.

[0097] In some embodiments, the cancer is a leukemia, such as a leukemia selected from acute monocytic leukemia, acute myeloid leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia (MLL). In another embodiment, the cancer is a NUT midline carcinoma. In another embodiment, the cancer is multiple myeloma. In another embodiment, the cancer is lung cancer, such as small cell lung cancer (SCLC). In another embodiment, the cancer is neuroblastoma. In another embodiment, the cancer is Burkitt's lymphoma. In another embodiment, the cancer is cervical cancer. In another embodiment, the cancer is esophageal cancer. In another embodiment, the cancer is ovarian cancer. In another embodiment, the cancer is colorectal cancer. In another embodiment, the cancer is prostate cancer. In another embodiment, the cancer is breast cancer.

[0098] In some embodiments, the present invention provides a method of treating triple-negative breast cancer in a patient in need of such treatment, comprising administering an MDM2 degrading agent of the present invention (e.g., compound A, B, C, D or E) or a pharma- ceutically acceptable salt thereof.

[0099] In some embodiments, the present invention provides a method of treating acute lymphoblastic leukemia (ALL), comprising administering an MDM2 degrading agent of the present invention (e.g., compound A, B, C, D or E) or a pharma- ceutically acceptable salt thereof.

[0100] In some embodiments, the present invention provides a method of treating chronic lymphocytic leukemia (CLL), comprising administering an MDM2 degrading agent of the present invention (e.g., compound A, B, C, D or E) or a pharma- ceutically acceptable salt thereof.

[0101] In some embodiments, the present invention provides a method of treating large granular lymphocytic leukemia (LGL-L), comprising administering an MDM2 degrading agent of the present invention (e.g., compound A, B, C, D or E) or a pharma- ceutically acceptable salt thereof.

[0102] In some embodiments, the present invention provides a method of treating B-cell prolymphocytic leukemia comprising administering an MDM2 degrading agent of the present invention (e.g., compound A, B, C, D or E) or a pharma- ceutically acceptable salt thereof.

[0103] In some embodiments, the present invention provides a method of treating acute myeloid leukemia (AML), comprising administering an MDM2 degrading agent of the present invention (e.g., compound A, B, C, D or E) or a pharma- ceutically acceptable salt thereof.

[0104] In some embodiments, the present invention provides a method of treating Burkitt's lymphoma / leukemia comprising administering an MDM2 degrading agent of the present invention (e.g., compound A, B, C, D or E) or a pharma- ceutically acceptable salt thereof.

[0105] In some embodiments, the present invention provides a method of treating primary effusion lymphoma, comprising administering an MDM2 degrading agent of the present invention (e.g., compound A, B, C, D or E) or a pharma- ceutically acceptable salt thereof.

[0106] In some embodiments, the present invention provides a method of treating peripheral T-cell lymphoma (PTCL), comprising administering an MDM2 degrading agent of the present invention (e.g., compound A, B, C, D or E) or a pharma- ceutically acceptable salt thereof.

[0107] In some embodiments, the present invention provides a method of treating cutaneous T-cell lymphoma (CTCL), comprising administering an MDM2 degrading agent of the present invention (e.g., compound A, B, C, D or E) or a pharma- ceutically acceptable salt thereof.

[0108] In some embodiments, the present invention provides a method of treating diffuse large B-cell lymphoma (DLBCL), comprising administering an MDM2 degrading agent of the present invention (e.g., compound A, B, C, D or E) or a pharma- ceutically acceptable salt thereof.

[0109] In some embodiments, the present invention provides a method of treating aggressive B-cell diffuse large B-cell lymphoma (ABC DLBCL), comprising administering an MDM2 degrading agent of the present invention (e.g., compound A, B, C, D or E) or a pharma- ceutically acceptable salt thereof.

[0110] In some embodiments, the present invention provides a method of treating intravascular large B-cell lymphoma, comprising administering an MDM2 degrading agent of the present invention (e.g., compound A, B, C, D or E) or a pharma- ceutically acceptable salt thereof.

[0111] In some embodiments, the present invention provides a method of treating lymphoplasmacytic lymphoma comprising administering an MDM2 degrading agent of the present invention (e.g., compound A, B, C, D or E) or a pharma- ceutically acceptable salt thereof.

[0112] In some embodiments, the present invention provides a method of treating Waldenstrom's Macroglobulinemia (WM), comprising administering an MDM2 degrading agent of the present invention (e.g., compound A, B, C, D or E) or a pharma- ceutically acceptable salt thereof.

[0113] In some embodiments, the present invention provides a method of treating splenic marginal zone lymphoma comprising administering an MDM2 degrading agent of the present invention (e.g., compound A, B, C, D or E) or a pharma- ceutically acceptable salt thereof.

[0114] In some embodiments, the present invention provides a method of treating multiple myeloma comprising administering an MDM2 degrading agent of the present invention (e.g., compound A, B, C, D or E) or a pharma- ceutically acceptable salt thereof.

[0115] In some embodiments, the present invention provides a method of treating plasmacytoma comprising administering an MDM2 degrading agent of the present invention (e.g., compound A, B, C, D or E) or a pharma- ceutically acceptable salt thereof.

[0116] In some embodiments, the present invention provides a method of treating myelodysplastic syndrome (MDS), comprising administering an MDM2 degrading agent of the present invention (e.g., compound A, B, C, D or E) or a pharma- ceutically acceptable salt thereof.

[0117] In some embodiments, the present invention provides a method of treating malignant peripheral nerve sheath tumor (MPNST) in a patient in need of such treatment, comprising administering an MDM2 degrading agent of the present invention (e.g., compound A, B, C, D or E) or a pharma- ceutically acceptable salt thereof.

[0118] In some embodiments, the present invention provides a method of treating pancreatic cancer in a patient in need of such treatment, comprising administering an MDM2 degrading agent of the present invention (e.g., compound A, B, C, D or E) or a pharma- ceutically acceptable salt thereof.

[0119] In some embodiments, the present invention provides a method of treating primary CNS lymphoma in a patient in need of such treatment, comprising administering an MDM2 degrading agent of the present invention (e.g., compound A, B, C, D or E) or a pharma- ceutically acceptable salt thereof.

[0120] In some embodiments, the present invention provides a method of treating Hodgkin's lymphoma in a patient in need of such treatment, comprising administering an MDM2 degrading agent of the present invention (e.g., compound A, B, C, D or E) or a pharma- ceutically acceptable salt thereof.

[0121] In some embodiments, the present invention provides a method of treating primary cutaneous T-cell lymphoma in a patient in need of such treatment, comprising administering an MDM2 degrading agent of the present invention (e.g., compound A, B, C, D or E) or a pharma- ceutically acceptable salt thereof.

[0122] In some embodiments, the present invention provides a method of treating solid and liquid tumors in a patient in need thereof comprising administering an MDM2 degrading agent of the present invention (e.g., compound A, B, C, D or E) or a pharma- ceutically acceptable salt thereof.

[0123] In some embodiments, the present invention provides a method of treating MYD88 mutant Waldenstrom's macroglobulinemia in a patient in need of such treatment, comprising administering an MDM2 degrading agent of the present invention (e.g., compound A, B, C, D, or E) or a pharma- ceutically acceptable salt thereof.

[0124] In some embodiments, the present invention provides a method of treating NSCLC in a patient in need of such treatment, comprising administering an MDM2 degrading agent of the present invention (e.g., compound A, B, C, D or E) or a pharma- ceutically acceptable salt thereof.

[0125] In some embodiments, the present invention provides a method of treating uveal melanoma in a patient in need of such treatment, comprising administering an MDM2 degrading agent of the present invention (e.g., compound A, B, C, D or E) or a pharma- ceutically acceptable salt thereof.

[0126] In some embodiments, the present invention provides a method of treating Ewing's sarcoma in a patient in need of such treatment, comprising administering an MDM2 degrading agent of the present invention (e.g., compound A, B, C, D or E) or a pharma- ceutically acceptable salt thereof.

[0127] In some embodiments, the present invention provides a method of inhibiting the growth of refractory (e.g., treatment-resistant) tumors, comprising administering an MDM2 degrading agent of the present invention (e.g., Compound A, B, C, D, or E) or a pharma- ceutically acceptable salt thereof. In some embodiments, the present invention provides a method of treating refractory cancer, comprising administering an MDM2 degrading agent of the present invention (e.g., Compound A, B, C, D, or E) or a pharma-ceutically acceptable salt thereof. In some embodiments, refractory tumors include tumors that fail or are resistant to treatment with chemotherapy alone, radiation alone, or a combination thereof. Cancers may become resistant at the start of treatment or may become resistant during treatment. Refractory tumors result in rapid disease progression and usually have a poor prognosis. Examples of refractory tumors include carcinomas, gliomas, sarcomas, adenocarcinomas, adenosarcomas, and adenomas. Such tumors occur in virtually any part of the human body, including any organ. Tumors can be present, for example, in the breast, heart, lung, small intestine, colon, spleen, kidney, bladder, head and neck, ovaries, prostate, brain, pancreas, skin, bone, bone marrow, blood, thymus, uterus, testes, cervix, and liver.

[0128] In some embodiments, the present invention provides methods for treating adult patients with solid cancers or hematological malignancies who have received one prior therapy.

[0129] In some embodiments, the invention provides methods for treating adult patients with solid cancer or hematological malignancies who have received two prior therapies.

[0130] In some embodiments, the invention provides methods for treating adult patients with solid cancer or hematological malignancies who have received three prior therapies.

[0131] In some embodiments, the present invention provides methods for treating adult patients with solid cancer or hematological malignancies who have received at least one prior therapy.

[0132] In some embodiments, the invention provides methods for treating adult patients with solid cancer or hematological malignancies who have received at least two prior therapies.

[0133] In some embodiments, the invention provides methods for treating adult patients with solid cancer or hematological malignancies who have received at least three prior therapies.

[0134] In some embodiments, the invention provides methods of increasing one or more protein markers (e.g., GDF15, p53, p21 and PUMA) in a patient in need thereof comprising administering an MDM2 degrading agent of the invention (e.g., Compound A, B, C, D or E) or a pharma- ceutically acceptable salt thereof. In some embodiments, the methods of increasing one or more protein markers (e.g., GDF15, p53, p21 and PUMA) comprise treating a solid cancer or hematological malignancy in the patient.

[0135] Combination therapy Depending on the particular solid cancer or hematological malignancy being treated, additional therapeutic agents that are normally administered to treat that condition may be administered in combination with the compounds and compositions of the present invention. As used herein, additional therapeutic agents that are normally administered to treat a particular solid cancer or hematological malignancy are known as "appropriate for the disease or condition being treated."

[0136] In certain embodiments, the provided combinations, or compositions thereof, are administered in combination with another therapeutic agent.

[0137] In some embodiments, the present invention provides a method for treating the disclosed disease or condition, comprising administering to a patient in need thereof an effective amount of the compound disclosed herein or a pharma- ceutically acceptable salt thereof, and simultaneously or sequentially co-administering an effective amount of one or more additional therapeutic agents, such as those described herein. In some embodiments, the method comprises co-administering one additional therapeutic agent. In some embodiments, the method comprises co-administering two additional therapeutic agents. In some embodiments, the combination of the disclosed compound and additional therapeutic agent(s) acts synergistically.

[0138] Examples of agents with which the combinations of the present invention may be combined include, but are not limited to, anti-inflammatory agents, e.g., corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulators and immunosuppressants, such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine; neurotrophic factors, such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole, and anti-Parkinson's agents; beta blockers, ACE inhibitors, diuretics, nitrates, calcitonin, sero ... agents for treating cardiovascular disease, such as urinary channel blockers and statins; agents for treating liver disease, such as corticosteroids, cholestyramine, interferons and antivirals; agents for treating blood disorders, such as corticosteroids, anti-leukemia agents and growth factors; agents that prolong or improve pharmacokinetics, such as cytochrome P450 inhibitors (i.e., inhibitors of metabolic degradation) and CYP3A4 inhibitors (e.g., ketoconazole and ritonavir), and agents for treating immune deficiency disorders, such as gamma globulins.

[0139] In certain embodiments, the combination therapy of the invention, or a pharma- ceutically acceptable composition thereof, is administered in combination with a monoclonal antibody or siRNA therapeutic.

[0140] These additional agents may be administered as part of a multiple dose regimen, separate from the combination therapy provided. Alternatively, these agents may be part of a single dosage form, mixed together with the compounds of this invention as a single composition. When administered as part of a multiple dose regimen, the two active agents may be given simultaneously, sequentially, or within a period of each other, usually within 5 hours of each other.

[0141] As used herein, the terms "combination," "in combination," and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the invention. For example, the combination of the invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms, or together in a single unit dosage form.

[0142] The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the compositions of the present disclosure will range from about 50% to 100% of the amount that would normally be present in a composition comprising that agent as the only therapeutically active agent.

[0143] One or more other therapeutic agents may be administered separately from the compound or composition of the present invention as part of a multiple dose regimen. Alternatively, one or more other therapeutic agents may be part of a single dosage form mixed together with the compound of this invention in a single composition. When administered as a multiple dose regimen, one or more other therapeutic agents and the compound or composition of the present invention may be administered simultaneously, sequentially, or within a period of time from each other, for example, within 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 18 hours, 20 hours, 21 hours, 22 hours, 23 hours, or within 24 hours of each other. In some embodiments, one or more other therapeutic agents and the compound or composition of the present invention are administered as a multiple dose regimen, less than 24 hours apart.

[0144] In one embodiment, the present invention provides a composition comprising a provided MDM2 degrading agent or a pharma- ceutically acceptable salt thereof and one or more additional therapeutic agents. The therapeutic agents may be administered together with the provided MDM2 degrading agent or a pharma- ceutically acceptable salt thereof, or may be administered before or after administration of the provided MDM2 degrading agent or a pharma- ceutically acceptable salt thereof. Suitable therapeutic agents are described in further detail below. In certain embodiments, the provided MDM2 degrading agent or a pharma- ceutically acceptable salt thereof may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours or 18 hours before the therapeutic agent. In other embodiments, a provided MDM2 degrading agent or pharma- ceutically acceptable salt thereof may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours after the therapeutic agent.

[0145] In some embodiments, a provided MDM2 degrading agent or a pharma- ceutically acceptable salt thereof is administered to a patient at the doses and schedules provided herein, and the one or more additional therapeutic agents are administered to the patient once every 1, 2, 3, 4, 5, 6, 7, 14, or 21 days.

[0146] In some embodiments, the additional therapeutic agent administered in combination with the provided MDM2 degrading agent or pharma- ceutically acceptable salt thereof is a BCL-2 inhibitor (e.g., venetoclax) or MEK inhibitor (e.g., selumetinib) and is administered to the patient daily (QD). In some aspects, the BCL-2 inhibitor (e.g., venetoclax) or MEK inhibitor (e.g., selumetinib) is administered orally. In other aspects, the BCL-2 inhibitor (e.g., venetoclax) is administered at a dose of about 5 mg / kg to about 20 mg / kg (e.g., about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg). In other aspects, the MEK inhibitor (e.g., selumetinib) is administered at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 mg / kg, about 0.5 mg / kg, or about 1 mg / kg).

[0147] In another embodiment, the present invention provides a method of treating a solid tumor comprising administering to a patient in need thereof a provided MDM2 degrading agent or a pharma- ceutically acceptable salt thereof and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (hydrodaunorubicin®), vincristine (Oncovin®), prednisone, hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, SYK inhibitors, and combinations thereof.

[0148] In another embodiment, the present invention provides a method of treating diffuse large B-cell lymphoma (DLBCL), comprising administering to a patient in need thereof a provided MDM2 degrading agent or a pharma- ceutically acceptable salt thereof and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, and combinations thereof.

[0149] In some embodiments, the present invention provides methods of treating lymphoma comprising administering to a patient in need thereof a provided MDM2 degrading agent or a pharma- ceutical acceptable salt thereof and a CHOP (cyclophosphamide, hydrodaunorubicin®, Oncovin® and prednisone or prednisolone) or R-CHOP (rituximab, cyclophosphamide, hydrodaunorubicin®, Oncovin® and prednisone or prednisolone) chemotherapy regimen.

[0150] In some embodiments, the present invention provides a method of treating lymphoma comprising administering to a patient in need thereof a provided MDM2 degrading agent or a pharma- ceutically acceptable salt thereof and a rituximab or bendamustine chemotherapy regimen.

[0151] In some embodiments, the present invention provides a method of treating lymphoma, comprising administering to a patient in need thereof a provided MDM2 degrading agent or a pharma- ceutical acceptable salt thereof and a BTK inhibitor (e.g., ibrutinib).

[0152] In some embodiments, the present invention provides a method of treating lymphoma, comprising administering to a patient in need thereof a provided MDM2 degrading agent or a pharma- ceutical acceptable salt thereof and an anti-CD20 antibody (e.g., rituximab).

[0153] In some embodiments, the invention provides a method of treating lymphoma comprising administering to a patient in need thereof a provided MDM2 degrading agent, or a pharma- ceutical acceptable salt thereof, and an anti-CD79B ADC (e.g., polatuzumab).

[0154] In some embodiments, the present invention provides a method of treating lymphoma, comprising administering to a patient in need thereof a provided MDM2 degrading agent or a pharma- ceutical acceptable salt thereof and a BCL-2 inhibitor (e.g., venetoclax).

[0155] In some embodiments, the present invention provides a method of treating leukemia (e.g., AML), comprising administering to a patient in need thereof a provided MDM2 degrading agent or a pharma- ceutically acceptable salt thereof and a BCL-2 inhibitor (e.g., venetoclax). In some aspects of the methods of treating leukemia (e.g., AML) with a combination of a provided MDM2 degrading agent and a BCL-2 inhibitor (e.g., venetoclax), the combination is additive. In some aspects of the methods of treating leukemia (e.g., AML) with a combination of a provided MDM2 degrading agent and a BCL-2 inhibitor (e.g., venetoclax), the combination acts synergistically.

[0156] In some embodiments, the present invention provides a method of treating leukemia (e.g., AML), comprising administering to a patient in need thereof a provided MDM2 degrading agent or a pharma- ceutically acceptable salt thereof and a BCL-2 inhibitor (e.g., venetoclax), wherein the lymphoma is resistant to treatment with a BCL-2 inhibitor (e.g., venetoclax) alone.

[0157] In some embodiments, the present invention provides a method of treating melanoma (e.g., uveal melanoma), comprising administering to a patient in need thereof a provided MDM2 degrading agent or a pharma- ceutically acceptable salt thereof and a BCL-2 inhibitor (e.g., venetoclax). In some aspects of the methods of treating melanoma (e.g., uveal melanoma) with a combination of a provided MDM2 degrading agent and a BCL-2 inhibitor (e.g., venetoclax), the combination is additive. In some aspects of the methods of treating melanoma (e.g., uveal melanoma) with a combination of a provided MDM2 degrading agent and a BCL-2 inhibitor (e.g., venetoclax), the combination acts synergistically.

[0158] In some embodiments, the present invention provides a method of treating melanoma (e.g., uveal melanoma), comprising administering to a patient in need thereof a provided MDM2 degrading agent or a pharma- ceutical acceptable salt thereof and a BCL-2 inhibitor (e.g., venetoclax), wherein the melanoma is resistant to treatment with a BCL-2 inhibitor (e.g., venetoclax) alone.

[0159] In some embodiments, the present invention provides a method of treating leukemia (e.g., AML), comprising administering to a patient in need thereof a provided MDM2 degrading agent or a pharma- ceutically acceptable salt thereof and an FLT3 inhibitor (e.g., midostaurin). In some aspects of the provided methods of treating leukemia (e.g., AML) with a combination of an MDM2 degrading agent and an FLT3 inhibitor (e.g., midostaurin), the combination is additive. In some aspects of the provided methods of treating leukemia (e.g., AML) with a combination of an MDM2 degrading agent and an FLT3 inhibitor (e.g., midostaurin), the combination acts synergistically.

[0160] In some embodiments, the present invention provides a method of treating leukemia (e.g., AML), comprising administering to a patient in need thereof a provided MDM2 degrading agent or a pharma- ceutically acceptable salt thereof and an FLT3 inhibitor (e.g., midostaurin), wherein the lymphoma is resistant to treatment with an FLT3 inhibitor (e.g., midostaurin) alone.

[0161] In some embodiments, the present invention provides a method of treating lymphoma comprising administering to a patient in need thereof a provided MDM2 degrading agent or a pharma- ceutically acceptable salt thereof and lenalidomide or pomalidomide.

[0162] In some embodiments, the present invention provides a method of treating lymphoma, comprising administering to a patient in need thereof a provided MDM2 degrading agent or a pharma- ceutical acceptable salt thereof and a PI3K inhibitor (e.g., umbralisib).

[0163] In some embodiments, the present invention provides a method of treating a T cell disease or T cell deficiency described herein, comprising administering to a patient in need thereof a provided MDM2 degrading agent or a pharma- ceutical acceptable salt thereof and a PI3K inhibitor (e.g., umbralisib).

[0164] In some embodiments, the present invention provides a method of treating lymphoma, comprising administering to a patient in need thereof a provided MDM2 degrading agent or a pharma- ceutical acceptable salt thereof and a proteasome inhibitor (e.g., bortezomib).

[0165] In some embodiments, the present invention provides a method of treating lymphoma comprising administering to a patient in need thereof a provided MDM2 degrading agent or a pharma- ceutical acceptable salt thereof and chimeric antigen receptor T cells.

[0166] In another embodiment, the present invention provides a method of treating multiple myeloma, comprising administering to a patient in need thereof a provided MDM2 degrading agent or a pharma- ceutically acceptable salt thereof and one or more additional therapeutic agents selected from bortezomib (Velcade®) and dexamethasone (Decadron®), hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, SYK inhibitors in combination with lenalidomide (Revlimid®).

[0167] In another embodiment, the present invention provides a method of treating Waldenstrom's Macroglobulinemia comprising administering to a patient in need thereof a provided MDM2 degrading agent or a pharma- ceutically acceptable salt thereof and one or more additional therapeutic agents selected from chlorambucil (Leukeran®), cyclophosphamide (Cytoxan®, Neosar®), fludarabine (Fludara®), cladribine (Leustatin®), rituximab (Rituxan®), hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, and SYK inhibitors.

[0168] In some embodiments, one or more other therapeutic agents are antagonists of the hedgehog pathway.Approved hedgehog pathway inhibitors that can be used in the present invention include sonidegib (Odomzo®, Sun Pharmaceuticals); and vismodegib (Erivedge®, Genentech), both of which are for the treatment of basal cell carcinoma.

[0169] In some embodiments, the one or more other therapeutic agents are poly ADP ribose polymerase (PARP) inhibitors. In some embodiments, the PARP inhibitor is selected from olaparib (Lynparza®, AstraZeneca); rucaparib (Rubraca®, Clovis Oncology); niraparib (Zejula®, Tesaro); talazoparib (MDV3800 / BMN 673 / LT00673, Medivation / Pfizer / Biomarin); veliparib (ABT-888, AbbVie); and BGB-290 (BeiGene, Inc.).

[0170] In some embodiments, the one or more other therapeutic agents are histone deacetylase (HDAC) inhibitors. In some embodiments, the HDAC inhibitor is selected from vorinostat (Zolinza®, Merck); romidepsin (Istodax®, Celgene); panobinostat (Farydak®, Novartis); belinostat (Beleodaq®, Spectrum Pharmaceuticals); entinostat (SNDX-275, Syndax Pharmaceuticals) (NCT00866333); and chidamide (Epidaza®, HBI-8000, Chipscreen Biosciences, China).

[0171] In some embodiments, the one or more other therapeutic agents is a CDK inhibitor, such as a CDK4 / CDK6 inhibitor. In some embodiments, the CDK 4 / 6 inhibitor is selected from palbociclib (Ibrance®, Pfizer); ribociclib (Kisqali®, Novartis); abemaciclib (Ly2835219, Eli Lilly); and trilaciclib (G1T28, G1 Therapeutics).

[0172] In some embodiments, the one or more other therapeutic agents is a folate inhibitor. Approved folate inhibitors useful in the present invention include pemetrexed (Alimta®, Eli Lilly).

[0173] In some embodiments, the one or more other therapeutic agents are CC chemokine receptor 4 (CCR4) inhibitors. CCR4 inhibitors currently under investigation that may be useful in the present invention include mogamulizumab (Poteligeo®, Kyowa Hakko Kirin, Japan).

[0174] In some embodiments, the one or more other therapeutic agents are isocitrate dehydrogenase (IDH) inhibitors.Currently investigated IDH inhibitors that can be used in the present invention include AG120 (Celgene; NCT02677922); AG221 (Celgene, NCT02677922; NCT02577406); BAY1436032 (Bayer, NCT02746081); IDH305 (Novartis, NCT02987010).

[0175] In some embodiments, the present invention provides a method of treating a solid cancer or hematological malignancy in a patient in need of such treatment, comprising administering a therapeutically effective amount of an MDM2 degrader or a pharmacologic acceptable salt thereof and an IDH inhibitor (e.g., AG120, AG221, BAY1436032, IDH305, etc.).

[0176] In some embodiments, one or more other therapeutic agents are arginase inhibitors.The currently investigated arginase inhibitors that can be used in the present invention include AEB1102 (pegylated recombinant arginase, Aeglea Biotherapeutics), which is currently being investigated in Phase 1 clinical trials for acute myeloid leukemia and myelodysplastic syndrome (NCT02732184) and solid tumors (NCT02561234); and CB-1158 (Calithera Biosciences).

[0177] In some embodiments, the one or more other therapeutic agents are glutaminase inhibitors. Glutaminase inhibitors currently under investigation that can be used in the present invention include CB-839 (Calithera Biosciences).

[0178] In some embodiments, the one or more other therapeutic agents are antibodies that bind to tumor antigens, i.e., proteins expressed on the cell surface of tumor cells. Approved antibodies that bind to tumor antigens that can be used in the present invention include rituximab (Rituxan®, Genentech / BiogenIdec); ofatumumab (anti-CD20, Arzerra®, GlaxoSmithKline); obinutuzumab (anti-CD20, Gazyva®, Genentech), ibritumomab (anti-CD20 and yttrium-90, Zevalin®, Spectrum Pharmaceuticals); daratumumab (anti-CD38, Darzalex®, Janssen Biotech), dinutuximab (anti-glycolipid GD2, Unituxin®, United Therapeutics); trastuzumab (anti-HER2, Herceptin®, Genentech); ado-trastuzumab emtansine (anti-HER2, fused to emtansine, Kadcyla®, Genentech); and pertuzumab (anti-HER2, Perjeta®, Genentech); and brentuximab vedotin (anti-CD30-drug conjugate, Adcetris®, Seattle Genetics).

[0179] In some embodiments, the one or more other therapeutic agents are topoisomerase inhibitors. Approved topoisomerase inhibitors useful in the present invention include irinotecan (Onivyde®, Merrimack Pharmaceuticals); topotecan (Hycamtin®, GlaxoSmithKline). Topoisomerase inhibitors currently under investigation that can be used in the present invention include pixantrone (Pixuvri®, CTI Biopharma).

[0180] In some embodiments, the one or more other therapeutic agents are inhibitors of anti-apoptotic proteins, such as BCL-2. Approved anti-apoptotic agents that can be used in the present invention include venetoclax (Venclexta®, AbbVie / Genentech); and blinatumomab (Blincyto®, Amgen). Other therapeutic agents that target apoptotic proteins that are undergoing clinical trials and can be used in the present invention include navitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740).

[0181] In some embodiments, the present invention provides a method of treating a solid cancer or hematological malignancy in a patient in need of such treatment, comprising administering a therapeutically effective amount of an MDM2 degrading agent, or a pharma- ceutical acceptable salt thereof, and an apoptosis regulator (e.g., a BCL-2 inhibitor).

[0182] In some embodiments, the one or more other therapeutic agents are androgen receptor inhibitors. Approved androgen receptor inhibitors useful in the present invention include enzalutamide (Xtandi®, Astellas / Medivation). Approved inhibitors of androgen synthesis include abiraterone (Zytiga®, Centocor / Ortho); approved antagonists of the gonadotropin-releasing hormone (GnRH) receptor (degalarix, Firagon®, Ferring Pharmaceuticals).

[0183] In some embodiments, the one or more other therapeutic agents are selective estrogen receptor modulators (SERMs), which interfere with the synthesis or activity of estrogen. Approved SERMs useful in the present invention include raloxifene (Evista®, Eli Lilly).

[0184] In some embodiments, the one or more other therapeutic agents are inhibitors of bone resorption. An approved therapeutic agent that inhibits bone resorption is denosumab (Xgeva®, Amgen), an antibody that binds to RANKL and inhibits the binding of RANKL to its receptor RANK, which is found on the surface of osteoclasts, their precursors, and osteoclast-like giant cells and mediates bone pathology in solid tumors with bone metastasis. Other approved therapeutic agents that inhibit bone resorption include bisphosphonates, such as zoledronic acid (Zometa®, Novartis).

[0185] In some embodiments, the one or more other therapeutic agents are inhibitors of the interaction between MDMX and MDM2, two major p53 inhibitory proteins. Investigative inhibitors of p53 inhibitory proteins that can be used in the present invention include ALRN-6924 (Aileron), a stapled peptide that binds equally to MDMX and MDM2 and disrupts their interaction with p53. ALRN-6924 is currently being evaluated in clinical trials for the treatment of AML, progressive myelodysplastic syndrome (MDS) and peripheral T-cell lymphoma (PTCL) (NCT02909972; NCT02264613).

[0186] In some embodiments, the one or more other therapeutic agents are inhibitors of transforming growth factor-beta (TGF-beta or TGFβ). Inhibitors of TGF-beta protein currently under investigation that can be used in the present invention include NIS793 (Novartis), an anti-TGF-beta antibody currently being tested in outpatient clinics for the treatment of various cancers, including breast, lung, hepatocellular, colorectal, pancreatic, prostate and renal cancer (NCT02947165). In some embodiments, the inhibitor of TGF-beta protein is fresolimumab (GC1008; Sanofi-Genzyme), currently under investigation for melanoma (NCT00923169); renal cell carcinoma (NCT00356460); and non-small cell lung cancer (NCT02581787). Moreover, in some embodiments, the additional therapeutic agent is a TGF-beta capture agent, such as those described in Connolly et al. (2012) Int'l J.Biological Sciences 8:964-978. For the treatment of solid tumors, one therapeutic compound currently in clinical trials is M7824 (Merck KgaA-formerly MSB0011459X); and (NCT02517398), a bispecific anti-PD-L1 / TGFβ capture compound (NCT02699515). M7824 consists of a fully human IgG1 antibody against PD-L1 fused to the extracellular domain of human TGF-beta receptor II, which functions as a TGFβ "capture agent".

[0187] In some embodiments, the one or more other therapeutic agents are selected from glembatumumab vedotin-monomethylauristatin E (MMAE) (Celldex), an anti-glycoprotein NMB (gpNMB) antibody linked to a cytotoxic MMAE (CR011). gpNMB is a protein overexpressed by multiple tumor types that is associated with the ability of cancer cells to metastasize.

[0188] In some embodiments, the one or more other therapeutic agents are anti-proliferative compounds. Such anti-proliferative compounds include, but are not limited to, aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors; compounds that induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platin compounds; compounds that target / reduce protein or lipid kinase activity and further anti-angiogenic compounds; compounds that target, reduce or inhibit the activity of protein or lipid phosphatases; gonadorelin agonists. stomatitis;antiandrogens;methionine aminopeptidase inhibitors;matrix metalloproteinase inhibitors;bisphosphonates;biological response modifiers;antiproliferative antibodies;heparanase inhibitors;inhibitors of Ras oncogenic isoforms;telomerase inhibitors;proteasome inhibitors;compounds used in the treatment of hematological malignancies;compounds that target, decrease or inhibit the activity of Flt-3 (e.g., sunitinib, lestaurtinib, tandutinib, crenolanib, gilteritinib, midostaurin, quizartinib and sorafenib, FLX925 and G-749);Conforma Hsp90 inhibitors such as 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 from Therapeutics; temozolomide (Temodal®); kinesin spindle protein inhibitors such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine / chlorpromazine from CombinatoRx; MEK inhibitors, e.g., ARRY142886 from Array BioPharma, AZd6244 from AstraZeneca, PD181461 and leucovorin from Pfizer.

[0189] In some embodiments, the one or more other therapeutic agents are taxane compounds that cause disruption of microtubules, which are essential for cell division. In some embodiments, the taxane compounds are selected from paclitaxel (Taxol®, Bristol-Myers Squibb), docetaxel (Taxotere®, Sanofi-Aventis; Docefrez®, Sun Pharmaceutical), albumin-bound paclitaxel (Abraxane®; Abraxis / Celgene), cabazitaxel (Jevtana®, Sanofi-Aventis), and SID530 (SK Chemicals, Co.) (NCT00931008).

[0190] In some embodiments, the one or more other therapeutic agents are nucleoside inhibitors or therapeutic agents that interfere with normal DNA synthesis, protein synthesis, cell replication, or otherwise inhibit rapidly proliferating cells.

[0191] In some embodiments, the nucleoside inhibitor is selected from the group consisting of trabectedin (a guanidine alkylating agent, Yondelis®, Janssen Oncology), mechlorethamine (an alkylating agent, Valchlor®, Aktelion Pharmaceuticals); vincristine (Oncovin®, Eli Lilly; Vincasar®, Teva Pharmaceuticals; Marqibo®, Talon Therapeutics); temozolomide (a prodrug for the alkylating agent 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC), Temodar®, Merck); cytarabine injectable (ara-C, an antimetabolite cytidine analog, Pfizer); lomustine (an alkylating agent, CeeNU®, Bristol-Myers Squibb; Gleostine®, NextSource). Biotechnology); azacitidine (a pyrimidine nucleoside analogue of cytidine, Vidaza®, Celgene); omacetaxine mepesuccinate (a cephalotaxine ester) (a protein synthesis inhibitor, Synribo®; Teva Pharmaceuticals); asparaginase Erwinia chrysanthemi (an enzyme that depletes asparagine, Elspar®, Lundbeck; Erwinaze®, EUSA Pharma); eribulin mesylate (microtubule inhibitor, tubulin-based antimitotic agent, Halaven®, Eisai); cabazitaxel (microtubule inhibitor, tubulin-based antimitotic agent, Jevtana®, Sanofi-Aventis); capacetrin (thymidylate synthase inhibitor, Xeloda®, Genentech); bendamustine (bifunctional mechlorethamine derivative, believed to form interstrand DNA crosslinks, Treanda®, Cephalon / Teva); ixabepilone (semi-synthetic analog of epothilone B, microtubule inhibitor, tubulin-based antimitotic agent, Ixempra®, Bristol-Myers Squibb);Selected from nelarabine (prodrug of a deoxyguanosine analog, nucleoside metabolic inhibitor, Arranon®, Novartis); clofarabine (prodrug of a ribonucleotide reductase inhibitor, competitive inhibitor of deoxycytidine, Clolar®, Sanofi-Aventis); and triflidine and tipiracil (thymidine-based nucleoside analog and thymidine phosphorylase inhibitor, Lonsurf®, Taiho Oncology);

[0192] In some embodiments, the present invention provides a method of treating a solid cancer comprising administering to a patient in need thereof a provided MDM2 degrading agent or a pharma- ceutical acceptable salt thereof and azacitidine.

[0193] In some embodiments, the present invention provides a method of treating a solid tumor comprising administering to a patient in need thereof a provided MDM2 degrading agent or a pharma- ceutical acceptable salt thereof and cytarabine.

[0194] In some embodiments, the one or more other therapeutic agents are kinase inhibitors or VEGF-R antagonists. Approved VEGF inhibitors and kinase inhibitors useful in the present invention include: bevacizumab (Avastin®, Genentech / Roche), an anti-VEGF monoclonal antibody; ramucirumab (Cyramza®, Eli Lilly), an anti-VEGFR-2 antibody, and ziv-aflibercept (also known as VEGF Trap (Zaltrap®; Regeneron / Sanofi)). VEGFR inhibitors, such as regorafenib (Stivarga®, Bayer); vandetanib (Caprelsa®, AstraZeneca); axitinib (Inlyta®, Pfizer); and lenvatinib (Lenvima®, Eisai); sorafenib (Nexavar®, Bayer). Raf inhibitors such as dabrafenib (Tafinlar®, Novartis); and vemurafenib (Zelboraf®, Genentech / Roche); MEK inhibitors such as cobimetinib (Cotellic®, Exelexis / Genentech / Roche), selumetinib (Koselugo™), binimetinib, trametinib, mirametinib (PD-325901) or TAK-733. anti-cancer drugs; trametinib (Mekinist®, Novartis); Bcr-Abl tyrosine kinase inhibitors such as imatinib (Gleevec®, Novartis); nilotinib (Tasigna®, Novartis); dasatinib (Sprycel®, BristolMyersSquibb); bosutinib (Bosulif®, Pfizer); and ponatinib (Inclusig®, Ariad Pharmaceuticals); Her2 and EGFR inhibitors such as gefitinib (Iressa®, AstraZeneca); erlotinib (Tarceeva®, Genentech / Roche / Astellas); lapatinib (Tykerb®, Novartis);afatinib (Gilotrif®, Boehringer Ingelheim); osimertinib (targets activated EGFR, Tagrisso®, AstraZeneca); and brigatinib (Alunbrig®, Ariad Pharmaceuticals; c-Met and VEGFR2 inhibitors, such as cabozantinib (Cometriq®, Exelexis); and multikinase inhibitors, such as sunitinib (Sutent®, Pfizer); pazopanib (Votrient®, Novartis); ALK inhibitors, such as crizotinib (Xalkori®, Pfizer); ceritinib (Zykadia®, Novartis); and alectinib (Alecenza®, Genentech / Roche); Bruton's tyrosine kinase inhibitors, such as ibrutinib (Imbruvica®, Pharmacyclics / Janssen); and Flt3 receptor inhibitors, such as midostaurin (Rydapt®, Novartis).

[0195] In some embodiments, the present invention provides a method of treating a solid tumor comprising administering to a patient in need thereof a provided MDM2 degrading agent or a pharma- ceutical acceptable salt thereof and a MEK inhibitor (e.g., selumetinib).

[0196] In some embodiments, the present invention provides a method of treating a solid cancer or hematological malignancy in a patient in need of such treatment, comprising administering a therapeutically effective amount of an MDM2 degrading agent, or a pharmaceutically acceptable salt thereof, and an Flt3 inhibitor (e.g., midostaurin).

[0197] Other kinase inhibitors and VEGF-R antagonists that are under development and may be used in the present invention include tivozanib (Aveo Pharmaecuticals); vatalanib (Bayer / Novartis); lucitanib (Clovis Oncology); dovitinib (TKI258, Novartis); chiauanib (Chipscreen Biosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories); neratinib (HKI-272, Puma Biotechnology); radotinib (Supect®, IY5511, Il-Yang Pharmaceuticals, S.Korea); ruxolitinib (Jakafi®, Incyte Corporation); PTC299 (PTC Therapeutics); CP-547,632 (Pfizer); foretinib (Exelexis, GlaxoSmithKline); quizartinib (Daiichi Sankyo) and motesanib (Amgen / Takeda).

[0198] In another embodiment, the invention provides a method of treating or lessening the severity of a disease comprising administering an MDM2 degrader or a pharma- ceutical acceptable salt thereof and a BTK inhibitor to a patient in need thereof, wherein the disease is a B-cell proliferative disorder, e.g., diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma. / Waldenstrom's macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma (also known as plasma cell myeloma), non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, or lymphomatoid granulomatosis.

[0199] In another embodiment, the present invention provides a method of treating or lessening the severity of a disease, comprising administering to a patient in need thereof a provided MDM2 degrading agent or a pharma- ceutically acceptable salt thereof and a PI3K inhibitor, wherein the disease is selected from lymphoma (e.g., including non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (also called Hodgkin or Hodgkin's disease)).

[0200] In some embodiments, the one or more other therapeutic agents are a phosphatidylinositol 3-kinase (PI3K) inhibitor selected from idelalisib (Zydelig®, Gilead), alpelisib (BYL719, Novartis), taselisib (GDC-0032, Genentech / Roche); pictilisib (GDC-0941, Genentech / Roche); copanlisib (BAY806946, Bayer); duvelisib (formerly IPI-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TGR1202 (formerly RP5230, TG Therapeutics).

[0201] The compounds of the present invention may also be advantageously used in combination with other antiproliferative compounds. Such antiproliferative compounds include, but are not limited to, aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors; compounds that induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platin compounds; compounds that target / reduce protein or lipid kinase activity and further antiangiogenic compounds; compounds that target, reduce or inhibit the activity of protein or lipid phosphatases; gonadorelin agonists. stomatitis;antiandrogens;methionine aminopeptidase inhibitors;matrix metalloproteinase inhibitors;bisphosphonates;biological response modifiers;antiproliferative antibodies;heparanase inhibitors;inhibitors of Ras oncogenic isoforms;telomerase inhibitors;proteasome inhibitors;compounds used in the treatment of hematological malignancies;compounds that target, decrease or inhibit the activity of Flt-3 (e.g., sunitinib, lestaurtinib, tandutinib, crenolanib, gilteritinib, midostaurin, quizartinib and sorafenib, FLX925 and G-749);Conforma Hsp90 inhibitors such as 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 from Therapeutics; temozolomide (Temodal®); kinesin spindle protein inhibitors such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine / chlorpromazine from CombinatoRx; MEK inhibitors, e.g., ARRY142886 from Array BioPharma, AZD6244 from AstraZeneca, PD181461 and leucovorin from Pfizer.

[0202] The term "aromatase inhibitor" as used herein refers to a compound that inhibits estrogen production, for example the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. This term includes, but is not limited to, steroids, particularly atamestane, exemestane and formestane, and nonsteroids, particularly aminoglutethimide, rogletimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole and letrozole. Exemestane is commercially available under the trade name Aromasin™. Formestane is commercially available under the trade name Lentaron™. Fadrozole is commercially available under the trade name Afema™. Anastrozole is commercially available under the trade name Arimidex™. Letrozole is commercially available under the trade name Femara™ or Femar™. Aminoglutethimide is commercially available under the trade name Orimeten™. The combinations of the present invention which include a chemotherapeutic agent that is an aromatase inhibitor are particularly useful in the treatment of hormone receptor positive tumors, such as breast tumors.

[0203] In some embodiments, the one or more other therapeutic agents are mTOR inhibitors, which inhibit cell proliferation, angiogenesis, and glucose uptake. In some embodiments, the mTOR inhibitor is everolimus (Afinitor®, Novartis); temsirolimus (Torisel®, Pfizer); and sirolimus (Rapamune®, Pfizer).

[0204] In some embodiments, the one or more other therapeutic agents is an aromatase inhibitor. In some embodiments, the aromatase inhibitor is selected from exemestane (Aromasin®, Pfizer); anastazole (Arimidex®, AstraZeneca) and letrozole (Femara®, Novartis).

[0205] The term "anti-estrogen" as used herein relates to a compound that antagonizes the effect of estrogen at the estrogen receptor level. This term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen is marketed under the trade name Nolvadex™. Raloxifene hydrochloride is marketed under the trade name Evista™. Fulvestrant can be administered under the trade name Faslodex™. The combination of the present invention that includes a chemotherapeutic agent that is an anti-estrogen is particularly useful for treating estrogen receptor positive tumors, such as breast tumors.

[0206] The term "antiandrogen" as used herein relates to any substance capable of inhibiting the biological effects of androgens, including, but not limited to, bicalutamide (Casodex™). The term "gonadorelin agonist" as used herein includes, but is not limited to, abarelix, goserelin and goserelin acetate. Goserelin can be administered under the trade name Zoladex™.

[0207] The term "topoisomerase I inhibitors" as used herein includes, but is not limited to, topotecan, gimatecan, irinotecan, camptothecian and its analogs, 9-nitrocamptothecin and polymeric camptothecin conjugate PNU-166148. Irinotecan can be administered, for example, in the form as it is marketed, for example, under the trademark Camptosar™. Topotecan is marketed under the trade name Hycamptin™.

[0208] The term "topoisomerase II inhibitors" as used herein includes, but is not limited to, anthracyclines (e.g., doxorubicin (including liposomal formulations such as Caelyx™), daunorubicin, epirubicin, idarubicin, and nemorubicin, the anthraquinones mitoxantrone and rosoxantrone, and the podophyllotoxins etoposide and teniposide. Etoposide is commercially available under the trade name Etopophos™. Teniposide is commercially available under the trade name VM 26-Bristol. Doxorubicin is commercially available under the trade name Acriblastin™ or Adriamycin™. Epirubicin is commercially available under the trade name Farmorubicin™. Idarubicin is commercially available under the trade name Zavedos™. Mitoxantrone is commercially available under the trade name Novantron.

[0209] The term "microtubule active agent" refers to microtubule stabilizing compounds, microtubule destabilizing compounds and microtubulin polymerization inhibitors, including, but not limited to, taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine; discodermolide; cochicine and epothilones and their derivatives. Paclitaxel is commercially available under the trade name Taxol™. Docetaxel is commercially available under the trade name Taxotere™. Vinblastine sulfate is commercially available under the trade name Vinblastin RP™. Vincristine sulfate is commercially available under the trade name Farmistin™.

[0210] The term "alkylating agent" as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan, or nitrosourea (BCNU or Gliadel). Cyclophosphamide is commercially available under the trade name Cyclostin™. Ifosfamide is commercially available under the trade name Holoxan™.

[0211] The term "histone deacetylase inhibitors" or "HDAC inhibitors" relates to compounds which inhibit histone deacetylase and which possess antiproliferative activity, including, but not limited to, suberoylanilide hydroxamic acid (SAHA).

[0212] The term "antitumor antimetabolites" includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds (e.g., 5-azacytidine and decitabine), methotrexate and edatrexate, and folate antagonists (e.g., pemetrexed). Capecitabine is commercially available under the trade name Xeloda™. Gemcitabine is commercially available under the trade name Gemzar™.

[0213] The term "platin compound" as used herein includes, but is not limited to, carboplatin, cisplatin, cisplatinum and oxaliplatin. Carboplatin can be administered, e.g., in the form as it is marketed, e.g., under the trademark Carboplat™. Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g., under the trademark Eloxatin™.

[0214] As used herein, the term "Bcl-2 inhibitor" includes, but is not limited to, ABT-199, ABT-731, ABT-737, apogossypol, Ascenta's pan Bcl-2 inhibitors, curcumin (and analogs thereof), dual Bcl-2 / Bcl-xL inhibitors (Infinity Pharmaceuticals / Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and analogs thereof; see WO 2008 / 118802, US 2010 / 0197686), navitoclax (and analogs thereof, see US 7,390,799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and analogs thereof, see WO 2004 / 106328, US 2005 / 0014802), S-001 (Gloria The present invention includes, but is not limited to, compounds having inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including, but ...). In some embodiments, the Bcl-2 inhibitor is a small molecule therapeutic agent. In some embodiments, the Bcl-2 inhibitor is a peptidomimetic.

[0215] The term "compounds targeting / reducing the activity of protein kinases or lipid kinases; or compounds targeting / reducing the activity of protein phosphatases or lipid phosphatases; or further anti-angiogenic compounds" as used herein includes, but is not limited to, protein tyrosine kinase and / or serine and / or threonine kinase inhibitors, or lipid kinase inhibitors, such as a) compounds targeting, reducing or inhibiting the activity of platelet derived growth factor receptors (PDGFRs) (e.g. compounds targeting, reducing or inhibiting the activity of PDGFRs, in particular compounds that inhibit PDGF receptors, such as N-phenyl-2-pyrimidine-amine derivatives, e.g. imatinib, SU101, SU6668 and GFB-111); b) compounds targeting, reducing or inhibiting the activity of fibroblast growth factor receptors (FGFRs); c) compounds targeting, reducing or inhibiting the activity of insulin-like growth factor receptor I (IGF-IR) (e.g. For example, compounds that target, reduce or inhibit the activity of IGF-IR, in particular compounds that inhibit the kinase activity of the IGF-I receptor, or antibodies that target the extracellular domain of the IGF-I receptor or its growth factors; d) compounds that target, reduce or inhibit the activity of the Trk receptor tyrosine kinase family, or ephrin B4 inhibitors; e) compounds that target, reduce or inhibit the activity of the AxI receptor tyrosine kinase family; f) compounds that target, reduce or inhibit the activity of the Ret receptor tyrosine kinase; g) compounds that target, reduce or inhibit the activity of the Kit / SCFR receptor tyrosine kinase, for example imatinib; h) compounds that target, reduce or inhibit the activity of the C-kit receptor tyrosine kinase, which is part of the PDGFR family (for example compounds that target, reduce or inhibit the activity of the c-Kit receptor tyrosine kinase family, in particular compounds that inhibit the c-Kit receptor, for example imatinib);i) Compounds that target, reduce or inhibit the activity of c-Abl family members, their gene fusion products (e.g., BCR-Abl kinase) and mutants (e.g., compounds that target, reduce or inhibit the activity of c-Abl family members and their gene fusion products, e.g., N-phenyl-2-pyrimidine-amine derivatives, e.g., imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 (from ParkeDavis); or dasatinib (BMS-354825); j) compounds that target, decrease or inhibit the activity of members of the protein kinase C (PKC) and Raf families of serine / threonine kinases, MEK, SRC, JAK / pan-JAK, FAK, PDK1, PKB / Akt, Ras / MAPK, PI3K, SYK, TYK2, BTK and TEC families, and / or members of the cyclin-dependent kinase family (CDK), including staurosporine derivatives, e.g., midostaurin; further exemplary compounds include UCN-01, safingol, BAY 43-9006, bryostatin 1, perifosine; llmofosine; RO 318220 and RO 320432; GO 6976; lsis 3521; LY333531 / LY379196; isochinoline compounds; FTI; PD184352 or QAN697 (P13K inhibitor) or AT7519 (CDK inhibitor); k) compounds that target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors, for example compounds that target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors such as imatinib mesylate (Gleevec™) or tyrphostins (e.g. tyrphostin A23 / RG-50810; AG 99; tyrphostin AG 213; tyrphostin AG 1748; tyrphostin AG 490; tyrphostin B44; tyrphostin B44(+) enantiomer; tyrphostin AG 555; AG 494;tyrphostin AG 556, AG957) and adahostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC 680410, adahostin); l) compounds which target, reduce or inhibit the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR1, ErbB2, ErbB3, ErbB4, as homodimers or heterodimers) and mutants thereof, for example compounds which target, reduce or inhibit the activity of the epidermal growth factor receptor family are in particular compounds, proteins or antibodies which inhibit members of the EGF receptor tyrosine kinase family, for example the EGF receptor, ErbB2, ErbB3 and ErbB4, or which bind to EGF or EGF-related ligands (e.g. CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin™), cetuximab (Erbitux™), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives); m) compounds which target, reduce or inhibit the activity of the c-Met receptor, e.g. compounds which target, reduce or inhibit the activity of c-Met, in particular , compounds that inhibit the kinase activity of the c-Met receptor or antibodies that target the extracellular domain of c-Met or bind to HGF, n) compounds that target, decrease or inhibit the kinase activity of one or more JAK family members (JAK1 / JAK2 / JAK3 / TYK2 and / or pan-JAK) (including but not limited to PRT-062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, and ruxolitinib);o) compounds that target, decrease or inhibit the kinase activity of PI3 kinase (PI3K), including but not limited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictorelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib; and q) compounds that target, decrease or inhibit the signaling effects of the Hedgehog protein (Hh) or Smoothened receptor (SMO) pathways, including but not limited to cyclopamine, vismodegib, itraconazole, erismodegib, and IPI-926 (salidegib);

[0216] Compounds which target, decrease or inhibit the activity of protein or lipid phosphatases are for example inhibitors of phosphatase 1, inhibitors of phosphatase 2A or inhibitors of CDC25 (eg okadaic acid or a derivative thereof).

[0217] In some embodiments, the one or more other therapeutic agents are growth factor antagonists, such as platelet-derived growth factor (PDGF) or epidermal growth factor (EGF) or its receptor (EGFR) antagonists. Approved PDGF antagonists that can be used in the present invention include olaratumab (Lartruvo®; Eli Lilly). Approved EGFR antagonists that can be used in the present invention include cetuximab (Erbitux®, Eli Lilly); necitumumab (Portrazza®, Eli Lilly), panitumumab (Vectibix®, Amgen); and osimertinib (targeting activated EGFR, Tagrisso®, AstraZeneca).

[0218] The term "PI3K inhibitor", as used herein, includes, but is not limited to, compounds having inhibitory activity against one or more enzymes of the phosphatidylinositol-3-kinase family (including, but not limited to, PI3K α, PI3K γ, PI3K δ, PI3K β, PI3K-C2 α, PI3K-C2 β, PI3K-C2 γ, Vps34, p110-α, p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87). Examples of PI3K inhibitors useful in the present invention include, but are not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictorelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.

[0219] The term "BTK inhibitor", as used herein, includes, but is not limited to, compounds that have inhibitory activity against Bruton's tyrosine kinase (BTK), including, but not limited to, AVL-292 and ibrutinib.

[0220] The term "SYK inhibitors" as used herein includes, but is not limited to, compounds having inhibitory activity against spleen tyrosine kinase (SYK), including, but not limited to, PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.

[0221] Additional anti-angiogenic compounds include compounds that have another mechanism for their activity, such as a mechanism unrelated to protein kinase inhibition or lipid kinase inhibition, such as thalidomide (Thalomid™) and TNP-470.

[0222] Examples of useful proteasome inhibitors for use in combination with the compounds of the invention include, but are not limited to, bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.

[0223] Compounds which target, decrease or inhibit the activity of protein or lipid phosphatases are for example inhibitors of phosphatase 1, inhibitors of phosphatase 2A or inhibitors of CDC25 (eg okadaic acid or a derivative thereof).

[0224] Compounds that induce cell differentiation processes include, but are not limited to, retinoic acid, α-, γ- or δ-tocopherol, or α-, γ- or δ-tocotrienol.

[0225] The term cyclooxygenase inhibitors as used herein includes, but is not limited to, Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acids and derivatives, such as celecoxib (Celebrex™), rofecoxib (Vioxx™), etoricoxib, valdecoxib, or 5-alkyl-2-arylaminophenylacetic acids, such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenylacetic acid, lumiracoxib.

[0226] The term "mTOR inhibitors" relates to compounds with antiproliferative activity, such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779 and ABT578, which inhibit the mammalian target of rapamycin (mTOR).

[0227] The term "heparanase inhibitor" as used herein refers to a compound that targets, reduces or inhibits heparin sulfate degradation. This term includes, but is not limited to, PI-88. The term "biological response modifier" as used herein refers to lymphokines or interferons.

[0228] The term "inhibitor of Ras oncogenic isoform" (e.g., H-Ras, K-Ras, or N-Ras) as used herein refers to a compound that targets, reduces or inhibits the oncogenic activity of Ras; for example, "farnesyltransferase inhibitors" such as L-744832, DK8G557, or R115777 (Zarnestra™). The term "telomerase inhibitor" as used herein refers to a compound that targets, reduces or inhibits the activity of telomerase. Compounds that target, reduce or inhibit the activity of telomerase are, in particular, compounds that inhibit the telomerase receptor, such as telomestatin.

[0229] The term "proteasome inhibitor" as used herein refers to a compound that targets, reduces or inhibits the activity of proteasome. Compounds that target, reduces or inhibit the activity of proteasome include, but are not limited to, bortezomib (Velcade™), carfilzomib (Kyprolis®, Amgen); and ixazomib (Ninlaro®, Takeda), and MLN 341.

[0230] The term "matrix metalloproteinase inhibitors" or ("MMP" inhibitors), as used herein, includes, but is not limited to, collagen peptidomimetic and non-peptidomimetic inhibitors, tetracycline derivatives (e.g., the hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogs marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551) BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996).

[0231] The term "compounds used in the treatment of hematological malignancies" as used herein includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds that target, decrease or inhibit the activity of FMS-like tyrosine kinase receptor (Flt-3R); interferon, 1-β-D-arabinofuransylcytosine (ara-c) and busulfan; and ALK inhibitors, which are compounds that target, decrease or inhibit anaplastic lymphoma kinase.

[0232] Compounds which target, decrease or inhibit the activity of the FLT-3R-like tyrosine kinase receptor are in particular compounds, proteins or antibodies which inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, staurosporine derivatives, SU11248 and MLN518.

[0233] The term "HSP90 inhibitor" as used herein includes, but is not limited to, compounds that target, reduce or inhibit the intrinsic ATPase activity of HSP90; compounds that degrade, target, reduce or inhibit HSP90 client proteins via the ubiquitin proteosome pathway. Compounds that target, reduce or inhibit the intrinsic ATPase activity of HSP90 are, in particular, compounds, proteins or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino, 17-demethoxygeldanamycin (17AAG), geldanamycin derivatives; other geldanamycin-related compounds; radicicol and HDAC inhibitors.

[0234] The term "antiproliferative antibody" as used herein includes, but is not limited to, trastuzumab (Herceptin™), trastuzumab-DM1, erbitux, bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553 (anti-CD40) and 2C4 antibodies. By antibody is meant intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments so long as they exhibit the desired biological activity.

[0235] Also included are EDG binders and ribonucleotide reductase inhibitors.The term "EDG binders" as used herein refers to a class of immunosuppressants that modulate lymphocyte recirculation, such as FTY720.The term "ribonucleotide reductase inhibitors" refers to pyrimidine or purine nucleoside analogs, including but not limited to fludarabine and / or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (particularly in combination with ara-C for ALL) and / or pentostatin.The ribonucleotide reductase inhibitor is in particular hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivative.

[0236] In particular, VEGF compounds, proteins or monoclonal antibodies such as 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharma- ceutically acceptable salt thereof, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; Angiostatin™; Endostatin™; anthranilic acid amide; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies (e.g., rhuMAb and RHUFab), VEGF aptamers (e.g., Macugon); FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibodies, Angiozyme (RPI 4610) and bevacizumab (Avastin™) are also included.

[0237] Photodynamic therapy, as used herein, refers to the treatment of using certain chemicals known as photosensitizing compounds to treat or prevent cancer.Examples of photodynamic therapy include treatment with compounds such as Visudyne™ and porfimer sodium.

[0238] Angiogenic antisteroids, as used herein, refer to compounds that block or inhibit angiogenesis, such as anecortave, triamcinolone, hydrocortisone, 11-α-epihydrocortisol, cortexolone, 17α-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone, and dexamethasone.

[0239] Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanisms of action.

[0240] Other useful combinations of the compounds of the invention with anti-inflammatory drugs are with antagonists of chemokine receptors, such as CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, in particular CCR-5 antagonists, such as Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D, and Takeda antagonists, such as N-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminium chloride (TAK-770).

[0241] The structures of the active compounds identified by code number, generic name or trade name can be obtained from the current edition of the standard overview book "The Merck Index" or from databases such as Patents International (eg IMS World Publications).

[0242] The compounds of the present invention may also be used in combination with known therapeutic processes, such as the administration of hormones or radiation. In certain embodiments, provided MDM2 degraders are used as radiosensitizers, particularly for the treatment of tumors that are poorly sensitive to radiation therapy.

[0243] The compounds of the present invention can be administered alone or in combination with one or more other therapeutic compounds, and possible combination therapy can take the form of a fixed combination, or the compound of the present invention and one or more other therapeutic compounds are administered alternately or independently, or a fixed combination and one or more other therapeutic compounds are administered in combination.The compounds of the present invention can also be administered in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination thereof, in particular for tumor treatment.As described above, long-term treatment is possible, as well as adjunctive treatment, in the context of other treatment strategies.Other possible treatments are treatments to maintain the patient's condition after tumor regression, or even chemopreventive treatment, for example in patients at risk.

[0244] Exemplary Tumor Immunotherapy Agents In some embodiments, one or more other therapeutic agents are tumor immunotherapy agents.As used herein, the term "tumor immunotherapy agent" refers to an agent that is effective for enhancing, stimulating, and / or upregulating immune response in a subject.In some embodiments, administration of tumor immunotherapy agent and the compound of the present invention has synergistic effect in the treatment of solid cancer or hematological malignancies.

[0245] The tumor immunotherapy agent may be, for example, a small molecule drug, an antibody, or a biological or small molecule. Examples of biological tumor immunotherapy agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the monoclonal antibody is a humanized antibody or a human antibody.

[0246] In some embodiments, the tumor immunomodulatory agent is (i) an agonist of a stimulatory (including costimulatory) receptor or (ii) an antagonist of an inhibitory (including co-inhibitory) signal on a T cell, both of which result in amplification of an antigen-specific T cell response.

[0247] Certain of the stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). One important family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane-bound ligands that bind to costimulatory or coinhibitory receptors is the TNF family of molecules that bind to cognate TNF receptor family members, including CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, TRAILR3, TRAILR4, OP G, RANK, RANKL, TWEAKR / Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTβR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / D Contains R3, EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin α / TNFβ, TNFR2, TNFα, LTβR, lymphotoxin α1β2, FAS, FASL, RELT, DR6, TROY, NGFR.

[0248] In some embodiments, the tumor immunomodulatory agent is a cytokine that inhibits T cell activation (e.g., IL-6, IL-10, TGF-β, VEGF, and other immunosuppressive cytokines) or a cytokine that stimulates T cell activation to stimulate an immune response.

[0249] In some embodiments, the combination of a compound of the present invention with a tumor immunotherapy agent may stimulate a T cell response. In some embodiments, the immuno-oncology agent is (i) an antagonist (e.g., an immune checkpoint inhibitor) of a protein that inhibits T cell activation (e.g., CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4); or (ii) an agonist of a protein that stimulates T cell activation (e.g., B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3, and CD28H).

[0250] In some embodiments, the tumor immunotherapy agent is an antagonist of an inhibitory receptor of an NK cell or an agonist of an activating receptor of an NK cell. In some embodiments, the tumor immunotherapy agent is an antagonist of a KIR, such as lirilumab.

[0251] In some embodiments, the tumor immunotherapeutic agent is RG7155 (WO2011 / 070024, US2011 / 0165156, WO2011 / 0107553, US2012 / 0329997, WO2011 / 131407, US2013 / 0005949, WO2013 / 087699, US2014 / 0336363, WO2013 / 119716, WO2013 / 132044, US2014 / 0329997 ... and agents that inhibit or deplete macrophages or monocytes, including, but not limited to, CSF-1R antagonists such as CSF-1R antagonist antibodies including FPA-008 (WO2011 / 140249, US2011 / 0274683; WO2013 / 169264; WO2014 / 036357, US2014 / 0079699).

[0252] In some embodiments, the immuno-oncology agent is selected from agonistic agents that ligate positive costimulatory receptors, blocking agents that attenuate signaling via inhibitory receptors, antagonists, and one or more agents that systemically increase the frequency of anti-tumor T cells, agents that overcome different immune suppressive pathways within the tumor microenvironment (e.g., blocking the engagement of inhibitory receptors (e.g., PD-L1 / PD-1 interactions), depleting or inhibiting Tregs (e.g., using anti-CD25 monoclonal antibodies (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), inhibiting metabolic enzymes such as IDO, or reversing / preventing T cell energy or exhaustion), and agents that induce innate immune activation and / or inflammation at the tumor site.

[0253] In some embodiments, the tumor immunotherapy agent is a CTLA-4 antagonist. In some embodiments, the CTLA-4 antagonist is an antagonistic CTLA-4 antibody. In some embodiments, the antagonistic CTLA-4 antibody is YERVOY (ipilimumab) or tremelimumab.

[0254] In some embodiments, the tumor immunotherapy agent is a PD-1 antagonist. In some embodiments, the PD-1 antagonist is administered by injection. In some embodiments, the tumor immunotherapy agent is an antibody or antigen-binding portion thereof that specifically binds to the programmed cell death-1 (PD-1) receptor and inhibits PD-1 activity. In some embodiments, the PD-1 antagonist is an antagonistic PD-1 antibody. In some embodiments, the antagonistic PD-1 antibody is OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514; WO2012 / 145493). In some embodiments, the tumor immunotherapy agent can be pidilizumab (CT-011). In some embodiments, the tumor immunotherapy agent is a recombinant protein called AMP-224, which consists of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1.

[0255] In some embodiments, the immuno-oncology agent is a PD-L1 antagonist. In some embodiments, the PD-L1 antagonist is an antagonistic PD-L1 antibody. In some embodiments, the PD-L1 antibody is MPDL3280A (RG7446; WO2010 / 077634, US2010 / 0203056), durvalumab (MEDI4736), BMS-936559 (WO2007 / 005874, US2009 / 0055944), and MSB0010718C (WO2013 / 079174, US2014 / 0341917).

[0256] In some embodiments, the tumor immunotherapy agent is a LAG-3 antagonist. In some embodiments, the LAG-3 antagonist is an antagonistic LAG-3 antibody. In some embodiments, the LAG3 antibody is BMS-986016 (WO2010 / 019570, US2010 / 0150892, WO2014 / 008218, US2014 / 0093511), or IMP-731 or IMP-321 (WO2008 / 132601, US2010 / 0233183, WO2009 / 044273, US2011 / 0008331).

[0257] In some embodiments, the tumor immunotherapy agent is a CD137 (4-1BB) agonist. In some embodiments, the CD137 (4-1BB) agonist is an agonistic CD137 antibody. In some embodiments, the CD137 antibody is urelumab or PF-05082566 (WO12 / 32433).

[0258] In some embodiments, the tumor immunotherapy agent is a GITR agonist. In some embodiments, the GITR agonist is an agonistic GITR antibody. In some embodiments, the GITR antibody is BMS-986153, BMS-986156, TRX-518 (WO2006 / 105021, US2007 / 0098719, WO2009 / 009116, US2009 / 0136494), or MK-4166 (WO2011 / 028683, US2012 / 0189639).

[0259] In some embodiments, the immuno-oncology agent is an indoleamine (2,3)-dioxygenase (IDO) antagonist. In some embodiments, the IDO antagonist is selected from the group consisting of epacadostat (INCB024360, Incyte); indoximod (NLG-8189, NewLink Genetics Corporation); capmanitinib (INC280, Novartis); GDC-0919 (Genentech / Roche); PF-06840003 (Pfizer); BMS:F001287 (Bristol-Myers Squibb); Phy906 / KD108 (Phytoceutica); and an enzyme that breaks down kynurenine (Kynase, Kyn Therapeutics); and NLG-919 (WO2009 / 073620, US2011 / 053941, WO2009 / 132238, US2011 / 136796, WO2011 / 056652, US2012 / 277217, WO2012 / 142237, US2014 / 066625).

[0260] In some embodiments, the tumor immunotherapy agent is an OX40 agonist. In some embodiments, the OX40 agonist is an agonistic OX40 antibody. In some embodiments, the OX40 antibody is MEDI-6383 or MEDI-6469.

[0261] In some embodiments, the tumor immunotherapy agent is an OX40L antagonist. In some embodiments, the OX40L antagonist is an antagonistic OX40 antibody. In some embodiments, the OX40L antagonist is RG-7888 (WO2006 / 029879, US7,501,496).

[0262] In some embodiments, the tumor immunotherapy agent is a CD40 agonist. In some embodiments, the CD40 agonist is an agonistic CD40 antibody. In some embodiments, the tumor immunotherapy agent is a CD40 antagonist. In some embodiments, the CD40 antagonist is an antagonistic CD40 antibody. In some embodiments, the CD40 antibody is lucatumumab or dacetuzumab.

[0263] In some embodiments, the tumor immunotherapy agent is a CD27 agonist. In some embodiments, the CD27 agonist is an agonistic CD27 antibody. In some embodiments, the CD27 antibody is varlilumab.

[0264] In some embodiments, the tumor immunoagent is MGA271 (against B7H3) (WO2011 / 109400, US2013 / 0149236).

[0265] In some embodiments, the immuno-oncology agent is selected from the group consisting of abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, atezolimab, avelumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab, pidilizumab, rituximab, ticilimumab, samalizumab, or tremelimumab.

[0266] In some embodiments, the tumor immunotherapy agent is an immunostimulant. For example, antibodies that block the PD-1 and PD-L1 inhibitory axis can release activated tumor-reactive T cells and have been shown in clinical trials to induce durable antitumor responses in an increasing number of tumor histologies, including some tumor types that were not previously considered sensitive to immunotherapy. See, for example, Okazaki, T. et al. (2013) Nat.Immunol. 14, 1212-1218; Zou et al. (2016) Sci.Transl.Med. 8. Nivolumab (Opdivo®, Bristol-Myers Squibb, also known as ONO-4538, MDX1106 and BMS-936558), an anti-PD-1 antibody, has shown the potential to improve overall survival in patients with RCC who have experienced disease progression during or after previous antiangiogenic therapy.

[0267] In some embodiments, the immunomodulatory therapeutic agent specifically induces apoptosis of tumor cells. Approved immunomodulatory therapeutic agents that can be used in the present invention include pomalidomide (Pomalyst®, Celgene); lenalidomide (Revlimid®, Celgene); ingenol mebutate (Picato®, LEO Pharma).

[0268] In some embodiments, the immunomodulatory therapeutic agent is a cancer vaccine. In some embodiments, the cancer vaccine is selected from sipuleucel-T (Provenge®, Dendreon / Valeant Pharmaceuticals), approved for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant (hormone refractory) prostate cancer; and talimogene laherparepvec (Imlygic®, BioVex / Amgen, formerly known as T-VEC), a genetically modified oncolytic virus therapy approved for the treatment of unresectable cutaneous, subcutaneous and nodal lesions of melanoma.In some embodiments, the tumor immunotherapy agent is an oncolytic virotherapy such as PexaVec / JX-594 (SillaJen / formerly Jennerex Biotherapeutics), a thymidine kinase-(TK-) deficient vaccinia virus engineered to express GM-CSF, for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312); Biotech) (mutants of respiratory enterovirus that do not replicate in cells that are not activated by RAS in a number of cancers, including colorectal cancer (NCT01622543); prostate cancer (NCT01619813); head and neck squamous cell carcinoma (NCT01166542); pancreatic adenocarcinoma (NCT00998322); and non-small cell lung cancer (NSCLC) (NCT00861627); metastatic or progressive cancers, such as ovarian cancer (NCT02028117), colorectal cancer, bladder cancer, head and neck squamous cell carcinoma, and salivary gland cancer (NCT02636036) Enadenotusileb (NG-348, PsiOxus, formerly known as ColoAd1) (an adenovirus engineered to express full-length CD80 and an antibody fragment specific for the T-cell receptor CD3 protein) in skin tumors; ONCOS-102 (Targovax / formerly Oncos) (an adenovirus engineered to express GM-CSF) in melanoma (NCT03003676), and peritoneal disease, colorectal cancer, or ovarian cancer (NCT02963831); GL-ONC1 (GLV-1h68 / GLV-1h153, Genelux) (an adenovirus engineered to express GM-CSF) in melanoma (NCT03003676), and peritoneal disease, colorectal cancer, or ovarian cancer (NCT02963831). GmbH) (vaccinia viruses engineered to express beta-galactosidase (beta-gal) / beta-glucoronidase or beta-gal / human sodium iodide symporter (hNIS) have been investigated in peritonitis carcinoma (NCT01443260); fallopian tube and ovarian cancers (NCT02759588), respectively); or CG0070 (Cold Genesys) (adenovirus engineered to express GM-CSF) in bladder cancer (NCT02365818).

[0269] In some embodiments, the immuno-oncology agents include JX-929 (SillaJen / formerly Jennerex Biotherapeutics) (TK and vaccinia growth factor deficient vaccinia viruses engineered to express cytosine deaminase capable of converting the prodrug 5-fluorocytosine to the cytotoxic drug 5-fluorouracil); TG01 and TG02 (Targovax / formerly Oncos) (peptide-based immunotherapeutics targeting refractory RAS mutations); and TILT-123 (TILT Biotherapeutics) (an engineered adenovirus designated Ad5 / 3-E2F-delta24-hTNFα-IRES-hIL20); and VSV-GP (ViraTherapeutics) (an engineered adenovirus engineered to express the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV) and expressing antigen-specific CD8 + The antibodies are selected from vesicular stomatitis virus (VSV), which can be further engineered to express antigens designed to enhance T cell responses.

[0270] In some embodiments, the tumor immunotherapy agent is a T cell that has been engineered to express a chimeric antigen receptor, or CAR. Such T cells that have been engineered to express a chimeric antigen receptor are called CAR-T cells.

[0271] CARs are constructed that consist of a binding domain, which can be derived from a single chain variable fragment (scFv) that is a natural ligand derived from a monoclonal antibody specific for a cell surface antigen, and is fused to an endodomain that is the functional end of a T cell receptor (TCR), such as the CD3-zeta signaling domain derived from the TCR, which can generate an activation signal in T lymphocytes. Upon binding to an antigen, such a CAR links to an endogenous signaling pathway in an effector cell, generating an activation signal similar to that initiated by the TCR complex.

[0272] For example, in some embodiments, the CAR-T cell is one of those described in US8,906,682 (each of which is incorporated herein by reference in its entirety), which discloses CAR-T cells engineered to include an extracellular domain with an antigen-binding domain (e.g., a domain that binds to CD19) fused to an intracellular signaling domain of the T cell antigen receptor complex zeta chain (e.g., CD3 zeta). When expressed in T cells, CARs can redirect antigen recognition based on antigen-binding specificity. In the case of CD19, the antigen is expressed on malignant B cells. Over 200 clinical trials are currently underway using CAR-T in a wide range of indications. [https: / / clinicaltrials.gov / ct2 / results?term=chimeric+antigen+receptors&pg=1].

[0273] In some embodiments, the immune stimulant is an activator of retinoic acid receptor-related orphan receptor gamma (RORγt). RORγt is a transcription factor that plays a key role in the differentiation and maintenance of type 17 effector subsets of CD4+ (Th17) and CD8+ (Tc17) T cells, as well as in the differentiation of innate immune cell subsets that express IL-17, such as NK cells. In some embodiments, the activator is LYC-55716 (Lycera), which is currently being evaluated in clinical trials for the treatment of solid tumors (NCT02929862).

[0274] In some embodiments, the immune stimulant is a toll-like receptor (TLR) agonist or activator. Suitable activators of TLR include TLR9 agonists or activators, such as SD-101 (Dynavax). SD-101 is an immune stimulatory CpG currently under investigation for follicular B-cell and other lymphomas (NCT02254772). TLR8 agonists or activators that can be used in the present invention include motolimod (VTX-2337, VentiRx Pharmaceuticals), currently under investigation for head and neck squamous cell carcinoma (NCT02124850) and ovarian cancer (NCT02431559).

[0275] Other tumor immunotherapy agents that may be used in the present invention include urelumab (BMS-663513, Bristol-Myers Squibb), an anti-CD137 monoclonal antibody; varilumab (CDX-1127, Celldex Therapeutics), an anti-CD27 monoclonal antibody; BMS-986178 (Bristol-Myers Squibb), an anti-OX40 monoclonal antibody; lirilumab (IPH2102 / BMS-986015, Innate Pharma, Bristol-Myers Squibb), an anti-KIR monoclonal antibody; monalizumab (IPH2201, Innate Pharma, AstraZeneca) an anti-NKG2A monoclonal antibody; andecaliximab (GS-5745, Gilead Sciences), an anti-MMP9 antibody; MK-4166 (Merck & Co., Inc., 2011). Co.), and anti-GITR monoclonal antibody.

[0276] In some embodiments, the immune stimulant is selected from elotuzumab, mifamurtide, agonists or activators of toll-like receptors, and activators of RORγt.

[0277] In some embodiments, the immunostimulatory therapeutic is recombinant human interleukin 15 (rhIL-15). rhIL-15 has been tested in the clinic as a therapeutic for melanoma and renal cell carcinoma (NCT01021059 and NCT01369888), and leukemia (NCT02689453). In some embodiments, the immunostimulatory agent is recombinant human interleukin 12 (rhIL-12). In some embodiments, the IL-15-based immunotherapeutic agent is heterodimeric IL-15 (hetIL-15, Novartis / Admune), a fusion complex consisting of a synthetic form of endogenous IL-15 complexed to the soluble IL-15 binding protein IL-15 receptor alpha chain (IL15:sIL-15RA), which has been tested in phase 1 clinical trials for melanoma, renal cell carcinoma, non-small cell lung cancer, and head and neck squamous cell carcinoma (NCT02452268). In some embodiments, the recombinant human interleukin-12 (rhIL-12) is NM-IL-12 (Neumedicines, Inc.), NCT02544724, or NCT02542124.

[0278] In some embodiments, the immuno-oncology agent is selected from those described in Jerry L. Adams et al., "Big opportunities for small molecules in immuno-oncology," Cancer Therapy 2015, Vol. 14, pages 603-622, the entire contents of which are incorporated herein by reference. In some embodiments, the immuno-oncology agent is selected from the examples described in Table 1 of Jerry L. Adams et al. In some embodiments, the immuno-oncology agent is a small molecule that targets a tumor immunological target selected from those listed in Table 2 of Jerry L. Adams et al. In some embodiments, the immuno-oncology agent is a small molecule agent selected from those listed in Table 2 of Jerry L. Adams et al.

[0279] In some embodiments, the tumor immunotherapy agent is selected from the small molecule tumor immunotherapy agents described in Peter L. Toogood, "Small molecule immuno-oncology therapeutic agents," Bioorganic & Medicinal Chemistry Letters 2018, Vol. 28, pages 319-329, the contents of which are incorporated by reference in their entirety. In some embodiments, the tumor immunotherapy agent is an agent that targets a pathway described in Peter L. Toogood.

[0280] In some embodiments, the tumor immunotherapy agent is selected from those described in Sandra L. Ross et al., "Bispecific T cell engager (BiTE®) antibody constructs can mediate bystander tumor cell killing", PLoS ONE 12(8):e0183390, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the tumor immunotherapy agent is a bispecific T cell engager (BiTE®) antibody construct. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct is a CD19 / CD3 bispecific antibody construct. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct is an EGFR / CD3 bispecific antibody construct. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct activates T cells. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct activates T cells, which release cytokines that induce upregulation of intercellular adhesion molecule 1 (ICAM-1) and FAS on bystander cells. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct activates T cells, which results in induction of bystander cell lysis. In some embodiments, the bystander cells are in a solid tumor. In some embodiments, the bystander cells that lyse are in the vicinity of the BiTE®-activated T cells. In some embodiments, the bystander cells comprise tumor-associated antigen (TAA) negative cancer cells. In some embodiments, the bystander cells comprise EGFR negative cancer cells. In some embodiments, the tumor immunoagent is an antibody that blocks the PD-L1 / PD1 axis and / or CTLA4. In some embodiments, the tumor immunoagent is ex vivo expanded tumor infiltrating T cells.In some embodiments, the tumor immunotherapeutic agent is a bispecific antibody construct or a chimeric antibody receptor (CAR) that directly links T cells to tumor-associated surface antigens (TAAs).

[0281] Exemplary Immune Checkpoint Inhibitors In some embodiments, the tumor immunotherapy agent is an immune checkpoint inhibitor as described herein.

[0282] The term "checkpoint inhibitor" as used herein refers to an agent that is useful for preventing cancer cells from evading the immune system of patients.One of the main mechanisms of antitumor immune destruction is known as "T cell exhaustion", which is caused by long-term exposure to antigen, which leads to the upregulation of inhibitory receptors.These inhibitory receptors act as immune checkpoints to prevent indiscriminate immune responses.

[0283] PD-1 and co-inhibitory receptors such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), B- and T-lymphocyte attenuator (BTLA; CD272), T-cell immunoglobulin and mucin domain-3 (Tim-3), and lymphocyte-activation gene-3 (Lag-3; CD223) are often referred to as checkpoint regulators. They act as molecular "gatekeepers" that allow extracellular information to dictate whether cell cycle progression and other intracellular signaling processes should proceed.

[0284] In some embodiments, the immune checkpoint inhibitor is an antibody to PD-1, which binds to the programmed cell death 1 receptor (PD-1) and blocks the receptor from binding to the inhibitory ligand PDL-1, thus abolishing the ability of the tumor to suppress the host's anti-tumor immune response.

[0285] In one aspect, the checkpoint inhibitor is a biological therapeutic agent or a small molecule.In another aspect, the checkpoint inhibitor is a monoclonal antibody, a humanized antibody, a fully human antibody, a fusion protein, or a combination thereof.In a further aspect, the checkpoint inhibitor inhibits checkpoint proteins selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligand, or a combination thereof. In additional aspects, the checkpoint inhibitor interacts with a ligand of a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligands, or combinations thereof. In some aspects, the checkpoint inhibitor is an immunostimulant, a T cell growth factor, an interleukin, an antibody, a vaccine, or combinations thereof. In further aspects, the interleukin is IL-7 or IL-15. In certain aspects, the interleukin is glycosylated IL-7. In additional aspects, the vaccine is a dendritic cell (DC) vaccine.

[0286] Checkpoint inhibitors include any agent that blocks or inhibits an inhibitory pathway of the immune system in a statistically significant manner. Such inhibitors can include small molecule inhibitors, or can include antibodies or antigen-binding fragments thereof that bind to and block or inhibit immune checkpoint receptors, or antibodies that bind to and block or inhibit immune checkpoint receptor ligands. Exemplary immune checkpoint molecules that can be targeted for blocking or inhibition include, but are not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (belonging to the CD2 family of molecules, and inhibiting NK, gamma delta, and memory CD8 +(expressed on all αβ T cells), CD160 (also called BY55), CGEN-15049, CHK1 and CHK2 kinases, A2aR and various B-7 family ligands. B7 family ligands include, but are not limited to, B7-1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7-H4, B7-H5, B7-H6 and B7-H7. Checkpoint inhibitors include antibodies or antigen-binding fragments thereof, other binding proteins, biotherapeutics or small molecules that bind to and block or inhibit the activity of one or more of CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160 and CGEN-15049. Exemplary immune checkpoint inhibitors include tremelimumab (CTLA-4 blocking antibody) (anti-OX40), PD-L1 monoclonal antibody (anti-B7-H1; MEDI4736), MK-3475 (PD-1 blocker), nivolumab (Inlyta®; axitinib; anti-PD1 antibody), CT-011 (anti-PD1 antibody), BY55 monoclonal antibody, AMP224 (anti-PDL1 antibody), BMS-936559 (anti-PDL1 antibody), MPLDL3280A (anti-PDL1 antibody), MSB0010718C (anti-PDL1 antibody), and ipilimumab (anti-CTLA-4 checkpoint inhibitor). Checkpoint protein ligands include, but are not limited to, PD-L1, PD-L2, B7-H3, B7-H4, CD28, CD86, and TIM-3.

[0287] In certain embodiments, the immune checkpoint inhibitor is selected from a PD-1 antagonist, a PD-L1 antagonist, and a CTLA-4 antagonist. In some embodiments, the checkpoint inhibitor is selected from the group consisting of nivolumab (Opdivo®), ipilimumab (Yervoy®), and pembrolizumab (Keytruda®). In some embodiments, the checkpoint inhibitor is selected from nivolumab (anti-PD-1 antibody, Opdivo®, Bristol-Myers Squibb); pembrolizumab (anti-PD-1 antibody, Keytruda®, Merck); ipilimumab (anti-CTLA-4 antibody, Yervoy®, Bristol-Myers Squibb); durvalumab (anti-PD-L1 antibody, Imfinzi®, AstraZeneca); and atezolizumab (anti-PD-L1 antibody, Tecentriq®, Genentech).

[0288] In some embodiments, the checkpoint inhibitor is selected from the group consisting of lambrolizumab (MK-3475), nivolumab (BMS-936558), pidilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A, BMS-936559, ipilimumab, lirlumab, IPH2101, pembrolizumab (Keytruda®), or tremelimumab.

[0289] In some embodiments, the immune checkpoint inhibitor is REGN2810 (Regeneron), an anti-PD-1 antibody tested in patients with basal cell carcinoma (NCT03132636); NSCLC (NCT03088540); cutaneous squamous cell carcinoma (NCT02760498); lymphoma (NCT02651662); and melanoma (NCT03002376); pidilizumab (CureTech), an antibody that binds to PD-1, also known as CT-011, in clinical trials for diffuse large B-cell lymphoma and multiple myeloma; avelumab (Bavencio®, Pfizer / Merck), in clinical trials for non-small cell lung cancer, Merkel cell carcinoma, mesothelioma, solid tumors, renal cancer, ovarian cancer, bladder cancer, head and neck cancer, and gastric cancer. KGaA) (also known as MSB0010718C, a fully human IgG1 anti-PD-L1 antibody); or PDR001 (Novartis), an inhibitory antibody that binds to PD-1, in clinical trials for non-small cell lung cancer, melanoma, triple-negative breast cancer and advanced, metastatic solid tumors. Tremelimumab (CP-675,206; Astrazeneca) is a fully human monoclonal antibody against CTLA-4 that has been investigated in clinical trials for several indications, including mesothelioma, colorectal cancer, renal cancer, breast cancer, lung and non-small cell lung cancer, pancreatic ductal adenocarcinoma, pancreatic cancer, germ cell cancer, squamous cell carcinoma of the head and neck, hepatocellular carcinoma, prostate cancer, endometrial cancer, metastatic cancer in the liver, liver cancer, large B-cell lymphoma, ovarian cancer, cervical cancer, metastatic anaplastic thyroid cancer, urothelial carcinoma, fallopian tube cancer, multiple myeloma, bladder cancer, soft tissue sarcoma, and melanoma. AGEN-1884 (Agenus) is an anti-CTLA4 antibody currently being investigated in a Phase 1 clinical trial for advanced solid tumors (NCT02694822).

[0290] In some embodiments, the checkpoint inhibitor is an inhibitor of T cell immunoglobulin mucin-containing protein-3 (TIM-3). TIM-3 inhibitors that can be used in the present invention include TSR-022, LY3321367, and MBG453. TSR-022 (Tesaro) is an anti-TIM-3 antibody currently under investigation in solid tumors (NCT02817633). LY3321367 (Eli Lilly) is an anti-TIM-3 antibody currently under investigation in solid tumors (NCT03099109). MBG453 (Novartis) is an anti-TIM-3 antibody currently under investigation in advanced malignancies (NCT02608268).

[0291] In some embodiments, the checkpoint inhibitor is an inhibitor of T cell immunoreceptor with Ig and ITIM domains, i.e. TIGIT, which is an immunoreceptor on certain T cells and NK cells.The TIGIT inhibitors that can be used in the present invention include BMS-986207 (Bristol-Myers Squibb), anti-TIGIT monoclonal antibody (NCT02913313); OMP-313M32 (Oncomed); and anti-TIGIT monoclonal antibody (NCT03119428).

[0292] In some embodiments, the checkpoint inhibitor is an inhibitor of lymphocyte activation gene-3 (LAG-3). LAG-3 inhibitors that can be used in the present invention include BMS-986016 and REGN3767 and IMP321. BMS-986016 (Bristol-Myers Squibb), an anti-LAG-3 antibody, is currently being investigated in glioblastoma and gliosarcoma (NCT02658981). REGN3767 (Regeneron) is also an anti-LAG-3 antibody, and is currently being investigated in malignant diseases (NCT03005782). IMP321 (Immutep SA) is a LAG-3-Ig fusion protein, and is currently being investigated in melanoma (NCT02676869); adenocarcinoma (NCT02614833); and metastatic breast cancer (NCT00349934).

[0293] Other checkpoint inhibitors that can be used in the present invention include OX40 agonists. OX40 agonists currently being investigated in clinical trials include PF-04518600 / PF-8600 (Pfizer) (agonistic anti-OX40 antibodies) in metastatic kidney cancer (NCT03092856) and advanced cancers and neoplasms (NCT02554812; NCT05082566); GSK3174998 (Merck) (agonistic anti-OX40 antibodies) in Phase 1 clinical trials for cancer (NCT02528357); MCT02318394 and NCT02705482 in advanced solid tumors. These include EDI0562 (Medimmune / AstraZeneca) (agonistic anti-OX40 antibody); MEDI6469 (agonistic anti-OX40 antibody) (Medimmune / AstraZeneca) in patients with colorectal cancer (NCT02559024), breast cancer (NCT01862900), head and neck cancer (NCT02274155) and metastatic prostate cancer (NCT01303705); and BMS-986178 (Bristol-Myers Squibb) (agonistic anti-OX40 antibody) in advanced cancers (NCT02737475).

[0294] Other checkpoint inhibitors that can be used in the present invention include CD137 (also called 4-1BB) agonists.CD137 agonists currently being investigated in clinical trials include utomirumab (PF-05082566, Pfizer) (agonistic anti-CD137 antibody) in diffuse large B-cell lymphoma (NCT02951156) and advanced cancer and neoplasms (NCT02554812 and NCT05082566); urelumab (BMS-663513, Bristol-Myers Squibb) (agonistic anti-CD137 antibody) in melanoma and skin cancer (NCT02652455) and glioblastoma and gliosarcoma (NCT02658981).

[0295] Other checkpoint inhibitors that can be used in the present invention include CD27 agonists.CD27 agonists currently being investigated in clinical trials include varlilumab (CDX-1127, Celldex Therapeutics) (agonistic anti-CD27 antibody) in squamous cell head and neck cancer, ovarian cancer, colorectal cancer, renal cell carcinoma and glioblastoma (NCT02335918), lymphoma (NCT01460134), and glioma and astrocytoma (NCT02924038).

[0296] Other checkpoint inhibitors that can be used in the present invention include glucocorticoid-induced tumor necrosis factor receptor (GITR) agonists. GITR agonists currently being investigated in clinical trials include TRX518 (Leap Therapeutics) (agonistic anti-GITR antibody) in melanoma and other solid tumors (NCT01239134 and NCT02628574); GWN323 (Novartis) (agonistic anti-GITR antibody) in solid tumors and lymphomas (NCT 02740270); INCAGN01876 (Incyte / Agenus) (agonistic anti-GITR antibody) in advanced cancers (NCT02697591 and NCT03126110); MK-4166 (Merck) (agonistic anti-GITR antibody) in solid tumors (NCT02132754), and MEDI1873 (Medimmune / AstraZeneca) (human IgG1 agonistic hexameric GITR ligand molecules having an Fc domain.

[0297] Other checkpoint inhibitors that can be used in the present invention include inducible T cell costimulator (ICOS, also known as CD278) agonists. ICOS agonists currently being investigated in clinical trials include MEDI-570 (Medimmune) (agonistic anti-ICOS antibody) in lymphoma (NCT02520791); GSK3359609 (Merck) (agonistic anti-ICOS antibody) in phase 1 trial (NCT02723955); JTX-2011 (Jounce Therapeutics) (agonistic anti-ICOS antibody) in phase 1 trial (NCT02904226).

[0298] Other checkpoint inhibitors that can be used in the present invention include killer IgG-like receptor (KIR) inhibitors. KIR inhibitors currently being investigated in clinical trials include lirilumab (IPH2102 / BMS-986015, Innate Pharma / Bristol-Myers Squibb), an anti-KIR antibody, in leukemia (NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma (NCT02252263), and lymphoma (NCT01592370); IPH2101 (1-7F9, Innate Pharma), in myeloma (NCT01222286 and NCT01217203); and IPH4102 (Innate Pharma), an anti-KIR antibody that binds to the long cytoplasmic tail three domain (KIR3DL2), in lymphoma (NCT02593045).

[0299] Other checkpoint inhibitors that can be used in the present invention include CD47 inhibitors of the interaction between CD47 and signal regulatory protein alpha (SIRPa). CD47 / SIRPa inhibitors currently under investigation in clinical trials include ALX-148 (Alexo Therapeutics), in a Phase 1 trial (NCT03013218), an antagonistic variant of (SIRPa) that binds to CD47 and blocks CD47 / SIRPa-mediated signaling; TTI-621 (SIRPa-Fc, Trillium Therapeutics), in Phase 1 clinical trials (NCT02890368 and NCT02663518), a soluble recombinant fusion protein generated by linking the N-terminal CD47-binding domain of SIRPa to the Fc domain of human IgG1, which binds to human CD47 and blocks human CD47 from its "do not eat me" message. These include CC-90002 (Celgene), an anti-CD47 antibody, in leukemia (NCT02641002); and Hu5F9-G4 (Forty Seven, Inc.), in colorectal neoplasia and solid tumors (NCT02953782), acute myeloid leukemia (NCT02678338), and lymphoma (NCT02953509).

[0300] Other checkpoint inhibitors that can be used in the present invention include CD73 inhibitors. CD73 inhibitors currently being investigated in clinical trials include MEDI9447 (Medimmune), an anti-CD73 antibody, in solid tumors (NCT02503774); and BMS-986179 (Bristol-Myers Squibb), an anti-CD73 antibody, in solid tumors (NCT02754141).

[0301] Other checkpoint inhibitors that can be used in the present invention include agonists of the stimulator of interferon genes protein (STING, also known as transmembrane protein 173 or TMEM173). Agonists of STING currently being investigated in clinical trials include MK-1454 (Merck), an agonistic synthetic cyclic dinucleotide, in lymphoma (NCT03010176); and ADU-S100 (MIW815, Aduro Biotech / Novartis), an agonistic synthetic cyclic dinucleotide, in Phase 1 trials (NCT02675439 and NCT03172936).

[0302] Other checkpoint inhibitors that can be used in the present invention include CSF1R inhibitors. CSF1R inhibitors currently being investigated in clinical trials include pexidartinib (PLX3397, Plexxikon) (CSF1R small molecule inhibitor) in colorectal cancer, pancreatic cancer, metastatic and advanced cancers (NCT02777710), as well as melanoma, non-small cell lung cancer, squamous cell head and neck cancer, gastrointestinal stromal tumor (GIST) and ovarian cancer (NCT02452424); and pancreatic cancer (NCT03153410), melanoma (NCT031012 54) and solid tumors (NCT02718911); and BLZ945 (4-[2((1R,2R)-2-hydroxycyclohexylamino)-benzothiazol-6-yloxyl]-pyridine-2-carboxylic acid methylamide, Novartis) (an orally available inhibitor of CSF1R) in advanced solid tumors (NCT02829723).

[0303] Other checkpoint inhibitors that can be used in the present invention include NKG2A receptor inhibitors.NKG2A receptor inhibitors currently being investigated in clinical trials include monalizumab (IPH2201, Innate Pharma), an anti-NKG2A antibody, in head and neck neoplasms (NCT02643550) and chronic lymphocytic leukemia (NCT02557516).

[0304] In some embodiments, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab. EXAMPLES

[0305] Example General synthesis method The following examples are intended to illustrate the invention and should not be construed as limitations thereon. Temperatures are given in degrees Celsius. Unless otherwise stated, all evaporations were carried out under reduced pressure, preferably at about 15 mmHg to 100 mmHg (=20 to 133 mbar). The structures of final products, intermediates and starting materials were confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, NMR. Abbreviations used are conventional in the art.

[0306] All starting materials, building blocks, reagents, acids, bases, solvents and catalysts utilized to synthesize the compounds of the present invention are either commercially available or can be prepared by organic synthesis methods known to those skilled in the art (Houben-Weyl 4th Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21). Additionally, the compounds of the present invention can be prepared by organic synthesis methods known to those skilled in the art, as shown in the following examples.

[0307] Unless otherwise stated, all reactions were carried out under nitrogen or argon.

[0308] Proton NMR ( 1 1 H NMR) was performed in a deuterated solvent. For certain compounds disclosed herein, one or more 1 The H shift overlaps with residual proteo solvent signals; these signals are not reported in the experiments presented below. [Table 2]

[0309] For acidic LCMS data: LCMS were recorded on an Agilent 1200 series LC / MSD or Shimadzu LCMS2020 equipped with electrospray ionization and quadrupole MS detector [ES+ve giving MH+], equipped with a Chromolith Flash RP-18e 25*2.0 mm, eluting with 0.0375 vol% TFA in water (solvent A) and 0.01875 vol% TFA in acetonitrile (solvent B). Other LCMS were recorded on an Agilent 6120 Infinity RRLC equipped with an Agilent 1290 mass detector. The column used was a BEH C18 50*2.1mm, 1.7 micron. The column flow rate was 0.55ml / min, and the mobile phases used were (A) 2mM ammonium acetate in 0.1% formic acid in water and (B) 0.1% formic acid in acetonitrile.

[0310] For basic LCMS data: LCMS was performed using electrospray ionization and a quadruple MS detector [ES+ve as MH + [giving a] and an Xbridge C18, 2.1 × 50 mm column packed with 5 mm of C18-coated silica, or a Kinetex EVO C18 2.1 × 30 mm column packed with 5 mm of C18-coated silica, and recorded on an Agilent 1200 Series LC / MSD or Shimadzu LCMS 2020 equipped with 0.05 vol% NH3·H2O in water (solvent A) and acetonitrile (solvent B).

[0311] HPLC analysis method: HPLC was performed on X Bridge C18 150*4.6mm, 5 micron. The column flow rate was 1.0ml / min, and the mobile phases were (A) 0.1% ammonia in water and (B) 0.1% ammonia in acetonitrile.

[0312] Preparative HPLC analytical method: Compounds were purified on a Shimadzu LC-20AP and UV detector. The column used was X-BRIDGE C18 (250×19) mm, 5μ. The column flow rate was 16.0 ml / min. The mobile phases used were (A) 0.1% formic acid in water and (B) acetonitrile. The basic method used was (A) 5 mM ammonium bicarbonate and 0.1% NH3 in water, and (B) acetonitrile or (A) 0.1% ammonium hydroxide in water and (B) acetonitrile. UV spectra were recorded at 202 nm and 254 nm.

[0313] NMR Methods: 1H NMR spectra were recorded on a Bruker Ultra Shield Advance 400MHz / 5mm Probe (BBFO). Chemical shifts are reported in parts per million.

[0314] As shown in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures: While the general methods are shown to synthesize certain specific compounds of the invention, it is understood that the following general methods, and other methods known to those of skill in the art, can be applied to all compounds and each subclass and species of these compounds as described herein.

[0315] Intermediates [1-[(4-Methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]trifluoromethanesulfonate (Intermediate A) [ka]

[0316] Step 1 - 5-Oxotetrahydrofuran-2-carboxylic acid To a solution of 2-aminopentanedioic acid (210 g, 1.43 mol, CAS#617-65-2) in HO (800 mL) and HCl (12 M, 210 mL) was added a solution of NaNO (147 g, 2.13 mol) in HO (400 mL) at -5 °C. The mixture was stirred at 15 °C for 12 h. Upon completion, the mixture was concentrated, then dissolved in EA (500 mL), filtered and washed with EA (3 x 100 mL). The filtrate and washing solution were dried over NaSO, filtered and concentrated in vacuo to give the title compound (200 g, crude) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ 6.43 (s, 1H), 5.02 - 4.95 (m, 1H), 2.67 - 2.38 (m, 4H)

[0317] Step 2 - N-[(4-Methoxyphenyl)methyl]-5-oxo-tetrahydrofuran-2-carboxamide To 5-oxotetrahydrofuran-2-carboxylic acid (120 g, 922 mmol) was added SOCl2 (246 g, 2.07 mol) slowly at 0 °C. The mixture was stirred at 85 °C for 3 h, then the mixture was stirred at 15 °C for 6 h. The mixture was concentrated in vacuum. The residue was dissolved in dry DCM (1 L) under N2 at 0 °C. Then, a solution of Et3N (187 g, 1.84 mol) and 4-methoxybenzylamine (101 g, 738 mmol) in DCM (400 mL) was added, then the mixture was stirred at 15 °C for 3 h. Upon completion, water (600 mL) was added and the mixture was extracted with DCM (3 x 300 mL). The combined organic phase was washed with 0.5 M HCl (500 mL), brine (500 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash silica gel chromatography (PE:EA=1:1) to give the title compound (138 g, 60% yield) as a yellow solid. 1H NMR (400MHz, CDCl3) δ 7.22 - 7.20 (d, J = 8.0, 1H), 6.89 - 6.87 (d, J = 8.0, 1H), 4.90 - 4.86 (m, 1H), 4.47 - 4.4.36 (m, 2H) 3.81 (s, 3H), 2.67 - 2.64 (m, 1H), 2.59 - 2.54 (m, 2H), 2.40 - 2.38 (m, 1H); LC-MS (ESI + ) m / z 272.0 (M+Na) + .

[0318] Step 3 - 3-Hydroxy-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione A solution of N-[(4-methoxyphenyl)methyl]-5-oxo-tetrahydrofuran-2-carboxamide (138 g, 553 mmol) in anhydrous THF (1500 mL) was cooled to -78 °C. Then, t-BuOK (62.7 g, 559 mmol) in a solution of anhydrous THF (1000 mL) was slowly added dropwise at -78 °C under nitrogen atmosphere. The resulting reaction mixture was stirred at -40 °C for 1 h. Upon completion, the reaction mixture was quenched with saturated NH4Cl solution (100 mL). The mixture was extracted with ethyl acetate (3 x 1500 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (PE:EA = 1:1) to give the title compound (128 g, 92% yield) as a white solid. 1 H NMR (400MHz, CDCl3) δ 7.39 - 7.32 (m, 2H), 6.89 - 6.81 (m, 2H), 4.91 (s, 2H), 4.17 - 4.11 (m, 1H), 3.80 (s, 3H), 3.54 (s, 1H), 2.98 - 2.87 (m, 1H), 2.73 - 2.60 (m, 1H), 2.26 - 2.20 (m, 1H), 1.80 (dq, J = 4.8, 13.1 Hz, 1H).

[0319] Step 4 - [1-[(4-Methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]trifluoromethanesulfonate To a solution of 3-hydroxy-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (43.0 g, 173 mmol) and pyridine (27.3 g, 345 mmol) in DCM (500 mL) was added trifluoromethylsulfonyl trifluoromethanesulfonate (73.0 g, 258 mmol) dropwise at 0° C. The mixture was stirred at −10° C. under N2 for 1.5 h. Upon completion, the mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE:EA=20:1 / 8:1) to give the title compound (45.0 g, 68% yield) as a pale yellow gum. 1 H NMR (400MHz, CDCl3) δ 7.36 (d, J = 8.4 Hz, 2H), 6.85 - 6.82 (m, 2H), 5.32 - 5.28 (m, 1H), 4.91 (s, 2H), 3.79 (s, 3H), 3.02 - 2.97 (m, 1H), 2.79 - 2.74 (m, 1H), 2.41 - 2.35 (m, 2H).

[0320] 5-Bromo-3-methyl-1H-benzimidazol-2-one (Intermediate D) [ka]

[0321] Step 1 - 5-Bromo-N-methyl-2-nitro-aniline 4-Bromo-2-fluoro-1-nitro-benzene (230 g, 1.05 mol, CAS#321-23-3) was added to a solution of mehylamine in tetrahydrofuran (2 M, 1.51 L). The mixture was stirred at 15° C. for 10 min. Upon completion, the mixture was diluted with H2O (250 mL) and extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound (200 g, 83% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ 8.22 (s, 1H), 7.98 (d, J = 9.2 Hz, 1H), 7.16 (d, J = 1.6 Hz, 1H), 6.82 (dd, J = 8.4, 1.6 Hz, 1H), 2.95 (d, J = 4.8 Hz, 3H).

[0322] Step 2 - 4-Bromo-N2-methyl-benzene-1,2-diamine To a mixture of 5-bromo-N-methyl-2-nitro-aniline (200 g, 865 mmol) in EtOAc (1 L) and H2O (500 mL) was added AcOH (1.00 L). The mixture was warmed to 50 °C, and then Fe (174 g, 3.11 mol) was added to the reaction mixture. The reaction mixture was then stirred at 80 °C for 6 h. Upon completion, the mixture was filtered through Celite. The filtrate was concentrated in vacuum and the residue was diluted with H2O (250 mL) and extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with aq. NaHCO3 and brine (300 mL), dried over Na2SO4, filtered, and concentrated in vacuum. The residue was purified by flash silica gel chromatography to give the title compound (130 g, 75% yield) as a black oil. 1H NMR (400MHz, DMSO-d6) δ 6.55 - 6.52 (m, 1H), 6.48 - 6.45(m, 1H), 6.43 - 6.42 (m, 1H), 4.89 - 4.88 (m, 1H), 4.61 (s, 2H), 2.70 (d, J = 4.0Hz, 3H).

[0323] Step 3 - 5-Bromo-3-methyl-1H-benzimidazol-2-one To a solution of 4-bromo-N2-methyl-benzene-1,2-diamine (110 g, 547 mmol) in CH3CN (1.3 L) was added CDI (177 g, 1.09 mol). The mixture was stirred at 80 °C under N2 for 6 h. Upon completion, the mixture was concentrated under reduced pressure. The mixture was diluted with H2O (1.0 L) and filtered. The filter cake was washed with water (3 x 200 mL) and dried in vacuum to give the title compound (106 g, 85% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ 11.00 (s, 1H), 7.33 (s, 1H), 7.13 (d, J =8.0 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 3.27 (s, 3H).

[0324] 3-(5-Bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (3-(5-Bromo-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)piperidine-2,6-dione) (Intermediate E) [ka]

[0325] Step 1 - 3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione To a solution of 5-bromo-3-methyl-1H-benzimidazol-2-one (4.90 g, 21.6 mmol, intermediate D) in THF (300 mL) was added t-BuOK (3.63 g, 32.3 mmol) at 0 °C. The mixture was stirred at 0-10 °C under N2 for 1 h. Then, a solution of [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]trifluoromethanesulfonate (9.87 g, 25.9 mmol, intermediate A) in THF (100 mL) was added to the reaction mixture over 30 min at 0-10 °C. The mixture was stirred at 0-10 °C under N2 for 30 min. An additional solution of [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]trifluoromethanesulfonate (2.47 g, 6.47 mmol) in THF (20 mL) was added dropwise to the reaction mixture at 0-10 °C. The mixture was then stirred for an additional 30 min at 0-10 °C under N2. Upon completion, the reaction was quenched with water (400 mL) and extracted with EA (3 x 200 mL). The combined organic layers were concentrated in vacuo. The residue was triturated with EA (80 mL) and filtered. The filter cake was collected and dried in vacuo to give the title compound (6.70 g, 67% yield) as a pale yellow solid. The filtrate was also concentrated in vacuo and the residue was purified by column chromatography to give another batch of the title compound (1.80 g, 18% yield) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d6) δ 7.47 (d, J = 1.6 Hz, 1H), 7.21 -7.16 (m, 3H), 7.01 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 8.8 Hz, 2H),5.55 - 5.51 (m, 1H), 4.84 - 4.73 (m, 2H), 3.72 (s, 3H), 3.33 (s, 3H), 3.04 -3.00 (m, 1H), 2.83 - 2.67 (m, 2H), 2.07 - 2.05 (m, 1H).

[0326] Step 2 - 3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione To a mixture of 3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (8.50 g, 18.6 mmol) in toluene (50 mL) was added methanesulfonic acid (33.8 g, 351 mmol, 25 mL) at room temperature (15° C.). The mixture was stirred at 120° C. for 2 h. Upon completion, the reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was poured into ice / water (200 mL) and extracted with EA (3×100 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated with EA (80 mL) and filtered. The filtrate cake was collected and dried in vacuo to give the title compound (4.20 g, 67% yield) as an off-white solid. 1 H NMR (400MHz, DMSO-d6) δ 11.12 (s, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.22(d, J = 8.4 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 5.40 - 5.35 (m,1H), 2.34 (s, 3H), 2.92 - 2.88 (m, 1H), 2.71 - 2.60 (m, 2H), 2.03 - 1.99 (m,1H).

[0327] 3-[3-Methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine-2,6-dione (Intermediate F) [ka]

[0328] Step 1-tert-Butyl 4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidine-1-carboxylate To a 40 mL vial equipped with a stir bar was added 3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (1.00 g, 2.96 mmol, intermediate E), tert-butyl 4-bromopiperidine-1-carboxylate (1.02 g, 3.84 mmol, CAS number 180695-79-8), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (33.18 mg, 29.57 umol), NiCl2.dtbbpy (5.88 mg, 14.7 umol), TTMSS (735 mg, 2.96 mmol), 2,6-dimethylpyridine (633.75 mg, 5.91 mmol) in DME (15 mL). The vial was sealed and placed under nitrogen. The reaction was stirred and irradiated with a 50 W [455 nm] blue LED lamp (3 cm away) and the reaction temperature was maintained at 25 °C for 14 h with cooling water. Upon completion, the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, DCM / ethyl acetate = 1:0 to 1:1) to give the title compound (1.13 g, 86% yield) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 11.18-10.94(m,1H),7.11(s,1H),7.01(d,J=8.0 Hz,1H),6.91(dd,J=0.8,8.0 Hz,1H),5.75(s,1H),5.33(dd,J=5.6,12.8 Hz,1H),4.09(d,J=11.2 Hz,2H),3.33(s,3H),2.95-2.83(m,2H),2.76-2.57(m,4H),1.75(d,J=12.0 Hz,2H),1.55(dq,J=4.0,12.4 Hz,2H),1.42(s,9H);LC-MS(ESI+)m / z 443.2(M+H) + .

[0329] Step 2-3-[3-Methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine-2,6-dione. To a solution of tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidine-1-carboxylate (150 mg, 338 umol) in DCM (3 mL) was added TFA (773 mg, 6.78 mmol). The mixture was stirred at 25° C. for 0.5 h. Upon completion, the mixture was concentrated to give the title compound (150 mg, 96.95% yield, TFA salt) as a colorless oil. LC-MS (ESI+) m / z 343.1 (M+H) + .

[0330] Chloro-(3-chloro-2-fluoro-phenyl)-oxo-dispiro[BLAH]carboxylic acid (Intermediate G) [ka]

[0331] Step 1 - (3E)-6-chloro-3-[(3-chloro-2-fluoro-phenyl)methylene]indolin-2-one A 500 mL three-neck round bottom flask was charged with 6-chloroindolin-2-one (89.6 g, 535 mmol, CAS number 56341-37-8), 3-chloro-2-fluoro-benzaldehyde (84.8 g, 535 mmol, CAS number 85070-48-0), MeOH (1700 mL) and piperidine (9.11 g, 107 mmol). The mixture was stirred at 65° C. for 5 h and then at 25° C. for 12 h. Upon completion, the reaction mixture was filtered and the filter cake was dried under reduced pressure to give the title product (160 g, 94% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.87 (s, 1H), 7.82 - 7.63 (m, 2H), 7.56 (s, 1H), 7.39 (t, J = 8.0 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.03 - 6.77 (m, 2H).

[0332] Step 2 - Chloro-(3-chloro-2-fluoro-phenyl)-diphenyl-dispiro[BLAH]dione (3E)-6-chloro-3-[(3-chloro-2-fluoro-phenyl)methylene]indolin-2-one (50 g, 162 mmol), (5R,6S)-5,6-diphenylmorpholin-2-one (49.3 g, 194 mmol, CAS number 282735-66-4) and cyclohexanone (31.8 g, 324 mmol, 33.6 mL) were dissolved in THF (75 mL) and toluene (750 mL) at 140 °C for 12 h. Upon completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 8 / 1 to 5 / 1) to give the title compound (160 g, purity 97%). 1 H NMR (400 MHz, DMSO-d6) δ = 10.79 (s, 1H), 7.95 ( t, J = 6.8 Hz, 1H), 7.45 - 7.37 (m, 1H), 7.33 - 7.20 (m, 4H), 7.18 - 7.09 (m, 4H), 7.07 - 6.98 (m, 2H), 6.86 - 6.75 (m, 3H), 6.66 (dd, J = 2.0, 8.4 Hz, 1H), 6.35 (d, J = 8.4 Hz, 1H), 5.44 (d, J = 11.2 Hz, 1H), 4.90 (d, J = 2.8 Hz, 1H), 4.58 (d, J = 11.2 Hz, 1H), 2.39 (d, J = 12.8 Hz, 1H), 2.24 - 2.09 (m, 1H), 1.42 - 1.18 (m, 4H), 1.10 - 0.78 (m, 1H).

[0333] Step 3 - Methyl chloro-(3-chloro-2-fluoro-phenyl)-[(1R,2S)-2-hydroxy-1,2-diphenyl-ethyl]-oxo-dispiro[BLAH]carboxylate To a solution of intermediate chloro-(3-chloro-2-fluoro-phenyl)-diphenyl-dispiro[BLAH]dione (9.0 g, 14.03 mmol) dissolved in MeOH (70 mL) was added H2SO4 (9.07 g, 92.5 mmol, 4.93 mL) and the resulting solution was heated to 50 °C for 5 h. Upon completion, the reaction mixture was cooled to 0 °C and slowly neutralized with saturated sodium bicarbonate solution. The aqueous solution was extracted with ethyl acetate and the organic layer was dried over sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by reverse phase flash [ACN / (0.1% FA in water), 0%-90%] to give the title compound (7.0 g, 84.2% purity). 1 H NMR (400 MHz, DMSO-d6) δ = 7.74 - 7.68 (m, 1H), 7.57 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 7.2 Hz, 4H), 7.25 (d, J = 7.6 Hz, 6H), 7.19 - 7.11 (m, 6H), 7.10 - 6.98 (m, 4H), 6.94 - 6.88 (m, 1H), 6.65 - 6.58 (m, 1H), 5.39 - 5.27 (m, 1H), 4.89 - 4.75 (m, 1H), 4.42 - 4.29 (m, 2H), 4.04 (q, J = 6.8 Hz, 1H), 3.63 - 3.53 (m, 2H), 3.40 (s, 3H), 2.22 - 2.12 (m, 1H), 2.05 - 1.94 (m, 3H), 1.40 - 1.32 (m, 2H), 1.28 - 1.13 (m, 3H).

[0334] Step 4 - Methyl chloro-(3-chloro-2-fluoro-phenyl)-oxo-dispiro[BLAH]carboxylate The resulting intermediate methyl chloro-(3-chloro-2-fluoro-phenyl)-[(1R,2S)-2-hydroxy-1,2-diphenyl-ethyl]-oxo-dispiro[BLAH]carboxylate (7.0 g, 10.3 mmol) was dissolved in ACN (78 mL) and then CAN (11.3 g, 20.7 mmol) was added followed by H2O (78 mL). The reaction was stirred at 25 °C for 30 min. Upon completion, the reaction mixture was quenched by adding it to cold saturated aqueous NaHCO3 solution (50 mL). The aqueous layer was extracted with ethyl acetate (20 mL x 3). The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 5 / 1) to give the title compound (1.58 g, purity 31%). LC-MS (ESI + ) m / z 477.2 (M+H) + .

[0335] Step 5 - Chloro-(3-chloro-2-fluoro-phenyl)-oxo-dispiro[BLAH]carboxylic acid Methyl chloro-(3-chloro-2-fluoro-phenyl)-oxo-dispiro[BLAH]carboxylate (2.00 g, 4.19 mmol) was dissolved in THF (14 mL) and diluted with LiOH . HO (527 mg, 12.5 mmol) was added followed by water (14 mL) and MeOH (2 mL) and the reaction was stirred at 25° C. for 15 min. Upon completion, water (20 mL) was added and the reaction was slowly neutralized with 2M HCl and the suspension was stirred for 15 min. The resulting precipitate was filtered and washed with water to give the title compound (1.50 g, 70% yield). 1H NMR (400 MHz, DMSO-d6) δ = 10.75 - 10.57 (m, 1H), 10.55 (s, 1H), 7.61 - 7.54 (m, 1H), 7.50 - 7.44 (m, 1H), 7.41 - 7.34 (m, 1H), 7.18 - 7.12 (m, 1H), 7.08 - 7.02 (m, 1H), 6.72 - 6.66 (m, 1H), 4.72 - 4.65 (m, 1H), 4.54 - 4.47 (m, 1H), 3.18 - 3.15 (m, 1H), 2.22 - 2.13 (m, 1H), 1.83 - 1.70 LC-MS (ESI) + ) m / z 463.2 (M+H) + .

[0336] tert-Butyl N-[4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidine-1-carbonyl]cyclohexyl]carbamate (Intermediate B) [ka]

[0337] To a solution of 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine-2,6-dione (4.30 g, 12.5 mmol) and 4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (3.67 g, 15.0 mmol, CAS number 130309-46-5) in ACN (80 mL) was added 1-methylimidazole (33.0 g, 401 mmol) and [chloro(dimethylamino)methylene]-dimethyl-ammonium;hexafluorophosphate (10.5 g, 37.6 mmol) at 25° C. The reaction solution was stirred at 25° C. for 2 minutes (the reaction was complete when the reaction became clear). Upon completion, the reaction mixture was concentrated in vacuo. The concentrated residue was purified by reverse phase flash [CAN / (0.1% TFA in water), 0%-90%] to give the title compound (6.70 g, 84% yield) as a white solid. LC-MS (ESI+) m / z 568.4 (M+H) +.

[0338] 3-[5-[1-(4-aminocyclohexanecarbonyl)-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate C) [ka]

[0339] To a mixture of tert-butyl N-[4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidine-1-carbonyl]cyclohexyl]carbamate (5.70 g, 10.0 mmol) in DCM (5 mL) was added HCl / dioxane (4 M, 58 mL) in one portion under N2 at 25° C. The mixture was stirred at 25° C. for 30 min. Upon completion. The reaction mixture was concentrated in vacuo to give the title compound (4.69 g, crude, HCl salt) as a white solid. LC-MS (ESI+) m / z 468.3 (M+H) +.

[0340] Example 1. Synthesis of (3'R,4'S,5'R)-6''-chloro-4'-(3-chloro-2-fluorophenyl)-N-((1r,4R)-4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-1-carbonyl)cyclohexyl)-2''-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indoline]-5'-carboxamide (Compound A) [ka] To a solution of 3-[5-[1-(4-aminocyclohexanecarbonyl)-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate C, 4.24 g, 9.06 mmol) and chloro-(3-chloro-2-fluoro-phenyl)-oxo-dispiro[BLAH]carboxylic acid (Intermediate G, 3.50 g, 7.55 mmol) in ACN (100 mL) was added [chloro(dimethylamino)methylene]-dimethyl-ammonium;hexafluorophosphate (6.36 g, 22.6 mmol) and 1-methylimidazole (19.8 g, 241 mmol) at 25° C. The reaction solution was stirred at 25° C. for 2 minutes (the reaction was complete when the reaction became clear). Upon completion, the reaction mixture was concentrated in vacuo. The concentrated residue was purified by reverse phase flash [ACN / (0.1% FA in water), 0%-90%] to give the title compound (5.10 g, 72% yield) as a white solid. 1H NMR(400 MHz,DMSO-d6)δ 11.08(s,1H),10.52(s,1H),7.77(d,J=8.0 Hz,1H),7.58(t,J=6.8 Hz,1H),7.41(d,J=8.0 Hz,1H),7.32(t,J=7.2 Hz,1H),7.15-7.08(m,2H),7.06-6.98(m,2H),6.92(d,J=8.0 Hz,1H),6.67(s,1H),5.34(dd,J=5.2,12.7 Hz,1H),4.56(d,J=9.2 Hz,2H),4.37(d,J=9.2 Hz,1H),4.09(br d,J=11.6 Hz,1H),3.55-3.45(m,1H),3.36-3.33(m,3H),3.16-3.05(m,1H),2.94-2.84(m,1H),2.80(t,J=12.0 Hz,1H),2.75-2.67(m,1H),2.64(s,1H),2.60(s,1H),2.56-2.52(m,1H),2.05- 1.91(m,2H),1.90-1.82(m,2H),1.81-1.70(m,5H),1.59(s,4H),1.48(d,J=13.6 Hz,4H),1.41-1.28(m,4H),1.00-0.74(m,2H).LC-MS(ESI+)m / z 912.4(M+H) +

[0341] Compounds B, C, D and E can be prepared by methods similar to compound A or as disclosed in WO2021 / 188948, the contents of which are incorporated herein by reference in their entirety.

[0342] Example 2. In vitro and in vivo experiments Compound A was tested in vitro in MDM2-dependent cell lines and in subcutaneous and disseminated mouse AML and ALL xenograft models. Methods included in vitro cell proliferation and apoptosis assays, gene expression profiling, and in vivo pharmacological studies.

[0343] Cell line:

[0344] All cell lines (RS4;11, MOLM-13, MV-4-11, OCI-Ly10, OCI-Ly19, Kasumi-1, 92-1, Mel202, SK-MEL-28) were sourced from ATCC (https: / / www.atcc.org), ECACC (https: / / www.sigmaaldrich.com) or DSMZ (https: / / www.dsmz.de) and cultured at 37 °C and 5% CO2 in the recommended culture medium. The identity of each cell line was confirmed by a 48-mutant SNP panel and confirmed to be mycoplasma-free.

[0345] In vitro cell viability and apoptosis:

[0346] In vitro cell viability in all cell lines was assessed using the Cell Titer Glo (Promega) assay, performed over 24-96 hours of compound treatment at optimized growth conditions. Compound treatment was performed using an 11-point dose response, 3-fold serial dilutions starting at a maximum concentration of 1 uM. IC 50 ,I C 90 Values ​​were calculated by curve fitting using appropriate nonlinear regression fits in GraphPad Prism. Cell cycle arrest and / or apoptosis in response to single agent or combination treatments was assessed using flow cytometry analysis for cells treated for 24 hours.

[0347] For washout assays, cells were treated with the serial dilutions described above for 4–24 h. At the end of the treatment period (4, 8, 16, and 24 h), cells were washed twice with complete medium, plated in 384-well plates, and incubated for 24–72 h. Cells were assessed for viability using the Cell Titer Glo (Promega) assay and for apoptosis using the Caspase Glo 3 / 7 (Promega) assay 24, 48, and 72 h after the start of treatment.

[0348] In vivo studies using subcutaneous xenografts:

[0349] Female mice, 5-8 week old mice NOD / SCID mice from SPF(Beijing)experimental Animal Science Technology Co.,ltd. Animals were received, housed and observed for 7 days before the start of the study. For tumor development, each mouse was subcutaneously inoculated with RS4;11 tumor cells (1×107) in 0.1 ml of RPMI1640 containing 10% FBS. Groups and treatments were initiated when the mean tumor volume reached approximately 100 mm3 for the study. Mice were randomly assigned to their respective groups based on tumor volume using a computer-generated randomization procedure. Compound A was formulated in 20% HP-β-CD at a concentration up to 0.1 mg / mL and administered intravenously to tumor-bearing animals. Tumor size was measured in three dimensions 2-3 times a week using calipers. Tumor size measurements were performed twice a week using calipers and recorded. Tumor volume (mm 3 ) was estimated using the formula: TV=a×b2 / 2, where "a" and "b" are the long and short diameters of the tumor, respectively.

[0350] At various time points, tumor-bearing animals were sacrificed and plasma and tumors were collected for pharmacokinetic and pharmacodynamic determinations.

[0351] In vivo studies using seeded xenografts:

[0352] Female mice, 5-8 week old NOD / SCID mice from SPF(Beijing)experimental Animal Science Technology Co.,ltd. Animals were received, housed, and observed for 7 days before the start of the study. Each mouse would bear tumor cells in 0.1ml PBS via tail vein injection. Groups and treatments began 4 days after inoculation. Mice were randomly assigned to their respective groups based on body weight using a computer-generated randomization procedure. Compound A was formulated in 20% HP-β-CD at concentrations up to 0.1mg / mL and administered intravenously to tumor-bearing animals.

[0353] PD assessment in in vitro and in vivo samples:

[0354] Downstream markers of altered p53 activity were identified using TaqMan™ Array, Human p53-Mediated Apoptosis (Thermo Fisher Scientific, 4418812) and TaqMan™ Array, Human p53 Signaling (Thermo Fisher Scientific, 4418813). A short list of eight markers (MDM2, GDF15, CDKN1A, GADD45A, TNFRSF10B, FAS, BBC3, BAX) was validated and used for PD assessment. Cataloged Taqman assays for all markers were obtained from Thermo Fisher Scientific.

[0355] In vivo AML experiments

[0356] AML patient cells from leukapheresis were injected intravenously (IV) and established in immunocompromised host strain mice. Surrogates were used to determine the level of engraftment targeting a threshold of approximately 20% huCD45+ cells in the BM. Mice were randomized at the time of study and treatment was initiated. Vehicle and Compound A, 1 mg / kg, were administered IV every 3 weeks for 6 weeks (total of 2 doses of Compound A). At the end of the study, whole blood, bone marrow and spleen were evaluated by flow cytometry.

[0357] result:

[0358] Figure 1 shows that Compound A exhibits rapid and potent degradation of MDM2. 293T cells stably expressing C-terminal HiBiT-tagged MDM2 were treated with Compound A or the small molecule inhibitor DS-3032 in a 3-fold serial dilution dose response with a maximum concentration of 1 mM for 4 hours. Degradation efficacy was measured as a decrease in HiBiT signal and quantified using the Nano-Glo® HiBiT lysis detection system (Promega).

[0359] Figure 2 shows that compound A in cancer cells shows strong stabilization of p53. Acute lymphoblastic leukemia cells (RS4;11) were treated with compound A or the small molecule inhibitor DS-3032 in a 3-fold serial dilution dose response at a maximum concentration of 1 mM for 2 hours (4 hours, 8 hours and 24 hours - data not shown). p53 levels were quantified using the p53 MSD assay (total p53 whole cell lysate kit, MSD, K150DBD-2).

[0360] Figure 3 shows that Compound A potently inhibits cancer cell proliferation compared to SMI. Acute lymphoblastic leukemia cells (RS4;11) were treated with Compound A or the small molecule inhibitor DS-3032 in a 3-fold serial dilution dose response with a maximum concentration of 1 mM for 24 hours. Growth inhibition was quantified using the Cell titer glo (Promega) assay with continuous treatment for 24 hours.

[0361] Figure 4 shows that short-term exposure to Compound A is sufficient to induce apoptosis. Acute lymphoblastic leukemia cells (RS4;11) were treated with the indicated concentrations of Compound A or the small molecule inhibitor DS-3032 for 4 hours (8 hours, 16 hours, 24 hours - data not shown). Apoptotic activity was quantified as an increase in caspase activity measured using the Caspase Glo® 3 / 7 Assay System (Promega). Compared to DS-3032, a short 4-hour exposure to Compound A followed by washout was sufficient to potently induce apoptosis in cancer cells measured 24 or 48 hours after treatment. Figure 5 shows a schematic of the washout experiment performed on RS4;11 cells.

[0362] Compound A was administered as a single intravenous bolus at doses of 1, 3 and 10 mg / kg in RS411 tumor-bearing mice. In panel A, FIG. 6 shows that compound A demonstrated dose-responsive antitumor activity, resulting in sustained tumor regression at doses as low as 1 mg / kg. In panel B, FIG. 6 shows that MDM2 degradation by compound A at 1 mg / kg caused a significant upregulation of protein markers (such as, but not limited to, p53, p21 and PUMA) in tumor xenografts, peaking at 6 hours after administration. Changes in the levels of protein markers in degrader-treated xenografts were quantified compared to vehicle-treated xenografts using Western blot assays. Clinically equivalent doses of SMI had no significant in vivo effects in these xenograft models.

[0363] Using a mouse xenograft model, an intermittent dosing schedule that drives antitumor efficacy is demonstrated. Importantly, a single dose of 1 mg / kg of Compound A resulted in sustained tumor regression in the RS4;11 mouse xenograft model. In this model, Compound A exposure correlated with induction of apoptotic p53 target genes and tumor growth inhibition. Furthermore, weekly administration of Compound A significantly extended survival in a disseminated AML model when compared to vehicle-treated animals.

[0364] Summarizing Figures 1-6, Compound A exhibits significantly improved potency compared to reversible SMI, resulting in potent in vitro and in vivo efficacy superior to all clinically active agents. For example, total cell killing CTG IC in RS4;11 50are 0.3 nm for Compound A; 67 nm for DS-3032 (Sankyo / Rain); 220 nm for RG7388 (Roche); 620 nm for SAR405838 (Sanofi); 163 nm for HDM201 (Novartis); and 280 nm for AMG-232 (Amgen / Kartos). Furthermore, an intermittent dosing schedule of Compound A can induce rapid apoptosis in MDM2-dependent cancer cells, potentially leading to improved efficacy and safety profiles.

[0365] Figures 7A and 7B show that Compound A (1 mg / kg, Q3W) achieves tumor regression in the CTG-2227 AML patient-derived xenograft (PDX) model and partial responses in the CTG-2240 and CTG-2700 AML PDX models. Compound A significantly reduces hCD45+ cells in bone marrow and AML blasts.

[0366] Figures 8A and 8B show the benefit of combining Compound A with venetoclax and midostaurin in MOLM-13 cell lines. The data show that the combination of Compound A with venetoclax and midostaurin enhances the induction of apoptosis and cell death in MOLM-12 AML cell lines.

[0367] Figure 9 shows significant combination benefit of Compound A with standard of care in an AML in vivo model. A single dose of Compound A combined with daily administration of venetoclax achieves durable tumor regression in a MOLM-13 xenograft model, whereas cytarabine or the combination of cytarabine and venetoclax show no significant antitumor activity.

[0368] FIG. 10 shows that Compound A is active across multiple heme indications in vitro, with AML, T-cell lymphoma, mantle cell lymphoma, and DLBCL being the most sensitive.

[0369] FIG. 11 shows that compound A inhibits p53WT Compound A shows high activity in ABC subtype DLBCL. WT Highly active in ABC subtype DLBCL xenograft model (A), but not TMD8 p53 MUT It was not active in an ABC subtype DLBCL xenograft model (B).

[0370] Summarizing Figures 7-11, Compound A administered intermittently is highly active, leading to responses and complete regressions in AML PDX xenograft models. Compound A shows benefit in combination with SoC agents in AML in vitro and in vivo models, suggesting that the Compound A combination could be used in a larger patient population. Preclinical data suggests that Compound A may be active in additional hematological malignancies such as DLBCL.

[0371] Although the inventors have described several embodiments of the invention, it is clear that the inventors' basic examples may be modified to provide other embodiments that utilize the compounds and methods of the invention. It will therefore be understood that the scope of the invention should be defined by the appended claims, and not by the specific embodiments represented by way of example.

Claims

1. 1. A method of treating a solid cancer or hematological malignancy in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of an MDM2 degrading agent, or a pharma- ceutical acceptable salt thereof, wherein said MDM2 degrading agent is (3'R,4'S,5'R)-6''-chloro-4'-(3-chloro-2-fluorophenyl)-N-((1R,4R)-4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-1-carbonyl)cyclohexyl)-2''-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indoline]-5'-carboxamide (compound A), (3'R,4'S,5'R)-6''-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-N-((6S)-6-((5-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)pentyl)carbamoyl)tetrahydro-2H-pyran-3-yl)-4,4-dimethyl-2''-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indoline]-5'-carboxamide (compound B); (3'R,4'S,5'R)-6''-chloro-4'-(3-chloro-2-fluorophenyl)-N-((1r,4R)-4-((2-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)cyclohexyl)-1'-methyl-2''-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indoline]-5'-carboxamide (compound C); (3'R,4'S,5'R)-6''-chloro-4'-(3-chloro-2-fluorophenyl)-N-(4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-1-carbonyl)phenyl)-2''-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indoline]-5'-carboxamide (compound D); or (3'R,4'S,5'R)-6''-chloro-4'-(3-chloro-2-fluorophenyl)-N-((1r,4R)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidine-1-carbonyl)cyclohexyl)-2''-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indoline]-5'-carboxamide (Compound E).

2. 10. The method of claim 1, wherein the MDM2 degrading agent or a pharma- ceutically acceptable salt thereof is administered to the patient at a dose of up to 0.8 mg / kg.

3. 3. The method of claim 1 or claim 2, wherein the MDM2 degrading agent or a pharma- ceutically acceptable salt thereof is administered to the patient at a dose of up to 0.65 mg / kg.

4. The method of any one of claims 1 to 3, wherein the MDM2 degrading agent or a pharma- ceutically acceptable salt thereof is administered to the patient at a dose of up to 0.5 mg / kg.

5. 10. The method of claim 1, wherein the MDM2 degrading agent or a pharma- ceutically acceptable salt thereof is administered to the patient at a dose of about 0.3 mg / kg to about 0.6 mg / kg.

6. 10. The method of claim 1, wherein the MDM2 degrading agent or a pharma- ceutically acceptable salt thereof is administered to the patient at a dose of about 0.5 mg / kg to about 0.8 mg / kg.

7. 10. The method of claim 1, wherein the MDM2 degrading agent, or a pharma- ceutically acceptable salt thereof, is administered to the patient at a dose of up to 50 mg.

8. 10. The method of claim 1, wherein the MDM2 degrading agent or a pharma- ceutically acceptable salt thereof is administered to the patient at a dose of up to 40 mg.

9. 10. The method of claim 1, wherein the MDM2 degrading agent, or a pharma- ceutically acceptable salt thereof, is administered to the patient at a dose of up to 30 mg.

10. 10. The method of claim 1, wherein the MDM2 degrading agent, or a pharma- ceutically acceptable salt thereof, is administered to the patient in a dose of about 10 mg to about 40 mg.

11. 10. The method of claim 1, wherein the MDM2 degrading agent, or a pharma- ceutically acceptable salt thereof, is administered to the patient in a dose of about 20 mg to about 50 mg.

12. The MDM2 degrader or a pharma- ceutically acceptable salt thereof is administered in a dose of up to 30 mg / m ２ The method of claim 1, wherein the patient is administered a dose of

13. The MDM2 degrader or a pharma- ceutically acceptable salt thereof is administered in a dose of up to 20 mg / m ２ The method of claim 1, wherein the patient is administered a dose of

14. The MDM2 degrader or a pharma- ceutically acceptable salt thereof is administered in a dose of up to 10 mg / m ２ The method of claim 1, wherein the patient is administered a dose of

15. The MDM2 degrading agent or a pharma- ceutically acceptable salt thereof is administered in an amount of about 1 mg / m ２ ~Approx. 10mg / m ２ The method of claim 1, wherein the patient is administered a dose of

16. The MDM2 degrading agent or a pharma- ceutically acceptable salt thereof is administered in an amount of about 5 mg / m ２ ~Approx. 15mg / m ２ The method of claim 1, wherein the patient is administered a dose of

17. The method of any one of claims 1 to 16, wherein the MDM2 degrading agent or a pharma- ceutically acceptable salt thereof is administered orally to the patient.

18. 18. The method of claim 17, wherein the oral administration of the MDM2 degrading agent to the patient comprises a solution, suspension, emulsion, tablet, pill, capsule, powder, or sustained release formulation.

19. The method of any one of claims 1 to 16, wherein the MDM2 degrading agent, or a pharma- ceutically acceptable salt thereof, is administered intravenously to the patient.

20. 20. The method of claim 19, wherein said intravenous administration of said MDM2 degrading agent to said patient comprises a sterile injectable solution.

21. The method of any one of claims 1 to 20, wherein the MDM2 degrading agent, or a pharma- ceutically acceptable salt thereof, is administered to the patient once weekly (QW).

22. The method of any one of claims 1 to 20, wherein the MDM2 degrading agent, or a pharma- ceutically acceptable salt thereof, is administered to the patient once every two weeks (Q2W).

23. 21. The method of any one of claims 1 to 20, wherein the MDM2 degrading agent, or a pharma- ceutically acceptable salt thereof, is administered to the patient once every three weeks (Q3W).

24. 24. The method of any one of claims 1 to 23, wherein the MDM2 degrading agent or a pharma- ceutically acceptable salt thereof is administered as a pharmaceutical composition comprising one or more pharma- ceutically acceptable excipients or carriers.

25. 25. The pharmaceutical composition of claim 24, wherein the one or more pharma- ceutically acceptable excipients or carriers comprise one or more diluents, preservatives, binders, lubricants, disintegrants, swelling agents, fillers or stabilizers.

26. 25. The pharmaceutical composition of claim 24, wherein the one or more pharma- ceutically acceptable excipients or carriers comprise one or more buffers, surfactants, dispersing agents, emulsifiers or viscosity modifiers.

27. The solid cancer or hematological malignancy is selected from the group consisting of acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), large granular lymphocytic leukemia (LGL-L), B-cell prolymphocytic leukemia, acute myeloid leukemia (AML), Burkitt's lymphoma / leukemia, primary effusion lymphoma, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), diffuse large B-cell lymphoma (DLBCL), aggressive B-cell diffuse large B-cell lymphoma (ABCCL), and / or aggressive B-cell lymphoma (BCCL).

27. The method of any one of claims 1 to 26, wherein the tumor is selected from: DLBCL), intravascular large B-cell lymphoma, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, uveal melanoma, or myelodysplastic syndrome (MDS).

28. The method of any one of claims 1 to 27, wherein the patient has undergone at least one previous treatment.

29. The method of any one of claims 1 to 28, wherein the patient is a human.

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