Methods of treating cancer

Abstract

This invention describes treatment methods and pharmaceutical compositions for treating cancers in human individuals, including myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis. In some embodiments, the invention includes a treatment method for MPN using an MDM2 inhibitor of formula (I) or formula (II).

Description

Methods for treating cancer Disclosed herein are methods of using mouse double minute 2 homolog (MDM2) inhibitors to treat cancers including myeloproliferative neoplasms (MPNs). p53 is a tumor suppressor and transcription factor that responds to cellular stress by activating the transcription of a large number of genes associated with cell cycle arrest, apoptosis, aging, and DNA repair. Unlike normal cells that rarely cause p53 activation, tumor cells are under constant cellular stress from a variety of damages, including hypoxia and activation of pro-apoptotic oncogenes. Therefore, inactivation of the p53 pathway in tumors has great selective benefits, and it has been proposed that eliminating p53 function may be a prerequisite for tumor survival. Supporting this concept, three groups of researchers have used mouse models to demonstrate that the lack of p53 function is required to maintain established tumors. When researchers restored p53 function to tumors with inactivated p53, the tumors regressed. In 50% of solid tumors and 10% of liquid tumors, p53 is inactivated by mutation and / or deletion. Other key members of the p53 pathway are also genetically or epigenetically altered in cancer. MDM2 is an oncoprotein that inhibits p53 function and is activated by gene amplification, with a reported incidence of up to 10%. MDM2 is in turn inhibited by another tumor suppressor, p14ARF. It has been proposed that changes downstream of p53 may be responsible for at least partial inactivation of the p53 pathway in p53 WT (p53 wild type) tumors. Supporting this concept, some p53WT tumors appear to exhibit reduced apoptosis ability, but their ability to undergo cell cycle arrest remains intact. A cancer treatment strategy involves the use of small molecules that bind to MDM2 and neutralize its interaction with p53. MDM2 inhibits p53 activity through three mechanisms: 1) acting as an E3 ubiquitin ligase to promote p53 degradation; 2) binding to and blocking the p53 transcriptional activation domain; and 3) exporting p53 from the nucleus to the cytoplasm. All three of these mechanisms are blocked by neutralizing the MDM2-p53 interaction. Specifically, this treatment strategy can be applied to p53 WT tumors, and studies using small molecule MDM2 inhibitors have shown promise in reducing tumor growth in vitro and in vivo. Furthermore, in patients with p53-inactivated tumors, stabilizing wild-type p53 in normal tissues through MDM2 inhibition may allow for selective protection of normal tissues from mitogenic toxins. As used herein, MDM2 refers to the human MDM2 protein and p53 refers to the human p53 protein. It should be noted that human MDM2 may also be referred to as HDM2 or hMDM2. Several MDM2 inhibitors are in human clinical trials for the treatment of various cancers. Myeloproliferative neoplasms (MPNs), including but not limited to polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are disorders of the selective proliferation of terminally differentiated myeloid cells that affect hematopoietic stem cells (HSCs). Approximately 1%, 4%, and 20% of patients with ET, PV, and PMF, respectively, progress to blast crisis (BP), known as MPN-BP, within 10 years of diagnosis. Cervantes F et al., Acta Haematol.1991 ;85 (3 ):124 -127. MPN-BP and de novo acute myeloid leukemia (AML) have different mutation patterns and clinical courses. Rampal R et al., Proc Natl Acad Sci USA. 2014; 111(50):E5401-10. The prognosis for patients with MPN-BP is particularly dismal, with a median survival of less than 6 months with currently available therapies. The present invention relates to methods of treating myeloproliferative neoplasms in human subjects using MDM2 inhibitors, alone or in combination with one or more other pharmaceutically active agents. The present invention relates to the use of MDM2 inhibitors, alone or in combination with one or more other pharmaceutically active agents, for the treatment of myeloproliferative neoplasms (MPNs). The present invention relates to a method for treating myeloproliferative neoplasms (MPNs), comprising administering to a human in need thereof a therapeutically effective amount of an MDM2 inhibitor, wherein the MDM2 inhibitor is a compound of formula (I) or formula (II): or a pharmaceutically acceptable salt thereof. In one embodiment, the MPN is selected from the group consisting of polycythemia vera (PV), myelofibrosis, primary myelofibrosis, thrombocythemia, essential thrombocythemia, idiopathic myelofibrosis, systemic mastocytosis (SM), chronic neutrophilic leukemia (CNL), myelodysplastic syndrome (MDS), and systemic mast cell disease (SMCD). In one embodiment, the MPN is selected from the group consisting of polycythemia vera (PV), primary myelofibrosis, and essential thrombocythemia. In one embodiment, the MPN is polycythemia vera (PV). In one embodiment, the MPN is essential thrombocythemia. In one embodiment, the MPN is myelofibrosis. In one embodiment, the myelofibrosis is selected from primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV MF), and post-essential thrombocythemia myelofibrosis (post-ET MF). In one embodiment, the human subject has failed treatment with ruxolitinib for any of the above MPNs. In one embodiment, the human subject has failed treatment with ruxolitinib for myelofibrosis. In one embodiment, the human subject has failed treatment with ruxolitinib for primary myelofibrosis (PMF). In one embodiment, the human subject has failed treatment with ruxolitinib for post-polycythemia vera myelofibrosis (post-PV MF). In one embodiment, the human subject has failed treatment with ruxolitinib for post-essential thrombocythemia myelofibrosis (post-ET MF). In one embodiment, the present invention relates to a method for treating polycythemia vera (PV), comprising the step of administering to a human in need thereof a therapeutically effective amount of an MDM2 inhibitor, wherein the MDM2 inhibitor is a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention relates to a method for treating essential thrombocythemia, comprising administering to a human in need thereof a therapeutically effective amount of an MDM2 inhibitor, wherein the MDM2 inhibitor is a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention relates to a method for treating primary myelofibrosis, comprising administering to a human in need thereof a therapeutically effective amount of an MDM2 inhibitor, wherein the MDM2 inhibitor is a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention relates to a method for treating idiopathic myelofibrosis, comprising administering to a human in need thereof a therapeutically effective amount of an MDM2 inhibitor, wherein the MDM2 inhibitor is a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention relates to a method for treating chronic myeloid leukemia (CML), comprising administering to a human in need thereof a therapeutically effective amount of an MDM2 inhibitor, wherein the MDM2 inhibitor is a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention relates to a method for treating acute myeloid leukemia (AML), comprising administering to a human in need thereof a therapeutically effective amount of an MDM2 inhibitor, wherein the MDM2 inhibitor is a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention relates to a method for treating Merkel cell carcinoma (MCC), comprising administering to a human in need thereof a therapeutically effective amount of an MDM2 inhibitor, wherein the MDM2 inhibitor is a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention relates to a method for treating systemic mastocytosis (SM), comprising the step of administering to a human in need thereof a therapeutically effective amount of an MDM2 inhibitor, wherein the MDM2 inhibitor is a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention relates to a method for treating chronic neutrophilic leukemia (CNL), comprising administering to a human in need thereof a therapeutically effective amount of an MDM2 inhibitor, wherein the MDM2 inhibitor is a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention relates to a method for treating myelodysplastic syndrome (MDS), comprising administering to a human in need thereof a therapeutically effective amount of an MDM2 inhibitor, wherein the MDM2 inhibitor is a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention relates to a method for treating systemic mast cell disease (SMCD), comprising administering to a human in need thereof a therapeutically effective amount of an MDM2 inhibitor, wherein the MDM2 inhibitor is a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof. In one embodiment, the thrombocythemia is essential thrombocythemia (ET). In one embodiment, the compound of Formula (I) or Formula (II) is in a crystalline form. In one embodiment, the crystalline form is characterized by a powder X-ray diffraction pattern comprising at least three peaks at a diffraction angle 2θ° selected from the group consisting of: peaks at approximately 11.6, 12.4, 18.6, 19.0, 21.6, and 23.6±0.1. In one embodiment, the compound of Formula (I) or Formula (II) is in amorphous form. In one embodiment, the compound of formula (I) or formula (II) is in free form. In one embodiment, the MDM2 inhibitor is a pharmaceutically acceptable salt of a compound of Formula (I) or Formula (II). In one embodiment, the compound of Formula (I) or Formula (II) is administered once daily at a dose selected from the group consisting of 15 mg, 25 mg, 30 mg, 50 mg, 60 mg, 75 mg, 90 mg, 100 mg, 120 mg, 150 mg, 175 mg, 180 mg, 200 mg, 225 mg, 240 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 360 mg, 375 mg, and 480 mg. In one embodiment, the compound of Formula (I) or Formula (II) is administered twice daily at a dose selected from the group consisting of 15 mg, 25 mg, 30 mg, 50 mg, 60 mg, 75 mg, 90 mg, 100 mg, 120 mg, 150 mg, 175 mg, 180 mg, 200 mg, 225 mg, 240 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 360 mg, 375 mg, and 480 mg. In one embodiment, the human is treated with a compound of Formula (I) for a period selected from the group consisting of about 14 days, about 21 days, about 28 days, about 35 days, about 42 days, about 49 days, and about 56 days. In one embodiment, the compound of Formula (I) or Formula (II) is administered orally. An MDM2 inhibitor for treating myeloproliferative neoplasms (MPNs), comprising administering a therapeutically effective amount of the MDM2 inhibitor to a human in need thereof, wherein the MDM2 inhibitor is a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof. While preferred embodiments of the present invention are shown and described herein, such embodiments are provided by way of example only and are not intended to limit the scope of the invention in other respects. Various alternatives to the described embodiments of the invention may be used to implement the invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, the terms "administered in combination" and "co-administered" encompass the administration of two or more active pharmaceutical ingredients to a subject such that both agents and / or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration of separate compositions at different times, or administration in a composition in which both agents are present. The term "effective amount" or "therapeutically effective amount" refers to an amount of an active pharmaceutical ingredient or combination of active pharmaceutical ingredients, as described herein, sufficient to achieve the intended application, including, but not limited to, disease treatment. A therapeutically effective amount can vary depending on the intended application (in vitro or in vivo) or the subject and disease condition being treated (e.g., the subject's weight, age, and sex), the severity of the disease condition, the route of administration, and other factors readily determined by one of ordinary skill. The term also applies to a dose that induces a specific response in target cells (e.g., a decrease in platelet adhesion and / or cell migration). The specific dose will vary depending on the specific compound selected, the dosing regimen followed, whether the compound is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system used to deliver it. As used herein, the terms "enantiomerically enriched," "enantiomerically pure," and "non-racemic" refer to compositions in which the weight percentage of one enantiomer exceeds the amount of the other enantiomer in a controlled mixture of racemic compositions (e.g., greater than 1:1 by weight). For example, an enantiomerically enriched preparation of the (S)-enantiomer means a preparation of a compound having greater than about 50% by weight (such as at least 75% by weight, such as at least 80% by weight) of the (S)-enantiomer relative to the (R)-enantiomer. In some embodiments, the enrichment can be far greater than 80% by weight, thereby resulting in a "substantially enantiomerically enriched," "substantially enantiomerically pure," or "substantially non-racemic" preparation, which refers to a preparation of a composition having at least 85% by weight, such as at least 90% by weight, and for example, at least 95% by weight, of one enantiomer relative to the other enantiomer. As used herein, the terms "diastereomerically enriched" and "diastereomerically pure" refer to compositions in which the weight percentage of one diastereomer exceeds the amount of the other diastereomer in a controlled mixture of diastereomers. In some embodiments, the enrichment can be well over 80% by weight, thereby resulting in a "substantially diastereomerically enriched" or "substantially diastereomerically pure" preparation, which refers to a composition preparation having at least 85%, such as at least 90%, and for example at least 95% by weight of one diastereomer relative to the other diastereomer. In preferred embodiments, the enantiomerically enriched composition has a higher potency per unit mass of therapeutic utility than the racemic mixture of the composition. Enantiomers can be separated from the mixture using methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions, Wiley Interscience, New York (1981); EL Eliel and SH Wilen, Stereochemistry of Organic Compounds, Wiley-Interscience, New York (1994). As used herein, "enantiomeric purity" refers to the relative amount of one particular enantiomer present relative to the other enantiomer, expressed as a percentage. For example, if a compound that may have either (R)- or (S)-isomer configurations exists as a racemic mixture, the enantiomeric purity with respect to either the (R)-isomer or the (S)-isomer is about 50%. If the compound has a significant excess of one isomer form over the other, for example, 80% ( S)-isomer and 20% ( R)-isomer, then about ( The enantiomeric purity of the compound in its (S)-isomer form was 80%. The enantiomeric purity of a compound can be determined by a variety of methods known in the art, including, but not limited to, chromatography using a chiral support, polarimetric measurement of polarized light rotation, nuclear magnetic resonance spectroscopy using chiral shift reagents including, but not limited to, lanthanide-containing chiral complexes or Pirkle alcohol, or compound derivatization using a chiral compound such as Mosher's acid, followed by chromatography or nuclear magnetic resonance spectroscopy. The term "IC 50 ” refers to the half-maximal inhibitory concentration, which is the activity required to inhibit 50%. The term “EC 50 ” refers to the drug concentration that achieves a half-maximal response. "Isomers" are different compounds with the same molecular formula. "Stereoisomers" are isomers that differ only in the arrangement of their atoms in space, i.e., have different stereochemical configurations. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term "(±)" is used to indicate a racemic mixture where appropriate. "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When a compound is pure enantiomerically, it can be determined by R or S specifies the stereochemistry at each chiral carbon. Resolved compounds whose absolute configuration is unknown may be assigned (+) or (-), depending on the direction (right-handed or left-handed) in which the compound rotates plane-polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and may therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms, which, in terms of absolute stereochemistry, may be defined as ( R)-or( S)-. The chemical entities, pharmaceutical compositions and methods of the present invention are intended to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active ( R)-and( S)-isomers can be prepared using chiral synthetic components or reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry and unless otherwise indicated, it is intended that the compounds include E and Z-type geometric isomer. "MPN-BP" refers to the blast crisis phase of myeloproliferative neoplasms (MPNs) described in this invention. "Pharmaceutically acceptable carriers" or "pharmaceutically acceptable excipients" are intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents. The use of such media and agents for active pharmaceutical ingredients is well known in the art. Unless any conventional media or agents are incompatible with the active pharmaceutical ingredient, they are contemplated for use in the therapeutic compositions of the present invention. Supplementary active ingredients may also be incorporated into the compositions. The term "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counterions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines; substituted amines including naturally occurring substituted amines; cyclic amines; and basic ion exchange resins. Specific examples include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In selected embodiments, pharmaceutically acceptable base addition salts are selected from potassium, sodium, calcium, and magnesium salts. The term "co-crystal" refers to a molecular complex derived from a large number of co-crystal formers known in the art. Unlike salts, co-crystals generally do not involve proton transfer between the co-crystal and the drug, and actually involve intermolecular interactions between the co-crystal former and the drug in the crystal structure, such as hydrogen bonding, aromatic ring stacking, or dispersion forces. The term "QD," "qd," or "qd" means once daily, once a day, or once daily. The term "BID," "bid," or "bid" means twice a day, twice a day, or twice daily. The term "TID," "tid," or "tid" means three times a day, three times a day, or three times daily. The term "QID," "qid," or "qid" means four times a day, four times a day, or four times daily. "Solvate" refers to a compound in physical association with one or more molecules of a pharmaceutically acceptable solvent. "Therapeutic effect" as the term is used herein encompasses therapeutic benefit and / or prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, arresting or reversing the progression of a disease or condition, or any combination thereof. When ranges are used herein to describe a physical property, such as molecular weight, or a chemical property, such as a chemical formula, all combinations and subcombinations of the ranges and specific embodiments herein are intended to be included. The use of the term "about" in reference to a number or numerical range means that the referenced number or numerical range is an approximation within experimental variability (or within statistical experimental error), such that the number or numerical range may vary, for example, from 1% to 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") includes embodiments such as embodiments of any composition of matter, method, or process that "consists of" or "consists essentially of" the stated features. The compounds of the present invention also include crystalline and amorphous forms of the compounds of Formula (I) or Formula (II), including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), configurational polymorphs, and amorphous forms of the compounds, and mixtures thereof. Unless a specific crystalline or amorphous form is mentioned, "crystalline form" and "polymorph" are intended to include all crystalline and amorphous forms of the compound, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), configurational polymorphs, and amorphous forms, and mixtures thereof. Methods for treating cancer The present invention relates to a method for treating cancer, comprising the step of administering a mouse double minute 2 homolog (MDM2) inhibitor or a pharmaceutically acceptable salt thereof to a human in need thereof, wherein the cancer is selected from the group consisting of carcinomas such as bladder cancer, breast cancer, colon cancer, rectal cancer, kidney cancer, liver cancer, lung cancer (small cell lung cancer and non-small cell lung cancer), esophageal cancer, gallbladder-bladder cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer, head and neck cancer, and skin cancer (including basal cell carcinoma and squamous cell carcinoma, melanoma skin cancer, Merkel cell carcinoma, Kaposi Sarcoma, cutaneous lymphoma); hematopoietic tumors of the lymphoid lineage (including leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma); The invention relates to a novel class of cancers that are classified as MDM2 inhibitors, including hematopoietic neoplasms (including acute and chronic myeloid leukemias, myelodysplastic syndromes, and promyelocytic leukemias); mesenchymal tumors (including fibrosarcomas and rhabdomyosarcomas, and other sarcomas, such as those of soft tissue and bone); central and peripheral nervous system tumors (including astrocytomas, neuroblastomas, gliomas, glioblastomas, and schwannomas); and other tumors (including melanomas, seminoma, teratocarcinomas, osteosarcomas, xeroderma pigmentosum, keratoacanthoma, and follicular thyroid carcinoma). In one embodiment, the MDM2 inhibitor is a compound of Formula (I) or Formula (II). In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, Serdemetan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. The present invention relates to the use of a mouse double minute 2 homolog (MDM2) inhibitor or a pharmaceutically acceptable salt thereof for treating cancer in a human in need thereof, wherein the cancer is selected from the group consisting of carcinomas such as bladder cancer, breast cancer, colon cancer, rectal cancer, kidney cancer, liver cancer, lung cancer (small cell lung cancer and non-small cell lung cancer), esophageal cancer, gallbladder-bladder cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer, head and neck cancer, and skin cancer (including basal cell carcinoma and squamous cell carcinoma, melanoma skin cancer, Merkel cell carcinoma, Kaposi's sarcoma, cutaneous lymphoma); hematopoietic tumors of the lymphoid lineage (including leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, acute myeloid leukemia); The invention also includes the following: hematopoietic neoplasms (including acute and chronic myeloid leukemias, myelodysplastic syndromes, and promyelocytic leukemias); mesenchymal tumors (including fibrosarcomas and rhabdomyosarcomas and other sarcomas, such as those of soft tissue and bone); central and peripheral nervous system tumors (including astrocytomas, neuroblastomas, gliomas, glioblastomas, and schwannomas); and other tumors (including melanomas, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, and follicular thyroid carcinoma). In one embodiment, the MDM2 inhibitor is a compound of formula (I) or formula (II). In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. Treatment of myeloproliferative neoplasms (MPN) The present invention relates to a method for treating MPNs, comprising administering a mouse double minute 2 homolog (MDM2) inhibitor or a pharmaceutically acceptable salt thereof to a human in need thereof. In one embodiment, the MPN is selected from the group consisting of polycythemia vera (PV), myelofibrosis, primary myelofibrosis, thrombocythemia, essential thrombocythemia (ET), idiopathic myelofibrosis, systemic mastocytosis (SM), chronic neutrophilic leukemia (CNL), myelodysplastic syndrome (MDS), and systemic mastocytosis (SMCD). In one embodiment, the myelofibrosis is selected from the group consisting of primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV MF), and post-essential thrombocythemia myelofibrosis (post-ET MF). In one embodiment, primary myelofibrosis (PMF) is selected from the group consisting of pre-fibrotic / early PMF and overt fibrotic PMF. In one embodiment, the MPN is selected from the group consisting of chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia, chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), juvenile myelomonocytic leukemia (JMML), hypereosinophilic syndrome (HES), and myelodysplasia / myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS / MPN-RS-T). In one embodiment, the polycythemia vera is phlebotomy-dependent polycythemia vera. In one embodiment, the human subject is determined to be hydroxyurea (HU) intolerant (unacceptable side effects). In one embodiment, the human subject is determined to be resistant to hydroxyurea (HU) (inadequate response). In one embodiment, the human subject has splenomegaly. In one embodiment, the human subject has splenomegaly and is phlebotomy-dependent. In one embodiment, the human subject is phlebotomy-dependent and does not have splenomegaly. In one embodiment, the human subject has failed treatment with ruxolitinib. Failure of ruxolitinib treatment includes, but is not limited to, (i) failure to reduce the severity of any MPN in the human subject receiving ruxolitinib or progression of any MPN; or (ii) recurrence of any MPN in the human subject following ruxolitinib treatment. In one embodiment, failure of ruxolitinib treatment is failure to reduce the severity of any MPN in the human subject receiving ruxolitinib or progression of any MPN. In one embodiment, failure of ruxolitinib treatment is recurrence of any MPN in the human subject following ruxolitinib treatment. In one embodiment, the MDM2 inhibitor is a compound of Formula (I) or Formula (II).In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the present invention relates to a method for treating an MPN, comprising administering to a human in need thereof a mouse double minute 2 homolog (MDM2) inhibitor, wherein the MDM2 inhibitor is a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, wherein the MPN is selected from the group consisting of polycythemia vera (PV), myelofibrosis, and essential thrombocythemia (ET). In one embodiment, the polycythemia vera is phlebotomy-dependent polycythemia vera. In one embodiment, the human subject is determined to be hydroxyurea (HU)-intolerant (unacceptable side effects). In one embodiment, the human subject is determined to be hydroxyurea (HU)-resistant (inadequate response). In one embodiment, the human subject has splenomegaly. In one embodiment, the human subject has splenomegaly and is phlebotomy-dependent. In one embodiment, the human subject is phlebotomy-dependent and does not have splenomegaly. In one embodiment, the human subject has previously failed MPN therapy with ruxolitinib. The present invention also relates to a method for treating blast crisis MPN (MPN-BP), comprising administering to a human in need thereof a mouse double minute 2 homolog (MDM2) inhibitor or a pharmaceutically acceptable salt thereof. In one embodiment, the MPN-BP is selected from the group consisting of blast crisis polycythemia vera (BP-PV), blast crisis myelofibrosis, blast crisis essential myelofibrosis, blast crisis thrombocythemia, blast crisis essential thrombocythemia (BP-ET), blast crisis idiopathic myelofibrosis, blast crisis systemic mastocytosis (BP-SM), blast crisis chronic neutrophilic leukemia (BP-CNL), blast crisis myelodysplastic syndrome (BP-MDS), and blast crisis systemic mastocytosis (BP-SMCD). In one embodiment, the blast crisis myelofibrosis is selected from the group consisting of blast crisis primary myelofibrosis (BP-PMF), blast crisis post-polycythemia vera myelofibrosis (BP-post-PV MF), and blast crisis post-essential thrombocythemia myelofibrosis (BP-ET MF). In one embodiment, the blast crisis primary myelofibrosis (BP-PMF) is selected from the group consisting of pre-blast crisis fibrosis / early PMF and blast crisis marked fibrosis PMF. In one embodiment, the MPN-BP is selected from the group consisting of blast crisis chronic neutrophilic leukemia (BP-CNL), blast crisis chronic eosinophilic leukemia, blast crisis chronic myelomonocytic leukemia (BP-CMML), blast crisis atypical chronic myeloid leukemia (BP-aCML), blast crisis juvenile myelomonocytic leukemia (BP-JMML), blast crisis hypereosinophilic syndrome (BP-HES), and blast crisis myelodysplasia / myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (BP-MDS / MPN-RS-T). In one embodiment, the blast crisis polycythemia vera is phlebotomy-dependent polycythemia vera. In one embodiment, the human subject is determined to be intolerant to (unacceptable side effects of) hydroxyurea (HU). In one embodiment, the human subject is determined to be resistant to (inadequate response to) hydroxyurea (HU). In one embodiment, the human subject has splenomegaly. In one embodiment, the human subject has splenomegaly and is phlebotomy-dependent. In one embodiment, the human subject is phlebotomy-dependent and does not have splenomegaly. In one embodiment, the human subject has failed treatment with ruxolitinib. Failure of ruxolitinib treatment includes, but is not limited to, (i) failure to reduce or progression of any MPN-BP in the human subject receiving ruxolitinib; or (ii) recurrence of any MPN-BP in the human subject following ruxolitinib treatment. In one embodiment, failure of ruxolitinib treatment is failure to reduce or progression of any MPN-BP in the human subject receiving ruxolitinib.In one embodiment, ruxolitinib treatment failure is recurrence of any MPN-BP in the human subject following ruxolitinib treatment. In one embodiment, the MDM2 inhibitor is a compound of Formula (I) or Formula (II). In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is administered at a dose selected from the group consisting of 15 mg QD, 25 mg QD, 30 mg QD, 50 mg QD, 60 mg QD, 75 mg QD, 90 mg QD, 100 mg QD, 120 mg QD, 150 mg QD, 175 mg QD, 180 mg QD, 200 mg QD, 225 mg QD, 240 mg QD, 250 mg QD, 275 mg QD, 300 mg QD, 325 mg QD, 350 mg QD, 360 mg QD, 375 mg QD, 480 mg QD, 15 mg BID, 25 mg BID, 30 mg BID, 50 mg BID, 60 mg BID, 75 mg BID, 90 mg BID, 100 mg BID, 120 mg BID, 150 mg BID, 175 mg In one embodiment, the MDM2 inhibitor is administered to a human according to the section "Dosage and Dosage Regimens". In one embodiment, the myelofibrosis is selected from primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV MF), and post-essential thrombocythemia myelofibrosis (post-ET MF). In one embodiment, the myelofibrosis is selected from primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV MF), and post-essential thrombocythemia myelofibrosis (post-ET MF), and the human subject has failed treatment with ruxolitinib for PMF, post-PV MF, or post-ET MF. In one embodiment, the MPN is characterized by a CALR mutation (calreticulin, located on chromosome 19p13.2), as described in Massie et al., N Engl J. Med. 2013, 25: 2379-2390 and incorporated herein by reference in its entirety. In one embodiment, the MPN is characterized by a mutation in MPL (myeloproliferative leukemia viral oncogene; located on chromosome 1p34) as described in Pikman et al., Plos Med. 2006; 3(7):e270 and incorporated herein by reference in its entirety. In one embodiment, the MPN is characterized by the JAK2V617F mutation. JAK2V617F is a functional mutation that promotes cytokine-independent myeloid cell growth and explains the majority of myeloproliferative neoplasms (MPNs), as described in Nakatake et al. (Oncogene, 2012, 31, 1323-1333) and incorporated herein by reference in its entirety. In one embodiment, the MPN is characterized by one or more mutations selected from the group consisting of JAK2V617F, MPL, CALR, and mixtures thereof. In one embodiment, the present invention relates to a method of treating polycythemia vera (PV) in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the MDM2 inhibitor is a compound of formula (I) or formula (II). In one embodiment, the present invention relates to a method for treating polycythemia vera (PV) in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the present invention relates to a method for treating polycythemia vera (PV) in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the present invention relates to a method of treating essential thrombocythemia (ET) in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the MDM2 inhibitor is a compound of formula (I) or formula (II). In one embodiment, the present invention relates to a method for treating essential thrombocythemia (ET) in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the present invention relates to a method for treating essential thrombocythemia (ET) in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the present invention relates to a method of treating primary myelofibrosis in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the MDM2 inhibitor is a compound of formula (I) or formula (II). In one embodiment, the present invention relates to a method for treating primary myelofibrosis in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the present invention relates to a method for treating primary myelofibrosis in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the present invention relates to a method for treating post-polycythemia vera myelofibrosis (post-PV MF) in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the MDM2 inhibitor is a compound of Formula (I) or Formula (II). In one embodiment, the present invention relates to a method for treating post-polycythemia vera myelofibrosis (post-PV MF) in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the MDM2 inhibitor is selected from the group consisting of: a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM09 70B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedametan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601 and pharmaceutically acceptable salts thereof. In one embodiment, the present invention relates to a method for treating post-polycythemia vera myelofibrosis (post-PV MF) in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the present invention relates to a method of treating post-essential thrombocythemia myelofibrosis (post-ET MF) in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the MDM2 inhibitor is a compound of formula (I) or formula (II). In one embodiment, the present invention relates to a method for treating post-essential thrombocythemia myelofibrosis (post-ET MF) in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the MDM2 inhibitor is selected from the group consisting of: a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0 970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedametan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the present invention relates to a method for treating post-essential thrombocythaemia myelofibrosis (post-ET MF) in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the present invention relates to a method of treating chronic neutrophilic leukemia (CNL) in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the MDM2 inhibitor is a compound of formula (I) or formula (II). In one embodiment, the present invention relates to a method for treating chronic neutrophilic leukemia (CNL) in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the MDM2 inhibitor is selected from the group consisting of: a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970 B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601 and pharmaceutically acceptable salts thereof. In one embodiment, the present invention relates to a method for treating chronic neutrophilic leukemia (CNL) in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the present invention relates to a method of treating chronic eosinophilic leukemia in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the MDM2 inhibitor is a compound of formula (I) or formula (II). In one embodiment, the present invention relates to a method for treating chronic eosinophilic leukemia in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the present invention relates to a method for treating chronic eosinophilic leukemia in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the present invention relates to a method for treating chronic myelomonocytic leukemia (CMML) in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the MDM2 inhibitor is a compound of formula (I) or formula (II). In one embodiment, the present invention relates to a method for treating chronic myelomonocytic leukemia (CMML) in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the MDM2 inhibitor is selected from the group consisting of: a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM097 0B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedametan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601 and pharmaceutically acceptable salts thereof. In one embodiment, the present invention relates to a method for treating chronic myelomonocytic leukemia (CMML) in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the present invention relates to a method for treating atypical chronic myeloid leukemia (aCML) in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the MDM2 inhibitor is a compound of formula (I) or formula (II). In one embodiment, the present invention relates to a method for treating atypical chronic myeloid leukemia (aCML) in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the MDM2 inhibitor is selected from the group consisting of: a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM097 0B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedametan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601 and pharmaceutically acceptable salts thereof. In one embodiment, the present invention relates to a method for treating atypical chronic myeloid leukemia (aCML) in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the present invention relates to a method for treating juvenile myelomonocytic leukemia (JMML) in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the MDM2 inhibitor is a compound of formula (I) or formula (II). In one embodiment, the present invention relates to a method for treating juvenile myelomonocytic leukemia (JMML) in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the MDM2 inhibitor is selected from the group consisting of: a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM097 0B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedametan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601 and pharmaceutically acceptable salts thereof. In one embodiment, the present invention relates to a method for treating juvenile myelomonocytic leukemia (JMML) in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the present invention relates to a method for treating hypereosinophilic syndrome (HES) in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the MDM2 inhibitor is a compound of formula (I) or formula (II). In one embodiment, the present invention relates to a method for treating hypereosinophilic syndrome (HES) in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the MDM2 inhibitor is selected from the group consisting of: a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B , SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedametan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601 and pharmaceutically acceptable salts thereof. In one embodiment, the present invention relates to a method for treating hypereosinophilic syndrome (HES) in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the present invention relates to a method for treating myelosuppression / myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS / MPN-RS-T) in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the MDM2 inhibitor is a compound of formula (I) or formula (II). In one embodiment, the present invention relates to a method for treating myelosuppressive / myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS / MPN-RS-T) in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the MDM2 inhibitor is selected from the group consisting of: a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, C GM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedametan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the present invention relates to a method for treating myelosuppressive / myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS / MPN-RS-T) in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the present invention relates to a method of treating MPN in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof at a dose selected from the group consisting of 15 mg QD, 25 mg QD, 30 mg QD, 50 mg QD, 60 mg QD, 75 mg QD, 90 mg QD, 100 mg QD, 120 mg QD, 150 mg QD, 175 mg QD, 180 mg QD, 200 mg QD, 225 mg QD, 240 mg QD, 250 mg QD, 275 mg QD, 300 mg QD, 325 mg QD, 350 mg QD, 360 mg QD, 375 mg QD, 480 mg QD, 15 mg BID, 25 mg BID, 30 mg BID, 50 mg BID, 60 mg BID, 75 mg BID, 90 mg In one embodiment, the MPN is selected from the group consisting of polycythemia vera (PV), myelofibrosis, primary myelofibrosis, thrombocythemia, essential thrombocythemia (ET), idiopathic myelofibrosis, systemic mastocytosis (SM), chronic neutrophilic leukemia (CNL), myelodysplastic syndrome (MDS), and systemic mast cell disease (SMCD). In one embodiment, the myelofibrosis is selected from the group consisting of primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV MF), and post-essential thrombocythemia myelofibrosis (post-ET MF). In one embodiment, primary myelofibrosis (PMF) is selected from the group consisting of pre-fibrotic / early PMF and marked fibrotic PMF. In one embodiment, the MPN is selected from the group consisting of chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia, chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), juvenile myelomonocytic leukemia (JMML), hypereosinophilic syndrome (HES), and myelodysplasia / myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS / MPN-RS-T). In one embodiment, the present invention relates to a method of treating MPN in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof at a dose selected from the group consisting of 15 mg QD, 25 mg QD, 30 mg QD, 50 mg QD, 60 mg QD, 75 mg QD, 90 mg QD, 100 mg QD, 120 mg QD, 150 mg QD, 175 mg QD, 180 mg QD, 200 mg QD, 225 mg QD, 240 mg QD, 250 mg QD, 275 mg QD, 300 mg QD, 325 mg QD, 350 mg QD, 360 mg QD, 375 mg QD, 480 mg QD, 15 mg BID, 25 mg BID, 30 mg BID, 50 mg BID, 60 mg BID, 75 mg BID, 90 mg

[00145] The invention relates to a pharmaceutical composition comprising the following: a) 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 24, 25, 26, 27, 30, 32, 35, 36, 37, 38, 40, 51, 61, 62, 73, 74, 85, 86, 97, 108, 114, 120, 135, 136, 147, 158, 161, 175, 180, 200, 215, 225, 240, 250, 275, 300, 325, 350, 360, 375, and 480 mg BID, wherein the MPN is selected from the group consisting of polycythemia vera (PV), primary myelofibrosis, and essential thrombocythemia (ET). In one embodiment, the present invention relates to a method of treating MPN in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof at a dose selected from the group consisting of 15 mg QD, 25 mg QD, 30 mg QD, 50 mg QD, 60 mg QD, 75 mg QD, 90 mg QD, 100 mg QD, 120 mg QD, 150 mg QD, 175 mg QD, 180 mg QD, 200 mg QD, 225 mg QD, 240 mg QD, 250 mg QD, 275 mg QD, 300 mg QD, 325 mg QD, 350 mg QD, 360 mg QD, 375 mg QD, 480 mg QD, 15 mg BID, 25 mg BID, 30 mg BID, 50 mg BID, 60 mg BID, 75 mg BID, 90 mg BID, 100 mg BID, 120 mg BID, 150 mg BID, 175 mg BID, 180 mg BID, 200 mg BID, 225 mg BID, 240 mg BID, 250 mg BID, 275 mg BID, 300 mg BID, 325 mg BID, 350 mg BID, 360 mg BID, 375 mg BID, and 480 mg BID, wherein the MPN is selected from the group consisting of chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia, chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), juvenile myelomonocytic leukemia (JMML), hypereosinophilic syndrome (HES), and myelodysplasia / myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS / MPN-RS-T). In one embodiment, the present invention relates to a method of treating polycythemia vera (PV) in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof at a dose selected from the group consisting of 15 mg QD, 25 mg QD, 30 mg QD, 50 mg QD, 60 mg QD, 75 mg QD, 90 mg QD, 100 mg QD, 120 mg QD, 150 mg QD, 175 mg QD, 180 mg QD, 200 mg QD, 225 mg QD, 240 mg QD, 250 mg QD, 275 mg QD, 300 mg QD, 325 mg QD, 350 mg QD, 360 mg QD, 375 mg QD, 480 mg QD, 15 mg BID, 25 mg BID, 30 mg BID, 50 mg BID, 60 mg BID, 75 mg 480 mg BID. In one embodiment, the present invention relates to a method of treating primary myelofibrosis in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof at a dose selected from the group consisting of 15 mg QD, 25 mg QD, 30 mg QD, 50 mg QD, 60 mg QD, 75 mg QD, 90 mg QD, 100 mg QD, 120 mg QD, 150 mg QD, 175 mg QD, 180 mg QD, 200 mg QD, 225 mg QD, 240 mg QD, 250 mg QD, 275 mg QD, 300 mg QD, 325 mg QD, 350 mg QD, 360 mg QD, 375 mg QD, 480 mg QD, 15 mg BID, 25 mg BID, 30 mg BID, 50 mg BID, 60 mg BID, 75 mg BID, 90 mg BID, 100 mg BID, 120 mg BID, 150 mg BID, 175 mg BID, 180 mg BID, 200 mg BID, 225 mg BID, 240 mg BID, 250 mg BID, 275 mg BID, 300 mg BID, 325 mg BID, 350 mg BID, 360 mg BID, 375 mg BID and 480 mg BID. In one embodiment, the present invention relates to a method of treating post-polycythemia vera myelofibrosis (post-PV MF) in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof at a dose selected from the group consisting of 15 mg QD, 25 mg QD, 30 mg QD, 50 mg QD, 60 mg QD, 75 mg QD, 90 mg QD, 100 mg QD, 120 mg QD, 150 mg QD, 175 mg QD, 180 mg QD, 200 mg QD, 225 mg QD, 240 mg QD, 250 mg QD, 275 mg QD, 300 mg QD, 325 mg QD, 350 mg QD, 360 mg QD, 375 mg QD, 480 mg QD, 15 mg BID, 25 mg BID, 30 mg BID, 50 mg BID, 60 mg BID, 75 mg BID, 90 mg BID, 100 mg BID, 120 mg BID, 150 mg BID, 175 mg BID, 180 mg BID, 200 mg BID, 225 mg BID, 240 mg BID, 250 mg BID, 275 mg BID, 300 mg BID, 325 mg BID, 350 mg BID, 360 mg BID, 375 mg BID and 480 mg BID. In one embodiment, the present invention relates to a method of treating post-essential thrombocythaemia myelofibrosis (post-ET MF) in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof at a dose selected from the group consisting of 15 mg QD, 25 mg QD, 30 mg QD, 50 mg QD, 60 mg QD, 75 mg QD, 90 mg QD, 100 mg QD, 120 mg QD, 150 mg QD, 175 mg QD, 180 mg QD, 200 mg QD, 225 mg QD, 240 mg QD, 250 mg QD, 275 mg QD, 300 mg QD, 325 mg QD, 350 mg QD, 360 mg QD, 375 mg QD, 480 mg QD, 15 mg BID, 25 mg BID, 30 mg BID, 50 mg BID, 60 mg BID, 75 mg BID, 90 mg BID, 100 mg BID, 120 mg BID, 150 mg BID, 175 mg BID, 180 mg BID, 200 mg BID, 225 mg BID, 240 mg BID, 250 mg BID, 275 mg BID, 300 mg BID, 325 mg BID, 350 mg BID, 360 mg BID, 375 mg BID and 480 mg BID. In one embodiment, the present invention relates to a method of treating essential thrombocythemia (ET) in a human, comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof at a dose selected from the group consisting of 15 mg QD, 25 mg QD, 30 mg QD, 50 mg QD, 60 mg QD, 75 mg QD, 90 mg QD, 100 mg QD, 120 mg QD, 150 mg QD, 175 mg QD, 180 mg QD, 200 mg QD, 225 mg QD, 240 mg QD, 250 mg QD, 275 mg QD, 300 mg QD, 325 mg QD, 350 mg QD, 360 mg QD, 375 mg QD, 480 mg QD, 15 mg BID, 25 mg BID, 30 mg BID, 50 mg BID, 60 mg BID, 75 mg 480 mg BID. In one embodiment, the present invention relates to a method of treating MPN in a human, comprising administering to the human a therapeutically effective amount of a composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof at a dose selected from the group consisting of 15 mg QD, 25 mg QD, 30 mg QD, 50 mg QD, 60 mg QD, 75 mg QD, 90 mg QD, 100 mg QD, 120 mg QD, 150 mg QD, 175 mg QD, 180 mg QD, 200 mg QD, 225 mg QD, 240 mg QD, 250 mg QD, 275 mg QD, 300 mg QD, 325 mg QD, 350 mg QD, 360 mg QD, 375 mg QD, 480 mg QD, 15 mg BID, 25 mg BID, 30 mg BID, 50 mg BID, 60 mg BID, 75 mg BID, 90 mg The dosage of the drug is 100 mg BID, 100 mg BID, 120 mg BID, 150 mg BID, 175 mg BID, 180 mg BID, 200 mg BID, 225 mg BID, 240 mg BID, 250 mg BID, 275 mg BID, 300 mg BID, 325 mg BID, 350 mg BID, 360 mg BID, 375 mg BID, and 480 mg BID. In one embodiment, the MPN is selected from the group consisting of polycythemia vera (PV), myelofibrosis, primary myelofibrosis, thrombocythemia, essential thrombocythemia (ET), idiopathic myelofibrosis, systemic mastocytosis (SM), chronic neutrophilic leukemia (CNL), myelodysplastic syndrome (MDS), and systemic mastocytosis (SMCD). In one embodiment, the MDM2 inhibitor is a compound of Formula (I) or Formula (II). In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof.In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the myelofibrosis is selected from the group consisting of primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV MF), and post-essential thrombocythemia vera myelofibrosis (post-ET MF). In one embodiment, the primary myelofibrosis (PMF) is selected from the group consisting of pre-fibrotic / early PMF and overt fibrotic PMF. In one embodiment, the MPN is selected from the group consisting of chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia, chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), juvenile myelomonocytic leukemia (JMML), hypereosinophilic syndrome (HES), and myelodysplasia / myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS / MPN-RS-T). In one embodiment, the present invention relates to a method of treating MPN in a human, comprising administering to the human a therapeutically effective amount of a composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof at a dose selected from the group consisting of 15 mg QD, 25 mg QD, 30 mg QD, 50 mg QD, 60 mg QD, 75 mg QD, 90 mg QD, 100 mg QD, 120 mg QD, 150 mg QD, 175 mg QD, 180 mg QD, 200 mg QD, 225 mg QD, 240 mg QD, 250 mg QD, 275 mg QD, 300 mg QD, 325 mg QD, 350 mg QD, 360 mg QD, 375 mg QD, 480 mg QD, 15 mg BID, 25 mg BID, 30 mg BID, 50 mg BID, 60 mg BID, 75 mg BID, 90 mg In one embodiment, the MPN is selected from the group consisting of polycythemia vera (PV), myelofibrosis, and essential thrombocythemia (ET). In one embodiment, the MDM2 inhibitor is a compound of formula (I) or formula (II). In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof.In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the myelofibrosis is selected from the group consisting of primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV MF), and post-essential thrombocythemia vera myelofibrosis (post-ET MF). In one embodiment, the primary myelofibrosis (PMF) is selected from the group consisting of pre-fibrotic / early PMF and overt fibrotic PMF. In one embodiment, the MPN is selected from the group consisting of chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia, chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), juvenile myelomonocytic leukemia (JMML), hypereosinophilic syndrome (HES), and myelodysplasia / myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS / MPN-RS-T). In one embodiment, the present invention relates to a method of treating polycythemia vera (PV) in a human, comprising administering to the human a therapeutically effective amount of a composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof at a dose selected from the group consisting of 15 mg QD, 25 mg QD, 30 mg QD, 50 mg QD, 60 mg QD, 75 mg QD, 90 mg QD, 100 mg QD, 120 mg QD, 150 mg QD, 175 mg QD, 180 mg QD, 200 mg QD, 225 mg QD, 240 mg QD, 250 mg QD, 275 mg QD, 300 mg QD, 325 mg QD, 350 mg QD, 360 mg QD, 375 mg QD, 480 mg QD, 15 mg BID, 25 mg BID, 30 mg BID, 50 mg BID, 60 mg In one embodiment, the MDM2 inhibitor is a compound of formula (I) or formula (II). In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the present invention relates to a method of treating primary myelofibrosis in a human, comprising administering to the human a therapeutically effective amount of a composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof at a dose selected from the group consisting of 15 mg QD, 25 mg QD, 30 mg QD, 50 mg QD, 60 mg QD, 75 mg QD, 90 mg QD, 100 mg QD, 120 mg QD, 150 mg QD, 175 mg QD, 180 mg QD, 200 mg QD, 225 mg QD, 240 mg QD, 250 mg QD, 275 mg QD, 300 mg QD, 325 mg QD, 350 mg QD, 360 mg QD, 375 mg QD, 480 mg QD, 15 mg BID, 25 mg BID, 30 mg BID, 50 mg BID, 60 mg BID, 75 mg In one embodiment, the MDM2 inhibitor is a compound of formula (I) or formula (II). In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the present invention relates to a method of treating post-polycythemia vera myelofibrosis (post-PV MF) in a human, comprising administering to the human a therapeutically effective amount of a composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof at a dose selected from the group consisting of 15 mg QD, 25 mg QD, 30 mg QD, 50 mg QD, 60 mg QD, 75 mg QD, 90 mg QD, 100 mg QD, 120 mg QD, 150 mg QD, 175 mg QD, 180 mg QD, 200 mg QD, 225 mg QD, 240 mg QD, 250 mg QD, 275 mg QD, 300 mg QD, 325 mg QD, 350 mg QD, 360 mg QD, 375 mg QD, 480 mg QD, 15 mg BID, 25 mg BID, 30 mg BID, 50 mg In one embodiment, the MDM2 inhibitor is a compound of formula (I) or formula (II). In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the present invention relates to a method of treating post-essential thrombocythaemia myelofibrosis (post-ET MF) in a human, comprising administering to the human a therapeutically effective amount of a composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof at a dose selected from the group consisting of 15 mg QD, 25 mg QD, 30 mg QD, 50 mg QD, 60 mg QD, 75 mg QD, 90 mg QD, 100 mg QD, 120 mg QD, 150 mg QD, 175 mg QD, 180 mg QD, 200 mg QD, 225 mg QD, 240 mg QD, 250 mg QD, 275 mg QD, 300 mg QD, 325 mg QD, 350 mg QD, 360 mg QD, 375 mg QD, 480 mg QD, 15 mg BID, 25 mg BID, 30 mg BID, 50 mg In one embodiment, the MDM2 inhibitor is a compound of formula (I) or formula (II). In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the present invention relates to a method of treating essential thrombocythemia (ET) in a human, comprising administering to the human a therapeutically effective amount of a composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof at a dose selected from the group consisting of 15 mg QD, 25 mg QD, 30 mg QD, 50 mg QD, 60 mg QD, 75 mg QD, 90 mg QD, 100 mg QD, 120 mg QD, 150 mg QD, 175 mg QD, 180 mg QD, 200 mg QD, 225 mg QD, 240 mg QD, 250 mg QD, 275 mg QD, 300 mg QD, 325 mg QD, 350 mg QD, 360 mg QD, 375 mg QD, 480 mg QD, 15 mg BID, 25 mg BID, 30 mg BID, 50 mg BID, 60 mg In one embodiment, the MDM2 inhibitor is a compound of formula (I) or formula (II). In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the present invention relates to a method of treating chronic neutrophilic leukemia (CNL) in a human, comprising administering to the human a therapeutically effective amount of a composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof at a dose selected from the group consisting of 15 mg QD, 25 mg QD, 30 mg QD, 50 mg QD, 60 mg QD, 75 mg QD, 90 mg QD, 100 mg QD, 120 mg QD, 150 mg QD, 175 mg QD, 180 mg QD, 200 mg QD, 225 mg QD, 240 mg QD, 250 mg QD, 275 mg QD, 300 mg QD, 325 mg QD, 350 mg QD, 360 mg QD, 375 mg QD, 480 mg QD, 15 mg BID, 25 mg BID, 30 mg BID, 50 mg BID, 60 In one embodiment, the MDM2 inhibitor is a compound of formula (I) or formula (II). In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the present invention relates to a method of treating chronic eosinophilic leukemia in a human, comprising administering to the human a therapeutically effective amount of a composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof at a dose selected from the group consisting of 15 mg QD, 25 mg QD, 30 mg QD, 50 mg QD, 60 mg QD, 75 mg QD, 90 mg QD, 100 mg QD, 120 mg QD, 150 mg QD, 175 mg QD, 180 mg QD, 200 mg QD, 225 mg QD, 240 mg QD, 250 mg QD, 275 mg QD, 300 mg QD, 325 mg QD, 350 mg QD, 360 mg QD, 375 mg QD, 480 mg QD, 15 mg BID, 25 mg BID, 30 mg BID, 50 mg BID, 60 mg In one embodiment, the MDM2 inhibitor is a compound of formula (I) or formula (II). In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the present invention relates to a method of treating chronic myelomonocytic leukemia (CMML) in a human, comprising administering to the human a therapeutically effective amount of a composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof at a dose selected from the group consisting of 15 mg QD, 25 mg QD, 30 mg QD, 50 mg QD, 60 mg QD, 75 mg QD, 90 mg QD, 100 mg QD, 120 mg QD, 150 mg QD, 175 mg QD, 180 mg QD, 200 mg QD, 225 mg QD, 240 mg QD, 250 mg QD, 275 mg QD, 300 mg QD, 325 mg QD, 350 mg QD, 360 mg QD, 375 mg QD, 480 mg QD, 15 mg BID, 25 mg BID, 30 mg BID, 50 mg BID, 60 mg In one embodiment, the MDM2 inhibitor is a compound of formula (I) or formula (II). In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the present invention relates to a method of treating atypical chronic myeloid leukemia (aCML) in a human, comprising administering to the human a therapeutically effective amount of a composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof at a dose selected from the group consisting of 15 mg QD, 25 mg QD, 30 mg QD, 50 mg QD, 60 mg QD, 75 mg QD, 90 mg QD, 100 mg QD, 120 mg QD, 150 mg QD, 175 mg QD, 180 mg QD, 200 mg QD, 225 mg QD, 240 mg QD, 250 mg QD, 275 mg QD, 300 mg QD, 325 mg QD, 350 mg QD, 360 mg QD, 375 mg QD, 480 mg QD, 15 mg BID, 25 mg BID, 30 mg BID, 50 mg BID, 60 mg In one embodiment, the MDM2 inhibitor is a compound of formula (I) or formula (II). In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the present invention relates to a method of treating juvenile myelomonocytic leukemia (JMML) in a human, comprising administering to the human a therapeutically effective amount of a composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof at a dose selected from the group consisting of 15 mg QD, 25 mg QD, 30 mg QD, 50 mg QD, 60 mg QD, 75 mg QD, 90 mg QD, 100 mg QD, 120 mg QD, 150 mg QD, 175 mg QD, 180 mg QD, 200 mg QD, 225 mg QD, 240 mg QD, 250 mg QD, 275 mg QD, 300 mg QD, 325 mg QD, 350 mg QD, 360 mg QD, 375 mg QD, 480 mg QD, 15 mg BID, 25 mg BID, 30 mg BID, 50 mg In one embodiment, the MDM2 inhibitor is a compound of formula (I) or formula (II). In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof.In one embodiment, the present invention relates to a method of treating hypereosinophilic syndrome (HES) in a human, comprising administering to the human a therapeutically effective amount of a composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof at a dose selected from the group consisting of 15 mg QD, 25 mg QD, 30 mg QD, 50 mg QD, 60 mg QD, 75 mg QD, 90 mg QD, 100 mg QD, 120 mg QD, 150 mg QD, 175 mg QD, 180 mg QD, 200 mg QD, 225 mg QD, 240 mg QD, 250 mg QD, 275 mg QD, 300 mg QD, 325 mg QD, 350 mg QD, 360 mg QD, 375 mg QD, 480 mg QD, 15 mg BID, 25 mg BID, 30 mg BID, 50 mg BID, 60 mg In one embodiment, the MDM2 inhibitor is a compound of formula (I) or formula (II). In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the present invention relates to a method for treating myelosuppression / myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS / MPN-RS-T) in a human, comprising administering to the human a therapeutically effective amount of a composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof at a dose selected from the group consisting of 15 mg QD, 25 mg QD, 30 mg QD, 50 mg QD, 60 mg QD, 75 mg QD, 90 mg QD, 100 mg QD, 120 mg QD, 150 mg QD, 175 mg QD, 180 mg QD, 200 mg QD, 225 mg QD, 240 mg QD, 250 mg QD, 275 mg QD, 300 mg QD, 325 mg QD, 350 mg QD, 360 mg QD, 375 mg QD, 480 mg QD, 15 mg QD, In one embodiment, the MDM2 inhibitor is a compound of formula (I) or formula (II). In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the present invention relates to the use of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a myeloproliferative neoplasm (MPN), the treatment comprising administering one or more doses of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof to a human. In one embodiment, the MPN is selected from the group consisting of polycythemia vera (PV), myelofibrosis, primary myelofibrosis, thrombocythemia, essential thrombocythemia (ET), idiopathic myelofibrosis, systemic mastocytosis (SM), chronic neutrophilic leukemia (CNL), myelodysplastic syndrome (MDS), and systemic mast cell disease (SMCD). In one embodiment, the myelofibrosis is selected from the group consisting of primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV MF), and post-essential thrombocythemia myelofibrosis (post-ET MF). In one embodiment, primary myelofibrosis (PMF) is selected from the group consisting of prefibrotic / early PMF and overt fibrotic PMF. In one embodiment, MPN is selected from the group consisting of chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia, chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), juvenile myelomonocytic leukemia (JMML), hypereosinophilic syndrome (HES), and myelodysplasia / myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS / MPN-RS-T). In one embodiment, the present invention relates to the use of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a myeloproliferative neoplasm (MPN), the treatment comprising the step of administering one or more doses of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the MPN is selected from the group consisting of polycythemia vera (PV), primary myelofibrosis, and essential thrombocythemia (ET). In one embodiment, the present invention relates to the use of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating polycythemia vera (PV), wherein the treatment comprises the step of administering one or more doses of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof to a human. In one embodiment, the present invention relates to the use of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating essential thrombocythemia (ET), wherein the treatment comprises the step of administering one or more doses of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof to a human. In one embodiment, the present invention relates to the use of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating primary myelofibrosis, wherein the treatment comprises the step of administering one or more doses of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof to a human. In one embodiment, the present invention relates to the use of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating post-polycythemia vera myelofibrosis (post-PV MF), wherein the treatment comprises the step of administering one or more doses of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof to a human. In one embodiment, the present invention relates to the use of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating post-essential thrombocythaemia myelofibrosis (post-ET MF), wherein the treatment comprises the step of administering one or more doses of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof to a human. In one embodiment, the present invention relates to the use of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating chronic neutrophilic leukemia (CNL), wherein the treatment comprises the step of administering one or more doses of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof to a human. In one embodiment, the present invention relates to the use of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating chronic eosinophilic leukemia, wherein the treatment comprises the step of administering one or more doses of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof to a human. In one embodiment, the present invention relates to the use of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating chronic myelomonocytic leukemia (CMML), wherein the treatment comprises the step of administering one or more doses of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof to a human. In one embodiment, the present invention relates to the use of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating atypical chronic myeloid leukemia (aCML), wherein the treatment comprises the step of administering one or more doses of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof to a human. In one embodiment, the present invention relates to the use of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating juvenile myelomonocytic leukemia (JMML), wherein the treatment comprises the step of administering one or more doses of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof to a human. In one embodiment, the present invention relates to the use of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating hypereosinophilic syndrome (HES), wherein the treatment comprises the step of administering one or more doses of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof to a human. In one embodiment, the present invention relates to the use of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of myelodysplasia / myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS / MPN-RS-T), wherein the treatment comprises the step of administering one or more doses of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof to a human. In one embodiment, the MDM2 inhibitor is a compound of Formula (I) or Formula (II). In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of Formula (I), a compound of Formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the present invention relates to the use of a composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a myeloproliferative neoplasm (MPN), the treatment comprising administering one or more doses of a composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof to a human. In one embodiment, the MPN is selected from the group consisting of polycythemia vera (PV), myelofibrosis, primary myelofibrosis, thrombocythemia, essential thrombocythemia (ET), idiopathic myelofibrosis, systemic mastocytosis (SM), chronic neutrophilic leukemia (CNL), myelodysplastic syndrome (MDS), and systemic mast cell disease (SMCD). In one embodiment, the myelofibrosis is selected from the group consisting of primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV MF), and post-essential thrombocythemia myelofibrosis (post-ET MF). In one embodiment, primary myelofibrosis (PMF) is selected from the group consisting of prefibrotic / early PMF and overt fibrotic PMF. In one embodiment, MPN is selected from the group consisting of chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia, chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), juvenile myelomonocytic leukemia (JMML), hypereosinophilic syndrome (HES), and myelodysplasia / myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS / MPN-RS-T). In one embodiment, the present invention relates to the use of a composition comprising an MDM2 inhibitor, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a myeloproliferative neoplasm (MPN), wherein the treatment comprises administering to a human one or more doses of a composition comprising an MDM2 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the MPN is selected from the group consisting of polycythemia vera (PV), primary myelofibrosis, and essential thrombocythemia (ET). In one embodiment, the present invention relates to the use of a composition comprising an MDM2 inhibitor, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating polycythemia vera (PV), wherein the treatment comprises administering to a human one or more doses of a composition comprising an MDM2 inhibitor, or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention relates to the use of a composition comprising an MDM2 inhibitor, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating essential thrombocythemia (ET), wherein the treatment comprises administering one or more doses of a composition comprising an MDM2 inhibitor, or a pharmaceutically acceptable salt thereof, to a human. In one embodiment, the present invention relates to the use of a composition comprising an MDM2 inhibitor, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating primary myelofibrosis, wherein the treatment comprises administering one or more doses of a composition comprising an MDM2 inhibitor, or a pharmaceutically acceptable salt thereof, to a human. In one embodiment, the MDM2 inhibitor is a compound of Formula (I) or Formula (II). In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the present invention relates to an MDM2 inhibitor or a pharmaceutically acceptable salt thereof for use in treating a myeloproliferative neoplasm (MPN). In one embodiment, the MPN is selected from the group consisting of polycythemia vera (PV), myelofibrosis, primary myelofibrosis, thrombocythemia, essential thrombocythemia (ET), idiopathic myelofibrosis, systemic mastocytosis (SM), chronic neutrophilic leukemia (CNL), myelodysplastic syndrome (MDS), and systemic mast cell disease (SMCD). In one embodiment, the myelofibrosis is selected from the group consisting of primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV MF), and post-essential thrombocythemia myelofibrosis (post-ET MF). In one embodiment, primary myelofibrosis (PMF) is selected from the group consisting of pre-fibrotic / early PMF and marked fibrotic PMF. In one embodiment, the MPN is selected from the group consisting of chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia, chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), juvenile myelomonocytic leukemia (JMML), hypereosinophilic syndrome (HES), and myelodysplasia / myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS / MPN-RS-T). In one embodiment, the present invention relates to an MDM2 inhibitor, or a pharmaceutically acceptable salt thereof, for use in treating polycythemia vera (PV). In one embodiment, the present invention relates to an MDM2 inhibitor, or a pharmaceutically acceptable salt thereof, for use in treating primary myelofibrosis. In one embodiment, the present invention relates to an MDM2 inhibitor, or a pharmaceutically acceptable salt thereof, for use in treating essential thrombocythemia (ET). In one embodiment, the MDM2 inhibitor is a compound of Formula (I) or Formula (II). In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. The above methods can be used as first-line cancer therapy or after treatment with conventional chemotherapeutic active pharmaceutical ingredients including cyclophosphamide, fludarabine (FC chemotherapy) and chlorambucil. In one embodiment, the present invention relates to a method for treating myelofibrosis selected from the group consisting of primary myelofibrosis (also known as chronic idiopathic myelofibrosis) and primary myelofibrosis secondary to polycythemia vera or essential thrombocythemia, comprising the step of administering a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention relates to a method for treating myelofibrosis selected from the group consisting of primary myelofibrosis (also known as chronic idiopathic myelofibrosis) and primary myelofibrosis secondary to polycythemia vera or essential thrombocythemia, comprising the step of administering a therapeutically effective amount of a composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention relates to a method of treating an MPN in a human, comprising the step of administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the MPN is selected from the group consisting of polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis, wherein the therapeutically effective amount is selected from the group consisting of 15 mg QD, 25 mg QD, 30 mg QD, 50 mg QD, 60 mg QD, 75 mg QD, 90 mg QD, 100 mg QD, 120 mg QD, 150 mg QD, 175 mg QD, 180 mg QD, 200 mg QD, 225 mg QD, 240 mg QD, 250 mg QD, 275 mg QD, 300 mg QD, 325 mg QD, 350 mg QD, 360 mg QD, 375 mg QD and 480 mg QD. In one embodiment, the MDM2 inhibitor is a compound of Formula (I) or Formula (II). In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of Formula (I), a compound of Formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the present invention relates to a method for treating a human MPN comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the MPN is selected from the group consisting of polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis, wherein the therapeutically effective amount is 120 mg QD. In one embodiment, the MDM2 inhibitor is a compound of Formula (I) or Formula (II). In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the present invention relates to a method of treating an MPN in a human, comprising the step of administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the MPN is selected from the group consisting of polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis, wherein the therapeutically effective amount is selected from the group consisting of 15 mg BID, 25 mg BID, 30 mg BID, 50 mg BID, 60 mg BID, 75 mg BID, 90 mg BID, 100 mg BID, 120 mg BID, 150 mg BID, 175 mg BID, 180 mg BID, 200 mg BID, 225 mg BID, 240 mg BID, 250 mg BID, 275 mg BID, 300 mg BID, 325 mg BID, 350 mg BID, 360 mg BID, 375 mg BID, and 480 mg BID. BID. In one embodiment, the MDM2 inhibitor is a compound of Formula (I) or Formula (II). In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of Formula (I), a compound of Formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the present invention relates to a method for treating a human MPN comprising administering to the human a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the MPN is selected from the group consisting of polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis, wherein the therapeutically effective amount is 120 mg twice daily. In one embodiment, the MDM2 inhibitor is a compound of Formula (I) or Formula (II). In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. MDM2 inhibitors or pharmaceutically acceptable salts thereof can also be used in combination with radiation therapy, hormone therapy, surgery, and immunotherapy known to those skilled in the art to treat MPNs selected from the group consisting of polycythemia vera (PV), myelofibrosis, primary myelofibrosis, thrombocythemia, essential thrombocythemia (ET), idiopathic myelofibrosis, systemic mastocytosis (SM), chronic neutrophilic leukemia (CNL), myelodysplastic syndrome (MDS), and systemic mast cell disease (SMCD). In one embodiment, myelofibrosis is selected from the group consisting of primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV MF), and post-essential thrombocythemia myelofibrosis (post-ET MF). In one embodiment, primary myelofibrosis (PMF) is selected from the group consisting of pre-fibrotic / early PMF and marked fibrotic PMF. In one embodiment, the MPN is selected from the group consisting of chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia, chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), juvenile myelomonocytic leukemia (JMML), hypereosinophilic syndrome (HES), and myelodysplasia / myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS / MPN-RS-T). Treatment of chronic myeloid leukemia (CML) and acute myeloid leukemia (AML) Method The present invention relates to a method for treating chronic myeloid leukemia (CML), comprising administering to a human in need thereof a mouse double minute 2 homolog (MDM2) inhibitor or a pharmaceutically acceptable salt thereof. In one embodiment, the MDM2 inhibitor is a compound of formula (I) or formula (II). In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is administered at a dose selected from the group consisting of 15 mg QD, 25 mg QD, 30 mg QD, 50 mg QD, 60 mg QD, 75 mg QD, 90 mg QD, 100 mg QD, 120 mg QD, 150 mg QD, 175 mg QD, 180 mg QD, 200 mg QD, 225 mg QD, 240 mg QD, 250 mg QD, 275 mg QD, 300 mg QD, 325 mg QD, 350 mg QD, 360 mg QD, 375 mg QD, 480 mg QD, 15 mg BID, 25 mg BID, 30 mg BID, 50 mg BID, 60 mg BID, 75 mg BID, 90 mg BID, 100 mg BID, 120 mg BID, 150 mg BID, 175 mg BID, 180 mg BID, 200 mg BID, 225 mg BID, 240 mg BID, 250 mg BID, 275 mg BID, 300 mg BID, 325 mg BID, 350 mg BID, 360 mg BID, 375 mg BID and 480 mg BID.In one embodiment, the MDM2 inhibitor is administered to a human according to the section "Dosage and Administration Regimens." The present invention relates to the use of a mouse double minute 2 homolog (MDM2) inhibitor or a pharmaceutically acceptable salt thereof for treating chronic myeloid leukemia (CML) in a human in need thereof. In one embodiment, the MDM2 inhibitor is a compound of formula (I) or formula (II). In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is administered at a dose selected from the group consisting of 15 mg QD, 25 mg QD, 30 mg QD, 50 mg QD, 60 mg QD, 75 mg QD, 90 mg QD, 100 mg QD, 120 mg QD, 150 mg QD, 175 mg QD, 180 mg QD, 200 mg QD, 225 mg QD, 240 mg QD, 250 mg QD, 275 mg QD, 300 mg QD, 325 mg QD, 350 mg QD, 360 mg QD, 375 mg QD, 480 mg QD, 15 mg BID, 25 mg BID, 30 mg BID, 50 mg BID, 60 mg BID, 75 mg BID, 90 mg BID, 100 mg BID, 120 mg BID, 150 mg BID, 175 mg BID, 180 mg BID, 200 mg BID, 225 mg BID, 240 mg BID, 250 mg BID, 275 mg BID, 300 mg BID, 325 mg BID, 350 mg BID, 360 mg BID, 375 mg BID and 480 mg BID.In one embodiment, the MDM2 inhibitor is administered to a human according to the section "Dosage and Administration Regimens." The present invention relates to a method for treating acute myeloid leukemia (AML), comprising administering to a human in need thereof a mouse double minute 2 homolog (MDM2) inhibitor or a pharmaceutically acceptable salt thereof. In one embodiment, the MDM2 inhibitor is a compound of formula (I) or formula (II). In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is administered at a dose selected from the group consisting of 15 mg QD, 25 mg QD, 30 mg QD, 50 mg QD, 60 mg QD, 75 mg QD, 90 mg QD, 100 mg QD, 120 mg QD, 150 mg QD, 175 mg QD, 180 mg QD, 200 mg QD, 225 mg QD, 240 mg QD, 250 mg QD, 275 mg QD, 300 mg QD, 325 mg QD, 350 mg QD, 360 mg QD, 375 mg QD, 480 mg QD, 15 mg BID, 25 mg BID, 30 mg BID, 50 mg BID, 60 mg BID, 75 mg BID, 90 mg BID, 100 mg BID, 120 mg BID, 150 mg BID, 175 mg BID, 180 mg BID, 200 mg BID, 225 mg BID, 240 mg BID, 250 mg BID, 275 mg BID, 300 mg BID, 325 mg BID, 350 mg BID, 360 mg BID, 375 mg BID and 480 mg BID.In one embodiment, the MDM2 inhibitor is administered to a human according to the section "Dosage and Administration Regimens." The present invention relates to the use of a mouse double minute 2 homolog (MDM2) inhibitor or a pharmaceutically acceptable salt thereof for treating acute myeloid leukemia (AML) in a human in need thereof. In one embodiment, the MDM2 inhibitor is a compound of formula (I) or formula (II). In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is administered at a dose selected from the group consisting of 15 mg QD, 25 mg QD, 30 mg QD, 50 mg QD, 60 mg QD, 75 mg QD, 90 mg QD, 100 mg QD, 120 mg QD, 150 mg QD, 175 mg QD, 180 mg QD, 200 mg QD, 225 mg QD, 240 mg QD, 250 mg QD, 275 mg QD, 300 mg QD, 325 mg QD, 350 mg QD, 360 mg QD, 375 mg QD, 480 mg QD, 15 mg BID, 25 mg BID, 30 mg BID, 50 mg BID, 60 mg BID, 75 mg BID, 90 mg BID, 100 mg BID, 120 mg BID, 150 mg BID, 175 mg BID, 180 mg BID, 200 mg BID, 225 mg BID, 240 mg BID, 250 mg BID, 275 mg BID, 300 mg BID, 325 mg BID, 350 mg BID, 360 mg BID, 375 mg BID and 480 mg BID.In one embodiment, the MDM2 inhibitor is administered to a human according to the section "Dosage and Administration Regimens." Methods for treating chronic Merkel cell carcinoma The present invention relates to a method for treating Merkel cell carcinoma (MCC), comprising administering to a human in need thereof a mouse double minute 2 homolog (MDM2) inhibitor or a pharmaceutically acceptable salt thereof. In one embodiment, the MDM2 inhibitor is a compound of formula (I) or formula (II). In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is administered at a dose selected from the group consisting of 15 mg QD, 25 mg QD, 30 mg QD, 50 mg QD, 60 mg QD, 75 mg QD, 90 mg QD, 100 mg QD, 120 mg QD, 150 mg QD, 175 mg QD, 180 mg QD, 200 mg QD, 225 mg QD, 240 mg QD, 250 mg QD, 275 mg QD, 300 mg QD, 325 mg QD, 350 mg QD, 360 mg QD, 375 mg QD, 480 mg QD, 15 mg BID, 25 mg BID, 30 mg BID, 50 mg BID, 60 mg BID, 75 mg BID, 90 mg BID, 100 mg BID, 120 mg BID, 150 mg BID, 175 mg BID, 180 mg BID, 200 mg BID, 225 mg BID, 240 mg BID, 250 mg BID, 275 mg BID, 300 mg BID, 325 mg BID, 350 mg BID, 360 mg BID, 375 mg BID and 480 mg BID.In one embodiment, the MDM2 inhibitor is administered to a human according to the section "Dosage and Administration Regimens." The present invention relates to the use of a mouse double minute 2 homolog (MDM2) inhibitor or a pharmaceutically acceptable salt thereof for treating Merkel cell carcinoma (MCC) in a human in need thereof. In one embodiment, the MDM2 inhibitor is a compound of formula (I) or formula (II). In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is administered at a dose selected from the group consisting of 15 mg QD, 25 mg QD, 30 mg QD, 50 mg QD, 60 mg QD, 75 mg QD, 90 mg QD, 100 mg QD, 120 mg QD, 150 mg QD, 175 mg QD, 180 mg QD, 200 mg QD, 225 mg QD, 240 mg QD, 250 mg QD, 275 mg QD, 300 mg QD, 325 mg QD, 350 mg QD, 360 mg QD, 375 mg QD, 480 mg QD, 15 mg BID, 25 mg BID, 30 mg BID, 50 mg BID, 60 mg BID, 75 mg BID, 90 mg BID, 100 mg BID, 120 mg BID, 150 mg BID, 175 mg In one embodiment, the MDM2 inhibitor is administered to a human according to the section "Dosage and Dosage Regimens".. MDM2 inhibitors The compounds of formula (I) have the structures and names shown below. 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid: . The synthesis of compounds of formula (I) is described in the following International Applications: WO2011 / 153509 and WO2014 / 200937; U.S. Patent Nos. 8,569,341; 9,593,129; 9,296,736; 9,623,018; 9,757,367; 9,801,867; 9;376;386; and 9,855,259, the disclosures of which are incorporated herein by reference in their entireties. In one embodiment, the compound of Formula (I) or Formula (II) is in an amorphous form. In one embodiment, the MDM2 inhibitor is a compound of Formula (I) or Formula (II) in a crystalline form. In one embodiment, the MDM2 inhibitor is in an anhydrous crystalline form. In one embodiment, the MDM2 inhibitor is a compound of Formula (I) in an anhydrous crystalline form characterized by a powder X-ray diffraction pattern comprising peaks at diffraction angles 2θ of approximately 11.6, 12.4, 18.6, 19.0, 21.6, and 23.6. In one embodiment, the MDM2 inhibitor is a compound of Formula (I) in an anhydrous crystalline form having an X-ray diffraction pattern substantially as shown in Figure 1. Methods for producing such crystalline forms are disclosed in International Application WO2014200937, the disclosure of which is incorporated herein by reference in its entirety. In one embodiment, the MDM2 inhibitor has the compound of formula (II) with the structure and name shown below. 4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-chloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetyl)-2-methoxybenzoic acid. The synthesis of compounds of formula (II) is described in US Pat. No. 8,952,036, the disclosure of which is incorporated herein by reference in its entirety. RG7388 ( Idanusu (Idasanutlin) ) In one embodiment, the MDM2 inhibitor is RG7388. RG7388 has the following chemical structure and name: 4-[[(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carbonyl]amino]-3-methoxybenzoic acid Triptolide (PG490) In one embodiment, the MDM2 inhibitor is triptolide. Triptolide has the following chemical structure and name: (5bS,6aS,7aS,8R,8aR,9aS,9bS,10aS,10bS)-8-Hydroxy-8a-isopropyl-10b-methyl-2,5,5b,6,6a,8,8a,9a,9b,10b-decahydrophenanthro[2',3':4b,5;2'',3'':6,7;2''',3''':8a,9]phenanthro[1,2-c]furan-3(1H)-one Nutlin-3a In one embodiment, the MDM2 inhibitor is Nutlin-3a. Nutlin-3a has the following chemical structure and name: 4-[(4S,5R)-4,5-bis(4-chlorophenyl)-2-(4-methoxy-2-propan-2-yloxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazin-2-one HDM201 In one embodiment, the MDM2 inhibitor is HDM201. HDM201 has the chemical structure and name shown below: (4S)-5-(5-chloro-1-methyl-2-oxopyridin-3-yl)-4-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-3-propan-2-yl-4H-pyrrolo[3,4-d]imidazol-6-one RG7112 In one embodiment, the MDM2 inhibitor is RG7112. RG7112 has the chemical structure and name shown below: [(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis(4-chlorophenyl)-4,5-dimethylimidazol-1-yl]-[4-(3-methylsulfonylpropyl)piperazin-1-yl]methanone CGM097A In one embodiment, the MDM2 inhibitor is CGM097A. CGM097A has the following chemical structure and name: (1S)-1-(4-chlorophenyl)-6-methoxy-2-[4-[methyl-[[4-(4-methyl-3-oxopiperazin-1-yl)cyclohexyl]methyl]amino]phenyl]-7-propan-2-yloxy-1,4-dihydroisoquinolin-3-one Nutlin-3 In one embodiment, the MDM2 inhibitor is nutlin-3. Nutlin-3 has the following chemical structure and name: 4-[4,5-bis(4-chlorophenyl)-2-(4-methoxy-2-propan-2-yloxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazin-2-one SJ-172550 In one embodiment, the MDM2 inhibitor is SJ-172550. SJ-172550 has the following chemical structure and name: Methyl 2-[2-chloro-6-ethoxy-4-[(3-methyl-5-oxo-1-phenylpyrazol-4-ylidene)methyl]phenoxy]acetate SAR405838 (MI-77301) In one embodiment, the MDM2 inhibitor is SAR405838. SAR405838 has the chemical structure and name shown below: (2'R,3R,3'S,5'S)-6-chloro-3'-(3-chloro-2-fluorophenyl)-5'-(2,2-dimethylpropyl)-N-(4-hydroxycyclohexyl)-2-oxospiro[1H-indole-3,4'-pyrrolidine]-2'-carboxamide MI-773 In one embodiment, the MDM2 inhibitor is MI-773. MI-773 has the following chemical structure and name: (2'R,3S,3'S,5'R)-6-chloro-3'-(3-chloro-2-fluorophenyl)-5'-(2,2-dimethylpropyl)-N-(4-hydroxycyclohexyl)-2-oxospiro[1H-indole-3,4'-pyrrolidine]-2'-carboxamide MX69 In one embodiment, the MDM2 inhibitor is MX69. MX69 has the chemical structure and name shown below: 4-[8-[(3,4-Dimethylphenyl)sulfaminyl]-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-4-yl]benzoic acid YH239-EE In one embodiment, the MDM2 inhibitor is YH239-EE. YH239-EE has the following chemical structure and name: 3-[2-(tert-Butylamino)-1-[(4-chlorophenyl)methyl-formylamino]-2-oxoethyl]-6-chloro-1H-indole-2-carboxylic acid ethyl ester RO8994 In one embodiment, the MDM2 inhibitor is RO8994. RO8994 has the following chemical structure and name: (2'R,3R,3'S,5'S)-N-(4-aminoformyl-2-methoxyphenyl)-6-chloro-3'-(3-chloro-2-fluorophenyl)-5'-(2,2-dimethylpropyl)-2-oxospiro[1H-indole-3,4'-pyrrolidine]-2'-formamide Nutlin-3b In one embodiment, the MDM2 inhibitor is nutlin-3b. Nutlin-3b has the following chemical structure and name: 4-[(4R,5S)-4,5-bis(4-chlorophenyl)-2-(4-methoxy-2-propan-2-yloxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazin-2-one Sidemetan (JNJ-26854165) In one embodiment, the MDM2 inhibitor is sidometan. sidometan has the following chemical structure and name: 1-N-[2-(1H-indol-3-yl)ethyl]-4-N-pyridin-4-ylbenzene-1,4-diamine NSC59984 In one embodiment, the MDM2 inhibitor is NSC59984. NSC59984 has the following chemical structure and name: (E)-1-(4-Methylpiperazin-1-yl)-3-(5-nitrofuran-2-yl)prop-2-en-1-one CHEMBL2386350 In one embodiment, the MDM2 inhibitor is CHEMBL2386350. CHEMBL2386350 has the following chemical structure and name: 2-[4-[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis(4-chlorophenyl)-4,5-dimethylimidazol-1-carbonyl]piperazin-1-yl]-1-morpholin-4-ylethanone CGM0970B In one embodiment, the MDM2 inhibitor is CGM0970B. CGM0970B has the following chemical structure and name: (1R)-1-(4-chlorophenyl)-6-methoxy-2-[4-[methyl-[[4-(4-methyl-3-oxopiperazin-1-yl)cyclohexyl]methyl]amino]phenyl]-7-propan-2-yloxy-1,4-dihydroisoquinolin-3-one MK-8242 In one embodiment, the MDM2 inhibitor is MK-8242. MK-8242 has the following chemical structure and name: 4-Amino-1-[(2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one DS-3032 In one embodiment, the MDM2 inhibitor is DS-3032. DS-3032 has the following chemical structure and name: (3'R,4'S,5'R)-N-((3R,6S)-6-aminoformyltetrahydro-2H-pyran-3-yl)-6''-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2''-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indoline]-5'-formamide DS-3032B In one embodiment, the MDM2 inhibitor is DS-3032B. DS-3032B has the following chemical structure and name: (3'R,4'S,5'R)-N-((3R,6S)-6-aminoformyltetrahydro-2H-pyran-3-yl)-6''-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2''-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indoline]-5'-formamide 4-methylbenzenesulfonate HDM201 In one embodiment, the MDM2 inhibitor is HDM201. HDM201 has the chemical structure and name shown below: (4S)-5-(5-chloro-1-methyl-2-oxopyridin-3-yl)-4-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-3-propan-2-yl-4H-pyrrolo[3,4-d]imidazol-6-one APG-115 In one embodiment, the MDM2 inhibitor is APG-115. APG-115 has the following chemical structure and name: 4-((3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-1′-ethyl-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamido)bicyclo[2.2.2]octane-1-carboxylic acid MI-1061 In one embodiment, the MDM2 inhibitor is APG-115. APG-115 has the following chemical structure and name: 4-((3'R,4'S,5'R)-6''-chloro-4'-(3-chloro-2-fluorophenyl)-2''-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indoline]-5'-carboxamido)benzoic acid Pharmaceutical compositions In some embodiments, the present invention provides a pharmaceutical composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof for use in treating cancer, wherein the cancer is selected from the group consisting of: carcinomas such as bladder cancer, breast cancer, colon cancer, rectal cancer, kidney cancer, liver cancer, lung cancer (small cell lung cancer and non-small cell lung cancer), esophageal cancer, gallbladder-bladder cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer, head and neck cancer, and skin cancer (including basal cell carcinoma and squamous cell carcinoma, melanoma skin cancer, Merkel cell carcinoma, Kaposi's sarcoma, cutaneous lymphoma); hematopoietic tumors of the lymphoid lineage (including leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia); The invention also includes hematopoietic neoplasms of the myeloid lineage (including acute and chronic myeloid leukemias, myelodysplastic syndromes, and promyelocytic leukemias); mesenchymal tumors (including fibrosarcomas and rhabdomyosarcomas and other sarcomas, such as those of soft tissue and bone); central and peripheral nervous system tumors (including astrocytomas, neuroblastomas, gliomas, glioblastomas, and schwannomas); and other tumors (including melanomas, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, and follicular thyroid carcinoma). In one embodiment, the MDM2 inhibitor is a compound of formula (I) or formula (II). In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In some embodiments, the present invention provides a pharmaceutical composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof for treating a myeloproliferative neoplasm (MPN), wherein the MPN is selected from the group consisting of polycythemia vera (PV), myelofibrosis, primary myelofibrosis, thrombocythemia, essential thrombocythemia (ET), idiopathic myelofibrosis, systemic mastocytosis (SM), chronic neutrophilic leukemia (CNL), myelodysplastic syndrome (MDS), and systemic mast cell disease (SMCD), wherein the MDM2 inhibitor is selected from the group consisting of: Formula (I) compound, compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedimetan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601 and pharmaceutically acceptable salts thereof. In some embodiments, the present invention provides a pharmaceutical composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof for treating chronic myeloid leukemia (CML), wherein the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In some embodiments, the present invention provides a pharmaceutical composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof for treating acute myeloid leukemia (AML), wherein the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In some embodiments, the present invention provides a pharmaceutical composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof for treating Merkel cell carcinoma (MCC), wherein the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In some embodiments, the present invention provides a pharmaceutical composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof for treating a myeloproliferative neoplasm (MPN), wherein the MPN is selected from the group consisting of polycythemia vera (PV), myelofibrosis, primary myelofibrosis, thrombocythemia, essential thrombocythemia (ET), idiopathic myelofibrosis, systemic mastocytosis (SM), chronic neutrophilic leukemia (CNL), myelodysplastic syndrome (MDS), and systemic mastocytosis (SMCD), wherein the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is a compound of Formula (I) or Formula (II). In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof for treating a myeloproliferative neoplasm (MPN), wherein the MPN is selected from the group consisting of polycythemia vera (PV), myelofibrosis, primary myelofibrosis, thrombocythemia, essential thrombocythemia (ET), idiopathic myelofibrosis, systemic mastocytosis (SM), chronic neutrophilic leukemia (CNL), myelodysplastic syndrome (MDS), and systemic mast cell disease (SMCD). In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof for use in treating a myeloproliferative neoplasm (MPN), wherein the MPN is selected from the group consisting of polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof for use in treating polycythemia vera (PV). In some embodiments, the present invention provides a pharmaceutical composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof for treating polycythemia vera (PV), wherein the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In some embodiments, the present invention provides a pharmaceutical composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof for treating polycythemia vera (PV), wherein the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof for treating essential thrombocythemia (ET). In some embodiments, the present invention provides a pharmaceutical composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof for treating essential thrombocythemia (ET), wherein the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In some embodiments, the present invention provides a pharmaceutical composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof for treating essential thrombocythemia (ET), wherein the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof for use in treating primary myelofibrosis. In some embodiments, the present invention provides a pharmaceutical composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof for treating primary myelofibrosis, wherein the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In some embodiments, the present invention provides a pharmaceutical composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof for treating primary myelofibrosis, wherein the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the myelofibrosis is selected from primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV MF), and post-essential thrombocythemia myelofibrosis (post-ET MF). Pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof. Where necessary, pharmaceutical compositions contain a pharmaceutically acceptable salt and / or coordination complex thereof, and one or more pharmaceutically acceptable excipients and carriers, including inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers, and adjuvants. Where necessary, ingredients other than the MDM2 inhibitor or a pharmaceutically acceptable salt thereof may be incorporated into the formulation, or the two components may be formulated into separate formulations for separate or simultaneous use. In selected embodiments, the concentration of the MDM2 inhibitor, or a pharmaceutically acceptable salt thereof, provided in the pharmaceutical compositions of the present invention is less than, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% w / w, w / v or v / v. In selected embodiments, the concentration of the MDM2 inhibitor or a pharmaceutically acceptable salt thereof provided in the pharmaceutical compositions of the present invention independently exceeds 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25%, 16%, 15. 75%, 15.50%, 15.25%, 15%, 14.75%, 14.50%, 14.25%, 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25%, 11%, 10.75%, 10.50%, 10.25%, 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.2 5%, 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09% , 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% w / w, w / v or v / v. In selected embodiments, the concentration of the MDM2 inhibitor, or a pharmaceutically acceptable salt thereof, is independently in the range of about 0.0001% to about 50%, about 0.001% to about 40%, about 0.01% to about 30%, about 0.02% to about 29%, about 0.03% to about 28%, about 0.04% to about 27%, about 0.05% to about 26%, about 0.06% to about 25%, about 0.07% to about 24%, about 0.08% to about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%, or about 1% to about 10% w / w, w / v, or v / v. In selected embodiments, the concentration of the MDM2 inhibitor, or a pharmaceutically acceptable salt thereof, independently ranges from about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, about 0.1% to about 0.9% w / w, w / v, or v / v. In selected embodiments, the amount of the MDM2 inhibitor, or a pharmaceutically acceptable salt thereof, is independently equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g or 0.0001 g. In selected embodiments, the amount of the MDM2 inhibitor, or a pharmaceutically acceptable salt thereof, independently exceeds 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g, 0.3 g, 0.35 g, 0.4 g, 0.45 g, 0.5 g, 0.55 g, 0.6 g, 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g, 7.5 g, 8 g, 8.5 g, 9 g, 9.5 g or 10 g. MDM2 inhibitors or pharmaceutically acceptable salts thereof are effective over a wide dosage range. For example, for treating adults, doses in the range of 0.01 to 1000 mg, 0.5 to 100 mg, 1 to 50 mg, and 5 to 40 mg per day are examples of dosages that may be used. The exact dosage will depend on the route of administration, the form of compound administration, the sex and age of the individual being treated, the weight of the individual being treated, and the preference and experience of the attending physician. Non-limiting exemplary pharmaceutical compositions and methods for their preparation are described below. Pharmaceutical composition for oral administration In selected embodiments, the present invention provides a pharmaceutical composition for oral administration comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof and a pharmaceutical excipient suitable for oral administration. In selected embodiments, the present invention provides a solid pharmaceutical composition for oral administration, comprising: (i) an effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutical excipient suitable for oral administration. In selected embodiments, the composition further comprises (iii) an effective amount of at least one additional active ingredient. In selected embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral administration. The pharmaceutical composition of the present invention suitable for oral administration may be presented as a discontinuous dosage form, such as a capsule, cachet, or tablet; or a liquid or aerosol spray, each containing a predetermined amount of a powdered or granular active ingredient; a solution or suspension in an aqueous or non-aqueous liquid; an oil-in-water emulsion; or a water-in-oil liquid emulsion. Although such dosage forms may be prepared by any method, all methods include the step of associating the active ingredient with a carrier comprising one or more necessary ingredients. Generally speaking, the composition is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a finely powdered solid carrier, or both, and then, if necessary, shaping the product into the desired presentation form. For example, tablets can be manufactured by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and / or a surfactant or dispersant. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Because water can promote the degradation of some compounds, the present invention further encompasses anhydrous pharmaceutical compositions and dosage forms. For example, water (e.g., 5%) can be added in the pharmaceutical field as a means of simulating long-term storage in order to determine characteristics such as shelf life or the stability of the formulation over time. The anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low-water-containing ingredients and low-moisture or low-humidity conditions. If substantial contact with moisture and / or humidity is expected during manufacturing, packaging, and / or storage, the pharmaceutical compositions and dosage forms of the present invention containing lactose can be made anhydrous. Anhydrous pharmaceutical compositions can be prepared and stored to maintain their anhydrous properties. Therefore, anhydrous compositions can be packaged using materials known to prevent exposure to water so that they can be included in suitable prescription kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foil, plastic, or the like, unit dose containers, blister packs, and strip packs. According to conventional pharmaceutical compounding techniques, the MDM2 inhibitor or its pharmaceutically acceptable salt can be combined with a pharmaceutical carrier into an intimate mixture. Depending on the form of the preparation required for administration, the carrier can take a variety of forms. When preparing a composition for oral dosage form, any of the commonly used pharmaceutical media can be used as a carrier, such as water, glycols, oils, alcohols, flavorings, preservatives, colorants and the like in the case of oral liquid preparations (such as suspensions, solutions and elixirs) or aerosols; or in the case of oral solid preparations, carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders and disintegrants can be used. In some embodiments, lactose is not used. For example, in the case of solid oral preparations, suitable carriers include powders, capsules and tablets. If necessary, tablets can be coated by standard aqueous or non-aqueous techniques. Suitable binders for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, carboxymethylcellulose calcium, sodium carboxymethylcellulose), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropyl methylcellulose, microcrystalline cellulose, and mixtures thereof. Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. Disintegrants can be used in the compositions of the present invention to provide tablets that disintegrate when exposed to an aqueous environment. Too much disintegrant can produce tablets that disintegrate in the bottle. Too little may not be enough to cause disintegration to occur, thus changing the release rate and degree of the active ingredient from the dosage form. Therefore, a sufficient amount of disintegrant that is neither too little nor too much, thereby not adversely changing the release of the active ingredient, can be used to form the dosage form of the compound disclosed herein. The amount of the disintegrant used can be based on the type and mode of administration of the formulation, and is easily distinguished by a person of ordinary skill. About 0.5 to about 15% by weight of a disintegrant, or about 1 to about 5% by weight of a disintegrant can be used in a pharmaceutical composition. Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato starch or tapioca starch, other starches, pregelatinized starch, other starches, clays, other alginics, other celluloses, gums, or mixtures thereof. Lubricants that can be used in the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, or mixtures thereof. Other lubricants include, for example, syloid silica, condensation aerosols of synthetic silica, or mixtures thereof. Lubricants can be added, if appropriate, in an amount of less than about 1% by weight of the pharmaceutical composition. When aqueous suspensions and / or elixirs are required for oral administration, the essential active ingredient may be combined with various sweeteners or flavorings, coloring matter or dyes and emulsifiers and / or suspending agents (if necessary) together with diluents such as water, ethanol, propylene glycol, glycerol and various combinations thereof. Tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period of time. For example, a time-delaying material such as glyceryl monostearate or glyceryl distearate may be employed. Formulations for oral use may also be presented in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin; or in the form of soft gelatin capsules in which the active ingredient is mixed with water or an oily medium such as peanut oil, liquid paraffin, or olive oil. Surfactants that can be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants, a mixture of lipophilic surfactants, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant can be used. Suitable hydrophilic surfactants generally have an HLB value of at least 10, while suitable lipophilic surfactants generally have an HLB value of less than or equal to about 10. The experimental parameter used to characterize the relative hydrophilicity and hydrophobicity of nonionic amphoteric compounds is the hydrophilicity-lipophilicity balance (HLB value). Surfactants with lower HLB values ​​are more lipophilic or hydrophobic and have greater solubility in oils, while surfactants with higher HLB values ​​are more hydrophilic and have greater solubility in aqueous solutions. Hydrophilic surfactants are generally considered to be those compounds with an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB rating is generally not applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds with an HLB value equal to or less than about 10. However, the HLB value of a surfactant is only a rough guide that is commonly used to formulate industrial, pharmaceutical, and cosmetic emulsions. The hydrophilic surfactant may be ionic or nonionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithin and hydrogenated lecithin; lysolecithin and hydrogenated lysolecithin; phospholipids and their derivatives; lysolecithin and their derivatives; carnitine fatty acid ester salts; salts of alkyl sulfates; fatty acid salts; sodium docusate; acylacetates; monoacetylated and diacetylated tartaric acid esters of monoglycerides and diglycerides; succinylated monoglycerides and diglycerides; citric acid esters of monoglycerides and diglycerides; and mixtures thereof. Within the aforementioned group, ionic surfactants include, by way of example, lecithin, lysolecithin, phospholipids, lysophospholipids and their derivatives; carnitine fatty acid ester salts; salts of alkyl sulfates; fatty acid salts; sodium docusate; acylacetic acid esters; monoacetylated and diacetylated tartaric acid esters of monoglycerides and diglycerides; succinylated monoglycerides and diglycerides; citric acid esters of monoglycerides and diglycerides; and mixtures thereof. Ionic surfactants may be ionized forms of the following: lecithin, lysophosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, fatty acid lactyl esters, stearyl-2-lactate, stearyl lactate, succinylcholine ... Acylated monoglycerides, mono- and diacetylated tartaric acid esters of mono- and diglycerides, citrates of mono- and diglycerides, cholestyrrosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, myristyl sulfate, docusate, lauryl carnitine, palmitoyl carnitine, myristyl carnitine, their salts, and mixtures thereof. The hydrophilic nonionic surfactant may include, but is not limited to, alkyl glucosides; alkyl maltosides; alkyl thioglucosides; lauryl polyethylene glycol glycerides; polyoxyalkylene alkyl ethers, such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols, such as polyethylene glycol alkylphenols; polyoxyalkylene alkylphenol fatty acid esters, such as polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters, such as polyethylene glycol sorbitan Sugar alcohol fatty acid esters; hydrophilic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, their derivatives, and analogs; polyoxyethylated vitamins and their derivatives; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters and hydrophilic transesterification products of a polyol with at least one member of the group consisting of triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a sugar. Other hydrophilic nonionic surfactants include, but are not limited to, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 triolein, PEG-32 dioleate, PEG-20 laurin, PEG-30 laurin, PEG-20 stearin, PEG-20 olein, PEG-30 olein, PEG-30 laurin, PEG-40 laurin Esters, PEG-40 Palm Kernel Oil, PEG-50 Hydrogenated Castor Oil, PEG-40 Castor Oil, PEG-35 Castor Oil, PEG-60 Castor Oil, PEG-40 Hydrogenated Castor Oil, PEG-60 Hydrogenated Castor Oil, PEG-60 Corn Oil, PEG-6 Caprate / Caprylate Glycerides, PEG-8 Caprate / Caprylate Glycerides, Polyglyceryl-10 Laurate, PEG-30 Cholesterol, PEG-25 Plant Sterols, PEG-3 0 Soybean Sterols, PEG-20 Trioleate, PEG-40 Sorbitan Oleate, PEG-80 Sorbitan Laurate, Polysorbate 20, Polysorbate 80, POE-9 Lauryl Ether, POE-23 Lauryl Ether, POE-10 Oleyl Ether, POE-20 Oleyl Ether, POE-20 Stearyl Ether, Tocopheryl PEG-100 Succinate, PEG-24 Cholesterol, Polyglyceryl-10 Oleate, Tween 40, Tween 60, Sucrose Monostearate, Sucrose Monolaurate, Sucrose Monopalmitate, PEG 10-100 Nonylphenol Series, PEG 15-100 Octylphenol Series and Poloxamer. By way of example only, suitable lipophilic surfactants include: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acid esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of monoglycerides and diglycerides; hydrophobic transesterification products of polyols with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; oil-soluble vitamins / vitamin derivatives; and mixtures thereof. Within this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or hydrophobic transesterification products of polyols with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides. In one embodiment, the composition may include a solubilizer to ensure good dissolution and / or decomposition of the compound of the invention and to minimize precipitation of the compound of the invention. This is particularly important for compositions intended for parenteral use, such as compositions for injection. A solubilizer may also be added to increase the solubility of a hydrophilic drug and / or other components (such as a surfactant) or to maintain a stable or homogeneous solution or dispersion. Examples of suitable solubilizers include, but are not limited to, the following: alcohols and polyols such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, diethylene glycol monoethyl ether, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycol having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (tetrahydrofuran glycol ether) or methoxy PEG; amides and other nitrogen-containing compounds such as 2-pyrrolidone, 2-piperidone, ε-caprolactam , N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributyl citrate, triethyl acetyl citrate, tributyl acetyl citrate, triethyl citrate, ethyl oleate, ethyl octanoate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and its isomers, δ-valerolactone and its isomers, β-butyrolactone and its isomers; and other solubilizers known in the art such as dimethylacetamide, dimethyl isosorbide, N-methylpyrrolidone, monooctanoin, diethylene glycol monoethyl ether and water. Mixtures of solubilizers may also be used. Examples include, but are not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin, ethanol, polyethylene glycol 200-100, glycofurol, diethylene glycol monoethyl ether, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethanol, PEG-400, glycofurol, and propylene glycol. The amount of the solubilizing agent that can be included is not subject to specific restrictions.The amount of a given solubilizing agent can be limited to the amount that is acceptable to the organism, and this amount is easily determined by a person skilled in the art. In some cases, it is advisable to include a solubilizing agent that far exceeds the amount of the acceptable amount of the organism, for example, so that drug concentration is maximized, wherein before using conventional techniques (such as distillation or evaporation) to provide compositions to the patient, remove excess solubilizing agent. Therefore, if present, then in the combined weight of medicine and other excipients, solubilizing agent can be 10 wt %, 25 wt %, 50 wt %, 100 wt % or a weight ratio of at most about 200 wt %. Optionally, a small amount of solubilizing agent can also be used, such as 5%, 2%, 1% or even less. Typically, solubilizing agent can exist with an amount of about 1 wt % to about 100 wt %, more typically about 5 wt % to about 25 wt %. The composition may further include one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, but are not limited to, detackifying agents, defoaming agents, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, tonicity modifiers, flavoring agents, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof. In addition, acids or bases may be incorporated into the composition to facilitate handling, enhance stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium bicarbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic calcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS), and the like. Also suitable alkali is the salt of pharmaceutically acceptable acid, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acid, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acid, formic acid, fumaric acid, gluconic acid, hydroquinonesulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, p-bromobenzenesulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid and the like. Salts of polyprotic acids can also be used, such as sodium phosphate, disodium hydrogen phosphate and sodium dihydrogen phosphate. When the alkali is a salt, the cation can be any suitable and pharmaceutically acceptable cation, such as ammonium, alkali metal and alkaline earth metal. Examples can include but are not limited to sodium, potassium, lithium, magnesium, calcium and ammonium. Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinonesulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, p-bromobenzenesulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, and uric acid. Pharmaceutical compositions for injection In selected embodiments, the present invention provides a pharmaceutical composition for injection, comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof and a pharmaceutical excipient suitable for injection. The components and amounts of the pharmaceutical agents in the composition are as described herein. The compositions of the present invention may be incorporated into forms for administration by injection including aqueous or oily suspensions or emulsions containing sesame oil, corn oil, cottonseed oil or peanut oil, as well as elixirs, mannitol, dextrose or sterile aqueous solutions and similar pharmaceutical vehicles. Aqueous solutions in physiological saline are also commonly used for injection. Ethanol, glycerol, propylene glycol, and liquid polyethylene glycols (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be used. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the desired particle size (in the case of dispersions), and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and thimerosal. Sterile injectable solutions are prepared by incorporating the desired amount of the MDM2 inhibitor or a pharmaceutically acceptable salt thereof in a suitable solvent along with various other ingredients as listed above. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle containing a basic dispersion medium and the desired other ingredients from those listed above. Where sterile powders are used to prepare sterile injectable solutions, some desirable preparation methods are vacuum drying and freeze drying techniques to produce a powder of the active ingredient plus any additional desired ingredients from a previously sterile-filtered solution. Administration of an MDM2 inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of such a compound can be achieved by any method capable of delivering the compound to the site of action. Such methods include oral, intraduodenal, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal, or infusion), topical (e.g., transdermal application), rectal administration, local delivery via a catheter or stent, or via inhalation. Combinations of compounds can also be administered intraadiposely or intrathecally. Exemplary parenteral administration forms include solutions or suspensions of the active compound in sterile aqueous solutions, such as aqueous propylene glycol or dextrose solutions. Such dosage forms may be suitably buffered, if necessary. The present invention also provides kits. The kits include an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, alone or in combination, in suitable packaging, and written materials that may include instructions for use, clinical study discussions, and a list of side effects. Such kits may also include information, such as scientific literature references, drug package inserts, clinical trial results, and / or summaries of such content, and the like, that demonstrate or confirm the activity and / or advantages of the composition, and / or describe dosage, administration, side effects, drug interactions, or other information suitable for healthcare providers. Such information may be based on the results of various studies, such as studies using experimental animals involving in vivo models and studies based on human clinical trials. The kits may further contain another active pharmaceutical ingredient. Suitable packaging and other items for use (e.g., measuring cups for preparing liquids, foil wrapping to minimize air exposure, and the like) are known in the art and may be included in the kits. The kits described herein may be provided, sold, and / or marketed to healthcare providers, including physicians, nurses, pharmacists, formulary officers, and the like. In selected embodiments, the kits may also be sold directly to consumers. In one embodiment, the present invention provides a kit comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof for use in treating an MPN. In one embodiment, the MPN is selected from the group consisting of polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis. In one embodiment, the present invention provides a kit comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof for use in treating chronic myeloid leukemia (CML). In one embodiment, the present invention provides a kit comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof for use in treating acute myeloid leukemia (AML). In one embodiment, the present invention provides a kit comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof for use in treating Merkel cell carcinoma (MCC). Dosage and administration schedule The amount of the MDM2 inhibitor or its pharmaceutically acceptable salt administered will depend on the human being treated, the severity of the disease or condition, the rate of administration, the configuration of the compound, and the judgment of the prescribing physician. However, an effective dose is in the range of about 0.001 to about 100 mg per kilogram of body weight per day, such as about 1 to about 35 mg / kg per day, in single or divided doses. For a 70 kg human, this would be equivalent to about 0.05 to 7 g per day, such as about 0.05 to about 2.5 g per day. In some cases, dosage levels below the lower limit of the aforementioned range may be entirely sufficient, while in other cases, larger doses may still be used without causing any adverse side effects, for example, by dividing such larger doses into several smaller doses for administration throughout the day. In some embodiments, the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered in a single dose. Typically, such administration will be by injection, such as intravenous injection, to allow for rapid introduction of the agent. However, other routes may be used as appropriate. A single dose of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof may also be used to treat acute conditions. In some embodiments, the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered in multiple doses to treat MPN. In one embodiment, the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered in multiple doses. In one embodiment, the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered by injection, such as intravenous injection, in multiple doses. In one embodiment, administration may be about once, twice, three times, four times, five times, six times, or more than six times per day. In one embodiment, administration may be selected from the group consisting of: once a day, twice a day, three times a day, four times a day, five times a day, six times a day, every other day, once a week, twice a week, three times a week, four times a week, once every two weeks, and once a month. In other embodiments, the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered from about once a day to about six times a day. In some embodiments, the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered once daily, while in other embodiments, the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered twice daily, and in other embodiments, the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered three times daily. In some embodiments, the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered three times a week, including on Mondays, Wednesdays, and Fridays. Administration of the MDM2 inhibitor or a pharmaceutically acceptable salt thereof can be continued for as long as needed. In some embodiments, the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered for more than 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days or more. In some embodiments, the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered for less than 28 days, 14 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days or 1 day. In some embodiments, the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered for about 14 days, about 21 days, about 28 days, about 35 days, about 42 days, about 49 days, or about 56 days. In some embodiments, the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered continuously over a long period of time, for example, to treat a chronic effect. In another embodiment, the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered continuously for less than about 7 days. In another embodiment, administration continues for more than about 6 days, 10 days, 14 days, 28 days, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, or one year. In some embodiments, administration continues for more than about one year, two years, three years, four years, or five years. In some embodiments, administration is continued and maintained for as long as necessary. In some embodiments, the effective dose of an MDM2 inhibitor, or a pharmaceutically acceptable salt thereof, is between about 1 mg to about 500 mg, about 10 mg to about 300 mg, about 20 mg to about 250 mg, about 25 mg to about 200 mg, about 10 mg to about 200 mg, about 20 mg to about 150 mg, about 30 mg to about 120 mg, about 10 mg to about 90 mg, about 20 mg to about 80 mg, about 30 mg to about 70 mg, about 40 mg to about 60 mg, about 45 mg to about 55 mg, about 48 mg to about 52 mg, about 50 mg to about 150 mg, about 60 mg to about 140 mg, about 70 mg to about 130 mg, about 80 mg to about 120 mg, about 90 mg to about 110 mg, about 95 mg to about 105 mg, about 150 mg to about 250 mg, about 160 mg to about 240 mg, about 170 mg to about 230 mg, about 180 mg to about 220 In some embodiments, the effective dose of the MDM2 inhibitor, or a pharmaceutically acceptable salt thereof, is about 15 mg, about 25 mg, about 30 mg, about 50 mg, about 50 mg, about 75 mg, about 90 mg, about 100 mg, about 120 mg, about 125 mg, about 150 mg, about 175 mg, about 180 mg, about 200 mg, about 225 mg, about 240 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 360 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 480 mg, or about 500 mg. In some embodiments, the effective dose of an MDM2 inhibitor, or a pharmaceutically acceptable salt thereof, is 15 mg, 25 mg, 30 mg, 50 mg, 60 mg, 75 mg, 90 mg, 100 mg, 120 mg, 150 mg, 175 mg, 180 mg, 200 mg, 225 mg, 240 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 360 mg, 375 mg, and 480 mg. In some embodiments, an effective dose of an MDM2 inhibitor, or a pharmaceutically acceptable salt thereof, is between about 0.01 mg / kg and about 4.3 mg / kg, about 0.15 mg / kg and about 3.6 mg / kg, about 0.3 mg / kg and about 3.2 mg / kg, about 0.35 mg / kg and about 2.85 mg / kg, about 0.15 mg / kg and about 2.85 mg / kg, about 0.3 mg and about 2.15 mg / kg, about 0.45 mg / kg and about 1.7 mg / kg, about 0.15 mg / kg and about 1.3 mg / kg, about 0.3 mg / kg and about 1.15 mg / kg, about 0.45 mg / kg and about 1 mg / kg, about 0.55 mg / kg and about 0.85 mg / kg, about 0.65 mg / kg and about 0.8 mg / kg, about 0.7 mg / kg and about 0.75 mg / kg, about 0.7 mg / kg and about 2.15 mg / kg, about 0.85 In some embodiments, the present invention may be in the range of about 1 mg / kg to about 2 mg / kg, about 1 mg / kg to about 1.85 mg / kg, about 1.15 mg / kg to about 1.7 mg / kg, about 1.3 mg / kg to about 1.6 mg / kg, about 1.35 mg / kg to about 1.5 mg / kg, about 2.15 mg / kg to about 3.6 mg / kg, about 2.3 mg / kg to about 3.4 mg / kg, about 2.4 mg / kg to about 3.3 mg / kg, about 2.6 mg / kg to about 3.15 mg / kg, about 2.7 mg / kg to about 3 mg / kg, about 2.8 mg / kg to about 3 mg / kg, or about 2.85 mg / kg to about 2.95 mg / kg. In some embodiments, the effective dose of the MDM2 inhibitor, or a pharmaceutically acceptable salt thereof, is about 0.35 mg / kg, about 0.7 mg / kg, about 1 mg / kg, about 1.4 mg / kg, about 1.8 mg / kg, about 2.1 mg / kg, about 2.5 mg / kg, about 2.85 mg / kg, about 3.2 mg / kg, or about 3.6 mg / kg. In some embodiments, the MDM2 inhibitor, or a pharmaceutically acceptable salt thereof, is administered at a dose of 10 to 500 mg BID, including 15 mg, 25 mg, 30 mg, 50 mg, 60 mg, 75 mg, 90 mg, 100 mg, 120 mg, 150 mg, 175 mg, 180 mg, 200 mg, 225 mg, 240 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 360 mg, 375 mg, and 480 mg BID. In some embodiments, the MDM2 inhibitor, or a pharmaceutically acceptable salt thereof, is administered at a dose of 10 to 500 mg QD, including 15 mg, 25 mg, 30 mg, 50 mg, 60 mg, 75 mg, 90 mg, 100 mg, 120 mg, 150 mg, 175 mg, 180 mg, 200 mg, 225 mg, 240 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 360 mg, 375 mg, and 480 mg QD. An effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof can be administered in single or multiple doses by any of the generally accepted modes of administration with similar efficacy, including buccal, sublingual, and transdermal routes, by intraarterial injection, intravenously, parenterally, intramuscularly, subcutaneously, or orally. In some embodiments, the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a subject intermittently, referred to as intermittent administration. "Intermittent administration" means a period of administration of a therapeutically effective dose of the MDM2 inhibitor or a pharmaceutically acceptable salt thereof, followed by a break period, and then another administration period, and so on. During each administration period, the dosing frequency can be independently selected from three times a day, twice a day, once a day, once a week, twice a week, three times a week, four times a week, five times a week, six times a week, or once a month. In one embodiment, the MDM2 inhibitor is a compound of Formula (I) or Formula (II). In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. "Period of discontinuance" or "discontinuance period" or "rest period" refers to the length of time during which administration of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof is discontinued. The discontinuance period can be longer or shorter than the administration period, or the same as the administration period. During the discontinuance period, other therapeutic agents other than the MDM2 inhibitor or a pharmaceutically acceptable salt thereof can be administered. In one embodiment, for the treatment of a myeloproliferative neoplasm (MPN), an MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a human subject in need thereof for a first administration period, followed by a rest period, followed by a second administration period, and so on, wherein the MPN is selected from the group consisting of polycythemia vera (PV), myelofibrosis, primary myelofibrosis, thrombocythemia, essential thrombocythemia (ET), idiopathic myelofibrosis, systemic mastocytosis (SM), chronic neutrophilic leukemia (CNL), myelodysplastic syndrome (MDS), and systemic mast cell disease (SMCD). The first administration period, the second administration period, and the interruption period are independently selected from the group consisting of: more than 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, one month, five weeks, six weeks, seven weeks, two months, nine weeks, ten weeks, eleven weeks, three months, thirteen weeks, fourteen weeks, fifteen weeks, four months, and more days, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject three times a day, twice a day, once a day, once a week, twice a week, three times a week, four times a week, five times a week, six times a week, or once a month. In one embodiment, the length of the first administration period is the same as the second administration period. In one embodiment, the first dosing period is shorter than the second dosing period. In one embodiment, the first dosing period is longer than the second dosing period. In one embodiment, the first dosing period and the second dosing period are about one week, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once daily; and the break period is about two weeks. In one embodiment, the first dosing period and the second dosing period are about three weeks, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once daily; and the break period is about two weeks. In one embodiment, the first dosing period and the second dosing period are about three weeks, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once weekly; and the break period is about two weeks. In one embodiment, the first dosing period and the second dosing period are about four weeks, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once daily; and the break period is about two weeks. In one embodiment, the first administration period and the second administration period are about four weeks, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once a week; and the rest period is about two weeks. In one embodiment, the MDM2 inhibitor is a compound of Formula (I) or Formula (II).In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, to treat polycythemia vera (PV), a MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a human subject in need thereof for a first administration period, followed by a rest period, followed by a second administration period, and so on. The first administration period, the second administration period, and the interruption period are independently selected from the group consisting of: more than 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, one month, five weeks, six weeks, seven weeks, two months, nine weeks, ten weeks, eleven weeks, three months, thirteen weeks, fourteen weeks, fifteen weeks, four months, and more days, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject three times a day, twice a day, once a day, once a week, twice a week, three times a week, four times a week, five times a week, six times a week, or once a month. In one embodiment, the length of the first administration period is the same as the second administration period. In one embodiment, the first dosing period is shorter than the second dosing period. In one embodiment, the first dosing period is longer than the second dosing period. In one embodiment, the first dosing period and the second dosing period are about one week, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once daily; and the break period is about two weeks. In one embodiment, the first dosing period and the second dosing period are about three weeks, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once daily; and the break period is about two weeks. In one embodiment, the first dosing period and the second dosing period are about three weeks, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once weekly; and the break period is about two weeks. In one embodiment, the first dosing period and the second dosing period are about four weeks, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once daily; and the break period is about two weeks. In one embodiment, the first administration period and the second administration period are about four weeks, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once a week; and the rest period is about two weeks. In one embodiment, the MDM2 inhibitor is a compound of Formula (I) or Formula (II).In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, to treat essential thrombocythemia (ET), a MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a human subject in need thereof for a first administration period, followed by a rest period, followed by a second administration period, and so on. The first administration period, the second administration period, and the interruption period are independently selected from the group consisting of: more than 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, one month, five weeks, six weeks, seven weeks, two months, nine weeks, ten weeks, eleven weeks, three months, thirteen weeks, fourteen weeks, fifteen weeks, four months, and more days, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject three times a day, twice a day, once a day, once a week, twice a week, three times a week, four times a week, five times a week, six times a week, or once a month. In one embodiment, the length of the first administration period is the same as the second administration period. In one embodiment, the first dosing period is shorter than the second dosing period. In one embodiment, the first dosing period is longer than the second dosing period. In one embodiment, the first dosing period and the second dosing period are about one week, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once daily; and the break period is about two weeks. In one embodiment, the first dosing period and the second dosing period are about three weeks, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once daily; and the break period is about two weeks. In one embodiment, the first dosing period and the second dosing period are about three weeks, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once weekly; and the break period is about two weeks. In one embodiment, the first dosing period and the second dosing period are about four weeks, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once daily; and the break period is about two weeks. In one embodiment, the first administration period and the second administration period are about four weeks, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once a week; and the rest period is about two weeks. In one embodiment, the MDM2 inhibitor is a compound of Formula (I) or Formula (II).In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, to treat primary myelofibrosis, a MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a human subject in need thereof for a first administration period, followed by a rest period, followed by a second administration period, and so on. The first administration period, the second administration period, and the interruption period are independently selected from the group consisting of: more than 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, one month, five weeks, six weeks, seven weeks, two months, nine weeks, ten weeks, eleven weeks, three months, thirteen weeks, fourteen weeks, fifteen weeks, four months, and more days, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject three times a day, twice a day, once a day, once a week, twice a week, three times a week, four times a week, five times a week, six times a week, or once a month. In one embodiment, the length of the first administration period is the same as the second administration period. In one embodiment, the first dosing period is shorter than the second dosing period. In one embodiment, the first dosing period is longer than the second dosing period. In one embodiment, the first dosing period and the second dosing period are about one week, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once daily; and the break period is about two weeks. In one embodiment, the first dosing period and the second dosing period are about three weeks, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once daily; and the break period is about two weeks. In one embodiment, the first dosing period and the second dosing period are about three weeks, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once weekly; and the break period is about two weeks. In one embodiment, the first dosing period and the second dosing period are about four weeks, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once daily; and the break period is about two weeks. In one embodiment, the first administration period and the second administration period are about four weeks, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once a week; and the rest period is about two weeks. In one embodiment, the MDM2 inhibitor is a compound of Formula (I) or Formula (II). In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof.In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, to treat chronic myeloid leukemia (CML), a MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a human subject in need thereof for a first administration period, followed by a rest period, followed by a second administration period, and so on. The first administration period, the second administration period, and the interruption period are independently selected from the group consisting of: more than 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, one month, five weeks, six weeks, seven weeks, two months, nine weeks, ten weeks, eleven weeks, three months, thirteen weeks, fourteen weeks, fifteen weeks, four months, and more days, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject three times a day, twice a day, once a day, once a week, twice a week, three times a week, four times a week, five times a week, six times a week, or once a month. In one embodiment, the length of the first administration period is the same as the second administration period. In one embodiment, the first dosing period is shorter than the second dosing period. In one embodiment, the first dosing period is longer than the second dosing period. In one embodiment, the first dosing period and the second dosing period are about one week, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once daily; and the break period is about two weeks. In one embodiment, the first dosing period and the second dosing period are about three weeks, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once daily; and the break period is about two weeks. In one embodiment, the first dosing period and the second dosing period are about three weeks, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once weekly; and the break period is about two weeks. In one embodiment, the first dosing period and the second dosing period are about four weeks, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once daily; and the break period is about two weeks. In one embodiment, the first administration period and the second administration period are about four weeks, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once a week; and the rest period is about two weeks. In one embodiment, the MDM2 inhibitor is a compound of Formula (I) or Formula (II).In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, to treat acute myeloid leukemia (AML), a MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a human subject in need thereof for a first administration period, followed by a rest period, followed by a second administration period, and so on. The first administration period, the second administration period, and the interruption period are independently selected from the group consisting of: more than 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, one month, five weeks, six weeks, seven weeks, two months, nine weeks, ten weeks, eleven weeks, three months, thirteen weeks, fourteen weeks, fifteen weeks, four months, and more days, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject three times a day, twice a day, once a day, once a week, twice a week, three times a week, four times a week, five times a week, six times a week, or once a month. In one embodiment, the length of the first administration period is the same as the second administration period. In one embodiment, the first dosing period is shorter than the second dosing period. In one embodiment, the first dosing period is longer than the second dosing period. In one embodiment, the first dosing period and the second dosing period are about one week, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once daily; and the break period is about two weeks. In one embodiment, the first dosing period and the second dosing period are about three weeks, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once daily; and the break period is about two weeks. In one embodiment, the first dosing period and the second dosing period are about three weeks, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once weekly; and the break period is about two weeks. In one embodiment, the first dosing period and the second dosing period are about four weeks, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once daily; and the break period is about two weeks. In one embodiment, the first administration period and the second administration period are about four weeks, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once a week; and the rest period is about two weeks. In one embodiment, the MDM2 inhibitor is a compound of Formula (I) or Formula (II).In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, to treat Merkel cell carcinoma (MCC), a MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a human subject in need thereof for a first administration period, followed by a rest period, followed by a second administration period, and so on. The first administration period, the second administration period, and the interruption period are independently selected from the group consisting of: more than 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, one month, five weeks, six weeks, seven weeks, two months, nine weeks, ten weeks, eleven weeks, three months, thirteen weeks, fourteen weeks, fifteen weeks, four months, and more days, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject three times a day, twice a day, once a day, once a week, twice a week, three times a week, four times a week, five times a week, six times a week, or once a month. In one embodiment, the length of the first administration period is the same as the second administration period. In one embodiment, the first dosing period is shorter than the second dosing period. In one embodiment, the first dosing period is longer than the second dosing period. In one embodiment, the first dosing period and the second dosing period are about one week, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once daily; and the break period is about two weeks. In one embodiment, the first dosing period and the second dosing period are about three weeks, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once daily; and the break period is about two weeks. In one embodiment, the first dosing period and the second dosing period are about three weeks, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once weekly; and the break period is about two weeks. In one embodiment, the first dosing period and the second dosing period are about four weeks, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once daily; and the break period is about two weeks. In one embodiment, the first administration period and the second administration period are about four weeks, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once a week; and the rest period is about two weeks. In one embodiment, the MDM2 inhibitor is a compound of Formula (I) or Formula (II). In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof.In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, to treat cancer, an MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof on days 1-7 of a 21 day cycle (without administration of an MDM2 inhibitor on days 8-21) for a period selected from 3 weeks, 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 27 weeks, 30 weeks, 33 weeks, 36 weeks, 39 weeks, 42 weeks, 45 weeks, 48 ​​weeks, 51 weeks, 54 weeks, 57 weeks, 60 weeks, 63 weeks, 66 weeks, 69 weeks, 72 weeks, 75 weeks, 78 weeks, 81 weeks, 84 weeks, 87 weeks, 90 weeks, 93 weeks, 96 weeks, 99 weeks, 102 weeks, 105 weeks, 108 weeks, 111 weeks, 114 weeks, 117 weeks, 120 weeks , 123 weeks, 126 weeks, 129 weeks, 132 weeks, 135 weeks, 138 weeks, 141 weeks, 144 weeks, 147 weeks, 150 weeks, 153 weeks and 156 weeks, wherein the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHE MBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601 and pharmaceutically acceptable salts thereof, wherein the cancer is selected from the group consisting of carcinomas such as bladder cancer, breast cancer, colon cancer, rectal cancer, kidney cancer, liver cancer, lung cancer (small cell lung cancer and non-small cell lung cancer), esophageal cancer, gallbladder-bladder cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer, head and neck cancer and skin cancer (including basal cell carcinoma and squamous cell carcinoma, melanoma skin cancer, Merkel cell carcinoma, Kaposi's sarcoma, cutaneous lymphoma); hematopoietic tumors of the lymphoid lineage (including leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, and Burkitt's lymphoma); hematopoietic neoplasms of the myeloid lineage (including acute and chronic myeloid leukemias, myelodysplastic syndromes, and promyelocytic leukemias); tumors of mesenchymal origin (including fibrosarcoma and rhabdomyosarcoma and other sarcomas, such as those of soft tissue and bone); tumors of the central and peripheral nervous system (including astrocytomas, neuroblastomas, gliomas, glioblastomas, and schwannomas); and other tumors (including melanomas, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, and follicular thyroid carcinoma).In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, to treat MPN, an MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof on days 1-7 of a 21-day cycle (on days 8-21, the MDM2 inhibitor is not administered) for a period selected from 3 weeks, 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 27 weeks, 30 weeks, 33 weeks, 36 weeks, 39 weeks, 42 weeks, 45 weeks, 48 ​​weeks, 51 weeks, 54 weeks, 57 weeks, 60 weeks, 63 weeks, 66 weeks, 69 weeks, 72 weeks. , 75 weeks, 78 weeks, 81 weeks, 84 weeks, 87 weeks, 90 weeks, 93 weeks, 96 weeks, 99 weeks, 102 weeks, 105 weeks, 108 weeks, 111 weeks, 114 weeks, 117 weeks, 120 weeks, 123 weeks, 126 weeks, 129 weeks, 132 weeks, 135 weeks, 138 weeks, 141 weeks, 144 weeks, 147 weeks, 150 weeks, 153 weeks and 156 weeks, wherein the MDM2 inhibitor is selected from the group consisting of: a compound of formula (I), a compound of formula (II) Compound, RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedimetan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS -3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof, wherein the MPN is selected from the group consisting of polycythemia vera (PV), myelofibrosis, primary myelofibrosis, thrombocythemia, essential thrombocythemia (ET), idiopathic myelofibrosis, systemic mastocytosis (SM), chronic neutrophilic leukemia (CNL), myelodysplastic syndrome (MDS), and systemic mastocytosis (SMCD). In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, to treat primary myelofibrosis, an MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof on days 1-7 of a 21-day cycle (on days 8-21, the MDM2 inhibitor is not administered) for a period selected from 3 weeks, 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 27 weeks, 30 weeks, 33 weeks, 36 weeks, 39 weeks, 42 weeks, 44 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 53 weeks, 54 weeks, 55 weeks, 56 weeks, 57 weeks, 58 weeks, 59 weeks, 50 weeks, 51 weeks, 52 weeks, 53 weeks, 54 weeks, 57 weeks, 58 weeks, 59 weeks, 51 weeks, 52 weeks, 53 weeks, 54 weeks, 58 weeks, 5 weeks, 48 ​​weeks, 51 weeks, 54 weeks, 57 weeks, 60 weeks, 63 weeks, 66 weeks, 69 weeks, 72 weeks, 75 weeks, 78 weeks, 81 weeks, 84 weeks, 87 weeks, 90 weeks, 93 weeks, 96 weeks, 99 weeks, 102 weeks, 105 weeks, 108 weeks, 111 weeks, 114 weeks, 117 weeks, 120 weeks, 123 weeks, 126 weeks, 129 weeks, 132 weeks, 135 weeks, 138 The invention relates to a period of 141 weeks, 144 weeks, 147 weeks, 150 weeks, 153 weeks and 156 weeks, wherein the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601 and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, to treat polycythemia vera, an MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof on days 1-7 of a 21-day cycle (on days 8-21, no MDM2 inhibitor is administered) for a period selected from 3 weeks, 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 27 weeks, 30 weeks, 33 weeks, 36 weeks, 39 weeks, 42 weeks, 44 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 53 weeks, 54 weeks, 55 weeks, 56 weeks, 57 weeks, 58 weeks, 59 weeks, 50 weeks, 51 weeks, 52 weeks, 53 weeks, 54 weeks, 57 weeks, 58 weeks, 59 weeks, 51 weeks, 52 weeks, 53 weeks, 54 ... 5 weeks, 48 ​​weeks, 51 weeks, 54 weeks, 57 weeks, 60 weeks, 63 weeks, 66 weeks, 69 weeks, 72 weeks, 75 weeks, 78 weeks, 81 weeks, 84 weeks, 87 weeks, 90 weeks, 93 weeks, 96 weeks, 99 weeks, 102 weeks, 105 weeks, 108 weeks, 111 weeks, 114 weeks, 117 weeks, 120 weeks, 123 weeks, 126 weeks, 129 weeks, 132 weeks, 135 weeks, 138 The invention relates to a period of 141 weeks, 144 weeks, 147 weeks, 150 weeks, 153 weeks and 156 weeks, wherein the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601 and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, to treat phlebotomy-dependent polycythemia vera, an MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof on days 1-7 of a 21-day cycle (on days 8-21, no MDM2 inhibitor is administered) for a period selected from 3 weeks, 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 27 weeks, 30 weeks, 33 weeks, 36 weeks, 39 weeks. , 42 weeks, 45 weeks, 48 ​​weeks, 51 weeks, 54 weeks, 57 weeks, 60 weeks, 63 weeks, 66 weeks, 69 weeks, 72 weeks, 75 weeks, 78 weeks, 81 weeks, 84 weeks, 87 weeks, 90 weeks, 93 weeks, 96 weeks, 99 weeks, 102 weeks, 105 weeks, 108 weeks, 111 weeks, 114 weeks, 117 weeks, 120 weeks, 123 weeks, 126 weeks, 129 weeks, 132 weeks, 135 weeks , 138 weeks, 141 weeks, 144 weeks, 147 weeks, 150 weeks, 153 weeks and 156 weeks, wherein the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601 and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of Formula (I), a compound of Formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is a compound of Formula (I) or Formula (II), and pharmaceutically acceptable salts thereof; and the MDM2 inhibitor is administered orally once daily (QD) at a dose of 120 mg or 240 mg. In one embodiment, the human subject is intolerant to hydroxyurea (HU) (unacceptable side effects). In one embodiment, the human subject is resistant to hydroxyurea (HU) (inadequate response). In one embodiment, the human subject has splenomegaly. In one embodiment, the human subject has splenomegaly and is phlebotomy-dependent. In one embodiment, the human subject is phlebotomy dependent and does not have splenomegaly. In one embodiment, the human subject has failed treatment with ruxolitinib. In one embodiment, to treat essential thrombocythemia, an MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof on days 1-7 of a 21-day cycle (on days 8-21, the MDM2 inhibitor is not administered) for a period selected from 3 weeks, 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 27 weeks, 30 weeks, 33 weeks, 36 weeks, 39 weeks, 42 weeks, 45 weeks, 48 ​​weeks, 51 weeks, 54 weeks, 57 weeks, 60 weeks, 63 weeks, 66 weeks, 69 weeks, 72 weeks, 75 weeks, 78 weeks, 81 weeks, 84 weeks, 87 weeks, 90 weeks, 93 weeks, 96 weeks, 99 weeks, 102 weeks, 105 weeks, 108 weeks, 111 weeks, 114 weeks, 117 weeks, 120 weeks, 123 weeks, 126 weeks, 129 weeks, 132 weeks, 135 weeks, 136 weeks 8 weeks, 141 weeks, 144 weeks, 147 weeks, 150 weeks, 153 weeks and 156 weeks, wherein the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601 and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, for the treatment of chronic myeloid leukemia (CML), an MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof on days 1-7 of a 21-day cycle (on days 8-21, no MDM2 inhibitor is administered) for a period selected from 3 weeks, 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 27 weeks, 30 weeks, 33 weeks, 36 weeks, 39 weeks, 4 weeks, 5 ...0 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks 2 weeks, 45 weeks, 48 ​​weeks, 51 weeks, 54 weeks, 57 weeks, 60 weeks, 63 weeks, 66 weeks, 69 weeks, 72 weeks, 75 weeks, 78 weeks, 81 weeks, 84 weeks, 87 weeks, 90 weeks, 93 weeks, 96 weeks, 99 weeks, 102 weeks, 105 weeks, 108 weeks, 111 weeks, 114 weeks, 117 weeks, 120 weeks, 123 weeks, 126 weeks, 129 weeks, 132 weeks, 135 weeks, 138, 141, 144, 147, 150, 153, and 156 weeks, wherein the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, for the treatment of acute myeloid leukemia (AML), an MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof on days 1-7 of a 21-day cycle (on days 8-21, the MDM2 inhibitor is not administered) for a period selected from 3 weeks, 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 27 weeks, 30 weeks, 33 weeks, 36 weeks, 39 weeks, 4 weeks, 5 ...0 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 2 weeks, 45 weeks, 48 ​​weeks, 51 weeks, 54 weeks, 57 weeks, 60 weeks, 63 weeks, 66 weeks, 69 weeks, 72 weeks, 75 weeks, 78 weeks, 81 weeks, 84 weeks, 87 weeks, 90 weeks, 93 weeks, 96 weeks, 99 weeks, 102 weeks, 105 weeks, 108 weeks, 111 weeks, 114 weeks, 117 weeks, 120 weeks, 123 weeks, 126 weeks, 129 weeks, 132 weeks, 135 weeks, 138, 141, 144, 147, 150, 153, and 156 weeks, wherein the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, for the treatment of Merkel cell carcinoma (MCC), an MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof on days 1-7 of a 21-day cycle (on days 8-21, the MDM2 inhibitor is not administered) for a period selected from 3 weeks, 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 27 weeks, 30 weeks, 33 weeks, 36 weeks, 39 weeks, 42 weeks. , 45 weeks, 48 ​​weeks, 51 weeks, 54 weeks, 57 weeks, 60 weeks, 63 weeks, 66 weeks, 69 weeks, 72 weeks, 75 weeks, 78 weeks, 81 weeks, 84 weeks, 87 weeks, 90 weeks, 93 weeks, 96 weeks, 99 weeks, 102 weeks, 105 weeks, 108 weeks, 111 weeks, 114 weeks, 117 weeks, 120 weeks, 123 weeks, 126 weeks, 129 weeks, 132 weeks, 135 weeks, 1 38 weeks, 141 weeks, 144 weeks, 147 weeks, 150 weeks, 153 weeks and 156 weeks, wherein the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601 and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, to treat cancer, an MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a human subject in need thereof on days 1-7 of a 28-day cycle (without administration of the MDM2 inhibitor on days 8-28) for a period selected from 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, 52 weeks, 56 weeks, 60 weeks, 64 weeks, 68 weeks, 72 weeks, 76 weeks, 80 weeks, 84 weeks, 88 weeks, 92 weeks, 96 weeks, 100 weeks, 104 weeks, 108 weeks, 112 weeks, 116 weeks, 120 weeks, 124 weeks, 128 weeks, 132 weeks, 136 weeks, 140 weeks , 144 weeks, 148 weeks, 152 weeks and 156 weeks, wherein the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032 , DS-3032B, APG-115, MI-1601 and pharmaceutically acceptable salts thereof, wherein the cancer is selected from the group consisting of: carcinomas such as bladder cancer, breast cancer, colon cancer, rectal cancer, kidney cancer, liver cancer, lung cancer (small cell lung cancer and non-small cell lung cancer), esophageal cancer, gallbladder-bladder cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer, head and neck cancer and skin cancer (including basal cell carcinoma and squamous cell carcinoma, melanoma skin cancer, Merkel cell carcinoma, Kaposi's sarcoma, cutaneous lymphoma); hematopoietic tumors of the lymphoid lineage (including leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, leukemias, B-cell lymphomas, T-cell lymphomas, Hodgkin's lymphomas, non-Hodgkin's lymphomas, hairy cell lymphomas, and Burkitt's lymphomas); hematopoietic neoplasms of the myeloid lineage (including acute and chronic myeloid leukemias, myelodysplastic syndromes, and promyelocytic leukemias); tumors of mesenchymal origin (including fibrosarcomas and rhabdomyosarcomas and other sarcomas, such as those of soft tissue and bone); tumors of the central and peripheral nervous system (including astrocytomas, neuroblastomas, gliomas, glioblastomas, and schwannomas); and other tumors (including melanomas, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, and follicular thyroid carcinoma).In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is a compound of formula (I) or formula (II), and a pharmaceutically acceptable salt thereof; and the MDM2 inhibitor is administered orally once daily (QD) at a dose of 120 mg or 240 mg. In one embodiment, to treat MPN, an MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a human subject in need thereof on days 1-7 of a 28-day cycle (without administration of an MDM2 inhibitor on days 8-28) for a period selected from 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, 52 weeks, 56 weeks, 60 weeks, 64 weeks, 68 weeks, 72 weeks, 76 weeks, 80 weeks. , 84 weeks, 88 weeks, 92 weeks, 96 weeks, 100 weeks, 104 weeks, 108 weeks, 112 weeks, 116 weeks, 120 weeks, 124 weeks, 128 weeks, 132 weeks, 136 weeks, 140 weeks, 144 weeks, 148 weeks, 152 weeks and 156 weeks, wherein the MDM2 inhibitor is selected from the group consisting of: a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7 112. CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, Cedermetane, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-11 5. MI-1601 and pharmaceutically acceptable salts thereof, wherein the MPN is selected from the group consisting of polycythemia vera (PV), myelofibrosis, primary myelofibrosis, thrombocythemia, essential thrombocythemia (ET), idiopathic myelofibrosis, systemic mastocytosis (SM), chronic neutrophilic leukemia (CNL), myelodysplastic syndrome (MDS), and systemic mastocytosis (SMCD). In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is a compound of Formula (I) or Formula (II) and pharmaceutically acceptable salts thereof; and the MDM2 inhibitor is orally administered once a day (QD) at a dose of 120 mg or 240 mg. In one embodiment, to treat primary myelofibrosis, an MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a human subject in need thereof on days 1-7 of a 28-day cycle (without administration of the MDM2 inhibitor on days 8-28) for a period selected from 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, 52 weeks, 56 weeks, 60 weeks, 64 weeks, 68 weeks, 72 weeks, 76 weeks, 80 weeks, 84 weeks, 88 weeks, 92 weeks, 96 weeks, 100 weeks, 104 weeks, 108 weeks, 112 weeks, 116 weeks, 120 weeks, 124 weeks, 128 weeks, 132 weeks, 136 weeks, 140 weeks, 144 weeks, 148 weeks, 152 weeks and a period of 156 weeks, wherein the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is a compound of formula (I) or formula (II), and a pharmaceutically acceptable salt thereof; and the MDM2 inhibitor is administered orally once daily (QD) at a dose of 120 mg or 240 mg. In one embodiment, to treat polycythemia vera, an MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a human subject in need thereof on days 1-7 of a 28-day cycle (without administration of the MDM2 inhibitor on days 8-28) for a period selected from 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, 52 weeks, 56 weeks, 60 weeks, 64 weeks, 68 weeks, 72 weeks, 76 weeks, 80 weeks, 84 weeks, 88 weeks, 92 weeks, 96 weeks, 100 weeks, 104 weeks, 108 weeks, 112 weeks, 116 weeks, 120 weeks, 124 weeks, 128 weeks, 132 weeks, 136 weeks, 140 weeks, 144 weeks, 148 weeks, 152 weeks and a period of 156 weeks, wherein the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is a compound of formula (I) or formula (II), and a pharmaceutically acceptable salt thereof; and the MDM2 inhibitor is administered orally once daily (QD) at a dose of 120 mg or 240 mg. In one embodiment, to treat essential thrombocythemia, an MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a human subject in need thereof on days 1-7 of a 28-day cycle (without administration of the MDM2 inhibitor on days 8-28) for a period selected from 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, 52 weeks, 56 weeks, 60 weeks, 64 weeks, 68 weeks, 72 weeks, 76 weeks, 80 weeks, 84 weeks, 88 weeks, 92 weeks, 96 weeks, 100 weeks, 104 weeks, 108 weeks, 112 weeks, 116 weeks, 120 weeks, 124 weeks, 128 weeks, 132 weeks, 136 weeks, 140 weeks, 144 weeks, 148 weeks, 152 weeks and a period of 156 weeks, wherein the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is a compound of formula (I) or formula (II), and a pharmaceutically acceptable salt thereof; and the MDM2 inhibitor is administered orally once daily (QD) at a dose of 120 mg or 240 mg. In one embodiment, for the treatment of chronic myeloid leukemia (CML), an MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a human subject in need thereof on days 1-7 of a 28-day cycle (without administration of the MDM2 inhibitor on days 8-28) for a period selected from 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, 52 weeks, 56 weeks, 60 weeks, 64 weeks, 68 weeks, 72 weeks, 76 weeks, 80 weeks, 84 weeks, 88 weeks, 92 weeks, 96 weeks, 100 weeks, 104 weeks, 108 weeks, 112 weeks, 116 weeks, 120 weeks, 124 weeks, 128 weeks, 132 weeks, 136 weeks, 140 weeks, 144 weeks, 148 weeks, 15 2-week and 156-week periods, wherein the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is a compound of formula (I) or formula (II), and a pharmaceutically acceptable salt thereof; and the MDM2 inhibitor is administered orally once daily (QD) at a dose of 120 mg or 240 mg. In one embodiment, for the treatment of acute myeloid leukemia (AML), an MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a human subject in need thereof on days 1-7 of a 28-day cycle (without administration of the MDM2 inhibitor on days 8-28) for a period selected from 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, 52 weeks, 56 weeks, 60 weeks, 64 weeks, 68 weeks, 72 weeks, 76 weeks, 80 weeks, 84 weeks, 88 weeks, 92 weeks, 96 weeks, 100 weeks, 104 weeks, 108 weeks, 112 weeks, 116 weeks, 120 weeks, 124 weeks, 128 weeks, 132 weeks, 136 weeks, 140 weeks, 144 weeks, 148 weeks, 15 2-week and 156-week periods, wherein the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is a compound of formula (I) or formula (II), and a pharmaceutically acceptable salt thereof; and the MDM2 inhibitor is administered orally once daily (QD) at a dose of 120 mg or 240 mg. In one embodiment, to treat Merkel cell carcinoma (MCC), an MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a human subject in need thereof on days 1-7 of a 28-day cycle (without administration of the MDM2 inhibitor on days 8-28) for a period selected from 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, 52 weeks, 56 weeks, 60 weeks, 64 weeks, 68 weeks, 72 weeks, 76 weeks, 80 weeks, 84 weeks, 88 weeks, 92 weeks, 96 weeks, 100 weeks, 104 weeks, 108 weeks, 112 weeks, 116 weeks, 120 weeks, 124 weeks, 128 weeks, 132 weeks, 136 weeks, 140 weeks, 144 weeks, 148 weeks, 152 weeks, The invention relates to a method for administering an MDM2 inhibitor for a period of 156 weeks to a patient receiving the drug, wherein the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is a compound of formula (I) or formula (II), and a pharmaceutically acceptable salt thereof; and the MDM2 inhibitor is administered orally once daily (QD) at a dose of 120 mg or 240 mg. In one embodiment, to treat phlebotomy-dependent polycythemia vera, an MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a human subject in need thereof on days 1-7 of a 28-day cycle (without administration of the MDM2 inhibitor on days 8-28) for a period selected from 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, 52 weeks, 56 weeks, 60 weeks, 64 weeks, 68 weeks, 72 weeks, 76 weeks, 80 weeks, 84 weeks, 88 weeks, 92 weeks, 96 weeks, 100 weeks, 104 weeks, 108 weeks, 112 weeks, 116 weeks, 120 weeks, 124 weeks, 128 weeks, 132 weeks, 136 weeks, 140 weeks, 144 weeks, 148 weeks, 152-week and 156-week periods, wherein the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, triptolide, HDM201, RG7112, CGM097A, CGM0970B, SJ-172550, SAR405838, MI-773, MX69, YH239-EE, RO8994, Nutlin-3, Nutlin-3a, Nutlin-3b, cedometan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is selected from the group consisting of a compound of formula (I), a compound of formula (II), RG7388, HDM201, RG7112, CGM097A, CGM0970B, SAR405838, MK-8242, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof. In one embodiment, the MDM2 inhibitor is a compound of formula (I) or formula (II), and a pharmaceutically acceptable salt thereof; and the MDM2 inhibitor is administered orally once daily (QD) at a dose of 120 mg or 240 mg. In one embodiment, for the treatment of phlebotomy-dependent polycythemia vera, 120 mg / dL of dapoxetine is administered daily on days 1-7 of a 28-day cycle (no MDM2 inhibitor is administered on days 8-28). A compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, is administered to a human subject in need thereof at a dose of 1 mg for a period selected from 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, 52 weeks, 56 weeks, 60 weeks, 64 weeks, 68 weeks, 72 weeks, 76 weeks, 80 weeks, 84 weeks, 88 weeks, 92 weeks, 96 weeks, 100 weeks, 104 weeks, 108 weeks, 112 weeks, 116 weeks, 120 weeks, 124 weeks, 128 weeks, 132 weeks, 136 weeks, 140 weeks, 144 weeks, 148 weeks, 152 weeks, and 156 weeks. In one embodiment, the human subject is intolerant to hydroxyurea (HU) (unacceptable side effects). In one embodiment, the human subject is resistant to hydroxyurea (HU) (inadequate response). In one embodiment, the human subject has splenomegaly. In one embodiment, the human subject has splenomegaly and is phlebotomy-dependent. In one embodiment, the human subject is phlebotomy-dependent and does not have splenomegaly. In one embodiment, the human subject has failed treatment with ruxolitinib. In one embodiment, for the treatment of phlebotomy-dependent polycythemia vera, 240 mg / dL of dapoxetine is administered daily on days 1-7 of a 28-day cycle (no MDM2 inhibitor is administered on days 8-28). A compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, is administered to a human subject in need thereof at a dose of 1 mg for a period selected from 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, 52 weeks, 56 weeks, 60 weeks, 64 weeks, 68 weeks, 72 weeks, 76 weeks, 80 weeks, 84 weeks, 88 weeks, 92 weeks, 96 weeks, 100 weeks, 104 weeks, 108 weeks, 112 weeks, 116 weeks, 120 weeks, 124 weeks, 128 weeks, 132 weeks, 136 weeks, 140 weeks, 144 weeks, 148 weeks, 152 weeks, and 156 weeks. In one embodiment, the human subject is determined to be intolerant (unacceptable side effects) to hydroxyurea (HU). In one embodiment, the human subject is resistant (inadequately responsive) to hydroxyurea (HU). In one embodiment, the human subject has splenomegaly. In one embodiment, the human subject has splenomegaly and is phlebotomy-dependent. In one embodiment, the human subject is phlebotomy-dependent and does not have splenomegaly. In one embodiment, the human subject has failed treatment with ruxolitinib. In one embodiment, to treat phlebotomy-dependent polycythemia vera, a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, is administered to a human subject in need thereof at a dose of 120 mg daily on days 1-7 of a 21-day cycle (no MDM2 inhibitor is administered on days 8-21) for a period selected from 3 weeks, 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 27 weeks, 30 weeks, 33 weeks, 36 weeks, 39 weeks, 42 weeks, 45 weeks, 48 ​​weeks, 51 weeks, 54 weeks, 57 weeks, 60 weeks, 63 weeks, 66 weeks, 69 weeks, 70 weeks, 71 weeks, 72 weeks, 73 weeks, 74 weeks, 75 weeks, 76 weeks, 77 weeks, 78 weeks, 79 weeks, 80 weeks, 81 weeks, 82 weeks, 83 weeks, 84 weeks, 85 weeks, 86 weeks, 87 weeks, 88 weeks, 89 weeks, 90 weeks, 91 weeks, 92 weeks, 93 weeks, 94 weeks, 95 weeks, 96 weeks, 97 weeks, 98 weeks, 99 weeks, 100 weeks, 101 weeks, 102 weeks, 103 weeks, 104 weeks, 105 weeks, 106 weeks, 107 weeks, 108 weeks, 109 weeks, 110 weeks 2 weeks, 75 weeks, 78 weeks, 81 weeks, 84 weeks, 87 weeks, 90 weeks, 93 weeks, 96 weeks, 99 weeks, 102 weeks, 105 weeks, 108 weeks, 111 weeks, 114 weeks, 117 weeks, 120 weeks, 123 weeks, 126 weeks, 129 weeks, 132 weeks, 135 weeks, 138 weeks, 141 weeks, 144 weeks, 147 weeks, 150 weeks, 153 weeks, and 156 weeks. In one embodiment, the human subject is intolerant to hydroxyurea (HU) (unacceptable side effects). In one embodiment, the human subject is resistant to hydroxyurea (HU) (inadequate response). In one embodiment, the human subject has splenomegaly. In one embodiment, the human subject has splenomegaly and is phlebotomy-dependent. In one embodiment, the human subject is phlebotomy-dependent and does not have splenomegaly. In one embodiment, the human subject has failed treatment with ruxolitinib. In one embodiment, to treat phlebotomy-dependent polycythemia vera, a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, is administered to a human subject in need thereof at a dose of 240 mg daily on days 1-7 of a 21-day cycle (no MDM2 inhibitor is administered on days 8-21) for a period selected from 3 weeks, 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 27 weeks, 30 weeks, 33 weeks, 36 weeks, 39 weeks, 42 weeks, 45 weeks, 48 ​​weeks, 51 weeks, 54 weeks, 57 weeks, 60 weeks, 63 weeks, 66 weeks, 69 weeks, 70 weeks, 71 weeks, 72 weeks, 73 weeks, 74 weeks, 75 weeks, 76 weeks, 77 weeks, 78 weeks, 79 weeks, 80 weeks, 81 weeks, 82 weeks, 83 weeks, 84 weeks, 85 weeks, 86 weeks, 87 weeks, 88 weeks, 89 weeks, 90 weeks, 91 weeks, 92 weeks, 93 weeks, 94 weeks, 95 weeks, 96 weeks, 97 weeks, 98 weeks, 99 weeks, 100 weeks, 101 weeks, 102 weeks, 103 weeks, 104 weeks, 105 weeks, 106 weeks, 107 weeks, 108 weeks, 109 weeks, 110 weeks 2 weeks, 75 weeks, 78 weeks, 81 weeks, 84 weeks, 87 weeks, 90 weeks, 93 weeks, 96 weeks, 99 weeks, 102 weeks, 105 weeks, 108 weeks, 111 weeks, 114 weeks, 117 weeks, 120 weeks, 123 weeks, 126 weeks, 129 weeks, 132 weeks, 135 weeks, 138 weeks, 141 weeks, 144 weeks, 147 weeks, 150 weeks, 153 weeks and 156 weeks. In one embodiment, the human subject is hydroxyurea (HU) intolerant (unacceptable side effects). In one embodiment, the human subject is hydroxyurea (HU) resistant (insufficient response). In one embodiment, the human subject has splenomegaly. In one embodiment, the human subject has splenomegaly and is phlebotomy dependent. In one embodiment, the human subject is phlebotomy dependent and does not have splenomegaly. In one embodiment, the human subject has failed treatment with ruxolitinib. Examples The embodiments encompassed herein are now described with reference to the following examples. These examples are provided for illustrative purposes only and the invention should in no way be construed as being limited to these examples, but rather should be construed to encompass any and all variations thereof that become apparent as a result of the teachings provided herein. Examples 1 : Mode (I) Effects of Compounds on Polycythemia Vera Cells The procedure for testing the effects of compounds of formula (I) on polycythemia vera cells followed the procedure described in Lu et al., Blood, 2012, 120(15); 3098-3105, the entire contents of which are incorporated by reference. The procedure is briefly described below. Preparation of cells: Peripheral blood was obtained from patients with polycythemia vera (PV). Appropriate approval was obtained from the Institutional Review Board. Informed consent was obtained before the study. All patients met the World Health Organization diagnostic criteria for polycythemia vera (PV). Peripheral blood samples were layered on Ficoll-Hypaque (1.077 g / mL; GE Healthcare) and low-density mononuclear cells were isolated by centrifugation. CD34+ cells were isolated using a human CD34+ cell selection kit (StemCell Technologies) according to the manufacturer's instructions. The purity of the CD34+ cell population was analyzed using a FACSCalibur flow cytometer (BD Biosciences); and a purity of at least 85% was required for all experiments. Fresh normal human bone marrow CD34+ cells will be purchased from ALLCELLS as a control. HPC analysis The effects of compounds of formula (I) on patients with polycythemia vera (PV) can be assessed by HPC analysis, as described in Lu et al., Blood, 2012, 3098-3105 (incorporated by reference in its entirety). Briefly, CD34+ cells are cultured in serum-free medium (StemCell Technologies) containing 50 ng / mL stem cell factor (SCF), 50 ng / mL thrombopoietin (TPO), 50 ng / mL fms-like tyrosine kinase 3 (Flt-3) ligand, and 50 ng / mL IL-3 and treated with multiple doses of compounds of formula (I) for 4 days. After 4 days of treatment, CD34+ cells are analyzed in semisolid culture medium, as described in Bruno et al., Blood, 2006, 3128-3134 (incorporated by reference in its entirety). Briefly, 5×10 cells are plated per dish. 2CD34+ cells were plated in duplicate cultures containing 1 mL of IMDM with 1.1% methylcellulose and 20% FBS, supplemented with 50 ng / mL each of SCF, TPO, Flt-3 ligand, IL-3, and GM-CSF, and 2 U / mL erythropoietin (EPO). Colonies were counted after 14 days of culture, and individual colonies were harvested and genotyped for JAK2V617F. Nested allele-specific PCR for JAK2V617F-positive colonies Genomic DNA was isolated from randomized colonies using the Extract-N-Amp Blood PCR kit (Sigma-Aldrich). JAK2V617F was detected using nested allele-specific PCR as described in Bruno et al., Blood, 2006, 3128-3134 (incorporated by reference in its entirety). Final PCR products were analyzed on a 2.0% agarose gel. A 279 bp product indicated allele-specific JAK2V617F positivity, while a 229 bp product indicated JAK2V617F negativity. If it contained only the 279 bp band, the colony was classified as JAK2V617F homozygous, while a heterozygous colony was determined based on the presence of both the 279 bp and 229 bp bands. Apoptosis analysis Treated cells were collected and washed with PBS for staining with phospholipid binding protein-V (BD Biosciences); the staining procedure was performed according to the manufacturer's protocol. Data were acquired on a FACSCalibur flow cytometer (BD Biosciences), and at least 10,000 viable cells were obtained for each analysis (BD FACS Diva software; BD Biosciences). Western blot analysis CD34+ cells were purified from peripheral blood of patients with polycythemia vera (PV) and cultured in serum-free medium containing SCF, FL-3 ligand, IL-3, and TPO. The cells were treated with multiple doses of a compound of Formula (I) for 4 hours. The cells were harvested and whole-cell protein extracts were prepared using RIPA lysis buffer (Boston BioProducts) for Western blotting. To prepare cytoplasmic and nuclear protein fractions from cells with polycythemia vera (PV), CD34+ cells were expanded for 10 days in serum-free medium containing SCF, FL-3 ligand, and IL-3. The CD34+ cells were then repurified and treated with multiple doses of a compound of Formula (I) in the presence of SCF, FL-3 ligand, IL-3, and TPO for 48 hours. Protein extracts were prepared using NE-PER Nuclear and Cytoplasmic Extraction Reagent (Thermo Scientific) according to the manufacturer's instructions. Prior to Western blotting, all samples were denatured with Laemmli SDS-sample buffer (Boston BioProducts) by heating at 95°C for 5 minutes. Samples were separated on SDS-PAGE gels and transferred to polyvinylidene difluoride membranes (Bio-Rad). Phosphorylated p53, p53, MDM2, p21, p-STAT1, PUMA, and Bak were visualized using antibodies (Cell Signaling Technologies) and ECL Western blotting reagents (Denville Scientific). Statistical analysis Results are reported as mean ± SD of individual data points obtained from multiple experiments. Statistical significance was determined using Student's t-test or paired sample t-test. Examples 2 :Mode (I) Effects of compounds on essential thrombocythemia cells The experiment was performed according to Example 1 except that essential thrombocythemia cells were used instead of polycythemia vera (PV) cells. Examples 3 : Mode (I) Effects of compounds on primary myelofibrosis cells The experiment was performed according to Example 1 except that primary myelofibrosis cells were used instead of polycythemia vera (PV) cells. Examples 4 : Mode (I) Compounds for use as monotherapy in patients with polycythemia vera This study aims to investigate the safety and efficacy of the compound of formula (I) in patients with polycythemia vera (PV). A similar clinical study (NCT02407080) using RG7388 is underway. Thirty patients with PV will be enrolled in this study and administered 120 mg of the compound of formula (I) once daily (QD) on days 1-7 (without compound of formula (I) on days 8-21) for two years, according to a 21-day cycle. Inclusion criteria are as follows: ● JAK2V617F-positive polycythemia vera (PV) ● Not previously treated with at least one other agent (hydroxyurea, interferon, anagrelide) ● ≥18 years of age ● Acceptable pre-study organ function during the screening period, defined as follows: total bilirubin ≤1.5 times the upper limit of normal (ULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 times ULN, serum creatinine ≤1.5×ULN unless attributed to Gilbert's disease or hemolysis ● Females and males of childbearing potential must agree to use adequate contraception (i.e., hormonal or barrier methods for birth control; abstinence) prior to study entry and throughout the duration of study participation. If a female subject becomes pregnant or suspected of pregnancy while participating in this study, she or he should be immediately excluded from the study During or at the end of the study, each polycythemia vera (PV) patient will be evaluated to determine the safety and efficacy of the compound of formula (I) by the following criteria: 1) hematological response; 2) reduction in JAK2V617F allele burden; 3) change in bone marrow histopathological abnormalities; 4) reduction in baseline reticulin / collagen fibrosis; 5) development of venous and arterial embolism; and 5) change in MPN-related symptoms as measured by MPN-SAF. Examples 5 : Mode (I) Compounds for use as monotherapy in patients with essential thrombocythemia This investigational study was conducted according to the procedures described in Example 4, except that patients with essential thrombocythemia (ET) were enrolled instead of patients with polycythemia vera (PV). Examples 6 : Mode (I) Compounds used as monotherapy in patients with primary myelofibrosis This investigational study was conducted according to the procedures described in Example 4, except that patients with primary myelofibrosis were enrolled instead of patients with polycythemia vera (PV). Examples 7 : Mode (I) The compound's efficacy against cancer The procedure for testing the efficacy of compounds of formula (I) against cancer is described in Canon et al., Molecular Cancer Therapeutics, 2015; 649-658 and Rew et al., J. Med. Chem. 2012; 55; 4936-54 (the entire contents of which are incorporated by reference). The procedure is briefly described below. Cell SJSA-1, HCT116, ACHN, NCI-H460, MOLM-13, RKO, MCF7, 22RV1, HT-29, PC-3, NCI-H82, NCI-SNU1, and MG-63 cell lines were purchased from ATCC and subsequently verified by short tandem repeat analysis (PowerPlex 18D kit from Promega). NCI-H2452, SW982, C32, SK-HEP-1, A375, RT4, RPMI-2650, MDA-MB-134-VI, NCI-H2347, and A427 cell lines were purchased from ATCC and used within 6 months. IGR-1 and CML-T1 cell lines were purchased from the German Collection of Microorganisms and Cell Cultures (DSMZ) and used within 6 months. A375sq2 cells were generated by in vivo passage of A375 cells in mice. HCT116 p53 was obtained from Bert Vogelstein - / - Cells. KS-1 and SNG-M were purchased from the Japanese Collection of Research Bioresources (HSRRB) and used within 6 months. G-401, G-361, LS174T cells (purchased from ATCC), EOL-1 cells (purchased from DSMZ), and KP-4 cells (purchased from HSRRB) were used within 6 months of purchase. Surface plasmon resonance (SRP) spectroscopy binding analysis Materials: Biacore T100 instrument (GE Healthcare), CM5 sensor chip (BR-1000-12), amine coupling kit containing 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC), N-hydroxysuccinimide (NHS), and ethanolamine-HCl (BR-1000-50), GST capture kit (BR-1002-23), and HBS-N buffer (BR-1006-70) were all from GE Healthcare. All buffers were filtered through a 0.2 μM nylon membrane (VWR 87006-076). Inhibitor kinetic studies on Biacore: The CM5 chip was pretreated with HBS-N buffer containing 10 mM NaOH, 10 mM HCl, and 0.1% SDS. Two injections were performed at 100 μL / min for 10 s each. Immobilization and capture steps were performed as described: 1. Equal volumes of 0.4 M EDC and 0.1 M NHS were mixed and injected over the chip surface at 10 μL / min for 10 minutes to activate them; 2. Anti-GST antibody (30 μg / ml in 10 mM sodium acetate, pH 5) was immobilized to the chip by injecting it over the surface at 8 μL / min for 15 minutes; 3. To inactivate excess reactive groups and wash away unbound anti-GST antibody, 1 M ethanolamine-HCl, pH 8.5, was pumped over the surface at 8 μL / min for 10 minutes. The resulting antibody immobilization level was approximately 18,000 RU. 4. A control surface of 1,500 RU was established by injecting 10 μg / ml GST in HBS-N buffer at 5 μl / min over one flow cell for 15 minutes. 5. A sample surface was generated by injecting 20 μg / ml MDM2 over the other flow cell twice at 5 μl / min for 15 minutes, reaching a capture level of approximately 2,000 RU. Kinetic binding studies of inhibitors (molecular weight range 450-600) were performed at 25°C at a constant flow rate of 90 μl / min. The sample assay buffer consisted of 25 mM Tris pH 7.5, 150 mM NaCl, 0.005% (v / v) Tween 20, 0.2 mM TCEP, and 2.5% (v / v) DMSO. Inhibitors were diluted from 1 mM stocks (in 100% DMSO) to 12 nM in the sample assay buffer. The inhibitor was then serially diluted 2-fold to generate 8 points. The diluted inhibitor was injected onto the control and sample surfaces for 1-2 minutes, and dissociation was observed for 3-4 minutes. A DMSO calibration curve was constructed by injecting buffer containing 2.3%-3.5% DMSO. All sensor spectra were processed using Biacore evaluation software (GE Healthcare) using a double-referencing procedure and DMSO calibration.KD values ​​were determined using a 1:1 binding model including a mass transfer limitation period. SJSA-1 cell proliferation assay (Click-iT EdU HCS assay). SJSA-1 cells were cultured in 40 μl of growth medium (RPMI 1640 supplemented with 10 mM HEPES, 1 mM sodium pyruvate, 1× penicillin-streptomycin, 2 mM glutamine, and 10% fetal bovine serum) at a rate of 2.8×10 3 Cells were plated at a density of 10 cells / well in a 384-well cell culture plate (Perkin Elmer, #6007460). The cells were cultured at 37°C and 5% CO. 2 for 24 hours. The next day, the cells were treated with MDM2 inhibitors for 16 hours in the presence of 10% human serum. On the 3rd day, the Click-iT EdU assay was performed according to the manufacturer's instructions, wherein the assay volume was reduced to 25 μL to adjust for a 384-well format (Invitrogen, #C10357). In brief, EdU (5-ethynyl-2'-deoxyuridine) was added to the cells at a final concentration of 10 μM and cultivated for 1 hour. After labeling, the cells were fixed with 4% formaldehyde and permeabilized with 0.1% Triton-X 100. After washing, the cells were incubated with Click-iT reaction buffer and then incubated with a nuclear stain. The cells were then washed and imaged using an Opera high content filtration system (Perkin Elmer). The EdU incorporation percentage was calculated and used to calculate the IC50. The IC50 value was determined using the four-parameter logistic (4PL) Hill model. BrdU proliferation assay (HCT116-specific assay) The efficacy of MDM2 inhibitors was also determined by analyzing the effect on cell proliferation by quantifying the amount of 5-bromo-2-deoxyuridine (BrdU) incorporation in compound-treated cells versus DMSO-treated control cells. − / − Cells were cultured in 100 μl of growth medium (McCoy's 5A, 1X PSQ, and 10% fetal bovine serum (all components from Invitrogen)) at a rate of 6×10 3 Cells were plated in a 96-well cell culture plate at a density of 10 cells / well. Initially, cells were cultured at 37°C and 5% CO 2 for 24 hours, followed by compound addition. MDM2 inhibitors were serially diluted in DMSO (Sigma #D2650) and then diluted again in assay medium (McCoy's 5A, 1X PSQ, 10% human serum (Bioreclamation #HMSRM)) to a final DMSO concentration of 1%. Cells were incubated in the presence of inhibitors at 37°C and 5% CO. 2 for 16 hours and then incubate at 37°C and 5% CO 2 with diluted BrdU labeling reagent (1: 100 final dilution, Invitrogen #00-0103) pulse for 1 hour. After the BrdU pulse, the culture medium was removed and the cells were fixed and stained for BrdU incorporation. The amount of BrdU incorporation was analyzed using flow cytometry or Cellomics Array Scan Vti plate reader using target activation bioapplication. The percentage of BrdU positive cells in the DMSO-treated control wells was used to correct the signal and calculate the percentage of inhibition for each of the compound-treated wells. Dose-response curves were generated using XLFit software to calculate the IC50 value of each test inhibitor. HCT116 p21 TaqMan® Assay (HCT116 Specific Assay) This analysis was performed exactly as described above for the SJSA-1 p21 analysis, with the following exceptions: HCT116 p53WT or p53 − / − The growth medium for both cells consisted of McCoy's 5A, 1X PSQ, and 10% fetal bovine serum (all components were from Invitrogen). Biochemical (HTRF) Analysis Materials: Human MDM2 (GST-thrombin-hMDM2(1-188)) was produced in-house. It was expressed in E. coli and purified by glutathione sepharose 4B, Q-HP, and Superdex 200 columns. Human p53 (Avi-TrxA-6His-thrombin-S-tag-EK-p53(1-83)) was expressed in E. coli and purified by Ni-NTA, hydroxyapatite, and Superdex 75 columns to a purity exceeding 80%. Human serum was from Bioreclamation (HMSRM, unfiltered). Monoclonal anti-GST antibodies labeled with europium cryptate (Eu-anti-GST, 61GSTLB) and SA-Xlent (611SAXLB) were from Cisbio. DTT, BSA, KH 2PO 4. Na 2HPO 4. DMSO, NaCl, and KF were from Sigma. The serum-free reaction buffer consisted of 1.06 mM KH 2PO 4. 2.96 mM Na 2HPO 4, 0.155 M NaCl, 0.1% BSA, and 1 mM DTT. HTRF analysis in serum used a reaction buffer supplemented with 15% human serum. The HTRF assay plate was a white 384 Opti plate from Perkin Elmer (6007299). The Envison (Perkin Elmer) was set for 320 nm excitation. Emission was measured at 665 nm and 615 nm, and the ratio of Em665 / Em615 indicates MDM2-p53 interaction. After each excitation, a 60 μs delay was applied, and 50 time-difference fluorescence flashes were measured from both detectors. The read time was 300 μs. Vprep was a product from Velocity11. The Wellmate microplate dispenser was from Thermo Scientific. Serial Killer was manufactured in-house. Method (Determination of Inhibitor Potency in HTRF Assay): Serially dilute 20 μL of 1.5 mM inhibitor into 20 μL of DMSO for 22 points using a serial dilution system. Transfer 1 μL of this diluted inhibitor to a reaction plate with 9 μL of reaction buffer using Vprep. Dispense 10 μL of 1 nM MDM2 onto the reaction plate and incubate with the inhibitor for 20 minutes, followed by the addition of 20 μL of 1.25 nM p53. After 60 minutes, dispense the detection mix (10 μL of 1 nM SA-Xlent, 3 nM Eu-anti-GST, and 0.5 μM KF) into the reaction mixture, and read the plate on an Envision after an 18-hour incubation. The total reaction volume is 50 μL. MDM2, p53, and the detector are delivered to the assay plate using a Wellmate. Determine the IC50 from replicate data. For HTRF assays in 15% serum: The order of addition is the same as for the serum-free assay. 10 μL of 12.5 nM MDM2 diluted in reaction buffer containing 30% human serum was added to 10 μL of the buffer and compound mixture to create 15% serum. 20 nM p53 was diluted in buffer with 15% human serum. Detection buffer was 15% serum with 10 nM SA-Xlent, 3 nM Eu-anti-GST, and 0.5 M KF. Immunoblot analysis Tumor cells were treated with DMSO (0.1%) or a compound of formula (I) (0.1, 1, or 10 mmol / L). After 24 hours, protein lysates were collected, electrophoresed, and transferred to polyvinylidene difluoride membranes (Life Technologies). Primary antibodies: p53 (DO-1, Calbiochem), MDM2 (BD Pharmingen), p21 (R&D Systems), PUMA (Abcam), or β-actin-HRP (Sigma). Cell viability assay (72 hours) Cell lines were plated in 96- or 384-well plates at the optimal initial seeding density to ensure that cells did not reach confluence by the end of the assay. Cells were treated with a DMSO control or various concentrations of the compound of Formula (I) for 72 hours. The CellTiter-Glo Fluorescent Cell Viability Assay (Promega) or the ATPlite 1step Fluorescence Assay (PerkinElmer) was used to determine viable cell counts. Luminescence was measured for each cell line at time zero (V0) before compound addition and 72 hours after compound treatment using an EnVision multilabel reader (PerkinElmer). Growth inhibition (GI) was calculated based on a 200-point scale according to the following equation, where V72 is the luminescence of the DMSO control at 72 hours and T72 is the luminescence of the compound-treated sample: if T72 > V0, GI = 100 × (1 - ((T72 - V0) / (V72 - V0))); if T72 < V0, GI = 100 × (1 - ((T72 - V0) / V0)). GI values ​​of 0, 100, and 200 represent uninhibited cell growth (i.e., DMSO control), cell arrest, and complete cell killing, respectively. Dose-response curves were generated using XLFit software (IDBS) to calculate the IC50 values ​​of the compounds of formula (I) in each tested cell line. Animal studies All animal experimental procedures were performed in accordance with the standards of the Association for Assessment and Accreditation of Laboratory Animal Care. All studies utilized 4- to 6-week-old female athymic nude mice (Harlan Laboratories, Hsd: athymic nude-Foxn1nu). The mice were housed in a sterile room in an environmentally controlled room (temperature 23±2°C, relative humidity 50±20%), five per covered cage, with a 12-hour light / dark cycle. The mice were fed a commercial rodent chow (Harlan Laboratories, #2920X) and had ad libitum access to filter-purified tap water. The mice were individually identified by a microchip (Bio Medic Data Systems) implanted subcutaneously at least 2 days prior to the study. Efficacy analysis Tumor cells (SJSA-1: 5×10 6 cells, HCT 116∶2×10 6 Cells were injected subcutaneously into the flank of female athymic nude mice at a cell to matrigel ratio of 2:1. When the average tumor size reached approximately 300 to 450 mm 3 (n = 4 / group) were administered with the compound of formula (I) by oral gavage. Tumors were harvested 1, 2, 4, 8, and 24 hours after administration (SJSA-1) or 6 hours after administration (HCT116) and quick-frozen in liquid nitrogen. Total RNA was purified using a Qiagen RNeasy 96 kit (Qiagen). The levels of p21 and the housekeeping gene GAPDH were analyzed by qRT-PCR from total RNA from each sample, technically in duplicate. qRT-PCR reactions were analyzed on an Applied Biosystems Prism 7900HT instrument and data were analyzed using Applied Biosystems SDS2.2 software. SDS2.2 software calculated the number of p21 and GAPDH copies in each tumor sample. The number of p21 copies was corrected for the number of GAPDH copies, and the fold increase in the corrected p21 level for each sample was calculated relative to the vehicle control. For MIC-1, plasma was collected at sacrifice and detected using the R&D Quantikine Human MIC-1 Immunoassay (Cat. No. DGD150) according to the manufacturer's instructions. ELISA assays were read using a Spectramax M5 microplate reader using Softmax pro version 4 (Molecular Devices). Xenograft studies SJSA-1 cells (5×10 6 cells, the ratio of cells to matrigel was 2:1), NCI-H460 cells (5×10 6 cells, the cell-to-Matrigel ratio was 2:1), A375sq2 (5×10 6 cells, with a cell to matrigel ratio of 2:1) or HCT116 (2×10 6 cells) were injected subcutaneously into the flank of female athymic nude mice (n = 10 / group). 3Treatment was started at 1 hr. The compound of formula (I) was administered once daily by oral gavage. Tumor size was assessed twice weekly using a Pro-Max electronic digital caliper (Sylvac) and tumor volume was calculated using the following formula: length × width × height, and expressed in mm. 3 Data are presented as mean ± SEM. Body weights were recorded twice weekly to assess tolerance (data not shown). Analysis of p21 mRNA at the end of the xenograft study was performed as described for the p21 efficacy analysis. Detection of BrdUrd and cleaved caspase-3 in xenografts Tumors were harvested 6 hours after the last treatment, fixed with formalin, and processed into paraffin. Two hours before harvest, mice were injected intraperitoneally with BrdUrd (50 mg / kg). Tumor sections were immunostained for BrdUrd or cleaved caspase-3 using commercially available antibodies and counterstained with hematoxylin. Sections were scanned at ×20 using an Aperio digital scanner, and the density of positive cell nuclei was determined using Visiomorph image analysis software. Statistical Analysis For the in vivo dose-response efficacy studies of compounds of formula (I), the statistical significance of observed differences was assessed using repeated measures ANOVA (RMANOVA) followed by Dunnett post hoc test for multiple comparisons. A broader panel of tumor cell lines, including p53 wild-type (n = 23) and mutant (n = 7) cell lines representing a range of tumor types and genetic backgrounds, was analyzed, and the effect of treatment with the compound of formula (I) on cell growth was determined over a 72-hour period. In all 23 p53 wild-type cell lines evaluated, treatment with the compound of formula (I) inhibited cell growth with IC50 values ​​ranging from 0.1 to 1 mmol / L (Figure 2). The antitumor activity of the compound of formula (I) was evaluated in xenograft models representing diverse genetic backgrounds and multiple tumor types. All tumor cell lines utilized in the xenograft models possessed wild-type p53. Daily oral administration of the compound of formula (I) resulted in significant tumor growth inhibition (TGI) in all models (Figures 3-5). SJSA-1, an MDM2-amplified osteosarcoma model, was most sensitive to treatment with the compound of Formula (I), with an ED50 of 9.1 mg / kg ( FIG3 ). In the highest dose group, 75 mg / kg, 10 of 10 tumors completely regressed and were undetectable after 10 days of treatment. In this group, treatment with the compound of Formula (I) was terminated after 25 days, and the mice were observed for an additional 50 days. There was no detectable regeneration of SJSA-1 tumors in any of the mice. Other xenograft models demonstrated a range of in vivo antitumor activities of the compounds of Formula (I) or Formula (II). In the HCT116 colorectal cancer model (KRAS mutant), the highest dose of the compound of Formula (I) produced an 86% TGI compared to the control, with an ED50 of 31 mg / kg ( FIG4 ). Treatment with the compound of Formula (I) in the A375sq2 BRAF-mutant melanoma model produced a 97% TGI, with an ED50 of 18 mg / kg ( FIG5 ). Tumors were harvested at the conclusion of each xenograft study to determine the effect of treatment with the compound of Formula (I) on p53 pathway activity. Treatment with the compound of Formula (I) resulted in dose- and time-dependent induction of p21 mRNA compared to vehicle-treated tumors ( FIG6 ). The level of p21 induction correlated with the degree of TGI within each tumor model, with p21 levels being highest in tumors with the most suppressed growth. However, the maximum level of p21 induction varied across tumor models. Examples 8 : clinical trials A two-part, randomized, open-label, multicenter, Phase 2a / 2b study of the efficacy, safety, pharmacokinetics, and pharmacodynamics of the compound of formula (I) compared to ruxolitinib in patients with phlebotomy-dependent polycythemia vera. Polycythemia vera (PV) is classified as a myeloproliferative neoplasm (MPN). Long-term survival is poor, with a survival rate of 18% after 20 years. For PV patients, particularly those intolerant / resistant to hydroxyurea (HU), treatment options are limited, and despite unacceptable side effects and unsatisfactory responses, these patients are often treated with HU. With a 21% response rate to ruxolitinib, there is a significant unmet need for effective treatment in this subset of PV patients. The compound of Formula (I) or Formula (II) is an orally bioavailable small molecule cytotoxic chemotherapeutic agent that binds to murine double minute chromosome 2 (MDM2) and inhibits the MDM2 / tumor protein 53 (p53) protein-protein interaction. The compound of Formula (I) has been shown to inhibit the growth of p53 wild-type (p53WT) tumor cells in vitro and tumor xenografts in vivo. p53 is a tumor suppressor and transcription factor that responds to cellular stress by activating the transcription of numerous genes involved in cell cycle arrest, apoptosis, senescence, and DNA repair. Preclinically, a key determinant of sensitivity to MDM2 inhibition is the p53 mutational status of the cell, with p53WT cells being sensitive to this inhibitor. MDM2 is a negative regulator of p53 and is overexpressed in CD34+ myeloproliferative neoplasia cells harboring p53WT. MDM2 degrades and inactivates p53, allowing clonal hematopoietic stem cell proliferation. Study Design The study is being conducted in two parts. In Part A (initial proof-of-concept phase), the efficacy and safety of the three treatment groups will be evaluated in subjects with polyps. If the overall response rate is at least 40% in subjects with splenomegaly in Part A, Part B will begin, in which subjects with polyps with splenomegaly will be randomly assigned to treatment with any of the recommended doses and schedules from Part A, or to receive ruxolitinib according to the prescribing label. All subjects in Part A and Part B will continue treatment with the compound of formula (I) until disease progression or lack of tolerance. Disease progression is defined as: • Eligibility for phlebotomy (after Week 8): Confirmed hematocrit (HCT) >45%, at least 3 percentage points higher than the HCT obtained at baseline, or confirmed HCT >48%, where confirmation is performed 2 to 14 days after the initial observation. • Splenic progression: ≥25% increase in volume as measured by central imaging relative to the best documented spleen volume response. • Myelofibrosis / transformation: Increase in myelofibrosis from baseline and / or transformation to myelofibrosis (MF), myelodysplastic syndrome (MDS), or acute leukemia. Part A - Proof of Concept / Dose Finding of Compound of Formula (I): Part A will evaluate the safety and efficacy of two different doses and two different schedules of Compound of Formula (I) in three treatment groups in subjects with PV. A total of 75 randomized subjects will be evaluated in Part A. Subjects will be randomly assigned to one of three treatment groups: • Group 1, N=15 with splenomegaly, plus N=10 without splenomegaly: 120 mg once daily on Days 1 to 7, interrupted on Days 8 to 21 (21-day cycle) • Group 2, N=15 with splenomegaly, plus N=10 without splenomegaly: 240 mg once daily on Days 1 to 7, interrupted on Days 8 to 21 (21-day cycle) • Group 3, N=15 with splenomegaly, plus N=10 without splenomegaly: 120 mg once daily on Days 1 to 7, interrupted on Days 8 to 28 (28-day cycle) Part B - Compound of Formula (I) versus Ruxolitinib at the Suggested Doses and Schedules from Part A in Subjects with PV: A total of 220 randomized subjects with splenomegaly will be evaluated in Part B. Subjects in Part B will be randomly assigned to treatment with Compound of Formula (I) at the suggested doses and schedules determined by the DMC from Part A, or Ruxolitinib according to the prescription label: • Group 1, N=110: Subjects with splenomegaly will be treated with Compound of Formula (I) at the suggested doses and schedules from Part A. • Group 2, N=110: Subjects with splenomegaly will be treated with Ruxolitinib according to the prescription label. Approximately 295 randomized subjects are planned: Part A: N=75, Part B: N=220 (110 subjects receiving Compound of Formula (I) and 110 subjects receiving Ruxolitinib) Research objectives : Inclusion criteria : 1. Adults >18 years of age. 2. Patients must meet the revised 2016 World Health Organization (WHO) criteria for the diagnosis of polyps. 3. Subjects must be phlebotomy-dependent. Phlebotomy dependence is defined as: • A hematocrit level of 40%-45% on two or more phlebotomies at least 4 weeks apart within 24 weeks prior to screening or • A hematocrit level greater than 45% on at least one phlebotomy within 16 weeks prior to screening. 4. In Part A, splenomegaly (defined as a spleen volume ≥450 cm3) as determined by MRI (or CT) 3) and without splenomegaly are eligible. In Part B, only subjects with splenomegaly as determined by MRI or CT are eligible. 5. Previous treatment with hydroxyurea (HU) (Parts A and B) or interferon (Part A only). If previously treated with HU, the subject must be resistant / intolerant to HU according to the following criteria: HU resistance is defined as: a dose ≥ 2 g / day or a maximum tolerated dose < 2 g / day for a minimum of 12 weeks, resulting in the need for phlebotomy to maintain a hematocrit < 45% or a platelet count > 400 × 10 9 / L and white blood cell (WBC) count>10×10 9 / L. HU intolerance is defined as: hematocrit <45% and / or platelet count ≤ 400×10 9 / L, WBC count ≤ 10 × 10 9 The minimum dose of HU required for ANC is <1.0×10 9 / L or platelet count <100×10 9 / L or hemoglobin <100 g / L (i.e., 10 g / dL) or presence of leg ulcers or other unacceptable HU-related non-hematologic toxicities (such as mucocutaneous manifestations, gastrointestinal symptoms, pneumonia, or fever at any HU dose), defined as: Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 Grade 3-4 adverse events (AEs) or CTCAE version 5.0 Grade 2 AEs for >1 week or permanent discontinuation of HU or interruption of HU until toxicity resolves or hospitalization due to HU toxicity. 6. Eastern Cooperative Oncology Group (ECOG) efficacy status of 0, 1, or 2. 7. Females of childbearing potential and males with partners of childbearing potential must agree to use effective contraception during the study. In addition, males must continue contraception for 3 months after the last dose of study drug, and females must continue contraception for 1 week after the last dose of study drug. Effective birth control includes (a) combined estrogen and progestin hormonal contraception (oral, intravaginal, transdermal); (b) progestin-only hormonal contraception (oral, injectable, implantable); (c) intrauterine devices; (d) intrauterine hormone-releasing systems; (e) bilateral tubal occlusion; (f) partner vasectomy; and (g) abstinence. Exclusion Criteria: 1. Fulfilling criteria for post-PV myelofibrosis as defined by the International Group for Myeloproliferative Neoplasms Research and Treatment (IWG-MRT). 2. >10% blasts. 3. Clinically significant thrombosis within 3 months of screening. 4. Insufficient hepatic or renal function: a. Renal impairment (estimated creatinine clearance <45 mL / min by Cockcroft Gault): b. Known history of hepatocellular disease (e.g., hepatitis B or C, cirrhosis, or other hepatocellular disease). c. Total bilirubin ≥ 2 × laboratory upper limit of normal (ULN), unless Gilbert's syndrome. d. Alanine aminotransferase (ALT) > 2.5 × ULN. 5. Part B only: Prior treatment with a JAK inhibitor. 6. Prior treatment with a histone deacetylase (HDAC) inhibitor or BCL-2 inhibitor. 7. Patients previously treated with MDM2 antagonist therapy, p53-directed therapy, or interferon-α, anagrelide, or ruxolitinib within 28 days or approximately 5 half-lives of the patient's treatment, or hydroxyurea within 1 day of the patient's treatment, or any other cytoreductive or investigational agent within 28 days or 5 half-lives of the initial dose. Aspirin is permitted according to treatment guidelines unless medically contraindicated. 8. Absolute neutrophil count < 1.5 × 10-1 before dosing on Day 1 of Cycle 1 9 9. Platelet count ≤ 150 × 10 9 / L. 10. Spleen irradiated within 3 months prior to the first dose of the compound of formula (I). 11. Pregnant or lactating women. 12. History of major organ transplant. 13. Uncontrolled intercurrent illnesses, including (but not limited to) the following: acute hepatitis A; known history of human immunodeficiency virus (HIV) positivity; clinically significant cardiac disease (New York Heart Association class III or IV); symptomatic congestive heart failure; unstable angina; ventricular arrhythmia; or psychiatric / social conditions that would limit compliance with study requirements. 14. Subjects with clinically significant bacterial, fungal, parasitic, or viral infections requiring treatment. Subjects with acute bacterial infections requiring antibiotics should have screening / enrollment delayed until the course of antibiotic therapy has been completed. 15. Other malignancies within the past 3 years, except for curatively treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, organ-confined or treated non-metastatic prostate cancer with normal prostate-specific antigen, breast cancer in situ after complete surgical resection, or superficial transitional cell bladder cancer. 16. Grade 2 or higher QTc prolongation (>480 milliseconds according to NCI-CTCAE criteria, version 5.0). Randomization procedure In Part A, subjects will be randomly assigned to one of three treatment groups. In Part B, subjects will be randomized to either a compound of Formula (I) or ruxolitinib. Subjects in Part B only will be stratified based on HU status: HU intolerance (unacceptable side effects) versus HU resistance (inadequate response). Subjects will be classified as HU resistant or intolerant at the screening visit, and this classification will be used to stratify subjects at randomization (study day 1). Statistical analysis This study is conducted in two parts. In Part A (initial proof-of-concept phase), study subjects will be randomly assigned to one of three treatment groups: 120 mg of the compound of formula (I) for a 21-day treatment cycle; 240 mg of the compound of formula (I) for a 21-day treatment cycle; or 120 mg of the compound of formula (I) for a 28-day treatment cycle. All three groups are conducted identically and follow the same study assessments. The primary efficacy analysis of Part A is based on an mITT analysis of subjects with baseline splenomegaly only in p53WT. All subjects with baseline splenomegaly in Part A have the opportunity to have the dose / schedule of the compound of formula (I) recommended for Part B by the DMC after the end of Week 32. For Part B, subjects with baseline splenomegaly will be randomly assigned to treatment with the recommended dose / schedule of any compound of formula (I) from Part A, or to ruxolitinib according to the prescription label. Statistical analysis results, descriptive summary statistics, and supportive tables will be presented by study part (A or B), treatment group, and dose. All analyses, summaries, and tabulations were performed using SAS software (version 9.4 or higher). A summary of the data collected in this study and detailed statistical analysis methods are described in the Statistical Analysis Plan (SAP), which was finalized before the database was locked. The SAP may modify the data analysis plan outlined in the protocol; if so, these modifications will be clearly documented in the SAP. Any major changes to the study design or study endpoints and / or their analyses will also be reflected in a protocol amendment. Study duration The study will be considered complete 2 years after the last subject is enrolled, at which time subjects remaining on study treatment will be assessed for eligibility for enrollment in the extended study. Examples 9 : In patients with primary myelofibrosis (PMF) , after polycythemia vera MF(PV back MF) or after essential thrombocythemia MF(ET back MF) Individuals who have failed ruxolitinib treatment (I) Open label of compound 2a / 2b Phase II study There is a significant unmet need for improved therapies in patients with myelofibrosis (MF) who are primary resistant to, have a suboptimal response to, or have relapsed after treatment with ruxolitinib. The compound of formula (I) is an orally bioavailable small molecule cytotoxic chemotherapeutic agent that binds to murine double minute chromosome 2 (MDM2) and inhibits the MDM2 / tumor protein 53 (p53) protein-protein interaction. The compound of formula (I) has been shown to inhibit the growth of p53 wild-type (p53WT) tumor cells in vitro and tumor xenografts in vivo. p53 is a tumor suppressor and transcription factor that responds to cellular stress by activating the transcription of a large number of genes involved in cell cycle arrest, apoptosis, senescence, and deoxyribonucleic acid (DNA) repair. Preclinically, a key determinant of sensitivity to MDM2 inhibition is the p53 mutation status of the cell, with p53WT cells being sensitive to such inhibitors. MDM2 is a negative regulator of p53 and is overexpressed in CD34+ myeloproliferative neoplasia cells containing p53WT. MDM2 degrades and inactivates p53, allowing clonal hematopoietic stem cell proliferation. Study Design This is an open-label, two-part (Part A and Part B) Phase 2a / 2b study of the compound of formula (I) in subjects with PMF, post-PV MF, or post-ET MF who have failed ruxolitinib treatment. Approximately 190 subjects will be enrolled in the study (90 in Part A and 100 in Part B). Part A (N=90): In Part A of the study, subjects will be randomly assigned to one of three treatment groups: • Cohort 1, N=30 subjects: 120 mg of the compound of Formula (I) once daily on Days 1 to 7, with treatment interrupted on Days 8 to 21 (21-day cycle) • Cohort 2, N=30 subjects: 240 mg of the compound of Formula (I) once daily on Days 1 to 7, with treatment interrupted on Days 8 to 21 (21-day cycle) • Cohort 3, N=30 subjects: 240 mg of the compound of Formula (I) once daily on Days 1 to 7, with treatment interrupted on Days 8 to 28 (28-day cycle) Part B (N=100): Approximately 100 subjects will be enrolled in Part B and treated with the recommended dose and schedule from Part A. During the study, the Data Monitoring Committee (DMC) will gather every 3 months for Part A and Part B to review the safety data of the clinical study. After all subjects in Part A have the opportunity to complete the 24-week assessment, the DMC will also gather. The DMC will determine the recommended dose and schedule of the compound of formula (I) for Part B based on the efficacy and safety data from Part A. In Part A and Part B, subjects will receive the compound of formula (I) orally (PO) QD on Day 1 to Day 7 of each 21-day or 28-day cycle. Dose reduction will be allowed for hematologic and non-hematologic toxicities. All subjects should be treated until disease progression or lack of tolerance. The definition of disease progression was based on imaging and modified ELN criteria: • Increase in spleen volume ≥25% from study nadir by MRI (or CT) by central imaging • Leukemic transformation confirmed by bone marrow blast count ≥20% or • Absolute blast count ≥1×10 9 / L-related peripheral blood blast content ≥ 20% Research objectives Inclusion criteria Subjects in both Parts A and B must meet all of the following criteria to be eligible for the study: 1. Adults >18 years of age 2. Palpable splenomegaly at least 5 cm below the left costal margin 3. Confirmed diagnosis of PMF, post-PV MF, or post-ET MF as assessed by the treating physician according to World Health Organization (WHO) criteria 4. High risk, intermediate 2 risk, or intermediate 1 risk as defined by the Dynamic International Prognostic System (DIPSS) 5. ECOG performance status of 0 to 2 6. Adequate hematologic, hepatic, and renal organ function (as defined in the protocol and within 14 days prior to the first dose of a compound of Formula (I)) Hematologic: ANC ≥1.0 × 10-1 during the first 7 days in the absence of growth factors 9 / L; platelet count ≥100 × 10 9 / L; peripheral blood blast count <10%. Liver: Unless Gilbert's syndrome occurs, total bilirubin ≤2.0 times the upper limit of normal (ULN); aspartate aminotransferase / serum glutamine oxaloacetate transaminase (AST / SGOT) and alanine aminotransferase / serum glutamine pyruvate transaminase (ALT / SGPT) ≤2.5 ULN. Kidney: Estimated creatinine clearance >45 mL / min by Cockcroft-Galter test. 7. Females of childbearing potential and males with potential partners must agree to use effective contraception during the study. Additionally, males must continue contraception for 3 months after the last dose of study medication, and females must continue contraception for 1 week after the last dose of study medication. Effective birth control includes (a) combined estrogen and progestin hormonal contraception (oral, intravaginal, transdermal); (b) progestin-only hormonal contraception (oral, injectable, implantable); (c) intrauterine device; (d) intrauterine hormone-releasing system; (e) bilateral fallopian tube occlusion; (f) vasectomy for the partner; and (g) abstinence. Subjects in Part A must meet the following criteria for ruxolitinib treatment failure to be eligible for the study: Failure of ruxolitinib in Part A must meet either criterion (a) or (b): a) Lack of splenic response, defined as at least 12 weeks of ruxolitinib treatment with both of the following: • Persistent splenomegaly palpable ≥5 cm below the lower costal margin (LCM) on physical examination • AND TSS >10 according to the MPN-SAF TSS 2.0, or a single symptom score >5 or two symptom scores >3, including only symptoms of left upper quadrant pain, bone pain, itching, or night sweats b) or disease progression at any time while on ruxolitinib treatment, as defined by any of the following: • ≥25% increase in spleen volume from nadir as assessed by MRI or CT • Appearance of new splenomegaly palpable at least 5 cm below the LCM • ≥100% increase in the palpable distance below the LCM for baseline splenomegaly of 5 to 10 cm • ≥50% increase in the palpable distance below the LCM for baseline splenomegaly >10 cm Subjects in Part B must meet the following ruxolitinib treatment failure criteria to be eligible for the study: Failure of ruxolitinib in Part B must meet either criterion (a) or (b): a) Lack of splenic response, defined as a splenic response in individuals who received at least 12 weeks of ruxolitinib treatment and had at least one of the following: • Failure to reduce spleen volume by at least 35% in individuals assessed by MRI or CT for ruxolitinib treatment • Baseline splenomegaly that was palpable 5 to 10 cm below the LCM before ruxolitinib treatment but remained palpable • Baseline splenomegaly that was palpable >10 cm below the LCM before ruxolitinib treatment but did not reduce by at least 50% • Baseline splenomegaly that was palpable <5 cm below the LCM before ruxolitinib treatment was not eligible for ruxolitinib treatment failure b) or disease progression at any time while on ruxolitinib treatment, as defined by any of the following: • ≥25% increase in spleen volume from nadir as assessed by MRI or CT • Appearance of new splenomegaly palpable at least 5 cm below the LCM • ≥100% increase in the palpable distance below the LCM for baseline splenomegaly of 5 to 10 cm • ≥50% increase in the palpable distance below the LCM for baseline splenomegaly >10 cm Exclusion criteria Subjects in both Parts A and B who meet any of the following criteria will be ineligible for the study: 1. Participation in another interventional clinical trial within the past 4 weeks of the first dose of the compound of Formula (I) (participation in observational studies is permitted). 2. Recent / concurrent treatment, such as major surgery, chemotherapy, immunomodulatory therapy, biologic therapy, radiation therapy, or investigational therapy, within 4 weeks or approximately 5 half-lives of the first dose of the compound of Formula (I). 3. Prior splenectomy. 4. Splenic irradiation within 3 months prior to the first dose of the compound of Formula (I). 5. Prior allogeneic stem cell transplantation or eligibility for allogeneic stem cell transplantation. 6. Prior treatment with a histone deacetylase (HDAC) inhibitor or BCL-2 inhibitor. 7. Prior MDM2 inhibitor therapy or p53-directed therapy. 8. Pregnant or lactating women. 9. History of major organ transplantation. 10. Uncontrolled intermittent illness, including (but not limited to) the following: acute hepatitis A; known history of human immunodeficiency virus (HIV) positivity; clinically significant cardiac disease (New York Heart Association class III or IV); symptomatic congestive heart failure; unstable angina; ventricular arrhythmias; or psychiatric / social conditions that would limit compliance with study requirements. 11. Subjects with clinically significant bacterial, fungal, parasitic, or viral infections requiring treatment. Subjects with acute bacterial infections requiring antibiotics should have screening / enrollment delayed until the course of antibiotic therapy has been completed. 12. Other malignancies within the past 3 years, except for curatively treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, organ-confined or treated non-metastatic prostate cancer with a normal prostate-specific antigen, breast cancer in situ after complete surgical resection, or superficial transitional cell bladder cancer. 13. Grade 2 or higher QTc prolongation (>480 milliseconds according to NCI-CTCAE criteria, version 5.0). 14. Hematopoietic growth factors (i.e., erythropoietin (Epo), granulocyte colony-stimulating factor (GCSF), romiplostim) within 28 days prior to receiving the first dose of a compound of formula (I). 15. Active bleeding or chronic bleeding within 4 weeks prior to receiving the first dose of a compound of formula (I). Randomization procedure Part A: Subjects will be randomized to one of three treatment groups using a 1:1:1 allocation scheme. A contract clinical service provider will develop the Part A randomization schedule, and actual randomization will be performed via the Interactive Reaction Technology (IRT) system. Part B: Subjects will be randomized to the dose and schedule of the compound of Formula (I) recommended by the DMC. Statistical analysis During the study, the DMC will meet every 3 months for Part A and Part B to review the safety data of the clinical study. The DMC will also meet after all subjects in Part A have the opportunity to complete the 24-week assessment. The DMC will determine the recommended dose and schedule of the compound of Formula (I) for Part B based on the efficacy and safety data from Part A. The statistical analysis results, descriptive summary statistics, and supportive tables will be presented by study part (A or B) and within Part A (by group). Study duration The study will be considered complete 2 years after the last subject is enrolled, at which time subjects remaining on study treatment will be assessed for eligibility for enrollment in the extended study. Examples 10 : Mode (I) Compound pairs MPN-BP The role of stem cells MPN-BP Cell preparation Currently, from 1 with WT CD3 of MPN-BP patients with TP53 gene + Cell-depleted mononuclear cells (MNCs) have been shown to be capable of serial transplantation and leukemia in NSG mice. To harvest sufficient cells to evaluate the effects of the compound of Formula (I) on MPN-BP stem cells, MPN-BP cells collected from the bone (BM) or spleen of NSG mice will be serially passaged in NSG mice. The mutation patterns and karyotypic abnormalities present in the cells after serial transplantation will be determined by capture-based next-generation sequencing (NGS) and fluorescence in situ hybridization (FISH). Mode (I) Compound pairs MPN-BP The role of stem cells To examine the effects of the compound of formula (I) on MPN-BP stem cells, 0.5-2×10 61 cell / mouse was transplanted into 8-9 week old NSG mice that had been sublethally irradiated (220 cGy). The mice were then monitored daily for overall condition and weighed weekly. Twenty-eight days after transplantation, peripheral blood was collected from the recipient mice and analyzed by complete blood count (CBC) and flow cytometry to determine whether human MPN-BP was expressed in these mice. These mice will be used in the following studies. Mode (I) High-dose studies of compounds Mice that have developed MPN-BP and have similar leukemic burden in peripheral blood are randomly divided into two groups of 3-4 mice each. These two groups of mice are treated with vehicle or compound of formula (I) (high dose, 100 or 150 mg / kg) once daily by oral gavage for 7 days. After treatment, peripheral blood blast counts will be monitored once a week using flow cytometry analysis. Tolerance to treatment will be assessed by measuring daily body weight (BW). These analyses will allow the establishment of MPN-BP recovery dynamics after each drug treatment, which will be used to determine the treatment-free interval for the following survival and combination therapy studies. Mode (I) Survival study of compounds Mice that have developed MPN-BP and have similar leukemia burden in peripheral blood are randomly divided into 3 groups of 4-5 mice each and treated with high doses (100 or 150 mg / kg) and low doses (30-50 mg / kg) of the compound of formula (I) once daily by oral gavage for 7 days. These cycles will be repeated for up to 3 cycles. After treatment, blood counts and flow cytometric analysis of mouse blood are used to monitor overall survival and disease progression every 14 days. Mice are sacrificed if any of the following criteria are met: symptoms of the disease are shown, such as more than 20% weight loss, hunchback, decreased activity; palpable splenomegaly extending across the midline; severe anemia, thrombocytopenia, or leukopenia. Mice are tracked until they meet the criteria for sacrifice. In addition, after completing 3 treatment cycles, 2-3 mice receiving high or low doses of the compound of formula (I) are sacrificed, even if they do not show symptoms of the disease. After mice were sacrificed, cells were recovered from BM, spleen, and peripheral blood, and the expression of human CD45 in these organs was determined by mAb staining and flow cytometric analysis. + 、CD34 + 、CD33 + 、CD14 +, Gly A + 、CD41a + 、CD19 + and CD3 + These analyses will allow determination of whether treatment with the compound of formula (I) improves survival and reduces the leukemic cell burden in the mouse BM and reduces the spread of leukemic cells to the mouse spleen and peripheral blood. After flow cytometric analysis, the remaining BMCs and spleen cells will be cryopreserved for quantification of MPN-BP cell burden and assessment of the targeting effect of the compound of formula (I). hCD33 in the BM of recipient mice + Cells will be selected using a FACSAria cell sorter (BD) and analyzed using FISH for marker chromosomal abnormalities and variant allele frequencies of mutated myeloid malignancy genes. The foregoing summary, as well as the following detailed description of the invention, will be better understood when read in conjunction with the appended drawings. Figure 1 shows the XRPD pattern of the compound of formula (I) in crystalline anhydrous form. Figure 2 shows that the compound of formula (I) inhibits the proliferation of p53 WT tumor cells. Figure 3 shows that the compound of formula (I) inhibits the growth of SJSA-1 (MDM2 amplified) tumors in vivo in a dose-dependent manner. 50 = 9.0 mg / kg. Figure 4 shows that the compound of formula (I) inhibits the growth of HCT116 (KRAS) tumors in vivo in a dose-dependent manner. 50 = 31.6 mg / kg. Figure 5 shows that the compound of formula (I) inhibits the growth of A375sq2 (BRAF) tumors in vivo in a dose-dependent manner. 50 = 18 mg / kg. Figure 6 shows the p21 induction fold of the compound of formula (I) at different doses. Figure 7 shows that the compound of formula (I) inhibits AML tumor growth in a dose-dependent manner. Figure 8 shows that the compound of formula (I) inhibits AML tumor growth in a mouse model in a dose-dependent manner. Figure 9 shows that compounds of formula (I) inhibit cell cycle. FIG10 shows that the compound of formula (I) induces apoptosis in p53 wild-type AML cell lines.

Claims

1. Use of an MDM2 inhibitor for the preparation of a medicament for treating myeloproliferative neoplasm (MPN) in a human individual, wherein the MDM2 inhibitor is a compound of formula (I): (I) or a pharmaceutically acceptable salt thereof; wherein the compound of formula (I) is administered once daily at a dose of 240 mg, wherein the human individual is treated with the MDM2 inhibitor on days 1-7 of a 28-day cycle, and wherein the human individual is not treated with the MDM2 inhibitor on days 8-28.

2. As requested in item 1, wherein the MPN is polycythemia vera (PV).

3. As requested in claim 2, wherein the MPN is venotomy-dependent polycythemia vera.

4. As requested in item 1, wherein the MPN is thrombocytosis.

5. As requested in item 4, where thrombocytosis is primary thrombocytosis (ET).

6. As requested in item 1, wherein the MPN is myelofibrosis.

7. For the purposes of claim 6, wherein the human individual experiences a relapse of disease after treatment with ruxolitinib.

8. As requested in item 6, wherein myelofibrosis is selected from primary myelofibrosis (PMF), post-PV myelofibrosis (post-PV MF), and post-ET myelofibrosis (post-ET MF).

9. As requested in claim 8, wherein the human individual does not respond to prior ruxolitinib treatment.

10. As requested in claim 1, wherein the MPN is characterized by the JAK2V617F mutation.

11. As claimed in claim 1, wherein the compound of formula (I) is administered orally.

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