Methods of treating cancer

Abstract

Methods of treating cancer are provided. Therapeutic methods and pharmaceutical compositions for the treatment of cancers, including myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), idiopathic thrombocythemia (ET), and primary myelofibrosis, in a human subject are described. In certain embodiments, the invention includes methods of treatment of MPN using an MDM2 inhibitor of formula (I) or formula (II). # imgabs0 #

Description

[0001] This application is a divisional application of the invention application with the application date of April 30, 2019, the Chinese national application number of 201980043405.4, and the invention name of "Methods for Treating Cancer". Technical Field

[0002] Disclosed herein are methods for treating cancer, including myeloproliferative neoplasms (MPNs), using murine double minute 2 homolog (MDM2) inhibitors. Background Art

[0003] p53 is a tumor suppressor and transcription factor that responds to cellular stress by activating the transcription of multiple genes involved in cell cycle arrest, apoptosis, senescence, and DNA repair. Unlike normal cells, which infrequently cause p53 activation, tumor cells are under constant cellular stress from various insults, including hypoxia and pro-apoptotic oncogene activation. Thus, there is a strong selective advantage for the inactivation of the p53 pathway in tumors, and it has been proposed that the elimination of p53 function may be a prerequisite for tumor survival. To support this view, three groups of investigators used mouse models to demonstrate that the lack of p53 function is a continuing requirement for the maintenance of established tumors. When investigators restored p53 function in p53-inactivated tumors, the tumors regressed.

[0004] In 50% of solid tumors and 10% of liquid tumors, p53 is inactivated by mutation and / or loss. Other key members of the p53 pathway are also genetically or epigenetically altered in cancer. MDM2, an oncoprotein, inhibits p53 function and it is activated by gene amplification at a reported incidence of up to 10%. MDM2 is in turn inhibited by another tumor suppressor, p14ARF. Alterations downstream of p53 have been shown to be responsible for at least partial inactivation of the p53 pathway in p53 WT tumors (p53 wild type). To support this view, some p53WT tumors appear to show reduced apoptotic capacity, although their ability to undergo cell cycle arrest remains intact. One cancer treatment strategy involves using small molecules that bind 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 and blocking the p53 transcriptional activation domain; and 3) exporting p53 from the nucleus to the cytoplasm. All three of these mechanisms would be blocked by neutralizing the MDM2-p53 interaction. In particular, this treatment strategy can be applied to tumors that are p53 WT, and studies using small molecule MDM2 inhibitors have produced promising reductions in tumor growth both in vitro and in vivo. In addition, in patients with p53-inactivated tumors, stabilizing wild-type p53 in normal tissues by MDM2 inhibition can allow selective protection of normal tissues from the effects of mitotic poisons. As used herein, MDM2 refers to the human MDM2 protein and p53 refers to the human p53 protein. Note 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.

[0005] Myeloproliferative neoplasms (MPNs), including but not limited to: polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are clonal hematopoietic stem cell (HSC) disorders characterized by the clonal proliferation of terminally differentiated myeloid cells. Approximately 1%, 4%, and 20% of ET, PV, and PMF patients, respectively, progress to blast phase (BP), known as MPN-BP, over a 10-year period from the time of diagnosis. Cervantes F et al., Acta Haematol. 1991;85(3):124–127. MPN-BP and de novo acute myeloid leukemia (AML) each have distinct mutational patterns and clinical courses. Rampal R et al., Proc Natl Acad Sci USA. 2014;111(50):E5401-10. MPN-BP patients have a particularly dismal prognosis, with a median survival of less than 6 months for currently available therapies.

[0006] The present invention relates to a method of treating myeloproliferative neoplasms in a human subject with an MDM2 inhibitor, either alone or in combination with one or more other pharmaceutically active agents.

[0007] The present invention relates to the use of an MDM2 inhibitor, either alone or in combination with one or more other pharmaceutically active agents, in the treatment of myeloproliferative neoplasms (MPNs). SUMMARY OF THE INVENTION

[0008] The present invention relates to a method of treating myeloproliferative neoplasms (MPNs) comprising the step of administering to a person in need a therapeutically effective amount of an MDM2 inhibitor, wherein the MDM2 inhibitor is a compound of formula (I) or formula (II):

[0009]

[0010] or a pharmaceutically acceptable salt thereof. In one embodiment, the MPN is selected from the group consisting of polycythemia vera (PV), myelofibrosis, primary myelofibrosis, thrombocytosis, essential thrombocytosis, congenital 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 thrombocytosis. In one embodiment, the MPN is polycythemia vera (PV). In one embodiment, the MPN is essential thrombocytosis. 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 thrombocytosis myelofibrosis (post-ET MF). In one embodiment, ruxolitinib therapy for any of the above MPNs in a human subject has failed. In one embodiment, ruxolitinib therapy for myelofibrosis in a human subject has failed. In one embodiment, ruxolitinib therapy for primary myelofibrosis (PMF) in a human subject has failed. In one embodiment, ruxolitinib therapy for post-polycythemia vera myelofibrosis (post-PV MF) in a human subject has failed. In one embodiment, ruxolitinib therapy for post-essential thrombocytosis myelofibrosis (post-ET MF) in a human subject has failed.

[0011] In one embodiment, the present invention relates to a method of treating polycythemia vera (PV) comprising the step of administering to a person in need 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.

[0012] In one embodiment, the present invention relates to a method for treating essential thrombocythemia, comprising the step of administering to a person in need 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.

[0013] In one embodiment, the present invention relates to a method for treating primary myelofibrosis, comprising the step of administering to a person in need 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.

[0014] In one embodiment, the present invention relates to a method for treating congenital myelofibrosis, comprising the step of administering to a person in need 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.

[0015] In one embodiment, the present invention relates to a method for treating chronic myeloid leukemia (CML), comprising the step of administering to a person in need 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.

[0016] In one embodiment, the present invention relates to a method for treating acute myeloid leukemia (AML), comprising the step of administering to a person in need 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.

[0017] In one embodiment, the present invention relates to a method for treating Merkel cell carcinoma (MCC), comprising the step of administering to a person in need 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.

[0018] In one embodiment, the present invention relates to a method for treating systemic mastocytosis (SM), comprising the step of administering to a person in need 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.

[0019] In one embodiment, the present invention relates to a method for treating chronic neutrophilic leukemia (CNL), comprising the step of administering to a person in need 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.

[0020] In one embodiment, the present invention relates to a method for treating myelodysplastic syndromes (MDS), comprising the step of administering to a person in need 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.

[0021] In one embodiment, the present invention relates to a method for treating systemic mastocytosis disease (SMCD), comprising the step of administering to a person in need 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.

[0022] In one embodiment, the thrombocytosis is essential thrombocythemia (ET).

[0023] In one embodiment, the compound of formula (I) or formula (II) is in crystalline form. In one embodiment, the crystalline form is characterized by a powder X-ray diffraction pattern that comprises at least three peaks selected from the group consisting of peaks at diffraction angles 2θ degrees of about 11.6, 12.4, 18.6, 19.0, 21.6, and 23.6 ± 0.1.

[0024] In one embodiment, the compound of formula (I) or formula (II) is in amorphous form.

[0025] In one embodiment, the compound of formula (I) or formula (II) is in free form.

[0026] In one embodiment, the MDM2 inhibitor is a pharmaceutically acceptable salt of a compound of formula (I) or formula (II).

[0027] 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.

[0028] 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.

[0029] In one embodiment, a human is treated with a compound of formula (I) for a period of time continuously 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.

[0030] In one embodiment, a compound of formula (I) or formula (II) is administered orally.

[0031] An MDM2 inhibitor for treating myeloproliferative neoplasms (MPNs) comprising the step of administering a therapeutically effective amount of an 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. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] The foregoing summary of the invention, as well as the following detailed description of the invention, will be better understood when read in conjunction with the accompanying drawings.

[0033] Figure 1 The XRPD pattern of the crystalline anhydrous form of the compound of formula (I) is illustrated.

[0034] Figure 2 The compound of formula (I) is illustrated to inhibit the proliferation of p53 WT tumor cells.

[0035] Figure 3 The compound of formula (I) is illustrated to inhibit the in vivo growth of SJSA-1 (MDM2 amplified) tumors in a dose-dependent manner. ED 50 = 9.0 mg / kg.

[0036] Figure 4 The compound of formula (I) is illustrated to inhibit the in vivo growth of HCT116 (KRAS) tumors in a dose-dependent manner. ED 50 = 31.6 mg / kg.

[0037] Figure 5 The compound of formula (I) is illustrated to inhibit the in vivo growth of A375sq2 (BRAF) tumors in a dose-dependent manner. ED 50 = 18 mg / kg.

[0038] Figure 6 The p21 dual induction by different doses of the compound of formula (I) is illustrated.

[0039] Figure 7 The compound of formula (I) is illustrated to inhibit AML tumor growth in a dose-dependent manner.

[0040] Figure 8 The compound of formula (I) is illustrated to inhibit AML tumor growth in a mouse model in a dose-dependent manner.

[0041] Figure 9 It is demonstrated that the compound of formula (I) inhibits the cell cycle.

[0042] Figure 10 It is demonstrated that the compound of formula (I) induces apoptosis in p53 wild-type AML cell lines. Detailed Description

[0043] Although the preferred embodiments of the present invention have been shown and described herein, these embodiments are provided by way of example only and are not intended to limit the scope of the present invention in any other way. Various alternatives of the embodiments described in the present invention may be employed in practicing the present invention.

[0044] Unless otherwise defined, 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.

[0045] As used herein, the terms "administered in combination with" and "co-administered" include administering to a subject two or more active pharmaceutical ingredients such that both agents and / or their metabolites are present in the subject at the same time. Co-administration includes administering simultaneously in separate compositions, administering at different times in separate compositions, or administering in a composition in which two or more agents are present.

[0046] The term "effective amount" or "therapeutically effective amount" refers to an amount of the active pharmaceutical ingredient or combination of active pharmaceutical ingredients described herein sufficient to achieve the intended application, including but not limited to the treatment of a disease. The therapeutically effective amount may vary depending on the intended application (in vitro or in vivo), the subject being treated and the disease condition (e.g., the weight, age and sex of the subject), the severity of the disease condition, the mode of administration, and other factors readily determinable by one of ordinary skill in the art. The term also applies to the dose that will cause a specific response (e.g., reduced platelet adhesion and / or cell migration) in a target cell. The specific dose will vary depending on the particular compound selected, the dosing regimen to be followed, whether the compound is co-administered with other compounds, the time of administration, the tissue to which it is administered, and the physical delivery system in which the compound is carried.

[0047] As used herein, the terms "enantiomerically enriched", "enantiomerically pure", and "non-racemic" refer to a composition in which the weight percentage of one enantiomer is greater than the amount of that enantiomer in a control mixture of a racemic composition (e.g., greater than a 1:1 weight ratio). For example, an enantiomerically enriched preparation of the (S)-enantiomer refers to a preparation of a compound having greater than 50% by weight (e.g., at least 75% by weight, e.g., at least 80% by weight) of the (S)-enantiomer relative to the (R)-enantiomer. In some embodiments, the enrichment can be significantly greater than 80% by weight, providing a "substantially enantiomerically enriched", "substantially enantiomerically pure", or "substantially non-racemic" preparation, which refers to a composition having at least 85% by weight, e.g., at least 90% by weight, and e.g., 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 a composition in which the weight percentage of one diastereomer is greater than the amount of that diastereomer in a control mixture of diastereomers. In some embodiments, the enrichment can be significantly greater than 80% by weight, providing a "substantially diastereomerically enriched" or "substantially diastereomerically pure" preparation, which refers to a composition having at least 85% by weight, e.g., at least 90% by weight, and e.g., at least 95% by weight of one diastereomer relative to the other diastereomers.

[0048] In a preferred embodiment, an enantiomerically enriched composition has a higher potency in terms of therapeutic utility per unit mass relative to the racemic mixture of the composition. Enantiomers can be separated from a mixture by methods known to those skilled in the art, including chiral high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or the preferred enantiomer can be prepared by asymmetric synthesis. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions, Wiley Interscience, New York (1981); E.L. Eliel and S.H. Wilen, Stereochemistry of Organic Compounds, Wiley Interscience, New York (1994).

[0049] As used herein, "enantiomeric purity" refers to the relative abundance of a particular enantiomer relative to other enantiomers, expressed as a percentage. For example, if a compound that may exist in the form of a racemic mixture has (R)- or (S)-isomer configurations, the enantiomeric purity is approximately 50% relative to the (R)- or (S)-isomer. If the compound has a more predominant isomer form than the other, such as 80% (S)- and 20% (R)-, the enantiomeric purity of the compound relative to the (S)-isomer form is 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, polarimetry of the rotation of plane-polarized light, nuclear magnetic resonance spectroscopy using a chiral shift reagent (including but not limited to lanthanide-containing chiral complexes or Pirkle alcohols), or derivatizing the compound with a chiral compound such as Mosher's acid followed by chromatography or nuclear magnetic resonance spectroscopy.

[0050] The term "IC 50 " refers to the half-maximal inhibitory concentration, i.e., the concentration that inhibits 50% of the desired activity. The term "EC 50 " refers to the drug concentration at which half of the maximal response is achieved.

[0051] "Isomers" are different compounds having the same molecular formula. "Stereoisomers" are isomers that differ only in the way the atoms are arranged in space, i.e., having 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. When appropriate, the term "(±)" is used to denote a racemic mixture. "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is assigned according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry of each chiral carbon can be designated as R or S. Based on the direction (right-handed or left-handed) in which they rotate plane-polarized light at the sodium D-line wavelength, a resolved compound of unknown absolute configuration can be designated as (+) or (-). Certain compounds described herein contain one or more asymmetric centers and can therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- according to absolute stereochemistry. 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 synthons or chiral reagents, or resolved using conventional techniques. When a compound described herein contains an olefinic double bond or other geometrically asymmetric center, and unless otherwise specified, the compound is intended to include E and Z geometric isomers.

[0052] "MPN-BP" refers to the blast phase (BP) of myeloproliferative neoplasm (MPN) described in the present disclosure.

[0053] "Pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents. The use of such media and agents for active pharmaceutical ingredients is well known in the art. Unless to the extent that any conventional media or agent is incompatible with the active pharmaceutical ingredient, it is contemplated for use in the therapeutic compositions of the present invention. Supplementary active ingredients can also be incorporated into the compositions.

[0054] The term "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counterions known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids 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 bases 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, the pharmaceutically acceptable base addition salts are selected from ammonium, potassium, sodium, calcium, and magnesium salts. The term "cocrystal" refers to a molecular complex derived from a variety of cocrystal formers known in the art. Different from salts, cocrystals generally do not involve proton transfer between the cocrystal and the drug, but involve intermolecular interactions between the cocrystal former and the drug in the crystal structure, such as hydrogen bonding, aromatic ring stacking, or dispersion forces.

[0055] The terms "QD", "qd", or "q.d." mean once daily, one time a day, or every day once. The terms "BID", "bid", or "b.i.d." mean twice daily, two times a day, or every day twice. The terms "TID", "tid", or "t.i.d." mean three times daily, three times a day, or every day three times. The terms "QID", "qid", or "q.i.d." mean four times daily, four times a day, or every day four times.

[0056] "Solvate" refers to a compound physically associated with one or more molecules of a pharmaceutically acceptable solvent.

[0057] As used herein, the term "therapeutic effect" encompasses the therapeutic and / or prophylactic benefits as described above. Prophylactic effects include delaying or eliminating the onset of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting or reversing the progression of a disease or condition, or any combination thereof.

[0058] When ranges are used herein to describe, for example, physical or chemical properties such as molecular weight or chemical formula, all combinations and sub-combinations of the ranges and specific embodiments therein are intended to be included. When referring to a number or numerical range, the term "about" is used to indicate that the recited number or numerical range is an approximation within experimental variability (or within statistical experimental error), and thus, the number or numerical range may vary, for example, between 1% and 15% of the recited number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") includes those embodiments that are any combination of substances, methods or processes, such as embodiments "consisting of the described features" or "consisting essentially of the described features".

[0059] 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), conformational polymorphs and amorphous forms of the compounds, and mixtures thereof. The terms "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), conformational polymorphs and amorphous forms, and mixtures thereof, unless a specific crystalline or amorphous form is mentioned.

[0060] Method for treating cancer

[0061] The present invention relates to a method for treating cancer, comprising the step of administering to a person in need a murine double minute 2 homolog (MDM2) inhibitor or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from the group consisting of: cancers 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 cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer, head and neck cancer, and skin cancer (including basal and squamous cell carcinoma, melanoma skin cancer, Merkel cell carcinoma, Kaposi sarcoma, cutaneous lymphoma); hematopoietic tumors of lymphoid lineage (including leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, and Burkitt lymphoma); hematopoietic tumors of myeloid lineage (including acute and chronic myelogenous leukemia, myelodysplastic syndrome, and promyelocytic leukemia); tumors of mesenchymal origin (including fibrosarcoma and rhabdomyosarcoma and other sarcomas such as soft tissue and bone); tumors of the central and peripheral nervous systems (including astrocytoma, neuroblastoma, glioma, glioblastoma, and schwannoma); and other tumors (including melanoma, 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, 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.

[0062] The present invention also relates to the use of a murine 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: cancers 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 cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer, head and neck cancer, and skin cancer (including basal and squamous cell carcinomas, melanoma skin cancer, Merkel cell carcinoma, Kaposi sarcoma, cutaneous lymphoma); hematopoietic tumors of lymphoid lineage (including leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, and Burkitt lymphoma); hematopoietic tumors of myeloid lineage (including acute and chronic myelogenous leukemia, myelodysplastic syndromes, and promyelocytic leukemia); tumors of mesenchymal origin (including fibrosarcoma and rhabdomyosarcoma and other sarcomas such as soft tissue and bone); tumors of the central and peripheral nervous systems (including astrocytoma, neuroblastoma, glioma, glioblastoma, and schwannoma); and other tumors (including melanoma, 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, 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.

[0063] Method for treating myeloproliferative neoplasm (MPN)

[0064] The present invention also relates to a method for treating MPN, comprising the step of administering to a person in need a murine double minute 2 homolog (MDM2) inhibitor or a pharmaceutically acceptable salt thereof. In one embodiment, the MPN is selected from the group consisting of: polycythemia vera (PV), myelofibrosis, primary myelofibrosis, thrombocytosis, essential thrombocythemia (ET), congenital 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, 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 myelodysplastic / 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, a person is determined to be hydroxyurea (HU) intolerant (unacceptable side effects). In one embodiment, a human subject is determined to be hydroxyurea (HU) resistant (insufficient response). In one embodiment, a human subject is determined to have splenomegaly. In one embodiment, the human subject has splenomegaly and is phlebotomy-dependent. In one embodiment, the human subject is phlebotomy-dependent but does not have splenomegaly. In one embodiment, the ruxolitinib therapy in humans fails. The failure of ruxolitinib therapy includes, but is not limited to: (i) no reduction in the severity or progression of any MPN in a human subject receiving ruxolitinib, or (ii) recurrence of any MPN in a human subject after ruxolitinib therapy. In one embodiment, the failure of ruxolitinib therapy is no reduction in the severity or progression of any MPN in a human subject receiving ruxolitinib. In one embodiment, the failure of ruxolitinib therapy is recurrence of any MPN in a human subject after ruxolitinib therapy. 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.

[0065] In one embodiment, the present invention relates to a method for treating MPN, comprising the step of administering a murine double minute 2 homolog (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, and wherein 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, a human subject is determined to be hydroxyurea (HU) intolerant (unacceptable side effects). In one embodiment, a human subject is determined to be hydroxyurea (HU) resistant (insufficient response). In one embodiment, the human subject has splenomegaly. In one embodiment, the person has splenomegaly and is phlebotomy-dependent. In one embodiment, the human subject is phlebotomy-dependent but does not have splenomegaly. In one embodiment, the previous ruxolitinib MPN therapy of the human subject has failed.

[0066] The present invention also relates to a method for treating myeloproliferative neoplasm in blast phase (MPN-BP), which comprises the step of administering a murine double minute 2 homolog (MDM2) inhibitor or a pharmaceutically acceptable salt thereof to a person in need. In one embodiment, MPN-BP is selected from the group consisting of: blast phase polycythemia vera (BP-PV), blast phase myelofibrosis, blast phase primary myelofibrosis, blast phase thrombocythemia, blast phase essential thrombocythemia (BP-ET), blast phase congenital myelofibrosis, blast phase systemic mastocytosis (BP-SM), blast phase chronic neutrophilic leukemia (BP-CNL), blast phase myelodysplastic syndrome (BP-MDS), and blast phase systemic mast cell disease (BP-SMCD). In one embodiment, blast phase myelofibrosis is selected from the group consisting of: blast phase primary myelofibrosis (BP-PMF), blast phase post-polycythemia vera myelofibrosis (BP-post-PV MF), and blast phase post-essential thrombocythemia myelofibrosis (BP-post-ET MF). In one embodiment, blast phase primary myelofibrosis (BP-PMF) is selected from the group consisting of: blast phase pre-fibrotic / early PMF and blast phase overt fibrotic PMF. In one embodiment, MPN-BP is selected from the group consisting of: blast phase chronic neutrophilic leukemia (BP-CNL), blast phase chronic eosinophilic leukemia, blast phase chronic myelomonocytic leukemia (BP-CMML), blast phase atypical chronic myeloid leukemia (BP-aCML), blast phase juvenile myelomonocytic leukemia (BP-JMML), blast phase hypereosinophilic syndrome (BP-HES), and blast phase myelodysplastic / myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (BP-MDS / MPN-RS-T). In one embodiment, blast phase polycythemia vera is phlebotomy-dependent polycythemia vera. In one embodiment, a person is determined to be hydroxyurea (HU)-intolerant (unacceptable side effects). In one embodiment, a human subject is determined to be 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 but does not have splenomegaly. In one embodiment, the ruxolitinib therapy for humans fails. The failure of ruxolitinib therapy includes, but is not limited to: (i) no reduction in the severity or progression of any MPN-BP in a human subject receiving ruxolitinib, or (ii) recurrence of any MPN-BP in a human subject after ruxolitinib therapy. In one embodiment, the failure of ruxolitinib therapy is no reduction in the severity or progression of any MPN-BP in a human subject receiving ruxolitinib.In one embodiment, failure of ruxolitinib therapy is any recurrence of MPN-BP in a human subject after ruxolitinib therapy. 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. 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 "Dose and Administration" section.

[0067] In one embodiment, myelofibrosis is selected from primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV MF), and post-essential thrombocythemia myelofibrosis (post-ET MF).

[0068] In one embodiment, myelofibrosis is selected from primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV MF), and post-essential thrombocythemia myelofibrosis (post-ET MF), and the ruxolitinib therapy for PMF, post-PV MF, or post-ET MF in a human subject has failed.

[0069] In one embodiment, 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, which is incorporated herein by reference in its entirety.

[0070] In one embodiment, MPN is characterized by an MPL mutation (myeloproliferative leukemia virus oncogene; located on chromosome 1p34), as described in Pikman et al., Plos Med. 2006; 3(7):e270, which is incorporated herein by reference in its entirety.

[0071] In one embodiment, MPN is characterized by the JAK2V617F mutation. JAK2V617F is a gain-of-function mutation that promotes cytokine-independent growth of myeloid cells and accounts for the majority of myeloproliferative neoplasms (MPNs), as described in Nakatake et al. (Oncogene, 2012, 31, 1323-1333), which is incorporated herein by reference in its entirety.

[0072] In one embodiment, MPN is characterized by one or more mutations selected from the group consisting of JAK2V617F, MPL, CALR, and mixtures thereof.

[0073] In one embodiment, the present invention relates to a method for treating polycythemia vera (PV) 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 MDM2 inhibitor is a compound of formula (I) or formula (II).

[0074] In one embodiment, the present invention relates to a method for treating polycythemia vera (PV) 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 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.

[0075] In one embodiment, the present invention relates to a method for treating polycythemia vera (PV) 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 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.

[0076] In one embodiment, the present invention relates to a method for treating essential thrombocythemia (ET) 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 MDM2 inhibitor is a compound of formula (I) or formula (II).

[0077] In one embodiment, the present invention relates to a method for treating idiopathic thrombocythemia (ET) 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 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.

[0078] In one embodiment, the present invention relates to a method for treating idiopathic thrombocythemia (ET) 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 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.

[0079] In one embodiment, the present invention relates to a method for treating primary myelofibrosis 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 MDM2 inhibitor is a compound of formula (I) or formula (II).

[0080] In one embodiment, the present invention relates to a method for treating primary myelofibrosis 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 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.

[0081] In one embodiment, the present invention relates to a method for treating primary myelofibrosis 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 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.

[0082] In one embodiment, the present invention relates to a method for treating post-polycythemia vera myelofibrosis (post-PV MF) 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 MDM2 inhibitor is a compound of formula (I) or formula (II).

[0083] In one embodiment, the present invention relates to a method for treating post-polycythemia vera myelofibrosis (post-PV MF) 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 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.

[0084] In one embodiment, the present invention relates to a method for treating post-polycythemia vera myelofibrosis (post-PV MF) 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 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.

[0085] In one embodiment, the present invention relates to a method for treating post-essential thrombocythemia myelofibrosis (post-ET MF) 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 MDM2 inhibitor is a compound of formula (I) or formula (II).

[0086] In one embodiment, the present invention relates to a method for treating post-essential thrombocythemia myelofibrosis (post-ET MF) 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 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.

[0087] In one embodiment, the present invention relates to a method for treating post-essential thrombocythemia myelofibrosis (post-ET MF) 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 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.

[0088] In one embodiment, the present invention relates to a method for treating chronic neutrophilic leukemia (CNL) 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 MDM2 inhibitor is a compound of formula (I) or formula (II).

[0089] In one embodiment, the present invention relates to a method for treating chronic neutrophilic leukemia (CNL) 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 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.

[0090] In one embodiment, the present invention relates to a method for treating chronic neutrophilic leukemia (CNL) 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 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.

[0091] In one embodiment, the present invention relates to a method for treating chronic eosinophilic leukemia 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 MDM2 inhibitor is a compound of formula (I) or formula (II).

[0092] In one embodiment, the present invention relates to a method for treating human chronic eosinophilic leukemia, comprising the step of 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, Serdemetan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601 and pharmaceutically acceptable salts thereof.

[0093] In one embodiment, the present invention relates to a method for treating human chronic eosinophilic leukemia, comprising the step of 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.

[0094] In one embodiment, the present invention relates to a method for treating human chronic myelomonocytic leukemia (CMML), comprising the step of 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).

[0095] In one embodiment, the present invention relates to a method for treating human chronic myelomonocytic leukemia (CMML), comprising the step of 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, Serdemetan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601 and pharmaceutically acceptable salts thereof.

[0096] In one embodiment, the present invention relates to a method for treating human chronic myelomonocytic leukemia (CMML), comprising the step of 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.

[0097] In one embodiment, the present invention relates to a method for treating human atypical chronic myeloid leukemia (aCML), comprising the step of 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).

[0098] In one embodiment, the present invention relates to a method for treating a human with atypical chronic myeloid leukemia (aCML), comprising the step of 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, Serdemetan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof.

[0099] In one embodiment, the present invention relates to a method for treating a human with atypical chronic myeloid leukemia (aCML), comprising the step of 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.

[0100] In one embodiment, the present invention relates to a method for treating a human with juvenile myelomonocytic leukemia (JMML), comprising the step of 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).

[0101] In one embodiment, the present invention relates to a method for treating juvenile myelomonocytic leukemia (JMML) 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 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.

[0102] In one embodiment, the present invention relates to a method for treating juvenile myelomonocytic leukemia (JMML) 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 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.

[0103] In one embodiment, the present invention relates to a method for treating hypereosinophilic syndrome (HES) 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 MDM2 inhibitor is a compound of formula (I) or formula (II).

[0104] In one embodiment, the present invention relates to a method for treating human hypereosinophilic syndrome (HES), comprising the step of 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, Serdemetan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof.

[0105] In one embodiment, the present invention relates to a method for treating human hypereosinophilic syndrome (HES), comprising the step of 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.

[0106] In one embodiment, the present invention relates to a method for treating human myelodysplastic / myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS / MPN-RS-T), comprising the step of 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).

[0107] In one embodiment, the present invention relates to a method for treating myelodysplastic / myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS / MPN-RS-T) 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 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.

[0108] In one embodiment, the present invention relates to a method for treating myelodysplastic / myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS / MPN-RS-T) 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 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.

[0109] In one embodiment, the present invention relates to a method for treating 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 in 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 MPN is selected from the group consisting of: polycythemia vera (PV), myelofibrosis, primary myelofibrosis, thrombocytosis, essential thrombocythemia (ET), congenital 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, the primary myelofibrosis (PMF) is selected from the group consisting of: prefibrotic / 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 myelodysplastic / myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS / MPN-RS-T).

[0110] In one embodiment, the present invention relates to a method for treating 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 in 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: polycythemia vera (PV), primary myelofibrosis, and essential thrombocythemia (ET).

[0111] In one embodiment, the present invention relates to a method for treating 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 in 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 myelodysplastic / myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS / MPN-RS-T).

[0112] In one embodiment, the present invention relates to a method for treating polycythemia vera (PV) 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 in 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.

[0113] In one embodiment, the present invention relates to a method for treating primary myelofibrosis 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 in 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.

[0114] In one embodiment, the present invention relates to a method of treating post-PV myelofibrosis (post-PV MF) 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 in 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.

[0115] In one embodiment, the present invention relates to a method for treating post-essential thrombocythemia myelofibrosis (post-ET MF) 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 in 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.

[0116] In one embodiment, the present invention relates to a method for treating idiopathic thrombocythemia (ET) 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 in 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.

[0117] In one embodiment, the present invention relates to a method for treating MPN in a human, comprising the step of administering to the human a therapeutically effective amount of a composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof in 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 MPN is selected from the group consisting of: polycythemia vera (PV), myelofibrosis, primary myelofibrosis, thrombocytosis, essential thrombocythemia (ET), congenital myelofibrosis, systemic mastocytosis (SM), chronic neutrophilic leukemia (CNL), myelodysplastic syndrome (MDS), and systemic mast cell disease (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, 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. 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: 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 myelodysplastic / myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS / MPN-RS-T).

[0118] In one embodiment, the present invention relates to a method for treating MPN in a human, comprising the step of administering to the human a therapeutically effective amount of a composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof in 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 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, 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.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: 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 myelodysplastic / myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS / MPN-RS-T).

[0119] In one embodiment, the present invention relates to a method for treating polycythemia vera (PV) in a human, comprising the step of administering to the human a therapeutically effective amount of a composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof in 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 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.

[0120] In one embodiment, the present invention relates to a method for treating primary myelofibrosis in a human, comprising the step of administering to the human a therapeutically effective amount of a composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof in 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 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.

[0121] In one embodiment, the present invention relates to a method for treating post-polycythemia vera myelofibrosis (post-PV MF) in a human, comprising the step of administering to the human a therapeutically effective amount of a composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof in 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 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.

[0122] In one embodiment, the present invention relates to a method for treating post-essential thrombocythemia myelofibrosis (post-ET MF) in a human, comprising the step of administering to the human a therapeutically effective amount of a composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof in 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 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.

[0123] In one embodiment, the present invention relates to a method for treating idiopathic thrombocythemia (ET) in a human, comprising the step of administering to the human a therapeutically effective amount of a composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof in 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 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.

[0124] In one embodiment, the present invention relates to a method for treating human chronic neutrophilic leukemia (CNL), comprising the step of administering to the human a therapeutically effective amount of a composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof in 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 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.

[0125] In one embodiment, the present invention relates to a method for treating human chronic eosinophilic leukemia, comprising the step of administering to the human a therapeutically effective amount of a composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof in 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 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.

[0126] In one embodiment, the present invention relates to a method for treating human chronic myelomonocytic leukemia (CMML), comprising the step of administering to the human a therapeutically effective amount of a composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof in 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 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.

[0127] In one embodiment, the present invention relates to a method for treating a human with atypical chronic myeloid leukemia (aCML), comprising the step of administering to the human a therapeutically effective amount of a composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof in 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 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.

[0128] In one embodiment, the present invention relates to a method for treating juvenile myelomonocytic leukemia (JMML) in a human, comprising the step of administering to the human a therapeutically effective amount of a composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof in 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 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.

[0129] In one embodiment, the present invention relates to a method for treating human hypereosinophilic syndrome (HES), comprising the step of administering to the human a therapeutically effective amount of a composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof in 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 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.

[0130] In one embodiment, the present invention relates to a method for treating myelodysplastic / myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS / MPN-RS-T) in a human, comprising the step of administering to the human a therapeutically effective amount of a composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof in 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 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.

[0131] In one embodiment, the present invention relates to the use of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating myeloproliferative neoplasms (MPN), comprising the step of administering to a human one or more doses of the MDM2 inhibitor or a pharmaceutically acceptable salt thereof. In one embodiment, the MPN is selected from the group consisting of: polycythemia vera (PV), myelofibrosis, primary myelofibrosis, thrombocytosis, essential thrombocythemia (ET), congenital 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, the primary myelofibrosis (PMF) is selected from the group consisting of: prefibrotic / 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 myelodysplastic / myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS / MPN-RS-T).

[0132] In one embodiment, the present invention relates to the use of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating myeloproliferative neoplasms (MPN), comprising the step of administering one or more doses of the 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).

[0133] In one embodiment, the present invention relates to the use of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating polycythemia vera (PV), wherein the treatment comprises the step of administering to a human one or more doses of the MDM2 inhibitor or a pharmaceutically acceptable salt thereof.

[0134] In one embodiment, the present invention relates to the use of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating essential thrombocythemia (ET), wherein the treatment comprises the step of administering to a human one or more doses of the MDM2 inhibitor or a pharmaceutically acceptable salt thereof.

[0135] In one embodiment, the present invention relates to the use of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of primary myelofibrosis, wherein the treatment comprises the step of administering to a human one or more doses of the MDM2 inhibitor or a pharmaceutically acceptable salt thereof.

[0136] In one embodiment, the present invention relates to the use of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of post-polycythemia vera myelofibrosis (post-PV MF), wherein the treatment comprises the step of administering to a human one or more doses of the MDM2 inhibitor or a pharmaceutically acceptable salt thereof.

[0137] In one embodiment, the present invention relates to the use of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of post-essential thrombocythemia myelofibrosis (post-ET MF), wherein the treatment comprises the step of administering to a human one or more doses of the MDM2 inhibitor or a pharmaceutically acceptable salt thereof.

[0138] In one embodiment, the present invention relates to the use of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of chronic neutrophilic leukemia (CNL), wherein the treatment comprises the step of administering to a human one or more doses of the MDM2 inhibitor or a pharmaceutically acceptable salt thereof.

[0139] In one embodiment, the present invention relates to the use of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of chronic eosinophilic leukemia, wherein the treatment comprises the step of administering to a human one or more doses of the MDM2 inhibitor or a pharmaceutically acceptable salt thereof.

[0140] In one embodiment, the present invention relates to the use of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of chronic myelomonocytic leukemia (CMML), wherein the treatment comprises the step of administering to a human one or more doses of the MDM2 inhibitor or a pharmaceutically acceptable salt thereof.

[0141] In one embodiment, the present invention relates to the use of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of atypical chronic myeloid leukemia (aCML), wherein the treatment comprises the step of administering to a human one or more doses of the MDM2 inhibitor or a pharmaceutically acceptable salt thereof.

[0142] In one embodiment, the present invention relates to the use of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of juvenile myelomonocytic leukemia (JMML), wherein the treatment comprises the step of administering to a human one or more doses of the MDM2 inhibitor or a pharmaceutically acceptable salt thereof.

[0143] In one embodiment, the present invention relates to the use of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of hypereosinophilic syndrome (HES), wherein the treatment comprises the step of administering to a human one or more doses of the MDM2 inhibitor or a pharmaceutically acceptable salt thereof.

[0144] In one embodiment, the present invention relates to the use of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of myelodysplastic / myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS / MPN-RS-T), wherein the treatment comprises the step of administering to a human one or more doses of the MDM2 inhibitor or a pharmaceutically acceptable salt thereof.

[0145] 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.

[0146] In one embodiment, the present invention relates to the use of a composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating myeloproliferative neoplasms (MPNs), which comprises the step of 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 MPN is selected from the group consisting of: polycythemia vera (PV), myelofibrosis, primary myelofibrosis, thrombocytosis, essential thrombocythemia (ET), congenital 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, the primary myelofibrosis (PMF) is selected from the group consisting of: prefibrotic / 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 myelodysplastic / myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS / MPN-RS-T).

[0147] In one embodiment, the present invention relates to the use of a composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating myeloproliferative neoplasms (MPNs), comprising the step of 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 in the preparation of a medicament for treating polycythemia vera (PV), wherein the treatment comprises the step of 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 in the preparation of a medicament for treating essential thrombocythemia (ET), wherein the treatment comprises the step of 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 in the preparation of a medicament for treating primary myelofibrosis, wherein the treatment comprises the step of 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 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.

[0148] In one embodiment, the present invention relates to an MDM2 inhibitor or a pharmaceutically acceptable salt thereof for treating myeloproliferative neoplasms (MPNs). In one embodiment, the MPN is selected from the group consisting of: polycythemia vera (PV), myelofibrosis, primary myelofibrosis, thrombocytosis, essential thrombocythemia (ET), congenital 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, the primary myelofibrosis (PMF) is selected from the group consisting of: prefibrotic / 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 myelodysplastic / myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS / MPN-RS-T).

[0149] In one embodiment, the present invention relates to an MDM2 inhibitor or a pharmaceutically acceptable salt thereof for treating polycythemia vera (PV). In one embodiment, the present invention relates to an MDM2 inhibitor or a pharmaceutically acceptable salt thereof for treating primary myelofibrosis. In one embodiment, the present invention relates to an MDM2 inhibitor or a pharmaceutically acceptable salt thereof for 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, 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.

[0150] The above method can be used as a first-line cancer therapy or after treatment with conventional chemotherapeutic active pharmaceutical ingredients (including cyclophosphamide, fludarabine (FC chemotherapy) and chlorambucil).

[0151] 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 congenital myelofibrosis) and primary myelofibrosis secondary to polycythemia vera or essential thrombocythemia, which comprises the step of administering a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof.

[0152] 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 congenital myelofibrosis) and primary myelofibrosis secondary to polycythemia vera or essential thrombocythemia, which comprises the step of administering a therapeutically effective amount of a composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof.

[0153] In one embodiment, the present invention relates to a method for treating 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, and 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, 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.

[0154] In one embodiment, the present invention relates to a method for treating 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, and 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, 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.

[0155] In one embodiment, the present invention relates to a method for treating 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, and 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. 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.

[0156] In one embodiment, the present invention relates to a method for treating 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, and wherein the therapeutically effective amount is 120 mg 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, 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.

[0157] The MDM2 inhibitor or a pharmaceutically acceptable salt thereof can also be used in combination with radiotherapy, hormone therapy, surgery, and immunotherapy for the treatment of MPNs, which are well-known to those skilled in the art. The MPNs are selected from the group consisting of: polycythemia vera (PV), myelofibrosis, primary myelofibrosis, thrombocytosis, essential thrombocythemia (ET), congenital 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: prefibrotic / early PMF and overt fibrotic PMF. In one embodiment, the MPNs are 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 myelodysplastic / myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS / MPN-RS-T).

[0158] Method for treating chronic myeloid leukemia (CML) and acute myeloid leukemia (AML)

[0159] The present invention relates to a method for treating chronic myeloid leukemia (CML), comprising the step of administering to a person in need thereof a murine 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, 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. 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 person according to the "Dose and Administration Regimen" section.

[0160] The present invention relates to the use of murine double minute 2 homolog (MDM2) inhibitors or pharmaceutically acceptable salts thereof for the treatment of chronic myelogenous 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, 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. 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 "Dose and Administration Regimen" section.

[0161] The present invention relates to a method for treating acute myeloid leukemia (AML), comprising the step of administering to a person in need a murine 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, 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. 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 person according to the "Dose and Administration Regimen" section.

[0162] The present invention relates to the use of mouse double minute 2 homolog (MDM2) inhibitors or pharmaceutically acceptable salts thereof for the treatment of 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, 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. 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 "Dose and Administration" section.

[0163] Method for treating chronic Merkel cell carcinoma

[0164] The present invention relates to a method for treating Merkel cell carcinoma (MCC), which comprises the step of administering to a person in need thereof a murine 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, 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. 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 person according to the "Dose and Administration Regimen" section.

[0165] The present invention relates to the use of murine double minute 2 homolog (MDM2) inhibitors or pharmaceutically acceptable salts thereof for the treatment of 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, 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. 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 "Dose and Administration Regimen" section.

[0166] MDM2 inhibitor

[0167] The compound of formula (I) has the structure and name as shown below.

[0168] 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:

[0169]

[0170] The synthesis of the compound of formula (I) is described in 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.

[0171] In one embodiment, the compound of formula (I) or formula (II) is in an amorphous form. In one embodiment, the MDM2 inhibitor is a crystalline form of the compound of formula (I) or formula (II). In one embodiment, the MDM2 inhibitor is a crystalline anhydrous form of the compound of formula (I). In one embodiment, the MDM2 inhibitor is a crystalline anhydrous form of the compound of formula (I), characterized by a powder X-ray diffraction pattern that includes peaks at diffraction angles 2θ degrees of about 11.6, 12.4, 18.6, 19.0, 21.6, and 23.6. In one embodiment, the MDM2 inhibitor is a crystalline anhydrous form of the compound of formula (I) that has substantially as Figure 1 the X-ray diffraction pattern shown. The method for preparing such crystalline forms is disclosed in International Application WO2014200937, the disclosure of which is incorporated herein by reference in its entirety.

[0172] In one embodiment, the MDM2 inhibitor is a compound of formula (II) having the structure and name shown below.

[0173]

[0174] (II)

[0175] 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)acetamido)-2-methoxybenzoic acid

[0176] The synthesis of the compound of formula (II) is described in U.S. Patent No. 8,952,036, the disclosure of which is incorporated herein by reference in its entirety.

[0177] RG7388 (Idasanutlin)

[0178] In one embodiment, the MDM2 inhibitor is RG7388. RG7388 has the chemical structure shown below

[0179] Triptolide (PG490)

[0180] In one embodiment, the MDM2 inhibitor is triptolide. Triptolide has the chemical structure and name shown below:

[0181] (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-decahydrotri(oxireno)[2',3':4b,5;2”,3”:6,7;2”',3”':8a,9]phenanthro[1,2-c]furan-3(1H)-one

[0182]

[0183] Nutlin-3a

[0184] In one embodiment, the MDM2 inhibitor is Nutlin-3a. Nutlin-3a has the chemical structure and name shown below:

[0185] 4-[(4S,5R)-4,5-Bis(4-chlorophenyl)-2-(4-methoxy-2-propan-2-yloxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazin-2-one

[0186]

[0187] HDM201

[0188] In one embodiment, the MDM2 inhibitor is HDM201. HDM201 has the chemical structure and name shown below:

[0189] (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

[0190]

[0191] RG7112

[0192] In one embodiment, the MDM2 inhibitor is RG7112. RG7112 has the chemical structure and name as shown below:

[0193] [(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

[0194]

[0195] CGM097A

[0196] In one embodiment, the MDM2 inhibitor is CGM097A. CGM097A has the chemical structure and name as shown below:

[0197] (1S)-1-(4-chlorophenyl)-6-methoxy-2-[4-[methyl-[[4-(4-methyl-3-oxopiperazin-1-yl)cyclohexyl]methyl]amino]phenyl]-7-prop-2-yloxy-1,4-dihydroisoquinolin-3-one

[0198]

[0199] Nutlin-3

[0200] In one embodiment, the MDM2 inhibitor is nutlin-3. nutlin-3 has the chemical structure and name as shown below:

[0201] 4-[4,5-bis(4-chlorophenyl)-2-(4-methoxy-2-prop-2-yloxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazin-2-one

[0202]

[0203] SJ-172550

[0204] In one embodiment, the MDM2 inhibitor is SJ-172550. SJ-172550 has the chemical structure and name as shown below:

[0205] Methyl 2-[2-chloro-6-ethoxy-4-[(3-methyl-5-oxo-1-phenylpyrazol-4-ylidene)methyl]phenoxy]acetate

[0206]

[0207] SAR405838 (MI-77301)

[0208] In one embodiment, the MDM2 inhibitor is SAR405838. SAR405838 has the chemical structure and name shown below:

[0209] (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

[0210]

[0211] MI-773

[0212] In one embodiment, the MDM2 inhibitor is MI-773. MI-773 has the chemical structure and name shown below:

[0213] (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

[0214]

[0215] MX69

[0216] In one embodiment, the MDM2 inhibitor is MX69. MX69 has the chemical structure and name shown below:

[0217] 4-[8-[(3,4-dimethylphenyl)sulfamoyl]-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-4-yl]benzoic acid

[0218]

[0219] YH239-EE

[0220] In one embodiment, the MDM2 inhibitor is YH239-EE. YH239-EE has the chemical structure and name shown below:

[0221] Ethyl 3-[2-(tert-butylamino)-1-[(4-chlorophenyl)methyl-formylamino]-2-oxoethyl]-6-chloro-1H-indole-2-carboxylate

[0222]

[0223] RO8994

[0224] In one embodiment, the MDM2 inhibitor is RO8994. RO8994 has the chemical structure and name as shown below:

[0225] (2'R,3R,3'S,5'S)-N-(4-carbamoyl-2-methoxyphenyl)-6-chloro-3'-(3-chloro-2-fluorophenyl)-5'-(2,2-dimethylpropyl)-2-oxospiro[1H-indole-3,4'-pyrrolidine]-2'-carboxamide

[0226]

[0227] Nutlin-3b

[0228] In one embodiment, the MDM2 inhibitor is nutlin-3b. nutlin-3b has the chemical structure and name as shown below:

[0229] 4-[(4R,5S)-4,5-bis(4-chlorophenyl)-2-(4-methoxy-2-prop-2-yloxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazin-2-one

[0230]

[0231] Serdemetan (JNJ-26854165)

[0232] In one embodiment, the MDM2 inhibitor is Serdemetan. Serdemetan has the chemical structure and name as shown below:

[0233] 1-N-[2-(1H-indol-3-yl)ethyl]-4-N-pyridin-4-ylbenzene-1,4-diamine

[0234]

[0235] NSC59984

[0236] In one embodiment, the MDM2 inhibitor is NSC59984. NSC59984 has the chemical structure and name as shown below:

[0237] (E)-1-(4-methylpiperazin-1-yl)-3-(5-nitrofuran-2-yl)prop-2-en-1-one

[0238]

[0239] CHEMBL2386350

[0240] In one embodiment, the MDM2 inhibitor is CHEMBL2386350. CHEMBL2386350 has the chemical structure and name shown below:

[0241] 2-[4-[(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis(4-chlorophenyl)-4,5-dimethylimidazol-1-ylcarbonyl]piperazin-1-yl]-1-morpholin-4-yl-ethanone

[0242]

[0243] CGM0970B

[0244] In one embodiment, the MDM2 inhibitor is CGM0970B. CGM0970B has the chemical structure and name shown below:

[0245] (1R)-1-(4-chlorophenyl)-6-methoxy-2-[4-[methyl-[[4-(4-methyl-3-oxopiperazin-1-yl)cyclohexyl]methyl]amino]phenyl]-7-prop-2-yloxy-1,4-dihydroisoquinolin-3-one

[0246]

[0247] MK-8242

[0248] In one embodiment, the MDM2 inhibitor is MK-8242. MK-8242 has the chemical structure and name shown below:

[0249] 4-amino-1-[(2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one

[0250]

[0251] DS-3032

[0252] In one embodiment, the MDM2 inhibitor is DS-3032. DS-3032 has the chemical structure and name shown below:

[0253] (3'R,4'S,5'R)-N-((3R,6S)-6-carbamoyl-tetrahydro-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'-carboxamide

[0254]

[0255] DS-3032B

[0256] In one embodiment, the MDM2 inhibitor is DS-3032B. DS-3032B has the chemical structure and name shown below:

[0257] (3'R,4'S,5'R)-N-((3R,6S)-6-carbamoyl-tetrahydro-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'-carboxamide 4-methylbenzenesulfonate

[0258]

[0259] HDM201

[0260] In one embodiment, the MDM2 inhibitor is HDM201. HDM201 has the chemical structure and name shown below:

[0261] (4S)-5-(5-chloro-1-methyl-2-oxopyridin-3-yl)-4-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-3-prop-2-yl-4H-pyrrolo[3,4-d]imidazol-6-one

[0262]

[0263] APG-115

[0264] In one embodiment, the MDM2 inhibitor is APG-115. APG-115 has the chemical structure and name shown below:

[0265] 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

[0266]

[0267] MI-1061

[0268] In one embodiment, the MDM2 inhibitor is APG-115. APG-115 has the chemical structure and name shown below:

[0269] 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

[0270]

[0271] Pharmaceutical composition

[0272] In some embodiments, the present invention provides a pharmaceutical composition for treating cancer, comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from the group consisting of: cancers 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 cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer, head and neck cancer, and skin cancer (including basal and squamous cell carcinoma, melanoma skin cancer, Merkel cell carcinoma, Kaposi sarcoma, cutaneous lymphoma); hematopoietic tumors of lymphoid lineage (including leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, and Burkitt lymphoma); hematopoietic tumors of myeloid lineage (including acute and chronic myelogenous leukemia, myelodysplastic syndrome, and promyelocytic leukemia); tumors of mesenchymal origin (including fibrosarcoma and rhabdomyosarcoma and other sarcomas, such as soft tissue and bone); tumors of the central and peripheral nervous systems (including astrocytoma, neuroblastoma, glioma, glioblastoma, and schwannoma); and other tumors (including melanoma, 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, 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.

[0273] In some embodiments, the present invention provides a pharmaceutical composition for treating myeloproliferative neoplasms (MPNs) comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the MPNs are selected from the group consisting of: polycythemia vera (PV), myelofibrosis, primary myelofibrosis, thrombocytosis, essential thrombocythemia (ET), congenital myelofibrosis, systemic mastocytosis (SM), chronic neutrophilic leukemia (CNL), myelodysplastic syndrome (MDS), and systemic mast cell disease (SMCD), and 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, Serdemetan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof.

[0274] In some embodiments, the present invention provides a pharmaceutical composition for treating chronic myelogenous leukemia (CML) comprising 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, Serdemetan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof.

[0275] In some embodiments, the present invention provides a pharmaceutical composition for treating acute myeloid leukemia (AML) comprising 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, Serdemetan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601 and pharmaceutically acceptable salts thereof.

[0276] In some embodiments, the present invention provides a pharmaceutical composition for treating Merkel cell carcinoma (MCC) comprising 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, Serdemetan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601 and pharmaceutically acceptable salts thereof.

[0277] In some embodiments, the present invention provides a pharmaceutical composition for treating myeloproliferative neoplasms (MPN) comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the MPN is selected from the group consisting of: polycythemia vera (PV), myelofibrosis, primary myelofibrosis, thrombocytosis, essential thrombocythemia (ET), congenital 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: 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.

[0278] 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 for treating myeloproliferative neoplasms (MPNs) comprising 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, primary myelofibrosis, thrombocytosis, essential thrombocythemia (ET), congenital myelofibrosis, systemic mastocytosis (SM), chronic neutrophilic leukemia (CNL), myelodysplastic syndrome (MDS), and systemic mast cell disease (SMCD).

[0279] In some embodiments, the present invention provides a pharmaceutical composition for treating myeloproliferative neoplasms (MPNs) comprising 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), essential thrombocythemia (ET), and primary myelofibrosis.

[0280] In some embodiments, the present invention provides a pharmaceutical composition for treating polycythemia vera (PV) comprising a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof.

[0281] In some embodiments, the present invention provides a pharmaceutical composition for treating polycythemia vera (PV) comprising 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, Serdemetan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof.

[0282] In some embodiments, the present invention provides a pharmaceutical composition for treating polycythemia vera (PV) comprising 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.

[0283] In some embodiments, the present invention provides a pharmaceutical composition for treating essential thrombocythemia (ET) comprising a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof.

[0284] In some embodiments, the present invention provides a pharmaceutical composition for treating essential thrombocythemia (ET) comprising 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, Serdemetan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof.

[0285] In some embodiments, the present invention provides a pharmaceutical composition for treating essential thrombocythemia (ET) comprising 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.

[0286] In some embodiments, the present invention provides a pharmaceutical composition for treating primary myelofibrosis comprising a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof.

[0287] In some embodiments, the present invention provides a pharmaceutical composition for treating primary myelofibrosis, comprising 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, Serdemetan, NSC59984, CHEMBL2386350, MK-8242, DS-3032, DS-3032B, APG-115, MI-1601, and pharmaceutically acceptable salts thereof.

[0288] In some embodiments, the present invention provides a pharmaceutical composition for treating primary myelofibrosis, comprising 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.

[0289] 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).

[0290] The pharmaceutical composition is generally formulated to provide a therapeutically effective amount of the MDM2 inhibitor or a pharmaceutically acceptable salt thereof. If desired, the pharmaceutical composition contains its pharmaceutically acceptable salts and / or coordination complexes, as well as one or more pharmaceutically acceptable excipients, carriers (including inert solid diluents and fillers), diluents (including sterile aqueous solutions and various organic solvents), penetration enhancers, solubilizers, and adjuvants. If desired, in addition to the MDM2 inhibitor or a pharmaceutically acceptable salt thereof, other ingredients may be incorporated into the formulation, or the two components may be formulated as separate formulations for use alone or in combination simultaneously.

[0291] In the selected embodiments, the concentration of the MDM2 inhibitor or a pharmaceutically acceptable salt thereof provided in the pharmaceutical composition of the present invention is lower 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.

[0292] In the selected embodiments, the concentration of the MDM2 inhibitor or its pharmaceutically acceptable salt provided in the pharmaceutical composition of the present invention is independently greater than 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%, 8.25%, 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.

[0293] In the selected embodiments, the concentration range of the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is independently from about 0.0001% to about 50%, from about 0.001% to about 40%, from about 0.01% to about 30%, from about 0.02% to about 29%, from about 0.03% to about 28%, from about 0.04% to about 27%, from about 0.05% to about 26%, from about 0.06% to about 25%, from about 0.07% to about 24%, from about 0.08% to about 23%, from about 0.09% to about 22%, from about 0.1% to about 21%, from about 0.2% to about 20%, from about 0.3% to about 19%, from about 0.4% to about 18%, from about 0.5% to about 17%, from about 0.6% to about 16%, from about 0.7% to about 15%, from about 0.8% to about 14%, from about 0.9% to about 12% or from about 1% to about 10% w / w, w / v or v / v.

[0294] In the selected embodiments, the concentration range of the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is independently from about 0.001% to about 10%, from about 0.01% to about 5%, from about 0.02% to about 4.5%, from about 0.03% to about 4%, from about 0.04% to about 3.5%, from about 0.05% to about 3%, from about 0.06% to about 2.5%, from about 0.07% to about 2%, from about 0.08% to about 1.5%, from about 0.09% to about 1%, from about 0.1% to about 0.9% w / w, w / v or v / v.

[0295] In the 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.

[0296] In the selected embodiments, the amount of the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is independently greater than 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.

[0297] The MDM2 inhibitor or a pharmaceutically acceptable salt thereof is effective over a wide dosage range. For example, in the treatment of adults, dosages in the ranges independently of 0.01 to 1000 mg, 0.5 to 100 mg, 1 to 50 mg per day and 5 to 40 mg per day are examples of dosages that can be used. The exact dosage will depend on the route of administration, the form of the compound administered, the sex and age of the subject to be treated, the weight of the subject to be treated, and the preference and experience of the attending physician.

[0298] The following describes non-limiting exemplary pharmaceutical compositions and methods for their preparation.

[0299] Pharmaceutical composition for oral administration

[0300] In the selected embodiments, the present invention provides an orally administered pharmaceutical composition comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof and a pharmaceutical excipient suitable for oral administration.

[0301] In selected embodiments, the present invention provides a solid pharmaceutical composition for oral administration, comprising: (i) a combined 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 contains (iii) an effective amount of at least one additional active ingredient.

[0302] In selected embodiments, the pharmaceutical composition can be a liquid pharmaceutical composition suitable for oral administration. The pharmaceutical compositions of the present invention suitable for oral administration can exist in a dispersed dosage form, such as capsules, cachets or tablets, or liquids or sprays, each containing a predetermined amount of the active ingredient, which is in the form of a powder or granules, a solution or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion. These dosage forms can be prepared by any method, but all methods include the step of combining the active ingredient with a carrier, which constitutes one or more essential ingredients. Generally, the composition is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired appearance. For example, tablets can be prepared by compressing or molding, optionally with one or more auxiliaries. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with excipients, which are, for example but not limited to, binders, lubricants, inert diluents and / or surfactants or dispersants. Molded tablets can be prepared by molding a mixture of a powdered compound moistened with an inert liquid diluent in a suitable machine.

[0303] The present invention further includes anhydrous pharmaceutical compositions and dosage forms, since water can promote the degradation of some compounds. For example, in the pharmaceutical field, water (e.g., 5%) can be added as a means of simulating long-term storage in order to determine characteristics such as the shelf life or stability of a formulation over time. The anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low-moisture ingredients and low-moisture or low-humidity conditions. If significant exposure to 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. The anhydrous pharmaceutical compositions can be prepared and stored such that their anhydrous nature is maintained. Thus, the anhydrous compositions can be packaged using materials known to prevent exposure to water, such that they can be included in a suitable formulation kit. Examples of suitable packaging include but are not limited to airtight sealed foils, plastics, etc., unit dose containers, blister packs and strip packs.

[0304] An MDM2 inhibitor or a pharmaceutically acceptable salt thereof can be combined in a tight mixture with a pharmaceutical carrier according to conventional pharmaceutical mixing techniques. The carrier can take a variety of forms, depending on the desired form of the formulation to be administered. In preparing a composition for an oral dosage form, in the case of an oral liquid preparation (such as a suspension, solution, and elixir) or an aerosol, any common pharmaceutical medium can be used as the carrier, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc.; or in some embodiments without using lactose, in the case of an oral solid preparation, carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrants can be used. For example, in the case of a solid oral preparation, suitable carriers include powders, capsules, and tablets. If desired, the tablets can be coated by standard aqueous or non-aqueous techniques.

[0305] Binders suitable for 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 gum arabic, sodium alginate, alginic acid, other alginates, tragacanth, guar gum, cellulose and its derivatives (such as ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures thereof.

[0306] Examples of suitable fillers for the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (such as granules or powders), microcrystalline cellulose, powdered cellulose, dextrose, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0307] 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 may result in tablets that disintegrate in the bottle. Too little may not be sufficient to cause disintegration, thus altering the rate and extent of release of the active ingredient from the dosage form. Therefore, an amount of disintegrant that is neither too little nor too much to adversely alter the release of the active ingredient can be used to form the dosage forms of the compounds disclosed herein. The amount of disintegrant used can vary depending on the type of formulation and the mode of administration and can be readily discerned by one of ordinary skill in the art. About 0.5 to about 15% by weight of disintegrant, or about 1 to about 5% by weight of disintegrant, can be used in the pharmaceutical composition. Disintegrants that can be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, potassium polacrilate, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starch, other starches, clays, other algae, other celluloses, gums, or mixtures thereof.

[0308] Lubricants useful in forming 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 (such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethylaureate, agar, or mixtures thereof. Additional lubricants include, for example, syloid silica gel, coagulated aerosol of synthetic silica, or mixtures thereof. The lubricant may be optionally added in an amount less than about 1% by weight of the pharmaceutical composition.

[0309] When aqueous suspensions and / or elixirs for oral administration are desired, the essential active ingredient therein can be combined with various sweetening or flavoring agents, coloring agents or dyes, and, if desired, with emulsifying and / or suspending agents, as well as diluents such as water, ethanol, propylene glycol, glycerin, and various combinations thereof.

[0310] Tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period of time. For example, time delay materials such as glyceryl monostearate or glyceryl distearate can be used. Preparations for oral use may also be in the form of hard gelatin capsules wherein 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 wherein the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil.

[0311] Surfactants useful in forming 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, mixtures of hydrophilic surfactants can be used, mixtures of lipophilic surfactants can be used, or mixtures of at least one hydrophilic surfactant and at least one lipophilic surfactant can be used.

[0312] Suitable hydrophilic surfactants can generally have an HLB value of at least 10, while suitable lipophilic surfactants can generally have an HLB value equal to or less than about 10. The empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of nonionic amphiphilic compounds is the hydrophilic-lipophilic balance value ("HLB" value). Surfactants with lower HLB values are more lipophilic or hydrophobic and can have greater solubility in oil, 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 scale generally does not apply. 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 generally used to enable the formulation of industrial, pharmaceutical, and cosmetic emulsions.

[0313] Hydrophilic surfactants can be ionic or nonionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidates; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glycerol ester derivatives of amino acids, oligopeptides, and polypeptides; lecithin and hydrogenated lecithin; lysophosphatidylcholine and hydrogenated lysophosphatidylcholine; phospholipids and their derivatives; lysophospholipids and their derivatives; carnitine fatty acid ester salts; salts of alkyl sulfates; fatty acid salts; sodium docusate; acyl acrylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citrate esters of mono- and di-glycerides; and mixtures thereof.

[0314] Among the above groups, ionic surfactants include, for example: lecithin, lysophosphatidylcholine, phospholipids, lysophospholipids and their derivatives; carnitine fatty acid ester salts; salts of alkyl sulfates; fatty acid salts; sodium docusate; acyl acrylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citrate esters of mono- and di-glycerides; and mixtures thereof.

[0315] Ionic surfactants can be lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactates of fatty acids, stearoyl-2-lactate, stearoyl lactate, succinylated monoglycerides, mono / diacetylated tartaric acid esters of mono / diglycerides, citric acid esters of mono / diglycerides, cholesteryl sarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, tetradecyl sulfate, dioctyl sulfosuccinate, lauroyl carnitine, palmitoyl carnitine, myristoyl carnitine and the ionized forms of their salts and mixtures.

[0316] Hydrophilic nonionic surfactants can include, but are not limited to, alkyl glucosides; alkyl maltosides; alkyl thio glucosides; lauryl polyoxyethylene glycerol esters; polyoxyalkylene alkyl ethers, such as polyethylene glycol alkyl ethers; polyoxyalkylene alkyl phenols, such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol 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 fatty acid esters; hydrophilic transesterification products of polyols with at least one member of the group consisting of glycerol esters, 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 polyols with at least one member of the group consisting of triglycerides, vegetable oils and hydrogenated vegetable oils. The polyol can be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol or sugar.

[0317] 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 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, 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 caprylic / capric glycerides, PEG-8 caprylic / capric glycerides, polyglyceryl 10 laurate, PEG-30 cholesterol, PEG-25 phytosterol, PEG-30 stigmasterol, 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.

[0318] Suitable lipophilic surfactants include (by way of example only): 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 mono- and di-glycerides; hydrophobic transesterification products of polyols with at least one member of the group consisting of glycerol esters, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins / vitamin derivatives; and mixtures thereof. Among 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.

[0319] In one embodiment, the composition may include solubilizers to ensure good solubilization and / or dissolution of the compounds of the present invention and to minimize precipitation of the compounds of the present invention. This may be particularly important for compositions for non-oral use, such as for injectable compositions. Solubilizers may also be added to increase the solubility of hydrophilic drugs and / or other components such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.

[0320] 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, butylene glycol and its isomers, 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 with an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (tetraglycol) or methoxy PEG; amides and other nitrogen-containing compounds, such as 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidones, N-hydroxyalkylpyrrolidones, N-alkylpiperidones, N-alkylcaprolactams, dimethylacetamide and polyvinylpyrrolidone; esters, such as ethyl propionate, tributyl citrate, triethyl acetylcitrate, tributyl acetylcitrate, triethyl citrate, ethyl oleate, ethyl caprylate, 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, monocaprylin, diethylene glycol monoethyl ether and water.

[0321] Mixtures of solubilizers can also be used. Examples include but are not limited to triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropyl cyclodextrin, ethanol, polyethylene glycol 200 - 100, tetraethylene glycol, diethylene glycol monoethyl ether, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethanol, PEG-400, tetraethylene glycol, and propylene glycol.

[0322] The amount of solubilizer that can be included is not particularly limited. The amount of a given solubilizer can be limited to a biologically acceptable amount, which can be readily determined by those skilled in the art. In some cases, it may be advantageous to include an amount of solubilizer far in excess of the biologically acceptable amount, for example to maximize the concentration of the drug and remove the excess solubilizer before administering the composition to a patient using conventional techniques such as distillation or evaporation. Thus, if present, the weight ratio of the solubilizer can be 10 wt%, 25 wt%, 50 wt%, 100 wt% or up to about 200 wt% based on the total weight of the drug and other excipients. If desired, very small amounts of solubilizer can also be used, such as 5%, 2%, 1% or even less. Generally, the solubilizer can be present in an amount of about 1 wt% to about 100 wt%, more typically about 5 wt% to about 25 wt%.

[0323] The composition can further include one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include but are not limited to: anti-adhesives, anti-foaming agents, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity regulators, tonicity regulators, flavoring agents, coloring agents, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0324] Alternatively, an acid or a base can be incorporated into the composition to facilitate processing, enhance stability or for other uses. 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 dihydrate, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS), etc. Also suitable are bases that are salts of pharmaceutically acceptable acids, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkane sulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinoline sulfonic 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, mercaptoacetic acid, toluenesulfonic acid, uric acid, etc. Salts of polybasic acids can also be used, such as sodium phosphate, disodium hydrogen phosphate and sodium dihydrogen phosphate. When the base is a salt, the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals and alkaline earth metals. Examples can include but are not limited to sodium, potassium, lithium, magnesium, calcium and ammonium.

[0325] 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, etc. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkane sulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinoline sulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, p-bromobenzenesulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, mercaptoacetic acid, toluenesulfonic acid and uric acid.

[0326] Pharmaceutical composition for injection

[0327] In selected embodiments, the present invention provides a pharmaceutical composition for injection comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient suitable for injection. The components and amounts of the reagents in the composition are as described herein.

[0328] Forms that can be incorporated into the compositions of the present invention for administration by injection include aqueous or oily suspensions or emulsions having sesame oil, corn oil, cottonseed oil or peanut oil, as well as elixirs, mannitol, dextrose or sterile aqueous solutions and similar pharmaceutical vehicles.

[0329] Aqueous solutions in saline are also commonly used for injection. Ethanol, glycerol, propylene glycol, and liquid polyethylene glycol (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be used. Appropriate fluidity can be maintained, for example, by using coatings such as lecithin to maintain the desired particle size in the case of dispersions, and by using surfactants. The action of microorganisms can be prevented by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and thimerosal.

[0330] A sterile injectable solution is prepared by incorporating the required amount of the MDM2 inhibitor or a pharmaceutically acceptable salt thereof with the various other ingredients enumerated above as required into a suitable solvent, and then filtering and sterilizing. Generally, a dispersion is prepared by incorporating the various sterilized active ingredients into a sterile vehicle, which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, certain desired preparation methods are vacuum drying and freeze-drying techniques, which yield a powder of the active ingredient and any other required ingredients from its previously sterile filtered solution.

[0331] Administration of the MDM2 inhibitor or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of these compounds can be achieved by any method capable of delivering the compound to the site of action. These methods include oral route, duodenal route, parenteral injection (including intravenous, arterial, subcutaneous, intramuscular, intra-arterial, intraperitoneal, or infusion), topical (e.g., transdermal application), rectal administration, local delivery through a catheter or stent, or by inhalation. Combinations of the compounds can also be administered intralipid or intrathecally.

[0332] Exemplary parenteral administration forms include solutions or suspensions of the active compound in a sterile aqueous solution such as an aqueous propylene glycol solution or a dextrose solution. If desired, such dosage forms can be appropriately buffered.

[0333] The present invention also provides a kit. The kit includes an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, either alone or in combination in a suitable package, and written materials which may include instructions for use, discussions of clinical studies, and lists of side effects. Such kits may also include information indicating or determining the activity and / or advantages and / or describing the dosage, administration, side effects, drug interactions, or other information useful to a health care provider, such as scientific literature references, package insert materials, clinical trial results, and / or summaries of these, etc. Such information may be based on the results of various studies, for example, studies using experimental animals involving in vivo models and studies based on human clinical trials. The kit may further contain another active pharmaceutical ingredient. Suitable packages and other articles for use (e.g., measuring cups for liquid formulations, foil packaging for minimizing exposure to air, etc.) are known in the art and may be included in the kit. The kits described herein may be provided, sold, and / or promoted to health care providers including physicians, nurses, pharmacists, prescribing officers, etc. In selected embodiments, the kits may also be sold directly to consumers. In one embodiment, the present invention provides a kit for treating MPN comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof. 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 for treating chronic myelogenous leukemia (CML) comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention provides a kit for treating acute myelogenous leukemia (AML) comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention provides a kit for treating Merkel cell carcinoma (MCC) comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof.

[0334] Dosage and administration regimen

[0335] The dosage of the MDM2 inhibitor or a pharmaceutically acceptable salt thereof will depend on the person being treated, the severity of the condition or disorder, the rate of administration, the disposition of the compound, and the judgment of the prescribing physician. However, in single or divided doses, an effective dosage range is from about 0.001 to about 100 mg per kilogram of body weight per day, such as about 1 to about 35 mg / kg / day. For a 70 kg person, this would correspond to about 0.05 to 7 g / day, such as about 0.05 to about 2.5 g / day. In some cases, dosage levels below the lower limit of the above range may be sufficient, while in other cases, larger doses may still be employed without causing any harmful side effects - for example, dividing such larger doses into several smaller doses for administration throughout the day.

[0336] In some embodiments, the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered as a single dose. Generally, such administration will be by injection - for example, intravenous injection - in order to rapidly introduce the agent. However, other routes may be appropriately used. The single dose of the MDM2 inhibitor or a pharmaceutically acceptable salt thereof can also be used to treat acute conditions.

[0337] 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 in multiple doses by injection - for example, intravenous injection. In one embodiment, the administration can be once, twice, three times, four times, five times, six times or more than six times a day. In one embodiment, the administration can 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, once every two days, 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 a day, while in other embodiments, it is administered twice a day, and in other embodiments, it is administered three times a day. In some embodiments, the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered three times a week (including on Mondays, Wednesdays and Fridays).

[0338] The MDM2 inhibitor or a pharmaceutically acceptable salt thereof can be administered continuously as needed. In some embodiments, the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered for more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 days or more. In some embodiments, the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered for less than 28, 14, 7, 6, 5, 4, 3, 2 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 chronically on a continuous basis, for example, for the treatment of chronic effects. In another embodiment, the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered for less than about 7 days. In yet another embodiment, the administration continues for more than about 6, 10, 14, 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, the administration continues for more than about one year, two years, three years, four years or five years. In some embodiments, continuous administration can be achieved and maintained as long as needed.

[0339] In some embodiments, the effective dose range of the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is from about 1 mg to about 500 mg, from about 10 mg to about 300 mg, from about 20 mg to about 250 mg, from about 25 mg to about 200 mg, from about 10 mg to about 200 mg, from about 20 mg to about 150 mg, from about 30 mg to about 120 mg, from about 10 mg to about 90 mg, from about 20 mg to about 80 mg, from about 30 mg to about 70 mg, from about 40 mg to about 60 mg, from about 45 mg to about 55 mg, from about 48 mg to about 52 mg, from about 50 mg to about 150 mg, from about 60 mg to about 140 mg, from about 70 mg to about 130 mg, from about 80 mg to about 120 mg, from about 90 mg to about 110 mg, from about 95 mg to about 105 mg, from about 150 mg to about 250 mg, from about 160 mg to about 240 mg, from about 170 mg to about 230 mg, from about 180 mg to about 220 mg, from about 190 mg to about 210 mg, from about 195 mg to about 205 mg, or from about 198 to about 202 mg. 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 the 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.

[0340] In some embodiments, the effective dose range of the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is from about 0.01 mg / kg to about 4.3 mg / kg, from about 0.15 mg / kg to about 3.6 mg / kg, from about 0.3 mg / kg to about 3.2 mg / kg, from about 0.35 mg / kg to about 2.85 mg / kg, from about 0.15 mg / kg to about 2.85 mg / kg, from about 0.3 mg to about 2.15 mg / kg, from about 0.45 mg / kg to about 1.7 mg / kg, from about 0.15 mg / kg to about 1.3 mg / kg, from about 0.3 mg / kg to about 1.15 mg / kg, from about 0.45 mg / kg to about 1 mg / kg, from about 0.55 mg / kg to about 0.85 mg / kg, from about 0.65 mg / kg to about 0.8 mg / kg, from about 0.7 mg / kg to about 0.75 mg / kg, from about 0.7 mg / kg to about 2.15 mg / kg, from about 0.85 mg / kg to about 2 mg / kg, from about 1 mg / kg to about 1.85 mg / kg, from about 1.15 mg / kg to about 1.7 mg / kg, from about 1.3 mg / kg to about 1.6 mg / kg, from about 1.35 mg / kg to about 1.5 mg / kg, from about 2.15 mg / kg to about 3.6 mg / kg, from about 2.3 mg / kg to about 3.4 mg / kg, from about 2.4 mg / kg to about 3.3 mg / kg, from about 2.6 mg / kg to about 3.15 mg / kg, from about 2.7 mg / kg to about 3 mg / kg, from about 2.8 mg / kg to about 3 mg / kg or from 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.

[0341] In some embodiments, the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered at a dose of 10 to 500 mg BID, including doses 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 BID.

[0342] In some embodiments, the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered at a dose of 10 to 500 mg QD, including doses 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 QD.

[0343] An effective amount of the MDM2 inhibitor or a pharmaceutically acceptable salt thereof can be administered by any acceptable route of administration of a reagent having a similar effect (including buccal, sublingual, and transdermal routes), by intraarterial injection, intravenously, parenterally, intramuscularly, subcutaneously, or orally, in a single dose or multiple doses.

[0344] In some embodiments, the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered intermittently to a subject, referred to as intermittent administration. "Intermittent administration" refers to a period of administration of a therapeutically effective dose of the MDM2 inhibitor or a pharmaceutically acceptable salt thereof, followed by a period of discontinuation of the drug, and then another period of administration, and so on. In each period of administration, 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, 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.

[0345] "Drug withdrawal period" or "drug holiday" or "rest period" means the duration during which the administration of the MDM2 inhibitor or its pharmaceutically acceptable salt is discontinued. The period of drug withdrawal may be longer or shorter than or the same as the administration period. During the drug withdrawal period, other therapeutic agents other than the MDM2 inhibitor or its pharmaceutically acceptable salt may be administered.

[0346] In one embodiment, an MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a human subject in need thereof for the treatment of a myeloproliferative neoplasm (MPN) for a first administration period, a subsequent drug-free period, a subsequent second administration period, and so on, wherein the MPN is selected from the group consisting of: polycythemia vera (PV), myelofibrosis, primary myelofibrosis, thrombocytosis, essential thrombocythemia (ET), congenital 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 drug-free period are independently selected from the group consisting of: greater than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 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 first administration period is the same length as the second administration period. In one embodiment, the first administration period is shorter than the second administration period. In one embodiment, the first administration period is longer than the second administration period. In one embodiment, the first administration period and the second administration period are about one week, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once a day; and the drug-free period is about two weeks. In one embodiment, the first administration period and the second administration period are about three weeks, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once a day; and the drug-free period is about two weeks. In one embodiment, the first administration period and the second administration period are about three weeks, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once a week; and the drug-free 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 day; and the drug-free 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 drug-free 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, 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.

[0347] In one embodiment, an MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a human subject in need thereof for the treatment of polycythemia vera (PV) for a first administration period, a subsequent drug-free period, a subsequent second administration period, and so on. The first administration period, the second administration period, and the drug-free period are independently selected from the group consisting of greater than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 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 first administration period is the same length as the second administration period. In one embodiment, the first administration period is shorter than the second administration period. In one embodiment, the first administration period is longer than the second administration period. In one embodiment, the first administration period and the second administration period are about one week, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once a day; and the drug-free period is about two weeks. In one embodiment, the first administration period and the second administration period are about three weeks, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once a day; and the drug-free period is about two weeks. In one embodiment, the first administration period and the second administration period are about three weeks, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once a week; and the drug-free 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 day; and the drug-free 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 drug-free 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, 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.

[0348] In one embodiment, an MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a human subject in need thereof for the treatment of essential thrombocythemia (ET) for a first administration period, a subsequent drug-free period, a subsequent second administration period, and so on. The first administration period, the second administration period, and the drug-free period are independently selected from the group consisting of greater than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 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 first administration period and the second administration period are of the same length. In one embodiment, the first administration period is shorter than the second administration period. In one embodiment, the first administration period is longer than the second administration period. In one embodiment, the first administration period and the second administration period are about one week, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once a day; and the drug-free period is about two weeks. In one embodiment, the first administration period and the second administration period are about three weeks, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once a day; and the drug-free period is about two weeks. In one embodiment, the first administration period and the second administration period are about three weeks, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once a week; and the drug-free 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 day; and the drug-free 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 drug-free 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, 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.

[0349] In one embodiment, an MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a human subject in need thereof for the treatment of primary myelofibrosis for a first administration period, a subsequent drug withdrawal period, a subsequent second administration period, and so on. The first administration period, the second administration period, and the drug withdrawal period are independently selected from the group consisting of greater than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 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 first administration period is the same length as the second administration period. In one embodiment, the first administration period is shorter than the second administration period. In one embodiment, the first administration period is longer than the second administration period. In one embodiment, the first administration period and the second administration period are about one week, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once a day; and the drug withdrawal period is about two weeks. In one embodiment, the first administration period and the second administration period are about three weeks, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once a day; and the drug withdrawal period is about two weeks. In one embodiment, the first administration period and the second administration period are about three weeks, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once a week; and the drug withdrawal 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 day; and the drug withdrawal 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 drug withdrawal 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, 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.

[0350] In one embodiment, an MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a human subject in need thereof for the treatment of chronic myelogenous leukemia (CML) for a first administration period, a subsequent drug withdrawal period, a subsequent second administration period, and so on. The first administration period, the second administration period, and the drug withdrawal period are independently selected from the group consisting of greater than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 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 first administration period and the second administration period are of the same length. In one embodiment, the first administration period is shorter than the second administration period. In one embodiment, the first administration period is longer than the second administration period. In one embodiment, the first administration period and the second administration period are about one week, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once a day; and the drug withdrawal period is about two weeks. In one embodiment, the first administration period and the second administration period are about three weeks, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once a day; and the drug withdrawal period is about two weeks. In one embodiment, the first administration period and the second administration period are about three weeks, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once a week; and the drug withdrawal 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 day; and the drug withdrawal 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 drug withdrawal 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, 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.

[0351] In one embodiment, an MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a human subject in need thereof for the treatment of acute myeloid leukemia (AML) for a first administration period, a subsequent drug-free period, a subsequent second administration period, and so on. The first administration period, the second administration period, and the drug-free period are independently selected from the group consisting of greater than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 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 first administration period is the same length as the second administration period. In one embodiment, the first administration period is shorter than the second administration period. In one embodiment, the first administration period is longer than the second administration period. In one embodiment, the first administration period and the second administration period are about one week, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once a day; and the drug-free period is about two weeks. In one embodiment, the first administration period and the second administration period are about three weeks, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once a day; and the drug-free period is about two weeks. In one embodiment, the first administration period and the second administration period are about three weeks, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once a week; and the drug-free 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 day; and the drug-free 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 drug-free 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, 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.

[0352] In one embodiment, an MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a human subject in need thereof for the treatment of Merkel cell carcinoma (MCC) for a first administration period, a subsequent drug-free period, a subsequent second administration period, and so on. The first administration period, the second administration period, and the drug-free period are independently selected from the group consisting of greater than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 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 first administration period is the same length as the second administration period. In one embodiment, the first administration period is shorter than the second administration period. In one embodiment, the first administration period is longer than the second administration period. In one embodiment, the first administration period and the second administration period are about one week, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once a day; and the drug-free period is about two weeks. In one embodiment, the first administration period and the second administration period are about three weeks, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once a day; and the drug-free period is about two weeks. In one embodiment, the first administration period and the second administration period are about three weeks, wherein the MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject once a week; and the drug-free 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 day; and the drug-free 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 drug-free 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, 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.

[0353] In one embodiment, 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 the treatment of cancer 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, Serdemetan, 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: cancer, 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 cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer, head and neck cancer, and skin cancer (including basal and squamous cell carcinoma, melanoma skin cancer, Merkel cell carcinoma, Kaposi sarcoma, cutaneous lymphoma); hematopoietic tumors of lymphoid lineage (including leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, and Burkitt lymphoma); hematopoietic tumors of myeloid lineage (including acute and chronic myelogenous leukemia, myelodysplastic syndrome, and promyelocytic leukemia); tumors of mesenchymal origin (including fibrosarcoma and rhabdomyosarcoma and other sarcomas, such as soft tissue and bone); tumors of the central and peripheral nervous system (including astrocytoma, neuroblastoma, glioma, glioblastoma, and schwannoma); and other tumors (including melanoma, 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.

[0354] In one embodiment, the 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 the treatment of MPN 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, Serdemetan, 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, thrombocytosis, essential thrombocythemia (ET), congenital myelofibrosis, systemic mastocytosis (SM), chronic neutrophilic leukemia (CNL), myelodysplastic syndrome (MDS), and systemic mast cell disease (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.

[0355] In one embodiment, an MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof from day 1 to day 7 of a 21-day cycle (from day 8 to day 21, no MDM2 inhibitor is administered) for the treatment of primary myelofibrosis 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, 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.

[0356] In one embodiment, an MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof from days 1 - 7 of a 21 - day cycle (from days 8 - 21, no MDM2 inhibitor is administered) for the treatment of polycythemia vera for a duration 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, 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.

[0357] In one embodiment, an MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof from days 1 - 7 of a 21 - day cycle (from days 8 - 21, the MDM2 inhibitor is not administered) for the treatment of phlebotomy - dependent polycythemia vera for a duration 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, 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. 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, 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 but does not have splenomegaly. In one embodiment, the ruxolitinib therapy of the human subject has failed.

[0358] In one embodiment, an MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof from days 1 - 7 of a 21 - day cycle (from days 8 - 21, no MDM2 inhibitor is administered) for the treatment of essential thrombocythemia for a duration 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, 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.

[0359] In one embodiment, an MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof from days 1 - 7 of a 21 - day cycle (from days 8 - 21, no MDM2 inhibitor is administered) for the treatment of chronic myelogenous leukemia (CML) 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, 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.

[0360] In one embodiment, an MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof from days 1-7 of a 21-day cycle (from days 8-21, no MDM2 inhibitor is administered) for the treatment of acute myeloid leukemia (AML) 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, 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.

[0361] In one embodiment, 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 the treatment of Merkel cell carcinoma (MCC) 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, 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.

[0362] In one embodiment, an MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof from days 1 - 7 of a 28 - day cycle (from days 8 - 28, no MDM2 inhibitor is administered) for the treatment of cancer 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, Serdemetan, 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: cancers 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 cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, head and neck cancer, and skin cancer (including basal and squamous cell carcinomas, melanoma skin cancer, Merkel cell carcinoma, Kaposi sarcoma, cutaneous lymphoma); hematopoietic tumors of lymphoid lineage (including leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, B - cell lymphoma, T - cell lymphoma, Hodgkin lymphoma, non - Hodgkin lymphoma, hairy cell lymphoma, and Burkitt lymphoma); hematopoietic tumors of myeloid lineage (including acute and chronic myelogenous leukemia, myelodysplastic syndromes, and promyelocytic leukemia); tumors of mesenchymal origin (including fibrosarcoma and rhabdomyosarcoma and other sarcomas such as soft tissue and bone); tumors of the central and peripheral nervous systems (including astrocytoma, neuroblastoma, glioma, glioblastoma, and schwannoma); and other tumors (including melanoma, 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 pharmaceutically acceptable salts thereof; and the MDM2 inhibitor is orally administered once daily (QD) at a dose of 120 mg or 240 mg.

[0363] In one embodiment, an MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof from days 1 - 7 of a 28 - day cycle (from days 8 - 28, no MDM2 inhibitor is administered) for the treatment of MPN for a period selected from the following: 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, Serdemetan, 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, thrombocytosis, essential thrombocythemia (ET), congenital myelofibrosis, systemic mastocytosis (SM), chronic neutrophilic leukemia (CNL), myelodysplastic syndrome (MDS), and systemic mast cell disease (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 a pharmaceutically acceptable salt thereof; and the MDM2 inhibitor is orally administered once daily (QD) at a dose of 120 mg or 240 mg.

[0364] In one embodiment, an MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof from day 1 to day 7 of a 28-day cycle (from day 8 to day 28, the MDM2 inhibitor is not administered) for the treatment of primary myelofibrosis 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, 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. 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 orally administered once daily (QD) at a dose of 120 mg or 240 mg.

[0365] In one embodiment, an MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof for the treatment of polycythemia vera during days 1-7 of a 28-day cycle (during days 8-28, no MDM2 inhibitor is administered) 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, 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. 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 orally administered once daily (QD) at a dose of 120 mg or 240 mg.

[0366] In one embodiment, an MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof from days 1 - 7 of a 28 - day cycle (from days 8 - 28, no MDM2 inhibitor is administered) for the treatment of essential thrombocythemia 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, 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. 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 orally administered once daily (QD) at a dose of 120 mg or 240 mg.

[0367] In one embodiment, an MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof from day 1 to day 7 of a 28-day cycle (from day 8 to day 28, no MDM2 inhibitor is administered) for the treatment of chronic myeloid leukemia (CML) 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, 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. 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 orally administered once daily (QD) at a dose of 120 mg or 240 mg.

[0368] In one embodiment, an MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof from day 1 to day 7 of a 28-day cycle (from day 8 to day 28, no MDM2 inhibitor is administered) for the treatment of acute myeloid leukemia (AML) 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, 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. 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 orally administered once daily (QD) at a dose of 120 mg or 240 mg.

[0369] In one embodiment, an MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof from days 1 - 7 of a 28 - day cycle (from days 8 - 28, no MDM2 inhibitor is administered) for the treatment of Merkel cell carcinoma (MCC) 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, 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. 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 orally administered once daily (QD) at a dose of 120 mg or 240 mg.

[0370] In one embodiment, an MDM2 inhibitor or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof from days 1 - 7 of a 28 - day cycle (from days 8 - 28, no MDM2 inhibitor is administered) for the treatment of phlebotomy - dependent polycythemia vera 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, 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. 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 orally administered once daily (QD) at a dose of 120 mg or 240 mg.

[0371] In one embodiment, a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof is administered once daily at a dose of 120 mg to a human subject in need thereof on days 1 - 7 of a 28 - day cycle (on days 8 - 28, no MDM2 inhibitor is administered) for the treatment of phlebotomy - dependent polycythemia vera, for a duration 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 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 but does not have splenomegaly. In one embodiment, the human subject's ruxolitinib therapy has failed.

[0372] In one embodiment, a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof is administered once daily at a dose of 240 mg to a human subject in need thereof on days 1 - 7 of a 28 - day cycle (on days 8 - 28, no MDM2 inhibitor is administered) for the treatment of phlebotomy - dependent polycythemia vera, for a duration 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 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 but does not have splenomegaly. In one embodiment, the human subject's ruxolitinib therapy has failed.

[0373] In one embodiment, a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof is administered once daily at a dose of 120 mg to a human subject in need thereof on days 1-7 of a 21-day cycle (on days 8-21, no MDM2 inhibitor is administered) for the treatment of phlebotomy-dependent polycythemia vera, 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. 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 but does not have splenomegaly. In one embodiment, the human subject's ruxolitinib therapy has failed.

[0374] In one embodiment, a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof is administered once daily at a dose of 240 mg to a human subject in need thereof on days 1 - 7 of a 21 - day cycle (on days 8 - 21, no MDM2 inhibitor is administered) for the treatment of phlebotomy - dependent polycythemia vera 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. 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 but does not have splenomegaly. In one embodiment, the ruxolitinib therapy of the human subject has failed.

[0375] Example

[0376] The embodiments encompassed herein are now described with reference to the following examples. These examples are provided for illustrative purposes only, and the disclosure encompassed herein should in no way be construed as limited to these examples, but rather should be construed to include any and all variations that become apparent as a result of the teachings provided herein.

[0377] Example 1: Effect of the compound of formula (I) on polycythemia vera cells

[0378] The procedure for testing the effect of the compound of formula (I) on polycythemia vera cells follows that described in Lu et al., Blood, 2012, 120(15); 3098 - 3105, which is incorporated herein by reference in its entirety. The procedure is briefly described below.

[0379] Cell preparation:

[0380] Peripheral blood will be obtained from patients with polycythemia vera (PV). Appropriate approval will be obtained from the institutional review board. Informed consent will be obtained prior to the study. All patients will meet the World Health Organization's diagnostic criteria for polycythemia vera (PV). Peripheral blood samples will be layered on Ficoll-Hypaque (1.077 g / mL; GE Healthcare) and low-density mononuclear cells will be isolated by centrifugation. CD34+ cells will be isolated using a human CD34+ cell selection kit (StemCell Technologies) according to the manufacturer's instructions. The purity of the CD34+ cell population will be analyzed using a FACSCalibur flow cytometer (BD Biosciences); and a purity of at least 85% will be required for all experiments. Fresh normal human bone marrow CD34+ cells will be purchased as controls from ALLCELLS.

[0381] HPC assay

[0382] The effect of the compound of formula (I) on patients with polycythemia vera (PV) can be evaluated by an HPC assay as described in Lu et al., Blood, 2012, 3098-3105, which is incorporated herein by reference in its entirety. Briefly, CD34+ cells will be 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 various doses of the compound of formula (I) for 4 days. After 4 days of treatment, CD34+ cells will be assayed in semi-solid medium as described in Bruno et al., Blood, 2006, 3128-3134, which is incorporated herein by reference in its entirety. Briefly, 5×10 2 CD34+ cells will be plated per dish, in duplicate, and the cultures will contain 1 mL IMDM with 1.1% methylcellulose and 20% FBS, to which SCF, TPO, Flt-3 ligand, IL-3, and GM-CSF (each 50 ng / mL) and 2 U / mL erythropoietin (EPO) will be added. After 14 days of incubation, the colonies will be counted and individual colonies will be harvested and genotyped for JAK2V617F.

[0383] Nested allele-specific PCR for JAK2V617F-positive colonies

[0384] Genomic DNA will be isolated from randomly collected colonies using the Extract-N-Amp Blood PCR Kit (Sigma-Aldrich). JAK2V617F will be detected by using nested allele-specific PCR as described by Bruno et al., Blood, 2006, 3128-3134, which is incorporated herein by reference in its entirety. The final PCR products will be analyzed on a 2.0% agarose gel. A 279-bp product indicates allele-specific JAK2V617F positive, while a 229-bp product indicates JAK2V617F negative. If a colony contains only the 279-bp band, it will be classified as JAK2V617F homozygous, while heterozygous colonies will be identified based on the presence of both the 279-bp and 229-bp bands.

[0385] Apoptosis assay

[0386] The treated cells will be collected and washed with PBS for staining with Annexin-V (BD Biosciences); the staining procedure will be performed according to the protocol provided by the manufacturer. Data will be acquired on a FACSCalibur flow cytometer (BD Biosciences), and at least 10,000 live cells will be acquired for each analysis (BD FACSDiva software; BD Biosciences).

[0387] Immunoblot analysis

[0388] CD34+ cells will be purified from the 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 will be treated with various doses of the compound of formula (I) for 4 hours. The cells will be harvested and whole cell protein extracts will be prepared using RIPA lysis buffer (Boston BioProducts) for immunoblotting.

[0389] To prepare cytoplasmic and nuclear protein fractions of cells from patients with polycythemia vera (PV), CD34+ cells will be expanded in serum-free medium containing SCF, FL-3 ligand, and IL-3 for 10 days. Then the CD34+ cells will be purified and treated with various doses of the compound of formula (I) in the presence of SCF, FL-3 ligand, IL-3, and TPO for 48 hours. Protein extracts will be prepared using the NE-PER nuclear and cytoplasmic extraction reagents (Thermo Scientific) according to the manufacturer's instructions.

[0390] Before immunoblotting, all samples were denatured with Laemmli SDS sample buffer (Boston BioProducts) by heating at 95 °C for 5 minutes; each sample was separated on an SDS-PAGE gel and transferred to a polyvinyldifluoridine membrane (Bio-Rad). Phospho-p53, p53, MDM2, p21, p-STAT1, PUMA, and Bak were visualized using antibodies (Cell Signaling Technologies) and ECL immunoblotting reagents (Denville Scientific).

[0391] Statistical analysis

[0392] Results will be reported as the mean ± SD of individual data points obtained from various numbers of experiments. Statistical significance will be determined using Student's t-test or paired-sample t-test.

[0393] Example 2: Effect of the compound of formula (I) on essential thrombocythemia cells

[0394] The experiment will be conducted according to Example 1, except that idiopathic thrombocythemia cells are used instead of polycythemia vera (PV) cells.

[0395] Example 3: Effect of the compound of formula (I) on primary myelofibrosis cells

[0396] The experiment will be conducted according to Example 1, except that primary myelofibrosis cells are used instead of polycythemia vera (PV) cells.

[0397] Example 4: The compound of formula (I) as monotherapy in patients with polycythemia vera

[0398] The aim of this study was to investigate the safety and efficacy of the compound of formula (I) in patients with polycythemia vera (PV). A similar clinical study of RG7388 (NCT02407080) is ongoing. In this study, 30 patients with polycythemia vera (PV) will be recruited and the compound of formula (I) will be administered at 120 mg once daily (QD) on days 1 - 7 of a 21-day cycle (days 8 - 21, the compound of formula (I) will not be administered), for two years. The inclusion criteria are as follows:

[0399] · JAK2V617F-positive polycythemia vera (PV)

[0400] · Not previously treated with at least one other drug (hydroxyurea, interferon, anagrelide)

[0401] · ≥ 18 years old

[0402] · The acceptable pre-study organ functions during screening are defined as: total bilirubin ≤ 1.5 times the upper limit of normal (ULN), unless due to Gilbert's disease or hemolysis, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 times ULN, and serum creatinine ≤ 1.5x ULN

[0403] · Women of childbearing age and men must agree to use appropriate contraceptive methods (i.e., hormonal or barrier methods of contraception; abstinence) before entering the study and during participation in the study. If a female subject becomes pregnant or suspects that she is pregnant during the study, she should be immediately excluded from the study

[0404] During the course of the study or at the end of the study, each polycythemia vera (PV) patient will be evaluated by the following to determine the safety and efficacy of the compound of formula (I): 1) hematological response; 2) reduction in JAK2V617F allele burden; 3) change in bone marrow histopathological abnormalities; 4) reduction in baseline reticulin / collagen fibrosis; 5) incidence of venous and arterial thrombosis; and 5) change in MPN-related symptoms measured by MPN-SAF.

[0405] Example 5: The compound of formula (I) as monotherapy in patients with essential thrombocythemia

[0406] The investigational study will be conducted according to the procedure described in Example 4, except that patients with essential thrombocythemia (ET) will be recruited instead of patients with polycythemia vera (PV).

[0407] Example 6: The compound of formula (I) as monotherapy in patients with primary myelofibrosis

[0408] The investigational study will be conducted according to the procedure described in Example 4, except that patients with primary myelofibrosis will be recruited instead of patients with polycythemia vera (PV).

[0409] Example 7: Efficacy of the compound of formula (I) against cancer

[0410] The procedures for testing the efficacy of the compound of formula (I) against cancer are described in Canon et al., Molecular Cancer Therapeutics, 2015; 649 - 658 and Rew et al., J. Med. Chem. 2012; 55; 4936 - 54, which are incorporated herein by reference in their entirety. The procedure is briefly described below.

[0411] Cells

[0412] SJSA-1, HCT116, ACHN, NCI-H460, MOLM-13, RKO, MCF7, 22RV1, HT-29, PC-3, NCI-H82, NCI-SNU1 and MG-63 cells were purchased from ATCC and have since been 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 cells were purchased from ATCC and used within 6 months. IGR-1 and CML-T1 cells were purchased from the German Collection of Microorganisms and Cell Cultures (DSMZ) and used within 6 months. A375sq2 cells were generated by passaging A375 cells in mice. HCT116 p53 - / - cells were obtained from Bert Vogelstein. KS-1 and SNG-M were purchased from the Health Science Research Resources Bank (HSRRB) in Japan and used within 6 months. After 6 months of purchase, G-401, G-361, LS174T cells (purchased from ATCC), EOL-1 cells (purchased from DSMZ) and KP-4 cells (purchased from HSRRB) were used.

[0413] Surface plasmon resonance (SPR) spectroscopy binding assay

[0414] Materials: Biacore T100 instrument (GE Healthcare), CM5 sensor chip (BR-1000-12), amine coupling kit (BR-1000-50) including 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC), N-hydroxysuccinimide (NHS) and ethanolamine-HCl, GST capture kit (BR-1002-23), HBS-N buffer (BR-1006-70) from GE Healthcare. All buffers were filtered through a 0.2 μM nylon membrane (VWR 87006-076). Kinetic studies of inhibitors on Biacore: The CM5 chip was pretreated with 10 mM NaOH, 10 mM HCl and 0.1% SDS, each injected twice at 100 μL / min in HBS-N buffer for 10 seconds each time. The immobilization and capture steps were carried out as described below: 1. Equal volumes of 0.4 M EDC and 0.1 M NHS were mixed and injected onto the chip surface at 10 μL / min for 10 minutes to activate; 2. Anti-GST antibody (30 μg / ml, in 10 mM sodium acetate, pH 5) was immobilized on the chip by injecting onto the surface at 8 μL / min for 15 minutes. 3. To inactivate the excess reactive groups and wash away the unbound anti-GST antibody, 1 M ethanolamine-HCl pH 8.5 was pumped across the entire surface at 8 μL / min for 10 minutes. The resulting antibody immobilization level was approximately 18000 RU; 4. 10 μg / ml GST in HBS-N buffer was injected onto one flow cell at 5 μl / min for 15 minutes to form a control surface of 1500 RU; 5. The sample surface was generated by injecting 20 μg / ml MDM2 onto another flow cell at 5 μl / min for 15 minutes twice to achieve a capture level of approximately 2000 RU. Kinetic binding studies of inhibitors (molecular weight range 450 - 600) were carried out at a constant flow rate of 90 μL / min at 25 °C. The sample analysis 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. The inhibitor was diluted from a 1 mM stock solution (in 100% DMSO) to 12 nM in the sample analysis buffer. The inhibitor was then serially diluted 2 times 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 buffer containing 2.3 - 3.5% DMSO was injected to construct a DMSO correction curve. All sensorgrams were processed using the Biacore evaluation software (GE Healthcare) with a dual-reference program and DMSO calibration. KD values were established using a 1:1 binding model including a mass transfer limitation term.

[0415] SJSA-1 Cell Proliferation Assay (Click-iT EdU HCS Assay)

[0416] Seed SJSA-1 cells at a density of 2.8×10 3 cells / well in 40 μl of growth medium (RPMI 1640 supplemented with 10 mM HEPES, 1 mM sodium pyruvate, 1X penicillin-streptomycin, 2 mM glutamine, and 10% fetal bovine serum) in a 384-well cell culture plate (PerkinElmer, #6007460). Incubate the cells at 37 °C and 5% CO 2 for 24 hours. The next day, treat the cells with the MDM2 inhibitor in the presence of 10% human serum for 16 hours. On day 3, perform the Click-iT EdU assay procedure according to the manufacturer's instructions, reducing the assay volume to 25 μL to accommodate the 384-well format (Invitrogen, #C10357). Briefly, add EdU (5-ethynyl-2'-deoxyuridine) to the cells to a final concentration of 10 μM and incubate for 1 hour. After labeling, fix the cells with 4% formaldehyde and permeabilize with 0.1% Triton-X 100. After washing, incubate the cells with Click-iT reaction buffer and then with nuclear stain. Then wash the cells and image using an Opera high-content screening system (Perkin Elmer). Calculate the percentage of EdU incorporation and use it for IC50 calculation. Determine the IC50 value using a four-parameter logistic (4PL) Hill model.

[0417] BrdU Proliferation Assay (HCT116 Specific Assay)

[0418] The potency of the MDM2 inhibitor was also determined by measuring its effect on cell proliferation by quantifying the amount of 5-bromo-2'-deoxyuridine (BrdU) incorporation in compound-treated cells relative to DMSO-treated control cells. Seed HCT116 p53WT or p53 - / - cells at a density of 6×10 3 cells / well in 100 μl of growth medium (McCoy’s 5A, 1X PSQ, and 10% fetal bovine serum (all components from Invitrogen)) in a 96-well cell culture plate. First, incubate the cells at 37 °C and 5% CO 2 for 24 hours before adding the compound. Serial dilute the MDM2 inhibitor in DMSO (Sigma #D2650) and then dilute again in assay medium (McCoy’s 5A, 1X PSQ, 10% human serum (Bioreclamation #HMSRM)) with a final DMSO concentration of 1%. Incubate the cells in the presence of the inhibitor at 37 °C and 5% CO 2Incubate for 16 hours, then pulse for 1 hour at 37°C and 5% CO 2 with diluted BrdU labeling reagent (final dilution: 1:100, Invitrogen #00 - 0103). After the BrdU pulse, remove the medium, fix the cells and stain for BrdU incorporation. BrdU incorporation was measured using flow cytometry or a Cellomics Array Scan Vti plate reader with target-activated bio applications. The percentage of BrdU-positive cells in DMSO-treated control wells was used to normalize the signal and calculate the percentage of inhibition for each compound-treated well. A dose-response curve was generated using XLFit software to calculate the IC50 value for each tested inhibitor.

[0419] HCT116 p21 Assay (HCT116-specific assay)

[0420] This assay was performed exactly as described above for the SJSA-1 p21 assay, except that: The growth medium for HCT116 p53WT or p53 - / - cells consisted of McCoy’s 5A, 1X PSQ, and 10% fetal bovine serum (all components from Invitrogen).

[0421] Biochemical (HTRF) assay

[0422] Materials: Human MDM2 (GST-thrombin-hMDM2(1 - 188)) was produced in-house. It was expressed in E. coli and purified by glutathione agarose 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 of over 80%. Human serum was from Bioreclamation (HMSRM, unfiltered). Monoclonal anti-GST antibody labeled with europium cryptate (Eu-anti-GST, 61GSTLB) and SA-Xlent (611SAXLB) were from Cisbio. DTT, BSA, KH 2 PO 4 、Na 2 HPO 4 、DMSO, NaCl, and KF were all from Sigma. Serum-free reaction buffer consisted of 1.06 mM KH 2 PO 4 、2.96 mM Na 2 HPO 4, consisting of 0.155 M NaCl, 0.1% BSA, and 1 mM DTT. The HTRF assay in serum uses a reaction buffer supplemented with 15% human serum. The HTRF assay plate is a White 384 Opti plate from Perkin Elmer (6007299). Envison (Perkin Elmer) is set to excite at 320 nm. Emissions are measured at 665 and 615 nm, and the ratio of Em665 / Em615 represents the MDM2-p53 interaction. After each excitation, the time-resolved fluorescence of 50 flashes of two detectors is measured with a 60 μs delay. The read time is 300 μs. Vprep is a product from Velocity11. The Wellmate microplate dispenser is from Thermo Scientific. Serial Killer is manufactured in-house. Method (determining inhibitor potency in the HTRF assay): Serial dilutions of 20 μL of 1.5 mM inhibitor to 20 μL of DMSO are made up to 22 points by Serial Killer. 1 μL of such diluted inhibitor is transferred to a reaction plate containing 9 μL of reaction buffer by Vprep. 10 μL of 1 nM MDM2 is dispensed into the reaction plate and incubated with the inhibitor for 20 minutes before adding 20 μL of 1.25 nM p53. After 60 minutes, the detection mixture (10 μL, 1 nM SA-Xlent, 3 nM Eu-anti-GST, and 0.5 M KF) is dispensed into the reaction mixture and the plate is read on Envision after an 18-hour incubation. The total reaction volume is 50 μL. MDM2, p53, and detection are delivered to the assay plate by Wellmate. The IC50 is determined from duplicate data. For the HTRF assay in 15% serum: The addition order is the same as in the serum-free assay. 10 μL of 12.5 nM MDM2 diluted in reaction buffer containing 30% human serum is added to 10 μL of buffer and compound mixture to give 15% serum. 20 nM p53 is diluted in buffer containing 15% human serum. The detection buffer is 15% serum containing 10 nM SA-Xlent, 3 nM Eu-anti-GST, and 0.5 M KF.

[0423] Immunoblot analysis

[0424] 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 a polyvinylidene difluoride membrane (Life Technologies). Primary antibodies: p53 (DO-1; Calbiochem), MDM2 (BD Pharmingen), p21 (R&D Systems), PUMA (Abcam), or β-actin-HRP (Sigma).

[0425] Cell viability assay (72 hours)

[0426] Cell lines were seeded at the optimal initial seeding density in 96- or 384-well plates to ensure that the cells did not reach confluence at the end of the assay. Cells were treated with DMSO control or different concentrations of the compound of formula (I) for 72 hours. The CellTiter-Glo Luminescent Cell Viability (Promega) or ATPlite 1-step Luminescence (PerkinElmer) assay kits were used to determine the number of viable cells. Luminescence of each cell line was measured with an EnVision Multilabel reader (PerkinElmer) at zero time (V0) before compound addition and 72 hours after compound treatment. Growth inhibition (GI) was calculated 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, then GI = 100x(1 - ((T72 - V0) / (V72 - V0))); if T72 < V0, then GI = 100x(1 - ((T72 - V0) / V0)). GI values of 0, 100, and 200 represent uninhibited cell growth (i.e., DMSO control), cell arrest, and complete cell kill, respectively. XLfit software (IDBS) was used to generate dose-response curves to calculate the IC50 value of the compound of formula (I) in each tested cell line.

[0427] Animal studies

[0428] All animal experimental procedures were conducted in accordance with the standards of the Association for Assessment and Accreditation of Laboratory Animal Care. All studies used female athymic nude mice (Harlan Laboratories, Hsd:Athymic Nude-Foxn1nu) at 4 - 6 weeks of age. Mice were housed in filter - topped cages in a sterile accommodation in an environmentally controlled room (temperature 23 ± 2 °C, relative humidity 50 ± 20%) on a 12 - hour light / dark cycle, with five mice per cage. Mice were fed a commercial rodent diet (Harlan Laboratories, #2920X) and had free access to filter - purified tap water. Mice were individually identified by subcutaneous implantation of a microchip (Bio Medic Data Systems) at least 2 days prior to the study.

[0429] Pharmacodynamic determination

[0430] Tumor cells (SJSA - 1: 5 x 10 6 cells, HCT 116: 2 x 10 6 cells) were subcutaneously injected into the flanks of female athymic nude mice at a ratio of 2:1 of cells to Matrigel (BD Bioscience). When the average tumor size reached approximately 300 to 450 mm 3 (n = 4 mice / group), the compound of formula (I) was administered by oral gavage. Tumors were harvested 1, 2, 4, 8, and 24 hours after dosing (SJSA - 1) or 6 hours after dosing (HCT116) and snap - frozen in liquid nitrogen. Total RNA was purified using the Qiagen RNeasy 96 kit (Qiagen). Levels of p21 and the housekeeping gene GAPDH were determined by qRTPCR from the total RNA of each sample in technical replicates. The qRT - PCR reactions were run on an Applied Biosystems Prism 7900HT instrument and the data were analyzed using Applied Biosystems SDS2.2 software. The SDS2.2 software calculated the copy numbers of p21 and GAPDH in each tumor sample. The copy number of p21 was normalized to the copy number of GAPDH, and for each sample, the fold increase in the normalized p21 level was calculated relative to the vehicle control. For MIC - 1, plasma was collected at the time of sacrifice and MIC - 1 was detected using the R&D Quantikine human MIC - 1 immunoassay (catalog number DGD150) according to the manufacturer's instructions. The ELISA assay was read using a Spectramax M5 microplate reader with Softmax pro v4 (Molecular Devices).

[0431] Xenograft study

[0432] SJSA - 1 cells (5 x 106 cells to Matrigel ratio of 2:1), NCI-H460 cells (5x10 6 cells to Matrigel ratio of 2:1), A375sq2 (5x10 6 cells to Matrigel ratio of 2:1) or HCT116 (2x10 6 cells) were subcutaneously injected into the flanks of female athymic nude mice (n = 10 per group). Treatment was initiated when tumors were established and approximately 200 mm 3 . The compound of formula (I) was administered once daily by oral gavage. Tumor size was evaluated twice weekly using a Pro-Max digital caliper (Sylvac), and tumor volume was calculated using the formula: length x width x height and expressed as mm 3 . Data are presented as mean ± SEM. Body weight was recorded twice weekly to assess tolerance (data not shown). p21 mRNA analysis was performed at the end of the xenograft study as described for the p21 pharmacodynamic assay.

[0433] Detection of BrdUrd and cleaved caspase-3 in xenografts

[0434] Tumors were harvested 6 hours after the last treatment, fixed in 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 x 20 using an Aperio Digital Scanner, and positive nuclear density was determined using Visiomorph image analysis software.

[0435] Statistical analysis

[0436] For the in vivo dose-response efficacy study of the compound of formula (I), repeated measures ANOVA (RMANOVA) was used, followed by Dunnett's post hoc test for multiple comparisons to evaluate the statistical significance of the observed differences.

[0437] Results

[0438] A broader panel of tumor cell lines, including p53 wild-type (n = 23) and mutant (n = 7) lines representing a range of tumor types and genetic backgrounds, was assayed, and the effect of treatment with the compound of formula (I) on cell growth was determined over 72 hours. In 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 ).

[0439] The anti-tumor activity of the compounds of formula (I) was evaluated in xenograft models representing different genetic backgrounds and various tumor types. All tumor cell lines used in the xenograft models carried wild-type p53. Oral administration of the compounds of formula (I) daily resulted in significant tumor growth inhibition (TGI) in all models ( Figures 3 - 5 ).

[0440] SJSA-1 is an MDM2-amplified osteosarcoma model that is most sensitive to treatment with the compounds of formula (I), and the ED50 is 9.1 mg / kg ( Figure 3 ). In the highest dose group of 75 mg / kg, 10 out of 10 tumors completely regressed and were undetectable 10 days after treatment. Treatment with the compounds of formula (I) was stopped in this group after 25 days, and the mice were observed for an additional 50 days. No SJSA-1 tumor regrowth was detected in any of the mice. Additional xenograft models demonstrated the in vivo anti-tumor activity range of the compounds of formula (I) or formula (II). In the HCT116 colorectal cancer model (KRAS mutant), the highest dose of the compounds of formula (I) resulted in 86% TGI and the ED50 was 31 mg / kg compared to the control ( Figure 4 ). In the A375sq2 BRAF mutant melanoma model, treatment with the compounds of formula (I) resulted in 97% TGI and the ED50 was 18 mg / kg ( Figure 5 ).

[0441] Tumors were harvested at the end of each xenograft study to determine the effect of treatment with the compounds of formula (I) on p53 pathway activity. Treatment with the compounds of formula (I) resulted in a dose- and time-dependent induction of p21 mRNA compared to vehicle-treated tumors ( Figure 6 ). The level of p21 induction in each tumor model was related to the extent of TGI, with the highest p21 levels in the tumors with the greatest growth inhibition. However, the maximum level of p21 induction varied depending on the tumor model.

[0442] Example 8: Clinical trial

[0443] A two-part, randomized, open-label, multi-center, phase 2a / 2b study of the efficacy, safety, pharmacokinetics, and pharmacodynamics of the compounds of formula (I) compared to ruxolitinib in patients with venesection-dependent polycythemia vera.

[0444] Polycythemia vera (PV) is classified as a myeloproliferative neoplasm (MPN). Long-term survival is poor, with a survival rate of 18% at 20 years. For PV patients, especially those intolerant / resistant to hydroxyurea (HU), treatment options are limited, and these patients are often treated with HU despite unacceptable side effects and suboptimal responses. In the case of a 21% response rate to ruxolitinib, there is a high unmet need for effective treatment in this subset of PV patients. The compounds of formula (I) or formula (II) are orally bioavailable small molecule cytotoxic chemotherapeutic agents that bind to murine double minute 2 (MDM2) and inhibit the MDM2 / tumor protein 53 (p53) protein-protein interaction. The compounds of formula (I) have been shown to inhibit the growth of p53 wild-type (p53WT) tumor cells in vitro and the growth of 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 deoxyribonucleic acid (DNA) repair. In preclinical settings, a key determinant of sensitivity to MDM2 inhibition is the p53 mutation status of the cell, and p53WT cells are sensitive to such inhibitors. MDM2 is a negative regulator of p53 and is overexpressed in CD34+ myeloproliferative tumor cells carrying p53WT. MDM2 degrades p53 and inactivates it, thereby allowing the proliferation of clonal hematopoietic stem cells.

[0445] Study design

[0446] The study will be conducted in two parts. In Part A, the initial proof-of-concept phase, the efficacy and safety of three treatment groups will be evaluated in PV subjects. If the overall response rate in Part A is at least 40% in splenomegaly subjects, Part B will be initiated, in which PV subjects with splenomegaly will be randomly assigned to be treated with the recommended dose and schedule of Part A or to be treated with ruxolitinib administered according to the prescription label.

[0447] All Part A and Part B subjects will continue treatment with the compound of formula (I) until disease progression or lack of tolerance. Disease progression is defined as:

[0448] · Phlebotomy eligibility (after week 8): confirmed hematocrit (HCT) > 45%, at least 3 percentage points higher than the HCT obtained at baseline, or confirmed HCT > 48%, confirmed 2 - 14 days after the initial observation.

[0449] · Splenic progression: volume assessment increase ≥ 25% relative to the volume measured at the time of the best recorded splenic volume response on central imaging examinations.

[0450] · Myelofibrosis / transformation: Increased myelofibrosis from baseline, and / or transformation to myelofibrosis (MF), myelodysplastic syndrome (MDS), or acute leukemia.

[0451] Proof-of-Concept / Dose Finding for Compounds of Part A - Formula (I): Part A will evaluate the safety and efficacy of two different doses of the compound of formula (I) and two different schedules in three treatment groups of PV subjects. A total of 75 randomized subjects will be evaluated in Part A. Subjects will be randomly assigned to one of three treatment groups:

[0452] · Group 1, N = 15 with splenomegaly, plus N = 10 without splenomegaly: Days 1 - 7, 120 mg once daily, off-treatment on Days 8 - 21 (21-day cycle)

[0453] · Group 2, N = 15 with splenomegaly, plus N = 10 without splenomegaly: Days 1 - 7, 240 mg once daily, off-treatment on Days 8 - 21 (21-day cycle)

[0454] · Group 3, N = 15 with splenomegaly, plus N = 10 without splenomegaly: Days 1 - 7, 120 mg once daily, off-treatment on Days 8 - 28 (28-day cycle)

[0455] Part B - In PV subjects, the recommended dose of the compound of formula (I) and schedule from Part A versus ruxolitinib: A total of 220 randomized splenomegaly subjects will be evaluated in Part B. Subjects in Part B will be randomly assigned to treatment with the recommended dose of the compound of formula (I) and schedule determined by the DMC from Part A, or to treatment with ruxolitinib according to the prescription label:

[0456] · Group 1, N = 110, subjects with splenomegaly treated with the recommended dose of the compound of formula (I) and schedule from Part A

[0457] · Group 2, N = 110, subjects with splenomegaly treated with ruxolitinib according to the prescription label

[0458] Approximately 295 randomized subjects are planned: Part A: N = 75 · Part B: N = 220 (110 subjects receiving the compound of formula (I) and 110 subjects receiving ruxolitinib)

[0459] Study Objectives:

[0460]

[0461]

[0462] Inclusion Criteria:

[0463] 1. Adults > 18 years old.

[0464] 2. The patient has a document that meets the 2016 revised World Health Organization (WHO) PV diagnostic criteria.

[0465] 3. The subject must be phlebotomy - dependent. Phlebotomy - dependent is defined as: · A hematocrit of 40 - 45% with two phlebotomies within 24 weeks before screening or more phlebotomies at least 4 weeks apart, or · A hematocrit level above 45% with at least one phlebotomy within 16 weeks before screening.

[0466] 4. In Part A, subjects with splenomegaly (defined as spleen volume ≥ 450 cubic centimeters cm3) and without splenomegaly detected by MRI (or CT) are eligible. In Part B, only subjects with splenomegaly detected by MRI or CT are eligible.

[0467] 5. Previously treated with hydroxyurea (HU) (in Part A and Part B) or interferon (only in Part A). If previously treated with HU, the subject must be resistant / intolerant to HU according to the following criteria:

[0468] HU resistance is defined as:

[0469] A dose ≥ 2 g / day or a maximum tolerated dose < 2 g / day for at least 12 weeks, resulting in the need for phlebotomy to maintain a hematocrit < 45% or a platelet count > 400x10 9 / L and a white blood cell (WBC) count > 10x10 9 / L.

[0470] HU intolerance is defined as:

[0471] At the lowest HU dose required to achieve a response, an ANC < 1.0x10 9 / L or a platelet count < 100x10 9 / L or a hemoglobin < 100 g / L (i.e., 10 g / dL) (hematocrit < 45% without phlebotomy and / or platelet count ≤ 400x10 9 / L, WBC count ≤ 10x10 9 / L and all 3 in a non - palpable spleen), or

[0472] The presence of lower extremity ulcers or other unacceptable non-hematological toxicities related to HU (e.g., mucocutaneous manifestations, gastrointestinal symptoms, pneumonia, or fever at any dose of HU), defined as: Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 3 - 4 adverse events (AE) or CTCAE version 5.0 grade 2 AE > 1 week or permanent discontinuation of HU or interruption of HU until the toxicity resolves or hospitalization due to HU toxicity.

[0473] 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

[0474] 7. Women of childbearing potential and men with a female partner of childbearing potential must agree to use effective contraception during the study. In addition, men must continue to use contraception for 3 months after the last dose of study drug, and women must continue to use contraception for 1 week after the last dose of study drug. Effective contraception includes: (a) combined estrogen and progestin hormonal contraception (oral, intravaginal, transdermal); (b) progestin-only hormonal contraception (oral, injectable, implantable); (c) intrauterine contraceptive device; (d) intrauterine hormone-releasing system; (e) bilateral tubal occlusion; (f) partner vasectomy; and (g) abstinence.

[0475] Exclusion Criteria

[0476] 1. Meeting the criteria for post-polycythemia vera myelofibrosis as defined by the International Working Group for Myeloproliferative Neoplasms Research and Treatment (IWG-MRT).

[0477] 2. > 10% blasts.

[0478] 3. Clinically significant thrombosis within 3 months of screening.

[0479] 4. Hepatic or renal insufficiency:

[0480] a. Renal impairment (Cockcroft Gault estimated creatinine clearance < 45 mL / min):

[0481]

[0482] b. Known history of hepatocellular disease (e.g., hepatitis B or C, cirrhosis, or other hepatocellular diseases).

[0483] c. Total bilirubin ≥ 2x upper limit of laboratory normal (ULN), unless Gilbert syndrome.

[0484] d. Alanine aminotransferase (ALT) > 2.5x ULN.

[0485] 5. Only for Part B: Prior treatment with JAK inhibitors.

[0486] 6. Prior treatment with a histone deacetylase (HDAC) inhibitor or a BCL-2 inhibitor.

[0487] 7. Patients previously treated with MDM2 antagonist therapy, p53-directed therapy, or subjects who have received interferon-α, anagrelide, or ruxolitinib within 28 days or approximately 5 half-lives, or hydroxyurea within 1 day, or any other cytoreductive procedure within 28 days or 5 half-lives of the initial dose. Aspirin is permitted according to PV treatment guidelines unless medically contraindicated.

[0488] 8. Absolute neutrophil count < 1.5 × 10 9 / L prior to dosing on Day 1 of Cycle 1.

[0489] 9. Platelet count ≤ 150 × 10 9 / L prior to dosing on Day 1 of Cycle 1.

[0490] 10. Splenic irradiation within 3 months prior to the first dose of the compound of formula (I).

[0491] 11. Pregnant or lactating women.

[0492] 12. History of major organ transplantation.

[0493] 13. Uncontrolled comorbidities including but not limited to acute hepatitis A; known history of human immunodeficiency virus (HIV) positivity; clinically significant heart disease (New York Heart Association class III or IV); symptomatic congestive heart failure; unstable angina; ventricular arrhythmia; or mental illness / social situation that may limit compliance with study requirements.

[0494] 14. Subjects with clinically significant bacterial, fungal, parasitic, or viral infections that require treatment. Subjects with acute bacterial infections that require antibiotic use should be delayed in screening / enrollment until the course of antibiotic therapy is completed.

[0495] 15. Other malignancies within the past 3 years, except for effectively 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, in situ breast cancer or superficial transitional cell bladder cancer after complete surgical resection.

[0496] 16. QTc prolongation of grade 2 or higher (> 480 milliseconds, according to NCI-CTCAE criteria, version 5.0).

[0497] Randomization procedure

[0498] In Part A, subjects will be randomly assigned to one of three treatment groups. In Part B, subjects will be randomly assigned to a compound of formula (I) or ruxolitinib. Only subjects in Part B will be classified according to HU status: HU-intolerant (unacceptable side effects) and HU-resistant (insufficient response). Subjects will be classified as HU-resistant or intolerant at the screening visit, and this classification will be used to stratify subjects at the time of randomization (Study Day 1).

[0499] Statistical Analysis

[0500] This study will be conducted in two parts. In Part A (initial proof-of-concept phase), subjects will be randomly assigned to one of 3 treatment groups: 120 mg of the compound of formula (I) in a 21-day treatment cycle, 240 mg of the compound of formula (I) in a 21-day treatment cycle, or 120 mg of the compound of formula (I) in a 28-day treatment cycle. All three groups will be run in parallel and will follow the same study assessments. The primary efficacy analysis for Part A will be based only on the mITT analysis of subjects with baseline splenomegaly who are p53WT. After all subjects with baseline splenomegaly in Part A have had the opportunity to complete Week 32, the DMC will recommend the dose / schedule of the compound of formula (I) for Part B. For Part B, subjects with baseline splenomegaly will be randomly assigned to treatment with the compound of formula (I) / schedule using the recommended dose from Part A, or to treatment with ruxolitinib administered according to the prescription label. Results of statistical analyses, descriptive summary statistics, and supportive listings will be presented by study part (A or B), treatment group, and dose. All analyses, summaries, and listings will be performed using SAS software (version 9.4 or higher). The detailed methods for the summary and statistical analysis of the data collected in this study will be documented in a Statistical Analysis Plan (SAP), which will be completed prior to database lock. The SAP may modify the data analysis plan outlined in the protocol; and if so, this will be clearly documented in the SAP. Any major modifications to the study design or study endpoints and / or their analysis will also be reflected in a protocol amendment.

[0501] Study Duration

[0502] Two years after the last subject is enrolled, the study will be considered complete, at which time subjects still on study treatment will be evaluated for eligibility in a long-term cumulative (rollover) study.

[0503] Example 9: In subjects with ruxolitinib failure in primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (Post-PV-MF) or post-essential thrombocythemia myelofibrosis (Post–ET-MF), open-label, phase 2a / 2b study of the compound of formula (I) Example 10: Effect of the compound of formula (I) on MPN-BP stem cells

[0504] There is a significant unmet need for improved therapies for patients with myelofibrosis (MF) who are primary resistant to, have poor response to, or relapse after ruxolitinib treatment. The compounds of formula (I) are orally bioavailable small molecule cytotoxic chemotherapeutic agents that bind to murine double minute 2 (MDM2) and inhibit the MDM2 / tumor protein 53 (p53) protein-protein interaction. The compounds of formula (I) have shown to inhibit the growth of p53 wild-type (p53WT) tumor cells in vitro and tumor xenograft growth 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 deoxyribonucleic acid (DNA) repair. In preclinical settings, a key determinant of sensitivity to MDM2 inhibition is the p53 mutation status of the cell, and p53WT cells are sensitive to such inhibitors. MDM2 is a negative regulator of p53 and is overexpressed in CD34+ myeloproliferative tumor cells carrying p53WT. MDM2 degrades p53 and inactivates it, thereby allowing the proliferation of clonal hematopoietic stem cells.

[0505] Study Design

[0506] This is an open-label, 2-part (Part A and Part B), Phase 2a / 2b study of the compounds of formula (I) in subjects with PMF, post-PV-MF, or post-ET-MF who have failed ruxolitinib. Approximately 190 subjects will be enrolled in the study (90 in Part A and 100 in Part B).

[0507] Part A (N = 90): In Part A of the study, subjects will be randomly assigned to 1 of 3 treatment groups:

[0508] · Group 1, N = 30 subjects: 120 mg of the compound of formula (I) once daily on Days 1 - 7, with treatment withheld on Days 8 - 21 (21-day cycle)

[0509] · Group 2, N = 30 subjects: 240 mg of the compound of formula (I) once daily on Days 1 - 7, with treatment withheld on Days 8 - 21 (21-day cycle)

[0510] · Group 3, N = 30 subjects: 240 mg of the compound of formula (I) once daily on Days 1 - 7, with treatment withheld on Days 8 - 28 (28-day cycle)

[0511] Part B (N = 100): Approximately 100 subjects will be enrolled in Part B and treated at the recommended dose and schedule from Part A. During the conduct of the study, the Data Monitoring Committee (DMC) will convene Parts A and B every 3 months to review the safety data of the clinical study. The DMC will also convene after all subjects in Part A have had the opportunity to complete the Week 24 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. In Parts A and B, subjects will receive the compound of formula (I) orally (PO) QD on Days 1 - 7 of each 21 - or 28 - day cycle. Dose reductions are permitted for blood and non - blood toxicities. All subjects should be treated until disease progression or lack of tolerance. Disease progression is defined based on imaging and modified ELN criteria:

[0512] · By central imaging, an increase in spleen volume of ≥25% compared to the study nadir is detected by MRI (or CT)

[0513] · Leukemic transformation confirmed by a bone marrow blasts count ≥20%, or

[0514] · ≥20% blasts in the peripheral blood and an absolute blasts count ≥1 x 10 9 / L for at least 2 weeks.

[0515] Study Objectives:

[0516]

[0517] Inclusion Criteria:

[0518] Subjects in both Part A and Part B must meet all of the following criteria to be eligible for the study:

[0519] 1. Adults > 18 years of age.

[0520] 2. Palpable splenomegaly, at least 5 cm below the left costal margin.

[0521] 3. Confirmed PMF, post–PV - MF, or post–ET - MF by the treating physician according to World Health Organization (WHO) criteria.

[0522] 4. High - risk, intermediate - 2 risk, or intermediate - 1 risk as defined by the Dynamic International Prognostic Scoring System (DIPSS).

[0523] 5. ECOG performance status of 0 - 2.

[0524] 6. Adequate blood, liver, and renal organ function (as defined by the protocol, within 14 days prior to the first dose of the compound of formula (I)) · Hematology: ANC ≥ 1.0 x 109 / L, without growth factors; platelet count ≥ 100 × 10 9 / L; peripheral blood blast cell count < 10%.

[0525] Liver: total bilirubin ≤ 2.0 times the upper limit of normal (ULN), unless Gilbert syndrome; aspartate aminotransferase / serum glutamate oxaloacetate transaminase (AST / SGOT) and alanine aminotransferase / serum glutamate pyruvate transaminase (ALT / SGPT) ≤ 2.5 ULN. Kidney: Cockcroft Gault estimated creatinine clearance > 45 mL / min

[0526]

[0527] 7. Women of childbearing potential and men with a female partner of childbearing potential must agree to use effective contraception during the study. In addition, men must continue to use contraception for 3 months after the last dose of study drug, and women must continue to use contraception for 1 week after the last dose of study drug. Effective contraception includes: (a) combined estrogen and progestin hormonal contraception (oral, intravaginal, transdermal); (b) progestin-only hormonal contraception (oral, injectable, implantable); (c) intrauterine contraceptive device; (d) intrauterine hormone-releasing system; (e) bilateral tubal occlusion; (f) partner vasectomy; and (g) abstinence.

[0528] Subjects in Part A must meet the following ruxolitinib treatment failure criteria to be eligible for the study:

[0529] Treatment failure of ruxolitinib in Part A must meet either criterion (a) or (b) below:

[0530] a) Lack of spleen response is defined as having received ruxolitinib treatment for at least 12 weeks and having two of the following:

[0531] · Permanent splenomegaly detected by physical examination, palpable ≥ 5 cm below the left costal margin (LCM)

[0532] · TSS > 10 on MPN-SAF TSS2.0, or patients with a single symptom score > 5 or two symptoms > 3, including only symptoms of left upper quadrant pain, bone pain, pruritus, or night sweats.

[0533] b) Or disease progression at any time during ruxolitinib treatment, as defined by any of the following:

[0534] · Spleen volume increased by ≥ 25% from the nadir, as assessed by MRI or CT; appearance of new splenomegaly, palpable at least 5 cm below the LCM

[0535] · For a baseline splenomegaly of 5 to 10 cm, the palpable distance under LCM increased by ≥ 100%

[0536] · For a baseline splenomegaly > 10 cm, the palpable distance under LCM increased by ≥ 50%.

[0537] Subjects in Part B must meet the following ruxolitinib treatment failure criteria to be eligible for the study:

[0538] Ruxolitinib treatment failure in Part B must meet one of the following criteria (a) or (b):

[0539] a) Lack of spleen response is defined as receiving ruxolitinib treatment for at least 12 weeks and having at least one of the following:

[0540] · For subjects evaluated by MRI or CT for ruxolitinib treatment, the spleen volume did not decrease by at least ≥ 35%

[0541] · The baseline splenomegaly before ruxolitinib treatment was palpable at 5 to 10 cm under LCM but was still palpable

[0542] · The baseline splenomegaly before ruxolitinib treatment was palpable at > 10 cm under LCM but did not decrease by at least 50%

[0543] · The baseline splenomegaly before ruxolitinib treatment was palpable at < 5 cm under LCM and did not meet the criteria to be considered a ruxolitinib...

Claims

1. Use of a therapeutically effective amount of an MDM2 inhibitor in the manufacture of a medicament for treating myelofibrosis in a human subject in need thereof, wherein the MDM2 inhibitor is a compound of formula (I): or a pharmaceutically acceptable salt thereof.

2. The use according to claim 1, wherein the myelofibrosis is relapsed myelofibrosis.

3. The use according to claim 1, wherein the myelofibrosis is selected from primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV MF), and post-essential thrombocythemia myelofibrosis (post-ET MF).

4. The use according to claim 1, wherein the human subject is non-responsive to a prior ruxolitinib therapy.

5. The use according to any one of claims 1 to 4, wherein the MDM2 inhibitor is a pharmaceutically acceptable salt of the compound of formula (I).

6. The use according to any one of claims 1 to 5, wherein the compound of formula (I) is formulated to be 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.

7. The use according to any one of claims 1 to 5, wherein the compound of formula (I) is formulated to be 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.

8. The use according to any one of claims 1 to 7, wherein the human is treated with the MDM2 inhibitor on days 1-7 of a 21-day cycle, wherein the human is not treated with the MDM2 inhibitor on days 8-21.

9. The use according to any one of claims 1 to 8, wherein the compound of formula (I) is formulated for oral administration.

10. The use according to any one of claims 1 to 9, wherein the MPN is characterized by a JAK2V617F mutation.

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