Pharmaceutical compositions including a MDM2-p53 inhibitor

Abstract

The present disclosure relates to pharmaceutical compositions comprising a solid dispersion comprising a compound of Formula (I): (I), or a pharmaceutically acceptable salt thereof, as well as methods of treatment.

Description

PHARMACEUTICAL COMPOSITIONS INCLUDING A MDM2-P53 INHIBITORFIELD

[0001] The present disclosure is directed to pharmaceutical compositions comprising a MDM2-p53 inhibitor. BACKGROUND

[0002] The transformation-related protein 53 (TP53) gene encodes a 53 KDa protein-p53. The tumor suppressor protein p53 reacts to cellular stresses, such as hypoxia, DNA damage and oncogenic activation, via a number of posttranslational modifications including phosphorylation, acetylation and methylation,and acts as a signaling node in the diverse pathways that become activated. p53 has additional roles in otherphysiological processes, including autophagy, cell adhesion, cell metabolism, fertility, and stem cell agingand development. The activity of p53 is negatively and tightly regulated by a binding interaction with the MDM2 protein, the transcription of which is itself directly regulated by p53. p53 is inactivated when its transactivation domain is bound by the MDM2 protein. Once inactivated the functions of p53 are repressed and the p53-MDM2 complex becomes a target for ubiquitination.

[0003] In normal cells the balance between active p53 and inactive MDM2-bound p53 is maintained in an autoregulatory negative feedback loop. That is to say that p53 can activate MDM2 expression, which inturn leads to the repression of p53. It has been found that inactivation of p53 by mutation is common inaround half of all common adult sporadic cancers. Furthermore, in around 10% of tumors, gene amplification and over-expression of MDM2 results in the loss of functional p53, thereby allowingmalignant transformation and uncontrolled tumor growth.

[0004] It has been contemplated that a potent inhibitor of the MDM2-p53 interaction will liberate p53from the repressive control of MDM2, and activate p53 mediated cell death in the tumor. In tumors, selectivity is envisioned to result from p53 sensing preexisting DNA-damage or oncogenic activation signals that had previously been blocked by the action of MDM2 at normal or overexpressed levels. Innormal cells, p53 activation is anticipated to result in activation of non-apoptotic pathways. In addition, dueto the non-genotoxic mechanism of action for MDM2-p53 inhibitors, they are suitable for the treatment ofcancer in particular in the pediatric population.

[0005] The present disclosure describes a formulation for a compound which selectively inhibit theMDM2-p53 interaction, and which have anticancer activity.SUMMARY

[0006] In some embodiments, provided herein is a solid dispersion comprising a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is molecularly dispersed within a polymer matrix comprising a stabilizing polymer.

[0007] In some embodiments, the stabilizing polymer is polyvinylpyrrolidone / vinyl acetate (PVPVA, copovidone), hydroxypropylmethyl cellulose (HPMC), or hydroxypropylmethyl cellulose acetate succinate (HPMCAS). In some embodiments, the stabilizing polymer is polyvinylpyrrolidone / vinyl acetate (PVPVA, copovidone). In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is present in the solid dispersion in an amount of about 50% to about 80%, or about 60% to about 70% by weight of the solid dispersion. In some embodiments of the solid dispersion the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is substantially amorphous. In some embodiments, at least 98% of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is in amorphous form. In some embodiments, the ratio of an amount by weight of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the solid dispersion to an amount by weight of the stabilizing polymer in the solid dispersion is from about 1:3 to about 3:1. In some embodiments, the ratio of an amount by weight of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the solid dispersion to an amount by weight of the stabilizing polymer in the solid dispersion is from about 1:1 to about 3:1. In some embodiments, the ratio of an amount by weight of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the solid dispersion to an amount by weight of the stabilizing polymer in the solid dispersion is from about 2:1. In some embodiments, the solid dispersion comprises a sodium salt or a tromethamine salt of the compound of Formula (I).

[0008] In some embodiments, provided herein is a pharmaceutical composition comprising about 50%- 70% w / w of a solid dispersion comprising a compound of Formula (I):or a pharmaceutically acceptable salt thereof.

[0009] In some embodiments, the solid dispersion comprises about 60%-75% w / w of the compound ofFormula (I) and about 25%-40% w / w of a stabilizing polymer. In some embodiments, the solid dispersioncomprises the compound of Formula (I) or a pharmaceutical salt thereof, and a stabilizing polymer, whereinthe compound of Formula (I) or a pharmaceutical salt thereof, and the stabilizing polymer has a weight ratioof 3:1 to 1:3. In some embodiments, the stabilizing polymer is a copolymer of N-vinylpyrrolidone andvinyl acetate. In some embodiments, the compound of Formula (I) or a pharmaceutical salt thereof, issubstantially amorphous. In some embodiments, the pharmaceutical composition further comprises: about 5%-15% w / w of microcrystalline cellulose; about 10%-30% w / w of lactose monohydrate;about 3%-10% w / w of croscarmellose sodium; about 0.1%-3% w / w of silicon dioxide; and about 0.1%-3%w / w of magnesium stearate. In some embodiments, the solid dispersion comprises a sodium salt or a tromethamine salt of the compound of Formula (I).

[0010] In some embodiments, also provided herein is a dosage form comprising the pharmaceuticalcomposition described in preceding paragraphs. The dosage form may be a tablet or a capsule. In someembodiments, the dosage form includes one or more additional anti-cancer agents. In some embodiments,the dosage form comprises about 50 mg or 200 mg of the compound of Formula (I) or a pharmaceuticalsalt thereof.

[0011] In some embodiments, also provided herein is a method of treating a cancer in a patient in needthereof. The method comprises administering an effective amount of the pharmaceutical composition described in any of the preceding paragraphs. In some embodiments, the cancer has wild-type TP53 gene. In some embodiments, the cancer has MDM2 amplification. In some embodiments the cancer is a tumour with BRCA 1 / 2 or ATM deleterious mutations or with BAP1 loss of function. In some embodiments, thecancer is selected from the group consisting of metastatic and refractory solid tumors, advanced metastaticand refractory solid tumors, mesothelioma, malignant peritoneal mesothelioma, malignant pleural mesothelioma, liposarcoma, dedifferentiated liposarcoma, well differentiated liposarcoma, glioblastomamultiforme, intimal sarcoma, hepatocellular carcinoma, oesophageal cancer, Ewing's sarcoma, soft tissue sarcoma, osteosarcoma, uveal melanoma, ovarian cancer, colorectal cancer, rectal cancer, cervical cancer,gastric cancer, gastrointestinal stromal tumor (GIST), breast cancer, lung cancer, brain cancer, glioma,neuroblastoma, acute myelogenous leukemia (AML), T-cell lymphomas, B-cell lymphomas, diffuse large B-cell lymphoma (DLBCL), MALT lymphoma. The T-cell lymphoma may be progressive or relapsed peripheral T-cell lymphoma (PTCL), or relapsed or refractory cutaneous T-cell lymphoma (CTCL).

[0012] In some embodiments, also provided herein is use of an effective amount of the pharmaceuticalcomposition described in any of the preceding paragraphs for the treatment of a cancer in a patient in need thereof.

[0013] In some embodiments, also provided herein is use of an effective amount of the pharmaceutical composition described in any of the preceding paragraphs for the manufacture of a medicament for treating a cancer in a patient in need thereof.

[0014] In some embodiments, also provided herein is a pharmaceutical composition for use in treating a cancer in a patient in need thereof. DETAILED DESCRIPTION Definitions

[0015] The following description sets forth exemplary embodiments of the present technology. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.

[0016] As used in the present specification, the following words, phrases, and symbols are generallyintended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0017] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount ± 10%. In other embodiments, the term “about” includes the indicated amount ± 5%. In certain other embodiments, the term “about” includes the indicated amount ± 1%. Also, the term “about X” includes description of “X”. Also, the singular forms “a” and “the” include plural references unless thecontext clearly dictates otherwise. Thus, e.g., reference to "the compound" includes a plurality of suchcompounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art.

[0018] “Alkyl” refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C1-20 alkyl), 1 to 8 carbon atoms (i.e., C1-8 alkyl), 1 to 6 carbon atoms (i.e., C1-6alkyl), or 1 to 4 carbon atoms (i.e., C1-4alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2- hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons may be encompassed; thus, for example, “butyl” includes n-butyl (i.e. -(CH2)3CH3), sec-butyl (i.e. -CH(CH3)CH2CH3), isobutyl (i.e. -CH2CH(CH3)2) and tert-butyl (i.e. -C(CH3)3); and “propyl” includes n-propyl (i.e. -(CH2)2CH3) and isopropyl (i.e. -CH(CH3)2).

[0019] Certain commonly used alternative chemical names may be used. For example, a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, a divalent heteroaryl group, etc., may also bereferred to as an “alkylene” group or an “alkylenyl” group (for example, methylenyl,, ethylenyl, andpropylenyl), an “arylene” group or an “arylenyl” group (for example, phenylenyl or napthylenyl, or quinolinyl for heteroarylene), respectively. Also, unless indicated explicitly otherwise, where combinations of groups are referred to herein as one moiety, e.g., arylalkyl or aralkyl, the last-mentioned group contains the atom by which the moiety is attached to the rest of the molecule.

[0020] “Alkenyl” refers to an alkyl group containing at least one carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C2-20 alkenyl), 2 to 8 carbon atoms (i.e., C2-8 alkenyl), 2 to 6 carbon atoms (i.e., C2-6alkenyl), or 2 to 4 carbon atoms (i.e., C2-4alkenyl). Examples of alkenyl groups include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0021] “Alkynyl” refers to an alkyl group containing at least one (e.g., 1-3, or 1) carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C2-20alkynyl), 2 to 12 carbon atoms (i.e., C2-12alkynyl), 2 to 8 carbon atoms (i.e., C2-8 alkynyl), 2 to 6 carbon atoms (i.e., C2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C2-4alkynyl). The term “alkynyl” also includes those groups having one triple bond and one double bond.

[0022] “Alkoxy” refers to the group “alkyl-O-”. Examples of alkoxy groups include, e.g., methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0023] “Alkoxyalkyl” refers to the group “alkyl-O-alkyl”.

[0024] “Alkylthio” refers to the group “alkyl-S-”. “Alkylsulfinyl” refers to the group “alkyl-S(O)-”. “Alkylsulfonyl” refers to the group “alkyl-S(O)2-”. “Alkylsulfonylalkyl” refers to -alkyl-S(O)2-alkyl.

[0025] “Acyl” refers to a group -C(O)Ry, wherein Ryis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of acyl include, e.g., formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0026] “Amido” refers to both a “C-amido” group which refers to the group -C(O)NRyRzand an “N- amido” group which refers to the group -NRyC(O)Rz, wherein Ryand Rzare independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein, or Ryand Rzare taken together to form a cycloalkyl or heterocyclyl; each of which may be optionally substituted, as defined herein.

[0027] “Amino” refers to the group -NRyRzwherein Ryand Rzare independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0028] “Amidino” refers to -C(NRy)(NRz2), wherein Ryand Rzare independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0029] “Aryl” refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiplerings (e.g., bicyclic or tricyclic) including fused systems. As used herein, aryl has 6 to 20 ring carbon atoms(i.e., C6-20aryl), 6 to 12 carbon ring atoms (i.e., C6-12aryl), or 6 to 10 carbon ring atoms (i.e., C6-10aryl). Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl, the resulting ring system is heteroaryl. If one or more aryl groups are fused with a heterocyclyl, the resulting ring system is heterocyclyl.

[0030] “Arylalkyl” or “Aralkyl” refers to the group “aryl-alkyl-”.

[0031] “Carbamoyl” refers to both an “O-carbamoyl” group which refers to the group -O-C(O)NRyRzand an “N-carbamoyl” group which refers to the group -NRyC(O)ORz, wherein Ryand Rzare independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0032] “Carboxyl ester” or “ester” refer to both -OC(O)Rxand -C(O)ORx, wherein Rxis alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0033] “Cyanoalkyl” refers to an alkyl group as defined above, wherein one or more (e.g., 1 or 2) hydrogen atoms are replaced by a cyano (-CN) group.

[0034] “Cycloalkyl” refers to a saturated or partially unsaturated cyclic alkyl group having a single ringor multiple rings including fused, bridged, and spiro ring systems. The term “cycloalkyl” includescycloalkenyl groups (i.e., the cyclic group having at least one double bond). As used herein, cycloalkyl hasfrom 3 to 20 ring carbon atoms (i.e., C3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-6cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0035] “Cycloalkylalkyl” refers to the group “cycloalkyl-alkyl-”.

[0036] “Imino” refers to a group -C(NRy)Rz, wherein Ryand Rzare each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0037] “Imido” refers to a group -C(O)NRyC(O)Rz, wherein Ryand Rzare each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0038] “Halogen” or “halo” refers to atoms occupying group VIIA of the periodic table, such as fluoro, chloro, bromo, or iodo.

[0039] “Haloalkyl” refers to an unbranched or branched alkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen. For example, where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl include, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0040] “Haloalkoxy” refers to an alkoxy group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen.

[0041] “Haloalkoxyalkyl” refers to an alkoxyalkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen.

[0042] “Hydroxyalkyl” refers to an alkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a hydroxy group.

[0043] “Heteroalkyl” refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms), excluding any terminal carbon atom(s), are each independently replaced withthe same or different heteroatomic group, provided the point of attachment to the remainder of the moleculeis through a carbon atom. The term “heteroalkyl” includes unbranched or branched saturated chains havingcarbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group. Heteroatomic groups include, but are not limited to, -NRy-, -O-, -S-, -S(O)-, -S(O)2-, and the like, wherein Ryis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of heteroalkyl groups include, e.g., ethers (e.g., -CH2OCH3, -CH(CH3)OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, etc.), thioethers (e.g., -CH2SCH3, -CH(CH3)SCH3,-CH2CH2SCH3,-CH2CH2SCH2CH2SCH3, etc.), sulfones (e.g., -CH2S(O)2CH3, -CH(CH3)S(O)2CH3,-CH2CH2S(O)2CH3, -CH2CH2S(O)2CH2CH2OCH3, etc.), and amines (e.g., -CH2NRyCH3, -CH(CH3)NRyCH3, -CH2CH2NRyCH3, -CH2CH2NRyCH2CH2NRyCH3, etc., where Ryis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein). As used herein, heteroalkyl includes 2 to 10 carbon atoms, 2 to 8 carbon atoms, or 2 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0044] “Heteroaryl” refers to an aromatic group having a single ring, multiple rings, or multiple fusedrings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl includes 1 to 20 ring carbon atoms (i.e., C1-20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C3-12heteroaryl), or 3 to 8 carbon ring atoms (i.e., C3-8heteroaryl), and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. In certain instances, heteroaryl includes 5-10 membered ring systems, 5-7 membered ring systems, or 5-6 membered ring systems, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, e.g., acridinyl, benzimidazolyl,benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1- oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, thiophenyl (i.e., thienyl), tetrazolyl, and triazinyl. Examples of the fused-heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl,pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, where the heteroaryl can be bound via either ring ofthe fused system. Any aromatic ring, having a single or multiple fused rings, containing at least one heteroatom, is considered a heteroaryl regardless of the attachment to the remainder of the molecule (i.e., through any one of the fused rings). Heteroaryl does not encompass or overlap with aryl as defined above.

[0045] “Heteroarylalkyl” refers to the group “heteroaryl-alkyl-”.

[0046] “Heterocyclyl” refers to a saturated or partially unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term “heterocyclyl”includes heterocycloalkenyl groups (i.e., the heterocyclyl group having at least one double bond), bridged-heterocyclyl groups, fused-heterocyclyl groups, and spiro-heterocyclyl groups. A heterocyclyl may be a single ring or multiple rings wherein the multiple rings may be fused, bridged, or spiro, and may comprise one or more (e.g., 1 to 3) oxo (=O) or N-oxide (-O-) moieties. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of the attachment (i.e., can be bound through a carbon atom or a heteroatom). Further, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to a cycloalkyl, an aryl, or heteroaryl ring, regardless of the attachment to the remainder of the molecule. As used herein, heterocyclyl has 2 to 20 ring carbon atoms (i.e., C2-20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C2-12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C2-10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C2-8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C3-12heterocyclyl), 3 to 8 ring carbon atoms (i.e., C3-8heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C3-6 heterocyclyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclyl groups include, e.g., azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4- benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl,dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl,imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. The term “heterocyclyl” also includes “spiroheterocyclyl” when there are two positions for substitution on the same carbon atom. Examples of the spiro-heterocyclyl rings include, e.g., bicyclic and tricyclic ring systems, such as oxabicyclo[2.2.2]octanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa- 6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of the fused-heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl,indolinyl, and isoindolinyl, where the heterocyclyl can be bound via either ring of the fused system.

[0047] “Heterocyclylalkyl” refers to the group “heterocyclyl-alkyl-.”

[0048] “Oxime” refers to the group -CRy(=NOH) wherein Ryis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0049] “Sulfonyl” refers to the group -S(O)2Ry, where Ryis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0050] “Sulfinyl” refers to the group -S(O)Ry, where Ryis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of sulfinyl are methylsulfinyl, ethylsulfinyl, phenylsulfinyl, and toluenesulfinyl.

[0051] “Sulfonamido” refers to the groups -SO2NRyRzand -NRySO2Rz, where Ryand Rzare each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0052] The terms “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. Also, the term “optionally substituted” refers to any one or more hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen.

[0053] The term “substituted” used herein means any of the above groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, and / or heteroalkyl)wherein at least one (e.g., 1 to 5 or 1 to 3) hydrogen atom is replaced by a bond to a non-hydrogen atom such as, but not limited to alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanadino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -NHNH2, =NNH2, imino, imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, -S(O)OH, -S(O)2OH, sulfonamido, thiol, thioxo, N-oxide, or - Si(Ry)3, wherein each Ryis independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl.

[0054] In certain embodiments, “substituted” includes any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups in which one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are independently replaced with deuterium, halo, cyano, nitro, azido, oxo, alkyl, alkenyl, alkynyl,=NORg, -S(O)1-2NRgRh, -SF5, -SCF3, or -OCF3. In certain embodiments, “substituted” also means any of the above groups in which one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are replaced with -C(O)Rg, -C(O)ORg, -C(O)NRgRh, -CH2SO2Rg, or -CH2SO2NRgRh. In the foregoing, Rgand Rhare the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl. In certain embodiments, “substituted” also means any of the above groups in which one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are replaced by a bond to an amino, cyano, hydroxy, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl, or two of Rgand Rhand Riare taken together with the atoms to which they are attached to form a heterocyclyl ring optionally substituted with oxo, halo, or alkyl optionally substituted with oxo, halo, amino, hydroxy, or alkoxy.

[0055] Some of the compounds exist as tautomers. Tautomers are in equilibrium with one another. Forexample, amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers. Likewise, the imidic acid containing compounds are understood to include their amide tautomers.

[0056] In many cases, the compounds of this disclosure, i.e., the compound of Formula (I), are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0057] The term “pharmaceutically acceptable salt” of a given compound refers to salts that retain the biological effectiveness and properties of the given compound, and which are not biologically or otherwise undesirable. “Pharmaceutically acceptable salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include lactic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium,ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to,salts of primary, secondary and tertiary amines, such as alkyl amines (i.e., NH2(alkyl)), dialkyl amines (i.e., HN(alkyl)2), trialkyl amines (i.e., N(alkyl)3), substituted alkyl amines (i.e., NH2(substituted alkyl)), di(substituted alkyl) amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl) amines (i.e., N(substituted alkyl)3), alkenyl amines (i.e., NH2(alkenyl)), dialkenyl amines (i.e., HN(alkenyl)2), trialkenyl amines (i.e., N(alkenyl)3), substituted alkenyl amines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl) amines(i.e., HN(substituted alkenyl)2), tri(substituted alkenyl) amines (i.e., N(substituted alkenyl)3, mono-, di- ortri- cycloalkyl amines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di- or tri-arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines, etc. Specific examples of suitable saltsfrom organic bases include, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N- ethylpiperidine, and the like.

[0058] As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0059] “Treatment” or “treating” is an approach for obtaining beneficial or desired results includingclinical results. Beneficial or desired clinical results may include one or more of the following: a) inhibitingthe disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition,and / or diminishing the extent of the disease or condition); b) slowing or arresting the development of oneor more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition,preventing or delaying the worsening or progression of the disease or condition, and / or preventing ordelaying the spread (e.g., metastasis) of the disease or condition); and / or c) relieving the disease, that is,causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or totalremission of the disease or condition, enhancing the effect of another medication, delaying the progressionof the disease, increasing the quality of life, and / or prolonging survival.

[0060] “Prevention” or “preventing” means any treatment of a disease or condition that causes theclinical symptoms of the disease or condition not to develop. Compounds may, in some embodiments, beadministered to a subject (including a human) who is at risk or has a family history of the disease or condition.

[0061] As used herein, the term “combination therapy” is intended to define therapies which comprise the use of a combination of two or more compounds / agents (as defined above). Thus, references to “combination therapy”, “combinations” and the use of compounds / agents “in combination” in this application may refer to compounds / agents that are administered as part of the same overall treatment regimen. As such, the posology of each of the two or more compounds / agents may differ: each may be administered at the same time or at different times. It will therefore be appreciated that the compounds / agents of the combination may be administered sequentially (e.g. before or after) or simultaneously. The posologies of each of the two or more compounds / agents in a combination therapy may also differ with respect to the route of administration.

[0062] “Subject” refers to an animal, such as a mammal (including a human), that has been or will be theobject of treatment, observation, or experiment. The methods described herein may be useful in humantherapy and / or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment,the subject is a human.

[0063] The term “therapeutically effective amount” or “effective amount” of a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, ordeuterated analog thereof means an amount sufficient to effect treatment when administered to a subject,to provide a therapeutic benefit such as amelioration of symptoms or slowing of disease progression. For example, a therapeutically effective amount may be an amount sufficient to decrease a symptom of T-cell lymphoma. The therapeutically effective amount may vary depending on the subject, and disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and themanner of administering, which can readily be determined by one of ordinary skill in the art.Compound and Salt

[0064] The compound of Formula (I) is described in US 10,544,132 and has a structure as follows:and is named (2S,3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-2-methylpropanoic acid.

[0065] Pharmaceutically acceptable salts of the compound of Formula (I) include an organic or inorganicbase, generating a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Li+, Na+and K+, alkaline earth metal cations such as Ca2+and Mg2+, and other cations such as Al3+or Zn+. Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH4+) and substituted ammonium ions (e.g., NH3R+, NH2R2+, NHR3+, NR+4). Examples of somesuitable substituted ammonium ions are those derived from: methylamine, ethylamine, diethylamine,propylamine, dicyclohexylamine, triethylamine, butylamine (e.g., tert-butylamine), ethylenediamine,ethanolamine, diethanolamine, epolamine, piperazine, benzylamine, benzathine, phenylbenzylamine, 2-(diethylamino)ethanol, deanol, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH3)4+. In one embodiment the compound is the tris(hydroxymethyl)aminomethane (TRIS) salt. In some embodiments, the pharmaceutically acceptable salts of the compound of Formula (I) are a sodium salt, or a tromethamine salt.

[0066] As used herein, the term “the compound of Formula (I)” may refer to the compound of Formula (I) or a pharmaceutically acceptable salt thereof. As used herein, the term “the compound of Formula (I)free acid” refers specifically to the compound of Formula (I) as an active ingredient.Pharmaceutical Compositions

[0067] Provided herein is a pharmaceutical composition comprising a solid dispersion comprising the compound of Formula (I). The solid dispersion further comprises a stabilizing polymer.

[0068] In some embodiments, the stabilizing polymer is hydroxypropylmethyl cellulose (HPMC), hydroxypropylmethyl cellulose acetate succinate (HPMCAS), or a copolymer of polyvinylpyrrolidone / vinyl acetate (PVP / VA, copovidone). In some embodiments, the stabilizing polymer is PVP / VA. In some embodiments, the stabilizing polymer is PVP / VA 64, which is a 6:4 linear random copolymer of N-vinylpyrrolidone and vinyl acetate. In some embodiments, the stabilizing polymer is water soluble. In some embodiments, the stabilizing polymer is selected from the group consisting of PVP / VA64, HPMCAS, Eudragit EPO, PVP-K30, HPMC E3, Eudragit L100, Soluplus, HEC, methyl cellulose, PEG, Carboxymethyl cellulose, cyclodextrin, Chitosan, PVA, or combinations thereof.

[0069] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is present in the solid dispersion in an amount of about 30% to about 95% by weight of the soliddispersion. In other words, in some embodiments, for every 100 g of the solid dispersion, 30 – 95 g of thetotal weight of the solid dispersion is from the weight of the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, and 5 – 70 g of the total weight of the solid dispersion is from the weight of thestabilizing polymer. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is present in the solid dispersion in an amount of about 40% to about 90% by weight of the solid dispersion. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is present in the solid dispersion in an amount of about 50% to about 90% by weight of the solid dispersion. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is present in the solid dispersion in an amount of about 50% to about 80% by weight of the solid dispersion. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is present in the solid dispersion in an amount of about 60% to about 80% by weight of the soliddispersion. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is present in the solid dispersion in an amount of about 60% to about 70% by weight of the solid dispersion. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is present in the solid dispersion in an amount of about 60% to about 75% by weight of the solid dispersion. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is present in the solid dispersion in an amount of about 65% to about 70% by weight of the solid dispersion.

[0070] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is present in the solid dispersion in an amount about 25%, about 30%, about 33.3%, about 35%,about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 66.7%, about 70%, about75%, about 80%, about 85%, about 90%, or about 95% by weight of the solid dispersion.

[0071] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof is substantially amorphous. In some embodiments, within the solid dispersion, at least 98% of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is in amorphous form. In some embodiments, within the solid dispersion, at least 95% of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is in amorphous form. In some embodiments, within the solid dispersion, at least 98% of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is in amorphous form. In some embodiments, within the solid dispersion, at least 90% of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is in amorphous form. In some embodiments, within the solid dispersion, the compound of Formula (I) is in a sodium salt form. In some embodiments, within the solid dispersion, the compound of Formula (I) is in a tromethamine salt form.

[0072] In some embodiments, the weight ratio of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the stabilizing polymer in the solid dispersion is from about 5:1 to about 1:5. In some embodiments, the weight ratio of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the stabilizing polymer is from about 3:1 to about 1:3. In some embodiments, the weight ratio of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the stabilizing polymer is from about 1:1 to about 3:1. In some embodiments, the weight ratio of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the stabilizing polymer is about 2:1. In some embodiments, the weight ratio of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the stabilizing polymer is about 3:1. In some embodiments, the weight ratio of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the stabilizing polymer is about 1:2. In some embodiments, the weight ratio of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the stabilizing polymer is about 1:1.

[0073] In some embodiments, the stabilizing polymer is present in an amount greater than about 10% by weight of the solid dispersion. In some embodiments, the stabilizing polymer is present in an amount greater than about 20% by weight of the solid dispersion. In some embodiments, the stabilizing polymer is present in an amount greater than about 30% by weight of the solid dispersion.

[0074] In some embodiments, the stabilizing polymer is present in an amount of about 10% to about 60% by weight of the solid dispersion In some embodiments, the stabilizing polymer is present in an amount of about 10% to about 50% by weight of the solid dispersion. In some embodiments, the stabilizing polymer is present in an amount of about 20% to about 50% by weight of the solid dispersion. In some embodiments, the stabilizing polymer is present in an amount of about 20% to about 40% by weight of the solid dispersion. In some embodiments, the stabilizing polymer is present in an amount of about 25% to about 40% by weightof the solid dispersion. In some embodiments, the stabilizing polymer is present in an amount of about 30%to about 40% by weight of the solid dispersion. In some embodiments, the stabilizing polymer is present in an amount of about 30% to about 35% by weight of the solid dispersion.

[0075] In some embodiments, the stabilizing polymer is present in an amount of about 50% by weight of the solid dispersion. In some embodiments the stabilizing polymer is present in an amount of about 33.3% by weight of the solid dispersion. In some embodiments, the stabilizing polymer is present in an amount of about 25% by weight of the solid dispersion. In some embodiments, the stabilizing polymer is present in an amount of about 20% by weight of the solid dispersion.

[0076] In some embodiments, the stabilizing polymer is present in an amount of about 33.3% by weight of the solid dispersion and the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is present in an amount of about 66.7% by weight of the solid dispersion. In some embodiments, the stabilizing polymer is present in an amount of about 25% by weight of the solid dispersion and the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is present in an amount of about 75% by weight of the solid dispersion. In some embodiments, the stabilizing polymer is present in an amount of about 20% by weight of the solid dispersion and the compound of Formula (I), or a pharmaceutically acceptable saltthereof, is present in an amount of about 80% by weight of the solid dispersion.

[0077] The solid dispersion including the compound of Formula (I) may be formed by any suitable technique known in the art. For example, the solid dispersion may be formed by fusion, hot-melt extrusion, co-precipitation, solvent method, spray drying, super-critical fluid, kneading, or electro-spinning. In some embodiments, the solid dispersion may be formed by spray drying.

[0078] In some embodiments, the pharmaceutical composition may include about 30% w / w to about 90% w / w, about 35% w / w to about 85% w / w, about 40% w / w to about 50% w / w, about 40% w / w to about55% w / w, about 40% w / w to about 60% w / w, about 40% w / w to about 65% w / w, about 40% w / w to about 70% w / w, about 40% w / w to about 75% w / w, about 40% w / w to about 80% w / w, about 40% w / w to about 85% w / w, about 40% w / w to about 90% w / w, about 45% w / w to about 50% w / w, about 45% w / w to about 55% w / w, about 45% w / w to about 60% w / w, about 45% w / w to about 65% w / w, about 45% w / w to about 70% w / w, about 45% w / w to about 75% w / w, about 45% w / w to about 80% w / w, about 45% w / w to about 85% w / w, about 45% w / w to about 90% w / w, about 50% w / w to about 55% w / w, about 50% w / w to about 60% w / w, about 50% w / w to about 65% w / w, about 50% w / w to about 70% w / w, about 50% w / w to about 75% w / w, about 50% w / w to about 80% w / w, about 50% w / w to about 85% w / w, about 50% w / w to about 90% w / w, about 55% w / w to about 60% w / w, about 55% w / w to about 65% w / w, about 55% w / w to about 70% w / w, about 55% w / w to about 75% w / w, about 55% w / w to about 80% w / w, about 55% w / w to about 85% w / w, about 55% w / w to about 90% w / w, about 60% w / w to about 65% w / w, about 60% w / w to about 70% w / w, about 60% w / w to about 75% w / w, about 60% w / w to about 80% w / w, about 60% w / w to about 85% w / w, about 60% w / w to about 90% w / w, about 65% w / w to about 70% w / w, about 65% w / w to about 75% w / w, about 65% w / w to about 80% w / w, about 65% w / w to about 85% w / w, about 65% w / w to about 90% w / w, about 70% w / w to about 75% w / w, about 70% w / w to about 80% w / w, about 70% w / w to about 85% w / w, about 70% w / w to about 90% w / w, about 75% w / w to about 80% w / w, about 75% w / w to about 85% w / w, about 75% w / w to about 90% w / w, about 80% w / w to about 85% w / w, about 80% w / w to about 90% w / w, or about 85% w / w to about 90% w / w of the solid dispersion comprising the compound of Formula (I).

[0079] In some embodiments, the pharmaceutical composition may include about 51% w / w to about 69% w / w, about 53% w / w to about 67% w / w, about 56% w / w to about 64% w / w, or about 58% w / w to about 62% w / w of the solid dispersion comprising the compound of Formula (I).

[0080] In some embodiments, a pharmaceutical composition may include about 30 % w / w, about 35 % w / w, about 40 % w / w, about 45 % w / w, about 50 % w / w, about 55 % w / w, about 60 % w / w, about 65 %w / w, about 70 % w / w, about 75 % w / w, about 80 % w / w, about 85 % w / w, or about 90 % w / w of the soliddispersion comprising the compound of Formula (I). In some embodiments, a pharmaceutical composition may include about 59 % w / w, 59.1% w / w, about 59.2 % w / w, about 59.3 % w / w, about 59.4 % w / w, about 59.5 % w / w, about 59.6 % w / w, about 59.7 % w / w, about 59.8 % w / w, about 59.9 % w / w of the solid dispersion comprising the compound of Formula (I).

[0081] For preparing solid compositions such as tablets, powders or capsules the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation compositioncontaining a homogeneous mixture of a compound described herein or a pharmaceutically acceptable salt,tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof. When referring tothese preformulation compositions as homogeneous, the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unitdosage forms such as tablets, pills, and capsules. Some examples of suitable and pharmaceuticallyacceptable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, sodium starchglycolate, lactose monohydrate, polyvinylpyrrolidone (PVP, povidone), polyvinylpyrrolidone vinyl acetatecopolymer (PVP / VA, copovidone), polyvinylpolypyrrolidone (PVPP, crospovidone), cellulose, sterilewater, syrup, and methyl cellulose. The formulations can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservingagents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents.

[0082] In some embodiments, the pharmaceutical composition includes one or more excipients selected from copovidone, crospovidone, microcrystalline cellulose, mannitol, lactose monohydrate, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate.

[0083] In some embodiments of the pharmaceutical composition comprises crospovidone. In some embodiments, the pharmaceutical composition comprises crospovidone, microcrystalline cellulose and lactose monohydrate. In some embodiments, the pharmaceutical composition comprises crospovidone, microcrystalline cellulose, lactose monohydrate, silicon dioxide, and magnesium stearate.

[0084] In some embodiments, the pharmaceutical composition comprises croscarmellose sodium, crospovidone or a combination thereof. In some embodiments, the pharmaceutical composition comprises croscarmellose sodium.

[0085] In some embodiments, the pharmaceutical composition comprises lactose monohydrate,microcrystalline cellulose or a combination thereof. In some embodiments, the pharmaceutical compositioncomprises lactose monohydrate and microcrystalline cellulose.

[0086] In some embodiments, the pharmaceutical composition comprises silicon dioxide, magnesiumstearate or a combination thereof. In some embodiments, the pharmaceutical composition comprises silicon dioxide and magnesium stearate.

[0087] In some embodiments, the pharmaceutical composition comprises croscarmellose sodium, lactose monohydrate and microcrystalline cellulose.

[0088] In some embodiments, a pharmaceutical composition may comprise about 50-70 % w / w of the solid dispersion comprising the compound of Formula (I), and one or more excipients. In someembodiments, the solid dispersion comprises about 60%-75% w / w of the compound of Formula (I) and about 25%-40% w / w of the stabilizing polymer. In some embodiments, the solid dispersion comprises the compound of Formula (I) and the stabilizing polymer, wherein the compound of Formula (I) and thestabilizing polymer have a weight ratio of 3:1 to 1:3. In some embodiments, the compound of Formula (I)is substantially amorphous. The one or more excipients may be selected from microcrystalline cellulose, mannitol, lactose monohydrate, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate. For example, the pharmaceutical composition may include about 10%-30% w / w of lactose monohydrate. The pharmaceutical composition may be provided in a tablet.

[0089] In some embodiments, the pharmaceutical composition comprises about 50-70% w / w of the solid dispersion comprising the compound of Formula (I) and about 5%-15% w / w of microcrystalline cellulose.

[0090] In some embodiments, the pharmaceutical composition comprises about 50-70% w / w of the solid dispersion comprising the compound of Formula (I), about 5%-15% w / w of microcrystalline cellulose and about 10%-30% w / w of lactose monohydrate.

[0091] In some embodiments, the pharmaceutical composition comprises about 50-70% w / w of the solid dispersion comprising the compound of Formula (I), about 3%-10% w / w of croscarmellose sodium.

[0092] In some embodiments, the pharmaceutical composition comprises about 50-70% w / w of the solid dispersion comprising the compound of Formula (I), about 5%-15% w / w of microcrystalline cellulose, about 10%-30% w / w of lactose monohydrate and about 3%-10% w / w of croscarmellose sodium.

[0093] In some embodiments, the pharmaceutical composition comprises about 50-70% w / w of the solid dispersion comprising the compound of Formula (I), about 5%-15% w / w of microcrystalline cellulose, about 10%-30% w / w of lactose monohydrate, about 3%-10% w / w of croscarmellose sodium, about 0.1%- 3% w / w of silicon dioxide; and about 0.1%-3% w / w of magnesium stearate.

[0094] In some embodiments, the pharmaceutical composition comprises about 60% w / w of the solid dispersion comprising the compound of Formula (I), about 10 % w / w of microcrystalline cellulose, about 20 % w / w of lactose monohydrate, about 8% w / w of croscarmellose sodium, about 1% w / w of silicondioxide; and about 1.25 % w / w of magnesium stearate. In some embodiments, the solid dispersioncomprises about 60%-75% w / w of the compound of Formula (I) and about 25%-40% w / w of the stabilizingpolymer. In some embodiments, the solid dispersion comprises the compound of Formula (I) and thestabilizing polymer, wherein the compound of Formula (I) and the stabilizing polymer have a weight ratioof 3:1 to 1:3. In some embodiments, the compound of Formula (I) is substantially amorphous. The one ormore excipients may be selected from microcrystalline cellulose, mannitol, lactose monohydrate, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate. For example, the pharmaceutical composition may include about 10%-30% w / w of lactose monohydrate. The pharmaceutical composition may be provided in a tablet.

[0095] The pharmaceutical composition may be manufactured by any appropriate method known in the art. For example, the pharmaceutical composition may be manufactured by dry blend process or the roller compaction process. Tablet Formulation

[0096] In some embodiments, the pharmaceutical composition is formulated as a tablet. In some embodiments, the composition is formulated as a tablet comprising an intra-granular layer and an extra- granular layer. In some of such embodiments, the solid dispersion is in the intra-granular layer and the intra- granular layer further comprises additional excipients as described herein. In some of such embodiments, the solid dispersion is in the extra-granular layer and the extra-granular layer further comprises additional excipients as described herein. In some of such embodiments, the solid dispersion is in the intra-granular layer and in the extra-granular layer and the intra-granular layer and / or the extra-granular layer further comprises additional excipients as described herein.

[0097] In some embodiments of the pharmaceutical composition formulated as a tablet, the intra-granular layer of the tablet comprises about 20-30% w / w of the solid dispersion comprising the compound of Formula (I), about 20-50% w / w of microcrystalline cellulose, about 20-50% w / w of lactose monohydrate, about 3%-10% w / w of crospovidone, about 0.1%-3% w / w of silicon dioxide; and about 0.1%-3% w / w of magnesium stearate, and the extra-granular layer of the tablet comprises about 0.1%-3% w / w of magnesium stearate, wherein the weight percentage is relative to the entire weight of the pharmaceutical composition. In one such embodiment, the tablet comprises about 20-30% w / w microcrystalline cellulose and about 40- 50% w / w lactose monohydrate. In another such embodiment, the tablet comprises about 40-50% w / w microcrystalline cellulose and about 20-30% lactose monohydrate, wherein the weight percentage is relative to the entire weight of the pharmaceutical composition.

[0098] In some embodiments of the pharmaceutical composition formulated as a tablet, the intra-granular layer of the tablet comprises about 50-70% w / w of the solid dispersion comprising the compound of Formula (I), about 5%-15% w / w of microcrystalline cellulose, about 10%-30% w / w of lactose monohydrate, about 3%-10% w / w of croscarmellose sodium, about 0.1%-3% w / w of silicon dioxide; and about 0.1%-3% w / w of magnesium stearate, and the extra-granular layer of the tablet comprises about 1%-3% w / w of croscarmellose sodium, about 0.1%-1% of colloidal silicon dioxide, and about 0.1% -1% of magnesium stearate, wherein the weight percentage is relative to the entire weight of the pharmaceutical composition. In some embodiments of the pharmaceutical composition formulated as a tablet, the intra- granular layer of the tablet comprises about 60% w / w of the solid dispersion comprising the compound of Formula (I), about 10% w / w of microcrystalline cellulose, about 20% w / w of lactose monohydrate, about 6% w / w of croscarmellose sodium, about 0.75% w / w of silicon dioxide; and about 0.75% w / w of magnesium stearate, and the extra-granular layer of the tablet comprises about 2% w / w of croscarmellose sodium, about 0.25% of colloidal silicon dioxide, and about 0.5% of magnesium stearate, wherein the weight percentage is relative to the entire weight of the pharmaceutical composition.

[0099] In some embodiments of the pharmaceutical composition formulated as a tablet, the tablet iscoated with a film. In some embodiments, the film coat comprises a polymer, a plasticizer and / or a pigment. Examples of polymers in a tablet film coating include and are not limited to polyvinyl alcohol (PVA), polyvinylpyrrolidone (povidone), hydroxypropylmethyl cellulose (HPMC), methacrylic acid copolymer,methyl cellulose, ethyl cellulose or any other suitable film forming polymer. Examples of plasticizers in atablet film coating include and are not limited to hydroxypropylmethyl cellulose (HPMC), polyethylene glycol, triacetin, stearates, citrates, phthalate esters or any other suitable plasticizers. In some embodiments,the film coating is OPADRY II®.Dosage Form

[0100] The pharmaceutical compositions or the compounds described herein may be administered in either single or multiple doses. The pharmaceutical composition or the compounds described herein may be administered by various methods including, for example, orally.

[0101] A dosage form for oral administration may be, for example, capsule or tablets. In making thepharmaceutical compositions that include the compound of Formula (I) or a pharmaceutically acceptablesalt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, the compoundof Formula (I) is usually mixed with an excipient, and the compositions can be in the form of tablets, pills,powders, granules, or sterile packaged powders. The compositions can be enclosed with in a carrier, suchas a capsule.

[0102] The tablets, pills or capsules of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can include an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components canbe separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[0103] In some embodiments, each dosage form may include 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg,or 300 mg of the compound of Formula (I) (free acid). In some embodiments, a suitable dosage form maybe a tablet including 15 mg of the compound of Formula (I) (free acid), 50 mg of the compound of Formula(I) (free acid), 60 mg of the compound of Formula (I) (free acid) or 200 mg of the compound of Formula(I) (free acid). In some embodiments, a suitable dosage form may be a tablet including 50 mg of the compound of Formula (I) (free acid) or 200 mg of the compound of Formula (I) (free acid). Kits

[0104] Provided herein are also kits that include a pharmaceutical composition including the solid dispersion including the compound of Formula (I) or a pharmaceutically acceptable salt. In one embodiment, a kit further includes instructions for use, a label and / or instructions for use of the compoundsin the treatment of the indications, including the diseases or conditions, described herein. The kit may beused for the treatment of cancer for patients in need thereof. For example, a kit including the pharmaceuticalcomposition including the compound of Formula (I) or a pharmaceutically acceptable salt thereof, and ablister pack or a bottle, such as the blister packs or bottles described herein, may be provided. Thepharmaceutical composition or its dosage form may be contained within the packaging, such as the blisterpacks or the sealed bottles.Uses and Method of Treatment

[0105] A pharmaceutical composition comprising the solid dispersion including the compound ofFormula (I), or a kit including the pharmaceutical composition described herein, may be used for the treatment of, or manufacture of a medicament for the treatment of one or more diseases or conditionsmediated by the MDM2-p53 pathway, including cancers mediated by the MDM2-p53 pathway. Alsoprovided herein are methods of treating one or more diseases or conditions mediated by the MDM2-p53pathway, including cancers mediated by the MDM2-p53 pathway.

[0106] The cancers may be cancers which are sensitive to treatment with MDM2 inhibitors. The cancers may include those with an MDM2 amplification and / or MDM2 overexpression. The cancers may have wild-type TP53 gene. In some embodiments, the cancer is p53 mutant tumor.

[0107] In one embodiment, the cancer is a solid tumor. The solid tumor may be metastatic and refractory solid tumors, advanced metastatic and refractory solid tumors, mesothelioma, malignant peritoneal mesothelioma, malignant pleural mesothelioma, liposarcoma, dedifferentiated liposarcoma, welldifferentiated liposarcoma, glioblastoma multiforme (GBM), intimal sarcoma, hepatocellular carcinoma,oesophageal cancer, Ewing's sarcoma, soft tissue sarcoma, osteosarcoma, melanoma (e.g. uveal melanoma), ovarian cancer, colorectal cancer, rectal cancer, head and neck squamous cell carcinoma, cervical cancer,gastric cancer, gastrointestinal stromal tumor (GIST), breast cancer, lung cancer (e.g. non-small cell lungcancer (NSCLC)), brain cancer, glioma, or neuroblastoma.

[0108] In some embodiments, the cancer can be leukemia or hematological cancer. The cancer may bemyelofibrosis, acute myelogenous leukemia (AML), T-cell lymphomas, B-cell lymphomas, diffuse largeB-cell lymphoma (DLBCL), MALT lymphoma. The T-cell lymphoma may be progressive or relapsedperipheral T-cell lymphoma (PTCL), or relapsed or refractory cutaneous T-cell lymphoma (CTCL). In some embodiments, the cancer can be Hodgkin’s lymphoma. Combination Therapies

[0109] In one embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt,compositions, or dosage forms disclosed herein may be used / administered in combination with one or moreadditional therapeutic agents that are being used and / or developed to treat cancers, such as T-celllymphomas. In one embodiment, a dosage form comprising the compound of Formula (I) or apharmaceutically acceptable salt or the pharmaceutical compositions disclosed herein, may further includesaid additional therapeutic agents that are being used and / or developed to treat cancers, such as T-celllymphomas.

[0110] In one embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt, compositions, or dosage forms disclosed herein may be used / administered in combination with one of more other compounds (or therapies) for treatment of a particular disease state, for example a neoplastic disease such as a cancer as hereinbefore defined. For the treatment of the above conditions, the compounds of the invention may be advantageously employed in combination with one or more other medicinal agents, more particularly, with other anti-cancer agents or adjuvants (supporting agents in the therapy) in cancer therapy. Examples of other therapeutic agents or treatments that may be administered together (whether concurrentlyor at different time intervals) with the compound of Formula (I) or pharmaceutically acceptable salt, compositions, or dosage forms disclosed herein include but are not limited to: ^Topoisomerase I inhibitors^ Antimetabolites^ Tubulin targeting agents^ DNA binder and topoisomerase II inhibitors^ Alkylating Agents^ Monoclonal Antibodies.^ Anti-Hormones^ Signal Transduction Inhibitors^ Proteasome Inhibitors^ DNA methyl transferase inhibitors^ Cytokines and retinoids^ Chromatin targeted therapies^ Radiotherapy, and,^ Other therapeutic or prophylactic agents.

[0111] Particular examples of anti-cancer agents or adjuvants (or salts thereof), include but are not limited to any of the agents selected from groups (i)-(xlviii), and optionally group (xlix), below:(i) Platinum compounds, for example cisplatin (optionally combined with amifostine), carboplatin oroxaliplatin;(ii) Taxane compounds, for example paclitaxel, paclitaxel protein bound particles (AbraxaneTM),docetaxel, cabazitaxel or larotaxel;(iii) Topoisomerase I inhibitors, for example camptothecin compounds, for example camptothecin,irinotecan(CPT11), SN-38, or topotecan;(iv) Topoisomerase II inhibitors, for example anti-tumour epipodophyllotoxins or podophyllotoxinderivatives for example etoposide, or teniposide;(v) Vinca alkaloids, for example vinblastine, vincristine, liposomal vincristine (Onco-TCS), vinorelbine,vindesine, vinflunine or vinvesir;(vi) Nucleoside derivatives, for example 5-fluorouracil (5-FU, optionally in combination withleucovorin), gemcitabine, capecitabine, tegafur, UFT, S1, cladribine, cytarabine (Ara-C, cytosine arabinoside), fludarabine, clofarabine, or nelarabine;(vii) Antimetabolites, for example clofarabine, aminopterin, or methotrexate, azacitidine, cytarabine,floxuridine, pentostatin, thioguanine, thiopurine, 6-mercaptopurine, or hydroxyurea (hydroxycarbamide);(viii) Alkylating agents, such as nitrogen mustards or nitrosourea, for example cyclophosphamide,chlorambucil, carmustine (BCNU), bendamustine, thiotepa, melphalan, treosulfan, lomustine (CCNU), altretamine, busulfan, dacarbazine, estramustine, fotemustine, ifosfamide (optionally in combination with mesna), pipobroman, procarbazine, streptozocin, temozolomide, uracil, mechlorethamine, methylcyclohexylchloroethylnitrosurea, or nimustine (ACNU);(ix) Anthracyclines, anthracenediones and related drugs, for example daunorubicin, doxorubicin(optionally in combination with dexrazoxane), liposomal formulations of doxorubicin (eg. Caelyx™, Myocet™, Doxil™), idarubicin, mitoxantrone, epirubicin, amsacrine, or valrubicin;(x) Epothilones, for example ixabepilone, patupilone, BMS-310705, KOS-862 and ZK-EPO, epothiloneA, epothilone B, desoxyepothilone B (also known as epothilone D or KOS-862), aza-epothilone B(also known as BMS-247550), aulimalide, isolaulimalide, or luetherobin;(xi) DNA methyl transferase inhibitors, for example temozolomide, azacytidine, or decitabine;(xii) Antifolates, for example methotrexate, pemetrexed disodium, or raltitrexed;(xiii) Cytotoxic antibiotics, for example antinomycin D, bleomycin, mitomycin C, dactinomycin,carminomycin, daunomycin, levamisole, plicamycin, or mithramycin;(xiv) Tubulin-binding agents, for example combrestatin, colchicines or nocodazole;(xv) Signal Transduction inhibitors such as Kinase inhibitors for example receptor tyrosine kinaseinhibitors (e.g. EGFR (epithelial growth factor receptor) inhibitors, VEGFR (vascular endothelial growth factor receptor) inhibitors, PDGFR (platelet-derived growth factor receptor) inhibitors, Axl inhibitors, MTKI (multi target kinase inhibitors), Raf inhibitors, ROCK inhibitors, mTOR inhibitors, MEK inhibitors or PI3K Inhibitors) for example imatinib mesylate, erlotinib, gefitinib, dasatinib, lapatinib, dovotinib, axitinib, nilotinib, vandetanib, vatalinib, pazopanib, sorafenib, sunitinib, , temsirolimus, everolimus (RAD 001), vemurafenib (PLX4032 or RG7204), dabrafenib, encorafenib,selumetinib (AZD6244), trametinib (GSK121120212), dactolisib (BEZ235), buparlisib (BKM-120; NVP-BKM-120), BYL719, copanlisib (BAY-80-6946), ZSTK-474, CUDC-907, apitolisib (GDC- 0980; RG-7422), pictilisib (pictrelisib, GDC-0941, RG-7321), GDC-0032, GDC-0068, GSK- 2636771, idelalisib (formerly CAL-101, GS 1101, GS-1101), MLN1117 (INK1117), MLN0128(INK128), IPI-145 (INK1197), LY-3023414, ipatasertib, afuresertib, MK-2206, MK-8156, LY- 3023414, LY294002, SF1126 or PI-103, sonolisib (PX-866), or AT13148.(xvi) Aurora kinase inhibitors for example AT9283, barasertib (AZD1152), TAK-901, MK0457 (VX680),cenisertib (R-763), danusertib (PHA-739358), alisertib (MLN-8237), or MP-470;(xvii) CDK inhibitors for example AT7519, roscovitine, seliciclib, alvocidib (flavopiridol), dinaciclib(SCH-727965), 7-hydroxy-staurosporine (UCN-01), JNJ-7706621, BMS-387032 (a.k.a. SNS-032), PHA533533, ZK-304709, or AZD-5438 and including CDK4 inhibitors such as palbociclib (PD332991) and ribociclib (LEE-011); (xviii)PKA / B inhibitors and PKB (akt) pathway inhibitors for example AT13148, AZ-5363, Semaphore, SF1126 and MTOR inhibitors such as rapamycin analogues, AP23841 and AP23573, calmodulin inhibitors (forkhead translocation inhibitors), API-2 / TCN (triciribine), RX-0201, enzastaurin HCl (LY317615), NL-71-101, SR-13668, PX-316, or KRX-0401 (perifosine / NSC 639966);(xix) Hsp90 inhibitors for example onalespib (AT13387), herbimycin, geldanamycin (GA), 17-allylamino-17-desmethoxygeldanamycin (17-AAG) e.g. NSC-330507, Kos-953 and CNF-1010, 17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride (17-DMAG) e.g. NSC-707545 and Kos-1022, NVP-AUY922 (VER-52296), NVP-BEP800, CNF-2024 (BIIB-021 an oralpurine), ganetespib (STA-9090), SNX-5422 (SC-102112) or IPI-504;(xx) Monoclonal Antibodies (unconjugated or conjugated to radioisotopes, toxins or other agents),antibody derivatives and related agents, such as anti-CD, anti-VEGFR, anti-HER2 or anti-EGFR antibodies, for example rituximab (CD20), ofatumumab (CD20), ibritumomab tiuxetan (CD20), GA101 (CD20), tositumomab (CD20), epratuzumab (CD22), lintuzumab (CD33), gemtuzumab ozogamicin (CD33), alemtuzumab (CD52), galiximab (CD80), trastuzumab (HER2 antibody), pertuzumab (HER2), trastuzumab-DM1 (HER2), ertumaxomab (HER2 and CD3), cetuximab (EGFR), panitumumab (EGFR), necitumumab (EGFR), nimotuzumab (EGFR), bevacizumab (VEGF), catumaxumab (EpCAM and CD3), abagovomab (CA125), farletuzumab (folate receptor), elotuzumab (CS1), denosumab (RANK ligand), figitumumab (IGF1R), CP751,871 (IGF1R), mapatumumab (TRAIL receptor), metMAB (met), mitumomab (GD3 ganglioside), naptumomab estafenatox (5T4), or siltuximab (IL6) or immunomodulating agents such as CTLA-4 blocking antibodies and / or antibodies against PD-1 and PD-L1 and / or PD-L2 for example ipilimumab (CTLA4), MK-3475 (pembrolizumab, formerly lambrolizumab, anti-PD-1), nivolumab (a anti-PD- 1), BMS-936559 (anti- PD-L1), MPDL320A, AMP-514 or MEDI4736 (anti-PD-L1), ortremelimumab (formerly ticilimumab, CP-675,206, anti-CTLA-4);(xxi) Estrogen receptor antagonists or selective estrogen receptor modulators (SERMs) or inhibitors ofestrogen synthesis, for example tamoxifen, fulvestrant, toremifene, droloxifene, faslodex, or raloxifene;(xxii) Aromatase inhibitors and related drugs, such as exemestane, anastrozole, letrazole, testolactoneaminoglutethimide, mitotane or vorozole;(xxiii)Antiandrogens (i.e. androgen receptor antagonists) and related agents for example bicalutamide, nilutamide, flutamide, cyproterone, or ketoconazole;(xxiv) Hormones and analogues thereof such as medroxyprogesterone, diethylstilbestrol (a.k.a.diethylstilboestrol) or octreotide;(xxv) Steroids for example dromostanolone propionate, megestrol acetate, nandrolone (decanoate,phenpropionate), fluoxymestrone or gossypol,(xxvi) Steroidal cytochrome P45017alpha-hydroxylase-17,20-lyase inhibitor (CYP17), e.g. abiraterone;(xxvii) Gonadotropin releasing hormone agonists or antagonists (GnRAs) for example abarelix, goserelinacetate, histrelin acetate, leuprolide acetate, triptorelin, buserelin, or deslorelin;(xxviii) Glucocorticoids, for example prednisone, prednisolone, dexamethasone;(xxix) Differentiating agents, such as retinoids, rexinoids, vitamin D or retinoic acid and retinoic acidmetabolism blocking agents (RAMBA) for example accutane, alitretinoin, bexarotene, or tretinoin;(xxx) Farnesyltransferase inhibitors for example tipifarnib;(xxxi) Chromatin targeted therapies such as histone deacetylase (HDAC) inhibitors for example sodiumbutyrate, suberoylanilide hydroxamide acid (SAHA), depsipeptide (FR 901228), dacinostat (NVP- LAQ824), R306465 / JNJ-16241199, JNJ-26481585, trichostatin A, vorinostat, chlamydocin, A-173, JNJ-MGCD-0103, PXD-101, or apicidin;(xxxii) Drugs targeting the ubiquitin-proteasome pathway including proteasome Inhibitors for examplebortezomib, carfilzomib, CEP-18770, MLN-9708, or ONX-0912; NEDD8 inhibitors; HDM2 antagonist and deubiquitinases (DUBs);(xxxiii) Photodynamic drugs for example porfimer sodium or temoporfin;(xxxiv) Marine organism-derived anticancer agents such as trabectidin;(xxxv) Radiolabelled drugs for radioimmunotherapy for example with a beta particle-emitting isotope (e.g., Iodine -131, Yittrium -90) or an alpha particle-emitting isotope (e.g., Bismuth-213 or Actinium-225) for example ibritumomab or Iodine tositumomab or alpha radium 223;(xxxvi) Telomerase inhibitors for example telomestatin;(xxxvii)Matrix metalloproteinase inhibitors for example batimastat, marimastat, prinostat or metastat;(xxxviii) Recombinant interferons (such as interferon-γ and interferon α) and interleukins (e.g.interleukin 2), for example aldesleukin, denileukin diftitox, interferon alfa 2a, interferon alfa 2b, or peginterferon alfa 2b;(xxxix) Selective immunoresponse modulators for example thalidomide, or lenalidomide;(xl) Therapeutic Vaccines such as sipuleucel-T (Provenge) or OncoVex;(xli) Cytokine-activating agents include Picibanil, Romurtide, Sizofiran, Virulizin, or Thymosin;(xlii) Arsenic trioxide;(xliii) Inhibitors of G-protein coupled receptors (GPCR) for example atrasentan ;(xliv) Enzymes such as L-asparaginase, pegaspargase, rasburicase, or pegademase;(xlv) DNA repair inhibitors such as PARP inhibitors for example, olaparib, velaparib, iniparib, INO-1001,AG-014699, or ONO-2231;(xlvi) Agonists of Death receptor (e.g. TNF-related apoptosis inducing ligand (TRAIL) receptor), such asmapatumumab (formerly HGS-ETR1), conatumumab (formerly AMG 655), PRO95780, lexatumumab, dulanermin, CS-1008 , apomab or recombinant TRAIL ligands such as recombinant Human TRAIL / Apo2 Ligand; (xlvii)Immunotherapies such as immune checkpoint inhibitors; cancer vaccines and CAR-T cell therapy;(xlviii) Regulators of Cell death (apoptosis) including Bcl-2 (B-cell lymphoma 2) antagonists such asvenetoclax (ABT-199 or GDC-0199), ABT-737, ABT-263, TW-37, sabutoclax, obatoclax, and MIM1 and IAP antagonists including LCL-161 (Novartis), Debio-1143 (Debiopharma / Ascenta),AZD5582, Birinapant / TL-32711 (TetraLogic), CUDC-427 / GDC-0917 / RG-7459 (Genentech), JP1201 (Joyant), T-3256336 (Takeda), GDC-0152 (Genentech) or HGS-1029 / AEG-40826 (HGS / Aegera);(xlix) Prophylactic agents (adjuncts); i.e. agents that reduce or alleviate some of the side effects associatedwith chemotherapy agents, for example– anti-emetic agents,– agents that prevent or decrease the duration of chemotherapy-associated neutropenia and preventcomplications that arise from reduced levels of platelets, red blood cells or white blood cells, for example interleukin-11 (e.g. oprelvekin), erythropoietin (EPO) and analogues thereof (e.g. darbepoetin alfa), colony-stimulating factor analogs such as granulocyte macrophage-colony stimulating factor (GM-CSF) (e.g. sargramostim), and granulocyte-colony stimulating factor (G- CSF) and analogues thereof (e.g. filgrastim, pegfilgrastim),– agents that inhibit bone resorption such as denosumab or bisphosphonates e.g. zoledronate,zoledronic acid, pamidronate and ibandronate,– agents that suppress inflammatory responses such as dexamethasone, prednisone, and prednisolone,– agents used to reduce blood levels of growth hormone and IGF-I (and other hormones) in patientswith acromegaly or other rare hormone-producing tumours, such as synthetic forms of the hormone somatostatin e.g. octreotide acetate,– antidote to drugs that decrease levels of folic acid such as leucovorin, or folinic acid,– agents for pain e.g. opiates such as morphine, diamorphine and fentanyl,– non-steroidal anti-inflammatory drugs (NSAID) such as COX-2 inhibitors for example celecoxib,etoricoxib and lumiracoxib,– agents for mucositis e.g. palifermin,– agents for the treatment of side-effects including anorexia, cachexia, oedema or thromoembolicepisodes, such as megestrol acetate.

[0112] For example, the one or more additional therapeutic agents may be selected from cedazuridine, azacitidine, venetoclax, decitabine, navitoclax, entinostat, cisplatin, dexamethasone, pembrolizumab, capecitabine, or tolinapant. In one embodiment, a dosage form comprising the compound of Formula (I) ora pharmaceutically acceptable salt or the pharmaceutical compositions disclosed herein, may further includesaid additional therapeutic agents that are being used and / or developed to treat cancers, such as T-celllymphomas.

[0113] In one embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt,compositions, or dosage forms disclosed herein, are administered in combination with a therapeuticprocedure, such as bone marrow / stem cell transplant, CAR T cell therapies, or radiation therapy. In someembodiments, the pharmaceutical composition or a dosage form described herein may include one or more anti-cancer agents in addition to the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0114] Each of the compounds present in the combinations of the invention may be given in individually varying dose schedules and via different routes. As such, the posology of each of the two or more agents may differ: each may be administered at the same time or at different times. A person skilled in the art would know through his or her common general knowledge the dosing regimes and combination therapies to use. For example, the compound of Formula (I) or pharmaceutically acceptable salt, compositions, or dosage forms disclosed herein may be using in combination with one or more other agents which are administered according to their existing combination regimen. Examples of standard combination regimens are provided below.

[0115] The taxane compound is advantageously administered in a dosage of 50 to 400 mg per square meter (mg / m2) of body surface area, for example 75 to 250 mg / m2, particularly for paclitaxel in a dosage of about 175 to 250 mg / m2and for docetaxel in about 75 to 150 mg / m2per course of treatment.

[0116] The camptothecin compound is advantageously administered in a dosage of 0.1 to 400 mg per square meter (mg / m2) of body surface area, for example 1 to 300 mg / m2, particularly for irinotecan in a dosage of about 100 to 350 mg / m2and for topotecan in about 1 to 2 mg / m2per course of treatment.

[0117] The anti-tumour podophyllotoxin derivative is advantageously administered in a dosage of 30 to 300 mg per square meter (mg / m2) of body surface area, for example 50 to 250mg / m2, particularly foretoposide in a dosage of about 35 to 100 mg / m2and for teniposide in about 50 to 250 mg / m2per course of treatment.

[0118] The anti-tumour vinca alkaloid is advantageously administered in a dosage of 2 to 30 mg per square meter (mg / m2) of body surface area, particularly for vinblastine in a dosage of about 3 to 12 mg / m2, for vincristine in a dosage of about 1 to 2 mg / m2, and for vinorelbine in dosage of about 10 to 30 mg / m2per course of treatment.

[0119] The anti-tumour nucleoside derivative is advantageously administered in a dosage of 200 to2500 mg per square meter (mg / m2) of body surface area, for example 700 to 1500 mg / m2, particularly for 5-FU in a dosage of 200 to 500mg / m2, for gemcitabine in a dosage of about 800 to 1200 mg / m2and for capecitabine in about 1000 to 2500 mg / m2per course of treatment.

[0120] The alkylating agents such as nitrogen mustard or nitrosourea is advantageously administered in a dosage of 100 to 500 mg per square meter (mg / m2) of body surface area, for example 120 to 200 mg / m2, particularly for cyclophosphamide in a dosage of about 100 to 500 mg / m2, for chlorambucil in a dosage of about 0.1 to 0.2 mg / kg, for carmustine in a dosage of about 150 to 200 mg / m2, and for lomustine in a dosage of about 100 to 150 mg / m2per course of treatment.

[0121] The anti-tumour anthracycline derivative is advantageously administered in a dosage of 10 to 75 mg per square meter (mg / m2) of body surface area, for example 15 to 60 mg / m2, particularly for doxorubicin in a dosage of about 40 to 75 mg / m2, for daunorubicin in a dosage of about 25 to 45mg / m2, and for idarubicin in a dosage of about 10 to 15 mg / m2per course of treatment.

[0122] The antiestrogen agent is advantageously administered in a dosage of about 1 to 100 mg daily depending on the particular agent and the condition being treated. Tamoxifen is advantageouslyadministered orally in a dosage of 5 to 50 mg, typically 10 to 20 mg twice a day, continuing the therapyfor sufficient time to achieve and maintain a therapeutic effect. Toremifene is advantageously administered orally in a dosage of about 60mg once a day, continuing the therapy for sufficient time toachieve and maintain a therapeutic effect. Anastrozole is advantageously administered orally in a dosageof about 1mg once a day. Droloxifene is advantageously administered orally in a dosage of about 20- 100mg once a day. Raloxifene is advantageously administered orally in a dosage of about 60mg once a day. Exemestane is advantageously administered orally in a dosage of about 25mg once a day.

[0123] Antibodies are advantageously administered in a dosage of about 1 to 5 mg per square meter (mg / m2) of body surface area, or as known in the art, if different. Trastuzumab is advantageously administered in a dosage of 1 to 5 mg per square meter (mg / m2) of body surface area, particularly 2 to 4mg / m2per course of treatment.

[0124] Where the compound of Formula (I) or a pharmaceutically acceptable salt, compositions, or dosage forms disclosed herein is administered in combination therapy with one, two, three, four or moreother therapeutic agents (typically one or two, more typically one), the compounds can be administeredsimultaneously or sequentially. In the latter case, the two or more compounds will be administered within a period and in an amount and manner that is sufficient to ensure that an advantageous or synergistic effect is achieved. When administered sequentially, they can be administered at closely spaced intervals (for example over a period of 5-10 minutes) or at longer intervals (for example 1, 2, 3, 4 or more hours apart, or even longer periods apart where required), the precise dosage regimen being commensurate with the properties of the therapeutic agent(s). These dosages may be administered for example once, twice or more per course of treatment, which may be repeated for example every 7, 14, 21 or 28 days. Dosing

[0125] The specific dose level of a compound of the present application for any particular subject willdepend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease in the subject undergoing therapy. For example, adosage may be expressed as a number of milligrams of the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof described herein per kilogram of the subject’s body weight (mg / kg). Dosages of between about 0.1 and 150 mg / kg may be appropriate. In some embodiments, about 0.1 and 100 mg / kgmay be appropriate. In other embodiments, a dosage of between 0.5 and 60 mg / kg may be appropriate.Normalizing according to the subject’s body weight is particularly useful when adjusting dosages between subjects of widely disparate size, such as when using the drug in both children and adult humans or when converting an effective dosage in a non-human subject such as a dog to a dosage suitable for a human subject.

[0126] The daily dosage may also be described as a total amount of the compound of Formula (I), or apharmaceutically acceptable salt described herein administered per dose or per day. For example, daily dosage of the compound of Formula (I) (free acid) may be between about 1 mg and 4,000 mg, between about 2,000 to 4,000 mg / day, between about 1 to 2,000 mg / day, between about 1 to 1,000 mg / day, betweenabout 10 to 1000 mg / day, between about 20 to 1000 mg / day, between about 30 to 700 mg / day, or betweenabout 50 to 700 mg / day.

[0127] When administered orally, the total daily dosage of the compound of Formula (I) (free acid) for a human subject may be between 1 mg and 1,000 mg, between about 1,000-2,000 mg / day, between about 10-500 mg / day, between about 50-500 mg / day, between about 100-500 mg / day, between about 200-500mg / day, between about 300-500 mg / day, or between 500-1000 mg / day. For example, the total daily dosagefor a human subject may be about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, or 700 mg / day. In some embodiments, the total daily dose for a human subject may be about 100, 200, 300, 400,500, 550, 600, 650, or 700 mg per day.

[0128] The compound of Formula (I) or a pharmaceutically acceptable salt or the compositions thereof may be administered once, twice, three, or four times daily, or twice or three times a week, using any suitable mode described above. Also, administration or treatment with the compound of Formula (I) may be continued for a number of days; for example, commonly treatment would continue for at least 7 days, 14 days, or 28 days, for one cycle of treatment. Treatment cycles are well known in cancer chemotherapy, and are frequently alternated with resting periods of about 1 to 28 days, commonly about 7 days or about 14 days, between cycles. The treatment cycles, in other embodiments, may also be continuous.

[0129] In some embodiments, the compound of Formula (I) may be administered once a day, orally, in an amount of about 200, 250, 300, 350, 400, 450, or 500 mg of the compound of Formula (I) (free acid). In some embodiments, such daily administration may continue for 7 days, 14 days, 28 days, 8 weeks, 12weeks, 16 weeks, 24 weeks or longer. In some embodiments, the compound of Formula (I) may beadministered once a day, orally, in an amount of about 400 mg or 420 mg of the compound of Formula (I)(free acid). In some embodiments, the compound of Formula (I) may be administered once a day, orally, in an amount of about 400 mg of the compound of Formula (I) (free acid). For example, the compound of Formula (I) may be administered once a day, orally, in an amount of about 400 mg of the compound ofFormula (I) (free acid) for 28 days, 8 weeks, 12 weeks, 16 weeks, 24 weeks or longer.

[0130] In some embodiments, the compound of Formula (I) may be administered twice a week, orally,in an amount of about 600 mg to 700 mg of the compound of Formula (I) (free acid). In some embodiments,such daily administration may continue for 7 days, 14 days, 28 days, 8 weeks, 12 weeks, 16 weeks, 24weeks or longer. For example, the compound of Formula (I) may be administered twice a week, orally, inan amount of about 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, or 700 mg of the compound ofFormula (I) (free acid) for 7 days, 14 days, 28 days, 8 weeks, 12 weeks, 16 weeks, 24 weeks or longer. Insome embodiments, the compound of Formula (I) may be administered twice a week, orally, in an amount of about 660 mg of the compound of Formula (I) (free acid). In some embodiments, the compound of Formula (I) may be administered twice a week, orally, in an amount of about 650 or 660 mg of thecompound of Formula (I) (free acid) for 28 days, 8 weeks, 12 weeks, 16 weeks, 24 weeks or longer. Insome embodiments, the compound of Formula (I) may be administered twice a week, orally, in an amount of about 660 mg of the compound of Formula (I) (free acid) for 28 days, 8 weeks, 12 weeks, 16 weeks, 24 weeks or longer.

[0131] In a particular embodiment, the method comprises administering to the subject an initial dailydose of about 50 to 200 mg of the compound of Formula (I) or a pharmaceutical salt thereof and increasingthe dose by increments until clinical efficacy is achieved. In some embodiments, increments of about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170,180, 190, or 200 mg can be used to increase the dose. The dosage can be increased daily, every other day,twice per week, or once per week. EXAMPLES

[0132] The following examples are included to demonstrate specific embodiments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques to function well in the practice of the disclosure, and thus can be considered to constitute specific modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made to the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure. Example 1: Preparation of Solid Dispersion

[0133] A spray dried dispersion of the compound of Formula (I) was prepared. The amorphous soliddispersion comprises the compound of Formula (I) in an amount of about 66.7% w / w and PVP / VA 64 as astabilizing polymer in an amount of about 33.3% w / w. The solid dispersion was manufactured by spraydrying a solution of the compound of Formula (I) and PVP / VA 64, out of a solvent. The spray drying process involved three steps: preparation of feed solution, spray drying and secondary drying.

[0134] The feed solution was prepared in the solvent (acetone / water at a weight ratio of 90 / 10 % w / w), with 6 % w / w solids load. The feed solution was prepared in a 200 L stainless steel reactor equipped with an impeller at the reactor bottom and a thermal circuit to control temperature. Nitrogen blanketing of thereactor was executed, before solvent addition, to minimize the oxygen content. Solution temperature was maintained between 15 and 25 ºC, preferably at 20 ºC, throughout the spray drying process. The target stirring speed was 200 rpm. The mixture was stirred until the solids dissolved. The solution was filtered inline through a stainless-steel filter while being fed to the spray dryer.

[0135] A scale spray dryer equipped with a pressure nozzle was used for the spray drying step. The spray drying unit was operated with nitrogen in either open-cycle or closed cycle mode. The flow rate of drying gas was controlled by a set-point in the nitrogen supply flow control valve. Before initiating the batch, the spray dryer is heated and stabilized with nitrogen, followed by solvent stabilization. During the stabilization period, the outlet temperature of the spray dryer was set to the target value by adjusting the inlet temperature of the drying gas. After stabilization of the inlet and outlet temperatures, the feeding was commuted to the solution to initiate the batch. A high-pressure pump was used, being controlled automatically by imposing the desired set-point. The feed is atomized at the nozzle’s tip and is dried in the drying chamber by the co- current hot nitrogen. The stream containing the dried product leaves the drying chamber and enters acyclone where most of the solids are separated and collected in the dry powder collector. The nitrogenleaving the cyclone passes through a filter bag, where fine particles are captured, before entering the exhaustfan. The exhaust fan speed of F2 is adjusted to control the system pressure within acceptable limits. Afterthe solution was entirely fed, the feed was commuted to the solvent. The wet spray dried dispersion (SDD)was collected. For the wet SDD, secondary drying was carried out in either a tray oven or agitated conicaldryer until the acetone content is not more than 1500 ppm. Example 2: Preparation of Pharmaceutical Composition

[0136] A pharmaceutical composition including the compound of Formula (I) was formed.

[0137] For intragranular material, the solid dispersion of the compound of Formula (I) of Example 1 waspassed through a 032R screen, at approximately 1050 RPM and collected into the bin. One scoop ofunmilled microcrystalline cellulose was added to each empty container for the solid dispersion of the compound of Formula (I), and rinsed by hand mixing the contents for approximately 30 seconds. The mixture was then passed through the 032R screen, at approximately 1050 RPM and collected into the bin. Then the remaining microcrystalline cellulose was passed through the 032R screen, at approximately 1050 RPM and collected into the bin. The other intragranular materials were passed through the 032R screen, directly into the bin at approximately 1050 RPM ± 20 RPM in the following order: lactose followed by croscarmellose sodium. Then, an approximately equal volume of blend was removed and added to the container of colloidal silicon dioxide (intragranular) and manually mixed for approximately 30 seconds andthen passed through the 032R screen, at approximately 1050 RPM ± 20 RPM and collected into the bin. For Batch 1, the materials were blended for 15 minutes, at 8 RPM, for 120 revolutions. For Batches 2-4, the materials were blended for 15 minutes, at 6 RPM, for 90 revolutions.

[0138] The magnesium stearate (intragranular) was manually mixed with an equal volume of the blendand co-screened directly into the bin through a 30-mesh hand screen. For Batch 1, the materials wereblended for 5 minutes, at 8 RPM, for 40 revolutions. For Batches 2-4, the materials were blended for 5 minutes, at 6 RPM, for 30 revolutions.

[0139] The blend was charged to the hopper of a roller compactor. The milled material was collectedinto a properly labeled container.

[0140] Extragranular adjustments were performed on the extragranular excipients based on the milled granule actual yield. Approximately half of the milled granulation was charged to an appropriately sized bin. Croscarmellose sodium was screened through a 20-mesh screen directly into the bin. An approximately equal volume of blend from the bin was added to the container of silicon dioxide and manually mixed for approximately 30 seconds. This material was then passed through the 20-mesh screen directly into the bin. Then the remaining half of the milled granulation was charged to the bin. For Batch 1, the materials were blended for 15 minutes, at 8 RPM, for 120 revolutions. For Batches 2-4, the materials were blended for 15 minutes, at 6 RPM, for 90 revolutions.

[0141] The magnesium stearate was manually mixed with an equal volume of blend and co-screened directly into the bin through a 30-mesh hand screen. For Batch 1, the materials were blended for 4 minutes, at 8 RPM, for 32 revolutions. For Batches 2-4, the materials were blended for 4 minutes, at 6 RPM, for 24 revolutions.

[0142] The final pharmaceutical formulation (also referred to as “Formula (I) common blend” herein) is shown in Table 1.Table 1 Composition (% w / w) Components Batch 1 / 2 Batch 3 / 4Intragranular Material Solid dispersion of the compound of Formula (I) (66.7%)159.70 59.97Microcrystalline Cellulose (Avicel PH102) 10.05 9.78Lactose Monohydrate Fast-Flo 316 NF 20.00Croscarmellose Sodium (Ac-Di-Sol) 6.00Colloidal Silicon Dioxide M-5P Cab-O-Sil 0.75Magnesium Stearate #5712 0.75Total Intragranular Materials 97.25Extragranular Material Croscarmellose Sodium (Ac-Di-Sol) 2.00Colloidal Silicon Dioxide M-5P Cab-O-Sil 0.25Magnesium Stearate #5712 0.50Total Extragranular Materials 2.75Total weight 1001 The solid dispersion includes 66.7% w / w of the compound of Formula (I) (free acid) in N-vinylpyrrolidone and vinyl acetate (PVPVA-64).Example 3: Formation of Core Tablet, 50 mg

[0143] The Korsch XL100 Tablet Press was set up using ¼” (0.2500”) round tooling. The tablet press was initially run using the blends from Batches 2-4. The target tablet weight for the 50 mg tablets was0.1250 g. The compression process was run with a tolerance of ± 5% of target weight for the in-processweight of 10 tablets and ±7.5% for the individual tablet weight. Tablets were passed through a tablet deduster and metal detector as they came off the press, and collected in properly labeled interim fiber drums, double lined with polyethylene bags.

[0144] After compression, the tablets were coated and collected into properly labeled drums andpackaged. Purified water was weighed and mixed with Opadry II Yellow as outlined in Table 2. The coatingsuspension was then sprayed onto the empty coating pan surface until a light film coated the exposed metal surfaces. The initial target spray rate was set at approximately 30 g / minute ± 3 g / minute. The core tablets were charged into the appropriate coating pan and the tablets were preheated at an outlet temperature of approximately 42°C ± 3°C. The tablets were coated until an actual weight gain of 3.0%-5.0% per tablet wasachieved. When the target weight gain was achieved, 4.0%, spraying of the coating suspension was stopped, the inlet air temperature was reduced to approximately 25°C, the pan speed was reduced, and the tablets dried / cooled for a minimum of 5 minutes. Table 2 Component 50 mg TabletFormula (I) common blend 125.0 mg per tabletOpadry II 85F92458 Yellow 5.000 mg per tabletPurified Water 800.0 gExample 4: Formulation of Core Tablet, 200 mg

[0145] The Korsch XL100 Tablet Press was set up using 0.2759” x 0.6285” modified oval tooling. Thetablet press was initially run using the blends from Batches 1-3. The target tablet weight for the 200 mgtablets was 0.5000 g. The compression process was run with a tolerance of ± 5% of target weight for thein-process weight of 10 tablets and ±7.5% for the individual tablet weight. Tablets were passed through a tablet deduster and metal detector as they came off the press, and collected in properly labeled interim fiber drums, double lined with polyethylene bags.

[0146] After compression, the tablets were coated and collected into properly labeled drums andpackaged. Purified water was weighed and mixed with Opadry II Blue as outlined in Table 3. The coatingsuspension was then sprayed onto the empty coating pan surface until a light film coated the exposed metal surfaces. The initial target spray rate was set at approximately 30 g / minute ± 3 g / minute. The core tablets were charged into the appropriate coating pan and the tablets were preheated at an outlet temperature of approximately 42°C ± 3°C. The tablets were coated until an actual weight gain of 3.0%-5.0% per tablet wasachieved. When the target weight gain was achieved, 4.0%, spraying of the coating suspension was stopped,the inlet air temperature was reduced to approximately 25°C, the pan speed was reduced, and the tablets dried / cooled for a minimum of 5 minutes. Table 3 Component 200 mg TabletFormula (I) common blend 500.0 mg per tabletOpadry II 85F105005 Blue 20.00 mg per tabletPurified Water 1520 gExample 5: Dissolution Testing of 50 mg Tablet

[0147] From Example 3, after compression and before coating using batch 4 of Formula (I) common blend, 50 tablets were pulled at approximately the beginning (Part 1), middle (Part 2), and end (Part 3) of the run for dissolution testing.

[0148] The dissolution performance of the tablets was determined in accordance with USP <711> withquantitation of the compound of Formula (I) by reversed-phase isocratic HPLC with UV detection. Tabletswere dissolved in 900 mL medium (10 mM Na2HPO4, pH 6.8, containing 0.05-1.0 w / v% Tween 80, in water) and paddled at 75 rpm, at 37.0 ± 0.5°C. 5 mL samples were collected at 5, 10, 15, 30, 45 and 60 minutes.

[0149] The dissolution sample solution was filtered and dispensed directly into a vial for HPLC analysis using an isocratic method with UV detection at 220 nm. The dissolution of the compound of Formula (I)tablets was determined by the comparison of the area of the Formula (I) peak in the sample chromatogramwith the area of the Formula (I) peak in the reference standard solution. The reference solution was preparedto contain approximately 0.0556 mg / mL of Formula (I) in diluent (80:20 acetonitrile:water) for the 50 mgtablets and at 0.20 mg / mL for the 200 mg tablets. The results are expressed as % dissolved (mean and range).

[0150] The results are shown in Table 4. Table 4 The Compound of Formula (I) Dissolution (%)Time (minutes) 5 10 15 30 45 60Part 1 42.072 77.021 91.169 100.289 100.982 102.524Part 2 45.587 79.319 92.199 100.695 101.730 102.649Part 3 35.773 70.362 89.812 101.426 102.592 103.281Example 6: Preparation of Solid Dispersion with Different Compositions

[0151] Three different spray dried dispersions of the compound of Formula (I) are prepared using thesimilar method described in Example 1, but the weight ratio of the compound of Formula (I) and PVP / VA 64 are 1:1, 3:1, and 1:2. The resulting spray dried dispersions are formed into tablets using similar methodsto those described in Example 3 and tested for dissolution as described in Example 5.

[0152] A spray dried dispersion of the compound of Formula (I) is prepared using the similar methoddescribed in Example 1, but HPMCAS is used as a stabilizing polymer instead of PVP / VA 64. Theresulting spray dried dispersion is formed into tablets using similar methods to those described in Example3 and tested for dissolution as described in Example 5. ** *

[0153] Unless otherwise defined, all technical and scientific terms used herein have the same meaningas commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0154] The disclosures illustratively described herein may suitably be practiced in the absence of anyelement or elements, limitation, or limitations, not specifically disclosed herein. Thus, for example, theterms “comprising,” “including,” “containing,” etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claims.

[0155] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety, to the same extent as if each were incorporated by reference individually. In case of conflict, the present specification, including definitions, will control.

[0156] It is to be understood that while the disclosure has been described in conjunction with the above embodiments, that the foregoing description and examples are intended to illustrate and not limit the scopeof the disclosure. Other aspects, advantages, and modifications within the scope of the disclosure will beapparent to those skilled in the art to which the disclosure pertains.

Claims

CLAIMS 1. A solid dispersion comprising a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is molecularly dispersed within a polymer matrix comprising a stabilizing polymer.

2. The solid dispersion of claim 1, wherein the stabilizing polymer is polyvinylpyrrolidone / vinylacetate (PVPVA), hydroxypropylmethyl cellulose (HPMC), or hydroxypropylmethyl cellulose acetate succinate (HPMCAS).

3. The solid dispersion of claim 1, wherein the stabilizing polymer is polyvinylpyrrolidone / vinylacetate (PVPVA).

4. The solid dispersion of any one of claims 1-3, wherein the compound of Formula (I), or apharmaceutically acceptable salt thereof, is present in the solid dispersion in an amount of about 50% to about 80% by weight of the solid dispersion.

5. The solid dispersion of any one of claims 1-4, wherein the compound of Formula (I), or apharmaceutically acceptable salt thereof, is present in the solid dispersion in an amount of about 60% to about 70% by weight of the solid dispersion.

6. The solid dispersion of any one of claims 1-5, wherein the compound of Formula (I), or apharmaceutically acceptable salt thereof, is substantially amorphous.

7. The solid dispersion of any one of claims 1-6, wherein at least 98% of the compound of Formula(I), or a pharmaceutically acceptable salt thereof, is in amorphous form.

8. The solid dispersion of any one of claims 1-7, wherein the stabilizing polymer is present in the soliddispersion in an amount of about 20% to about 50% by weight of the solid dispersion.

9. The solid dispersion of any one of claims 1-7, wherein the stabilizing polymer is present in the soliddispersion in an amount of about 30% to about 40% by weight of the solid dispersion.

10. The solid dispersion of any one of claims 1 to 9, wherein the ratio of an amount by weight of thecompound of Formula (I), or a pharmaceutically acceptable salt thereof, in the solid dispersion to an amount by weight of the stabilizing polymer in the solid dispersion is from about 1:3 to about3:1.

11. The solid dispersion of claim 10, wherein the ratio of an amount by weight of the compound ofFormula (I), or a pharmaceutically acceptable salt thereof, in the solid dispersion to an amount by weight of the stabilizing polymer in the solid dispersion is from about 1:1 to about 3:1.

12. The solid dispersion of claim 10, wherein the ratio of an amount by weight of the compound ofFormula (I), or a pharmaceutically acceptable salt thereof, in the solid dispersion to an amount by weight of the stabilizing polymer in the solid dispersion is about 2:1.

13. The solid dispersion of any one of claims 1-12, wherein the solid dispersion comprises thecompound of Formula (I) as free acid.

14. The solid dispersion of any one of claims 1-12, wherein the solid dispersion comprises a sodiumsalt or tromethamine salt of the compound of Formula (I).

15. A pharmaceutical composition comprising:about 50%-70% w / w of a solid dispersion comprising a compound of Formula (I):or a pharmaceutically acceptable salt thereof.

16. The pharmaceutical composition of claim 15, wherein the solid dispersion comprises about 60%-75% w / w of the compound of Formula (I) and about 25%-40% w / w of a stabilizing polymer.

17. The pharmaceutical composition of claim 15 or 16, wherein the solid dispersion comprises thecompound of Formula (I) and a stabilizing polymer, wherein the compound of Formula (I) and the stabilizing polymer has a weight ratio of 3:1 to 1:3.

18. The pharmaceutical composition of any one of claims 15- to 17, wherein the stabilizing polymer ispolyvinylpyrrolidone / vinyl acetate (PVPVA).

19. The pharmaceutical composition of any one of claims 15-18, wherein the compound of Formula (I)is substantially amorphous.

20. The pharmaceutical composition of any one of claims 18-19, further comprising:about 5%-15% w / w of microcrystalline cellulose; about 10%-30% w / w of lactose monohydrate; about 3%-10% w / w of croscarmellose sodium; about 0.1%-3% w / w of silicon dioxide; and about 0.1%-3% w / w of magnesium stearate.

21. The pharmaceutical composition of any one of claims 15-20, wherein the solid dispersioncomprises the compound of Formula (I) as a free acid.

22. The pharmaceutical composition of any one of claims 15-20, wherein the solid dispersioncomprises a sodium salt or tromethamine salt of the compound of Formula (I).

23. A dosage form comprising a pharmaceutical composition of any of claims 15-20.

24. The dosage form of claim 23, wherein the dosage form is a tablet.

25. The dosage form of claim 24, wherein the dosage form is a capsule.

26. The dosage form of any one of claims 23-25, wherein the dosage form includes one or moreadditional anti-cancer agents.

27. The dosage form of any one of claims 23-26, comprising about 50 mg of the compound of Formula(I) free acid.

28. The dosage form of any one of claims 23-26, comprising about 200 mg of the compound of Formula(I) free acid.

29. A method of treating a cancer in a patient in need thereof, the method comprising administering aneffective amount of the pharmaceutical composition of any one of claims 13-20 or a dosage formof any one of claims 23-28.

30. The method of claim 29, wherein the cancer has wild-type TP53 gene.

31. The method of claim 29, wherein the cancer is selected from the group consisting of: metastaticand refractory solid tumors, advanced metastatic and refractory solid tumors, mesothelioma, malignant peritoneal mesothelioma, malignant pleural mesothelioma, liposarcoma, dedifferentiated liposarcoma, well differentiated liposarcoma, glioblastoma multiforme, intimal sarcoma, hepatocellular carcinoma, oesophageal cancer, Ewing's sarcoma, soft tissue sarcoma, osteosarcoma, uveal melanoma, ovarian cancer, colorectal cancer, rectal cancer, cervical cancer, gastric cancer, gastrointestinal stromal tumor (GIST), breast cancer, lung cancer, brain cancer, glioma, neuroblastoma, acute myelogenous leukemia (AML), T-cell lymphomas, B-cell lymphomas, diffuse large B-cell lymphoma (DLBCL), MALT lymphoma, The T-cell lymphoma may be progressive or relapsed peripheral T-cell lymphoma (PTCL), and relapsed or refractory cutaneous T-cell lymphoma (CTCL).

32. The method of any one of claims 29-31, wherein the pharmaceutical composition is administeredonce daily for 28 days.

33. The method of any one of claims 29-31, wherein the pharmaceutical composition is administeredtwice a week for a 28-day cycle.

34. Use of an effective amount of the pharmaceutical composition of any one of claims 15-22 or adosage form of any one of claims 23-28 for the treatment of a cancer in a patient in need thereof.

35. Use of an effective amount of the pharmaceutical composition of any one of claims 15-22 or adosage form of any one of claims 23-28 for the treatment of a cancer in a patient in need thereof.

36. The use of claim 34 or 35, wherein the cancer has wild-type TP53 gene.

37. The use of claim 34 or 35, wherein the cancer is selected from the group consisting of metastaticand refractory solid tumors, advanced metastatic and refractory solid tumors, mesothelioma, malignant peritoneal mesothelioma, malignant pleural mesothelioma, liposarcoma, dedifferentiated liposarcoma, well differentiated liposarcoma, glioblastoma multiforme, intimal sarcoma, hepatocellular carcinoma, oesophageal cancer, Ewing's sarcoma, soft tissue sarcoma,osteosarcoma, uveal melanoma, ovarian cancer, colorectal cancer, rectal cancer, cervical cancer, gastric cancer, gastrointestinal stromal tumor (GIST), breast cancer, lung cancer, brain cancer, glioma, neuroblastoma, acute myelogenous leukemia (AML), T-cell lymphomas, B-cell lymphomas, diffuse large B-cell lymphoma (DLBCL), MALT lymphoma, The T-cell lymphoma may be progressive or relapsed peripheral T-cell lymphoma (PTCL), and relapsed or refractory cutaneous T-cell lymphoma (CTCL).

38. A pharmaceutical composition of any one of claims 15-22, for use in treating a cancer in a patientin need thereof.

39. The pharmaceutical composition for use according to claim 38, wherein the cancer has wild-typeTP53 gene.

40. The pharmaceutical composition for use according to claim 38 or 39, wherein the cancer is selectedfrom the group consisting of metastatic and refractory solid tumors, advanced metastatic and refractory solid tumors, mesothelioma, malignant peritoneal mesothelioma, malignant pleural mesothelioma, liposarcoma, dedifferentiated liposarcoma, well differentiated liposarcoma, glioblastoma multiforme, intimal sarcoma, hepatocellular carcinoma, oesophageal cancer, Ewing's sarcoma, soft tissue sarcoma, osteosarcoma, uveal melanoma, ovarian cancer, colorectal cancer, rectal cancer, cervical cancer, gastric cancer, gastrointestinal stromal tumor (GIST), breast cancer, lung cancer, brain cancer, glioma, neuroblastoma, acute myelogenous leukemia (AML), T-cell lymphomas, B-cell lymphomas, diffuse large B-cell lymphoma (DLBCL), MALT lymphoma, TheT-cell lymphoma may be progressive or relapsed peripheral T-cell lymphoma (PTCL), and relapsed or refractory cutaneous T-cell lymphoma (CTCL).

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