Pharmaceutical compositions containing MDM2-P53 inhibitors

Abstract

This disclosure relates to pharmaceutical compositions comprising solid dispersions, and to treatment methods thereof, wherein the solid dispersions comprise compounds of formula (I) or pharmaceutically acceptable salts thereof, (I).

Description

Technical Field

[0001] This disclosure relates to pharmaceutical compositions comprising an MDM2-p53 inhibitor. Background Technology

[0002] The transformation-associated protein 53 (TP53) gene encodes a 53 kDa protein, p53. The tumor suppressor protein p53 responds to cellular stresses (such as hypoxia, DNA damage, and oncogene activation) through numerous post-translational modifications, including phosphorylation, acetylation, and methylation, and acts as a signaling node in multiple activated pathways. p53 plays additional roles in other physiological processes, including autophagy, cell adhesion, cell metabolism, fertility, and stem cell aging and development. p53 activity is negatively and tightly regulated by its binding interaction with the MDM2 protein, whose transcription is directly regulated by p53. p53 is inactivated when its transactivation domain binds to MDM2. Once inactivated, p53 function is suppressed, and the p53-MDM2 complex becomes a target for ubiquitination.

[0003] In normal cells, the balance between active p53 and inactive p53 bound to MDM2 is maintained in an autoregulatory negative feedback loop. That is, p53 can activate MDM2 expression, while MDM2, in turn, inhibits p53 activity. Studies have found that p53 inactivation due to mutations is prevalent in approximately half of common sporadic adult cancers. Furthermore, in about 10% of tumors, MDM2 gene amplification and overexpression lead to the loss of functional p53, thereby allowing malignant transformation and uncontrolled tumor growth.

[0004] It is envisioned that a potent MDM2-p53 interaction inhibitor could unblock the inhibitory control of MDM2 on p53 and activate p53-mediated cell death in tumors. In tumors, the expected selectivity stems from p53's ability to sense pre-existing DNA damage or oncogene activation signals that have been previously blocked by the action of MDM2 at normal or overexpressed levels. In normal cells, p53 activation is expected to lead to activation of non-apoptotic pathways. Furthermore, due to the non-genotoxic mechanism of action of MDM2-p53 inhibitors, they are particularly suitable for treating cancers in pediatric populations.

[0005] This disclosure describes formulations of compounds that selectively inhibit MDM2-p53 interaction and have anticancer activity. Summary of the Invention

[0006] In some embodiments, this document provides solid dispersions comprising compounds of formula (I):

[0007] (I),

[0008] Or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is dispersed in molecular form in a polymer matrix comprising a stable polymer.

[0009] In some embodiments, the stabilizing polymer is polyvinylpyrrolidone / vinyl acetate (PVPVA, copovidone), hydroxypropyl methylcellulose (HPMC), or hydroxypropyl methylcellulose acetate succinate (HPMCAS). In some embodiments, the stabilizing polymer is polyvinylpyrrolidone / vinyl acetate (PVPVA, copovidone). In some embodiments, the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof present in the solid dispersion is about 50% to about 80%, or about 60% to about 70% of the 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 weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the solid dispersion to the weight of the stabilizing polymer in the solid dispersion is about 1:3 to about 3:1. In some embodiments, the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the solid dispersion to the weight ratio of the stable polymer in the solid dispersion 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 in the solid dispersion to the weight ratio of the stable 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).

[0010] In some embodiments, this document provides pharmaceutical compositions comprising about 50%-70% w / w solid dispersions, said solid dispersions comprising compounds of formula (I):

[0011] (I)

[0012] Or its pharmaceutically acceptable salt.

[0013] In some embodiments, the solid dispersion comprises about 60%-75% w / w of a compound of formula (I) and about 25%-40% w / w of a stable polymer. In some embodiments, the solid dispersion comprises a compound of formula (I) or a pharmaceutical salt thereof and a stable polymer, wherein the weight ratio of the compound of formula (I) or a pharmaceutical salt thereof to the stable polymer is 3:1 to 1:3. In some embodiments, the stable polymer is a copolymer of N-vinylpyrrolidone and vinyl acetate. In some embodiments, the compound of formula (I) or a pharmaceutical salt thereof is substantially 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 silica; and about 0.1%-3% w / w of magnesium stearate. In some embodiments, the solid dispersion comprises a sodium salt or tromethamine salt of the compound of formula (I).

[0014] In some embodiments, this document also provides dosage forms comprising the pharmaceutical compositions described in the preceding paragraphs. The dosage form may be a tablet or a capsule. In some embodiments, the dosage form includes one or more additional anticancer agents. In some embodiments, the dosage form comprises about 50 mg or 200 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0015] In some embodiments, this document also provides a method of treating cancer in patients in need. The method comprises administering an effective amount of the pharmaceutical composition described in any of the preceding paragraphs. In some embodiments, the cancer has a wild-type TP53 gene. In some embodiments, the cancer has MDM2 amplification. In some embodiments, the cancer is a tumor with a BRCA 1 / 2 or ATM harmful mutation or with loss of BAP1 function. In some implementations, the cancer is selected from 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, endometrial sarcoma, hepatocellular carcinoma, esophageal 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 myeloid leukemia (AML), T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), and 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).

[0016] In some embodiments, this document also provides for the use of an effective amount of the pharmaceutical composition described in any of the preceding paragraphs for the treatment of cancer in patients who require it.

[0017] In some embodiments, this document also provides the use of an effective amount of the pharmaceutical composition described in any of the preceding paragraphs in the preparation of a medicament for treating cancer in patients with this need.

[0018] In some embodiments, this document also provides pharmaceutical compositions for treating cancer in patients who require such treatment. Detailed Implementation

[0019] definition

[0020] The following description illustrates exemplary embodiments of the present technology. However, it should be understood that this description is not intended to limit the scope of this disclosure, but is provided as a description of exemplary embodiments.

[0021] As used in this specification, the following words, phrases and symbols are generally intended to have the meanings described below, unless the context in which they are used indicates otherwise.

[0022] The term "about" as used herein includes (and describes) embodiments of that value or parameter itself. In some embodiments, the term "about" includes the indicated amount ±10%. In other embodiments, the term "about" includes the indicated amount ±5%. In some other embodiments, the term "about" includes the indicated amount ±1%. Similarly, the term "about X" includes a description of "X". Furthermore, the singular forms "a" and "the" include plural references unless the context clearly specifies otherwise. Thus, for example, reference to "compound" includes a variety of such compounds, and reference to "assay" includes reference to one or more assays and their equivalents known to those skilled in the art.

[0023] "Alkyl" refers to a saturated hydrocarbon chain, whether unbranched or branched. As used herein, alkyl groups have 1 to 20 carbon atoms (i.e., C64-C ... 1-20 Alkyl groups, 1 to 8 carbon atoms (i.e., C64) 1-8 Alkyl groups, 1 to 6 carbon atoms (i.e., C64) 1-6 Alkyl groups, or 1 to 4 carbon atoms (i.e., C464) 1-4Alkyl groups. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, 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 a chemical name or determined by a molecular formula, it may include all positional isomers having that number of carbons; 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); "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0024] Certain commonly used alternative chemical names may be used. For example, divalent groups, such as divalent "alkyl" groups, divalent "aryl" groups, divalent heteroaryl groups, etc., may also be referred to as "alkylene" (e.g., methylene, ethylene, and propylene) and "arylene" (e.g., phenylene or naphthylene, or quinolinyl of heteroarylene). Furthermore, unless otherwise explicitly stated, when a combination of groups is referred to herein as a moiety, such as aralkyl, the last mentioned group includes the atoms of that moiety that are connected to the remainder of the molecule.

[0025] "Alkenyl" refers to a group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C24-C24-C24). 2-20 alkenyl), 2 to 8 carbon atoms (i.e., C) 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C) 2-6 Alkenyl) or 2 to 4 carbon atoms (i.e., C) 2-4 Alkyl groups (alkenyl). Examples of alkenyl groups include vinyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0026] "Alkyne" refers to a group containing at least one (e.g., 1-3 or 1) carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C20-20 carbon atoms). 2-20 alkynyl group), 2 to 12 carbon atoms (i.e., C 2-12 alkynyl group), 2 to 8 carbon atoms (i.e., C64) 2-8 alkynyl group), 2 to 6 carbon atoms (i.e., C64) 2-6 (alkynyl group) or 2 to 4 carbon atoms (i.e., C) 2-4 Alkyl groups (alkynyl). The term "alkynyl" also includes those groups having one triple bond and one double bond.

[0027] "Alkoxy" refers to the "alkyl-O-" group. Examples of alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0028] "Alkoxyalkyl" refers to the group "alkyl-O-alkyl".

[0029] "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.

[0030] As defined in this article, "acyl" refers to the group -C(O)R y , where R y It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of these may optionally be substituted. Examples of acyl groups include, for example, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, and benzoyl.

[0031] As defined in this article, "acylamino" refers to the "C-acylamino" group (referring to the group -C(O)NR). y R z ) and "N-amide" group (referring to the -NR group) y C(O)R z ), where R y and R z Independently, it is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each may be optionally substituted, or R y and R z Together they form cycloalkyl or heterocyclic groups; each of them may optionally be substituted.

[0032] As defined in this article, "amino" refers to the group -NR. y R z , where R y and R z It is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of them may optionally be substituted.

[0033] As defined in this article, "midazone" refers to -C(NR) y (NR) z 2), where R y and R z It is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of them may optionally be substituted.

[0034] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, aryl groups have 6 to 20 ring carbon atoms (i.e., C24 carbon atoms). 6-20 aryl), 6 to 12 carbon ring atoms (i.e., C 6-12 Aryl group, or 6 to 10 carbon ring atoms (i.e., C464-C ... 6-10 Aryl groups. Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthracene. However, aryl groups do not include or overlap with heteroaryl groups as defined below. If one or more aryl groups are fused with a heteroaryl group, the resulting ring system is a heteroaryl group. If one or more aryl groups are fused with a heterocyclic group, the resulting ring system is a heterocyclic group.

[0035] "Arylalkyl" or "arylalkyl" refers to the group "aryl-alkyl-".

[0036] As defined in this article, "carbamoyl" refers to the "O-carbamoyl" group (referring to the group -OC(O)NR). y R z ) and "N-carbamoyl" group (referring to the -NR group) y C(O)OR z ), where R y and R z It is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of them may optionally be substituted.

[0037] As defined in this article, "carboxylic ester" or "ester" refers to -OC(O)R x and -C(O)OR x , where R x It is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of them may optionally be substituted.

[0038] "Cyanoalkyl" refers to an alkyl group as defined above, in which one or more (e.g., 1 or 2) hydrogen atoms are replaced by a cyano group (-CN).

[0039] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl group having a monocyclic or polycyclic structure, including fused ring, bridged ring, and spirocyclic systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond). As used herein, cycloalkyl groups have 3 to 20 cyclic carbon atoms (i.e., C64 carbon atoms). 3-20 cycloalkyl groups, 3 to 12 cyclic carbon atoms (i.e., C12) 3-12 cycloalkyl groups, 3 to 10 cyclic carbon atoms (i.e., C14 and C24) 3-10 cycloalkyl), 3 to 8 cyclic carbon atoms (i.e., C 3-8 cycloalkyl groups, or 3 to 6 cyclic carbon atoms (i.e., C164-C ... 3-6(Cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0040] “Cycloalkylalkyl” refers to the group “cycloalkyl-alkyl-”.

[0041] As defined in this article, "imino" refers to the group -C(NR) y )R z , where R y and R z Each of them is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of them may be optionally substituted.

[0042] As defined in this article, "imide" refers to the group -C(O)NR. y C(O)R z , where R y and R z Each of them is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of them may be optionally substituted.

[0043] "Halogen" or "halogenated" refers to an atom that occupies Group VIIA of the periodic table, such as fluorine, chlorine, bromine, or iodine.

[0044] "Haloalkyl" refers to a straight-chain or branched alkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are substituted with a halogen. For example, when a residue is substituted with more than one halogen, a prefix corresponding to the number of halogen moieties attached may be used. Dihaloalkyl and trihaloalkyl refer to alkyl groups substituted with two ("di") or three ("tri") halogen groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl groups include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.

[0045] "Haloalkoxy" refers to an alkoxy group as defined above, in which one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by halogens.

[0046] "Haloalkoxyalkyl" refers to an alkoxyalkyl group as defined above, in which one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by halogens.

[0047] "Hydroxyalkyl" refers to an alkyl group as defined above, in which one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by hydroxyl groups.

[0048] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms), excluding any terminal carbon atoms, are independently substituted with the same or different heteroatoms, provided that the connection point to the rest of the molecule is through a carbon atom. The term "heteroalkyl" includes straight-chain or branched saturated chains containing carbon atoms and heteroatoms. For example, one, two, or three carbon atoms may be independently substituted with the same or different heteroatom groups. As defined herein, heteroatom groups include, but are not limited to, -NR. y -, -O-, -S-, -S(O)2-, etc., among which R y It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of them may optionally be substituted. Examples of heteroalkyl groups as defined herein include, for example, 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)2CH2OCH3, etc.), and amines (e.g., -CH2NR). y CH3、-CH(CH3)NR y CH3、-CH2CH2NR y CH3、-CH2CH2NR y CH2CH2NR y CH3, etc., of which R y It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl or heteroaryl; each of which may optionally be substituted. As used herein, heteroalkyl comprises 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.

[0049] "Heteroaryl" refers to an aromatic group having a monocyclic, polycyclic, or polyfused ring structure, wherein one or more cyclic heteroatoms are independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl groups comprise 1 to 20 cyclic carbon atoms (i.e., C atoms). 1-20 heteroaryl), 3 to 12 cyclic carbon atoms (i.e., C 3-12 (heteroaryl) or 3 to 8 carbon ring atoms (i.e., C) 3-8The heteroaryl group comprises 1 to 5 cyclic heteroatoms, 1 to 4 cyclic heteroatoms, 1 to 3 cyclic heteroatoms, 1 to 2 cyclic heteroatoms, or 1 cyclic heteroatomum, wherein the cyclic heteroatoms are independently selected from nitrogen, oxygen, and sulfur. In some cases, the heteroaryl group comprises a 5-10 membered ring system, a 5-7 membered ring system, or a 5-6 membered ring system, each independently having 1 to 4 cyclic heteroatoms, 1 to 3 cyclic heteroatoms, 1 to 2 cyclic heteroatoms, or 1 cyclic heteroatomum, wherein the cyclic heteroatoms are independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, for example, acridinel, benzimidazolyl, benzothiazolyl, benzoindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzooxazolyl, benzothiophene (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2a]pyridyl, carbazole, pyridazinyl, dibenzofuranyl, dibenzothiaphene, furanyl, isothiazolyl, imidazolyl, indazole, indolyl, indazole, isothiazolyl, isothiazolyl, imidazolyl, indazole ... Indolyl, isoquinolinyl, isoxazolyl, naphridinyl, oxadiazolyl, oxazolyl, 1-pyridinyl oxide, 1-pyrimidinyl oxide, 1-pyrazinyl oxide, 1-pyridazinyl oxide, phenazinyl, phthalazinyl, pteridinyl, purine, pyrroleyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxolinyl, quinolinyl, quinolinecycloyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, thiophene (i.e., thiophene), tetrazolyl, and triazinyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophene, inzolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, wherein the heteroaryl group can be linked to any ring of the fused system. Any aromatic ring containing at least one heteroatom and having one or more fused rings is considered a heteroaryl, regardless of its connection to the rest of the molecule (i.e., through any one of the fused rings). A heteroaryl does not contain or overlap with an aryl group as defined above.

[0050] "Heteroarylenealkyl" refers to the group "heteroarylene-alkyl-".

[0051] "Heterocyclic group" refers to a saturated or partially unsaturated cycloalkyl group having one or more cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclic group" includes heterocyclic alkenyl groups (i.e., heterocyclic groups having at least one double bond), bridged heterocyclic groups, fused heterocyclic groups, and spirocyclic groups. Heterocyclic groups can be monocyclic or polycyclic, wherein the polycyclic group can be a fused ring, a bridged ring, or a spiro ring, and can contain 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 heterocyclic group, regardless of its linkage (i.e., it can be linked by carbon atoms or heteroatoms). Furthermore, the term heterocyclic group is intended to include any non-aromatic ring containing at least one heteroatom that can be fused to a cycloalkyl, aryl, or heteroaryl ring, regardless of its linkage to the rest of the molecule. As used herein, heterocyclic groups have 2 to 20 cyclic carbon atoms (i.e., C64-C ... 2-20 Heterocyclic groups), 2 to 12 ring carbon atoms (i.e., C 2-12 Heterocyclic group), 2 to 10 ring carbon atoms (i.e., C 2-10 Heterocyclic group), 2 to 8 ring carbon atoms (i.e., C 2-8 Heterocyclic groups), 3 to 12 ring carbon atoms (i.e., C 3-12 Heterocyclic group), 3 to 8 ring carbon atoms (i.e., C 3-8 Heterocyclic group), or 3 to 6 ring carbon atoms (i.e., C 3-6Heterocyclic groups; having 1 to 5 cyclic heteroatoms, 1 to 4 cyclic heteroatoms, 1 to 3 cyclic heteroatoms, 1 to 2 cyclic heteroatoms, or 1 cyclic heteroatomide, wherein the cyclic heteroatoms are independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclic groups include, for example, azirrobutyl, azirroheptenyl, benzodioxaneheptenyl, benzo[b][1,4]dioxaneheptenyl, 1,4-benzodioxanehexyl, benzopyranyl, benzodioxanevinyl, benzofuranoneyl, benzofuranoneyl, dioxanepentyl, dihydropyranyl, hydropyranyl, thiophene[1,3]dithiaalkyl, decahydroisoquinolinyl, furanoneyl, imidazolinyl, imidazolinyl, indololinyl, indolazinyl, isoyindololinyl, isothiazazole Alkyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperidyl, oxazolyl, ethylene oxide, oxacyclobutyl, phenothiazinyl, phenothiazinyl, piperidinyl, piperazinyl, 4-piperidinyl, pyrrolyl, pyrazolyl, quininyl, thiazolyl, tetrahydrofuranyl, tetrahydropyranyl, trithienyl, tetrahydroquinolinyl, thiomorpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, and 1,1-dioxothiomorpholinyl. When there are two substitution positions on the same carbon atom, the term "heterocyclic group" also includes "spiroheterocyclic group". Examples of spiroheterocyclic rings include, for example, bicyclic and tricyclic systems such as oxabicyclo[2.2.2]octyl, 2-oxa-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.4]octyl, and 6-oxa-1-azaspiro[3.3]heptyl. Examples of fused heterocyclic rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridyl, indololinyl, and isoindolinyl, wherein the heterocyclic group can be linked by any ring of the fused system.

[0052] "Heterocyclic alkyl" refers to the group "heterocyclic-alkyl-".

[0053] As defined in this article, "oxime" refers to the group -CR y (=NOH), where R y It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of them may optionally be substituted.

[0054] As defined in this article, "sulfonyl" refers to the group -S(O)2R y , where R y It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of these may optionally be substituted. Examples of sulfonyl groups are methanesulfonyl, ethylsulfonyl, benzenesulfonyl, and toluenesulfonyl.

[0055] As defined in this article, "sulfinyl" refers to the group -S(O)R y , where R y It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of them may optionally be substituted. Examples of sulfinyl groups are methylsulfinyl, ethylsulfinyl, phenylsulfinyl, and toluenesulfinyl.

[0056] As defined in this article, "sulfonamide group" refers to the group -SO2NR. y R z and -, where R y and R z Each of them is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of them may be optionally substituted.

[0057] The terms "optional" or "optionally" mean that the event or situation described below may or may not occur, and the description includes both the possibility that the event or situation occurs and the possibility that it does not occur. Furthermore, the term "optionally substituted" means that any one or more hydrogen atoms on a specified atom or group may be substituted with or not substituted with hydrogen atoms other than hydrogen atoms.

[0058] As used herein, the term "substituted" refers to any of the aforementioned groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclic, heteroaryl, and / or heteroalkyl) wherein at least one (e.g., 1 to 5 or 1 to 3) hydrogen atom is substituted by a bond attached to a non-hydrogen atom, such as, but not limited to, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amide, amino, amidyl, aryl, aralkyl, azide, carbamoyl, carboxyl, carboxyl ester heterocyclic, heterocyclic alkyl, -NHNH2, =NNH2, imino, imino, hydroxyl, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, -S(O)OH, -S(O)2OH, sulfonylamino, thiol, thio, N-oxide, or -Si(R y )3, where each R y It is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic.

[0059] In some embodiments, "substituted" includes any of the above-mentioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups, wherein one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are independently replaced by deuterium, halogen, cyano, nitro, azide, oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -NR g R h -NRg C(O)R h -NR g C(O)NR g R h -NR g C(O)OR h -NR g S(O) 1-2 R h -C(O)R g -C(O)OR g -OC(O)OR g -OC(O)R g -C(O)NR g R h -OC(O)NR g R h -OR g -SR g -S(O)R g -S(O)2R g -OS(O) 1-2 R g -S(O) 1-2 OR g -NR g S(O) 1- 2NR g R h =NSO2R g =NOR g -S(O) 1-2 NR g R h -SF5, -SCF3, or -OCF3 are substituted. In some embodiments, "substituted" also refers to any of the above groups in which one or more (e.g., 1-5 or 1-3) hydrogen atoms are replaced by -C(O)R g -C(O)OR g -C(O)NR g R h -CH2SO2R g or -CH2SO2NR g R h Replace. In the above text, R g and R hThey are the same or different, and independently are hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclic, heterocyclic alkyl, heteroaryl and / or heteroarylalkyl. In some embodiments, "substituted" also means that one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms in any of the above groups are substituted by a bond connected to an amino, cyano, hydroxyl, imino, nitro, oxo, thio, halogen, alkyl, alkoxy, alkylamino, alkylthio, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclic, N-heterocyclic, heterocyclic alkyl, heteroaryl and / or heteroarylalkyl; or, R g and R h and R i The two atoms attached to it together form a heterocyclic ring, which may be optionally substituted with oxo, halogen or alkyl, and the alkyl may be optionally substituted with oxo, halogen or amino, hydroxy or alkoxy.

[0060] Some compounds exist as tautomers. These tautomers exist in equilibrium with each other. For example, amide-containing compounds can exist in equilibrium with imine tautomers. Regardless of the type of tautomer shown or the equilibrium nature between the tautomers, those skilled in the art will understand that the compound includes both amide and imine tautomers. Therefore, amide-containing compounds are understood to include their imine tautomers. Similarly, imine-containing compounds are understood to include their amide tautomers.

[0061] In many cases, the compounds of this disclosure, namely the compounds of formula (I), are capable of forming acid and / or base salts due to the presence of amino and / or carboxyl groups or similar groups.

[0062] The term "pharmaceutically acceptable salt" for a given compound refers to a salt that retains the biological efficacy and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salt" or "physiologically acceptable salt" includes, for example, inorganic acid salts and organic acid salts. Furthermore, if the compound described herein is obtained as an acid addition salt, the free base can be obtained by alkalizing the acidic salt solution. Conversely, if the product is a free base, the addition salt, particularly a pharmaceutically acceptable addition salt, can be prepared according to conventional methods for preparing acid addition salts from base compounds, by dissolving the free base in a suitable organic solvent and treating the solution with an acid. Those skilled in the art will recognize the various synthetic methods that can be used to prepare non-toxic, pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. 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-toluenesulfonic acid, and salicylic acid. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. By way of example only, salts derived from inorganic bases include 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 alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (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), alkenylamines (i.e., NH2(alkenyl)), dienylamines (i.e., HN(alkenyl)2), trienylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl)amines (i.e., HN(substituted alkenyl)2), and tri(substituted alkenyl)amines (i.e., N(substituted alkenyl)3). Di- or tri-cycloalkylamines (i.e., NH₂(cycloalkyl), HN(cycloalkyl)₂, N(cycloalkyl)₃), mono-, di- or tri-cycloalkylamines (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 salts derived from organic bases include isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, etc.

[0063] As used herein, "pharmaceuticalally acceptable carrier" or "pharmaceuticalally acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delay agents. The use of such media and agents for pharmaceutically active substances is well known in the art. Their use in therapeutic compositions is contemplated, except for any conventional media or agents incompatible with the active ingredient. Additional active ingredients may also be incorporated into the composition.

[0064] "Treatment" is a method used to obtain a beneficial or desired outcome (including clinical outcomes). A beneficial or desired clinical outcome may include one or more of the following: a) suppressing a disease or condition (e.g., reducing one or more symptoms caused by the disease or condition, and / or reducing the severity of the disease or condition); b) slowing or halting the development of one or 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 or delaying the spread of the disease or condition (e.g., metastasis)); and / or c) alleviating the disease, i.e. causing the remission of clinical symptoms (e.g., improving the disease state, providing partial or complete relief of the disease or condition, enhancing the effect of another drug treatment, delaying the progression of the disease, improving quality of life, and / or prolonging survival).

[0065] "Prevention" refers to the treatment of any disease or condition that prevents the development of clinical symptoms. In some implementations, the compound may be administered to subjects (including humans) who are at risk or have a family history of the disease or condition.

[0066] As used herein, the term "combination therapy" is intended to define a therapy that includes the use of a combination of two or more compounds / drugs (as defined above). Therefore, the terms "combination therapy," "combination," and "combination" used in this application can refer to compounds / drugs administered as part of the same overall treatment regimen. Consequently, the dosage of each of the two or more compounds / drugs can be different: each can be administered simultaneously or at different times. Therefore, it should be understood that the compounds / drugs in a combination can be administered sequentially (e.g., before or after) or simultaneously. In combination therapy, the dosage of each of the two or more compounds / drugs can also vary depending on the route of administration.

[0067] "Subject" refers to an animal, such as a mammal (including a human), that has been or will be a subject of treatment, observation, or experimentation. The methods described herein can be used for human treatment and / or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human.

[0068] The term "therapeutic effective amount" or "effective amount" refers to an amount sufficient to provide therapeutic benefit (such as symptom improvement or disease progression slowing) when administered to a subject. For example, a therapeutic effective amount could be an amount sufficient to alleviate symptoms of T-cell lymphoma. Therapeutic effective amounts can vary depending on the subject, the disease or condition being treated, the subject's weight and age, the severity of the disease or condition, and the method of administration, which can be readily determined by those skilled in the art.

[0069] Compounds and salts

[0070] The compound of formula (I) is described in US 10,544,132, with the following structure:

[0071] (I),

[0072] It was named (2S,3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxacyclohexane-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-2-methylpropionic acid.

[0073] Pharmaceutically acceptable salts of compounds of formula (I) include organic or inorganic bases that produce 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 Ca 2+ and Mg 2 + and other cations such as Al 3+ or Zn + Suitable examples of organic cations include, but are not limited to, ammonium ions (i.e., NH4+). + ) and substituted ammonium ions (e.g., NH3R) + NH2R2 + NHR3 + NR4 + Examples of suitable substituted ammonium ions are derived from: methylamine, ethylamine, diethylamine, propylamine, dicyclohexylamine, triethylamine, butylamine (e.g., tert-butylamine), ethylenediamine, ethanolamine, diethanolamine, glycidylamine, piperazine, benzylamine, benzathine, phenylbenzylamine, 2-(diethylamino)ethanol, dianophenoxyethanol, choline, meglumine, and tromethamine, as well as amino acids such as lysine and arginine. A common example of a quaternary ammonium ion is N(CH3)4. +In one embodiment, the compound is a tris(hydroxymethyl)aminomethane (TRIS) salt. In some embodiments, a pharmaceutically acceptable salt of the compound of formula (I) is a sodium salt or a tromethamine salt.

[0074] As used herein, the term "compound of formula (I)" may refer to a compound of formula (I) or a pharmaceutically acceptable salt thereof. As used herein, the term "free acid of compound (I)" specifically refers to a compound of formula (I) as an active ingredient.

[0075] Pharmaceutical Composition

[0076] This document provides pharmaceutical compositions comprising solid dispersions comprising compounds of formula (I). The solid dispersions also comprise stable polymers.

[0077] In some embodiments, the stabilizing polymer is a copolymer of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), or polyvinylpyrrolidone / vinyl acetate (PVP / VA, copolyvinylpyrrolidone). 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, methylcellulose, PEG, carboxymethylcellulose, cyclodextrin, chitosan, PVA, or combinations thereof.

[0078] In some embodiments, the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof present in the solid dispersion is from about 30% to about 95% of the weight of the solid dispersion. In other words, in some embodiments, for every 100 g of solid dispersion, 30-95 g of the total weight of the solid dispersion comes from the weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof, and 5-70 g of the total weight of the solid dispersion comes from the weight of the stable polymer. In some embodiments, the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof present in the solid dispersion is from about 40% to about 90% of the weight of the solid dispersion. In some embodiments, the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof present in the solid dispersion is from about 50% to about 90% of the weight of the solid dispersion. In some embodiments, the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof present in the solid dispersion is from about 50% to about 80% of the weight of the solid dispersion. In some embodiments, the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof present in the solid dispersion is from about 60% to about 80% of the weight of the solid dispersion. In some embodiments, the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof present in the solid dispersion is about 60% to about 70% of the weight of the solid dispersion. In some embodiments, the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof present in the solid dispersion is about 60% to about 75% of the weight of the solid dispersion. In some embodiments, the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof present in the solid dispersion is about 65% to about 70% of the weight of the solid dispersion.

[0079] In some embodiments, the amount of the compound of formula (I) or its pharmaceutically acceptable salt present in the solid dispersion is 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%, about 75%, about 80%, about 85%, about 90%, or about 95% of the weight of the solid dispersion.

[0080] In some embodiments, 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 in the solid dispersion is in amorphous form. In some embodiments, at least 95% of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the solid dispersion is in amorphous form. In some embodiments, at least 98% of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the solid dispersion is in amorphous form. In some embodiments, at least 90% of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the solid dispersion is in amorphous form. In some embodiments, the compound of formula (I) in the solid dispersion is in the form of a sodium salt. In some embodiments, the compound of formula (I) in the solid dispersion is in the form of a tromethamine salt.

[0081] In some embodiments, the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the stable 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 stable 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 stable 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 stable polymer is from about 2:1. In some embodiments, the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the stable polymer is from about 3:1. In some embodiments, the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the stable polymer is from about 1:2. In some embodiments, the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the stable polymer is from about 1:1.

[0082] In some embodiments, the amount of the stabilizing polymer is greater than about 10% of the weight of the solid dispersion. In some embodiments, the amount of the stabilizing polymer is greater than about 20% of the weight of the solid dispersion. In some embodiments, the amount of the stabilizing polymer is greater than about 30% of the weight of the solid dispersion.

[0083] In some embodiments, the stabilizing polymer is present in an amount of about 10% to about 60% by weight of the solids dispersion. In some embodiments, the stabilizing polymer is present in an amount of about 10% to about 50% by weight of the solids dispersion. In some embodiments, the stabilizing polymer is present in an amount of about 20% to about 50% by weight of the solids dispersion. In some embodiments, the stabilizing polymer is present in an amount of about 20% to about 40% by weight of the solids dispersion. In some embodiments, the stabilizing polymer is present in an amount of about 25% to about 40% by weight of the solids dispersion. In some embodiments, the stabilizing polymer is present in an amount of about 30% to about 40% by weight of the solids dispersion. In some embodiments, the stabilizing polymer is present in an amount of about 30% to about 35% by weight of the solids dispersion.

[0084] In some embodiments, the stabilizing polymer is present in an amount of about 50% by weight of the solids dispersion. In some embodiments, the stabilizing polymer is present in an amount of about 33.3% by weight of the solids dispersion. In some embodiments, the stabilizing polymer is present in an amount of about 25% by weight of the solids dispersion. In some embodiments, the stabilizing polymer is present in an amount of about 20% by weight of the solids dispersion.

[0085] In some embodiments, the stabilizing polymer is present in an amount of about 33.3% by weight of the solids 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 solids dispersion. In some embodiments, the stabilizing polymer is present in an amount of about 25% by weight of the solids 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 solids dispersion. In some embodiments, the stabilizing polymer is present in an amount of about 20% by weight of the solids dispersion, and the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 80% by weight of the solids dispersion.

[0086] Solid dispersions comprising compounds of formula (I) can be formed by any suitable technique known in the art. For example, solid dispersions can be formed by melt drying, hot melt extrusion, coprecipitation, solvent extraction, spray drying, supercritical fluid extraction, kneading, or electrospinning. In some embodiments, solid dispersions can be formed by spray drying.

[0087] In some embodiments, the pharmaceutical composition may comprise 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 about 55% 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, approximately 45% w / w to approximately 65% ​​w / w, approximately 45% w / w to approximately 70% w / w, approximately 45% w / w to approximately 75% w / w, approximately 45% w / w to approximately 80% w / w, approximately 45% w / w to approximately 85% w / w, approximately 45% w / w to approximately 90% w / w, approximately 50% w / w to approximately 55% w / w, approximately 50% w / w to approximately 60% w / w, approximately 50% w / w to approximately 65% ​​w / w, approximately 50% w / w to approximately 70% w / w, approximately 50% w / w to approximately 75% w / w, approximately 50% w / w to approximately 80% w / w, approximately 50% w / w to approximately 85% w / w, approximately 50% w / w to approximately 90% w / w, approximately 55% w / w %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 solid dispersions of 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, said solid dispersions comprising compounds of formula (I).

[0088] In some embodiments, the pharmaceutical composition may comprise a solid dispersion of 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, said solid dispersion comprising a compound of formula (I).

[0089] In some embodiments, the pharmaceutical composition may comprise a solid dispersion of 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, said solid dispersion comprising a compound of formula (I). In some embodiments, the pharmaceutical composition may include a solid dispersion of 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, or about 59.9% w / w, said solid dispersion comprising a compound of formula (I).

[0090] To prepare solid compositions such as tablets, powders, or capsules, a major active ingredient may be mixed with a pharmaceutical excipient to form a solid preformation composition containing a homogeneous mixture of the compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analogue thereof. Homogeneity, as used in the preformation composition, means that the active ingredient can be uniformly dispersed in the composition, facilitating its aliquoting into unit dosage forms of equal efficacy, such as tablets, pills, and capsules. Some examples of suitable and pharmaceutically acceptable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, sodium glycolate starch, lactose monohydrate, polyvinylpyrrolidone (PVP, povidone), polyvinylpyrrolidone / vinyl acetate copolymer (PVP / VA, copovidone), crospovidone (PVPP, crospovidone), cellulose, sterile water, syrup, and methylcellulose. The formulation may also contain lubricants such as talc, magnesium stearate and mineral oil; humectants; emulsifiers and suspending agents; preservatives such as methylparaben and propylparaben; sweeteners; and flavoring agents.

[0091] In some embodiments, the pharmaceutical composition includes one or more excipients selected from copovidone, crospovidone, microcrystalline cellulose, mannitol, lactose monohydrate, crospovidone sodium carboxymethyl cellulose, colloidal silica, and magnesium stearate.

[0092] In some embodiments, 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, silica, and magnesium stearate.

[0093] In some embodiments, the pharmaceutical composition comprises croscarmellose sodium, croscarmellose, or a combination thereof.

[0094] In some embodiments, the pharmaceutical composition comprises lactose monohydrate, microcrystalline cellulose, or a combination thereof. In some embodiments, the pharmaceutical composition comprises lactose monohydrate and microcrystalline cellulose.

[0095] In some embodiments, the pharmaceutical composition comprises silicon dioxide, magnesium stearate, or a combination thereof. In some embodiments, the pharmaceutical composition comprises silicon dioxide and magnesium stearate.

[0096] In some embodiments, the pharmaceutical composition comprises croscarmellose sodium, lactose monohydrate, and microcrystalline cellulose.

[0097] In some embodiments, the pharmaceutical composition may comprise about 50-70% w / w of a solid dispersion and one or more excipients, said solid dispersion comprising a compound of formula (I). In some embodiments, the solid dispersion comprises about 60-75% w / w of a compound of formula (I) and about 25-40% w / w of a stable polymer. In some embodiments, the solid dispersion comprises a compound of formula (I) and a stable polymer, wherein the w / w ratio of the compound of formula (I) and the stable polymer is 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 silica, and magnesium stearate. For example, the pharmaceutical composition may comprise about 10-30% w / w of lactose monohydrate. The pharmaceutical composition may be provided in tablet form.

[0098] In some embodiments, the pharmaceutical composition comprises about 50-70% w / w of a solid dispersion comprising a compound of formula (I) and about 5%-15% w / w of microcrystalline cellulose.

[0099] In some embodiments, the pharmaceutical composition comprises about 50-70% w / w of a solid dispersion comprising a compound of formula (I), about 5%-15% w / w of microcrystalline cellulose, and about 10%-30% w / w of lactose monohydrate.

[0100] In some embodiments, the pharmaceutical composition comprises about 50-70% w / w of a solid dispersion comprising a compound of formula (I) and about 3%-10% w / w of croscarmellose sodium.

[0101] In some embodiments, the pharmaceutical composition comprises about 50-70% w / w of a solid dispersion comprising a 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.

[0102] In some embodiments, the pharmaceutical composition comprises about 50-70% w / w of a solid dispersion comprising a 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 silica; and about 0.1%-3% w / w of magnesium stearate.

[0103] In some embodiments, the pharmaceutical composition comprises about 60% w / w of a solid dispersion comprising a 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 silica, and about 1.25% w / w of magnesium stearate. In some embodiments, the solid dispersion comprises about 60%-75% w / w of the compound of formula (I) and about 25%-40% w / w of a stable polymer. In some embodiments, the solid dispersion comprises the compound of formula (I) and a stable polymer, wherein the w / w ratio of the compound of formula (I) and the stable polymer is 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 silica, and magnesium stearate. For example, the pharmaceutical composition may contain about 10%-30% w / w lactose monohydrate. The pharmaceutical composition may be provided in tablet form.

[0104] Pharmaceutical compositions can be manufactured by any suitable method known in the art. For example, pharmaceutical compositions can be manufactured by dry mixing or rolling.

[0105] Tablet formulation

[0106] In some embodiments, the pharmaceutical composition is formulated into tablets. In some embodiments, the composition is formulated into tablets comprising an inner layer and an outer layer. In some such embodiments, the solid dispersion is in the inner layer, and the inner layer also contains additional excipients as described herein. In some such embodiments, the solid dispersion is in the outer layer, and the outer layer also contains additional excipients as described herein. In some such embodiments, the solid dispersion is in both the inner and outer layers, and the inner and / or outer layers also contain additional excipients as described herein.

[0107] In some embodiments of the pharmaceutical composition formulated into tablets, the intraparticle layer of the tablet comprises about 20-30% w / w of a solid dispersion comprising a 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 silica; and about 0.1-3% w / w of magnesium stearate, and the extraparticle layer of the tablet comprises about 0.1-3% w / w of magnesium stearate, wherein the weight percentages are relative to the total weight of the pharmaceutical composition. In one such embodiment, the tablet comprises about 20-30% w / w of microcrystalline cellulose and about 40-50% w / w of lactose monohydrate. In another such embodiment, the tablet comprises about 40-50% w / w of microcrystalline cellulose and about 20-30% of lactose monohydrate, wherein the weight percentages are relative to the total weight of the pharmaceutical composition.

[0108] In some embodiments of the pharmaceutical composition formulated into tablets, the inner layer of the tablet comprises about 50-70% w / w of a solid dispersion comprising a 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 silica; and about 0.1%-3% w / w of magnesium stearate, and the outer layer of the tablet comprises about 1%-3% w / w of croscarmellose sodium; about 0.1%-1% of colloidal silica and about 0.1%-1% of magnesium stearate, wherein the weight percentages are relative to the total weight of the pharmaceutical composition. In some embodiments of the pharmaceutical composition formulated into tablets, the inner layer of the tablet comprises about 60% w / w of a solid dispersion comprising a 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 silica; and the outer layer of the tablet comprises about 2% w / w of croscarmellose sodium; about 0.25% of colloidal silica and about 0.5% of magnesium stearate, wherein the weight percentages are relative to the total weight of the pharmaceutical composition.

[0109] In some embodiments of the pharmaceutical composition formulated into tablets, the tablets are coated with a film. In some embodiments, the film coating comprises a polymer, a plasticizer, and / or a pigment. Examples of polymers in the tablet film coating include, but are not limited to, polyvinyl alcohol (PVA), polyvinylpyrrolidone (povidone), hydroxypropyl methylcellulose (HPMC), methacrylic acid copolymer, methylcellulose, ethylcellulose, or any other suitable film-forming polymer. Examples of plasticizers in the tablet film coating include, but are not limited to, hydroxypropyl methylcellulose (HPMC), polyethylene glycol, triacetin, stearate, citrate, phthalate, or any other suitable plasticizer. In some embodiments, the film coating is OPADRY II®.

[0110] Dosage form

[0111] The pharmaceutical compositions or compounds described herein may be administered in single or multiple doses. They may be administered by various methods, including, for example, oral administration.

[0112] Dosage forms for oral administration may be, for example, capsules or tablets. In preparing pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analogue thereof, the compound of formula (I) is typically mixed with an excipient, and the composition may be in the form of tablets, pills, powders, granules, or aseptically packaged powders. The composition may be encapsulated in a carrier, such as a capsule.

[0113] The tablets, pills, or capsules of the compounds described herein may be coated or otherwise compounded to provide dosage forms with the advantage of prolonged action or to protect them from degradation by the acidic environment of the stomach. For example, tablets or pills may include an internal dose component and an external dose component, the latter being a coating on the outside of the former. These two components may be separated by an enteric coating layer, which serves to prevent disintegration in the stomach and allow the internal component to enter the duodenum intact or to delay release. A variety of materials may be used for such an enteric coating or coating, including many polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0114] In some embodiments, each dosage form may include 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 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 may be a tablet containing 15 mg, 50 mg, 60 mg, or 200 mg of the compound of formula (I) (free acid). In some implementations, a suitable dosage form may be a tablet containing 50 mg of compound (I) (free acid) or 200 mg of compound (I) (free acid).

[0115] Reagent test kit

[0116] This document also provides a kit comprising a pharmaceutical composition comprising a solid dispersion comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the kit further includes instructions for use, labeling, and / or instructions for use of the compound in a therapeutic indication, including the disease or condition described herein. This kit may be used to treat cancer in patients in need. For example, a kit comprising a pharmaceutical composition and a blister pack or bottle (e.g., the blister pack or bottle described herein), wherein the pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof. The pharmaceutical composition or dosage form thereof may be contained in a package (e.g., a blister pack or a resealable bottle).

[0117] Uses and treatments

[0118] Pharmaceutical compositions comprising a solid dispersion containing a compound of formula (I) or kits comprising pharmaceutical compositions described herein may be used to treat one or more diseases or conditions mediated by the MDM2-p53 pathway (including cancers mediated by the MDM2-p53 pathway) or to prepare medicaments for treating one or more diseases or conditions mediated by the MDM2-p53 pathway (including cancers mediated by the MDM2-p53 pathway). Methods for treating one or more diseases or conditions mediated by the MDM2-p53 pathway (including cancers mediated by the MDM2-p53 pathway) are also provided herein.

[0119] The cancer may be a cancer sensitive to MDM2 inhibitor treatment. The cancer may include those with MDM2 amplification and / or MDM2 overexpression. The cancer may possess the wild-type TP53 gene. In some embodiments, the cancer is a p53-mutant tumor.

[0120] In one implementation, the cancer is a solid tumor. The solid tumor may be a metastatic and refractory solid tumor, an advanced metastatic and refractory solid tumor, mesothelioma, malignant peritoneal mesothelioma, malignant pleural mesothelioma, liposarcoma, dedifferentiated liposarcoma, well-differentiated liposarcoma, glioblastoma multiforme (GBM), endometrial sarcoma, hepatocellular carcinoma, esophageal 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 lung cancer (NSCLC)), brain cancer, glioma, or neuroblastoma.

[0121] In some embodiments, the cancer may be leukemia or a blood cancer. The cancer may be myelofibrosis, acute myeloid leukemia (AML), T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), or 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). In some embodiments, the cancer may be Hodgkin's lymphoma.

[0122] Combination therapy

[0123] In one embodiment, the compound of formula (I) disclosed herein, or a pharmaceutically acceptable salt, composition, or dosage form thereof, may be used / administered in combination with one or more other therapeutic agents that are being used for and / or are being developed for the treatment of cancers such as T-cell lymphoma. In one embodiment, a dosage form comprising a compound of formula (I) disclosed herein, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, may further comprise said other therapeutic agents that are being used for and / or are being developed for the treatment of cancers such as T-cell lymphoma.

[0124] In one embodiment, the compounds of formula (I) disclosed herein, or pharmaceutically acceptable salts, compositions, or dosage forms, may be used / administered in combination with one or more other compounds (or therapies) to treat a specific disease state, such as an oncological disease (e.g., cancer) as defined above. For treating the aforementioned disease, the compounds of the present invention may be advantageously used in combination with one or more other drugs, more specifically, in combination with other anticancer agents or adjuvants (supportive agents in treatment) used in cancer treatment. Examples of other therapeutic agents or therapies that may be administered together with the compounds of formula (I) disclosed herein, or pharmaceutically acceptable salts, compositions, or dosage forms (whether simultaneously or at different time intervals) include, but are not limited to:

[0125] • Topoisomerase I inhibitors

[0126] •Antimetabolites

[0127] • Microtubule-targeting agents

[0128] • DNA binding agents and topoisomerase II inhibitors

[0129] • Alkylating agents

[0130] • Monoclonal antibodies

[0131] • Antihormones

[0132] • Signal transduction inhibitors

[0133] • Proteasome inhibitors

[0134] • DNA methyltransferase inhibitors

[0135] • Cytokines and retinoids

[0136] • Chromatin-targeted therapy

[0137] •Radiation therapy, and

[0138] • Other treatments or preventative agents.

[0139] Specific examples of anticancer agents or adjuvants (or salts thereof) include, but are not limited to, any agent selected from group (i)-(xlviii) and optional group (xlix):

[0140] (i) Platinum compounds, such as cisplatin (optionally in combination with amifostine), carboplatin or oxaliplatin;

[0141] (ii) Taxane compounds, such as paclitaxel, paclitaxel protein-bound particles (Abraxane) TM ), Dorsetas, Cabathas, or Larotas;

[0142] (iii) Topoisomerase I inhibitors, such as camptothecin compounds, such as camptothecin, irinotecan (CPT11), SN-38 or topotecan;

[0143] (iv) Topoisomerase II inhibitors, such as antitumor epipodophyllotoxin or podophyllotoxin derivatives, such as etoposide or teniposide;

[0144] (v) Vinca alkaloids, such as vincristine, vinblastine, liposomal vincristine (Onco-TCS), vinorelbine, vindesine, vinflunine, or vinvesir.

[0145] (vi) Nucleoside derivatives, such as 5-fluorouracil (5-FU, optionally in combination with folate), gemcitabine, capecitabine, tegafur, UFT, S1, cladribine, cytarabine (Ara-C, cytarabine), fludarabine, clofarabine, or nelabine.

[0146] (vii) Antimetabolites, such as clofarabine, aminopterin or methotrexate, azacitidine, cytarabine, fluorouracil, pentostatin, thioguanine, thiopurine, 6-mercaptopurine or hydroxyurea (hydroxyurea).

[0147] (viii) Alkylating agents, such as nitrogen mustard or nitrosourea, such as cyclophosphamide, chlorambucil, carmustine (BCNU), bendamustine, thiotepa, mefarlam, treosulfan, lomustine (CCNU), octreotide, busulfan, dacarbazine, estradiol, formustine, ifosfamide (optionally in combination with mesna), piperopram, procarbazine, strazoxine, temozolomide, uracil, nitrogen mustard, methylcyclohexylchloroethylnitrosourea, or nimustine (ACNU);

[0148] (ix) Anthracyclines, anthraquinones and related drugs, such as daunorubicin, doxorubicin (optionally in combination with dexrazoxane), liposomal formulations of doxorubicin (e.g., Caelyx™, Myocet™, Doxil™), idarubicin, mitoxantrone, epirubicin, acridine or valrubicin.

[0149] (x) Epomycins, such as ixaprilone, pertoprilone, BMS-310705, KOS-862 and ZK-EPO, epopril A, epopril B, deoxyepopril B (also known as epopril D or KOS-862), aza-epopril B (also known as BMS-247550), aulimalide, isolalimalide or luetherobin;

[0150] (xi) DNA methyltransferase inhibitors, such as temozolomide, azacytidine, or decitabine;

[0151] (xii) Antifolate agents, such as methotrexate, pemetrexed disodium or raltitrexed;

[0152] (xiii) Cytotoxic antibiotics, such as antinomycin D, bleomycin, mitomycin C, dacamycin, carmine, daunorubicin, levamisole, vomica or mitrazin;

[0153] (xiv) Microtubule-binding agents, such as cobuxostatin, colchicine, or nocodazole;

[0154] (xv) Signal transduction inhibitors, such as kinase inhibitors, such as receptor tyrosine kinase inhibitors (e.g., EGFR (epidermal 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), such as imatinib mesylate, erlotinib, gefitinib, dasatinib, lapatinib, dovorinib, axitinib, nilotinib, vandetinib, vatalinib, pazopanib, sorafenib, sunitinib, tesimolimus, everolimus (RAD). 001), Vemolfenib (PLX4032 or RG7204), Dabrafenib, Cannefenib, Sliminib (AZD6244), Trametinib (GSK121120212), Deterlizib (BEZ235), Buppanicillin (BKM-120, NVP-BKM-120), BYL719, Cupanicillin (BAY-80-6946), ZSTK-474, CUDC-907, Apiritisib (GDC-0980, RG-7422), Pictilisib (pictrelisib, GDC-0941, RG-7321), GDC-0032, GDC-0068, GSK-2636771, Adelaide (formerly known as CAL-101, GS) 1101, GS-1101), MLN1117 (INK1117), MLN0128 (INK128), IPI-145 (INK1197), LY-3023414, Iparstat, Afostat, MK-2206, MK-8156, LY-3023414, LY294002, SF1126 or PI-103, Sonolisibu (PX-866) or AT13148;

[0155] (xvi) Aurora kinase inhibitors, such as AT9283, balaseti (AZD1152), TAK-901, MK0457 (VX680), cenisertib (R-763), daruseti (PHA-739358), alisetti (MLN-8237), or MP-470.

[0156] (xvii) CDK inhibitors, such as AT7519, roscovitine, seliciclib, avozidil ​​(vrapindo), dinacib (SCH-727965), 7-hydroxy-staphylococcalin (UCN-01), JNJ-7706621, BMS-387032 (also known as SNS-032), PHA533533, ZK-304709 or AZD-5438, and including CDK4 inhibitors such as palbociclib (PD332991) and ribociclib (LEE-011);

[0157] (xviii) PKA / B inhibitors and PKB (akt) pathway inhibitors, such as AT13148, AZ-5363, Semaphore, SF1126 and MTOR inhibitors, such as rapamycin analogs, AP23841 and AP23573, calmodulin inhibitors (forkhead translocation inhibitors), API-2 / TCN (triceribine), RX-0201, enzatolin HCl (LY317615), NL-71-101, SR-13668, PX-316 or KRX-0401 (perifoxetine / NSC 639966);

[0158] (xix)Hsp90 inhibitors, such as onaspira (At13387), senna, galdromycin (GA), 17-allylamino-17-demethoxygaldromycin (17-AAG) such as NSC-330507, Kos-953 and CNF-1010, 17-dimethylaminoethylamino-17-demethoxygaldromycin hydrochloride (17-DMAG) such as NSC-707545 and Kos-1022, NVP-AUY922 (VER-52296), NVP-BEP800, CNF-2024 (BIIB-021 oral purine), gantaspir (STA-9090), SNX-5422 (SC-102112) or IPI-504;

[0159] (xx) Monoclonal antibodies (unconjugated or conjugated to radioactive isotopes, toxins, or other reagents), antibody derivatives, and related reagents, such as anti-CD, anti-VEGFR, anti-HER2, or anti-EGFR antibodies, such as rituximab (CD20), oflamb (CD20), teimozumab (CD20), GA101 (Cd20), tosimomumab (CD20), epazolizumab (CD22), lintuzumab (CD33), gemtuzumab oxazolidin (CD33), alemtuzumab (CD52), galiximab (CD80), trastuzumab (HER2 antibody), pertuzumab (HER2), trastuzumab-DM1 (HER2), Ertuxomab (HER2 and CD3), Cetuximab (EGFR), Panitumumab (EGFR), Nexituzumab (EGFR), Nimotuzumab (EGFR), Bevacizumab (VEGF), Caputuzumab (EpCAM and CD3), Abagovumab (CA125), Faletuzumab (folate receptor), Elotouzumab (CS1), Denosumab (RANK ligand), Futomumab (IGF1R), CP751,871 (IGF1R), Mapamumumab (TRAIL receptor), Met (met), Mitomumab (GD3 ganglioside) Eto-naptumomab (5T4), or sutuximab (IL6), or immunomodulatory drugs, such as CTLA-4 blocking antibodies and / or antibodies against PD-1 and PD-L1 and / or PD-L2, such as ipilimumab (CTLA4), MK-3475 (pembrolizumab, formerly known as lanololizumab, anti-PD-1), nivolumab (anti-PD-1), BMS-936559 (anti-PD-L1), MPDL320A, AMP-514 or MEDI4736 (anti-PD-L1) or trimemumab (formerly known as tesimumab, CP-675206, anti-CTLA-4).

[0160] (xxi) Estrogen receptor antagonists or selective estrogen receptor modulators (SERMs) or estrogen synthesis inhibitors, such as tamoxifen, fulvestrant, toremifene, droloxifen, fasilodin or raloxifene.

[0161] (xxii) Aromatase inhibitors and related drugs, such as exemestane, anastrozole, leprazole, testosterone-aminoglutate, mitotane or vorazole;

[0162] (xxiii) Antiandrogens (i.e. androgen receptor antagonists) and related agents, such as bicalutamide, nilumid, flutamide, cyproterone acetate or ketoconazole;

[0163] (xxiv) Hormones and their analogues, such as medroxyprogesterone, diethylstilbestrol (also known as diethylstilbestrol) or octreotide;

[0164] (xxv) Steroids, such as tramustone propionate, megestrol acetate, nandrolone (decanoate, phenylpropionate), fluorometholone or gossypol;

[0165] (xxvi) Steroidal cytochrome P450 17α-hydroxylase-17,20-lyase inhibitors (CYP17), such as abiraterone;

[0166] (xxvii) Gonadotropin-releasing hormone agonists or antagonists (GnRAs), such as abalenelin, goserelin acetate, histaminerelin acetate, leuprorelin acetate, triptorelin, buserrelin, or dilorine.

[0167] (xxviii) Glucocorticoids, such as prednisone, prednisolone, and dexamethasone;

[0168] (xxix) Differentiators, such as retinoids, vitamin D or retinoic acid and retinoic acid metabolism blockers (RAMBA), such as isotretinoin, alitivemectin, bexarotine or retinoic acid;

[0169] (xxx) Farnesyltransferase inhibitors, such as tepifrazil;

[0170] (xxxi) Chromatin-targeted therapies, such as histone deacetylase (HDAC) inhibitors, such as sodium butyrate, succinyl aniline isohydroxamic acid (SAHA), pentapeptide (FR 901228), dacinolone (NVP-LAQ824), R306465 / JNJ-16241199, JNJ-26481585, trichomycin A, vorinostat, chlamydia, A-173, JNJ-MGCD-0103, PXD-101, or apimycin;

[0171] (xxxii) Drugs that target the ubiquitin-proteasome pathway, including proteasome inhibitors such as bortezomib, carfilzomib, CEP-18770, MLN-9708 or ONX-0912; NEDD8 inhibitors; HDM2 antagonists and deubiquitinases (DUB).

[0172] (xxxiii) Photodynamic drugs, such as sodium poofen or temopofen;

[0173] (xxxiv) Marine organism-derived anticancer agents, such as trachocinone;

[0174] (xxxv) Radiolabeled drugs used in radioimmunotherapy, such as isotopes that emit beta particles (e.g., iodine-131, yttrium-90) or isotopes that emit alpha particles (e.g., bismuth-213 or actinium-225), such as ibuprofen or iotosimomab or alpha radium-223.

[0175] (xxxvi) Telomerase inhibitors, such as telomerase repressin;

[0176] (xxxvii) Matrix metalloproteinase inhibitors, such as bamastat, marimastat, prinostat or methastat;

[0177] (xxxviii) Recombinant interferons (such as interferon-γ and interferon-α) and interleukins (such as interleukin-2), such as adeleukin, denileukin diftitox, interferon α2a, interferon α2b or pegylated interferon α2b.

[0178] (xxxix) Selective immunomodulators, such as thalidomide or lenalidomide;

[0179] (xl) Therapeutic vaccines, such as sipuleucel-T (Provenge) or OncoVex;

[0180] (xli) Cytokine activators include sapelin, romotide, cizonan, verulin, or thymosin;

[0181] (xlii) Arsenic trioxide;

[0182] (xliii) Inhibitors of G protein-coupled receptors (GPCRs), such as atrasentan;

[0183] (xliv) enzymes, such as L-asparaginase, pegaspargase, rapburase or pegaspargase;

[0184] (xlv) DNA repair inhibitors, such as PARP inhibitors, such as olaparib, veliparib, iniparib, INO-1001, AG-014699 or ONO-2231;

[0185] (xlvi) death receptor agonists (e.g., TNF-associated apoptosis-inducing ligand (TRAIL) receptors), such as mapatumumab (formerly known as HGS-ETR1), sitatumumab (formerly known as AMG 655), PRO95780, lesatumumab, dulanamine, CS-1008, apomab, or recombinant TRAIL ligands, such as recombinant human TRAIL / Apo2 ligand;

[0186] (xlvii) Immunotherapy, such as immune checkpoint inhibitors; cancer vaccines and CAR-T cell therapy;

[0187] (xlviii) Regulators of cell death (apoptosis), including Bcl-2 (B-cell lymphoma 2) antagonists such as venetoclax (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);

[0188] (xlix) prophylactic agents (adjuvants); that is, drugs that reduce or alleviate some of the side effects associated with chemotherapy drugs, such as...

[0189] - Anti-nausea medication

[0190] - Medications that prevent or reduce the duration of chemotherapy-related neutropenia and prevent complications caused by decreased platelet, red blood cell, or white blood cell levels, such as interleukin-11 (e.g., olprespin), erythropoietin (EPO) and its analogues (e.g., dabepoetin), colony-stimulating factor analogues such as granulocyte-macrophage colony-stimulating factor (GM-CSF) (e.g., saxaglastine), and granulocyte colony-stimulating factor (G-CSF) and its analogues (e.g., filgrastim, pegfilgrastim).

[0191] - Medications that inhibit bone resorption, such as denosumab or bisphosphonates, such as zoledronate, zoledronic acid, pamidronate, and ibandronate.

[0192] - Medications that suppress the inflammatory response, such as dexamethasone, prednisone, and prednisolone.

[0193] - Medications used to lower blood levels of growth hormone and IGF-1 (and other hormones) in patients with acromegaly or other rare hormone-producing tumors, such as synthetic formulations of the hormone somatostatin, like octreotide acetate.

[0194] -An antidote for medications that lower folic acid levels, such as calcium folinate or folinic acid.

[0195] - Painkillers, such as opioid preparations like morphine, diacetylmorphine, and fentanyl,

[0196] - Nonsteroidal anti-inflammatory drugs (NSAIDs), such as COX-2 inhibitors, such as celecoxib, etoricoxib, and rumicoxib.

[0197] -Medications for mucositis, such as parivmin,

[0198] - Medications used to treat side effects including anorexia, cachexia, edema, or thromboembolic events, such as medroxyprogesterone acetate.

[0199] For example, the one or more additional therapeutic agents may be selected from chidanilide, azacitidine, venetoclax, decitabine, navitoclax, entecista, cisplatin, dexamethasone, pembrolizumab, capecitabine, or tolinapant. In one embodiment, a dosage form comprising a compound of formula (I) disclosed herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof may further comprise the additional therapeutic agent being used for and / or being developed for the treatment of cancers such as T-cell lymphoma.

[0200] In one embodiment, the compound of formula (I) disclosed herein, or a pharmaceutically acceptable salt, composition, or dosage form thereof, is administered in combination with a treatment method such as bone marrow / stem cell transplantation, CAR T-cell therapy, or radiotherapy. In some embodiments, in addition to the compound of formula (I) or a pharmaceutically acceptable salt thereof, the pharmaceutical compositions or dosage forms described herein may also include one or more anticancer agents.

[0201] Each compound present in the combinations of the present invention can be administered individually with different dosage regimens and via different routes. Therefore, the administration of each of two or more agents can differ: each can be administered simultaneously or at different times. Those skilled in the art will know by their common sense the appropriate administration regimens and combination therapies. For example, the compounds of formula (I) disclosed herein, or pharmaceutically acceptable salts, compositions, or dosage forms, can be used in combination with one or more other agents administered according to their existing combination regimens. Examples of standard combination regimens are provided below.

[0202] Each treatment course of treatment, taxane compounds are advantageously administered at a dose of 50 to 400 mg (mg / m²) per square meter of body surface area. 2 ) Administered at a dose, for example, 75 to 250 mg / m² 2 In particular, the dosage of paclitaxel is approximately 175 to 250 mg / m². 2 The dosage of docetaxel is approximately 75 to 150 mg / m². 2 .

[0203] Each treatment course, camptothecin compounds were preferably administered at a dose of 0.1 to 400 mg (mg / m²) per square meter of body surface area. 2 ) dosage, for example 1 to 300 mg / m² 2 In particular, the dosage of irinotecan is approximately 100 to 350 mg / m². 2 The dosage of topotecan is approximately 1 to 2 mg / m². 2 .

[0204] Each treatment cycle, the antitumor podophyllotoxin derivative is advantageously administered at a dose of 30 to 300 mg / m² of body surface area. 2 ) Administered at a dosage, for example, 50 to 250 mg / m². 2 In particular, the dosage of etoposide is approximately 35 to 100 mg / m². 2 The dosage of teniposide is approximately 50 to 250 mg / m². 2 .

[0205] Each course of treatment delivers antitumor periwinkle alkaloids at a rate of 2 to 30 mg (mg / m²) per square meter of body surface area. 2 The dosage of vinblastine, in particular, is approximately 3 to 12 mg / m². 2 The dosage of vincristine is approximately 1 to 2 mg / m². 2 The dosage of vinorelbine is approximately 10 to 30 mg / m². 2 .

[0206] Each treatment cycle, the antitumor nucleoside derivative is advantageously administered at a dose of 200 to 2500 mg (mg / m²) per square meter of body surface area. 2 ) dosage, for example 700 to 1500 mg / m² 2 In particular, the dosage of 5-FU is approximately 200 to 500 mg / m². 2 The dosage of gemcitabine is approximately 800 to 1200 mg / m². 2 The dosage of capecitabine is approximately 1000 to 2500 mg / m². 2 .

[0207] For each treatment cycle, alkylating agents such as nitrogen mustard or nitrosourea are advantageously administered at a dose of 100 to 500 mg per square meter of body surface area (mg / m²). 2 ) dosage, for example 120 to 200 mg / m 2 In particular, the dosage of cyclophosphamide is approximately 100 to 500 mg / m². 2 The dosage of chlorambucil is approximately 0.1 to 0.2 mg / kg, and the dosage of carmustine is approximately 150 to 200 mg / kg. 2 The dosage of lomustine is approximately 100 to 150 mg / m². 2 .

[0208] Each treatment cycle, anthracycline antibiotic derivatives for tumors are preferably administered at a dose of 10 to 75 mg / m² of body surface area. 2 ) Administered at a dose, for example, 15 to 60 mg / m² 2 In particular, the dosage of doxorubicin is approximately 40 to 75 mg / m². 2 The dosage of daunorubicin is approximately 25 to 45 mg / m². 2 The dosage of idarubicin is approximately 10 to 15 mg / m². 2 .

[0209] Depending on the specific medication and the condition being treated, anti-estrogens are preferably administered at doses of approximately 1 to 100 mg daily. Tamoxifen is preferably administered orally at doses of 5 to 50 mg, usually 10 to 20 mg, twice daily, for a sufficient duration to achieve and maintain its therapeutic effect. Toremifene is preferably administered orally at a dose of approximately 60 mg once daily, for a sufficient duration to achieve and maintain its therapeutic effect. Anastrozole is preferably administered orally at a dose of approximately 1 mg once daily. Draloxifene is preferably administered orally at a dose of approximately 20-100 mg once daily. Raloxifene is preferably administered orally at a dose of approximately 60 mg once daily. Exemestane is preferably administered orally at a dose of approximately 25 mg once daily.

[0210] Antibodies favorably produce approximately 1 to 5 mg (mg / m²) per square meter of body surface area. 2 Administered at the dose specified in the manual or, in different cases, at the doses known in the art. For each treatment cycle, trastuzumab is advantageously administered at a dose of 1 to 5 mg (mg / m²) per square meter of body surface area. 2 Dosage administration, especially 2 to 4 mg / m² 2 .

[0211] When a compound of formula (I) disclosed herein, or a pharmaceutically acceptable salt, composition, or dosage form, is administered in combination therapy with one, two, three, four, or more other therapeutic agents (usually one or two, more commonly one), these compounds may be administered simultaneously or sequentially. In the latter case, the two or more compounds will be administered over a period of time in an amount and manner sufficient to ensure a beneficial or synergistic effect. When administered sequentially, they may be administered at close intervals (e.g., 5-10 minutes) or longer intervals (e.g., intervals of 1, 2, 3, 4 hours, or longer, or even longer intervals if necessary), with the precise dosing regimen proportionate to the nature of the therapeutic agents. These doses may be administered, for example, once, twice, or more times in each course of treatment, and may be repeated, for example, every 7, 14, 21, or 28 days.

[0212] dose

[0213] The specific dose level of the compounds in this application for any particular subject will depend on a variety of factors, including the activity of the specific compound used, age, weight, general health condition, sex, diet, time of administration, route of administration and excretion rate, drug combination, and the severity of a specific disease in the subject being treated. For example, the dose may be expressed as milligrams (mg / kg) of the compound of formula (I) or its pharmaceutically acceptable salt per kilogram of subject body weight. A dose of about 0.1 to 150 mg / kg may be suitable. In some embodiments, about 0.1 to 100 mg / kg may be suitable. In other embodiments, a dose between 0.5 and 60 mg / kg may be suitable. Standardization based on subject weight is particularly useful when adjusting the dose among subjects with large differences in body size, such as when using the drug in children and adults, or when converting an effective dose for non-human subjects (such as dogs) to a dose suitable for human subjects.

[0214] The daily dose can also be described as the total amount of the compound of formula (I) or the pharmaceutically acceptable salt described herein administered per dose or per day. For example, the daily dose of the compound of formula (I) (free acid) can be from about 1 mg to 4000 mg, about 2000 to 4000 mg / day, about 1 to 2000 mg / day, about 1 to 1000 mg / day, about 10 to 1000 mg / day, about 20 to 1000 mg / day, about 30 to 700 mg / day, or about 50 to 700 mg / day.

[0215] When administered orally, the total daily dose of the compound of formula (I) (free acid) for use in human subjects may be between 1 mg and 1000 mg, between about 1000-2000 mg / day, between about 10-500 mg / day, between about 50-500 mg / day, between about 100-500 mg / day, between about 200-500 mg / day, between about 300-500 mg / day, or between 500-1000 mg / day. For example, the total daily dose for human subjects may be approximately 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 human subjects may be approximately 100, 200, 300, 400, 500, 550, 600, 650, or 700 mg per day.

[0216] Compounds of formula (I) or pharmaceutically acceptable salts thereof or combinations thereof may be administered once, twice, three or four times daily, or twice or three times weekly, in any of the suitable manner described above. Similarly, administration or treatment with compounds of formula (I) may continue for several days; for example, a treatment cycle typically lasts at least 7, 14, or 28 days. Treatment cycles are well known in cancer chemotherapy and are typically alternated between cycles with rest periods of approximately 1 to 28 days, typically approximately 7 or 14 days. In other embodiments, treatment cycles may also be continuous.

[0217] In some embodiments, the compound of formula (I) may be administered orally once daily at an amount of about 200, 250, 300, 350, 400, 450, or 500 mg of the compound of formula (I) (free acid). In some embodiments, this daily administration may continue for 7 days, 14 days, 28 days, 8 weeks, 12 weeks, 16 weeks, 24 weeks, or longer. In some embodiments, the compound of formula (I) may be administered orally once daily at 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 orally once daily at an amount of about 400 mg of the compound of formula (I) (free acid). For example, the compound of formula (I) may be administered orally once daily at an amount of about 400 mg of the compound of formula (I) (free acid) for 28 days, 8 weeks, 12 weeks, 16 weeks, 24 weeks, or longer.

[0218] In some embodiments, the compound of formula (I) may be administered orally twice weekly at an amount of about 600 mg to 700 mg of the compound of formula (I) (free acid). In some embodiments, this daily administration may continue for 7 days, 14 days, 28 days, 8 weeks, 12 weeks, 16 weeks, 24 weeks, or longer. For example, the compound of formula (I) may be administered orally twice weekly at an amount of about 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, or 700 mg of the compound of formula (I) (free acid) for 7 days, 14 days, 28 days, 8 weeks, 12 weeks, 16 weeks, 24 weeks, or longer. In some embodiments, the compound of formula (I) may be administered orally twice weekly at 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 orally twice weekly at an amount of about 650 or 660 mg of the compound of formula (I) (free acid) for 28 days, 8 weeks, 12 weeks, 16 weeks, 24 weeks, or longer.

[0219] In one specific implementation, the method involves administering a subject an initial daily dose of about 50 to 200 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and gradually increasing the dose until a clinical effect is achieved. In some implementations, the dose may be increased in 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. The dose may be increased daily, every other day, twice a week, or once a week.

[0220] Example

[0221] The following embodiments are incorporated to illustrate specific implementations of this disclosure. Those skilled in the art will understand that the techniques disclosed in the following embodiments represent techniques that work well in the practice of this disclosure and can therefore be considered to constitute a specific model of its practice. However, based on this disclosure, those skilled in the art should understand that many changes can be made to the disclosed specific embodiments without departing from the spirit and scope of this disclosure, and the same or similar results can still be obtained.

[0222] Example 1: Preparation of solid dispersions

[0223] A spray-dried dispersion of compound (I) was prepared. The amorphous solid dispersion contained approximately 66.7% w / w of compound (I) and approximately 33.3% w / w of PVP / VA 64 as a stabilizing polymer. This solid dispersion was prepared by removing the solvent through spray drying of a solution of compound (I) and PVP / VA 64. The spray drying process consisted of three steps: preparation of the feed solution, spray drying, and secondary drying.

[0224] The feed solution was prepared in a solvent (acetone / water, 90 / 10% w / w) with a solids loading of 6% w / w. The feed solution was prepared in a 200 L stainless steel reactor equipped with an impeller and a temperature-controlled thermal loop at the bottom. The reactor was covered with nitrogen before adding the solvent to minimize oxygen content. The solution temperature was maintained at 15–25 °C, preferably 20 °C, throughout the spray drying process. The target stirring speed was 200 rpm. The mixture was stirred until the solids dissolved. The solution was inline filtered through a stainless steel filter during delivery to the spray dryer.

[0225] The spray drying step utilizes a large-scale spray dryer equipped with pressure nozzles. The spray dryer operates under a nitrogen atmosphere and can be configured for open or closed circulation. The flow rate of the drying gas is controlled by a setpoint in the nitrogen supply flow control valve. Before starting batch production, the spray dryer is heated and stabilized with nitrogen, followed by solvent stabilization. During stabilization, the outlet temperature of the spray dryer is set to a target value by adjusting the inlet temperature of the drying gas. After the inlet and outlet temperatures have stabilized, the feed is introduced into the solution to begin batch production. A high-pressure pump is used, automatically controlled by applying the required setpoint. The feed is atomized at the nozzle tip and dried in the drying chamber by a co-current flow of hot nitrogen. The stream containing the dried product exits the drying chamber and enters a cyclone separator, where most of the solids are separated and collected in a dry powder collector. The nitrogen exiting the cyclone separator passes through a filter bag before entering the exhaust fan, where fine particles are captured. The exhaust fan speed of F2 is adjusted to keep the system pressure within acceptable limits. After complete incorporation into the solution, the feed is converted into solvent. Collect the wet spray-dried dispersion (SDD). For wet SDD, perform secondary drying in a tray oven or stirred cone dryer until the acetone content does not exceed 1500 ppm.

[0226] Example 2: Preparation of the pharmaceutical composition

[0227] A pharmaceutical composition comprising compound (I) was formed.

[0228] For the intragranular materials, the solid dispersion of the compound of formula (I) from Example 1 was passed through a 032R sieve at approximately 1050 RPM and collected in a hopper. A spoonful of unground microcrystalline cellulose was added to each empty container for the solid dispersion of the compound of formula (I) and rinsed by manually mixing the contents for approximately 30 seconds. The mixture was then passed through a 032R sieve at approximately 1050 RPM and collected in a hopper. The remaining microcrystalline cellulose was then passed through a 032R sieve at approximately 1050 RPM and collected in a hopper. Other intragranular materials were fed directly into the hopper through a 032R sieve in the following order: lactose, followed by croscarmellose sodium. Approximately equal volumes of the mixture were then removed and added to the container of colloidal silica (intragranular), manually mixed for approximately 30 seconds, then passed through a 032R sieve at approximately 1050 RPM ± 20 RPM and collected in a hopper. For batch 1, mix the materials at 8 RPM for 15 minutes at 120 rpm. For batches 2-4, mix the materials at 6 RPM for 15 minutes at 90 rpm.

[0229] Magnesium stearate (within granules) was manually mixed with an equal volume of the mixture and then co-sieved directly into the hopper through a 30-mesh hand sieve. For batch 1, the material was mixed at 8 RPM for 5 minutes at 40 rpm. For batches 2-4, the material was mixed at 6 RPM for 5 minutes at 30 rpm.

[0230] The mixture is loaded into the hopper of the roller press. The ground material is then collected into appropriately labeled containers.

[0231] Adjust the external additives according to the actual yield of the ground particles. Load approximately half of the ground particles into an appropriately sized hopper. Crosslinked sodium carboxymethyl cellulose is directly sieved into the hopper through a 20-mesh sieve. Add approximately an equal volume of the mixture from the hopper to the silica container and mix manually for approximately 30 seconds. Then, pass this material directly into the hopper through a 20-mesh sieve. Then, load the remaining half of the ground particles into the hopper. For batch 1, mix the material at 8 RPM for 15 minutes at 120 rpm. For batches 2-4, mix the material at 6 RPM for 15 minutes at 90 rpm.

[0232] Magnesium stearate was manually mixed with an equal volume of the mixture and then co-sieved directly into the hopper through a 30-mesh hand sieve. For batch 1, the material was mixed at 8 RPM for 4 minutes, continuously for 32 revolutions. For batches 2-4, the material was mixed at 6 RPM for 4 minutes, continuously for 24 revolutions.

[0233] The final pharmaceutical formulation (also referred to herein as “formula (I) common mixture”) is shown in Table 1.

[0234] Table 1

[0235]

[0236] 1 The solid dispersion comprises 66.7% w / w of the compound of formula (I) (free acid) in N-vinylpyrrolidone and vinyl acetate (PVPVA-64).

[0237] Example 3: Formation of a 50mg Core Tablet

[0238] The Korsch XL100 tablet press is assembled using a ¼” (0.2500”) circular tooling. The press is initially run using a batch size of 2-4. The target tablet weight for 50mg tablets is 0.1250g. During compression, the permissible deviation is ±5% of the target weight for 10 tablets in-process weight and ±7.5% for a single tablet. As tablets exit the press, they pass through a tablet dust collector and metal detector and are collected in a temporary fiber bin lined with double-layered polyethylene bags and appropriately labeled.

[0239] After compression, the tablets are coated and collected in appropriately labeled containers and packaged. Purified water is weighed and mixed with Opadry II Yellow as shown in Table 2. The coating suspension is then sprayed onto the surface of an empty coating pan until a thin film is formed on the exposed metal surface. The initial target spray rate is set to approximately 30 g / min ± 3 g / min. Tablet cores are loaded into a suitable coating pan and preheated at an outlet temperature of approximately 42°C ± 3°C. The tablets are coated until an actual weight gain of 3.0%–5.0% is achieved per tablet. When the target weight gain of 4.0% is reached, spraying of the coating suspension is stopped, the inlet air temperature is reduced to approximately 25°C, the pan speed is decreased, and the tablets are dried / cooled for at least 5 minutes.

[0240] Table 2

[0241]

[0242] Example 4: Formulation of 200 mg tablet core

[0243] The Korsch XL100 tablet press is assembled using a modified 0.2759” x 0.6285” oval die. The press is initially run using a batch of 1-3. The target tablet weight for 200mg tablets is 0.5000g. During compression, the permissible deviation is ±5% of the target weight for 10 tablets processed, and ±7.5% for a single tablet. As tablets exit the press, they pass through a tablet dust collector and metal detector, and are collected in temporary fiber bins lined with double-layered polyethylene bags and appropriately labeled.

[0244] After compression, the tablets are coated and collected in appropriately labeled containers and packaged. Purified water is weighed and mixed with Opadry II Blue, as shown in Table 3. The coating suspension is then sprayed onto the surface of an empty coating pan until a thin film is formed on the exposed metal surface. The initial target spray rate is set to approximately 30 g / min ± 3 g / min. Tablet cores are loaded into suitable coating pans and preheated at an outlet temperature of approximately 42°C ± 3°C. The tablets are coated until an actual weight gain of 3.0%–5.0% is achieved per tablet. When the target weight gain of 4.0% is reached, spraying the coating suspension is stopped, the inlet air temperature is reduced to approximately 25°C, the pan speed is decreased, and the tablets are dried / cooled for at least 5 minutes.

[0245] Table 3

[0246]

[0247] Example 5: Dissolution test of 50mg tablets

[0248] Following Example 3, 50 tablets were sampled at approximately the beginning (Part 1), middle (Part 2), and end (Part 3) of the run for dissolution testing after pressing and before coating with the common mixture of Formula (I) in batch 4.

[0249] According to USP <711> The dissolution properties of the tablets were determined by quantifying the compound of formula (I) using reversed-phase isocratic HPLC with UV detection. The tablets were dissolved in 900 mL of medium (10 mM Na₂HPO₄, pH 6.8, containing 0.05–1.0 w / v% Tween 80, soluble in water) and stirred at 75 rpm at 37.0 ± 0.5 °C. 5 mL samples were collected at 5, 10, 15, 30, 45, and 60 minutes.

[0250] The dissolved sample solution was filtered and directly dispensed into vials, and analyzed by HPLC using UV detection at 220 nm using the isocratic method. The dissolution rate of the compound (I) tablet was determined by comparing the peak area of ​​formula (I) in the sample chromatogram with the peak area of ​​formula (I) in the reference standard solution. For 50 mg tablets, the prepared reference solution contained approximately 0.0556 mg / mL of compound (I) in a diluent (80:20 acetonitrile:water), while for 200 mg tablets it was 0.20 mg / mL. Results are expressed as dissolution percentage (% dissolution, average, and range).

[0251] The results are shown in Table 4.

[0252] Table 4

[0253]

[0254] Example 6: Preparation of solid dispersions with different compositions

[0255] Three different spray-dried dispersions of compound (I) were prepared using a method similar to that described in Example 1, but with the weight ratios of compound (I) to PVP / VA 64 being 1:1, 3:1, and 1:2, respectively. The resulting spray-dried dispersions were formulated into tablets using a method similar to that described in Example 3, and their dissolution was tested as described in Example 5.

[0256] A spray-dried dispersion of compound (I) was prepared using a method similar to that described in Example 1, but HPMCAS was used instead of PVP / VA 64 as the stabilizing polymer. The resulting spray-dried dispersion was formulated into tablets using a method similar to that described in Example 3, and its dissolution was tested as described in Example 5.

[0257] * * *

[0258] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0259] The examples illustrated herein may be appropriately implemented without including any elements or limitations not expressly disclosed herein. Therefore, terms such as “comprising,” “containing,” and “including” should be interpreted broadly and without limitation. Furthermore, the terms and expressions used herein are descriptive rather than restrictive, and their use is not intended to exclude any equivalents of the features shown and described or portions thereof; however, it should be recognized that various modifications are possible within the scope of the claims.

[0260] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated herein by reference in their entirety as if each were individually incorporated herein by reference. In case of conflict, this specification (including definitions) shall prevail.

[0261] It should be understood that although this disclosure has been described in conjunction with the above embodiments, the foregoing description and examples are intended to illustrate and not limit the scope of this disclosure. Other aspects, advantages, and modifications within the scope of this disclosure will be apparent to those skilled in the art.

Claims

1. A solid dispersion comprising a compound of formula (I): (I)， Or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is dispersed in molecular form in a polymer matrix comprising a stable polymer.

2. The solid dispersion according to claim 1, wherein the stable polymer is polyvinylpyrrolidone / vinyl acetate (PVPVA), hydroxypropyl methylcellulose (HPMC), or hydroxypropyl methylcellulose acetate succinate (HPMCAS).

3. The solid dispersion according to claim 1, wherein the stable polymer is polyvinylpyrrolidone / vinyl acetate (PVPVA).

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

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

6. The solid dispersion according to any one of claims 1-5, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is substantially amorphous.

7. The solid dispersion according to any one of claims 1-6, wherein at least 98% of the compound of formula (I) or its pharmaceutically acceptable salt is in an amorphous form.

8. The solid dispersion according to any one of claims 1-7, wherein the amount of the stable polymer in the solid dispersion is about 20% to about 50% of the weight of the solid dispersion.

9. The solid dispersion according to any one of claims 1-7, wherein the amount of the stable polymer in the solid dispersion is about 30% to about 40% of the weight of the solid dispersion.

10. The solid dispersion according to any one of claims 1-9, wherein the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the solid dispersion to the weight of the stable polymer in the solid dispersion is from about 1:3 to about 3:

1.

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

1.

12. The solid dispersion according to claim 10, wherein the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the solid dispersion to the weight of the stable polymer in the solid dispersion is about 2:

1.

13. The solid dispersion according to any one of claims 1-12, wherein the solid dispersion comprises a compound of formula (I) in the form of a free acid.

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

15. A pharmaceutical composition comprising: A solid dispersion of approximately 50%-70% w / w, wherein the solid dispersion comprises a compound of formula (I): (I)， Or its pharmaceutically acceptable salt.

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

17. The pharmaceutical composition according to claim 15 or 16, wherein the solid dispersion comprises a compound of formula (I) and a stable polymer, wherein the weight ratio of the compound of formula (I) to the stable polymer is 3:1 to 1:

3.

18. The pharmaceutical composition according to any one of claims 15-17, wherein the stable polymer is polyvinylpyrrolidone / vinyl acetate (PVPVA).

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

20. The pharmaceutical composition according to any one of claims 18-19, further comprising: Approximately 5%-15% w / w microcrystalline cellulose; Approximately 10%-30% w / w lactose monohydrate; Approximately 3%-10% w / w of croscarmellose sodium; Approximately 0.1%-3% w / w of silica; and Magnesium stearate, approximately 0.1%-3% w / w.

21. The pharmaceutical composition according to any one of claims 15-20, wherein the solid dispersion comprises a compound of formula (I) in the form of a free acid.

22. The pharmaceutical composition according to any one of claims 15-20, wherein the solid dispersion comprises a sodium salt or tromethamine salt of a compound of formula (I).

23. A dosage form comprising the pharmaceutical composition according to any one of claims 15-20.

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

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

26. The dosage form according to any one of claims 23-25, wherein the dosage form comprises one or more other anticancer agents.

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

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

29. A method of treating cancer in patients in need, the method comprising administering an effective amount of the pharmaceutical composition of any one of claims 13-20 or the dosage form of any one of claims 23-28.

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

31. The method of claim 29, wherein the cancer is selected from 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, endometrial sarcoma, hepatocellular carcinoma, esophageal 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 myeloid leukemia (AML), T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), MALT lymphoma, wherein 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 according to any one of claims 29-31, wherein the pharmaceutical composition is administered once daily for 28 days.

33. The method according to any one of claims 29-31, wherein the pharmaceutical composition is administered twice a week in a 28-day cycle.

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

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

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

37. The use according to claim 34 or 35, wherein the cancer is selected from 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, endometrial sarcoma, hepatocellular carcinoma, esophageal 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 myeloid leukemia (AML), T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), MALT lymphoma, wherein the T-cell lymphoma may be progressive or relapsed peripheral T-cell lymphoma (PTCL) and relapsed or refractory cutaneous T-cell lymphoma (CTCL).

38. The pharmaceutical composition according to any one of claims 15-22, for treating cancer in patients with this need.

39. The pharmaceutical composition of claim 38, wherein the cancer has the wild-type TP53 gene.

40. The pharmaceutical composition according to claim 38 or 39, wherein the cancer is selected from 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, endometrial sarcoma, hepatocellular carcinoma, esophageal 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 myeloid leukemia (AML), T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), MALT lymphoma, wherein the T-cell lymphoma may be progressive or relapsed peripheral T-cell lymphoma (PTCL) and relapsed or refractory cutaneous T-cell lymphoma (CTCL).

Images