A pharmaceutical combination and the use thereof

Abstract

Provided herein are pharmaceutical combinations comprising an embryonic ectoderm development (EED) inhibitor and another inhibitor selected from the group consisting of a histone deacetylase (HDAC) inhibitor, a JAK inhibitor, and a BCL2 / BCL-XL inhibitor; wherein the EED inhibitor is a compound of formula I or a pharmaceutically acceptable salt or solvate thereof. An EED inhibitor in combination with another inhibitor selected from the group consisting of a histone deacetylase (HDAC) inhibitor, a JAK inhibitor, and a BCL2 / BCL-XL inhibitor produces a synergistic effect beyond a single use of the EED inhibitor or the another inhibitor. I, Formula I

Description

(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) ™ (19) World Intellectual Property ~S Organization , LAYOUT A AN A A International Bureau —— (10) International Publication Number (43) International Publication Date =— WO 2025 / 082481 Al 24 April 2025 (24.04.2025) WIPOI|PCT (51) International Patent Classification: HN, HR, HU, ID, IL, IN, IQ, IR, IS, IT, JM, JO, JP, KE, KG, A61K 45 / 06 (2006.01) KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, (21) International Application Number: MA, MD, MG, MK, MN, MU, > MX, MY, MZ, NA, PCT / CN2024 / 125773 NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, . RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, ST, SV, SY, TH, (22) International Filing Date: TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, WS, 18 October 2024 (18.10.2024) ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every oo. . . kind of regional protection available): ARIPO (BW, CV, (26) Publication Language:English GH, GM, KE, LR, LS, MW, MZ, NA, RW, SC, SD, SL, ST, (30) Priority Data: SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, PCT / CN2023 / 125670 RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, 20 October 2023 (20.10.2023) CN DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, ME, MK, MT, NL, NO, PL, PT, RO, RS, SE, (71) Applicants: ASCENTAGE PHARMA (SUZHOU) CO., SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, Cl, CM, GA, GN LTD. [CN / CN]; 68 Xinging Road, Suzhou Industrial Park, GO GW KM. ML. MR. NE SN TD TG) ue ee Suzhou, Jiangsu 215000 (CN). ASCENTAGE PHARMA 0 I II eee Se ee’ GROUP CORP LIMITED [CN / CN], Unit B, 17 / F., Unit- Published: cM 95 Queensway, Admiralty, Hong Kong 999077 __ with international search report (Art. 21(3)) == (72) Inventors: YANG, Dajun; 68 Xinqing Road, Suzhou In- = dustrial Park, Suzhou, Jiangsu 215000 (CN). ZHAI, Yifan; — 68 Xinqing Road, Suzhou Industrial Park, Suzhou, Jiang- — su 215000 (CN). LIANG, Eric; 68 Xinging Road, Suzhou — IndustrialPark, Suzhou, Jiangsu 215000 (CN). YIN, Yan; = 68 Xinqing Road, Suzhou Industrial Park, Suzhou, Jiangsu = 215000 (CN). === (74) Agent: KING & WOOD MALLESONS,; 20th Floor, -—— East Tower, World Financial Centre, No. 1 Dongsanhuan — Zhonglu, Chaoyang District, Beijing 100020 (CN). === (81) Designated States (unless otherwise indicated, for every — kind of national protection available); AE, AG, AL, AM, =— AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, = CA, CH, CL, CN, CO, CR, CU, CV, CZ, DE, DJ, DK, DM, — DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, === (54) Title: APHARMACEUTICAL COMBINATION AND THE USE THEREOF = Ri UR 2 SX Re ad = o 2) — CQ (57) Abstract: Provided herein is the pharmaceutical combination comprising an embryonic ectoderm development (EED) inhibitor and x another inhibitor selected from the group consisting of a histone deacetylase HDAC) inhibitor, a JAK inhibitor and a BCL2 / BCL-XL w inhibitor; wherein the EED inhibitor is a compound of Formula (I) or thepharmaceutically acceptable salt or solvate thereof. The EED qy inhibitor combined with another inhibitor selected from the group consisting of a histone deacetylase (HDAC) inhibitor, a JAK inhibitor 4 and a BCL2 / BCL-XL inhibitor produces synergistic effects over a single use of either the EED inhibitor or said another inhibitor. WO 2025 / 082481 PCT / CN2024 / 125773 A PHARMACEUTICAL COMBINATION AND THE USE THEREOF TECHNICAL FIELD 5 The present invention relates to the pharmaceutical field, and particularly relates to a pharmaceutical combination and the use thereof. BACKGROUND OF THE INVENTION Proliferative diseases represent a serious threat to modern society. 10 Cancerous growths pose serious challenges for modern medicine due to their unique characteristics, including uncontrollable cell proliferation, an ability to invade local and even remote tissues, lack of differentiation, lack of detectable symptoms and lack of effective therapy and prevention. Worldwide, more than 10 millionpeople are diagnosed with cancer every year, and cancer causes six 15 million deaths every year or 12% of the deaths worldwide. The embryonic ectoderm development (EED) inhibitor has been shown to be a potent anti-cancer drug, however, there 1s still a need to potentiate the use of the EED inhibitor further and improve the outcome of cancer treatment. T-cell lymphoma (TCL) is a highly heterogeneous group of invasive Non- 20 Hodgkin’s Lymphomas (NHLs) with adverse prognosis and limited treatment options. TCL comprise approximately 10-15% of all NHLs. The main subsets are peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL). In another aspect, T-cell malignancies are endemic in East Asia, the 25 Caribbean, intertropical Africa, the Middle East, South America, and Papua New Guinea. However, because of the comprehensive pathogenesis and limited therapeutics, patients with T-cell lymphomas usually have a poor prognosis and are prone to relapse. Currently, chemotherapy isthe most preferred treatment in T-cell lymphoma patients. With the development of chemotherapy, the prognosis 1 WO 2025 / 082481 PCT / CN2024 / 125773 of T-cell leukemia / lymphoma has gradually improved. However, due to the non- specific toxicity of current chemotherapeutic compounds to normal cells, the progressive loss of quality of life is a matter of concern. The treatment of patients with T-cell lymphomas is challenging. Novel 5 therapeutic strategies are urgently needed to improve the therapeutic effects of T-cell lymphomas. SUMMARY OF THE INVENTION The inventors discovered that the pharmaceutical combination comprising 10 an EED inhibitor and another inhibitor selected from the group consisting of a histone deacetylase (HDAC) inhibitor, a JAK inhibitor and a BCL2 / BCL-XL inhibitor produces synergistic anti-cancer effects compared with a single EED inhibitor or HDAC inhibitor. The inventors discovered that the EED inhibitor is particularly useful for T- 15 cell lymphoma treatment, and ismore effective and potent than other therapeutics (such as Valemetostat, MAK683, and Tazemetostat) for T-cell lymphoma treatment. In one aspect, the invention provides a pharmaceutical combination comprising an embryonic ectoderm development (EED) inhibitor and another 20 inhibitor selected from the group consisting of a histone deacetylase (HDAC) inhibitor, a JAK inhibitor and a BCL2 / BCL-XL inhibitor. In one aspect, the invention provides a pharmaceutical composition comprising the pharmaceutical combination disclosed herein and pharmaceutically acceptable carriers. 25 In one aspect, the invention provides a method for treating cancer in a subject, comprising administering a therapeutically effective amount of the pharmaceutical combination disclosed herein or the pharmaceutical composition disclosed herein to the subject. 2 WO 2025 / 082481 PCT / CN2024 / 125773 In one aspect, the invention provides a method for treating a disease in a subject, comprising administering a therapeuticallyeffective amount of an EED inhibitor to the subject. In one aspect, the invention provides use of the pharmaceutical combination 5 disclosed herein or the pharmaceutical composition disclosed herein in the manufacture of a medicament for treating cancer. In one aspect, the invention provides use of an EED inhibitor in the manufacture of a medicament for treating a disease. In one aspect, the invention provides the pharmaceutical combination 10 disclosed herein or the pharmaceutical composition disclosed herein for use in treating cancer. In one aspect, the invention provides an EED inhibitor for use in treating a disease. In one aspect, the invention provides a kit, comprising: 15 (a) a first component in a first container, the first component comprising an EED inhibitor, and optionally a pharmaceutically acceptable carrier; (b) a second component in a second container, the second component comprising an inhibitor selected from the group consisting of an HDAC inhibitor (preferably anHDAC inhibitor disclosed herein), a JAK inhibitor (preferably a 20 JAK inhibitor disclosed herein) and a BCL2 / BCL-XL inhibitor (preferably a BCL2 / BCL-XL inhibitor disclosed herein) and optionally a pharmaceutically acceptable carrier; and (c) optionally a specification. 25 BRIEF DESCRIPTION OF THE DRAWINGS Figure 1. Synergistic effect of Compound A in combination with HDAC inhibitor Tucidinostat on cell proliferation in Hut102 and HH cell lines. Hut102 Cells were treated with the Compound A for 4 days and then were treated with combination treatments for 3 days (A). HH cells were treated with Compound A 30 for 6 days and then were treated with the combination treatments for 2 days (B). 3 WO 2025 / 082481 PCT / CN2024 / 125773 A serial dilution of each drug was indicated. Cell proliferation was measured using Cell Titer-Glo luminescence assay. The percentage of cell viability was shown as Mean + SEM (n = 2 or 3). Figure 2. Synergistic effect of Compound A in combination with JAK1 5 inhibitorgolidocitinib on cell proliferation in HuT102 cell line. HuT102 cells treated with indicated concentrations of Compound A for 6 days, golidocitinib for 3 days, or their combination. Cell viability was assessed using the CellTiter- Glo® assay. The representative results from 3 independent experiments were shown. The results were presented as Mean + SD. n =2 replicates. 10 Figure 3. Synergistic effect of Compound A in combination with JAK1 inhibitor golidocitinib on cell proliferation in NK / TCL cell lines. SNK-1 (A) and SNK-6 (B) Cells were treated with a gradient concentration of Compound A for 10 days and Golidocitinib for 2 days. Cell viability was assessed using the CellTiter-Glo® assay. Cell viability data were represented as Mean + SEM, with 15 n=2or3 replicates. Figure 4. Synergistic effect of Compound A in combination with Compound B on cell proliferation in SNK-1 (A) and SNK-6 (B) cell lines. SNK- 1 and SNK-6 Cells were treated with a gradient concentration of Compound A for 10days and Compound B for 2 days, or their combination. Cell viability was 20. assessed using the CellTiter-Glo® assay. The results were presented as Mean + SD. n =2 or 3 replicates. DETAILED DESCRIPTION OF THE INVENTION Definitions 25 Unless otherwise defined below, all technical and scientific terms used herein have the same meanings as commonly understood by an ordinary skilled person in the art. References to techniques used herein are intended to refer to techniques that are generally understood in the art, including those obvious changes or equivalent replacements of the techniques for those skilled in the art. 4 WO 2025 / 082481 PCT / CN2024 / 125773 While it is believed that the following terms are well understood by those skilled in the art, the following definitions are set forth to better explain the invention. As used herein, the terms “including”, “comprising”, “having”, “containing” or “comprising”, and other variants thereof, are inclusive or open, and do not 5 exclude otherunlisted elements or method steps. The use of the terms “a’’, “‘an’’, “the”, and similar referents in the context of describing the invention (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated. Recitation of ranges of values herein merely are intended to serve as a shorthand 10 method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The use of any and all examples, or exemplary language (e.g., “such as”, “for example’) provided herein, is intended to better illustrate the disclosure and is not a limitation on the 15 scope of the disclosure unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosure. As used herein, the term “embodiment”,“disclosed herein” or “disclosure” is not meant to be limiting, but applies generally to any of the embodiments 20. defined in the claims or described herein. These terms are used interchangeably herein. As used herein, the terms “treat’’, “treating”, “treatment” and the like refer to eliminating, reducing, or ameliorating a disease or condition, and / or symptoms associated therewith. Although not precluded, treating a disease or condition 25 does not require that the disease, condition, or symptoms associated therewith be completely eliminated. The term “treat” and synonyms contemplate administering a therapeutically effective amount of a Compound of the Disclosure to a subject in need of such treatment. The treatment can be orientated symptomatically, for example, to suppress symptoms. It can be effected over a 5 WO 2025 / 082481 PCT / CN2024 / 125773 short period, be oriented over a medium term, or can be a long-term treatment, for example within the context of a maintenance therapy. Asused herein, the terms “prevent”, “preventing” and “prevention” refer to a method of preventing the onset of a disease or condition and / or its attendant 5 symptoms or barring a subject from acquiring a disease. As used herein, “prevent”, “preventing” and “prevention” also include delaying the onset of a disease and / or its attendant symptoms and reducing a subject’s risk of acquiring a disease. The terms “prevent”, “preventing” and “prevention” may include “prophylactic treatment”, which refers to reducing the probability of 10 redeveloping a disease or condition, or of a recurrence of a previously-controlled disease or condition, in a subject who does not have, but is at risk of or is susceptible to, redeveloping a disease or condition or a recurrence of the disease or condition. The term “synergistic effect” as used herein refers to action of two 15 therapeutic agents, for example, slowing the symptomatic progression of a proliferative disease, particularly cancer, or symptomsthereof, which is greater than the simple addition of the effects of each drug administered by themselves. A synergistic effect can be calculated, for example, using various methods and equations well known in the art, such as those listed in the Examples of the 20. present invention. The term “pharmaceutically acceptable salt”, as used herein, includes both acid addition salts and base addition salts of a compound. “Pharmaceutically acceptable carrier” in the context of the present invention refers to a diluent, adjuvant, excipient or vehicle together with which 25 the therapeutic agent is administered, and which 1s suitable for contacting a tissue of human and / or other animals within the scope of reasonable medical judgment, and without excessive toxicity, irritation, allergic reactions, or other problems or complications corresponding to a reasonable benefit / risk ratio. The pharmaceutically acceptable carriers that can be used in the 30 pharmaceutical compositions or kits of theinvention include, but are not limited 6 WO 2025 / 082481 PCT / CN2024 / 125773 to, sterile liquids such as water and oils, including those oils derived from petroleum, animals, vegetables or synthetic origins, for example, peanut oil, soybean oil, mineral oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. It is also possible to 5 use physiological saline and an aqueous solution of glucose and glycerin as a liquid carrier, particularly for injection. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene glycol, water, ethanol and the like. The 10 pharmaceutical composition may further contain a small amount of a wetting agent, an emulsifier or a pH buffering agent as needed. Oral formulations may contain standard carriers such as pharmaceutical grades ofmannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are as 15 described in Remington’s Pharmaceutical Sciences (1990). As used herein, “EED” refers to embryonic ectoderm development protein, which is overexpressed in many cancers including, but not limited to, breast cancer, prostate cancer, and hepatocellular carcinoma. See Moritz and Trievel, J. Biol. Chem. 293 (36):13805—13814 (2018). 20 As used herein, “HDAC” refers to histone deacetylase, which are a class of enzymes that remove acetyl groups from an amino acid on a histone. The HDACs are a family including at least eighteen enzymes, grouped in three classes (Class I, II and IT). Class I HDACs include, but are not limited to, HDACs 1, 2, 3, and 8. Class I HDACs can be found in the nucleus and are believed to be involved 25 with transcriptional control repressors. Class II HDACs include, but are not limited to, HDACS4, 5, 6, 7, and 9 and can be found in both the cytoplasm as well as the nucleus. Class III HDACs are believed to be NAD dependent proteins and include, but are not limited to, members of the Sirtuin family of proteins. Non-limiting examples of sirtuin proteins include SIRT1-7. The HDACs regulate 7 WO 2025 / 082481 PCT / CN2024 / 125773 the expression of many proteins associated with both cancer initiation and cancer progression. As used herein, “JAK” refers to Janus kinase, which is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated 5 signals via the JAK-STAT pathway. The JAK family includes at least four members: JAK1, JAK2, JAK3 and TYK2 (Tyrosine kinase 2). As used herein, “BCL2” is a member of the Bcl-2 family of regulator proteins. BCL2 blocks programmed cell death (apoptosis). As used herein, “BCL-XL” is a transmembrane protein in the mitochondria. 10 It is a member of the Bcl-2 family of proteins, and acts as an anti-apoptotic protein bypreventing the release of mitochondrial contents such as cytochrome C. As used herein, the term “HDAC inhibitor” refers to an agent or a compound that inhibits histone deacetylase activity of one or more HDACs. 15 As used herein, the term “JAK inhibitor” refers to an agent or a compound that inhibits the activity of one or more JAKs. As used herein, the term “BCL2 / BCL-XL inhibitor” refers to an agent or a compound that inhibits the activity of BCL2 and / or BCL-XL. The term “container” as used herein refers to a container for holding a 20 pharmaceutical component. This container can be used for preparation, storage, transportation and / or stand-alone / bulk sale, which is intended to include bottles, cans, vials, flasks, syringes, tubes (e.g., those used in cream products), or any other containers for preparation, containment, storage or distribution of a drug product. 25 The term “specification / instruction” as used herein refers to an insert, a tag, a label, etc., which records informationabout a pharmaceutical component located in the container. The information as recorded is typically determined by the regulatory agency (e.g., the United States Food and Drug Administration) that governs the area in which the product is to be sold. Preferably, the package 30 leaflet specifically lists an indication for which the use of the pharmaceutical 8 WO 2025 / 082481 PCT / CN2024 / 125773 component is approved. The package leaflet can be made of any material from which information contained therein or thereon can be read. Preferably, the package leaflet is a printable material (e.g., paper, plastic, cardboard, foil, adhesive paper or plastic, etc.) on which the desired information can be formed 5 (e.g., printed or applied). The term “effective amount” as used herein refers to an amount of active ingredient that, after administration, will relieve to some extent one or more symptoms of the condition being treated. As used herein, “subject” includes a human or a non-human animal. 10Exemplary human subject includes a human subject (referred to as a patient) suffering from a disease (such as the disease described herein) or a normal subject. “Non-human animal” in the present invention includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals, and / or domesticated animals (e.g., sheep, 15 dogs, cats, cows, pigs, etc.). The term “halo” as used herein by itself or as part of another group refers to -Cl, -F, -Br, or -I. The term “nitro” as used herein by itself or as part of another group refers to -NOz. 20 The term “cyano” as used herein by itself or as part of another group refers to -CN. The term “hydroxyl” as used herein by itself or as part of another group refers to -OH. The term “alkyl” as used herein, alone or as part of another group, refers to 25 anunsubstituted straight or branched aliphatic hydrocarbon containing from | to 12 carbon atoms (1.e., Cj.12 alkyl) or an indicatednumber of carbon atoms, for example, C; alkyl such as methyl, C2 alkyl such as ethyl, C3 alkyl such as n- propyl or isopropyl, Cy.; alkyl such as methyl, ethyl, n-propyl or isopropyl, or the like. In one embodiment, the alkyl is Ci4 alkyl. Non-limiting examples of C\- 30 = 42 alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, 9 WO 2025 / 082481 PCT / CN2024 / 125773 isobutyl, 3-pentyl, hexyl, heptyl, octyl, nonyl and decyl. Examples of Cy. alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, and isobutyl. The term “alkenyl” as used herein by itself or as part of another group refers 5 to an alkyl group containing one, two, or three carbon-to-carbon double bonds. In one embodiment, the alkenyl group is a C.-C, alkenyl group. In another embodiment, the alkenyl group is a C2-C, alkenyl group. In another embodiment, the alkenyl group has one carbon-to-carbon double bond. Non-limiting exemplary alkenyl groups include ethenyl, propenyl,isopropenyl, butenyl, 10 sec-butenyl, pentenyl, and hexenyl. The term “alkynyl” as used herein by itself or as part of another group refers to an alkyl group containing one, two, or three carbon-to-carbon triple bonds. In one embodiment, the alkynyl is a C2-C, alkynyl. In another embodiment, the alkynyl is a Co-C, alkynyl. In another embodiment, the alkynyl has one carbon- 15 to-carbon triple bond. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups. The term “haloalkyl” as used herein by itself or as part of another group refers to an alkyl group substituted by one or more fluorine, chlorine, bromine, and / or iodine atoms. In one embodiment, the alkyl is substituted by one, two, or 20. three fluorine and / or chlorine atoms. In another embodiment, the alkyl is substituted by one, two, or three fluorine atoms. In another embodiment, the alkyl is a Cy-Ce alkyl. In another embodiment, the alkyl is a C)-Cy alkyl. In anotherembodiment, the alkyl group is a Cy; or C2 alkyl. Non-limiting exemplary haloalkyl groups include fluoromethyl, difluoromethyl, 25 trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 44 .4-trifluorobutyl, and trichloromethyl groups. The term “alkoxy” as used herein by itself or as part of another group refers to an alkyl group attached to a terminal oxygen atom. In one embodiment, the 30 = alkyl is a Cy-C¢ alkyl and resulting alkoxy is thus referred to as a "C1-C¢ alkoxy." 10 WO 2025 / 082481 PCT / CN2024 / 125773 In another embodiment, the alkyl is a C)-C, alkyl group. Non-limiting exemplary alkoxy groups include methoxy, ethoxy, and tert-butoxy. The term “cycloalkyl” as used herein, alone or as part of another group, refers to a saturated or partially unsaturated (containing one or two double bonds) 5 cyclic aliphatic hydrocarbon, which comprises | or 2 rings having 3 to 12 carbon atoms or an indicated number of carbon atoms(i.¢., C3-12 cycloalkyl). In one embodiment, the cycloalkyl has two rings. In one embodiment, the cycloalkyl has one ring. In another embodiment, the cycloalkyl group is selected from the group consisting of C3. cycloalkyl groups. In another embodiment, the 10 cycloalkyl group is selected from the group consisting of C36 cycloalkyl groups. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decahydronaphthyl, adamantyl, cyclohexenyl, and cyclopentenyl. The term “heterocycle” or “heterocyclyl” as used herein, alone or as part of 15 another group, refers to a saturated or partially unsaturated (e.g., comprising one or two double bonds) cyclic group, which comprises 1, 2 or 3 rings having 3 to 14 ring members (i.¢., 3- to 14-membered heterocyclyl), wherein at least one carbon atom of one of the rings is replaced by a heteroatom. Each heteroatom is independently selected from the group consisting of atoms ofoxygen, sulfur 20. (including sulfoxide and sulfone) and / or nitrogen (which may be oxidized or quaternized). The term “heterocyclyl” is intended to include a group wherein - CH>- in the ring is replaced by -C(=O)-, for example, cyclic ureido (such as 2- imidazolidinone) and cyclic amido (such as B-lactam, y-lactam, 6-lactam, ¢- lactam) and piperazin-2-one. In one embodiment, the heterocyclyl is a 3- to 8- 25 membered cyclic group comprising | ring and | or 2 oxygen and / or nitrogen atoms. In one embodiment, the heterocyclyl is a 4-, 5- or 6-membered cyclic group comprising | ring and 1 or 2 oxygen and / or nitrogen atoms. In one embodiment, the heterocyclyl is a 4- or 6-membered cyclic group comprising 1 ring and | or 2 oxygen and / or nitrogen atoms. The heterocyclyl can be attached 30 to the remainder of molecule via any available carbon or nitrogen atom. Non- ra WO 2025 / 082481 PCT / CN2024 / 125773 limiting examples of the heterocyclyl include dioxanyl, tetrahydropyranyl, 2-oxopyrrolidin-3-yl, piperazin-2-one, piperazin-2,6-dione, 2-imidazolidinone, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl and dihydroindolyl. The term “aryl” as used herein by itself or as part of another group refers to 5 an aromatic ring system having six to fourteen carbon atoms, 1.e., Cs-Cy, aryl. Non-limiting exemplary aryl groups include phenyl (abbreviated as "Ph"), naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl, and fluorenyl groups. In one embodiment, the aryl group is phenyl or naphthyl. In another embodiment, the aryl group is phenyl. 10 The term “heteroaryl” as used herein by itself or as part of another group refers to monocyclic and bicyclic aromatic ring systems having five to fourteen ring members, 1.¢., 5- to 14-membered heteroaryl, comprising one, two, three, or four heteroatoms. Each heteroatom is independently oxygen, sulfur, or nitrogen. In one embodiment, the heteroaryl has three heteroatoms. In another embodiment, 15 theheteroaryl has two heteroatoms. In another embodiment, the heteroaryl has one heteroatom. In another embodiment, the heteroaryl is a 5- to 10-membered heteroaryl. In another embodiment, the heteroaryl has 5 ring atoms, e.g., thienyl, a 5-membered heteroaryl having four carbon atoms and one sulfur atom. In another embodiment, the heteroaryl has 6 ring atoms, e.g., pyridyl, a 20 6-membered heteroaryl having five carbon atoms and one nitrogen atom. Non- limiting exemplary heteroaryl groups include thienyl, benzo[b]thieny]l, naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl, isobenzofurany], benzooxazonyl, chromenyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, 25 indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, B-carboliny]l, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl,thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl, furazanyl, and phenoxazinyl. In one embodiment, the heteroaryl is chosen from thienyl (e.g., thien-2-yl and thien-3- 30 _—yi), furyl (e.g., 2-furyl and 3-furyl), pyrrolyl (e.g., 1 H-pyrrol-2-yl and 1H-pyrrol- 12 WO 2025 / 082481 PCT / CN2024 / 125773 3-yl), imidazolyl (e.g., 2H-imidazol-2-yl and 2H-imidazol-4-yl), pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and 1H-pyrazol-5-yl), pyridyl (e.g., pyridin- 2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, and pyrimidin-5-yl), thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, 5 and thiazol-5-yl), isothiazolyl (e.g., isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl), oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl, and oxazol-5-yl) and isoxazolyl (e.g., 1soxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl). The term heteroaryl also includes N-oxides. A non-limiting exemplary N-oxide is pyridyl N-oxide. 10 The term “carboxy” as used by itself or as part ofanother group refers to a radical of the formula -C(=O)OH. The term “amino” as used by itself or as part of another group refers to a radical of the formula -NR**R°*, wherein R>** and R*°> are independently hydrogen, optionally substituted alkyl, haloalkyl, (hydroxy)alkyl, (alkoxy)alkyl, 15 (amino)alkyl, heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, optionally substituted heteroaryl, (arylalkyl, (cycloalkylalkyl, (heterocyclo)alkyl, or (heteroaryl)alkyl. The combination of the present invention encompasses any of the compounds of the invention being isotopically-labelled (i.¢., radiolabeled) by 20 having one or more atoms replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 7H (or deuterium (D)), 7H, "C, 8C, BC BN, 80, 170, IP, ?P,3°S, '8F, and *°Cl, respectively, e.g., 7H, 'C, and MC. 25 In one embodiment, provided is a compound wherein substantially all of the atoms at a position within the compound of the invention are replaced by an atom having a different atomic mass or mass number. In another embodiment, provided is acompound wherein substantially all of the atoms at a position within the compound of the invention are replaced by deuterium atoms, e.g., all of the 30 hydrogen atoms of a -CH3 group are replaced by deuterium atoms to give a -CD3 13 WO 2025 / 082481 PCT / CN2024 / 125773 group. In another embodiment, provided is a compound wherein a portion of the atoms at a position within the compound of the invention are replaced, 1.e., the compound of the invention is enriched at a position with an atom having a different atomic mass or mass number. In another embodiment, provided is a 5 compound wherein none of the atoms of the compound of the invention are replaced by an atom having a different atomic mass ormass number. Isotopically-labelled compounds of the invention can be prepared by methods known in the art. The compounds in the combination of the invention may contain one or 10 more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. The present invention encompasses the use of all such possible forms, as well as their racemic and resolved forms and mixtures thereof. The individual enantiomers can be separated according to methods known in the art in view of the present disclosure. When the compounds 15 described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it 1s intended that they include both E and Z geometric isomers. All tautomers are also encompassed by the present invention. As used herein, the term “stereoisomers” is a general term for all isomers 20 ~~ of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomersand isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers). The term “chiral center” or “asymmetric carbon atom” refers to a carbon atom to which four different groups are attached. 25 The terms “enantiomer” and "enantiomeric" refer to a molecule that cannot be superimposed on its mirror image and hence is optically active wherein the enantiomer rotates the plane of polarized light in one direction and its mirror image compound rotates the plane of polarized light in the opposite direction. The term “racemic” refers to a mixture of equal parts of enantiomers and 30 ~=which mixture is optically inactive. 14 WO 2025 / 082481 PCT / CN2024 / 125773 The term “absolute configuration” refers to the spatial arrangement of the atoms of a chiral molecular entity (or group) and its stereochemical description, e.g.,RorS. The stereochemical terms and conventions used in the specification are 5 meant to be consistent with those described in Pure &Appl. Chem 68:2193 (1996), unless otherwise indicated. For a review of suitable salts, see “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing the pharmaceutically acceptable salts of the compounds 10 of the invention are known to those skilled in the art. The term “solvate” as used herein is a substance formed by combination, physical binding and / or solvation of a compound of the invention with a solvent molecule, such as a disolvate, a monosolvate or a hemisolvate, wherein the ratio of the solvent molecule to the compound of the invention is about 2:1, about 1:1 15 or about 1:2, respectively. This kind of physical bonding involves ionization and covalent bonding (including hydrogen bonding) in different degrees. In some cases (e.g., when one or more solvent molecules are incorporated into crystal lattice of crystalline solid), the solvate can be isolated. Thus, the solvate comprises both solution phase andisolatable solvates. The compounds of the 20 invention may be in solvated forms with pharmaceutically acceptable solvents (such as water, methanol and ethanol), and the present application is intended to encompass both solvated and unsolvated forms of the compounds of the invention, One type of solvate is a hydrate. “Hydrate” relates to a specific subset of 25 solvates wherein the solvent molecule is water. Solvates generally function in the form of pharmacological equivalents. The preparation of solvates is known in the art, see for example, M. Caira et al, J. Pharmaceut. Sci., 93(3): 601-611 (2004), which describes the preparation of a solvate of fluconazole with ethyl acetate and water. Similar methods for the preparation of solvates, hemisolvates, 30 hydrates and the like are described by van Tonder et al, AAPS Pharm. Sci. Tech., 15 WO 2025 / 082481 PCT / CN2024 / 125773 5(1): Article 12 (2004) and A.L. Bingham et al, Chem. Commun. 603-604 (2001). A representative and non-limiting methodfor the preparation of solvate involves dissolving a compound of the invention in a desired solvent (organic solvent, water or a mixture thereof) at a temperature above 20 °C to about 25 °C, and then 5 the solution is cooled at a rate sufficient to form a crystal, and the crystal is separated by a known method such as filtration. Analytical techniques such as infrared spectroscopy can be used to confirm the presence of the solvent in the crystal of the solvate. The term “about” as used herein, includes the recited number + 10%. Thus, 10 “about 10” means 9 to 11. EED inhibitor In an embodiment, the EED inhibitor is a compound of Formula I: Ri RS} y OA, ROR 15 wherein: R! is aralkyl; R? is selected from the group consisting of hydrogen and C,-C, alkyl; R? and R* taken together with the carbon atoms to which they are attached form a radical of Formula I-A, I-B, or I-C: RES oot x me “me TAS SY i x ar x Re BA 727 EB or 72" be; 20 . X is selected from the group consisting of -C(R**)(R®)-,-C(=O)-, and - S(=O)>-; 16 WO 2025 / 082481 PCT / CN2024 / 125773 R™* and R® are independently selected from the group consisting of hydrogen and C-C, alkyl; Y is selected from the group consisting of -C(R%)(R®™)-, -S-, -O-, and - N(R’)-; 5 Z is -C(R™)(R™ ne; R® and R® are independently selected from the group consisting of hydrogen and C-C, alkyl; each R® and R™ is independently selected from the group consisting of hydrogen and C;-C, alkyl; 10 m is 0, 1, or 2; R’ is selected from the group consisting of hydrogen, C)-C, alkyl, C1-Ce haloalkyl, optionally substituted C3-Cg cycloalkyl, optionally substituted C4-Cg heterocyclo, hydroxyalkyl, (alkoxy)alkyl, (cycloalkyl)alkyl, and (heterocyclo)alkyl; 15 R*®, R®. and R®* are independently selected from the group consisting of hydrogen, halo, Ci-C, alkyl, Ci-C, haloalkyl, Ci-C4 alkoxy, and alkylsulfonyl; “is a fused phenyl, fused 5-membered heteroaryl, or fused 6- membered heteroaryl; Nae is an optionally substituted fused 3- to 8-memberedcycloalkyl or 20 optionally substituted fused 4- to 8-membered heterocyclo; “is an optionally substituted fused 4- to 8-membered heterocyclo; the bond designated with a '"»~ " is attached at the R° position of Formula I and the bond designated with an "*" is attached at the R* position of Formula I; and 25 ~S* is a single or double bond, 17 WO 2025 / 082481 PCT / CN2024 / 125773 or a pharmaceutically acceptable salt or solvate thereof. In an embodiment, the EED inhibitor is a compound of Formula IT: Ry ne re , 5 or a pharmaceutically acceptable salt or solvate thereof. In an embodiment, Z is -CH»-, or a pharmaceutically acceptable salt or solvate thereof. In an embodiment, X is -C(=O)-, or a pharmaceutically acceptable salt or solvate thereof. 10 In an embodiment, Y is -N(R’)-, and preferably R’ is selected from the group consisting of Ci-C, alkyl, Ci-C¢ haloalkyl, and optionally substituted C3- Cs cycloalkyl, or a pharmaceutically acceptable salt or solvate thereof. In an embodiment, theEED inhibitor is selected from the group consisting of: 15 4-ethyl-12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-7- (trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a- pentaazabenzo[4,5|cycloocta[1,2,3-cd]inden-3-one; 12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-4-(2,2,2- trifluoroethyl)-7-(trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a- 20 pentaazabenzo[4,5|cycloocta[1,2,3-cd]inden-3-one; 4-cyclopropyl-12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 7-(trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a- pentaazabenzo[4,5|cycloocta[1,2,3-cd]inden-3-one; 18 WO 2025 / 082481 PCT / CN2024 / 125773 12-(((5-fluoro-2 ,3-dihydrobenzofuran-4-yl)methyl)amino)-4-isopropyl-7- (trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a- pentaazabenzo[4,5|cycloocta[1,2,3-cd]inden-3-one; and 11-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-6-methyl-4H-3- 5 thia-2,5,10,1la-tetraazadibenzo[cd,f]azulene-3 ,3-dioxide, or a pharmaceutically acceptable salt or solvate thereof. In an embodiment, theEED inhibitor is a compound having the structure of Formula III or the pharmaceutically acceptable salt or solvate thereof, . ‘i HN nk \ {7 10 Formula III. The chemical name of Formula III is 12-(((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)amino)-4-isopropyl-7-(trifluoromethyl)-4,5- dihydro-3H-2,4,8,11,12a-pentaazabenzo[4,5|cycloocta[1,2,3-cd]inden-3-one. The method for preparing or identifying the EED inhibitors described herein 15 is disclosed in the prior art, for example, in WO2022222932A1, WO2021228034A1 and WO2021011713A1. The full text of WO2022222932A1, WO02021228034A1 and WO2021011713A1 is incorporated herein by reference. In another embodiment, The EED inhibitors are any one or more of the compounds listed in Table 1, or a pharmaceutically acceptable salt or solvate 20 ‘thereof. 19 WO 2025 / 082481 PCT / CN2024 / 125773 Table | F HN , N-(2-fluoro-6-methylbenzyl)-3H, 5H-4-oxa- 1 os, 2,6,11,12a-tetraazabenzo[4,5]cycloocta[1,2,3- S cd]inden-12-amine N 0 myN-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)- 5 wis 3H,5SH-4-oxa-2,6,11,12a- oy tetraazabenzo[4,5 |cycloocta[1,2,3-cd]inden-12- Wy? 0 amine F . Ly 11-(((5-fluoro-2,3-dihydrobenzofuran-4- 3 oth yl)methyl)amino)-2,4,10,11a- Van : rs tetraazadibenzo[cd,f]azulen-3(4H)-one ey 11-(((5-fluoro-2,3-dihydrobenzofuran-4- 4 nee yl)methyl)amino)-2,4,5,10,11a- Se ae . pentaazadibenzo[cd,f]azulen-3(4H)-one mone 11-(((5-fluoro-2,3-dihydrobenzofuran-4- 5 \ a yl)methyl)amino)-6-(methyl sulfonyl)-2,4, 10, 11a- oy tetraazadibenzo[cd,f]azulen-3(4H)-one F uN ij 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- oo yl)methyl)amino)-3H,5H-4-oxa-2, 11, 12a- eee triazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3-one fey ‘Oo F HN i 7-fluoro-12-(((5-fluoro-2,3-dihydrobenzofuran-4- 7 ao yl)methyl)amino)-3H,5H-4-oxa-2, 11,1 a- at triazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3-one F Oo o rey 12-(((5-fluoro-2,3-dihydrobenzofuran-4- nat yl)methyl)amino)-7-(trifluoromethyl)-3H,5H-4- SOT oxa-2,11,12a-triazabenzo[4,5]cycloocta[1,2,3- BCyo cd]inden-3-one 20 WO 2025 / 082481 PCT / CN2024 / 125773 ce) uN oO 12-(((2,3-dihydrobenzofuran-4-yl)methyl)amino)- oo 7-fluoro-3H,5H-4-oxa-2, 11,12a- at triazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3-one F oO 10) r o9 HN a 12-(((5-fluorobenzofuran-4-yl)methyl)amino)- 10 aa 3H,5H-4-oxa-2,6, 11,12a- oy tetraazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3-one N’ Oo 0 ere nee 6-fluoro-12-(((5-fluoro-2,3-dihydrobenzofuran-4- 11 \ er yl)methyl)amino)-3H,5H-4-oxa-2, 11,12a- triazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3-one 0’ <0 F ere HN 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- 12 wo yl)methyl)amino)-3H,5H-4-oxa-2,6, 11,12a- vy tetraazabenzo[4,5 |cycloocta[ 1,2,3-cd]inden-3-one N* gy oO Bee 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- B na yl)methyl)amino)-7-(trifluoromethyl)-3H,5H-4- ot oxa-2,8,11,12a-tetraazabenzo[4,5|cycloocta[1,2,3- N . - lu fo cd]inden-3-one Bee 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- 4 =e yl)methyl)amino)-7-(trifluoromethyl)-3H,5H-4- ST oxa-2,6,11,12a-tetraazabenzo[4,5|cycloocta[1,2,3-~~ | o cd]inden-3-one F;C” “N o 0 Y - 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- 15 a yl)methyl)amino)-4,5-dihydro-3H-2,4, 11, 12a- \-* tetraazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3-one 21 WO 2025 / 082481 PCT / CN2024 / 125773 oy 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- 16 oe yl)methy!)amino)-4,5-dihydro-3H-2,4,6, 11,12a- ~ are pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- 2 3 one i. é 7-fluoro-12-(((5-fluoro-2,3-dihydrobenzofuran-4- 17 we yl)methyl)amino)-4,5-dihydro-3H-2,4, 11,12a- . tetraazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3-one aoe 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- 13 A yl)methyl)amino)-7-methyl-3H,5H-4-oxa- SU 2,6,11,12a-tetraazabenzo[4,5 |cycloocta[1,2,3- ~S | 2 5 cd]inden-3-one nee 12-(((5-fluoro-2,3-dihydrobenzofuran-4- 19 xX yl)methyl)amino)-7-(trifluoromethyl)-4,5- ove dihydro-3H-2,4,11,12a- RC x 80 tetraazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3-one . © : 6-fluoro-12-(((5-fluoro-2,3-dihydrobenzofuran-4- 20 \ <7 yl)methyl)amino)-4,5-dihydro-3H-2,4, 11, 12a-tetraazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3-one F - o 5 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- 71 ae yl)methyl)amino)-7-methyl-4,5-dihydro-3H- ~ \: ei 2,4,6,11,12a-pentaazabenzo[4,5 |cycloocta[ 1,2,3- | 2 cd]inden-3-one N N’ 10) H Bee 12-(((5-fluoro-2,3-dihydrobenzofuran-4- EN yl)methyl)amino)-7-(trifluoromethyl)-4,5- 22 on dihydro-3H-2,4,8, 11,12a- ] > y ; pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- “ x one » Si 8-fluoro-12-(((5-fluoro-2,3-dihydrobenzofuran-4- 23 o yl)methyl)amino)-4,5-dihydro-3H-2,4,11, 2a- een tetraazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3-one 22 WO 2025 / 082481 PCT / CN2024 / 125773 ty 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- 74 a yl)methyl)amino)-8-(trifluoromethyl)-3H,5H-4- ne VLU oxa-2,11,12a-triazabenzo[4,5]cycloocta[1,2,3- Se cd]inden-3-one : 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- = S yl)methyl)amino)-7-(trifluoromethyl)-4,5- 25 on dihydro-3H-2,4,6, 11,12a- ot pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- neo ow” one aoe12-(((5-fluoro-2,3-dihydrobenzofuran-4- 26 a yl)methyl)amino)-8-(trifluoromethyl)-4,5- “ote dihydro-3H-2,4, 11,12a- 780 tetraazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3-one SS o 12-((benzo[d][1,3 ]dioxol-4-ylmethyl)amino)-7- 27 on (trifluoromethyl)-3H,5H-4-oxa-2,11,12a- at triazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3-one uN 4 12-((2-fluoro-6-methoxybenzyl)amino)-7- 28 ‘on (trifluoromethyl)-3H,SH-4-oxa-2, 11, 12a- oe triazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3-one aes 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- 59 a yl)methyl)amino)-8-(trifluoromethyl)-3H,5H-4- spy “e oxa-2,9,11,12a-tetraazabenzo[4,5 |cycloocta[1,2,3- 2 80 cd]inden-3-one aoe 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- 30 a yl)methyl)amino)-8-(trifluoromethyl)-3H,5H-4- RO \. RU oxa-2,6,11,12a-tetraazabenzo[4,5|cycloocta[1,2,3- | 2 ro cd]inden-3-one aoe 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- 31 ~~ yl)methyl)amino)-7-(trifluoromethoxy)-3H,5H-4- \: a oxa-2,11,12a-triazabenzo[4,5]cycloocta[1,2,3- 00 sro cd]inden-3-one 23 WO2025 / 082481 PCT / CN2024 / 125773 aoe 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- 39 na yl)methyl)amino)-8-(trifluoromethyl)-3H,5H-4- RC \: a oxa-2,7,11,12a-tetraazabenzo[4,5 |cycloocta[1,2,3- 3 Ss Noe wo cd]inden-3-one oy 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- ~~ yl)methyl)amino)-4-methyl-7-(trifluoromethyl)- 33 a ar 4,5-dihydro-3H-2,4,6, 11,12a- (~ \* pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- F3C NZ N oO one “sy 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- t yl)methyl)amino)-4-methyl-7-(trifluoromethyl)- 34 7 NS 4,5-dihydro-3H-2,4,8,11,12a- ices pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- F,C~ ~7\_y7S0 one \ an 2 3 4-((1,4-dioxan-2-yl)methyl )-12-(((5-fluoro-2,3- on dihydrobenzofuran-4-yl)methyl )amino)-7- 35 at (trifluoromethyl)-4, 5-dihydro-3H-2,4,6, 11, 12a- Fe ~N7\_yS0 pentaazabenzo[4, 5 |cycloocta[1,2,3-cd]inden-3- rt one ad nee 4-cyclopropyl-12-(((5-fluoro-2,3- nt dihydrobenzofuran-4-yl)methyl)amino)-7- 36 \: eT (trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a- nS . aw 5pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- \ one . o, 5 4-((1,4-dioxan-2-yl)methyl)-12-(((5-fluoro-2,3- on dihydrobenzofuran-4-yl)methyl)amino)-7- 37 oe (trifluoromethyl)-4,5-dihydro-3H-2,4,8, 11, 12a- Fe 7 \_y / 0 pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- rt one L / , 24 WO 2025 / 082481 PCT / CN2024 / 125773 5 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- = yl)methyl)amino)-4-((1-methyl piperidin-4- 38 “~ ST yl)methyl)-7-(trifluoromethyl)-4,5-dihydro-3 H- ro A_, 0 2,4,8, 11, 12a-pentaazabenzo[4,5|cycloocta[1,2,3- “Oh cd]inden-3-one oy 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- 7 zt yl)methyl)amino)-4-methyl-8-(trifluoromethyl)- 39 a Ny 4,5-dihydro-3H-2,4,9, 11,12a- e SY pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- oa on one eee 4-((1,4-dioxan-2-yl)methyl)-12-(((5-fluoro-2,3- at dihydrobenzofuran-4-yl)methyl)amino)-8- 40 mee (trifluoromethyl)-4,5-dihydro-3H-2,4,9,11,12a- LZ 2, pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- <)> one oy 4-cyclopropyl-12-(((5-fluoro-2,3- adihydrobenzofuran-4-yl)methyl)amino)-7- 4] \\ eT (trifluoromethyl)-4,5-dihydro-3H-2,4,6,11,12a- ~~ ; - ° pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- \ one Ry 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- wo yl)methyl)amino)-4-((1-methylpiperidin-4- 42 netwh Jbo yl )methyl)-7-(trifluoromethyl)-4,5-dihydro-3 H- 2,4,6,11,12a-pentaazabenzo[4,5 |cycloocta[ 1,2,3- ' cd]inden-3-one / aoe 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- a yl)methyl)amino)-4-((1- 43 \ 7 hydroxycyclopropyl)methyl)-7-(trifluoromethyl)- ws * 4,5-dihydro-3H-2,4,8, 11,12a- B07 S7\_y / So0 pentaazabenzo[4, 5 |cycloocta[1,2,3-cd]inden-3- Low one 25 WO 2025 / 082481 PCT / CN2024 / 125773 aoe 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- ~~ yl)methyl)amino)-4-(( 1- 44 ot hydroxycyclopropyl)methyl)-7-(trifluoromethyl)- ‘ 4,5-dihydro-3H-2,4,6, 11,12a- eT NT Non’? pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- on one oy 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- x yl)methyl)amino)-4-((tetrahydro-2H-pyran-4- 45 ~ LLYyl)methyl)-7-(trifluoromethyl)-4,5-dihydro-3 H- coms 2,4,8,11,12a-pentaazabenzo[4,5 |cycloocta[ 1,2,3- “Os cd]inden-3-one hy 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- ne yl)methyl)amino)-4-((tetrahydro-2H-pyran-4- 46 ice: yl)methyl)-7-(trifluoromethyl)-4,5-dihydro-3H- we | WA _,?%0 2,4,6,11,12a-pentaazabenzo[4,5 |cycloocta[ 1,2,3- “Os cdjinden-3-one aoe 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- HN yl)methyl )amino)-4-((3-hydroxy-3- 47 ae methylcycl obutyl)methyl)-7-(trifluorom ethyl)-4,5- Ss YEN dihydro-3H-2,4,6, 11,12a- FAC | n7\_y7S0 pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- ~S<or one F ) uN , 3 12-(((5-fluoro-2,3-dihydrobenzofuran-4- un yl)methyl)amino)-4-(2-hydroxy-2-methylpropyl)- 48 \ a 7-(trifluoromethyl)-4,5-dihydro-3 H-2,4,8, 11,12a- 1 > pentaazabenzo[4, 5 |cycloocta[1,2,3-cd]inden-3- me ve one Lon hy 12-(((5-fluoro-2,3-dihydrobenzofuran-4- HN yl)methyl )amino)-4-((3-hydroxy-3- 49 ot methylcycl obutyl)methyl)-7-(trifluorom ethyl)-4,5- nS YEN dihydro-3 H-2,4,8, 11,12a- FAC[A w7 So pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- ~D<0r one 26 WO 2025 / 082481 PCT / CN2024 / 125773 ate 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- HN yl)methyl )amino)-4-((3-hydroxy-3- 50 on methylcyclobutyl)methyl)-7-methyl-4,5-dihydro- ‘~s YEN 3H-2,4,6,11,12a- N7\_y / 0 pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- ~Scon one oO uN ) 5 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- on yl)methyl)amino)-4-(tetrahydro-2H-pyran-4-yl)-7- 51 my (trifluoromethyl)-4,5-dihydro-3H-2,4,6,11,12a- C7 N* \_y7S0 pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- oe one (6) 2 Si a 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- \ 7 Ny yl)methyl)amino)-4-((tetrahydrofuran-3- 52 (~~ XEN yl)methyl)-7-(trifluoromethyl)-4,5-dihydro-3 H- B07 ~N7\_,7S0 2,4,6,11,12a-pentaazabenzo[4,5 |cycloocta[ 1,2,3- ) cd]inden-3-one Le) aoe 11-(((5-fluoro-2,3-dihydrobenzofuran-4- wt yl)methyl)amino)-6-methyl-5,6-dihydro- 53 \ ST 2,4,6,7,10,11a- 7~ Ys hexaazacyclopenta[4,5 |cycloocta[1,2,3-cd]inden- N x wh 80 3(4H)-one ate11-(((5-fluoro-2,3-dihydrobenzofuran-4- HN yl)methyl)amino)-7-methyl-5,7-dihydro-3H-4- 54 - oxa-2,6,7,10,1la- “On pentaazacyclopenta[4,5 ]cycloocta[1,2,3-cd]inden- —N CS 3-one N oO oO 27 WO 2025 / 082481 PCT / CN2024 / 125773 $5 HN 4-(cyclopropylmethyl)-12-(((5-fluoro-2,3 - ae dihydrobenzofuran-4-yl)methyl)amino)-7- 55 ~ \ Cl (trifluoromethyl)-4,5-dihydro-3H-2,4,6,11,12a- lL pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- me N ¢ ° one F re) HN 9 4-cyclopropyl-11-(((5-fluoro-2,3- N= dihydrobenzofuran-4-yl)methyl)amino)-6,8- 56 \\ at dimethyl-5,6-dihydro-2,4,6,7, 10, 11a- nv | » hexaazacyclopenta[4,5 |cycloocta[1,2,3-cd]inden- ; \ 0 3(4H)-one F co) EN e 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- - yl)methyl)amino)-4-(2-methoxyethyl)-7- 57 we ei (trifluoromethyl)-4,5-dihydro-3H-2,4,6,11,12a- Fe | x7\_, / S0 pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- ( one OMe F ° EN Oo} 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- ae yl)methyl)amino)-4-(2-hydroxy-2-methylpropyl)- 58 ~ \ Ch7-(trifluoromethyl)-4,5-dihydro-3 H-2,4,6, 11,12a- rc | n7\_y / 7S0 pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- one Z aoe 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- a yl)methyl)amino)-4-isopropyl-7-(trifluoromethyl)- 59 \: eT 4,5-dihydro-3H-2,4,6, 11,12a- | > pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- F,C” ~N nw? \ one 28 WO 2025 / 082481 PCT / CN2024 / 125773 ~ Si x 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- \ CT yl)methyl)amino)-4-(tetrahydro-2H-pyran-4-yl)-7- N (trifluoromethyl)-4,5-dihydro-3H-2,4,11,12a- ne >) tetraazabenzo[4,5]cycloocta[ 1,2,3-cd]inden-3-one oO ™ é a 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- \ wT] yl)methyl)amino)-4-(2-fluoroethyl)-7- 61 YUN . . (trifluoromethyl)-4,5-dihydro-3H-2,4,11,12a- Re ? ° tetraazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3-one F “ Si a 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- Ny yl)methyl)amino)-4-(2-fluoro-2-methylpropyl)-7- 62 S71 ; N (trifluoromethyl)-4,5-dihydro-3H-2,4,11,12a- BC nf 0 tetraazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3-one fr ere wt4-(2,2-difluoropropyl)-12-(((5-fluoro-2,3- \ 7 dihydrobenzofuran-4-yl)methyl)amino)-7- (trifluoromethyl)-4,5-dihydro-3H-2,4,11,12a- FC ve tetraazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3-one x » S HN 4-cyclopropyl-7-fluoro-12-(((5-fluoro-2,3 - me dihydrobenzofuran-4-yl)methyl )amino)-4,5- 64 Ve 7] . YEN dihydro-3H-2,4,11,12a- F a tetraazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3-one ™ ry a 7-fluoro-12-(((5-fluoro-2,3-dihydrobenzofuran-4- 65 \ 7 yl)methyl)amino)-4-(tetrahydro-2H-pyran-4-yl)- N 4,5-dihydro-3H-2,4, 11,12a- . >) tetraazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3-one 29 WO 2025 / 082481 PCT / CN2024 / 125773 uN Oy 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- on yl)methyl)amino)-4-((tetrahydro-2H-pyran-4- at yl)methyl)-7-(trifluoromethyl)-4,5-dihydro-3 H- FC a 2,4,11,12a-tetraazabenzo[4,5 |cycloocta[1,2,3- las cd]inden-3-one » é HN 4-cyclopropyl-12-(((5-fluoro-2,3- 67 ‘ 4 dihydrobenzofuran-4-yl)methyl )amino)-7- oe (trifluoromethy!)-4,5-dihydro-3H-2,4, 11, 12a- FC w / So tetraazabenzo[4,5|cycloocta[1,2,3-cd]inden-3-one ere x 4-((1,4-dioxan-2-yl)methyl)-12-(((5-fluoro-2,3- \ fT dihydrobenzofuran-4-yl)methyl)amino)-7- \-N (trifluoromethyl)-4,5-dihydro-3H-2,4, 11, 12a- FC x0, tetraazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3-one <) F HN a 4-cyclopropyl-12-((2-fluoro-6- n= methoxybenzyl)amino)-7-(trifluoromethyl)-4,5- \ C7 dihydro-3H-2,4,6, 11,12a- | > pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- B07 NZ \ ° one F aN a 4-cyclopropyl-12-((2-fluoro-6- n= methoxybenzyl)amino)-7-(trifluoromethyl)-4,5- 70 \\ a dihydro-3H-2,4,8,11,12a- , > pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- ro7 7 \ ° one 30 WO 2025 / 082481 PCT / CN2024 / 125773 HN OMe 12-((2-fluoro-6-methoxybenzyl)amino)-4- | oo isopropyl-7-(trifluoromethyl)-4,5-dihydro-3H- ~ VN 2,4,6,11,12a-pentaazabenzo[4,5 |cycloocta[ 1,2,3- F,C7 ~N% \_y / S0 cd]inden-3-one SO EN 12-(((5-fluoro-2,3-dihydrobenzofuran-4- ae yl)methyl)amino)-4-(2-fluoroethyl)-7- 72 wot \ ei (trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a- - l Z Yopentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- Me one F F ) aN 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- n— yl)methyl)amino)-4-isopropyl-7-(trifluoromethyl)- 73 \ eT 4,5-dihydro-3H-2,4,8, 11,12a- N —_ pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- RoW 7 a ° one 2 Si = 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- 74 \: al yl)methyl)amino)-4-(1 -methylpiperidin-4-yl)-7- ° (trifluoromethyl)-4,5-dihydro-3H-2,4,11,12a- me oO) tetraazabenzo[4,5]cycloocta[ 1,2,3-cd]inden-3-one N \ 2 ‘i a 7-fluoro-12-(((5-fluoro-2,3-dihydrobenzofuran-4- 75 \: eT yl)methyl)amino)-4-(1-methylpiperidin-4-yl)-4,5- . dihydro-3H-2,4, 11,12a- F o) tetraazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3-one \ 31 WO 2025 / 082481 PCT / CN2024 / 125773 “ é a 4-(2,2-difluoropropyl)-7-fluoro-12-(((5-fluoro- 16 \ fF 2,3-dihydrobenzofuran-4-yl)methyl)amino)-4,5- \* dihydro-3H-2,4,11,12a- F ve tetraazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3-one F ° uN , 3 4-(2,2-difluoropropyl)-12-(((5-fluoro-2,3- = dihydrobenzofuran-4-yl)methyl)amino)-7- 77 ~ \ i(trifluoromethyl)-4,5-dihydro-3H-2,4,6, 11,12a- ; | WZ " pentaazabenzo[4, 5 |cycloocta[1,2,3-cd]inden-3- Fs N F, one F » Si rx 7-fluoro-12-(((5-fluoro-2,3-dihydrobenzofuran-4- 78 \ AT yl)methyl)amino)-4-(2-fluoro-2-methylpropyl)- \* 4,5-dihydro-3H-2,4,11,12a- F yy) ° tetraazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3-one F » Si we 7-fluoro-12-(((5-fluoro-2,3-dihydrobenzofuran-4- 79 \ A yl)methyl)amino)-4-(2-fluoroethyl)-4,5-dihydro- \* 3H-2,4,11,12a-tetraazabenzo[4,5]cycloocta[1,2,3- F vO cd]inden-3-one ( 2 Si a 4-(2,2-difluoroethyl)-7-fluoro-12-(((5-fluoro-2,3- \ a dihydrobenzofuran-4-yl)methyl)amino)-4,5- dihydro-3H-2,4, 11,12a- F no tetraazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3-one w’ 7 H 32 WO 2025 / 082481 PCT / CN2024 / 125773 = e3 na 4-(2,2-difluoroethyl)-12-(((5-fluoro-2,3- 81 \ CT dihydrobenzofuran-4-yl)methyl)amino)-7- ‘ (trifluoromethyl)-4,5-dihydro-3H-2,4, 11, 12a- F3C Nn Oo tetraazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3-one 4 H F F i - 5 4-(2,2-difluoropropyl)-12-(((5-fluoro-2,3- n=dihydrobenzofuran-4-yl)methyl)amino)-7- 82 ~Ki (trifluoromethyl)-4,5-dihydro-3H-2,4,8, 11,12a- BC \Z So pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- ay one F F ij a 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- 83 \ OFT yl)methyl)amino)-4-(2,2,2-trifluoroethyl)-7- . (trifluoromethyl)-4,5-dihydro-3H-2,4, 11, 12a- me 7 ° tetraazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3-one F F ij - e 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- n= yl)methyl)amino)-4-(2,2,2-trifluoroethyl)-7- \ 7 . . 84 aN M (trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a- Hc |Z So pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- VV one F F 2 ‘i nat 4-(3,3-difluorocyclobutyl)-12-(((5-fluoro-2,3- . 7 N~ dihydrobenzofuran-4-yl)methyl)amino)-7- 85 wt (trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a- F,C \A NSO pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- u one YF 33 WO 2025 / 082481 PCT / CN2024 / 125773 F 7) HN 4-cyclopropyl-11-(((5-fluoro-2,3- n= dihydrobenzofuran-4-yl)methyl)amino)-7-methyl- > eh 4,5-dihydro-3H-8-thia-2,4,6,10, la- —~ ||pentaazacyclopenta[4,5 ]cycloocta[1,2,3-cd]inden- N iv 3-one F O HN 4-cyclopropyl-11-(((5-fluoro-2,3- Nx dihydrobenzofuran-4-yl)methyl)amino)-4,5- 87 ; \. Ch dihydro-3H-8-thia-2,4, 10, 1la- | tetraazacyclopenta[4,5]cycloocta[1,2,3-cd]inden- SO 3-one F O HN 4-cyclopropyl-11-(((5-fluoro-2,3- N= dihydrobenzofuran-4-yl)methyl)amino)-4,5- 88 \ ee dihydro-3H-6-thia-2,4, 10, 11a- C "| » tetraazacyclopenta[4,5]cycloocta[1,2,3-cd]inden- s \ 0 3-one $83 HN 4-(2,2-difluoroethyl)-12-(((5-fluoro-2,3- Ans dihydrobenzofuran-4-yl)methyl)amino)-7- wr fh (trifluoromethy!)-4,5-dihydro-3H-2,4,8,11,12a- FC \A axe pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- 3 H one at F F re) 4-ethyl-12-(((5-fluoro-2,3-dihydrobenzofuran-4- HN . . Nx yl)methyl)amino)-7-(trifluoromethyl)-4,5- \ C1 dihydro-3H-2,4,8, 11,12a- M > pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- FC ‘ ° one 34 WO 2025 / 082481 PCT / CN2024 / 125773 “ioe 4-cyclopropyl-11-(((5-fluoro-2,3- HN dihydrobenzofuran-4-yl)methyl)amino)-7- o1 “(trifluoromethyl)-4,5-dihydro-3H-8-thia- et L 2,4,6,10, 1la- N~\_y7 <0 pentaazacyclopenta[4,5 ]cycloocta[1,2,3-cd]inden- iS 3-one aes HN 4-cyclopropyl-8-fluoro-13-(((5-fluoro-2,3 - ne dihydrobenzofuran-4-yl)methyl)amino)-5,6- 92 ay dihydro-2,4,12,13a- S tetraazabenzo[4,5 |cyclonona[1,2,3-cd]inden- fe) : 3(4H)-one 2 rg HN 4-(2,6-dimethyltetrahydro-2H-pyran-4-yl)-12- . Ny (((5-fluoro-2,3-dihydrobenzofuran-4- 93 \-N yl)methyl)amino)-7-(trifluoromethyl)-4,5- wees dihydro-3H-2,4,11,12a- tetraazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3-one soy F ‘ee ° ; Na 11-(((5-fluoro-2,3-dihydrobenzofuran-4- 94 \ No yl)methyl)amino)-4H-3-thia-2,5,10,11a- oft tetraazadibenzo[cd,flazulene 3,3-dioxide N7 Sso fe) F ‘ee ° Nx’ 11-(((5-fluoro-2,3-dihydrobenzofuran-4- 95 \ No yl )methyl)amino)-6-methyl-4H-3-thia-2,5,10,11la- ice! tetraazadibenzo[cd,flazulene 3,3-dioxide N S50 O aoe HN 7-fluoro-12-(((5-fluoro-2,3-dihydrobenzofuran-4- n= yl)methyl)amino)-4,5-dihydro-3-thia-2,11,12a- ottriazabenzo[4,5]cycloocta[1,2,3-cd]indene 3,3- dioxide F — 35 WO 2025 / 082481 PCT / CN2024 / 125773 F re) HN , 3 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- 97 n= yl)methyl)amino)-7-methyl-4,5-dihydro-3-thia- me 2,6,11,12a-tetraazabenzo[4,5 |cycloocta[1,2,3- i. 5 cd]indene 3,3-dioxide Nn ae F 3) HN o 5 4-(2,6-dimethyltetrahydro-2H-pyran-4-yl)-12- N= (((5-fluoro-2,3-dihydrobenzofuran-4- \ C1 yl)methyl)amino)-7-(trifluoromethyl)-4,5- 1 dihydro-3H-2,4,8,11,12a- BC xO pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- oy one oO » ‘i HN 12-(((5-fluoro-2,3-dihydrobenzofuran-4- N= yl)methyl)amino)-4-isopropyl-7-methyl-4, 5- El \ fT dihydro-3H-2,4,6,11,12a- ‘S \-N pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- N7 a fe) one » 3 HN 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- N= yl)methyl)amino)-4-isopropyl-7-methyl-4,5- E2 \ AT dihydro-3H-2,4,8, 11,12a- N > \-N pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- 4 x ) one - 9 HN 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- N= yl)methyl)amino)-7-methyl-4-(2,2,2- E3 ie@etrifluoroethyl )-4,5-dihydro-3H-2,4,6,11,12a- | > pentaazabenzo[4,5 |cycloocta[ 1,2,3-cd]inden-3- N7\_y7S0 one ne 36 WO 2025 / 082481 PCT / CN2024 / 125773 ete HN 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- E4 ‘ = yl)methyl)amino)-4-isopropyl-3-oxo-4,5-dihydro- VN 3H-2,4,11,12a-tetraazabenzo[4,5]cycloocta[1,2,3- NC SO cd]indene-7-carbonitrile F re) HN ‘ 4-cyclobutyl-12-(((5-fluoro-2,3- N= dihydrobenzofuran-4-yl)methyl)amino)-7- ES5 N \: er (trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a- ly pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- CFs Ss one = 8 HN 4-(2,2-difluoroethyl)-12-(((5-fluoro-2,3- ‘ =e dihydrobenzofuran-4-yl)methyl)amino)-7-methyl- E6 ~ er 4,5-dihydro-3H-2,4,6, 11, 12a- - pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- vy? one - F $89 HN 4-(2,2-difluoropropyl)-12-(((5-fluoro-2,3- ae dihydrobenzofuran-4-yl)methyl)amino)-7-methyl- E7 ~ Se 7T 4,5-dihydro-3H-2,4,6, 11, 12a- | o pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- Oe one F FV » S; HN 4-(2,2-difluoroethyl)-12-(((5-fluoro-2,3- edihydrobenzofuran-4-yl)methyl)amino)-7- E8 ~ Ch (trifluoromethyl)-4,5-dihydro-3H-2,4,6,11,12a- CE; | N? : oO pentaazabenzo[4, *Tevetooeral 1,2,3-cd]inden-3- H FF 37 WO 2025 / 082481 PCT / CN2024 / 125773 one HN 4-(2,2-difluoroethyl)-12-(((5-fluoro-2,3- me dihydrobenzofuran-4-yl)methyl)amino)-7-methyl- E9 wi 4,5-dihydro-3H-2,4,8, 11,12a- \ A x80 pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- H one m4 F HN if N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)- E10 eo 5-methyl-8-(trifluoromethyl)-6H-2,3,5a,9,12,13a- wy hexaazabenzo[4,5]|cyclopenta[7,8]cycloocta[1,2,3- CF; 4 ‘I cd]inden-13-amine ¥ ° 7-(difluoromethyl)-12-(((5-fluoro-2,3- y NO dihydrobenzofuran-4-yl)methyl)amino)-4- Ell \: C1 isopropyl-4,5-dihydro-3H-2,4,8,11,12a- i > pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- HEC ‘ one F fe) HN 7-ethyl-12-(((5-fluoro-2,3-dihydrobenzofuran-4- N=( yl)methyl)amino)-4-(2,2,2-trifluoroethyl)-4,5- E12 wag dihydro-3H-2,4,6,11,12a- ~» | pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- Nn one > CF, F re)HN 4-(2,2-difluoroethyl)-7-ethyl-12-(((5-fluoro-2,3 - N= dihydrobenzofuran-4-yl)methyl)amino)-4,5- E13 wre dihydro-3H-2,4,6,11,12a- _ | pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- vn? one > F,HC F 0) HN 7-cyclopropyl-12-(((5-fluoro-2,3- N= dihydrobenzofuran-4-yl)methyl)amino)-4-(2,2,2- E14 ~ \: er trifluoroethyl )-4,5-dihydro-3H-2,4,6,11,12a- | pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- i Oe one > CF, 38 WO 2025 / 082481 PCT / CN2024 / 125773 F ¢) HN 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- N= yl)methyl)amino)-7-isopropyl-4-(2,2,2- E15 \: wh trifluoroethyl )-4,5-dihydro-3H-2,4,6,11,12a- _ . -_ pentaazabenzo[4,5 |cycloocta[ 1,2,3-cd]inden-3- N N oO 5 one CF; ose HN 4-(2,2-difluoropropyl)-7-ethyl-12-(((5-fluoro-2,3- N= dihydrobenzofuran-4-yl)methyl)amino)-4,5- E 16 SL dihydro-3H-2,4,6,11,12a- Ss . | nN” 0 pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- 5 one F oO 4 N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)- EV 7 N 5-methyl-6H-2,3,5a,7, 12, 13a- ~ \ Nhexaazabenzo[4,5]|cyclopenta[7,8]cycloocta[1,2,3- | cd]inden-13-amine N N= N F fe) HN N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)- E18 “oe 5,8-dimethyl-6H-2,3,5a,7, 12, 13a- ae hexaazabenzo[4,5]|cyclopenta[7,8]cycloocta[1,2,3- NZ Net cd]inden-13-amine mee: 12-(((5-fluoro-2,3-dihydrobenzofuran-4- NO yl)methyl)amino)-7-(methyl-d3)-4-(2,2,2- E19 ‘: Cy trifluoroethyl )-4,5-dihydro-3H-2,4,6,11,12a- [> benzo[4,5]cycloocta[1,2,3-cd Jinden-3- pc NA_y0 pentaazabenz |cyc 525 > one CF; F ¢) un—Lp 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- N= D yl)methyl-d2)amino)-7-methyl-4-(2,2,2- E20 \: CY trifluoroethyl )-4,5-dihydro-3H-2,4,6,11,12a- | > pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- Nw? one cx, 39 WO 2025 / 082481 PCT / CN2024 / 125773 F ce) . 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- HN-CD ; N= D yl)methyl-d2)amino)-7-(methyl-d3)-4-(2,2,2- E21 \: wr trifluoroethyl )-4,5-dihydro-3H-2,4,6,11,12a- ~» - pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- ) one CF; F re) HN—p D12-((G-fluoro-2,3-dihydrobenzofuran-4-yl-2,3- N= DD d2)methyl-d2)amino)-7-methyl-4-(2,2,2- E22 \. CY trifluoroethyl )-4,5-dihydro-3H-2,4,6,11,12a- | > pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- i he one > CF, eee! 12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl-2,3- ne bo d2)methyl-d2)amino)-7-(methyl-d3)-4-(2,2,2- E 23 \: ae trifluoroethyl )-4,5-dihydro-3H-2,4,6,11,12a- [- benzo[4,5]cycloocta[1,2,3-cd]inden-3 pcoNA_y0 pentaazabenzo[4,5 |cycloocta[1, - > one CF; F ce) . un_ / p 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- NX D yl)methyl-d2)amino)-N, N-dimethyl-3 -oxo-4- E24 \: a (2,2,2-trifluoroethyl)-4,5-dihydro-3H-2,4, 11, 12a- \ tetraazabenzo[4,5 |cycloocta[1,2,3-cd]indene-7- 0 ) carboxamide CF; Cn . 8-(2,6-dimethyl pyridin-3-yl)-5-(((5-fluoro-2,3- (* . 0 dihydrobenzofuran-4-yl)methyl)amino)-1- 2s ae hylsulfonyl)imidazo[1,5 idine-6 (TX ’ (met l ,»-a]pyr - Nano carbonitrile w 8-(6-cyclopropylpyridin-3-yl)-5-(((5-fluoro-2,3- £26 (* wen dihydrobenzofuran-4-yl)methyl)amino)-1- fl > ( ?(methylsulfonyl)imidazo[1,5-a]pyridine-6- “ Meoss carbonitrile F. «a 5-(((5-fluoro-2,3-dihydrobenzofuran-4- yy 0 yl)methyl)amino)-8-(2-methylpyridin-3-yl)-1- E27 N Lo 4 | S ( » (methylsulfonyl)imidazo[1,5-a]pyridine-6- n7 N carbonitrile McO,S 40 WO 2025 / 082481 PCT / CN2024 / 125773 F fe) HN 13-(((5-fluoro-2,3 -dihydrobenzofuran-4- £28 N a yl)methyl )amino)-5,6-dihydro-2,4, 12,13a- \ ay tetraazabenzo[4,5 |cyclonona[1,2,3-cd]inden- S 3(4H)-one fe) NH F 0 HN 13-(((5-fluoro-2,3 -dihydrobenzofuran-4- £29 neh yl)methyl)amino)-8-methyl-5,6-dihydro- \ mae 2,4,7,12,13a-pentaazabenzo[4,5 |cyclonona[1,2,3- ~N S cd]inden-3(4H)-one | o O N NH F fe) aN 13-(((5-fluoro-2,3 -dihydrobenzofuran-4- neh yl)methyl)amino)-8-methyl-4-(2,2,2- E 30 N LX, trifluoroethyl)-5,6-dihydro-2,4,7, 12, 13a- cs ° pentaazabenzo[4,5 ]|cyclonona[1,2,3-cd]inden- N’ N 3(4H)-one ) CF; F fe) 13-(((5-fluoro-2,3 -dihydrobenzofuran-4- wel yl)methyl)amino)-4-isopropyl-8-(trifluoromethyl)- E31 \ mae 5,6-dihydro-2,4,9, 12, 13a- ns Spentaazabenzo[4,5 ]|cyclonona[1,2,3-cd]inden- 0) cr, |Z Ne 3(4H)-one F HN ° N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)- 532 n= 8-(trifluoromethyl)-6H-2,3,5a,7,12,13a- ~ \: ae hexaazabenzo[4,5]|cyclopenta[7,8]cycloocta[1,2,3- cE | N7 Ly cd]inden-13-amine 3 N Vel F BN 9 N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)- B33 n= 8-(trifluoromethyl)-6H-2,3,5a,9,12,13a- ~ \: C1 hexaazabenzo[4,5]|cyclopenta[7,8]cycloocta[1,2,3- cr ly Ly cdjinden-13-amine 3 NI 41 WO 2025 / 082481 PCT / CN2024 / 125773 F HN ° N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)- £34 n= 8-methyl-6H-2,3,5a,7, 12, 13a- \, Ch hexaazabenzo[4,5]|cyclopenta[7,8]cycloocta[1,2,3- | > cd]inden-13-amine N NN \eel Qs N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)- ni 5-methyl-8-(trifluoromethyl)-6H-4-oxa- E35 \ Sy 2,3,9,12,13a- 1 > L pentaazabenzo[4,5 |cyclopenta[7,8]cycloocta[1,2,3 Cs \. 3 -cd]inden-13-amine F HN if N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)- £36 n= 8-methyl-6H-4-oxa-2,3,7, 12,13a- ~ \; er pentaazabenzo[4,5|cyclopenta[7,8]cycloocta[1,2,3 |v -cd]inden-13-amine N SN LL F ¢) HN og 5-ethyl-N-((5-fluoro-2,3-dihydrobenzofuran-4- N= yl)methyl)-8-(trifluoromethyl)-6H- E37 ~ SL 2,3,5a,9,12,13a- cr; lz WSN hexaazabenzo[4,5]cyclopenta[7,8]cycloocta[1,2,3- ‘4 cd]inden-13-amine _ 6: ne 5-ethyl-N-((5-fluoro-2,3-dihydrobenzofuran-4- £38 \ C7 yl)methyl)-8-methyl-6H-2,3,5a,7,12,13a- | S N hexaazabenzo[4,5]|cyclopenta[7,8]cycloocta[1,2,3- N7 cd]inden-13-amine ne 12-(((6-fluorochroman-5-yl)methyl)amino)-7- £39 \ ST methyl-4-(2,2,2-trifluoroethyl)-4,5-dihydro-3H- ; NN \N 2,4,6,11,12a-pentaazabenzo[4,5 ]|cycloocta[1,2,3- N7\_y7S0 cd]inden-3-one ) CF3 42 WO 2025 / 082481 PCT / CN2024 / 125773 F e 5 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- ni yl)methyl)amino)-4-isopropyl-7-(trifluoromethyl)- E 40 \\ C1 4,5-dihydro-3H-2,4,8, 11,12a- vs pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- cry a one ete HN 4-(2,2-difluoropropyl)-12-(((5-fluoro-2,3- n= . _A. . 7 _ o> dihydrobenzofuran 4-yl)methyl)amino)-7-methyl E41 we \UN4,5-dihydro-3H-2,4,6, 11,12a- | NZ © pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- y) one F F Bee 7-(difluoromethyl)-12-(((5-fluoro-2,3- a dihydrobenzofuran-4-yl)methyl )amino)-4-(2,2,2- E42 \ wr trifluoroethyl )-4,5-dihydro-3H-2,4,8,11,12a- 1 > pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- HF,C nO Lew, one ese HN 7-(difluoromethyl)-4-(2,2-difluoropropyl)-12-(((5- ne fluoro-2,3-dihydrobenzofuran-4- E 43 wos . Ch yl)methyl)amino)-4,5-dihydro-3H-2,4,8, 11,12a- HF,C \Z nO pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- one * » é HN 4-(2,2-difluoroethyl)-7-(difluoromethyl)-12-(((5- n= fluoro-2,3-dihydrobenzofuran-4- E44 Ki yl)methyl)amino)-4,5-dihydro-3H-2,4,8, 11, 12a- |Z pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- HE,C w oO NM, one 7 F 43 WO 2025 / 082481 PCT / CN2024 / 125773 = e3 HN 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- C = yl)methyl)amino)-7-(tetrahydro-2H-pyran-4-yl)-4- E45 —>KA (2,2,2-trifluoroethyl)-4,5-dihydro-3H- | o 6 2,4,6,11,12a-pentaazabenzo[4,5 |cycloocta[ 1,2,3- b N Ncd]inden-3-one rf FoF - r9 HN 7-(tert-butyl)-12-(((5-fluoro-2,3- N= dihydrobenzofuran-4-yl)methyl)amino)-4-(2,2,2- E46 yy A trifluoroethyl)-4,5-dihydro-3H-2,4,8,11,12a- \4 axe pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- F x one FF - @ HN 4-(2,2-difluoroethyl)-12-(((5-fluoro-2,3- ‘ mae dihydrobenzofuran-4-yl)methyl)amino)-7- E47 we Cu isopropyl-4,5-dihydro-3H-2,4,6,11,12a- | oC 6 pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- N N one - F » S; HN 7-(1,4-dioxan-2-yl)-12-(((5-fluoro-2,3 - N= dihydrobenzofuran-4-yl)methyl)amino)-4-(2,2,2- E48 ~ \ Ch trifluoroethyl )-4,5-dihydro-3H-2,4,6,11,12a- c° | N7\_y / S0 pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- O F x one FF » S' HN 7-((1,4-dioxan-2-yl)methyl)-12-(((5-fluoro-2,3- N= dihydrobenzofuran-4-yl)methyl)amino)-4-(2,2,2- E49 ~ \ CN trifluoroethyl )-4,5-dihydro-3H-2,4,6,11,12a- | N7\_yS0 pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- O one Lo 4 44 WO 2025 / 082481 PCT / CN2024 / 125773 » 9 HN 7-(tert-butyl)-12-(((5-fluoro-2,3- N=dihydrobenzofuran-4-yl)methyl)amino)-4-(2,2,2- E50 ~ \ ch trifluoroethyl )-4,5-dihydro-3H-2,4,6,11,12a- 2 axe pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- one i: 9 HN 12-(((5-fluoro-2,3 -dihydrobenzofuran-4- N= yl)methyl)amino)-7-(oxetan-3-yl)-4-(2,2,2- E51 ~ \ ch trifluoroethyl )-4,5-dihydro-3H-2,4,6,11,12a- 2 axe pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- ° x one F FF - e9 HN 7-cyclobutyl-12-(((5-fluoro-2,3- N= dihydrobenzofuran-4-yl)methyl)amino)-4-(2,2,2- E52 ~ \ Ch trifluoroethyl )-4,5-dihydro-3H-2,4,6,11,12a- l x80 pentaazabenzo[4,5 |cycloocta[1,2,3-cd]inden-3- one HDAC inhibitor The HDAC inhibitor can be various agents capable of inhibiting HDAC 5 protein. In some embodiments, the HDAC inhibitor is selected from the group consisting of are Tucidinostat (also known as Chidamide), Vorinostat (also known as SAHA), Belinostat (also known as PXD-101), Romidepsin (also known as FK-228), Panobinostat (also known as LBH589), Entinostat (also known as MS-275), Trichostatin A (TSA),Mocetinostat (also known as 10 MGCD0103) and MC1568. In a preferred embodiment, the HDAC inhibitor is Tucidinostat (Chidamide). The structure of Tucidinostat (Chidamide) is Formula IV: 45 WO 2025 / 082481 PCT / CN2024 / 125773 ee fF fo H jf vy ° ee eye N we Nea 0 . Formula IV Tucidinostat is also known as Chidamide, CS055 or HBI-8000. It is a potent and orally bioavailable inhibitor of HDAC enzymes class I (HDAC1,2,3) and 5 class IIb (HDAC10). Its inhibitory activity on HDAC8 and HDAC11 1s relatively lower and it has no detectable inhibitory activity on HDAC4 / 5 / 6 / 7 / 9. JAK inhibitors The JAK inhibitor can be various agents capable of inhibiting JAK kinases. 10 Insome embodiments, the JAK inhibitor is selected from the group consisting of Golidocitinib, Tofacitinib, Filgotinib, Upadacitinib, Ruxolitinib, Baricitinib, Pacritinib, Momelotinib, Fedratinib and Abrocitinib. In a preferred embodiment, the JAK inhibitor 1s Golidocitinib. The structure of Golidocitinib is Formula X: ae NH oan | a anoO == Ni 15 Formula X In some embodiments, the JAK inhibitor is a JAK1, JAK2, JAK3 and / or TYK2 inhibitor. BCL2 / BCLXL inhibitors 46 WO 2025 / 082481 PCT / CN2024 / 125773 The BCL2 / BCLXL inhibitor can be various agents capable of inhibiting BCL2 / BCLXL. In some embodiments, the BCL2 / BCL-XL inhibitor is selected from the group consisting of Compound B, Compound C and venetoclax. The term “Compound B” described herein represents a compound having 5 the structure of Formula VII or the pharmaceutically acceptable salt or solvate thereof; ‘20 K 38" oN eS ‘oree got} AR i ‘ pont S\4 Qf woe Q \e / Laat / and \ gna Ho Ok — a fh FOF Formula VIII. The term “Compound C” described herein represents a compound having 10 the structure of Formula LX or the pharmaceutically acceptable salt or solvate thereof; A ee a a ae é re . yom rd é pe &YN re HOmR srs Q y OF Formula IX. 47 WO 2025 / 082481 PCT / CN2024 / 125773 Without wishing to be bound by theory, it is understood that Compound C may be used as a prodrug ofCompound B in some embodiments of combinations, compositions, methods, and uses described herein. Without wishing to be bound by theory, it is understood that Compound B 5 may be a metabolite of Compound C in some embodiments of combinations, , compositions, methods, and uses described herein. In a preferred embodiment, the BCL2 / BCL-XL inhibitor is Compound B or Compound C. In some embodiments, the BCL2 / BCL-XL inhibitor is any one of the 10 BCL2 / BCL-XL inhibitor disclosed in CN113509475A, which is incorporated herein in its entirety. Pharmaceutical combinations, pharmaceutical compositions and the use thereof 15 In one aspect, the invention provides a pharmaceutical combination comprising an EED inhibitor disclosed herein and another inhibitor selected from the group consisting of a histone deacetylase (HDAC) inhibitor, a JAK inhibitor and a BCL2 / BCL-XL inhibitor. In some embodiments, the HDAC inhibitor is selected from the group 20. consisting of Tucidinostat (Chidamide), Vorinostat(SAHA), Belinostat (PXD- 101), Romidepsin (FK-228), Panobinostat (LBH589), Entinostat (MS-275), Trichostatin A (TSA), Mocetinostat (MGCD0103) and MC1568. In a preferred embodiment, the HDAC inhibitor is selected from the group consisting of Tucidinostat (Chidamide), romidepsin (FK-228) and Panobinostat 25 (LBH589). In some embodiments, the JAK inhibitor is a JAK1, JAK2, JAK3 and / or TYK2 inhibitor. In some embodiments, the JAK inhibitor is selected from the group consisting of Golidocitinib, Tofacitinib, Filgotinib, Upadacitinib, Ruxolitinib, 48 WO 2025 / 082481 PCT / CN2024 / 125773 Baricitinib, Pacritinib, Momelotinib, Fedratinib and Abrocitinib. In a preferred embodiment, the JAK inhibitor is Golidocitinib. In some embodiment, the BCL2 / BCL-XL inhibitor is selected from the group consisting of Compound B, Compound C and venetoclax. In a preferred 5 embodiment, the BCL2 / BCL-XL inhibitor is Compound B or Compound C. In some embodiments, the weight ratio of the EED inhibitor disclosed hereinand said another inhibitor ranges from 0.0001:1 to 1:0.0001, for example, 0.001:1 to 1:0.001, 0.01: 1 to 1:0.01 or 0.1:1 to 1:0.1. In some preferred embodiments, the weight ratio of the EED inhibitor disclosed herein and said 10 another inhibitor is 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9 or 1:10. In a more preferred embodiment, the weight ratio of Compound A and said another inhibitor is 1:1. In some embodiments, the molar ratio of the EED inhibitor disclosed herein and said another inhibitor ranges from 30:1 to 1:30, for example, 30:1, 27:1, 20:1, 15 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:20, 1:27or 1:30. In some preferred embodiments, the molar ratio of the EED inhibitor disclosed herein and said another inhibitor 1s 1:1, 9:1, 3:1 or 27:1. In one aspect, the invention provides a pharmaceutical composition comprising the pharmaceutical combination disclosed herein and 20pharmaceutically acceptable carriers. In some embodiments, the pharmaceutical combination or pharmaceutical composition comprises | ug to 500 mg of the EDD inhibitor disclosed herein, for example, comprises 1 ug, 2 ug, 5 ug, 10 ug, 15 ug, 20 ug, 50 ug, 100 ug, 200 ug, 500 ug, 1 mg, 2 mg, 5 mg, 10 mg, 20 mg, 50 mg, 100 mg, 200 mg, 500 25 mg, or any amounts disclosed therebetween, of the EDD inhibitor disclosed herein. In some embodiments, the pharmaceutical combination or pharmaceutical composition comprises | ug to 500 mg of said another inhibitor disclosed herein, for example, comprises 1 ug, 2 ug, 5 ug, 10 ug, 15 ug, 20 ug, 50 ug, 100 ug, 30 «6. 2200 ug, 500 ug, 1 mg, 2 mg, 5 mg, 10 mg, 20 mg, 50 mg, 100 mg, 200 mg, 500 49 WO 2025 / 082481 PCT / CN2024 / 125773 mg, or any amounts disclosed therebetween, of the EDD inhibitor disclosed herein. In some embodiments, the pharmaceutical composition is in the form of a tablet, a capsule, a granule, a syrup, a powder, a lozenge, a sachet, acachet, an 5 elixir, a suspension, an emulsion, a solution, an aerosol, an ointment, a cream or an injection. In one aspect, the invention provides a method for treating cancer in a subject, comprising administering a therapeutically effective amount of the pharmaceutical combination disclosed herein or the pharmaceutical composition 10 disclosed herein to the subject. In an embodiment, the cancer is selected from the group consisting of: T cell lymphoma, Non-Hodgkin lymphoma, Mature T- and NK-cell lymphoma, T cell neoplasms, Mycosis fungoides, Granulomatous slack skin, Sezary syndrome, Mature T cell lymphoma, Lymphoepithelioid lymphoma, Follicular T-cell 15 lymphoma, Nodal peripheral T-cell lymphoma with T follicular helper phenotype, Angioimmunoblastic T-cell lymphoma, Subcutaneous panniculitis-like T-cell lymphoma, Cutaneous T-cell lymphoma NOS, Primary cutaneous CD8-positive ageressive epidermotropic cytotoxic T-cell lymphoma, Primary cutaneous acral CD8 positive T-cell lymphoma,Anaplastic large cell lymphoma T cell and Null 20 ~cell type, Anaplastic large cell lymphoma NOS, Anaplastic large cell lymphoma ALK positive, Hepatosplenic T-cell lymphoma, Intestinal T-cell lymphoma, Monomorphic epitheliotropic intestinal T-cell lymphoma, Primary mucosal CD30+ T-cell lymphoproliferative disorder, NK / T-cell lymphoma nasal and nasal-type, Indolent T-cell lymphoproliferative disorder of gastrointestinal tract, 25 Primary cutaneous CD4 positive small / medium T-cell lymphoproliferative disorder, Primary cutaneous CD4-positive small / medium T-cell lymphoma, Intravascular large B-cell lymphoma, Intravascular large B-cell lymphoma, Anaplastic large cell lymphoma, ALK-positive, Anaplastic large cell lymphoma, ALK negative, Breast implant-associated anaplastic large cell lymphoma, 30 Primary cutaneous CD30+ T-cell lymphoproliferative disorder, Mature T-cell or 50 WO 2025 / 082481 PCT / CN2024 / 125773 NkK-cell neoplasms, T-cell prolymphocytic leukaemia, T-cell large granularlymphocytic leukaemia, Chronic lymphoproliferative disorders of NK-cells, Aggressive NK cell leukaemia, Systemic Epstein-Barr Virus-positive T-cell lymphoma of childhood, Adult T-cell lymphoma or leukaemia, human T-cell 5 lymphotropic virus type l-associated, Extranodal NK / T-cell lymphoma nasal type, Enteropathy associated T-cell lymphoma, Hepatosplenic T-cell lymphoma, Angioimmunoblastic T-cell lymphoma, Peripheral T-cell lymphoma and Subcutaneous panniculitis-like T-cell lymphoma. In one aspect, the invention provides a method for treating a disease in a 10 subject, comprising administering a therapeutically effective amount of the EED inhibitor disclosed herein to the subject. In an embodiment, the disease is selected from the group consisting of T cell lymphoma, Non-Hodgkin lymphoma, Mature T- and NK-cell lymphoma, T cell neoplasms, Mycosis fungoides, Granulomatous slack skin, Sezary syndrome, 15 Mature T cell lymphoma, Lymphoepithelioid lymphoma, Follicular T-cell lymphoma, Nodalperipheral T-cell lymphoma with T follicular helper phenotype, Angioimmunoblastic T-cell lymphoma, Subcutaneous panniculitis-like T-cell lymphoma, Cutaneous T-cell lymphoma NOS, Primary cutaneous CD8-positive ageressive epidermotropic cytotoxic T-cell lymphoma, Primary cutaneous acral 20 CD8 positive T-cell lymphoma, Anaplastic large cell lymphoma T cell and Null cell type, Anaplastic large cell lymphoma NOS, Anaplastic large cell lymphoma ALK positive, Hepatosplenic T-cell lymphoma, Intestinal T-cell lymphoma, Monomorphic epitheliotropic intestinal T-cell lymphoma, Primary mucosal CD30+ T-cell lymphoproliferative disorder, NK / T-cell lymphoma nasal and 25 nasal-type, Indolent T-cell lymphoproliferative disorder of gastrointestinal tract, Primary cutaneous CD4 positive small / medium T-cell lymphoproliferative disorder, Primary cutaneous CD4-positive small / medium T-cell lymphoma, Intravascular large B-cell lymphoma, Intravascular large B-cell lymphoma, Anaplastic large cell lymphoma, ALK-positive, Anaplastic large cell lymphoma, 30 ALK negative, Breast implant-associated anaplastic large cell lymphoma, 51 WO 2025 / 082481 PCT / CN2024 / 125773 Primary cutaneous CD30+ T-cell lymphoproliferative disorder, Mature T-cell or NkK-cell neoplasms, T-cell prolymphocytic leukaemia, T-cell large granular lymphocytic leukaemia, Chronic lymphoproliferative disorders of NK-cells, Aggressive NK cell leukaemia, Systemic Epstein-Barr Virus-positive T-cell 5 lymphoma of childhood, Adult T-cell lymphoma or leukaemia, human T-cell lymphotropic virus type l-associated, Extranodal NK / T-cell lymphoma nasal type, Enteropathy associated T-cell lymphoma, Hepatosplenic T-cell lymphoma, Angioimmunoblastic T-cell lymphoma, Peripheral T-cell lymphoma and Subcutaneous panniculitis-like T-cell lymphoma. 10 In some embodiments, the EED inhibitor disclosed herein is administered in an amount of from about 0.0005 mg / day to about 5000 mg / day, for example, about 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100,150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500 or 5000 mg / day. 15 In some embodiments, the EED inhibitor disclosed herein is administered in an amount of from about 1 ng / kg to about 200 mg / kg, about 1 g / kg to about 100 mg / kg, or about 1 mg / kg to about 50 mg / kg per unit dose, for example, administrated in an amount of about 1 pg / kg, about 10 g / kg, about 25 pg / kg, about 50 pg / kg, about 75 wg / kg, about 100 ug / kg, about 125 ug / kg, about 150 20 «g / kg, about 175 pg / kg, about 200 pg / kg, about 225 wg / kg, about 250 pg / kg, about 275 pg / kg, about 300 ug / kg, about 325 pg / kg, about 350 pg / kg, about 375 ug / kg, about 400 pg / kg, about 425 ug / kg, about 450 ug / kg, about 475 pg / kg, about 500 pg / kg, about 525 pg / kg, about 550 ug / kg, about 575 pg / kg, about 600 ug / kg, about 625 pg / kg, about 650 ug / kg, about 675 g / kg, about 700 ug / kg, 25 about 725 ug / kg, about 750 pg / kg, about 775 ug / kg, about 800 pg / kg, about 825 ug / kg,about 850 pg / kg, about 875 ug / kg, about 900 ug / kg, about 925 pg / kg, about 950 ug / kg, about 975 wg / kg, about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 60 mg / kg, 30 about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 125 52 WO 2025 / 082481 PCT / CN2024 / 125773 mg / kg, about 150 mg / kg, about 175 mg / kg, about 200 mg / kg per unit dose, and administrated with one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) unit doses per day. In some embodiments, said another inhibitor is administered in an amount 5 of from about 0.0005 mg / day to about 5000 mg / day, for example, about 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500 or 5000 mg / day. In some embodiments, said another inhibitor is administered in an amount 10 of from about1 ng / kg to about 200 mg / kg, about | ug / kg to about 100 mg / kg, or about 1 mg / kg to about 50 mg / kg per unit dose, for example, administrated in an amount of about 1 ug / kg, about 10 ng / kg, about 25 ug / kg, about 50 pg / kg, about 75 wg / kg, about 100 pg / kg, about 125 pg / kg, about 150 ug / kg, about 175 ug / kg, about 200 pg / kg, about 225 ug / kg, about 250 g / kg, about 275 pg / kg, about 300 15 g / kg, about 325 pg / kg, about 350 ug / kg, about 375 ug / kg, about 400 pg / kg, about 425 ug / kg, about 450 ug / kg, about 475 pg / kg, about 500 ug / kg, about 525 uwg / kg, about 550 ug / kg, about 575 wg / kg, about 600 g / kg, about 625 pg / kg, about 650 pg / kg, about 675 ug / kg, about 700 g / kg, about 725 pg / kg, about 750 ug / kg, about 775 pg / kg, about 800 ug / kg, about 825 ug / kg, about 850 pg / kg, 20 about 875 ug / kg, about 900 pg / kg, about 925 ug / kg, about 950 g / kg, about 975 ug / kg, about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 125 mg / kg, about 150 mg / kg, about 175 25 mg / kg, about 200 mg / kg per unit dose, and administrated with one or more (e.g., 1, 2,3, 4, 5, 6, 7, 8, 9 or 10) unit doses per day. In some embodiments, the EED inhibitor disclosed herein and said another inhibitor are administered together, simultaneously, sequentially or alternately. In some embodiments, the EED inhibitor disclosed herein and said another 30 inhibitor are administered continuously for at least 2 days, at least 3 days, at least 53 WO 2025 / 082481 PCT / CN2024 / 125773 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, 5 at least 24days, at least 25 days, at least 28 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days, or at least 50 days. In some embodiments, the EED inhibitor disclosed herein and said another inhibitor are administered for one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) courses of treatment, wherein each of the courses lasts at least 3 days, at least 4 10 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 30 days, at least 35 days, at least 40 days, at 15 least 45 days, or at least 50 days; and there is an interval of 0, 1, 2,3, 4, 5, 6, 7, 8, 9, 10 days, two weeks, three weeks or four weeks between every two courses of treatment. Insome embodiments, the EED inhibitor disclosed herein and said another inhibitor are administrated via the same (e.g., oral) or different routes (e.g., oral 20. and parenteral (e.g., injection), respectively). In one aspect, the invention provides use of the pharmaceutical combination disclosed herein or the pharmaceutical composition disclosed herein in the manufacture of a medicament for treating cancer. In one aspect, the invention provides use of the EED inhibitor disclosed 25 herein in the manufacture of a medicament for treating a disease. In one aspect, the invention provides the pharmaceutical combination disclosed herein or the pharmaceutical composition disclosed herein for use in treating cancer. In one aspect, the invention provides the EED inhibitor disclosed herein for 30 use in treating a disease. 54 WO 2025 / 082481 PCT / CN2024 / 125773 In one aspect, the invention provides a kit, comprising: (a) a first component in a first container, the first component comprising the EEDinhibitor disclosed herein, and optionally a pharmaceutically acceptable carrier; 5 (b) a second component in a second container, the second component comprising inhibitor selected from the group consisting of an HDAC inhibitor, a JAK inhibitor (preferably a JAK inhibitor disclosed herein) and a BCL2 / BCL- XL inhibitor (preferably a BCL2 / BCL-XL inhibitor disclosed herein) and optionally a pharmaceutically acceptable carrier; and 10 (c) an optional specification. Examples To make the objects and technical solutions of the present invention clearer, the present invention will be further described below in conjunction with specific 15 example. It should be understood that the examples are not intended to limit the scope of the invention. Further, specific experimental methods not mentioned in the following examples were carried out in accordance with a conventional experimental method. 20 Compound A was used as a representative EED inhibitor in the following Examples. Compound A representsa compound having the structure of Formula II or the pharmaceutically acceptable salt or solvate thereof, . ‘ me aN YN FC A \ 0 55 WO 2025 / 082481 PCT / CN2024 / 125773 Formula II Example 1: Anti-proliferative effect of Compound A alone on T cell lymphoma cell lines 5 The anti-proliferative effect of Compound A was tested and compared with other three compounds that are useful for treating T cell lymphoma. Materials and Methods: Valemetostat (CAS# 1809336-39-7 (free base)), also known as DS-3201, has the structure of Formula V. It is a potent, selective, orally active EZH1 / 2 10 (Enhancer of Zeste 1 Polycomb Repressive Complex 2 Subunit) inhibitor. oA ON N AA Sy cl A Formula V. MAK-683 (CAS# 1951408-58-4) is an EED inhibitor. It has the structure of Formula VI. NNN i: Formula VI. Tazemetostat (CAS# 1403254-99-8 (free base)), also known as EPZ-6438 and E7438, is an EZH2 (Enhancer of Zeste 2 Polycomb Repressive Complex 2 Subunit) inhibitor. It has the structure of Formula VII. 56 WO2025 / 082481 PCT / CN2024 / 125773 eo A NN 3 Formula VII. The cell viability was tested using CellTiter-Glo® cell proliferation experiment. In brief, T cell lymphoma cells were seeded in a 96-well plate and 5 exposed to solvent (vehicle control) or treated with increasing concentrations of Compound A and the HDAC inhibitor alone or in combination, in duplicate. After treatment, cell viability was assessed with CellTiter-Glo® Luminescent Cell Viability Assays (Promega, Madison, WI, USA; Cat# G7571). Luminescence signal was detected using a BioTek Synergy H1 Hybrid Multi- 10 Mode (Microplate) Reader (BioTek, Shanghai). In the CTG experiment, the in vitro proliferation inhibition effect of Compound A alone was tested on two commonly used T cell lymphoma cell lines Hut102 and HH. Hut1l02 cell line was purchased from Cobioer (Nanjing, China) and 15 maintained in vitro as suspension in RPMI 1640 medium (ATCC®, 30-2001™) supplemented with 10% fetal bovine serum (FBS, Gibco, Grand Island, NY, USA;Cat#10099141C), 1% penicillin / streptomycin, and 100 U / ml IL-2. HH cell line was from ATCC® CRL-2105™ and cultured in RPMI 1640 medium (ATCC®, 30-2001™) containing 10% fetal bovine serum (FBS, Gibco, 20 Grand Island, NY, USA; Cat#10099141C), 1% penicillin / streptomycin. H9 cell line was purchased from Cobioer (Nanjing, China) and maintained in vitro as suspension in RPMI 1640 medium (Gibco, Cat# C11875500BT) supplemented with 10% fetal bovine serum (FBS, Gibco, Grand Island, NY, USA; Cat#10099141C), 1% penicillin / streptomycin. 57 WO 2025 / 082481 PCT / CN2024 / 125773 Hut78 cell line was purchased from Cobioer (Nanjing, China) and propagated in vitro as suspension in Iscove’s Modified Dulbecco’s Medium (IMDM, Gibco, Grand Island, NY, USA Cat# C12440500BT) supplemented with 20% fetal bovine serum (FBS, Gibco, Grand Island, NY, USA; 5 Cat#10099141C), 1% penicillin / streptomycin. The cells were maintained at 37°C in an atmosphere of 5% CO, in air and passaged twice weekly. All the cell lines weresubjected to genetic identification and free of microbial contamination. Hut102, HH and H9 cell lines were treated with increasing concentrations 10 of Compound A, Valemetostat, MAK683 or Tazemetostat alone for 6 days. Hut78 cell lines were treated with increasing concentrations of Compound A, Valemetostat, MAK683 or Tazemetostat alone for 15 days. The anti-proliferative activity was assessed by CellTiter-Glo® assay (CTG) in vitro, and the growth inhibition curve is depicted using GraphPad Prism 9. The cell survival 15 percentage 1s represented as Mean + SEM, and n=2 or 3. Results and Conclusions: The results showed that Compound A as a single agent exerted antiproliferative activity against Hutl02, HH, H9 and Hut78 cells. It was noteworthy that under the same experimental conditions, Compound A was 20 ~~ efficacious in Hut102, HH, H9 and Hut78 cells with greater potent than MAK683, Valemetostat and Tazemetostat (Table 2). Table 2: Antiproliferative activity in TCL cell lines cell linecell line cell line cell line 58 WO 2025 / 082481 PCT / CN2024 / 125773 Note: >10 uM represents no detectable effects. In conclusion, Compound A has a more anti-proliferative effect on T cell lymphoma cells than other three compounds, i.e., Valemetostat, MAK683 and Tazemetostat. 5 Example 2: Synergistic anti-proliferative effect_of Compound A in combination with HDAC inhibitor Tucidinostat on TCL cell lines Materials and Methods: The cell viability was tested using CellTiter-Glo® cell proliferatio 10 experiment, as described in Example 1. In the CTG experiment, the in vitro proliferation inhibition effect of Compound A alone was tested on two commonly used T cell lymphoma cell lines Hut102 and HH. Hut1l02 cell line was purchased from Cobioer (Nanjing, China) and maintained / cultured in vitro as suspension in RPMI 1640 medium (Gibco, Cat# 15 C11875500BT) supplemented with 10% fetal bovine serum (FBS, Gibco, Grand Island, NY, USA; Cat#10099141C), 100U / mL penicillin, 100 wug / mL streptomycin and100 U / ml IL-2. HH cell line was from ATCC® CRL-2105™ and cultured in RPMI 1640 medium (ATCC®, 30-2001™) containing 10% fetal bovine serum, 100U / mL 20 ~=penicillin and 100ug / mL streptomycin. Cells were maintained at 37°C in an atmosphere of 5% CQO, in air and passaged twice weekly. All the cell lines were subjected to genetic identification and free of microbial contamination. The cell lines were treated with a gradient concentration of Compound A, 25 Tucidinostat alone or in combination, and the cell growth inhibiting activity is 59 WO 2025 / 082481 PCT / CN2024 / 125773 detected by CellTiter-Glo luminescence method. The cell survival percentage 1s represented as Mean + SEM, n = 2 or 3. Results and Conclusions: The growth inhibition effects of Compound A in combination with HDAC 5 inhibitor (Tucidinostat) on human TCL cell line are shown in Figures 1A and 1B. Compound A as a single agent not only exerted anti-proliferative activity against Hutl102 and HH cells, but also was outstanding thatCompound A in combination with HDAC inhibitor (Tucidinostat), exhibiting as after the 10 combined administration, the ICso value is reduced, and be compared by the IC50s of the combined administration curve and single drug curve, it is observed that the combined administration group curve is moved left. The results showed that when Compound A is combined with HDAC inhibitor Tucidinostat (chidamide), although either Compound A or Tucidinostat 15 (chidamide) alone displayed variable antiproliferative activity, their combination consistently exerted synergistic activity in two TCL cell lines, i.e., Hut102 and HH cell lines. The curves for cell proliferation shifted to the left, indicating a synergistic activity. Further analysis showed that the combined index (CI value) was less than 0.3 at multiple combination concentrations, confirming a 20 synergistic effect of the combination. The combination index (CI) 1s less than 0.9, which shows that the two-drug combination has a synergisticeffect. Combination index (CI) was calculated by CalcuSyn software v2.0 (Biosoft, Cambridge, UK), as follows: CI= (D)MDy)1+ (D)24(Dyx)2 25 Where (Dy)1 and (Dy)2 represent the concentration of each drug alone to exert X % effect, while (D)1 and (D)2 signify concentrations of the two drugs in combination to elicit the same effect. A CI value of less than 1 indicates synergism; 1, additivity; and greater than 1, antagonism. In the current combination study, cellular proliferative data were further analyzed with CI < 0.1 30 labeled as 5° for a very strong synergistic effect; CI between 0.1 and 0.3 labeled 60 WO 2025 / 082481 PCT / CN2024 / 125773 as 4° for a strong synergistic effect; and CI between 0.3 and 0.9 labeled as 3* for a medium synergistic effect. The combination, in which Compound A has different concentrations from that of Tucidinostat (chidamide), was also tested in different cell lines (e.g., 5 Hut102 and HH cell lines) and also showed a synergistic effect. Example 3: Synergisticanti-proliferative effect_of Compound A in combination with JAK1 inhibitor Golidocitinib on TCL cell lines Materials and Methods: 10 Cell viability was assessed using the CellTiter-Glo® Luminescent Cell Viability Assay, as described in Example 1. In this assay, the in vitro proliferation inhibitory effect of Compound A in combination with the JAK1 inhibitor Golidocitinib was evaluated on the HuT102 T cell lymphoma cell line. The HuT102 cell line was obtained from Cobioer (Nanjing, China) and 15 cultured as a suspension in RPMI 1640 medium (ATCC®, 30-2001™), supplemented with 10% fetal bovine serum (FBS, Gibco, Grand Island, NY, USA; Cat#10099141C), 100 U / mL penicillin, 100 g / mL streptomycin, and 100 U / mL IL-2 (Peprotech, Cat#200-02). Cells were maintained at 37°C in a humidified atmosphere with 5% CQO, and passaged twice weekly. All cell lines were 20 ~+genetically authenticated and confirmed to be free of microbial contamination. HuT102 cells were treated with indicated gradientconcentrations of Compound A for 6 days, Golidocitinib for 3 days, or their combination. The inhibitory effect on cell growth was determined using the CellTiter-Glo® luminescent assay. Cell viability data were represented as Mean + SD, with n = 25 2 replicates. Results and Conclusions: The growth inhibitory effects of Compound A in combination with the JAK 1 inhibitor Golidocitinib on the HuT102 cell line are shown in Figure 2. 61 WO 2025 / 082481 PCT / CN2024 / 125773 Compound A, as a single agent, demonstrated significant antiproliferative activity against HuT102 cells. Notably, the antiproliferative activity against the HuT102 cells was enhanced when Compound A was combined with golidocitinib. the curves for cell proliferation shifted to the left, indicating an 5 enhanced and / or synergistic activity. Further analysis indicated that the combination index (CI) values calculated using CalcuSyn software were all less than 0.3 at multiple combination concentrations, indicating strongsynergistic inhibitory effects. The CI values were calculated using CalcuSyn software v2.0 (Biosoft, Cambridge, UK), as described in Example 2. A CI value of less than 10 0.9 further supports the synergistic effect of the drug combination. Our study provides a scientific rationale for the future clinical development of Compound A and golidocitinib in treating TCL patients. Example 4: Synergistic anti-proliferative effect_of Compound A in 15 combination with JAK1 inhibitor Golidocitinib on NK / TCL cell lines Materials and Methods: Cell viability was assessed using the CellTiter-Glo® Luminescent Cell Viability Assay, as described in Example 1. In this assay, the in vitro proliferation inhibition effect of Compound A in combination with the JAK1 inhibitor 20. Golidocitinib was evaluated on two commonly used NK / T cell lymphoma cell lines, SNK-1 and SNK-6. The SNK-1 cell line was cultured as a suspension in RPMI 1640 medium (ATCC®, 30-2001™) supplemented with 10% human serum AB (GeminiBio,Cat#100-318), 100 U / mL penicillin, 100 pg / mL streptomycin, and 100 U / mL IL- 25 2 (Peprotech, Cat#200-02). The SNK-6 cell line was cultured under similar conditions in RPMI 1640 medium (ATCC®, 30-2001™) with the same supplements. Both cell lines were maintained at 37°C in a humidified atmosphere of 5% CQO, and passaged twice weekly. All cell lines were genetically authenticated and confirmed to be free of microbial contamination. 62 WO 2025 / 082481 PCT / CN2024 / 125773 Cells were treated with a gradient concentration of Compound A for 10 days and Golidocitinib for 2 days. The inhibitory effect on cell growth was determined using the CellTiter-Glo® luminescent assay. Cell viability data were represented as Mean + SEM, with n = 2 or 3 replicates. 5 Results and Conclusions: The growth inhibitory effects of Compound A in combination with the JAK1 inhibitor Golidocitinib on human NK / T cell lymphoma (NK / TCL) cell lines are shown in Figures 3A and 3B. As a single agent, Compound A 10 demonstratedsignificant antiproliferative activity against both SNK-1 and SNK-6 cells. Notably, the combination of Compound A with Golidocitinib further enhanced this antiproliferative activity. A leftward shift of concentration effect curves for combinations when compared to single agent curves indicates synergism, 15 The results showed that when Compound A is combined with JAK1 inhibitor (Golidocitinib), although either Compound A or Golidocitinib alone exerted limited antiproliferative activity in two NK / TCL cell lines, 1.e., SNK-1 and SNK-6, However, their combination consistently exerted synergistic activity in NK / TCL cell lines. The curves for cell proliferation shifted to the 20 left, indicating a synergistic activity. Further analysis showed that the combined index (CI value) was less than 0.3 at multiple combination concentrations, indicating moderate (CI score 3+) to very strong (CI score 5+) synergistic inhibitory effects. The combination index (CI) is less than 0.9, which shows thatthe two-drug combination has a synergistic effect. Combination index (CI) 25. was calculated by CalcuSyn software v2.0 (Biosoft, Cambridge, UK). These findings provide a scientific rationale for the future clinical development of Compound A and Golidocitinib in treating NK / TCL patients. 63 WO 2025 / 082481 PCT / CN2024 / 125773 Example5: Synergistic _anti-proliferative effect_of Compound A in combination with BCL2 / BCL-XL inhibitor Compound B on NK / TCL cell lines Materials and Methods: 5 Cell viability was assessed using the CellTiter-Glo® Luminescent Cell Viability Assay, as described in Example 1. In this assay, the in vitro proliferation inhibition effect of Compound A in combination with the BCL2 / BCL-XL inhibitor Compound B was evaluated on two commonly used NK / T cell lymphoma cell lines, SNK-1 and SNK-6. 10 The SNK-1 cell line was maintained in vitro as a suspension in RPMI 1640 medium (ATCC®, 30-2001™) supplemented with 10% human serum AB (GeminiBio, Cat#100-318), 100 U / mL penicillin,100 g / mL streptomycin, and 100 U / mL IL-2 (Peprotech, Cat#200-02). The SNK-6 cell line was cultured under the same conditions in RPMI 1640 medium (ATCC®, 30-2001™) with 15 the same supplements. Both cell lines were maintained at 37°C in a humidified atmosphere of 5% CO2 and passaged twice weekly. All cell lines were genetically authenticated and confirmed to be free of microbial contamination. Cells were treated with a gradient concentration of Compound A for 10 days and Compound B for 2 days. The inhibitory effect on cell growth was determined 20 using the CellTiter-Glo® luminescent assay. Cell viability data were represented as Mean + SD, with n = 2 or 3 replicates. Results and Conclusions: The growth inhibitory effects of Compound A in combination with the 25 BCL2 / BCL-XL inhibitor Compound B on human NK / T cell lymphoma (NK / TCL) cell lines are shown in Figures 4A and 4B. As a single agent, Compound A or Compound B alone demonstrated antiproliferative activity against both SNK-1 andSNK-6 cells. Notably, the combination of Compound A with Compound B further enhanced this antiproliferative activity, as evidenced 64 WO 2025 / 082481 PCT / CN2024 / 125773 by the leftward shift of the combination treatment curves compared to the single- agent curves. The results showed that when Compound A was combined with Compound B, although either agent alone displayed variable antiproliferative activity, their 5 combination consistently exerted synergistic effects in both NK / TCL cell lines (SNK-1 and SNK-6). The leftward shift in the proliferation curves indicates this synergistic activity. Further analysis revealed that the combination index (CI) values, calculated using CalcuSyn software v2.0 (Biosoft, Cambridge, UK), were less than 0.3 at multiple combination concentrations, confirming strong 10 synergistic inhibitory effects. A CI value of less than 0.9 further supports the synergistic interaction between the two drugs. These findings provide a scientific rationale for the futureclinical development of Compound A and Compound B in treating NK / TCL patients. Having now fully described the methods, compounds, and compositions 15 herein, it will be understood by those of skill in the art that the same can be performed within a wide and equivalent range of conditions, formulations, and other parameters without affecting the scope of the methods, compounds, and compositions provided herein or any embodiment thereof. All patents, patent applications, and publications cited herein are fully 20. incorporated by reference herein in their entirety. 65 WO 2025 / 082481 PCT / CN2024 / 125773 CLAIMS 1. A pharmaceutical combination comprising an embryonic ectoderm development (EED) inhibitor and another inhibitor selected from the group 5 consisting of a histone deacetylase (HDAC) inhibitor, a JAK inhibitor and a BCL2 / BCL-XL inhibitor. 2. The pharmaceutical combination of claim 1, wherein the EED inhibitor is a compound of Formula I: yoy ; RORY, 10 wherein: R! is aralkyl; R? isselected from the group consisting of hydrogen and C,-C, alkyl; R3 and R* taken together with the carbon atoms to which they are attached form a radical of Formula I-A, I-B, or I-C: RI y pe * “me A Re BA 72° EB or 727 be; 15 X is selected from the group consisting of -C(R**)(R®)-, -C(=O)-, and - S(=O)>-; R™* and R® are independently selected from the group consisting of hydrogen and C;-C, alkyl; 20 Y is selected from the group consisting of -C(R%)(R®™)-, -S-, -O-, and - N(R’)-; 66 WO 2025 / 082481 PCT / CN2024 / 125773 Z is -C(R™)(R™ )m-; R® and R® are independently selected from the group consisting of hydrogen and C-C, alkyl; each R®™ and R™ is independently selected from the group consisting of 5 hydrogen and C)-C, alkyl; m is 0, 1, or 2; R’ is selected from the group consisting of hydrogen, C)-C, alkyl, C1-Ce haloalkyl, optionally substituted C3-Cg cycloalkyl, optionally substituted C4-Cg heterocyclo, hydroxyalkyl, (alkoxy)alkyl, (cycloalkyl)alkyl, and 10 (heterocyclo)alkyl; R*®, R®. andR®* are independently selected from the group consisting of hydrogen, halo, C-C, alkyl, C)-C, haloalkyl, C,-C, alkoxy, and alkylsulfonyl; A ~" is a fused phenyl, fused 5-membered heteroaryl, or fused 6- membered heteroaryl; fo \B . ; 15 “—“ ig an optionally substituted fused 3- to 8-membered cycloalkyl or optionally substituted fused 4- to 8-membered heterocyclo; ~~" is an optionally substituted fused 4- to 8-membered heterocyclo; the bond designated with a '"»~ " is attached at the R° position of Formula I and the bond designated with an "*" is attached at the R* position of Formula I; 20 and =** is a single or double bond, or a pharmaceutically acceptable salt or solvate thereof. 3. The pharmaceutical combination of claim 2, wherein the EED inhibitor is a compound of Formula IT: 67 WO 2025 / 082481 PCT / CN2024 / 125773 or NOON eoee . ee tt, or a pharmaceutically acceptable salt or solvate thereof. 4. The pharmaceutical combination of claim 2 or 3, wherein Z is -CH-, or a pharmaceuticallyacceptable salt or solvate thereof. 5 5. The pharmaceutical combination of any one of claims 2-4, wherein X is -C(=O)-, or a pharmaceutically acceptable salt or solvate thereof. 6. The pharmaceutical combination of any one of claims 2-5, wherein Y is -N(R’)-, and preferably R’ is selected from the group consisting of C\-Cg alkyl, Ci-Cs haloalkyl, and optionally substituted C3-Cg cycloalkyl, or a 10 pharmaceutically acceptable salt or solvate thereof. 7. The pharmaceutical combination according to claim 2, wherein the EED inhibitor is selected from the group consisting of: 4-ethyl-12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-7- (trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a- 15 pentaazabenzo[4,5|cycloocta[1,2,3-cd]inden-3-one; 12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-4-(2,2,2- trifluoroethyl)-7-(trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a- pentaazabenzo[4,5|cycloocta[1,2,3-cd]inden-3-one; 4-cyclopropyl-12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 20~=©7-(trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a- pentaazabenzo[4,5|cycloocta[1,2,3-cd]inden-3-one; 12-(((5-fluoro-2 ,3-dihydrobenzofuran-4-yl)methyl)amino)-4-isopropyl-7- (trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a- pentaazabenzo[4,5|cycloocta[1,2,3-cd]inden-3-one; and 68 WO 2025 / 082481 PCT / CN2024 / 125773 11-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-6-methyl-4H-3- thia-2,5,10,11la-tetraazadibenzo[cd,flazulene-3 ,3-dioxide, or a pharmaceutically acceptable salt or solvate thereof. 8. The pharmaceutical combination according to claim 2, 5 wherein the EED inhibitor is a compound having the structure of Formula II or the pharmaceutically acceptable salt or solvate thereof, . ‘ Nos EN F3C A ‘ Formula III. 9. The pharmaceutical combination of any one of claims 1-8, wherein the 10 HDAC inhibitor is selected from the group consisting of Tucidinostat (Chidamide), Vorinostat (SAHA), Belinostat (PXD-101), Romidepsin (FK-228), Panobinostat (LBH589), Entinostat (MS-275), TrichostatinA (TSA), Mocetinostat (MGCD0103) and MC1568. 10. The pharmaceutical combination of any one of claims 1-8, wherein the 15 JAK inhibitor is a JAK1, JAK2, JAK3 and / or TYK2 inhibitor. 11. The pharmaceutical combination of any one of claims 1-8, wherein the JAK inhibitor is selected from the group consisting of Golidocitinib, Tofacitinib, Filgotinib, Upadacitinib, Ruxolitinib, Baricitinib, Pacritinib, Momelotinib, Fedratinib and Abrocitinib, preferably, the JAK inhibitor is Golidocitinib. 20 12. The pharmaceutical combination of any one of claims 1-8, wherein the BCL2 / BCL-XL inhibitor is selected from the group consisting of Compound B, Compound C and venetoclax, preferably, the BCL2 / BCL-XL inhibitor is Compound B or Compound C; 69 WO 2025 / 082481 PCT / CN2024 / 125773 wherein Compound B represents a compound having the structure of Formula VIII or the pharmaceutically acceptable salt or solvate thereof; ne a oN A T &y n / N ~s CY ee a o"*T ps aN o Sed ( NHN Son SNH aa, oo 6 “Sx or ae FOF FormulaVIII; 5 wherein Compound C represents a compound having the structure of Formula LX or the pharmaceutically acceptable salt or solvate thereof; \ ot & %, Sa! wf ces o \ S re) see — $ es i ° oad Oy * ad Q o FOF Formula IX. 13. The pharmaceutical combination of any one of claims 1-12, wherein the 10 weight ratio of the EED inhibitor and said another inhibitor ranges from 0.0001:1 to 1:0.0001, 0.01: 1 to 1:0.01 or 0.1:1 to 1:0.1, preferably the weight ratio of the EED inhibitor and said another inhibitor is 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9 or 1:10, more preferably 1:1. 14. The pharmaceutical combination of any one of claims 1-13, wherein the 15 molar ratio of the EED inhibitor and said another inhibitor ranges from 10:1 to 70 WO 2025 / 082481 PCT / CN2024 / 125773 1:10, for example, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9 or 1:10, preferably 1:1. 15. A pharmaceutical composition comprisingany one of the pharmaceutical combination of any one of preceding claims and 5 pharmaceutically acceptable carriers. 16. The pharmaceutical composition of claim 15 in the form of a tablet, a capsule, a granule, a syrup, a powder, a lozenge, a sachet, a cachet, an elixir, a suspension, an emulsion, a solution, an aerosol, an ointment, a cream or an injection. 10 17. A method for treating cancer in a subject, comprising administering a therapeutically effective amount of the pharmaceutical combination of any one of claims 1-14 or the pharmaceutical composition of claim 15 or 16 to the subject, optionally the cancer is selected from the group consisting of: T cell lymphoma, Non-Hodgkin lymphoma, Mature T- and NK-cell lymphoma, T cell 15 neoplasms, Mycosis fungoides, Granulomatous slack skin, Sezary syndrome, Mature T cell lymphoma, Lymphoepithelioid lymphoma, Follicular T-cell lymphoma, Nodal peripheral T-cell lymphoma with T follicular helper phenotype, Angioimmunoblastic T-celllymphoma, Subcutaneous panniculitis-like T-cell lymphoma, Cutaneous T-cell lymphoma NOS, Primary cutaneous CD8-positive 20 aggressive epidermotropic cytotoxic T-cell lymphoma, Primary cutaneous acral CD8 positive T-cell lymphoma, Anaplastic large cell lymphoma T cell and Null cell type, Anaplastic large cell lymphoma NOS, Anaplastic large cell lymphoma ALK positive, Hepatosplenic T-cell lymphoma, Intestinal T-cell lymphoma, Monomorphic epitheliotropic intestinal T-cell lymphoma, Primary mucosal 25 CD30+ T-cell lymphoproliferative disorder, NK / T-cell lymphoma nasal and nasal-type, Indolent T-cell lymphoproliferative disorder of gastrointestinal tract, Primary cutaneous CD4 positive small / medium T-cell lymphoproliferative disorder, Primary cutaneous CD4-positive small / medium T-cell lymphoma, Intravascular large B-cell lymphoma, Intravascular large B-cell lymphoma, 30 Anaplastic large cell lymphoma, ALK -positive, Anaplastic large cell lymphoma, 71 WO 2025 / 082481 PCT / CN2024 / 125773 ALKnegative, Breast implant-associated anaplastic large cell lymphoma, Primary cutaneous CD30+ T-cell lymphoproliferative disorder, Mature T-cell or NkK-cell neoplasms, T-cell prolymphocytic leukaemia, T-cell large granular lymphocytic leukaemia, Chronic lymphoproliferative disorders of NK-cells, 5 Aggressive NK cell leukaemia, Systemic Epstein-Barr Virus-positive T-cell lymphoma of childhood, Adult T-cell lymphoma or leukaemia, human T-cell lymphotropic virus type l-associated, Extranodal NK / T-cell lymphoma nasal type, Enteropathy associated T-cell lymphoma, Hepatosplenic T-cell lymphoma, Angioimmunoblastic T-cell lymphoma, Peripheral T-cell lymphoma and 10 Subcutaneous panniculitis-like T-cell lymphoma. 18. A method for treating a disease in a subject, comprising administering a therapeutically effective amount of the EED inhibitor described in any one of claims 1-14 to the subject, wherein the disease is selected from the group consisting of T cell 15 lymphoma, Non-Hodgkin lymphoma,Mature T- and NK-cell lymphoma, T cell neoplasms, Mycosis fungoides, Granulomatous slack skin, Sezary syndrome, Mature T cell lymphoma, Lymphoepithelioid lymphoma, Follicular T-cell lymphoma, Nodal peripheral T-cell lymphoma with T follicular helper phenotype, Angioimmunoblastic T-cell lymphoma, Subcutaneous panniculitis-like T-cell 20 lymphoma, Cutaneous T-cell lymphoma NOS, Primary cutaneous CD8-positive ageressive epidermotropic cytotoxic T-cell lymphoma, Primary cutaneous acral CD8 positive T-cell lymphoma, Anaplastic large cell lymphoma T cell and Null cell type, Anaplastic large cell lymphoma NOS, Anaplastic large cell lymphoma ALK positive, Hepatosplenic T-cell lymphoma, Intestinal T-cell lymphoma, 25 Monomorphic epitheliotropic intestinal T-cell lymphoma, Primary mucosal CD30+ T-cell lymphoproliferative disorder, NK / T-cell lymphoma nasal and nasal-type, Indolent T-cell lymphoproliferative disorder of gastrointestinal tract, Primary cutaneous CD4 positive small / medium T-celllymphoproliferative disorder, Primary cutaneous CD4-positive small / medium T-cell lymphoma, 30 Intravascular large B-cell lymphoma, Intravascular large B-cell lymphoma, 72 WO 2025 / 082481 PCT / CN2024 / 125773 Anaplastic large cell lymphoma, ALK-positive, Anaplastic large cell lymphoma, ALK negative, Breast implant-associated anaplastic large cell lymphoma, Primary cutaneous CD30+ T-cell lymphoproliferative disorder, Mature T-cell or NkK-cell neoplasms, T-cell prolymphocytic leukaemia, T-cell large granular 5 lymphocytic leukaemia, Chronic lymphoproliferative disorders of NK-cells, Aggressive NK cell leukaemia, Systemic Epstein-Barr Virus-positive T-cell lymphoma of childhood, Adult T-cell lymphoma or leukaemia, human T-cell lymphotropic virus type l-associated, Extranodal NK / T-cell lymphoma nasal type, Enteropathy associated T-cell lymphoma, Hepatosplenic T-cell lymphoma, 10 Angioimmunoblastic T-cell lymphoma, Peripheral T-cell lymphoma and Subcutaneous panniculitis-like T-cell lymphoma.19. The method of claim 17 or 18, wherein the EED inhibitor is administered in an amount of from about 0.0005 mg / day to about 5000 mg / day, for example, about 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 15 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500 or 5000 mg / day. 20. The method of any one of claims 17-19, wherein the EED inhibitor is administered in an amount of from about 1 ng / kg to about 200 mg / kg, about | ug / kg to about 100 mg / kg, or about 1 mg / kg to about 50 mg / kg per unit dose, for 20 example, administrated in an amount of about 1 ug / kg, about 10 g / kg, about 25 ug / kg, about 50 pg / kg, about 75 wg / kg, about 100 pg / kg, about 125 wg / kg, about 150 ug / kg, about 175 pg / kg, about 200 ug / kg, about 225 g / kg, about 250 ug / kg, about 275 pg / kg, about 300 ug / kg, about 325 pg / kg, about 350 pg / kg, about 375 ug / kg, about 400 pg / kg, about 425 ug / kg, about 450 ug / kg, about 475 pg / kg, 25 about 500 ug / kg, about525 g / kg, about 550 g / kg, about 575 wg / kg, about 600 ug / kg, about 625 pg / kg, about 650 ug / kg, about 675 g / kg, about 700 ug / kg, about 725 pg / kg, about 750 ug / kg, about 775 pe / kg, about 800 pg / kg, about 825 ug / kg, about 850 pg / kg, about 875 ug / kg, about 900 ug / kg, about 925 pg / kg, about 950 ug / kg, about 975 g / kg, about 1 mg / kg, about 5 mg / kg, about 10 30 ~©6omeg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 73 WO 2025 / 082481 PCT / CN2024 / 125773 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 125 mg / kg, about 150 mg / kg, about 175 mg / kg, about 200 mg / kg per unit dose, and administrated with one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) unit doses per 5 day. 21. The method of any one of claims 17 and 19-20, wherein the HDAC inhibitor is administered in an amount of from about 0.0005 mg / day to about 5000 mg / day, for example, about 0.005, 0.05, 0.5, 5, 10, 20, 30,40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 10 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500 or 5000 mg / day. 22. The method of any one of claims 17 and 19-21, wherein the HDAC inhibitor is administered in an amount of from about 1 ng / kg to about 200 mg / kg, about 1 pg / kg to about 100 mg / kg, or about 1 mg / kg to about 50 mg / kg per unit dose, for example, administrated in an amount of about 1 g / kg, about 10 pg / kg, 15 about 25 wg / kg, about 50 ng / kg, about 75 pg / kg, about 100 pg / kg, about 125 ug / kg, about 150 pg / kg, about 175 wg / kg, about 200 ug / kg, about 225 pg / kg, about 250 pg / kg, about 275 ug / kg, about 300 g / kg, about 325 pg / kg, about 350 ug / kg, about 375 pg / kg, about 400 ug / kg, about 425 ug / kg, about 450 pg / kg, about 475 pg / kg, about 500 ug / kg, about 525 ug / kg, about 550 pg / kg, about 20 575 pg / kg, about 600 ng / kg, about 625 pg / kg, about 650 g / kg, about 675 pg / kg, about 700 pg / kg, about 725 ug / kg, about 750 g / kg, about 775 pg / kg,about 800 ug / kg, about 825 pg / kg, about 850 ug / kg, about 875 ug / kg, about 900 pg / kg, about 925 g / kg, about 950 pg / kg, about 975 pg / kg, about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 25 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 125 mg / kg, about 150 mg / kg, about 175 mg / kg, about 200 mg / kg per unit dose, and administrated with one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) unit doses per day. 74 WO 2025 / 082481 PCT / CN2024 / 125773 23. The method of any one of claims 17and 19-22, wherein the EED inhibitor and the HDAC inhibitor are administered together, simultaneously, sequentially or alternately. 24. The method of any one of claims 17-23, wherein the EED inhibitor 5 and / or the HDAC inhibitor are administered continuously for at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, 10 at least 23 days, at least 24 days, at least 25 days, at least 28 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days, or at least 50 days. 25. The method of any one of claims 17-24, wherein the EED inhibitor and / or the HDAC inhibitor are administered for one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) courses of treatment, wherein each of the courses lasts at least 3 15 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 30 days, at least 35 days, at 20 least 40 days, at least 45 days, or at least 50 days; and there is an interval of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days, two weeks, three weeks or four weeks between every two courses of treatment. 26. The method of any one of claims 17 and 19-25, wherein the EED inhibitor and the HDAC inhibitor are administrated via the same (e.g., oral) or 25 different routes (e.g., oral and parenteral (e.g., injection), respectively). 27. Use of the pharmaceutical combination of any one of claims 1-11 or the pharmaceutical composition of claim 15 or 16 in the manufacture of a medicament for treating cancer, optionally the cancer is selected from the group consisting of T cell 30 ~=lymphoma, Non-Hodgkin lymphoma, Mature T- and NK-cell lymphoma, T cell 75 WO 2025 / 082481 PCT / CN2024 / 125773 neoplasms, Mycosis fungoides, Granulomatous slack skin, Sezary syndrome, Mature T cell lymphoma,Lymphoepithelioid lymphoma, Follicular T-cell lymphoma, Nodal peripheral T-cell lymphoma with T follicular helper phenotype, Angioimmunoblastic T-cell lymphoma, Subcutaneous panniculitis-like T-cell 5 lymphoma, Cutaneous T-cell lymphoma NOS, Primary cutaneous CD8-positive ageressive epidermotropic cytotoxic T-cell lymphoma, Primary cutaneous acral CD8 positive T-cell lymphoma, Anaplastic large cell lymphoma T cell and Null cell type, Anaplastic large cell lymphoma NOS, Anaplastic large cell lymphoma ALK positive, Hepatosplenic T-cell lymphoma, Intestinal T-cell lymphoma, 10 Monomorphic epitheliotropic intestinal T-cell lymphoma, Primary mucosal CD30+ T-cell lymphoproliferative disorder, NK / T-cell lymphoma nasal and nasal-type, Indolent T-cell lymphoproliferative disorder of gastrointestinal tract, Primary cutaneous CD4 positive small / medium T-cell lymphoproliferative disorder, Primary cutaneous CD4-positive small / medium T-cell lymphoma, 15 Intravascular large B-cell lymphoma,Intravascular large B-cell lymphoma, Anaplastic large cell lymphoma, ALK -positive, Anaplastic large cell lymphoma, ALK negative, Breast implant-associated anaplastic large cell lymphoma, Primary cutaneous CD30+ T-cell lymphoproliferative disorder, Mature T-cell or NkK-cell neoplasms, T-cell prolymphocytic leukaemia, T-cell large granular 20 lymphocytic leukaemia, Chronic lymphoproliferative disorders of NK-cells, Aggressive NK cell leukaemia, Systemic Epstein-Barr Virus-positive T-cell lymphoma of childhood, Adult T-cell lymphoma or leukaemia, human T-cell lymphotropic virus type l-associated, Extranodal NK / T-cell lymphoma nasal type, Enteropathy associated T-cell lymphoma, Hepatosplenic T-cell lymphoma, 25 Angioimmunoblastic T-cell lymphoma, Peripheral T-cell lymphoma and Subcutaneous panniculitis-like T-cell lymphoma. 28. Use of the EED inhibitor described in any one of claims 1-14 in the manufacture of a medicament for treating a disease, wherein the disease is selected from thegroup consisting of T cell 30 ~=lymphoma, Non-Hodgkin lymphoma, Mature T- and NK-cell lymphoma, T cell 16 WO 2025 / 082481 PCT / CN2024 / 125773 neoplasms, Mycosis fungoides, Granulomatous slack skin, Sezary syndrome, Mature T cell lymphoma, Lymphoepithelioid lymphoma, Follicular T-cell lymphoma, Nodal peripheral T-cell lymphoma with T follicular helper phenotype, Angioimmunoblastic T-cell lymphoma, Subcutaneous panniculitis-like T-cell 5 lymphoma, Cutaneous T-cell lymphoma NOS, Primary cutaneous CD8-positive ageressive epidermotropic cytotoxic T-cell lymphoma, Primary cutaneous acral CD8 positive T-cell lymphoma, Anaplastic large cell lymphoma T cell and Null cell type, Anaplastic large cell lymphoma NOS, Anaplastic large cell lymphoma ALK positive, Hepatosplenic T-cell lymphoma, Intestinal T-cell lymphoma, 10 Monomorphic epitheliotropic intestinal T-cell lymphoma, Primary mucosal CD30+ T-cell lymphoproliferative disorder, NK / T-cell lymphoma nasal and nasal-type, Indolent T-celllymphoproliferative disorder of gastrointestinal tract, Primary cutaneous CD4 positive small / medium T-cell lymphoproliferative disorder, Primary cutaneous CD4-positive small / medium T-cell lymphoma, 15 Intravascular large B-cell lymphoma, Intravascular large B-cell lymphoma, Anaplastic large cell lymphoma, ALK -positive, Anaplastic large cell lymphoma, ALK negative, Breast implant-associated anaplastic large cell lymphoma, Primary cutaneous CD30+ T-cell lymphoproliferative disorder, Mature T-cell or NkK-cell neoplasms, T-cell prolymphocytic leukaemia, T-cell large granular 20 lymphocytic leukaemia, Chronic lymphoproliferative disorders of NK-cells, Aggressive NK cell leukaemia, Systemic Epstein-Barr Virus-positive T-cell lymphoma of childhood, Adult T-cell lymphoma or leukaemia, human T-cell lymphotropic virus type l-associated, Extranodal NK / T-cell lymphoma nasal type, Enteropathy associated T-cell lymphoma, Hepatosplenic T-cell lymphoma, 25 Angioimmunoblastic T-cell lymphoma,Peripheral T-cell lymphoma and Subcutaneous panniculitis-like T-cell lymphoma. 29. The pharmaceutical combination of any one of claims 1-14 or the pharmaceutical composition of claim 15 or 16, for use in treating cancer; optionally wherein the cancer is selected from the group consisting of T cell 30 ~=lymphoma, Non-Hodgkin lymphoma, Mature T- and NK-cell lymphoma, T cell 71 WO 2025 / 082481 PCT / CN2024 / 125773 neoplasms, Mycosis fungoides, Granulomatous slack skin, Sezary syndrome, Mature T cell lymphoma, Lymphoepithelioid lymphoma, Follicular T-cell lymphoma, Nodal peripheral T-cell lymphoma with T follicular helper phenotype, Angioimmunoblastic T-cell lymphoma, Subcutaneous panniculitis-like T-cell 5 lymphoma, Cutaneous T-cell lymphoma NOS, Primary cutaneous CD8-positive ageressive epidermotropic cytotoxic T-cell lymphoma, Primary cutaneous acral CD8 positive T-cell lymphoma, Anaplastic large cell lymphoma T cell and Null cell type, Anaplastic large cell lymphoma NOS, Anaplastic largecell lymphoma ALK positive, Hepatosplenic T-cell lymphoma, Intestinal T-cell lymphoma, 10 Monomorphic epitheliotropic intestinal T-cell lymphoma, Primary mucosal CD30+ T-cell lymphoproliferative disorder, NK / T-cell lymphoma nasal and nasal-type, Indolent T-cell lymphoproliferative disorder of gastrointestinal tract, Primary cutaneous CD4 positive small / medium T-cell lymphoproliferative disorder, Primary cutaneous CD4-positive small / medium T-cell lymphoma, 15 Intravascular large B-cell lymphoma, Intravascular large B-cell lymphoma, Anaplastic large cell lymphoma, ALK -positive, Anaplastic large cell lymphoma, ALK negative, Breast implant-associated anaplastic large cell lymphoma, Primary cutaneous CD30+ T-cell lymphoproliferative disorder, Mature T-cell or NkK-cell neoplasms, T-cell prolymphocytic leukaemia, T-cell large granular 20 lymphocytic leukaemia, Chronic lymphoproliferative disorders of NK-cells, Aggressive NK cell leukaemia, Systemic Epstein-Barr Virus-positive T-cell lymphomaof childhood, Adult T-cell lymphoma or leukaemia, human T-cell lymphotropic virus type l-associated, Extranodal NK / T-cell lymphoma nasal type, Enteropathy associated T-cell lymphoma, Hepatosplenic T-cell lymphoma, 25 Angioimmunoblastic T-cell lymphoma, Peripheral T-cell lymphoma and Subcutaneous panniculitis-like T-cell lymphoma. 30. The EED inhibitor described in any one of claims 1-14 for use in treating a disease, wherein the disease is selected from the group consisting of T cell 30 ~=lymphoma, Non-Hodgkin lymphoma, Mature T- and NK-cell lymphoma, T cell 78 WO 2025 / 082481 PCT / CN2024 / 125773 neoplasms, Mycosis fungoides, Granulomatous slack skin, Sezary syndrome, Mature T cell lymphoma, Lymphoepithelioid lymphoma, Follicular T-cell lymphoma, Nodal peripheral T-cell lymphoma with T follicular helper phenotype, Angioimmunoblastic T-cell lymphoma, Subcutaneous panniculitis-like T-cell 5 lymphoma, Cutaneous T-cell lymphoma NOS, Primary cutaneous CD8-positive ageressive epidermotropiccytotoxic T-cell lymphoma, Primary cutaneous acral CD8 positive T-cell lymphoma, Anaplastic large cell lymphoma T cell and Null cell type, Anaplastic large cell lymphoma NOS, Anaplastic large cell lymphoma ALK positive, Hepatosplenic T-cell lymphoma, Intestinal T-cell lymphoma, 10 Monomorphic epitheliotropic intestinal T-cell lymphoma, Primary mucosal CD30+ T-cell lymphoproliferative disorder, NK / T-cell lymphoma nasal and nasal-type, Indolent T-cell lymphoproliferative disorder of gastrointestinal tract, Primary cutaneous CD4 positive small / medium T-cell lymphoproliferative disorder, Primary cutaneous CD4-positive small / medium T-cell lymphoma, 15 Intravascular large B-cell lymphoma, Intravascular large B-cell lymphoma, Anaplastic large cell lymphoma, ALK -positive, Anaplastic large cell lymphoma, ALK negative, Breast implant-associated anaplastic large cell lymphoma, Primary cutaneous CD30+ T-cell lymphoproliferative disorder, Mature T-cell or NkK-cell neoplasms, T-cell prolymphocyticleukaemia, T-cell large granular 20 lymphocytic leukaemia, Chronic lymphoproliferative disorders of NK-cells, Aggressive NK cell leukaemia, Systemic Epstein-Barr Virus-positive T-cell lymphoma of childhood, Adult T-cell lymphoma or leukaemia, human T-cell lymphotropic virus type l-associated, Extranodal NK / T-cell lymphoma nasal type, Enteropathy associated T-cell lymphoma, Hepatosplenic T-cell lymphoma, 25 Angioimmunoblastic T-cell lymphoma, Peripheral T-cell lymphoma and Subcutaneous panniculitis-like T-cell lymphoma. 31. Akit, comprising: (a) a first component in a first container, the first component comprising the EED inhibitor described in any one of claims 1-14, and optionally a 30 pharmaceutically acceptable carrier; 79 WO 2025 / 082481 PCT / CN2024 / 125773 (b) a second component in a second container, the second component comprising an inhibitor selected from the group consisting of an HDAC inhibitor (preferably an HDAC inhibitor as defined in claim 9), a JAK inhibitor (preferably aJAK inhibitor as defined in claim 11) and a BCL2 / BCL-XL 5 inhibitor (preferably a BCL2 / BCL-XL inhibitor as defined in claim 12), and optionally a pharmaceutically acceptable carrier; and (c) optionally a specification. 80 WO 2025 / 082481 PCT / CN2024 / 125773 Huite2 cell Hine +204 ~e Corpound A — 108 »® -*- Tucknostat Ze aod \\S “we Combination Compound A(AM) OG 27 4h 123 S / O Tit Besa 1Q000 Yucwinostat in) G@ 13% 43.2 188 370 fff? 3a88 ipogo a OM GOS GBS Gigs G2a8 GIs Cas (A) HH cell line 120 ~e- Compound A = 100 en ae ae ~*~ Tucidinostat ££ 80 —- Combination QS G 2 O 60 + = O nf 20 " 0+ 7 CompoundA(nM) 0 137 412 123° 370 1114 3333 10000 Tucidinostat (nM) 0 13.7 44.2 123 370 1111 3333 10000 Ci 0.08 6.31 6.62 6.20 G08 002 90.002 Seore At&t Bt 5+ (B) Figure | 1 / 4 WO 2025 / 082481 PCT / CN2024 / 125773 HUT102 420 ~*- Compound A _~ 100 ~*~ Golidocitinib >S sie — #E 80 a 4% Combination As = £S 60 5 AN 20 . 0 Compound A(nM} O 13.7% 41.2 123 370 4111 3333 10000 Golidocitnib (nM} 0 152 4.57 13.7 4412 723370 Vil Cl 0.923 1.098 0.883 0837 0.243 0.049 9.629 Scare 4+ 5+ 5+ Figure 2 2 / 4 WO 2025 / 082481 PCT / CN2024 / 125773 SNK-1 cell line 420 <* -e Compound A er NG ~%- Golidocitinib >s ceti 2s 80 s = + Combination 8S o° : G3 4 ~~ 20 wt 9 Compound A(nM) 0 13.7% 412 123 370 441 3393 10000 Golidocitinib (nM) Q 137 41.2 123 370 1411 3333 10000 Cl S SIE? O.434 of G.038 003 Oty BOTT Score 3+ A+ 5+ 5+ 5+ 5+ (A) SNK-6 cell line 120 ~* Compound A es . ~~ Golidocitinib 2 so EES, Combination ‘5 o 60 - = 3 : og 1 —_ 20- ry a 1 Compound A(nM} = 6 13.7 44.2 123 370 1117 3333 10000 Solidocitinib (nM} 0 3.7 442 9123 S370 141174 3333 10000 Cl 3.85E+01 0.239 0.085 6.139 O.114 0.026 9.002 Score 4 de 5+ 5+ (B) Figure 3 3 / 4 WO 2025 / 082481 PCT / CN2024 / 125773 SNK-1 cell line 420 ~& Compound A _. 100 ~~ Compound B as a = 5 80 “ Combination 8§ g © 60 =O Sx 4 26 0 Compound A (nM) G0 13.7 442 123 370 1111 3333 = 10000 CompoundBipM) 0 457 13.7 412 423 370 111 3333 cl O18 7.555 026 O4127 6.008 6.030 0.018 Score 4+ dt St StBt (A) SNK-6 cell line 120 hh ~e Compound A _. 100% PEA ~*~ Compound B — #2 80 - -& Combination 6 \ ocd oe 80 t = Oo ® os 4 20 e 0 2 Compound A(nM) @ 137 41.2 123 370 1174 3333 10006 Compound B(nM} 0 051 4.52 457 13.7 44.2 123 370 ch 1 20E-O1 B.B2E+13 1.734 5.409 2068 oO.072 0.003 Score St St (B) Figure 4 4 / 4 INTERNATIONAL SEARCH REPORT International application No. PCT / CN2024 / 125773 A. CLASSIFICATION OF SUBJECT MATTER A61K45 / 06(2006.01)i According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) IPC: A61K Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during the international search (name of data base and, where practicable, search terms used) CNABS,CNTXT,DWPLI VEN, USTXT, WOTXT,EPTXT,STN,CNKLASCENTAGE PHARMA, YANGDajun,ZHATY ifan,LIANGEric, YINYan,combin+,synerg+,plus,embryonic ectoderm development,EED, inhibitor,histone deacetylase, HDAC,JAK, BCL2 / BCL-XL,EEDI-5273,APG-5918,chidamide, tucidinostat, golidocitinib, AZD4205,BM-1244,APG-1251-M1,pelcitoclax, APG-1252,T cell lymphoma,Hut102,HH,H9,Hut78,2585648-55-9,1616493-44-7,209 1 134-68-6, 1619923-32-8,1619923-36-2 Cc. DOCUMENTS CONSIDERED TO BE RELEVANT Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. PX WO 2024215699 Al (ORIC PHARMACEUTICALS, INC.) 17 October 2024 (2024-10-17) 1-11, 13-31 description paraghraphs

[0003] ,

[0096] ,

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[00142] xX WO 2021195183 Al (EXO THERAPEUTICS, INC.) 30 September 2021 (2021-09-30) 1-11, 13-31 description paragraphs

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[0787] Y WO 2021195183 Al (EXO THERAPEUTICS, INC.) 30 September 2021 (2021-09-30) 17-20, 27-30 description paragraphs

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[0787] Xx SHALIMAN, Dilibaerguli et al."The PRC2 molecule EED is a target of epigenetic therapy for' 1-9, 13-17, neuroblastoma" 19-27, 29, 31 (European Journal of Cell Biology) , Vol. 101, 20 May 2022 (2022-05-20), pages 1-14 xX CN 115212311 A (ASCENTAGE PHARMA(SUZHOU) CO., LTD. et al.) 21 October 2022 1-8 (2022-10-21) description paraghraphs

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[0421] Further documents are listed in the continuation of Box C. See patent family annex. * Special categories of cited documents: «T” later document published after the international filing date or priority “a” document defining the general state of the art which is not considered date and not in conflict with the application but cited to understand the to be of particular relevance principle or theory underlying the invention “PD” document cited by the applicant in the international application “x” document of particular relevance; the claimed invention cannot be “BE” earlier application or patent but published on or after theinternational considered novel or cannot be considered to involve an inventive step filing date when the document is taken alone “{ document which may throw doubts on priority claim(s) or which is | “Y” document of particular relevance; the claimed invention cannot be cited to establish the publication date of another citation or other considered to involve an inventive step when the document is special reason (as specified) combined with one or more other such documents, such combination “OQ” document referring to an oral disclosure, use, exhibition or other being obvious to a person skilled in the art means «“&* document member of the same patent family «p” document published prior to the international filing date but later than the priority date claimed Date of the actual completion of the international search Date of mailing of the international search report 23 January 2025 06 February 2025 Name and mailing address of the ISA / CN Authorized officer CHINA NATIONAL INTELLECTUALPROPERTY ADMINISTRATION 6, Xitucheng Rd., Jimen Bridge, Haidian District, Beijing HAN,Song 100088, China Telephone No. (+86) 010-53961906 Form PCT / ISA / 210 (second sheet) (July 2022) INTERNATIONAL SEARCH REPORT International application No. PCT / CN2024 / 125773 Cc. DOCUMENTS CONSIDERED TO BE RELEVANT Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. Y CN 115212311 A (ASCENTAGE PHARMA(SUZHOU) CO., LTD. et al.) 21 October 2022 12-20, 27-31 (2022-10-21) description paraghraphs

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[0421] Y CN 113813268 A (ASCENTAGE PHARMA(SUZHOU) CO., LTD. et al.) 21 December 2021 12-20, 27-31 (2021-12-21) description paragraphs

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[0015] Xx SCHADE, Amy E. et al. "Combating castration-resistant prostate cancer by co-targeting the 1-9, 13-17, epigenetic regulators EZH2 and HDAC" 19-27, 29, 31 (PLOS Biology) , Vol. 21, No. 4, 27 April 2023 (2023-04-27), pages 1-21 4 REJ, Rohan Kalyan et al. "Discovery ofEEDi-5273 as an Exceptionally Potent and Orally 28, 30 Efficacious EED Inhibitor Capable of Achieving Complete and Persistent Tumor Regression” (Journal of Medicinal Chemistry) , Vol. 64, 06 October 2021 (2021-10-06), pages 14540-14556 A US 2020263185 Al (THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF 1-31 NEW YORK) 20 August 2020 (2020-08-20) description paragraphs

[0011] -

[0047] Form PCT / ISA / 210 (second sheet) (July 2022) INTERNATIONAL SEARCH REPORT International application No. PCT / CN2024 / 125773 Box No. II Observations where certain claims were found unsearchable (Continuation of item 2 of first sheet) This international search report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons: 1. Claims Nos.: 17-26,29,30 because they relate to subject matter not required to be searched by this Authority, namely: Claims 17-26 direct to a method for treating cancer in a subject or a method for treating a disease in a subject. Claim 29directs to the pharmaceutical combination of any one of claims 1-14 or the pharmaceutical composition of claim 15 or 16, for use in treating cancer. Claim 30 directs to the EED inhibitor described in any one of claims 1-14 for use in treating a disease. Claims 17-26, 29, 30 do not meet the criteria set out in PCT Rule 39.1(iv). The search report has been made and based on a therapeutically effective amount of the pharmaceutical combination of any one of claims 1-14 or the pharmaceutical composition of claim 15 or 16 for the manufacturing of a medicament for treating cancer or a therapeutically effective amount of the EED inhibitor described in any one of claims 1-14 for the manufacturing of a medicament for treating a disease. 2. [| Claims Nos.: because they relate to parts of the international application that do not comply with the prescribed requirements to such an extent that no meaningful international search can be carried out, specifically: 3. [| Claims Nos.: because they aredependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a). Form PCT / ISA / 210 (continuation of first sheet) July 2022) INTERNATIONAL SEARCH REPORT International application No. Information on patent family members P y PCT / CN2024 / 125773 Patent document Publication date Patent family member(s) Publication date cited in search report (day / month / year) y (day / month / year) WoO 2024215699 Al 17 October 2024 None WO 2021195183 Al 30 September 2021 None CN 115212311 A 21 October 2022 WoO 2022222932 = Al 27 October 2022 US 2024316051 Al 26 September 2024 CN 113813268 A 21 December 2021 None US 2020263185 Al 20 August 2020 WoO 2019108789 = Al 06 June 2019 US 2023167451 = Al 01 June 2023 US 11597933 _B2 07 March 2023 Form PCT / ISA / 210 (patent family annex) (July 2022) (19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480064139.4 (22) Application Date 2024.10.18 (66) Domestic Priority Data PCT / CN2023 / 125670 2023.10.20 CN (85) PCT international application enters national phase: April 3, 2026 (86) PCT international application data: PCT / CN2024 / 1257732024.10.18 (87) Publication data of PCT international application WO2025 / 082481 EN 2025.04.24 (71) Applicant Suzhou Ascentage Pharmaceutical Co., Ltd. Address 215000 No. 68 Xinqing Road, Suzhou Industrial Park, Suzhou City, Jiangsu Province Applicant Ascentage Pharmaceutical Group (Hong Kong) Limited (72) Inventors Yang Dajun, Zhai Yifan, Liang Zhiyan, Yin Yan (74) Patent Agency Beijing Zhongzi Law Firm 11247 Patent Attorneys Chen Runjie, Huang Gesheng (51) Int.Cl. A61K 45 / 06 (2006.01) (54) Invention title A drug combination and its use (57) Abstract This document provides a combination of an embryonic ectoderm development (EED) inhibitor and a histone deacetylase (HDAC) inhibitor, JAK A pharmaceutical combination comprising an inhibitor of embryonic ectoderm development (EED) and another inhibitor selected from the group consisting of an inhibitor of histone deacetylase (HDAC), a JAK inhibitor, and a BCL2 / BCL-XL inhibitor; wherein the EED inhibitor is a compound of formula I or a pharmaceutically acceptable salt or solvate thereof. An EED inhibitor combined with another inhibitor selected from the group consisting of histone deacetylase (HDAC) inhibitors, JAK inhibitors, and BCL2 / BCL-XL inhibitors produces a synergistic effect exceeding that of a single use of either the EED inhibitor or the other inhibitor. I, Formula I. Claims 8 pages. Description 43 pages. Drawings 4 pages. CN 121969392 A 2026.05.01 CN 1 21 96 93 92 A 1. A pharmaceutical combination comprising an inhibitor of embryonic ectoderm development (EED) and another inhibitor selected from the group consisting of histone deacetylase (HDAC) inhibitors, JAK inhibitors, and BCL2 / BCL-XL inhibitors. 2. The pharmaceutical combination according to claim 1, wherein the EED inhibitor is a compound of formula I: I, wherein: R1 is an aralkyl group; R2 is selected from the group consisting of hydrogen and C1-C4 alkyl groups; R3 and R4 together with the carbon atoms to which they are attached form a radical of formula I-A, I-B or I-C: I-A, I-B or I-C; X is selected from the group consisting of -C(R5a)(R5b)-, -C(=O)- and -S(=O)2-; R5a and R5b are independently selected from the group consisting of hydrogen and C1-C4 alkyl groups; Y is selected from the group consisting of -C(R6a)(R6b)-, -S-, -O- and -N(R7)-; Z is -C(R6c)(R6d)m-; R6a and R6b are independently selected from the group consisting of hydrogen and C1-C4 alkyl groups; each R6c and R6d is independently selected from the group consisting of hydrogen and C1-C4 alkyl groups; m is 0, 1 or 2; R7 is selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, optionally substituted C3-C8 cycloalkyl, and optionally...The substituted C4-C8 heterocyclic group, hydroxyalkyl, (alkoxy)alkyl, (cycloalkyl)alkyl, and (heterocyclic)alkyl; R8a, R8b, and R8c are independently selected from the group consisting of hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and alkylsulfonyl; is a fused phenyl, a fused 5-membered heteroaryl, or a fused 6-membered heteroaryl; is an optionally substituted fused 3-8-membered cycloalkyl or an optionally substituted fused 4-8-membered heterocyclic group; is an optionally substituted fused 4-8-membered heterocyclic group; the bond indicated by “ ” is attached to the R3 position of Formula I, and the bond indicated by “ ” is attached to the R4 position of Formula I; and is a single bond or a double bond, or a pharmaceutically acceptable salt or solvate thereof. 3. The pharmaceutical combination according to claim 2, wherein the EED inhibitor is a compound of formula II: (Claims 1 / 8 page 2 CN 121969392 A II), or a pharmaceutically acceptable salt or solvation thereof. 4. The pharmaceutical combination according to claim 2 or 3, wherein Z is -CH2-, or a pharmaceutically acceptable salt or solvation thereof. 5. The pharmaceutical combination according to any one of claims 2 to 4, wherein X is -C(=O)-, or a pharmaceutically acceptable salt or solvation thereof. 6. The pharmaceutical combination according to any one of claims 2 to 5, wherein Y is -N(R7)-, and preferably R7 is selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, and optionally substituted C3-C8 cycloalkyl, or a pharmaceutically acceptable salt or solvation thereof. 7. The pharmaceutical combination according to claim 2, wherein the EED inhibitor is selected from the group consisting of: 4-ethyl-12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-7-(trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a-pentazabenzo[4,5]cyclooctano[1,2,3-cd]indone; 12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-4-(2,2,2-trifluoroethyl)-7-(trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a-pentazabenzo[4,5]cyclooctano[1,2,3-cd]indone; 4-Cyclopropyl-12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-7-(trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a-pentazabenzo[4,5]cyclooctano[1,2,3-cd]indone; 12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-4-isopropyl-7-(trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a-pentazabenzo[4,5]cyclooctano[1,2,3-cd]indone; and11-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-6-methyl-4H-3-thia-2,5,10,11a-tetraazadibenzo[cd,f]azine-3,3-dioxide, or a pharmaceutically acceptable salt or solvation thereof. 8. The pharmaceutical combination according to claim 2, wherein the EED inhibitor is a compound having the structure of formula III or a pharmaceutically acceptable salt or solvation thereof, formula III. Claims 2 / 8, Page 3, CN 121969392, A 9. The pharmaceutical combination according to any one of claims 1 to 8, wherein the HDAC inhibitor is selected from the group consisting of: Tucidinostat (Chidamide), Vorinostat (SAHA), Belistat (PXD-101), Romidesin (FK-228), Pablistar (LBH589), Entecavir (MS-275), Trichostatin A (TSA), Mocetinostat (MGCD0103), and MC1568. 10. The pharmaceutical combination according to any one of claims 1 to 8, wherein the JAK inhibitor is a JAK1 inhibitor, a JAK2 inhibitor, a JAK3 inhibitor, and / or a TYK2 inhibitor. 11. The drug combination according to any one of claims 1 to 8, wherein the JAK inhibitor is selected from the group consisting of: golixitinib, tofacitinib, filgortinib, utpatinib, ruxolitinib, baricitinib, pappatinib, molotinib, filtatinib, and abuxitinib, preferably, the JAK inhibitor is golixitinib. 12. The drug combination according to any one of claims 1 to 8, wherein the BCL2 / BCL-XL inhibitor is selected from the group consisting of compound B, compound C, and venetoclax, preferably, the BCL2 / BCL-XL inhibitor is compound B or compound C; wherein compound B represents a compound having the structure of formula VIII or a pharmaceutically acceptable salt or solvation thereof; formula VIII; wherein compound C represents a compound having the structure of formula IX or a pharmaceutically acceptable salt or solvation thereof; formula IX. Claims 3 / 8, page 4, CN 121969392, A 13. The pharmaceutical combination according to any one of claims 1 to 12, wherein the weight ratio of the EED inhibitor to the other inhibitor ranges from 0.0001:1 to 1:0.0001, 0.01:1 to 1:0.01, or 0.1:1 to 1:0.1, preferably, the weight ratio of the EED inhibitor to the other inhibitor is 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10, more preferably 1:1.14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the molar ratio of the EED inhibitor to the other inhibitor ranges from 10:1 to 1:10, for example 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9 or 1:10, preferably 1:1. 15. A pharmaceutical composition comprising any one of the pharmaceutical compositions according to any one of the preceding claims and a pharmaceutically acceptable carrier. 16. The pharmaceutical composition according to claim 15, wherein the pharmaceutical composition is in the form of tablets, capsules, granules, syrups, powders, lozenges, small capsules, flat capsules, elixirs, suspensions, emulsions, solutions, aerosols, ointments, creams, or injections. 17. A method of treating a subject with cancer, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition according to any one of claims 1 to 14, or a pharmaceutical composition according to claim 15 or 16, optionally, the cancer being selected from the group consisting of: T-cell lymphoma, non-Hodgkin's lymphoma, mature T-cell and NK-cell lymphoma, T-cell tumor, mycosis fungoides, granulomatous skin laxity, Cezari syndrome, mature T-cell lymphoma, lymphoepithelioid lymphoma, follicular T-cell lymphoma, nodular peripheral T-cell lymphoma with a follicular helper T-cell phenotype, angioimmunoblastic T-cell lymphoma, and subcutaneous panniculitis-like T-cell lymphoma. Lymphoma, cutaneous T-cell lymphoma (not specifically identified), primary cutaneous CD8-positive aggressive epidermotropic T-cell lymphoma, primary cutaneous acral CD8-positive T-cell lymphoma, anaplastic large cell lymphoma T-cell and naked cell types, anaplastic large cell lymphoma (not specifically identified), anaplastic large cell lymphoma ALK-positive, hepatosplenic T-cell lymphoma, intestinal T-cell lymphoma, monomorphic epidermotropic intestinal T-cell lymphoma, primary mucosal CD30+ T-cell lymphoproliferative disorder, nasal and nasal NK / T-cell lymphoma, gastrointestinal indolent T-cell lymphoproliferative disorder, primary cutaneous CD4-positive small / medium T-cell lymphoproliferative disorder, primary cutaneous CD4-positive small / medium T-cell lymphoma, intravascular large B-cell lymphoma, intravascular large B-cell lymphoma, anaplastic large cell lymphoma ALK-positive, anaplastic large cell lymphoma ALK-negative, breast implant-associated anaplastic large cell lymphoma, primary cutaneous CD30+ T-cell lymphoproliferative disorder, mature T-cell or NK-cell tumors, T-cell prolymphocytic leukemia, T-cell large granular lymphocytic leukemia, NK-cell chronic lymphocytic disorder, aggressive NK-cell leukemia, pediatric systemic Epstein-Barr virus (EBV) positivity.T-cell lymphoma, adult T-cell lymphoma / leukemia associated with human T-cell lymphovirus type 1, extranodal nasal NK / T-cell lymphoma, enteropathy-associated T-cell lymphoma, hepatocellular T-cell lymphoma, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, and subcutaneous panniculitis-like T-cell lymphoma. 18. A method of treating a subject for a disease, the method comprising administering to the subject a therapeutically effective amount of an EED inhibitor according to any one of claims 1 to 14, wherein the disease is selected from the group consisting of: T-cell lymphoma, non-Hodgkin's lymphoma, mature T-cell and NK-cell lymphoma, T-cell tumor, mycosis fungoides, granulomatous skin laxity, Cezari syndrome, mature T-cell lymphoma, lymphoepithelioid lymphoma, follicular T-cell lymphoma, nodular peripheral T-cell lymphoma with a follicular helper T-cell phenotype, angioimmunoblastic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, cutaneous T-cell lymphoma (not specifically mentioned), primary cutaneous CD8-positive aggressive epidermotoxic T-cell lymphoma, primary cutaneous acral CD8-positive T-cell lymphoma. Cellular lymphoma, anaplastic large cell lymphoma T-cell and naked cell type, anaplastic large cell lymphoma (not specifically mentioned), anaplastic large cell lymphoma ALK positive, hepatosplenic T-cell lymphoma, intestinal T-cell lymphoma, monomorphic epidermophilic intestinal T-cell lymphoma, primary mucosal CD30+ T-cell lymphoproliferative disorder, nasal and nasal type NK / T-cell lymphoma, gastrointestinal indolent T-cell lymphoproliferative disorder, primary cutaneous CD4 positive small / medium T-cell lymphoproliferative disorder, primary cutaneous CD4 positive small / medium T-cell lymphoma, intravascular large B-cell lymphoma, intravascular large B-cell lymphoma, anaplastic large cell lymphoma ALK positive, anaplastic large cell lymphoma ALK negative, breast implant-associated anaplastic large cell lymphoma, primary cutaneous CD30+ T-cell lymphoproliferative disorders, mature T-cell or NK-cell tumors, T-cell prolymphocytic leukemia, T-cell large granular lymphocytic leukemia, NK-cell chronic lymphocytic dysplasia, aggressive NK-cell leukemia, childhood systemic Epstein-Barr virus-positive T-cell lymphoma, adult T-cell lymphoma / leukemia associated with human T-cell lymphovirus type 1, extranodal nasal NK / T-cell lymphoma, enteropathy-associated T-cell lymphoma, hepatosplenic T-cell lymphoma, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, and subcutaneous panniculitis-like T-cell lymphoma. 19. The method according to claim 17 or 18, wherein the EED inhibitor is administered at a dose of about 0.0005 mg / day to about 5000 mg / day, for example, about 0.005 mg / day, 0.05 mg / day, 0.5 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 30 mg / day,Administer at doses of 40 mg / day, 50 mg / day, 100 mg / day, 150 mg / day, 200 mg / day, 250 mg / day, 300 mg / day, 350 mg / day, 400 mg / day, 450 mg / day, 500 mg / day, 550 mg / day, 600 mg / day, 650 mg / day, 700 mg / day, 750 mg / day, 800 mg / day, 850 mg / day, 900 mg / day, 950 mg / day, 1000 mg / day, 1500 mg / day, 2000 mg / day, 2500 mg / day, 3000 mg / day, 3500 mg / day, 4000 mg / day, 4500 mg / day, or 5000 mg / day. 20. The method according to any one of claims 17 to 19, wherein the EED inhibitor is administered at a dose of about 1 ng / kg to about 200 mg / kg, about 1 μg / kg to about 100 mg / kg, or about 1 mg / kg to about 50 mg / kg, for example, at doses of about 1 μg / kg, about 10 μg / kg, about 25 μg / kg, about 50 μg / kg, about 75 μg / kg, about 100 μg / kg, about 125 μg / kg, about 150 μg / kg, about 175 μg / kg, about 200 μg / kg, about 225 μg / kg, about 250 μg / kg, about 275 μg / kg, about 300 μg / kg, etc. g / kg, approximately 325 μg / kg, approximately 350 μg / kg, approximately 375 μg / kg, approximately 400 μg / kg, approximately 425 μg / kg, approximately 450 μg / kg, approximately 475 μg / kg, approximately 500 μg / kg, approximately 525 μg / kg, approximately 550 μg / kg, approximately 575 μg / kg, approximately 600 μg / kg, approximately 625 μg / kg, approximately 650 μg / kg, approximately 675 μg / kg, approximately 700 μg / kg, approximately 725 μg / kg, approximately 750 μg / kg, approximately 775 μg / kg, approximately 800 μg / kg, approximately 825 μg / kg Administer at doses of approximately g / kg, about 850 μg / kg, about 875 μg / kg, about 900 μg / kg, about 925 μg / kg, about 950 μg / kg, about 975 μg / kg, about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 125 mg / kg, about 150 mg / kg, about 175 mg / kg, or about 200 mg / kg, and daily in one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) unit doses.21. The method according to any one of claims 17 and 19 to 20, wherein the HDAC inhibitor is administered at a dose of about 0.0005 mg / day to about 5000 mg / day, for example, about 0.005 mg / day, 0.05 mg / day, 0.5 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 30 mg / day, 40 mg / day, 50 mg / day, 100 mg / day, 150 mg / day, 200 mg / day, 250 mg / day, 300 mg / day, 350 mg / day, 400 mg / day, 450 mg / day, 500 mg / day, 550 mg / day, 600 mg / day, 650 mg / day, 700 mg / day. Administer at doses of 750 mg / day, 800 mg / day, 850 mg / day, 900 mg / day, 950 mg / day, 1000 mg / day, 1500 mg / day, 2000 mg / day, 2500 mg / day, 3000 mg / day, 3500 mg / day, 4000 mg / day, 4500 mg / day, or 5000 mg / day. 22. The method according to any one of claims 17 and 19 to 21, wherein the HDAC inhibitor is administered at a dose of about 1 ng / kg to about 200 mg / kg, about 1 μg / kg to about 100 mg / kg, or about 1 mg / kg to about 50 mg / kg, for example, at doses of about 1 μg / kg, about 10 μg / kg, about 25 μg / kg, about 50 μg / kg, about 75 μg / kg, about 100 μg / kg, about 125 μg / kg, about 150 μg / kg, about 175 μg / kg, etc. kg, about 200 μg / kg, about 225 μg / kg, about 250 μg / kg, about 275 μg / kg, about 300 μg / kg, about 325 μg / kg, about 350 μg / kg, about 375 μg / kg, about 400 μg / kg, about 425 μg / kg, about 450 μg / kg, about 475 μg / kg, about 500 μg / kg, about 525 μg / kg, about 550 μg / kg, about 575 μg / kg, about 600 μg / kg, about 625 μg / kg, about claims 5 / 8 Page 6 CN 121969392 A 650μg / kg, about 675μg / kg, about 700μg / kg, about 725μg / kg, about 750μg / kg, about 775μg / kg, about 800μg / kg, about 825μg / kg, about 850μg / kg, about 875μg / kg, about 900μg / kg, about 925μg / kg, about 950μg / kg, about 975μg / kg, about 1mg / kg, about 5mg / kg, about 10mg / kg, about 15mg / kg, about 20mg / kg, about 25mg / kg, about 30mg / kg, about 35mg / kgAdministered at doses of approximately 40 mg / kg, approximately 45 mg / kg, approximately 50 mg / kg, approximately 60 mg / kg, approximately 70 mg / kg, approximately 80 mg / kg, approximately 90 mg / kg, approximately 100 mg / kg, approximately 125 mg / kg, approximately 150 mg / kg, approximately 175 mg / kg, or approximately 200 mg / kg, and daily in one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) unit doses. 23. The method according to any one of claims 17 and 19 to 22, wherein the EED inhibitor and the HDAC inhibitor are administered together, simultaneously, sequentially, or alternately. 24. The method according to any one of claims 17 to 23, wherein the EED inhibitor and / or the HDAC inhibitor are continuously administered for at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 28 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days, or at least 50 days. 25. The method according to any one of claims 17 to 24, wherein the administration of the EED inhibitor and / or the HDAC inhibitor is sustained for one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) treatment cycles, wherein each treatment cycle lasts for at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days, or at least 50 days; and between every two treatment cycles there are 0 days, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, Intervals of 1 day, 7 days, 8 days, 9 days, 10 days, two weeks, three weeks, or four weeks. 26. The method according to any one of claims 17 and 19 to 25, wherein the EED inhibitor and the HDAC inhibitor are administered via the same (e.g., oral) or different routes (e.g., oral and parenteral (e.g., injection), respectively). 27. Use of a pharmaceutical combination according to any one of claims 1 to 11, or a pharmaceutical composition according to claim 15 or 16, in the preparation of a medicament for treating cancer, optionally, wherein the cancer is selected from the group consisting of: T-cell lymphoma, non-Hodgkin lymphoma, mature T-cell lymphoma, and...NK cell lymphoma, T-cell tumors, mycosis fungoides, granulomatous skin laxity, Cézari syndrome, mature T-cell lymphoma, lymphoepithelioid lymphoma, follicular T-cell lymphoma, nodular peripheral T-cell lymphoma with follicular helper T-cell phenotype, angioimmunoblastic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, cutaneous T-cell lymphoma (not specifically identified), primary cutaneous CD8-positive aggressive epidermotoxic T-cell lymphoma, primary cutaneous acral CD8-positive T-cell lymphoma, anaplastic large cell lymphoma T-cell and naked cell types, anaplastic large cell lymphoma (not specifically identified), anaplastic large cell lymphoma ALK-positive, hepatosplenic T-cell lymphoma, intestinal T-cell lymphoma, monomorphic epidermotoxic intestinal T-cell lymphoma, primary mucosal CD30+ T-cell lymphoproliferative disorders, nasal and nasal NK / T-cell lymphoma, gastrointestinal indolent T-cell lymphoproliferative disorders, primary cutaneous CD4-positive small / medium T-cell lymphoproliferative disorders, primary cutaneous CD4-positive small / medium T-cell lymphoma, intravascular large B-cell lymphoma, intravascular large B-cell lymphoma, anaplastic large cell lymphoma ALK-positive, anaplastic large cell lymphoma ALK-negative, breast implant-associated anaplastic large cell lymphoma, primary cutaneous CD30+ T-cell lymphoproliferative disorders, mature T-cell or NK-cell tumors, T-cell prolymphocytic leukemia, T-cell large granular lymphocytic leukemia, NK-cell chronic lymphocytic disorders, aggressive NK-cell leukemia, childhood systemic Epstein-Barr virus-positive T-cell lymphoma, adult T-cell lymphoma / leukemia associated with human T-cell lymphovirus type 1, extranodal nasal NK / T-cell lymphoma. T-cell lymphoma, enteropathy-associated T-cell lymphoma, hepatosplenic T-cell lymphoma, angioimmunoblastic T-cell lymphoma, peritoneal T-cell lymphoma, and subcutaneous panniculitis-like T-cell lymphoma (Claim 6 / 8, page 7, CN 121969392 A). 28. Use of the EED inhibitor according to any one of claims 1 to 14 in the preparation of a medicament for treating a disease; wherein the disease is selected from the group consisting of: T-cell lymphoma, non-Hodgkin's lymphoma, mature T-cell and NK-cell lymphoma, T-cell tumors, mycosis fungoides, granulomatous skin laxity, Cezari syndrome, mature T-cell lymphoma, lymphoepithelioid lymphoma, follicular T-cell lymphoma, nodular peripheral T-cell lymphoma with follicular helper T-cell phenotype, angioimmunoblastic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, cutaneous T-cell lymphoma (not specifically mentioned), primary cutaneous CD8-positive aggressive epidermotoxic T-cell lymphoma, primary cutaneous acral CD8-positive T-cell lymphoma, anaplastic large cell lymphoma T-cell and naked cell types, anaplastic large cell lymphoma (not specifically mentioned), anaplasticLarge cell lymphoma (ALK positive), hepatosplenic T-cell lymphoma, intestinal T-cell lymphoma, monomorphic epidermophilic intestinal T-cell lymphoma, primary mucosal CD30+ T-cell lymphoproliferative disorder, nasal and nasal NK / T-cell lymphoma, gastrointestinal indolent T-cell lymphoproliferative disorder, primary cutaneous CD4-positive small / medium T-cell lymphoproliferative disorder, primary cutaneous CD4-positive small / medium T-cell lymphoma, intravascular large B-cell lymphoma, intravascular large B-cell lymphoma, anaplastic large cell lymphoma (ALK positive), anaplastic large cell lymphoma (ALK negative), breast implant-associated anaplastic large cell lymphoma, primary cutaneous CD30+ T-cell lymphoproliferative disorders, mature T-cell or NK-cell tumors, T-cell prolymphocytic leukemia, T-cell large granular lymphocytic leukemia, NK-cell chronic lymphocytic disorders, aggressive NK-cell leukemia, childhood systemic Epstein-Barr virus-positive T-cell lymphoma, adult T-cell lymphoma / leukemia associated with human T-cell lymphovirus type 1, extranodal nasal NK / T-cell lymphoma, enteropathy-associated T-cell lymphoma, hepatosplenic T-cell lymphoma, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, and subcutaneous panniculitis-like T-cell lymphoma. 29. A pharmaceutical combination according to any one of claims 1 to 14 or a pharmaceutical composition according to claim 15 or 16, wherein the pharmaceutical combination or the pharmaceutical composition is used to treat cancer; optionally, wherein the cancer is selected from the group consisting of: T-cell lymphoma, non-Hodgkin lymphoma, mature T-cell and NK-cell lymphoma, T-cell tumor, mycosis fungoides, granulomatous cutanea laxa, Cezari syndrome, mature T-cell lymphoma, lymphoepithelioid lymphoma, follicular T-cell lymphoma, nodular peripheral T-cell lymphoma with follicular helper T-cell phenotype, angioimmunoblastic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, cutaneous T-cell lymphoma (not specifically mentioned), primary cutaneous CD8-positive aggressive epidermotoxic T-cell lymphoma, primary cutaneous acral CD8-positive T-cell lymphoma, anaplastic large cell lymphoma T-cell and naked cell types, anaplastic large cell lymphoma (not specifically mentioned). Anaplastic large cell lymphoma (ALK positive), hepatosplenic T-cell lymphoma, intestinal T-cell lymphoma, monomorphic epidermophilic intestinal T-cell lymphoma, primary mucosal CD30+ T-cell lymphoproliferative disorder, nasal and nasal NK / T-cell lymphoma, gastrointestinal indolent T-cell lymphoproliferative disorder, primary cutaneous CD4-positive small / medium T-cell lymphoproliferative disorder, primary cutaneous CD4-positive small / medium T-cell lymphoma, intravascular large B-cell lymphoma, intravascular large B-cell lymphoma, anaplastic large cell lymphoma (ALK positive), anaplastic large cell lymphoma (ALK negative), breast implant-associated anaplastic large cell lymphoma, primary cutaneous CD30+T-cell lymphoproliferative disorders, mature T-cell or NK-cell tumors, T-cell prolymphocytic leukemia, T-cell large granular lymphocytic leukemia, NK-cell chronic lymphocytic disorders, aggressive NK-cell leukemia, childhood systemic Epstein-Barr virus-positive T-cell lymphoma, adult T-cell lymphoma / leukemia associated with human T-cell lymphovirus type 1, extranodal nasal NK / T-cell lymphoma, enteropathy-associated T-cell lymphoma, hepatosplenic T-cell lymphoma, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, and subcutaneous panniculitis-like T-cell lymphoma. 30. The EED inhibitor according to any one of claims 1 to 14, wherein the EED inhibitor is used to treat a disease, wherein the disease is selected from the group consisting of: T-cell lymphoma, non-Hodgkin's lymphoma, mature T-cell and NK-cell lymphoma, T-cell tumor, mycosis fungoides, granulomatous skin laxity, Cezari syndrome, mature T-cell lymphoma, lymphoepithelioid lymphoma, follicular T-cell lymphoma, nodular peripheral T-cell lymphoma with follicular helper T-cell phenotype, angioimmunoblastic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, cutaneous T-cell lymphoma (not specifically mentioned), primary cutaneous CD8-positive aggressive epidermotoxic T-cell lymphoma, primary cutaneous acral CD8-positive T-cell lymphoma. Large cell lymphoma, anaplastic large cell lymphoma (T-cell and naked cell types), anaplastic large cell lymphoma (unspecified), anaplastic large cell lymphoma (ALK positive), hepatocellular T-cell lymphoma, intestinal T-cell lymphoma, monomorphic epidermophilic intestinal T-cell lymphoma, primary mucosal CD30+ T-cell lymphoproliferative disorder, nasal and nasal NK / T-cell lymphoma, gastrointestinal indolent T-cell lymphoproliferative disorder, primary cutaneous CD4-positive small / medium T-cell lymphoproliferative disorder, primary cutaneous CD4-positive small / medium T-cell lymphoma, intravascular large B-cell lymphoma, intravascular large B-cell lymphoma, anaplastic large cell lymphoma (ALK positive), anaplastic large cell lymphoma (ALK negative), breast implant-associated anaplastic large cell lymphoma, primary cutaneous CD30+ T-cell lymphoproliferative disorders, mature T-cell or NK-cell tumors, T-cell prolymphocytic leukemia, T-cell large granular lymphocytic leukemia, NK-cell chronic lymphocytic dysplasia, aggressive NK-cell leukemia, childhood systemic Epstein-Barr virus-positive T-cell lymphoma, adult T-cell lymphoma / leukemia associated with human T-cell lymphovirus type 1, extranodal nasal NK / T-cell lymphoma, enteropathy-associated T-cell lymphoma, hepatocellular and splenic T-cell lymphoma, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, and subcutaneous panniculitis-like T-cell lymphoma. 31. A kit comprising: (a)(a) A first component in a first container, the first component comprising an EED inhibitor according to any one of claims 1 to 14 and optionally a pharmaceutically acceptable carrier; (b) A second component in a second container, the second component comprising an inhibitor selected from the group consisting of HDAC inhibitors (preferably HDAC inhibitors as defined in claim 9), JAK inhibitors (preferably JAK inhibitors as defined in claim 11) and BCL2 / BCL-XL inhibitors (preferably BCL2 / BCL-XL inhibitors as defined in claim 12) and optionally a pharmaceutically acceptable carrier; and (c) Optional specification. Claims 8 / 8 pages 9 CN 121969392 A Pharmaceutical Combination and Its Use Technical Field

[0001] This invention relates to the pharmaceutical field, and more specifically to a pharmaceutical combination and its use. Background Art

[0002] Proliferative diseases are a serious threat to modern society. Cancerous growth poses a severe challenge to modern medicine due to its unique characteristics, including uncontrollable cell proliferation, the ability to invade local and even distant tissues, lack of differentiation, lack of detectable symptoms, and lack of effective treatment and prevention. More than 10 million people are diagnosed with cancer worldwide each year, and cancer causes 6 million deaths annually, or 12% of all deaths worldwide.

[0003] Embryonic ectodermal development (EED) inhibitors have proven to be effective anticancer drugs; however, further efforts are needed to strengthen the use of EED inhibitors and improve cancer treatment outcomes.

[0004] T-cell lymphoma (TCL) is a highly heterogeneous group of aggressive non-Hodgkin lymphomas (NHL) with poor prognosis and limited treatment options. TCL accounts for approximately 10% to 15% of all NHL. The major subgroups are peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL).

[0005] On the other hand, T-cell malignancies are prevalent in East Asia, the Caribbean, tropical Africa, the Middle East, South America, and Papua New Guinea. However, due to the complex pathogenesis and limited treatment options, patients with T-cell lymphoma generally have a poor prognosis and are prone to relapse. Currently, chemotherapy is the preferred treatment for patients with T-cell lymphoma. With the development of chemotherapy, the prognosis of T-cell leukemia / lymphoma has gradually improved. However, due to the non-specific toxicity of current chemotherapy compounds to normal cells, the continued decline in patients' quality of life has become a concern.

[0006] The treatment of T-cell lymphoma patients is challenging. There is an urgent need for new treatment strategies to improve the treatment effect of T-cell lymphoma. Summary of the Invention

[0007] The inventors have discovered that, compared with single EED inhibitors or HDAC inhibitors, a combination of EED inhibitors and selected components...A combination of drugs consisting of another inhibitor selected from the group consisting of histone deacetylase (HDAC) inhibitors, JAK inhibitors, and BCL2 / BCL-XL inhibitors produces a synergistic anticancer effect.

[0008] The inventors have found that EED inhibitors are particularly useful for the treatment of T-cell lymphoma and are more effective and potent for the treatment of T-cell lymphoma than other therapeutic agents such as valmettostat, MAK683, and tazestat.

[0009] In one aspect, the present invention provides a combination of drugs comprising an embryonic ectoderm development (EED) inhibitor and another inhibitor selected from the group consisting of histone deacetylase (HDAC) inhibitors, JAK inhibitors, and BCL2 / BCL-XL inhibitors.

[0010] In one aspect, the present invention provides a pharmaceutical composition comprising the pharmaceutical combination disclosed herein and a pharmaceutically acceptable carrier.

[0011] In one aspect, the present invention provides a method of treating a subject with cancer, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical combination or pharmaceutical composition disclosed herein.

[0012] In one aspect, the present invention provides a method for treating a disease in a subject, the method comprising administering to the subject a therapeutically effective amount of an EED inhibitor. Specification 1 / 43 pages 10 CN 121969392 A

[0013] In one aspect, the present invention provides the use of the pharmaceutical combinations or pharmaceutical compositions disclosed herein in the preparation of a medicament for treating cancer.

[0014] In one aspect, the present invention provides the use of an EED inhibitor in the preparation of a medicament for treating a disease.

[0015] In one aspect, the present invention provides the pharmaceutical combinations or pharmaceutical compositions disclosed herein for treating cancer.

[0016] In one aspect, the present invention provides an EED inhibitor for treating a disease.

[0017] In one aspect, the present invention provides a kit comprising: (a) a first component in a first container, the first component comprising an EED inhibitor and optionally a pharmaceutically acceptable carrier; (b) a second component in a second container, the second component comprising an inhibitor selected from the group consisting of HDAC inhibitors (preferably HDAC inhibitors disclosed herein), JAK inhibitors (preferably JAK inhibitors disclosed herein), and BCL2 / BCL-XL inhibitors (preferably BCL2 / BCL-XL inhibitors disclosed herein) and optionally a pharmaceutically acceptable carrier; and (c) optional instructions. Brief Description of the Drawings

[0018] Figure 1. Synergistic effect of compound A combined with the HDAC inhibitor Tucidinostat on cell proliferation in Hut102 and HH cell lines. Hut102 cells were treated with compound A for 4 days, followed by combination treatment for 3 days (A). HH cells were treated with compound A...Cells were treated with compound A for 6 days, followed by combination therapy for 2 days (B). Serial dilutions were set for each drug. Cell proliferation was measured using a Cell Titer-Glo luminescence assay. Percentage of cell viability is shown as mean ± SEM (n=2 or 3).

[0019] Figure 2. Synergistic effect of compound A in combination with the JAK1 inhibitor golixitinib on cell proliferation in the HuT102 cell line. HuT102 cells were treated with specified concentrations of compound A for 6 days, with golixitinib for 3 days, or with a combination thereof. Cell viability was assessed using a CellTiter-Glo® assay. Representative results from 3 independent experiments are shown. Results are expressed as mean ± SD. n=2 replicates.

[0020] Figure 3. Synergistic effect of compound A in combination with the JAK1 inhibitor golixitinib on cell proliferation in the NK / TCL cell line. SNK-1 (A) and SNK-6 (B) cells were treated with gradient concentrations of compound A for 10 days and with golixitinib for 2 days. Cell viability was assessed using the CellTiter-Glo® assay. Cell viability data are presented as mean ± SEM, n = 2 or 3 replicates.

[0021] Figure 4. Synergistic effect of combination of compound A and compound B on cell proliferation in SNK-1 (A) and SNK-6 (B) cell lines. SNK-1 and SNK-6 cells were treated with gradient concentrations of compound A for 10 days, compound B for 2 days, or a combination thereof. Cell viability was assessed using the CellTiter-Glo® assay. Results are presented as mean ± SD. n = 2 or 3 replicates. Detailed Description

[0022] Definitions

[0023] Unless otherwise defined below, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. References to the art as used herein are intended to refer to the art as commonly understood in the art, including those obvious modifications or equivalent substitutions of the art by one of ordinary skill in the art. While it is believed that the following terms are fully understood by one of ordinary skill in the art, the following definitions are set forth to better explain the invention.

[0024] As used herein, the terms “comprising,” “including,” “having,” “containing,” or “comprising,” and other variations thereof, are inclusive or open-ended and do not exclude other elements or method steps not listed.

[0025] In the context of describing the invention (especially in the context of the claims), the use of the terms “a,” “an,” “the,” and similar designations should be understood to cover both singular and plural forms unless otherwise stated. Unless otherwise stated herein, the enumeration of numerical ranges herein is intended only as a shorthand for each individual value falling within that range.The method, and each individual value is incorporated into the specification as if it were separately described herein. Unless otherwise required, the use of any and all examples or exemplary language (e.g., “such as”, “e.g.”) provided herein is intended to better illustrate the disclosure and not to limit the scope of the disclosure. The language in the specification should not be construed as indicating that any unclaimed element is necessary for the practice of the disclosure.

[0026] As used herein, the terms “implementation,” “disclosure,” or “disclosure” are not intended to be limiting but are generally applicable to any embodiment defined in the claims or described herein. These terms are used interchangeably herein.

[0027] As used herein, the term “treatment” means the elimination, relief, or improvement of a disease or condition and / or symptoms associated with such disease or / or condition. While this is not excluded, treatment of a disease or condition does not require the complete elimination of the disease, condition, or symptoms associated with such disease or condition. The term “treatment” and its synonyms cover the administration of a therapeutically effective amount of the compound of the disclosure to a subject who requires such treatment. Treatment may be directed at symptoms, for example, to suppress symptoms. Treatment may be effective in the short term, for the medium term, or may be long-term, such as in the context of maintenance therapy.

[0028] As used herein, the term “prevention” refers to a method of preventing the onset of a disease or condition and / or its accompanying symptoms or preventing a subject from becoming ill. As used herein, “prevention” also includes delaying the onset of a disease and / or its accompanying symptoms and reducing the risk of a subject becoming ill. The term “prevention” may include “preventive treatment,” which refers to reducing the risk of a subject who does not have, but has a risk of recurrence of, a disease or condition, or a relapse of such disease or condition, or who is prone to recurrence of such disease or condition, or who is previously controlled to relapse.

[0029] As used herein, the term “synergistic effect” refers to the effect of two therapeutic agents, such as slowing the progression of symptoms of a proliferative disease (particularly cancer) or its symptoms, which is greater than the simple sum of the effects of each drug administered alone. Synergistic effects can be calculated, for example, using various methods and equations known in the art (such as those listed in the embodiments of the present invention).

[0030] As used herein, the term "pharmaceutically acceptable salt" includes both acid addition salts and base addition salts of compounds.

[0031] In the context of this invention, "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient, or solvent administered with a therapeutic agent, and is suitable for contact with human and / or other animal tissues to a reasonable extent of medical judgment, and does not produce excessive toxicity, irritation, allergic reactions, or other problems or complications corresponding to a reasonable benefit / risk ratio.

[0032] Pharmaceutically acceptable carriers that can be used in pharmaceutical compositions or kits of the present invention include, but are not limited to, those without...Liquids, such as water and oils, include those derived from petroleum, animal, vegetable, or synthetic sources (e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.). Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Physiological saline and aqueous solutions of glucose and glycerol can also be used as liquid carriers, particularly for injection. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol, etc. The pharmaceutical composition may also contain small amounts of wetting agents, emulsifiers, or pH buffers as needed. Oral formulations may contain standard carriers such as pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

[0033] As used herein, “EED” refers to embryonic ectoderm development protein, which is overexpressed in many cancers, including but not limited to breast cancer, prostate cancer, and hepatocellular carcinoma. See Moritz and Trievel, J. Biol. Chem., 293 (36):13805–13814 (2018). Specification 3 / 43 pages 12 CN 121969392 A

[0034] As used herein, “HDAC” refers to histone deacetylase, which is a class of enzymes that remove acetyl groups from amino acids on histones. HDAC is a family of at least eighteen enzymes, divided into three classes (class I, class II, and class III). Class I HDACs include, but are not limited to, HDAC 1, 2, 3, and 8. Class I HDACs can be found in the cell nucleus and are considered to be associated with transcriptional repressors. Class II HDACs include, but are not limited to, HDAC 4, 5, 6, 7, and 9, and can be found in the cytoplasm and cell nucleus. Class III HDACs are considered NAD-dependent proteins and include, but are not limited to, members of the Sirtuin family of proteins. Non-limiting examples of sirtuin proteins include SIRT1-7. HDACs regulate the expression of many proteins associated with cancer initiation and progression.

[0035] As used herein, “JAK” refers to Janus kinases, a family of intracellular non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. The JAK family includes at least four members: JAK1, JAK2, JAK3, and TYK2 (tyrosine kinase 2).

[0036] As used herein, “BCL2” is a member of the Bcl-2 regulatory protein family. BCL2 blocks programmed cell death (apoptosis).

[0037] As used herein, “BCL-XL” is a transmembrane protein in mitochondria. It is a member of the Bcl-2 protein family and acts as an anti-apoptotic protein by preventing the release of mitochondrial contents such as cytochrome c.

[0038] As used herein, the term “HDAC inhibitor” refers to an agent or compound that inhibits the histone deacetylase activity of one or more HDACs.

[0039] As used herein, the term “JAK inhibitor” refers to an agent or compound that inhibits the activity of one or more JAKs.

[0040] As used herein, the term “BCL2 / BCL-XL inhibitor” refers to an agent or compound that inhibits the activity of BCL2 and / or BCL-XL.

[0041] As used herein, the term “container” refers to a container for containing pharmaceutical components. The container may be used for the preparation, storage, transport, and / or individual / bulk sale, and is intended to include bottles, jars, vials, flasks, syringes, tubes (e.g., tubes for use in cream products) or any other container for the preparation, containment, storage, or dispensing of pharmaceutical products.

[0042] As used herein, the term “instructions for use” refers to inserts, labels, stickers, etc., used to record information about the pharmaceutical components within the container. The recorded information is typically determined by the regulatory authority governing the product’s sales territory (e.g., the U.S. Food and Drug Administration). Preferably, the indications for which the pharmaceutical component is approved for use are clearly listed in the package insert. The package insert can be made of any material, provided that the information contained in or shown is legible. Preferably, the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive paper, or plastic, etc.) on which the desired information can be formed (e.g., printed or applied).

[0043] As used herein, the term “effective amount” refers to the amount of active ingredient that, upon administration, will alleviate one or more symptoms of the treated condition to a certain extent.

[0044] As used herein, “subject” includes humans or non-human animals. Exemplary human subjects include human subjects with a disease (such as the disease described herein) (referred to as patients) or normal subjects. The term "non-human animal" in this invention includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0045] As used herein, the term "halogen" when used alone or as part of another group refers to -Cl, -F, -Br, or -I.

[0046] As used herein, the term "nitro" when used alone or as part of another group refers to -NO2.

[0047] As used herein, the term "cyano" when used alone or as part of another group refers to -CN.

[0048] As used herein, the term "hydroxyl" when used alone or as part of another group refers to -OH. Specification 4 / 43 pages 13 CN121969392 A

[0049] As used herein, the term "alkyl" when used alone or as part of another group refers to an unsubstituted straight-chain or branched aliphatic hydrocarbon containing 1 to 12 carbon atoms (i.e., C1-12 alkyl) or a specified number of carbon atoms, such as C1 alkyl (e.g., methyl), C2 alkyl (e.g., ethyl), C3 alkyl (e.g., n-propyl or isopropyl), C1-3 alkyl (e.g., methyl, ethyl, n-propyl or isopropyl), etc. In one embodiment, the alkyl group is a C1-4 alkyl group. Non-limiting examples of C1-12 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl. Examples of C1-4 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, and isobutyl.

[0050] As used herein, the term "alkenyl" when used alone or as part of another group refers to an alkyl group containing one, two, or three carbon-carbon double bonds. In one embodiment, the alkenyl group is a C2-C6 alkenyl group. In another embodiment, the alkenyl group is a C2-C4 alkenyl group. In yet another embodiment, the alkenyl group has one carbon-carbon double bond. Non-limiting exemplary alkenyl groups include vinyl, propynyl, isopropynyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

[0051] As used herein, the term "alkynyl" when used alone or as part of another group refers to an alkyl group containing one, two, or three carbon-carbon triple bonds. In one embodiment, the alkynyl group is a C2-C6 alkynyl group. In another embodiment, the alkynyl group is a C2-C4 alkynyl group. In yet another embodiment, the alkynyl group has one carbon-carbon triple bond. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl.

[0052] As used herein, the term "haloalkyl" when used alone or as part of another group refers to an alkyl group substituted with one or more fluorine, chlorine, bromine, and / or iodine atoms. In one embodiment, the alkyl group is substituted with one, two, or three fluorine and / or chlorine atoms. In another embodiment, the alkyl group is substituted with one, two, or three fluorine atoms. In another embodiment, the alkyl group is a C1-C6 alkyl group. In another embodiment, the alkyl group is a C1-C4 alkyl group. In another embodiment, the alkyl group is a C1 or C2 alkyl group. Non-limiting exemplary haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and trichloromethyl.

[0053] As used herein, the term "alkoxy" when used alone or as part of another group refers to an alkyl group attached to a terminal oxygen atom. In one embodiment, the alkyl group is a C1-C6 alkyl group, and therefore the resulting alkoxy group is referred to as a "C1-C6 alkoxy group".In another embodiment, the alkyl group is a C1-C4 alkyl group. Non-limiting exemplary alkoxy groups include methoxy, ethoxy, and tert-butoxy groups.

[0054] As used herein, the term "cycloalkyl" when used alone or as part of another group refers to a saturated or partially unsaturated cyclic aliphatic hydrocarbon (containing one or two double bonds) comprising one or two rings having 3 to 12 carbon atoms or a specified number of carbon atoms (i.e., C3-12 cycloalkyl). In one embodiment, the cycloalkyl group has two rings. In one embodiment, the cycloalkyl group has one ring. In another embodiment, the cycloalkyl group is selected from the group consisting of C3-8 cycloalkyl groups. In another embodiment, the cycloalkyl group is selected from the group consisting of C3-6 cycloalkyl groups. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decahydronaphthalene, adamantyl, cyclohexenyl, and cyclopentenyl.

[0055] As used herein, the term “heterocyclic” or “heterocyclic group”, used alone or as part of another group, refers to a saturated or partially unsaturated (e.g., containing one or two double bonds) cyclic group comprising one, two, or three rings having three to fourteen ring members (i.e., a 3- to 14-membered heterocyclic group), wherein at least one carbon atom of one ring is replaced by a heteroatom. Each heteroatom is independently selected from the group consisting of oxygen atoms, sulfur atoms (including sulfoxides and sulfones), and / or nitrogen atoms (which may be oxidized or quaternized). The term “heterocyclic group” is intended to include groups in which -CH2- in the ring is replaced by -C(=O)-, for example, cyclic urea groups (such as 2-imidazolidineones) and cyclic amide groups (such as β-lactams, γ-lactams, δ-lactams, ε-lactams) and piperazine-2-ones. In one embodiment, the heterocyclic group is a 3-8 membered ring group comprising one ring and one or two oxygen and / or nitrogen atoms. In another embodiment, the heterocyclic group is a 4, 5, or 6 membered ring group comprising one ring and one or two oxygen and / or nitrogen atoms. The heterocyclic group may be linked to the remainder of the molecule via any available carbon or nitrogen atom. Non-limiting examples of heterocyclic groups include dioxyl, tetrahydropyranyl, 2-oxopyrrolidone-3-yl, piperazine-2-one, piperazine-2,6-dione, 2-imidazolyl ketone, piperidinyl, morpholinyl, piperazine, pyrrolylyl, and dihydroindole.

[0056] As used herein, the term "aryl" when used alone or as part of another group refers to an aromatic ring system having six to fourteen carbon atoms, i.e., C6-C14 aryl. Non-limiting exemplary aryl groups include phenyl (abbreviated as "Ph"), naphthyl, phenanthryl, anthraceneyl, indene, azulel, biphenyl, biphenylene, and fluorenyl. In one embodiment, the aryl group is phenyl or naphthyl.In another embodiment, the aryl group is phenyl.

[0057] As used herein, the term "heteroaryl" when used alone or as part of another group refers to a monocyclic and bicyclic aromatic ring system having five to fourteen ring atoms, i.e., a 5- to 14-membered heteroaryl, which contains one, two, three, or four heteroatoms. Each heteroatom is independently oxygen, sulfur, or nitrogen. In one embodiment, the heteroaryl has three heteroatoms. In another embodiment, the heteroaryl has two heteroatoms. In another embodiment, the heteroaryl has one heteroatom. In another embodiment, the heteroaryl is a 5- to 10-membered heteroaryl. In another embodiment, the heteroaryl has five ring atoms, such as a thiophene group, which is a 5-membered heteroaryl having four carbon atoms and one sulfur atom. In another embodiment, the heteroaryl has six ring atoms, such as a pyridinyl group, which is a 6-membered heteroaryl having five carbon atoms and one nitrogen atom. Non-limiting exemplary heteroaryl groups include thiophene, benzo[b]thiophene, naphtho[2,3-b]thiophene, thianyl, furanyl, benzofuranyl, pyranyl, isobenzofuranyl, benzoxazolyl, chromenyl, xanthonyl, 2H-pyrroleyl, pyrroleyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, indolyl, inzolyl, purinel, isoquinolinyl, quinolinyl, phthalazinyl, naphridinyl, cinolinyl, quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbazolyl, phenanthridine, acridineyl, pyrimidinyl, phenanthridine, phenazinyl, thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl, furazinyl, and phenothiazinyl. In one embodiment, the heteroaryl group is selected from thienyl (e.g., thien-2-yl and thien-3-yl), furanyl (e.g., 2-furanyl and 3-furanyl), pyrroloyl (e.g., 1H-pyrrolo-2-yl and 1H-pyrrolo-3-yl), imidazoyl (e.g., 2H-imidazo-2-yl and 2H-imidazo-4-yl), pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl and 1H-pyrazol-5-yl), and pyridyl (e.g., pyridin-2-yl, pyridinyl...). The terms "-3-yl" and "pyridin-4-yl", "pyrimidinyl" (e.g., "pyrimidin-2-yl", "pyrimidin-4-yl", and "pyrimidin-5-yl"), "thiazolyl" (e.g., "thiazolyl-2-yl", "thiazolyl-4-yl", and "thiazolyl-5-yl"), "isothiazolyl" (e.g., "isothiazolyl-3-yl", "isothiazolyl-4-yl", and "isothiazolyl-5-yl"), "oxazolyl" (e.g., "oxazolyl-2-yl", "oxazolyl-4-yl", and "oxazolyl-5-yl"), and "isooxazolyl" (e.g., "isooxazolyl-3-yl", "isooxazolyl-4-yl", and "isooxazolyl-5-yl"). The term heteroaryl also includes N-oxides. A non-limiting exemplary N-oxide is a pyridinyl N-oxide.

[0058] The term "carboxyl" when used alone or as part of another group refers to a free radical of the formula -C(=O)OH.

[0059] The term "amino" when used alone or as part of another group refers to the free radical of formula -NR55aR55b, wherein R55a and R55b are independently hydrogen, optionally substituted alkyl, haloalkyl, (hydroxy)alkyl, (alkoxy)alkyl, (amino)alkyl, heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, (aryl)alkyl, (cycloalkyl)alkyl, (heterocyclic)alkyl, or (heteroaryl)alkyl.

[0060] The combinations of the present invention cover any compound of the present invention that is isotopically labeled (i.e., radiolabeled) by substituting one or more atoms with atoms having different atomic masses or mass numbers. Examples of isotopes that can be incorporated into the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 2H (or deuterium (D)), 3H, 11C, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, for example, 3H, 11C, and 14C. In one embodiment, a compound is provided in which substantially all atoms at a certain position within the compound of the invention are replaced by atoms with different atomic masses or mass numbers. In another embodiment, a compound is provided in which substantially all atoms at a certain position within the compound of the invention are replaced by deuterium atoms, for example, all hydrogen atoms of a -CH3 group are replaced by deuterium atoms to obtain a -CD3 group. In yet another embodiment, a compound is provided in which a portion of the atoms at a certain position within the compound of the invention are replaced, i.e., a certain position of the compound of the invention is enriched with atoms with different atomic masses or mass numbers. In another embodiment, a compound is provided in which none of the atoms of the compound of the present invention are replaced by atoms having different atomic masses or mass numbers. The isotopically labeled compounds of the present invention can be prepared by methods known in the art.

[0061] The compounds in the combinations of the present invention may contain one or more asymmetric centers, and thus may produce enantiomers, diastereomers, and other stereoisomers. The present invention covers all such possible forms as well as their racemic and resolved forms and the use of mixtures thereof. In view of this disclosure, individual enantiomers can be isolated according to methods known in the art. When the compounds described herein contain alkene double bonds or other geometrically asymmetric centers, they are intended to include both E and Z geometrical isomers unless otherwise stated. All tautomers are also covered in the present invention.

[0062] As used herein, the term “stereoisomer” is a general term for all isomers of a single molecule that differ only in the spatial orientation of their atoms. Stereoisomers include enantiomers and isomers (diastereomers) of compounds having more than one chiral center and not being mirror images of each other.

[0063] The terms “chiral center” or “asymmetric carbon atom” refer to a carbon atom bonded to four different groups.

[0064] The terms “enantiomer” and “enantiomer” refer to a molecule that cannot be superimposed on its mirror image and is therefore optically active, wherein the enantiomer is rotated in one direction along a plane of polarization, while its mirror compound is rotated in the opposite direction along a plane of polarization.

[0065] The term “racemate” refers to a mixture of equal parts of enantiomers, and the mixture is not optically active.

[0066] The term “absolute configuration” refers to the spatial arrangement of atoms of a chiral molecular entity (or group) and its stereochemical description, such as R or S.

[0067] Unless otherwise stated, the stereochemical terminology and conventions used in this specification are consistent with those described in Pure & Appl. Chem, Vol. 68: p. 2193 (1996).

[0068] For a review of suitable salts, see Stahl and Wermuth's "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.

[0069] As used herein, the term "solvate" is a substance formed by combining, physically binding, and / or solvating the compounds of the present invention with solvent molecules, such as disolvates, monosolvates, or hemisolvates, wherein the ratio of solvent molecules to the compounds of the present invention is about 2:1, about 1:1, or about 1:2, respectively. Such physical binding involves varying degrees of ionization and covalent bonding (including hydrogen bonding). In some cases (e.g., when one or more solvent molecules are incorporated into the lattice of a crystalline solid), solvates can be separated. Thus, solvates include solution phases and separable solvates. The compounds of the present invention can be in a solvated form with pharmaceutically acceptable solvents such as water, methanol, and ethanol, and this application is intended to cover both solvated and unsolvated forms of the compounds of the present invention.

[0070] One type of solvate is a hydrate. "Hydrate" refers to a specific subgroup of solvates in which the solvent molecule is water. Solvates typically function as pharmacologically equivalents. The preparation of solvates is known in the art; see, for example, M. Caira et al., J. Pharmaceut. Sci., 93(3): 601-611 (2004), which describes the preparation of solvates of fluconazole with ethyl acetate and with water. Similar methods for preparing solvates, semisolvates, hydrates, etc., are described in van Tonder et al., AAPS Pharm. Sci. Tech., 5(1): Article 12 (2004) andALBingham et al., Chem. Commun., 603-604 (2001). Representative and non-limiting method for preparing solvates 7 / 43 pages 16 CN 121969392 A The method involves dissolving the compound of the invention in a desired solvent (organic solvent, water, or a mixture thereof) at a temperature above 20°C to about 25°C, then cooling the solution at a rate sufficient to form crystals, and separating the crystals by known methods such as filtration. Analytical techniques such as infrared spectroscopy can be used to confirm the presence of the solvent in the solvate crystals.

[0071] As used herein, the term “about” includes the referenced number ±10%. Thus, “about 10” means 9 to 11.

[0072] EED Inhibitor

[0073] In one embodiment, the EED inhibitor is a compound of formula I: I, wherein: R1 is an aralkyl group; R2 is selected from the group consisting of hydrogen and C1-C4 alkyl groups; R3 and R4 together with the carbon atoms to which they are attached form a radical of formula I-A, I-B or I-C: I-A, I-B or I-C; X is selected from the group consisting of -C(R5a)(R5b)-, -C(=O)- and -S(=O)2-; R5a and R5b are independently selected from the group consisting of hydrogen and C1-C4 alkyl groups; Y is selected from the group consisting of -C(R6a)(R6b)-, -S-, -O- and -N(R7)-; Z is -C(R6c)(R6d)m-; R6a and R6b are independently selected from the group consisting of hydrogen and C1-C4 alkyl groups; each R6c and R6d is independently selected from the group consisting of hydrogen and C1-C4 alkyl groups. m is 0, 1, or 2; R7 is selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C4-C8 heterocyclic, hydroxyalkyl, (alkoxy)alkyl, (cycloalkyl)alkyl, and (heterocyclic)alkyl; R8a, R8b, and R8c are independently selected from the group consisting of: hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and alkylsulfonyl; is a fused phenyl, a fused 5-membered heteroaryl, or a fused 6-membered heteroaryl; is an optionally substituted fused 3-8-membered cycloalkyl or an optionally substituted fused 4-8-membered heterocyclic; is an optionally substituted fused 4-8-membered heterocyclic; the bond indicated by “ ” is attached to the R3 position of Formula I, and the bond indicated by “ ” is attached to the R4 position of Formula I; and is a single or double bond. Or a pharmaceutically acceptable salt or solvation thereof.

[0074] In one embodiment, the EED inhibitor is a compound of formula II: (See specification 8 / 43 page 17 CN 121969392 A II), or a pharmaceutically acceptable salt or solvation thereof.

[0075] In one embodiment, Z is -CH2-, or a pharmaceutically acceptable salt or solvation thereof.

[0076] In one embodiment, X is -C(=O)-, or a pharmaceutically acceptable salt or solvation thereof.

[0077] In one embodiment, Y is -N(R7)-, and preferably R7 is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl and optionally substituted C3-C8 cycloalkyl, or a pharmaceutically acceptable salt or solvation thereof.

[0078] In one embodiment, the EED inhibitor is selected from the group consisting of: 4-ethyl-12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-7-(trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a-pentazabenzo[4,5]cyclooctano[1,2,3-cd]indone; 12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-4-(2,2,2-trifluoroethyl)-7-(trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a-pentazabenzo[4,5]cyclooctano[1,2,3-cd]indone; 4-Cyclopropyl-12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-7-(trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a-pentazazabenzo[4,5]cyclooctano[1,2,3-cd]indene-3-one; 12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-4-isopropyl-7-(trifluoromethyl)-4, 5-Dihydro-3H-2,4,8,11,12a-pentazabenzo[4,5]cyclooctano[1,2,3-cd]indene-3-one; and 11-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-6-methyl-4H-3-thia-2,5,10,11a-tetraazadibenzo[cd,f]azine-3,3-dioxide, or a pharmaceutically acceptable salt or solvation thereof.

[0079] In one embodiment, the EED inhibitor is a compound having the structure of Formula III or a pharmaceutically acceptable salt or solvation thereof,

[0080] Formula III.

[0081] The chemical name of Formula III is 12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-4-isopropyl-7-(trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a-pentazazabenzo[4,5]cyclooctano[1,2,3-cd]indene-3-one.

[0082] The preparation or identification method of the EED inhibitor described in this invention has been disclosed in the prior art, for example...WO2022222932A1, WO2021228034A1 and WO2021011713A1. WO2022222932A1, WO2021228034A1 and WO2021011713A1 are all incorporated herein by reference in their entirety.

[0083] In another embodiment, the EED inhibitor is any one or more of the compounds listed in Table 1, or a chemically acceptable salt or solvate thereof.

[0084] Table 1 Specification Page 10 / 43 19 CN 121969392 A Specification Page 11 / 43 20 CN 121969392 A Specification Page 12 / 43 21 CN 121969392 A Specification Page 13 / 43 22 CN 121969392 A Specification Page 14 / 43 23 CN 121969392 A Specification Page 15 / 43 24 CN 121969392 A Specification Page 16 / 43 25 CN 121969392 A Specification Page 17 / 43 26 CN 121969392 A Specification Page 18 / 43 27 CN 121969392 A Specification Page 19 / 43 28 CN 121969392 A Specification Page 20 / 43 29 CN 121969392 A Instruction Manual 21 / 43 Page 30 CN 121969392 A Instruction Manual 22 / 43 Page 31 CN 121969392 A Instruction Manual 23 / 43 Page 32 CN 121969392 A Instruction Manual 24 / 43 Page 33 CN 121969392 A Instruction Manual 25 / 43 Page 34 CN 121969392 A Instruction Manual 26 / 43 Page 35 CN 121969392 A Instruction Manual 27 / 43 Page 36 CN 121969392 A Instruction Manual 28 / 43 Page 37 CN 121969392 A Instruction Manual 29 / 43 Page 38 CN 121969392 A Instruction Manual 30 / 43 Page 39 CN 121969392 A Instruction Manual 31 / 43 Page 40 CN 121969392 A Instruction Manual Pages 32 / 43 41 CN 121969392 A

[0085] HDAC Inhibitor

[0086] HDAC inhibitors can be various agents capable of inhibiting HDAC proteins. In some embodiments, HDAC inhibitors are selected from the group consisting of: Tucidinostat (also known as Chidamide), Vorinostat (also known as SAHA), Belistat (also known as PXD-101), Romidesin (also known as FK-228), Pabistanastat (also known as LBH589), Entecavir (also known as MS-275), Trichostatin A (TSA), Mocetinostat (also known as MGCD0103), and MC1568.

[0087] In a preferred embodiment, the HDAC inhibitor is Tucidinostat (Chidamide). The structure of Tucidinostat (Chidamide) is Formula IV:

[0088] Formula IV

[0089] Tucidinostat is also known as Chidamide, CS055, or HBI-8000. It is an effective and orally bioavailable inhibitor of HDAC class I (HDAC1, 2, 3) and class IIb (HDAC10). It has relatively low inhibitory activity against HDAC8 and HDAC11, and no detectable inhibitory activity against HDAC4 / 5 / 6 / 7 / 9.

[0090] JAK Inhibitors

[0091] JAK inhibitors can be various agents capable of inhibiting JAK kinases. In some embodiments, the JAK inhibitor is selected from the group consisting of: golixitinib, tofacitinib, filgortinib, utpatinib, ruxolitinib, baricitinib, paktinib, molotinib, filtatinib, and abuxitinib. In a preferred embodiment, the JAK inhibitor is golixitinib. The structure of golixitinib is Formula X: .

[0092] Formula X

[0093] In some embodiments, the JAK inhibitor is a JAK1 inhibitor, a JAK2 inhibitor, a JAK3 inhibitor, and / or a TYK2 inhibitor.

[0094] BCL2 / BCLXL Inhibitor Specification Pages 33 / 43 42 CN 121969392 A

[0095] BCL2 / BCLXL inhibitors can be various agents capable of inhibiting BCL2 / BCLXL. In some embodiments, the BCL2 / BCL-XL inhibitor is selected from the group consisting of compound B, compound C, and venetoclax.

[0096] The term "compound B" as used herein refers to a compound having the structure of formula VIII or a pharmaceutically acceptable salt or solvation thereof;

[0097] Formula VIII.

[0098] The term "compound C" as used herein refers to a compound having the structure of formula IX or a pharmaceutically acceptable salt or solvation thereof;

[0099] Formula IX.

[0100] It should be understood, without being bound by theory, that in some embodiments of the combinations, compositions, methods, and uses described in this disclosure, compound C may be used as a prodrug of compound B.

[0101] It should be understood, without being bound by theory, that in some embodiments of the combinations, compositions, methods, and uses described in this disclosure, compound B may be a metabolite of compound C.

[0102] In a preferred embodiment, the BCL2 / BCL-XL inhibitor is either compound B or compound C.

[0103] In some embodiments, the BCL2 / BCL-XL inhibitor is any one of the BCL2 / BCL-XL inhibitors disclosed in CN113509475A, the entire contents of which are incorporated herein.

[0104] Pharmaceutical Combinations, Pharmaceutical Compositions, and Uses Thereof

[0105] In one aspect, the present invention provides a pharmaceutical combination comprising the EED inhibitors disclosed herein and another inhibitor selected from the group consisting of histone deacetylase (HDAC) inhibitors, JAK inhibitors, and BCL2 / BCL-XL inhibitors.

[0106] In some embodiments, the HDAC inhibitor is selected from the group consisting of: Tucidinostat (Chidamide), Vorinostat (SAHA), Belistat (PXD-101), Romidesin (FK-228), Pabilistat (LBH589), Entecavir (MS-275), Trichostatin A (TSA), Mocetinostat (MGCD0103), and MC1568.

[0107] In a preferred embodiment, the HDAC inhibitor is selected from the group consisting of Tucidinostat (Chidamide), Romidesin (FK-228), and Pabilistat (LBH589).

[0108] In some embodiments, the JAK inhibitor is a JAK1 inhibitor, a JAK2 inhibitor, a JAK3 inhibitor, and / or a TYK2 inhibitor.

[0109] In some embodiments, the JAK inhibitor is selected from the group consisting of: golixitinib, tofacitinib, filogrinib, utpatinib, ruxolitinib, baricitinib, paktinib, molotinib, filtatinib, and abuxitinib. In a preferred embodiment, the JAK inhibitor is golixitinib.

[0110] In some embodiments, the BCL2 / BCL-XL inhibitor is selected from the group consisting of compound B, compound C, and venetoclax. In a preferred embodiment, the BCL2 / BCL-XL inhibitor is compound B or compound C.

[0111] In some embodiments, the weight ratio of the EED inhibitor disclosed herein to the other inhibitor ranges from [missing information].The ratio is 0.0001:1 to 1:0.0001, for example, 0.001:1 to 1:0.001, 0.01:1 to 1:0.01, or 0.1:1 to 1:0.1. In some preferred embodiments, the weight ratio of the EED inhibitor disclosed herein to the other inhibitor is 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10. In a more preferred embodiment, the weight ratio of compound A to the other inhibitor is 1:1.

[0112] In some embodiments, the molar ratio of the EED inhibitor disclosed herein to the other inhibitor ranges from 30:1 to 1:30, for example 30:1, 27:1, 20:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:20, 1:27, or 1:30. In some preferred embodiments, the molar ratio of the EED inhibitor disclosed herein to the other inhibitor is 1:1, 9:1, 3:1, or 27:1.

[0113] In one aspect, the present invention provides a pharmaceutical composition comprising the pharmaceutical composition disclosed herein and a pharmaceutically acceptable carrier.

[0114] In some embodiments, the pharmaceutical combination or pharmaceutical composition comprises 1 μg to 500 mg of the EDD inhibitor disclosed herein, such as 1 μg, 2 μg, 5 μg, 10 μg, 15 μg, 20 μg, 50 μg, 100 μg, 200 μg, 500 μg, 1 mg, 2 mg, 5 mg, 10 mg, 20 mg, 50 mg, 100 mg, 200 mg, 500 mg or any amount of the EDD inhibitor disclosed herein disclosed herein.

[0115] In some embodiments, the pharmaceutical combination or pharmaceutical composition comprises 1 μg to 500 mg of another inhibitor disclosed herein, for example, comprising 1 μg, 2 μg, 5 μg, 10 μg, 15 μg, 20 μg, 50 μg, 100 μg, 200 μg, 500 μg, 1 mg, 2 mg, 5 mg, 10 mg, 20 mg, 50 mg, 100 mg, 200 mg, 500 mg, or any amount of the disclosed EDD inhibitor herein.

[0116] In some embodiments, the pharmaceutical composition is in the form of tablets, capsules, granules, syrups, powders, lozenges, small capsules, flat capsules, elixirs, suspensions, emulsions, solutions, aerosols, ointments, creams, or injections.

[0117] In one aspect, the present invention provides a method of treating a subject with cancer, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical combination or pharmaceutical composition disclosed herein.

[0118] In one implementation scheme, the cancer is selected from the group consisting of: T-cell lymphoma, non-Hodgkin's lymphoma, mature T-cell and NK-cell lymphoma, T-cell tumors, mycosis fungoides, granulomatous skin laxity, Cezari syndrome, mature T-cell lymphoma, lymphoepithelioid lymphoma, follicular T-cell lymphoma, nodular peripheral T-cell lymphoma with follicular helper T-cell phenotype, angioimmunoblastic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, cutaneous T-cell lymphoma (not specifically mentioned), primary cutaneous CD8-positive aggressive epidermotoxic T-cell lymphoma, primary cutaneous acral CD8-positive T-cell lymphoma, anaplastic large cell lymphoma T-cell and naked cell types, anaplastic large cell lymphoma (not specifically mentioned), anaplastic large cell lymphoma ALK-positive, hepatocellular and splenic T-cell lymphoma, intestinal T-cell lymphoma, monomorphic epidermotoxic T-cell lymphoma. (Instructions for use 35 / 43, page 44, CN) 121969392 A Intestinal T-cell lymphoma, primary mucosal CD30+ T-cell lymphoproliferative disorder, nasal and nasal NK / T-cell lymphoma, gastrointestinal indolent T-cell lymphoproliferative disorder, primary cutaneous CD4-positive small / medium T-cell lymphoproliferative disorder, primary cutaneous CD4-positive small / medium T-cell lymphoma, intravascular large B-cell lymphoma, intravascular large B-cell lymphoma, anaplastic large cell lymphoma ALK-positive, anaplastic large cell lymphoma ALK-negative, breast implant-associated anaplastic large cell lymphoma, primary cutaneous CD30+ T-cell lymphoproliferative disorders, mature T-cell or NK-cell tumors, T-cell prolymphocytic leukemia, T-cell large granular lymphocytic leukemia, NK-cell chronic lymphocytic disorders, aggressive NK-cell leukemia, childhood systemic EBV-positive T-cell lymphoma, adult T-cell lymphoma / leukemia associated with human T-cell lymphovirus type 1, extranodal nasal NK / T-cell lymphoma, enteropathy-associated T-cell lymphoma, hepatocellular and splenic T-cell lymphoma, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, and subcutaneous panniculitis-like T-cell lymphoma.

[0119] In one aspect, the present invention provides a method of treating a subject for a disease, the method comprising administering to the subject a therapeutically effective amount of the EED inhibitor disclosed herein.

[0120] In one embodiment, the disease is selected from the group consisting of: T-cell lymphoma, non-Hodgkin's lymphoma, mature T-cell and NK-cell lymphoma, T-cell tumor, mycosis fungoides, granulomatous skin laxity, Cezari syndrome, mature T-cell lymphoma, lymphoepithelioid lymphoma, follicular T-cell lymphoma, nodular peripheral T-cell lymphoma with follicular helper T-cell phenotype, angioimmunoblastic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, cutaneous T-cell lymphoma.T-cell lymphoma (not specifically identified), primary cutaneous CD8-positive aggressive epidermotoxic T-cell lymphoma, primary cutaneous acral CD8-positive T-cell lymphoma, anaplastic large cell lymphoma (T-cell and naked cell types), anaplastic large cell lymphoma (not specifically identified), anaplastic large cell lymphoma (ALK-positive), hepatocellular and splenic T-cell lymphoma, intestinal T-cell lymphoma, monomorphic epidermotoxic intestinal T-cell lymphoma, primary mucosal CD30+ T-cell lymphoproliferative disorder, nasal and nasal NK / T-cell lymphoma, gastrointestinal indolent T-cell lymphoproliferative disorder, primary cutaneous CD4-positive small / medium T-cell lymphoproliferative disorder, primary cutaneous CD4-positive small / medium T-cell lymphoma, intravascular large B-cell lymphoma, intravascular large B-cell lymphoma, anaplastic large cell lymphoma ALK-positive, anaplastic large cell lymphoma ALK-negative, breast implant-associated anaplastic large cell lymphoma, primary cutaneous CD30+ T-cell lymphoproliferative disorders, mature T-cell or NK-cell tumors, T-cell prolymphocytic leukemia, T-cell large granular lymphocytic leukemia, NK-cell chronic lymphocytic disorders, aggressive NK-cell leukemia, childhood systemic Epstein-Barr virus-positive T-cell lymphoma, adult T-cell lymphoma / leukemia associated with human T-cell lymphovirus type 1, extranodal nasal NK / T-cell lymphoma, enteropathy-associated T-cell lymphoma, hepatosplenic T-cell lymphoma, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, and subcutaneous panniculitis-like T-cell lymphoma.

[0121] In some embodiments, the EED inhibitors disclosed herein are administered at doses of about 0.0005 mg / day to about 5000 mg / day, for example, about 0.005 mg / day, 0.05 mg / day, 0.5 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 30 mg / day, 40 mg / day, 50 mg / day, 100 mg / day, 150 mg / day, 200 mg / day, 250 mg / day, 300 mg / day, 350 mg / day, 400 mg / day, 450 mg / day, 500 mg / day, 550 mg / day, 600 mg / day, 650 mg / day, 700 mg / day, 750 mg / day, 800 mg / day, 850 mg / day. Administered at doses of 900 mg / day, 950 mg / day, 1000 mg / day, 1500 mg / day, 2000 mg / day, 2500 mg / day, 3000 mg / day, 3500 mg / day, 4000 mg / day, 4500 mg / day, or 5000 mg / day.

[0122] In some embodiments, the EED inhibitors disclosed herein are administered at doses of about 1 ng / kg to about 200 mg / kg, about 1 μg / kg to about 100 mg / kg, or about 1 mg / kg to about 50 mg / kg, for example, at doses of about 1 μg / kg,Approximately 10 μg / kg, approximately 25 μg / kg, approximately 50 μg / kg, approximately 75 μg / kg, approximately 100 μg / kg, approximately 125 μg / kg, approximately 150 μg / kg, approximately 175 μg / kg, approximately 200 μg / kg, approximately 225 μg / kg, approximately 250 μg / kg, approximately 275 μg / kg, approximately 300 μg / kg, approximately 325 μg / kg, approximately 350 μg / kg, approximately 375μg / kg, approximately 400μg / kg, approximately 425μg / kg, approximately 450μg / kg, approximately 475μg / kg, approximately 500μg / kg, approximately 525μg / kg, approximately 550μg / kg, approximately 575μg / kg, approximately 600μg / kg, approximately 625μg / kg, approximately 650μg / kg, approximately 675μg / kg, approximately as per instructions 36 / 43 Page 45 CN 121969392 A 700μg / kg, about 725μg / kg, about 750μg / kg, about 775μg / kg, about 800μg / kg, about 825μg / kg, about 850μg / kg, about 875μg / kg, about 900μg / kg, about 925μg / kg, about 950μg / kg, about 975μg / kg, about 1mg / kg, about 5mg / kg, about 10mg / kg, about 15mg / kg, about 20mg / kg, about 25mg / kg, about 30mg / kg, about 35mg / kg, about 40mg / kg, about 45mg / kg Administer in doses of approximately 50 mg / kg, approximately 60 mg / kg, approximately 70 mg / kg, approximately 80 mg / kg, approximately 90 mg / kg, approximately 100 mg / kg, approximately 125 mg / kg, approximately 150 mg / kg, approximately 175 mg / kg, or approximately 200 mg / kg, and daily in one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) units.

[0123] In some embodiments, the other inhibitor is administered at a dose of about 0.0005 mg / day to about 5000 mg / day, for example, about 0.005 mg / day, 0.05 mg / day, 0.5 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 30 mg / day, 40 mg / day, 50 mg / day, 100 mg / day, 150 mg / day, 200 mg / day, 250 mg / day, 300 mg / day, 350 mg / day, 400 mg / day, 450 mg / day, 500 mg / day, 550 mg / day, 600 mg / day, 650 mg / day, 700 mg / day, 750 mg / day, 800 mg / day, 850 mg / day. 900mg / day, 950mg / day, 1000mg / day, 1500mg / day, 2000mg / day, 2500mg / day, 3000mg / day, 3500mg / dayAdministered at doses of 4000 mg / day, 4500 mg / day, or 5000 mg / day.

[0124] In some embodiments, the other inhibitor is administered at doses of about 1 ng / kg to about 200 mg / kg, about 1 μg / kg to about 100 mg / kg, or about 1 mg / kg to about 50 mg / kg, for example, at doses of about 1 μg / kg, about 10 μg / kg, about 25 μg / kg, about 50 μg / kg, about 75 μg / kg, about 100 μg / kg, about 125 μg / kg, about 150 μg / kg, about 175 μg / kg, about 200 μg / kg, about 225 μg / kg, about 250 μg / kg, about 275 μg / kg, about 300 μg / kg, about 325 μg / kg, about 350 ... kg, approximately 375 μg / kg, approximately 400 μg / kg, approximately 425 μg / kg, approximately 450 μg / kg, approximately 475 μg / kg, approximately 500 μg / kg, approximately 525 μg / kg, approximately 550 μg / kg, approximately 575 μg / kg, approximately 600 μg / kg, approximately 625 μg / kg, approximately 650 μg / kg, approximately 675 μg / kg, approximately 700 μg / kg, approximately 725 μg / kg, approximately 750 μg / kg, approximately 775 μg / kg, approximately 800 μg / kg, approximately 825 μg / kg, approximately 850 μg / kg, approximately 875 μg / kg The EED inhibitor is administered in doses of approximately 900 μg / kg, approximately 925 μg / kg, approximately 950 μg / kg, approximately 975 μg / kg, approximately 1 mg / kg, approximately 5 mg / kg, approximately 10 mg / kg, approximately 15 mg / kg, approximately 20 mg / kg, approximately 25 mg / kg, approximately 30 mg / kg, approximately 35 mg / kg, approximately 40 mg / kg, approximately 45 mg / kg, approximately 50 mg / kg, approximately 60 mg / kg, approximately 70 mg / kg, approximately 80 mg / kg, approximately 90 mg / kg, approximately 100 mg / kg, approximately 125 mg / kg, approximately 150 mg / kg, approximately 175 mg / kg, and approximately 200 mg / kg, and is administered daily in one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) unit doses.

[0125] In some embodiments, the EED inhibitor disclosed herein is administered together, simultaneously, sequentially, or alternately with the other inhibitor.

[0126] In some embodiments, the EED inhibitor disclosed herein and another inhibitor are administered continuously for at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, or at least...20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 28 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days, or at least 50 days.

[0127] In some embodiments, the administration of the EED inhibitor disclosed herein and the other inhibitor is continued for one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) cycles, wherein each of these cycles lasts for at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days or at least 50 days; and there is an interval of 0 days, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, two weeks, three weeks or four weeks between each two cycles.

[0128] In some embodiments, the EED inhibitor disclosed herein and the other inhibitor are administered via the same (e.g., oral, see specification 37 / 43 pages 46 CN 121969392 A) or different routes (e.g., oral and parenteral (e.g., injection) respectively).

[0129] In one aspect, the present invention provides the use of the pharmaceutical combinations or pharmaceutical compositions disclosed herein in the preparation of medicaments for treating cancer.

[0130] In one aspect, the present invention provides the use of the EED inhibitor disclosed herein in the preparation of medicaments for treating diseases.

[0131] In one aspect, the present invention provides the pharmaceutical combinations or pharmaceutical compositions disclosed herein for treating cancer.

[0132] In one aspect, the present invention provides the EED inhibitor disclosed herein for treating diseases.

[0133] In one aspect, the present invention provides a kit comprising: (a) a first component in a first container, the first component comprising an EED inhibitor disclosed herein and optionally a pharmaceutically acceptable carrier; (b) a second component in a second container, the second component comprising an inhibitor selected from the group consisting of HDAC inhibitors, JAK inhibitors (preferably JAK inhibitors disclosed herein) and BCL2 / BCL-XL inhibitors (preferably BCL2 / BCL-XL inhibitors disclosed herein) and optionally a pharmaceutically acceptable carrier; and (c) optionally instructions for use.

[0134] Examples

[0135] To make the objectives and technical solutions of the present invention clearer, the present invention will be further described below in conjunction with specific examples. It should be understood that these examples are not intended to limit the scope of this disclosure. In addition, examples not mentioned in the following examplesThe specific experimental methods were performed according to conventional experimental methods.

[0136] Compound A was used as a representative EED inhibitor in the following examples. Compound A represents a compound having the structure of Formula III or a pharmaceutically acceptable salt or solvate thereof.

[0137] Formula III

[0138] Example 1: Antiproliferative effect of compound A alone on T-cell lymphoma cell lines

[0139] The antiproliferative effect of compound A was tested and compared with three other compounds that can be used to treat T-cell lymphoma.

[0140] Materials and methods:

[0141] Valmettostat (CAS# 1809336-39-7 (free base)) (also known as DS-3201) has the structure of Formula V. It is a potent, selective, orally active EZH1 / 2 (Zeste enhancer 1 polycomb inhibitory complex 2 subunit) inhibitor. Specification 38 / 43 pages 47 CN 121969392 A

[0142]

[0143] Formula V.

[0144] MAK-683 (CAS# 1951408-58-4) is an EED inhibitor. It has the structure of Formula VI.

[0145]

[0146] Formula VI.

[0147] Tazesta (CAS# 1403254-99-8 (free base)) (also known as EPZ-6438 and E7438) is an EZH2 (Zeste enhancer 2-comb inhibitory complex 2 subunit) inhibitor. It has the structure of Formula VII.

[0148]

[0149] Formula VII.

[0150] Cell viability was tested using the CellTiter-Glo® cell proliferation assay. Briefly, T-cell lymphoma cells were seeded in 96-well plates and exposed to a solvent (solvent control) or treated alone or in combination with escalating concentrations of compound A and HDAC inhibitors, with each treatment set up in duplicate. After treatment, cell viability was assessed using a CellTiter-Glo® luminescent cell viability assay (Promega, Madison, WI, USA; catalog number G7571). The luminescent signal was detected using a BioTek Synergy H1 hybrid multimode (microplate) reader (Bestbio, Shanghai).

[0151] In the CTG experiment, the in vitro proliferation inhibitory effect of compound A alone on two commonly used T-cell lymphoma cell lines, Hut102 and HH, was tested.

[0152] The Hut102 cell line was purchased from Kebai Biotechnology (Nanjing, China) and maintained in vitro as a suspension in RPMI 1640 medium (ATCC®) supplemented with 10% fetal bovine serum (FBS, Gibco, Grand Island, NY, USA; catalog number: 10099141C), 1% penicillin / streptomycin, and 100 U / mL IL-2.

[0153] The HH cell line was derived from ATCC® CRL-2105™ and cultured in RPMI 1640 medium (ATCC® , 30-2001™) containing 10% fetal bovine serum (FBS, Gibco, Grand Island, NY, USA; catalog number: 10099141C) and 1% penicillin / streptomycin.

[0154] The H9 cell line was purchased from Kebai Biotechnology (Nanjing, China) and maintained in vitro as a suspension in RPMI 1640 medium (Gibco, catalog number: C11875500BT) supplemented with 10% fetal bovine serum (FBS, Gibco, Grand Island, NY, USA; catalog number: 10099141C) and 1% penicillin / streptomycin. Instructions for Use, Pages 39 / 43, 48, CN 121969392 A

[0155] The Hut78 cell line was purchased from Kebai Biotechnology (Nanjing, China) and proliferated in vitro as a suspension in Iscove modified Dulbecco medium (IMDM, Gibco, Grand Island, NY, USA; catalog number: 10099141C) supplemented with 20% fetal bovine serum (FBS, Gibco, Grand Island, NY, USA; catalog number: C12440500BT) and 1% penicillin / streptomycin.

[0156] The cells were maintained at 37°C in an air atmosphere containing 5% CO2 and passaged twice a week. Genetic identification of all cell lines was performed, and no microbial contamination was observed.

[0157] The Hut102, HH, and H9 cell lines were treated individually for 6 days with increasing concentrations of compound A, valmettostat, MAK683, or tazestat. Hut78 cell lines were treated for 15 days with increasing concentrations of compound A, valmettoxat, MAK683, or tazestat alone. Antiproliferative activity was assessed in vitro using the CellTiter-Glo® assay (CTG), and growth inhibition curves were plotted using a GraphPad Prism 9. Cell survival percentage is expressed as mean ± SEM, and n = 2 or 3.

[0158] Results and Conclusions: The results showed that compound A, as a single agent, had antiproliferative activity against Hut102, HH, H9, and Hut78 cells. Notably, under the same experimental conditions, compound A was effective in Hut102, HH, H9, and Hut78 cells, and its potency was higher than that of MAK683, valmettoxat, and tazestat (Table 2).

[0159] Table 2: Antiproliferative Activity in TCL Cell Lines

[0160] Note: >10 μM indicates no detectable effect.

[0161] In summary, compound A showed better activity against T-cell lymphoma than the other three compounds (i.e., valmetoxetine, MAK683, and tazestat).Lymphoma cells exhibit stronger anti-proliferative activity.

[0162] Example 2: Synergistic anti-proliferative effect of compound A combined with the HDAC inhibitor Tucidinostat on TCL cell lines

[0163] Materials and methods: As described in Example 1, cell viability was tested using the CellTiter-Glo® cell proliferation assay. In the CTG assay, the in vitro proliferation inhibitory effect of compound A alone on two commonly used T-cell lymphoma cell lines, Hut102 and HH, was tested. Instructions for Use, pages 40 / 43, 49, CN 121969392 A

[0164] The Hut102 cell line was purchased from Kebai Biotechnology (Nanjing, China) and was maintained / cultured as a suspension in RPMI 1640 medium (Gibco, catalog number: C11875500BT) supplemented with 10% fetal bovine serum (FBS, Gibco, Grand Island, NY, USA; catalog number: 10099141C), 100 U / mL penicillin, 100 μg / mL streptomycin and 100 U / mL IL-2.

[0165] The HH cell line was derived from ATCC® CRL-2105™ and cultured in RPMI 1640 medium (ATCC®, 30-2001™) containing 10% fetal bovine serum, 100 U / mL penicillin and 100 μg / mL streptomycin.

[0166] Cells were maintained at 37°C in an air atmosphere containing 5% CO2 and passaged twice a week. Genetic identification of all cell lines was performed, and no microbial contamination was observed.

[0167] Cell lines were treated with gradient concentrations of compound A, alone or in combination with Tucidinostat, and cell growth inhibition activity was detected by CellTiter-Glo luminescence assay. Cell survival percentage is expressed as mean ± SEM, n=2 or 3.

[0168] Results and conclusions: The growth inhibitory effect of compound A in combination with the HDAC inhibitor (Tucidinostat) on human TCL cell lines is shown in Figures 1A and 1B.

[0169] Compound A, as a single agent, not only exerted antiproliferative activity against Hut102 and HH cells, but the combination of compound A and the HDAC inhibitor (Tucidinostat) was also significant, showing a decrease in IC50 value after combination administration. By comparing the IC50 of the combination administration curve and the single-drug curve, a leftward shift was observed in the combination administration curve.

[0170] The results showed that when compound A was combined with the HDAC inhibitor tucidinostat, although compound A or tucidinostat alone showed different antiproliferative activities, their combination was effective in both TCL cells.The drugs consistently exhibited synergistic activity in the cell lines (Hut102 and HH). A leftward shift in the cell proliferation curve indicates synergistic activity. Further analysis showed that the combination index (CI) was less than 0.3 at multiple combined concentrations, confirming the synergistic effect of the combination. A CI less than 0.9 indicates a synergistic effect between the two drugs. The combination index (CI) was calculated using CalcuSyn software v2.0 (Biosoft, Cambridge, UK) as follows: CI = (D)1 (Dχ)1 + (D)2 (Dχ)2 where (Dχ)1 and (Dχ)2 represent the concentration at which each drug alone exerts a χ% effect, while (D)1 and (D)2 represent the concentration at which the two drugs produce the same effect when combined. A CI value less than 1 indicates synergistic effect; 1 indicates additive effect; and a CI value greater than 1 indicates antagonistic effect. In the current combination study, cell proliferation data were further analyzed, where CI < 0.1 was marked as 5+, indicating a very strong synergistic effect; CI between 0.1 and 0.3 was marked as 4+, indicating a strong synergistic effect; and CI between 0.3 and 0.9 was marked as 3+, indicating a moderate synergistic effect.

[0171] This combination (where the concentration of compound A differs from that of tucidinostat) was also tested in different cell lines (e.g., Hut102 and HH cell lines) and also showed a synergistic effect.

[0172] Example 3: Synergistic antiproliferative effect of compound A combined with the JAK1 inhibitor golixitinib on TCL cell lines

[0173] Materials and methods: Cell viability was assessed using the CellTiter-Glo® luminescent cell viability assay as described in Example 1. In this assay, the in vitro inhibitory effect of compound A combined with the JAK1 inhibitor golixitinib on the HuT102 T-cell lymphoma cell line was evaluated.

[0174] The HuT102 cell line was obtained from Kebai Biotechnology (Nanjing, China) and cultured as a suspension in RPMI 1640 medium (ATCC®, 30-2001™) supplemented with 10% fetal bovine serum (FBS, Gibco, Grand Island, NY, USA; catalog number: 10099141C), 100 U / mL penicillin, 100 μg / mL streptomycin, and 100 U / mL IL-2 (Peprotech, catalog number: 200-02). The cells were maintained at 37°C in a humidified atmosphere containing 5% CO2 and passaged twice a week. All cell lines were identified according to the genetic specification page 41 / 43, 50 CN 121969392 A, and confirmed to be free of microbial contamination.

[0175] The HuT102 cells were treated with compound A at specified gradient concentrations for 6 days, with golixitinib for 3 days, or with a combination thereof. Using CellTiter-Glo®The inhibitory effect on cell growth was detected by luminescence assay. Cell viability data are expressed as mean ± SD, n = 2 replicates.

[0176] Results and Conclusions:

[0177] The growth inhibitory effect of compound A in combination with the JAK1 inhibitor golixitinib on the HuT102 cell line is shown in Figure 2.

[0178] As a single agent, compound A exhibited significant antiproliferative activity against HuT102 cells. Notably, the antiproliferative activity against HuT102 cells was enhanced when compound A was combined with golixitinib. The cell proliferation curve shifted to the left, indicating enhanced activity and / or synergy. Further analysis showed that the combination index (CI) values ​​calculated using CalcuSyn software were all less than 0.3 at multiple combination concentrations, indicating a strong synergistic inhibitory effect. CI values ​​were calculated using CalcuSyn software v2.0 (Biosoft, Cambridge, UK) as described in Example 2. CI values ​​less than 0.9 further support the synergistic effect of the drug combination. Our study provides a scientific basis for the future clinical development of compound A and golixitinib in the treatment of TCL patients.

[0179] Example 4: Synergistic antiproliferative effect of compound A combined with the JAK1 inhibitor golixitinib on NK / TCL cell lines

[0180] Materials and methods: Cell viability was assessed using the CellTiter-Glo® luminescent cell viability assay as described in Example 1. In this assay, the in vitro proliferation inhibitory effect of compound A combined with the JAK1 inhibitor golixitinib on two commonly used NK / T cell lymphoma cell lines, SNK-1 and SNK-6, was evaluated.

[0181] The SNK-1 cell line was cultured as a suspension in RPMI 1640 medium (ATCC®, 30-2001™) supplemented with 10% human serum AB (GeminiBio, catalog number: 100-318), 100 U / mL penicillin, 100 μg / mL streptomycin, and 100 U / mL IL-2 (Peprotech, catalog number: 200-02). The SNK-6 cell line was cultured under similar conditions in RPMI 1640 medium (ATCC®, 30-2001™) supplemented with the same additives. Both cell lines were maintained in a humid atmosphere of 37°C and 5% CO2 and passaged twice a week. All cell lines were genetically identified and confirmed to be free of microbial contamination.

[0182] Cells were treated with gradient concentrations of compound A for 10 days and with golixitinib for 2 days. The inhibitory effect on cell growth was detected using CellTiter-Glo® luminescence assay. Cell viability data are expressed as mean ± SEM, n=2 or 3 replicates.

[0183] Results and conclusions: The combination of compound A and the JAK1 inhibitor golixitinib has an inhibitory effect on the growth of human NK / T-cell lymphoma (NK / TCL) cell lines.The long-term inhibitory effect is shown in Figures 3A and 3B. As a single agent, compound A exhibited significant antiproliferative activity against SNK-1 and SNK-6 cells. Notably, the combination of compound A with golixitinib further enhanced this antiproliferative activity. The leftward shift of the concentration-effect curve of the combination compared to the single agent curves indicates a synergistic effect.

[0184] The results show that when compound A is combined with the JAK1 inhibitor (golixitinib), although compound A or golixitinib alone exhibits limited antiproliferative activity in both NK / TCL cell lines (i.e., SNK-1 and SNK-6), their combination consistently exhibits synergistic activity in the NK / TCL cell lines. The leftward shift of the cell proliferation curve indicates synergistic activity. Further analysis showed that at multiple combination concentrations, the combination index (CI value) was less than 0.3, indicating moderate (CI score 3+) to very strong (CI score 5+) synergistic inhibitory effects. The combination index (CI) was less than 0.9, indicating a synergistic effect between the two drugs. The combination index (CI) was calculated using CalcuSyn software v2.0 (Biosoft, Cambridge, UK).

[0185] These findings provide a scientific basis for the future clinical development of compound A and golixitinib in the treatment of NK / TCL patients.

[0186] Example 5: Synergistic antiproliferative effect of compound A combined with BCL2 / BCL-XL inhibitor compound B on NK / TCL cell lines

[0187] Materials and methods: Cell viability was assessed using the CellTiter-Glo® luminescent cell viability assay as described in Example 1. In this assay, the in vitro proliferation inhibitory effect of compound A combined with BCL2 / BCL-XL inhibitor compound B on two commonly used NK / T cell lymphoma cell lines, SNK-1 and SNK-6, was evaluated.

[0188] The SNK-1 cell line was maintained as a suspension in RPMI 1640 medium (ATCC®, 30-2001™) supplemented with 10% human serum AB (GeminiBio, catalog number: 100-318), 100 U / mL penicillin, 100 μg / mL streptomycin, and 100 U / mL IL-2 (Peprotech, catalog number: 200-02). The SNK-6 cell line was cultured under the same conditions in RPMI 1640 medium (ATCC®, 30-2001™) with the same additives. Both cell lines were maintained at 37°C in a humidified atmosphere of 5% CO2 and passaged twice weekly. All cell lines were genetically identified and confirmed to be free of microbial contamination.

[0189] Cells were treated with gradient concentrations of compound A for 10 days and compound B for 2 days. CellTiter-Glo® was used.The inhibitory effect on cell growth was detected by luminescence assay. Cell viability data are expressed as mean ± SD, n = 2 or 3 replicates.

[0190] Results and conclusions: The growth inhibitory effect of compound A in combination with the BCL2 / BCL-XL inhibitor compound B on human NK / T-cell lymphoma (NK / TCL) cell lines is shown in Figures 4A and 4B. As single agents, compound A or compound B alone showed antiproliferative activity against SNK-1 and SNK-6 cells. Notably, the combination of compound A and compound B further enhanced this antiproliferative activity, as evidenced by the leftward shift of the combination treatment curve compared to the single agent curve.

[0191] The results indicate that when compound A and compound B are combined, although either agent alone exhibits variable antiproliferative activity, their combination consistently exerts a synergistic effect in both NK / TCL cell lines (SNK-1 and SNK-6). The leftward shift of the proliferation curve indicates this synergistic activity. Further analysis showed that at multiple combined concentrations, the combination index (CI) values ​​calculated using CalcuSyn software v2.0 (Biosoft, Cambridge, UK) were less than 0.3, confirming a strong synergistic inhibitory effect. CI values ​​less than 0.9 further support the synergistic interaction between the two drugs.

[0192] These findings provide a scientific basis for the future clinical development of compounds A and B in the treatment of NK / TCL patients.

[0193] Having fully described the methods, compounds, and compositions herein, those skilled in the art will understand that this disclosure can be made within a broad and equivalent scope of conditions, formulations, and other parameters without affecting the scope of the methods, compounds, and compositions provided herein or any embodiments thereof.

[0194] All patents, patent applications, and publications cited herein are incorporated herein by reference in their entirety. Instruction manual, page 43 / 43; 52 CN 121969392 A; Figure 1; Instruction manual, Figure 1 / 4; 53 CN 121969392 A; Figure 2; Instruction manual, Figure 2 / 4; 54 CN 121969392 A; Figure 3; Instruction manual, Figure 3 / 4; 55 CN 121969392 A; Figure 4; Instruction manual, Figure 4 / 4; 56 CN 121969392 A

Claims

1. A drug combination comprising an embryonic ectoderm development (EED) inhibitor and another inhibitor selected from the group consisting of histone deacetylase (HDAC) inhibitors, JAK inhibitors, and BCL2 / BCL-XL inhibitors.

2. The pharmaceutical combination according to claim 1, wherein the EED inhibitor is a compound of formula I: I， in: R 1 It is an aralkyl group; R 2 Select from the group consisting of hydrogen and C1-C4 alkyl groups; R 3 and R 4 Together with the carbon atoms they are attached to, they form free radicals of formula IA, IB, or IC: I-A, I-B or I-C; X Choose Freedom-C(R) 5a (R) 5b The group consists of -, -C(=O)- and -S(=O)2-; R 5a and R 5b Independently selected from the group consisting of hydrogen and C1-C4 alkyl groups; Y selects free - C(R) 6a (R) 6b -, -S-, -O- and -N(R) 7 - A group composed of; Z is -C(R) 6c (R) 6d ) m -; R 6a and R 6b Independently selected from the group consisting of hydrogen and C1-C4 alkyl groups; Each R 6c and R 6d Independently selected from the group consisting of hydrogen and C1-C4 alkyl groups; m is 0, 1, or 2; R 7 Choose from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C4-C8 heterocyclic, hydroxyalkyl, (alkoxy)alkyl, (cycloalkyl)alkyl and (heterocyclic)alkyl; R 8a R 8b and R 8c Independently selected from the group consisting of: hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy and alkylsulfonyl; It is a fused phenyl, a fused 5-membered heteroaryl, or a fused 6-membered heteroaryl; It is an optionally substituted fused 3-8 membered cycloalkyl group or an optionally substituted fused 4-8 membered heterocyclic group; It is a fused 4-8 membered heterocyclic group with optional substitution; by" The key connection in formula I is represented by "R". 3 Position, and with " The key connection in formula I is represented by "R". 4 Position; and Is it a single or double bond? Or its pharmaceutically acceptable salts or solvates.

3. The pharmaceutical combination according to claim 2, wherein the EED inhibitor is a compound of formula II: II, Or its pharmaceutically acceptable salts or solvates.

4. The pharmaceutical combination according to claim 2 or 3, wherein Z is -CH2-, or a pharmaceutically acceptable salt or solvate thereof.

5. The pharmaceutical combination according to any one of claims 2 to 4, wherein X is -C(=O)-, or a pharmaceutically acceptable salt or solvation thereof.

6. The pharmaceutical combination according to any one of claims 2 to 5, wherein Y is -N(R 7 )-, and preferably R 7 Choose from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl and optionally substituted C3-C8 cycloalkyl, or pharmaceutically acceptable salts or solvates thereof.

7. The drug combination according to claim 2, wherein the EED inhibitor is selected from the group consisting of: 4-Ethyl-12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-7-(trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a-pentazabenzo[4,5]cyclooctano[1,2,3-cd]inden-3-one; 12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-4-(2,2,2-trifluoroethyl)-7-(trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a-pentazazabenzo[4,5]cyclooctano[1,2,3-cd]inden-3-one; 4-Cyclopropyl-12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-7-(trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a-pentazabenzo[4,5]cyclooctano[1,2,3-cd]inden-3-one; 12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-4-isopropyl-7-(trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a-pentazabenzo[4,5]cyclooctano[1,2,3-cd]inden-3-one; and 11-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-6-methyl-4H-3-thia-2,5,10,11a-tetraazadibenzo[cd,f]azine-3,3-dioxide, Or its pharmaceutically acceptable salts or solvates.

8. The drug combination according to claim 2, The EED inhibitor is a compound having the structure of Formula III or a pharmaceutically acceptable salt or solvate thereof. Formula III.

9. The drug combination according to any one of claims 1 to 8, wherein the HDAC inhibitor is selected from the group consisting of: tucidinostat (chidamide), vorinostat (SAHA), belistat (PXD-101), romidesin (FK-228), pabistal (LBH589), entecavir (MS-275), trogostatin A (TSA), mocetinostat (MGCD0103), and MC1568.

10. The pharmaceutical combination according to any one of claims 1 to 8, wherein the JAK inhibitor is a JAK1 inhibitor, a JAK2 inhibitor, a JAK3 inhibitor, and / or a TYK2 inhibitor.

11. The drug combination according to any one of claims 1 to 8, wherein the JAK inhibitor is selected from the group consisting of: golixitinib, tofacitinib, filogrinib, utpatinib, ruxolitinib, baricitinib, paktinib, molotinib, filtatinib, and abuxitinib, preferably, the JAK inhibitor is golixitinib.

12. The drug combination according to any one of claims 1 to 8, wherein the BCL2 / BCL-XL inhibitor is selected from the group consisting of compound B, compound C and venetoclax, preferably, the BCL2 / BCL-XL inhibitor is compound B or compound C; Wherein compound B represents a compound having the structure of formula VIII or a pharmaceutically acceptable salt or solvation thereof; Formula VIII; Wherein compound C represents a compound having the structure of formula IX or a pharmaceutically acceptable salt or solvation thereof; Formula IX.

13. The drug combination according to any one of claims 1 to 12, wherein the weight ratio of the EED inhibitor to the other inhibitor ranges from 0.0001:1 to 1:0.0001, 0.01:1 to 1:0.01, or 0.1:1 to 1:0.1, preferably, the weight ratio of the EED inhibitor to the other inhibitor is 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10, more preferably 1:

1.

14. The drug combination according to any one of claims 1 to 13, wherein the molar ratio of the EED inhibitor to the other inhibitor ranges from 10:1 to 1:10, for example 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9 or 1:10, preferably 1:

1.

15. A pharmaceutical composition comprising any one of the pharmaceutical combinations according to any one of the preceding claims and a pharmaceutically acceptable carrier.

16. The pharmaceutical composition according to claim 15, wherein the pharmaceutical composition is in the form of tablets, capsules, granules, syrups, powders, lozenges, small capsules, flat capsules, elixirs, suspensions, emulsions, solutions, aerosols, ointments, creams, or injections.

17. A method of treating a subject with cancer, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical combination according to any one of claims 1 to 14, or a pharmaceutical composition according to claim 15 or 16. Optionally, the cancer is selected from the group consisting of: T-cell lymphoma, non-Hodgkin's lymphoma, mature T-cell and NK-cell lymphoma, T-cell tumor, mycosis fungoides, granulomatous skin laxity, Cezari syndrome, mature T-cell lymphoma, lymphoepithelioid lymphoma, follicular T-cell lymphoma, nodular peripheral T-cell lymphoma with follicular helper T-cell phenotype, angioimmunoblastic T-cell lymphoma, and subcutaneous panniculitis-like T-cell lymphoma. Lymphoma, cutaneous T-cell lymphoma (not specifically identified), primary cutaneous CD8-positive aggressive epidermotropic T-cell lymphoma, primary cutaneous acral CD8-positive T-cell lymphoma, anaplastic large cell lymphoma T-cell and naked cell types, anaplastic large cell lymphoma (not specifically identified), anaplastic large cell lymphoma ALK-positive, hepatosplenic T-cell lymphoma, intestinal T-cell lymphoma, monomorphic epidermotropic intestinal T-cell lymphoma, primary mucosal CD30+ T-cell lymphoproliferative disorder, nasal and nasal NK / T-cell lymphoma, gastrointestinal indolent T-cell lymphoproliferative disorder, primary cutaneous CD4-positive small / medium T-cell lymphoproliferative disorder, primary cutaneous CD4-positive small / medium T-cell lymphoma, intravascular large B-cell lymphoma, intravascular large B-cell lymphoma, anaplastic large cell lymphoma ALK-positive, anaplastic large cell lymphoma ALK-negative, breast implant-associated anaplastic large cell lymphoma, primary cutaneous CD30+ T-cell lymphoproliferative disorder, mature T cells Cellular or NK cell tumors, T-cell prolymphocytic leukemia, T-cell large granular lymphocytic leukemia, NK cell chronic lymphocytic dysplasia, aggressive NK cell leukemia, childhood systemic EBV-positive T-cell lymphoma, adult T-cell lymphoma / leukemia associated with human T-cell lymphovirus type 1, extranodal nasal NK / T-cell lymphoma, enteropathy-associated T-cell lymphoma, hepatosplenic T-cell lymphoma, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, and subcutaneous panniculitis-like T-cell lymphoma.

18. A method of treating a disease in a subject, the method comprising administering to the subject a therapeutically effective amount of an EED inhibitor according to any one of claims 1 to 14. The diseases mentioned are selected from the following groups: T-cell lymphoma, non-Hodgkin's lymphoma, mature T-cell and NK-cell lymphoma, T-cell tumors, mycosis fungoides, granulomatous skin laxity, Cezari syndrome, mature T-cell lymphoma, lymphoepithelioid lymphoma, follicular T-cell lymphoma, nodular peripheral T-cell lymphoma with follicular helper T-cell phenotype, angioimmunoblastic T-cell lymphoma, and subcutaneous panniculitis-like T-cell lymphoma. T-cell lymphoma, cutaneous T-cell lymphoma (not specifically identified), primary cutaneous CD8-positive aggressive epidermotoxic T-cell lymphoma, primary cutaneous acral CD8-positive T-cell lymphoma, anaplastic large cell lymphoma (T-cell and naked cell types), anaplastic large cell lymphoma (not specifically identified), anaplastic large cell lymphoma (ALK-positive), hepatosplenic T-cell lymphoma, intestinal T-cell lymphoma, monomorphic epidermotoxic intestinal T-cell lymphoma, primary mucosal CD30+ T-cell lymphoproliferative disorder, nasal and nasal NK / T-cell lymphoma, gastrointestinal indolent T-cell lymphoproliferative disorder, primary cutaneous CD4-positive small / medium T-cell lymphoproliferative disorder, primary cutaneous CD4-positive small / medium T-cell lymphoma, intravascular large B-cell lymphoma, intravascular large B-cell lymphoma, anaplastic large cell lymphoma ALK-positive, anaplastic large cell lymphoma ALK-negative, breast implant-associated anaplastic large cell lymphoma, primary cutaneous CD30+ T-cell lymphoproliferative disorder, mature T cells Cellular or NK cell tumors, T-cell prolymphocytic leukemia, T-cell large granular lymphocytic leukemia, NK cell chronic lymphocytic dysplasia, aggressive NK cell leukemia, childhood systemic EBV-positive T-cell lymphoma, adult T-cell lymphoma / leukemia associated with human T-cell lymphovirus type 1, extranodal nasal NK / T-cell lymphoma, enteropathy-associated T-cell lymphoma, hepatosplenic T-cell lymphoma, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, and subcutaneous panniculitis-like T-cell lymphoma.

19. The method according to claim 17 or 18, wherein the EED inhibitor is administered at a dose of about 0.0005 mg / day to about 5000 mg / day, for example, about 0.005 mg / day, 0.05 mg / day, 0.5 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 30 mg / day, 40 mg / day, 50 mg / day, 100 mg / day, 150 mg / day, 200 mg / day, 250 mg / day, 300 mg / day, 350 mg / day, 400 mg / day, etc. Administer at doses of g / day, 450 mg / day, 500 mg / day, 550 mg / day, 600 mg / day, 650 mg / day, 700 mg / day, 750 mg / day, 800 mg / day, 850 mg / day, 900 mg / day, 950 mg / day, 1000 mg / day, 1500 mg / day, 2000 mg / day, 2500 mg / day, 3000 mg / day, 3500 mg / day, 4000 mg / day, 4500 mg / day, or 5000 mg / day.

20. The method according to any one of claims 17 to 19, wherein the EED inhibitor is administered at a dose of about 1 ng / kg to about 200 mg / kg, about 1 μg / kg to about 100 mg / kg, or about 1 mg / kg to about 50 mg / kg, for example, at doses of about 1 μg / kg, about 10 μg / kg, about 25 μg / kg, about 50 μg / kg, about 75 μg / kg, about 100 μg / kg, about 125 μg / kg, about 150 μg / kg, about 175 μg / kg, etc. μg / kg, approximately 200 μg / kg, approximately 225 μg / kg, approximately 250 μg / kg, approximately 275 μg / kg, approximately 300 μg / kg, approximately 325 μg / kg, approximately 350 μg / kg, approximately 375 μg / kg, approximately 400 μg / kg, approximately 425 μg / kg, approximately 450 μg / kg, approximately 475 μg / kg, approximately 500 μg / kg, approximately 525 μg / kg, approximately 550 μg / kg, approximately 575 μg / kg, approximately 600 μg / kg, approximately 625 μg / kg Approximately 650 μg / kg, approximately 675 μg / kg, approximately 700 μg / kg, approximately 725 μg / kg, approximately 750 μg / kg, approximately 775 μg / kg, approximately 800 μg / kg, approximately 825 μg / kg, approximately 850 μg / kg, approximately 875 μg / kg, approximately 900 μg / kg, approximately 925 μg / kg, approximately 950 μg / kg, approximately 975 μg / kg, approximately 1 mg / kg, approximately 5 mg / kg, approximately 10 mg / kg, approximately 15 mg / kg, approximately 20 mg / kg, approximately Administer at doses of 25 mg / kg, approximately 30 mg / kg, approximately 35 mg / kg, approximately 40 mg / kg, approximately 45 mg / kg, approximately 50 mg / kg, approximately 60 mg / kg, approximately 70 mg / kg, approximately 80 mg / kg, approximately 90 mg / kg, approximately 100 mg / kg, approximately 125 mg / kg, approximately 150 mg / kg, approximately 175 mg / kg, or approximately 200 mg / kg, and daily in one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) unit doses.

21. The method according to any one of claims 17 and 19 to 20, wherein the HDAC inhibitor is administered at a dose of about 0.0005 mg / day to about 5000 mg / day, for example, about 0.005 mg / day, 0.05 mg / day, 0.5 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 30 mg / day, 40 mg / day, 50 mg / day, 100 mg / day, 150 mg / day, 200 mg / day, 250 mg / day, 300 mg / day, 350 mg / day, ... Administer at doses of 400 mg / day, 450 mg / day, 500 mg / day, 550 mg / day, 600 mg / day, 650 mg / day, 700 mg / day, 750 mg / day, 800 mg / day, 850 mg / day, 900 mg / day, 950 mg / day, 1000 mg / day, 1500 mg / day, 2000 mg / day, 2500 mg / day, 3000 mg / day, 3500 mg / day, 4000 mg / day, 4500 mg / day, or 5000 mg / day.

22. The method according to any one of claims 17 and 19 to 21, wherein the HDAC inhibitor is administered at a dose of about 1 ng / kg to about 200 mg / kg, about 1 μg / kg to about 100 mg / kg, or about 1 mg / kg to about 50 mg / kg, for example, at a dose of about 1 μg / kg, about 10 μg / kg, about 25 μg / kg, about 50 μg / kg, about 75 μg / kg, about 100 μg / kg, about 125 μg / kg, about 150 μg / kg, or about [missing information]. 175 μg / kg, approximately 200 μg / kg, approximately 225 μg / kg, approximately 250 μg / kg, approximately 275 μg / kg, approximately 300 μg / kg, approximately 325 μg / kg, approximately 350 μg / kg, approximately 375 μg / kg, approximately 400 μg / kg, approximately 425 μg / kg, approximately 450 μg / kg, approximately 475 μg / kg, approximately 500 μg / kg, approximately 525 μg / kg, approximately 550 μg / kg, approximately 575 μg / kg, approximately 600 μg / kg, approximately 625 μg / kg kg, approximately 650 μg / kg, approximately 675 μg / kg, approximately 700 μg / kg, approximately 725 μg / kg, approximately 750 μg / kg, approximately 775 μg / kg, approximately 800 μg / kg, approximately 825 μg / kg, approximately 850 μg / kg, approximately 875 μg / kg, approximately 900 μg / kg, approximately 925 μg / kg, approximately 950 μg / kg, approximately 975 μg / kg, approximately 1 mg / kg, approximately 5 mg / kg, approximately 10 mg / kg, approximately 15 mg / kg, approximately 20 mg / kg, Administer at doses of approximately 25 mg / kg, approximately 30 mg / kg, approximately 35 mg / kg, approximately 40 mg / kg, approximately 45 mg / kg, approximately 50 mg / kg, approximately 60 mg / kg, approximately 70 mg / kg, approximately 80 mg / kg, approximately 90 mg / kg, approximately 100 mg / kg, approximately 125 mg / kg, approximately 150 mg / kg, approximately 175 mg / kg, or approximately 200 mg / kg, and daily in one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) unit doses.

23. The method according to any one of claims 17 and 19 to 22, wherein the EED inhibitor and the HDAC inhibitor are administered together, simultaneously, sequentially, or alternately.

24. The method according to any one of claims 17 to 23, wherein the EED inhibitor and / or the HDAC inhibitor are continuously administered for at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 28 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days, or at least 50 days.

25. The method according to any one of claims 17 to 24, wherein the administration of the EED inhibitor and / or the HDAC inhibitor is sustained for one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) treatment cycles, wherein each treatment cycle lasts for at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days, or at least 50 days; and there is an interval of 0 days, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, two weeks, three weeks, or four weeks between every two treatment cycles.

26. The method according to any one of claims 17 and 19 to 25, wherein the EED inhibitor and the HDAC inhibitor are administered via the same (e.g., oral) or different routes (e.g., oral and parenteral (e.g., injection) respectively).

27. Use of the pharmaceutical composition according to any one of claims 1 to 11, or the pharmaceutical composition according to claim 15 or 16, in the preparation of a medicament for treating cancer. Optionally, the cancer is selected from the group consisting of: T-cell lymphoma, non-Hodgkin's lymphoma, mature T-cell and NK-cell lymphoma, T-cell tumor, mycosis fungoides, granulomatous skin laxity, Cezari syndrome, mature T-cell lymphoma, lymphoepithelioid lymphoma, follicular T-cell lymphoma, nodular peripheral T-cell lymphoma with follicular helper T-cell phenotype, angioimmunoblastic T-cell lymphoma, and subcutaneous panniculitis-like T-cell lymphoma. Lymphoma, cutaneous T-cell lymphoma (not specifically identified), primary cutaneous CD8-positive aggressive epidermotropic T-cell lymphoma, primary cutaneous acral CD8-positive T-cell lymphoma, anaplastic large cell lymphoma T-cell and naked cell types, anaplastic large cell lymphoma (not specifically identified), anaplastic large cell lymphoma ALK-positive, hepatosplenic T-cell lymphoma, intestinal T-cell lymphoma, monomorphic epidermotropic intestinal T-cell lymphoma, primary mucosal CD30+ T-cell lymphoproliferative disorder, nasal and nasal NK / T-cell lymphoma, gastrointestinal indolent T-cell lymphoproliferative disorder, primary cutaneous CD4-positive small / medium T-cell lymphoproliferative disorder, primary cutaneous CD4-positive small / medium T-cell lymphoma, intravascular large B-cell lymphoma, intravascular large B-cell lymphoma, anaplastic large cell lymphoma ALK-positive, anaplastic large cell lymphoma ALK-negative, breast implant-associated anaplastic large cell lymphoma, primary cutaneous CD30+ T-cell lymphoproliferative disorder, mature T cells Cellular or NK cell tumors, T-cell prolymphocytic leukemia, T-cell large granular lymphocytic leukemia, NK cell chronic lymphocytic dysplasia, aggressive NK cell leukemia, childhood systemic EBV-positive T-cell lymphoma, adult T-cell lymphoma / leukemia associated with human T-cell lymphovirus type 1, extranodal nasal NK / T-cell lymphoma, enteropathy-associated T-cell lymphoma, hepatosplenic T-cell lymphoma, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, and subcutaneous panniculitis-like T-cell lymphoma.

28. Use of the EED inhibitor according to any one of claims 1 to 14 in the preparation of a medicament for treating a disease; The diseases mentioned are selected from the following groups: T-cell lymphoma, non-Hodgkin's lymphoma, mature T-cell and NK-cell lymphoma, T-cell tumors, mycosis fungoides, granulomatous skin laxity, Cezari syndrome, mature T-cell lymphoma, lymphoepithelioid lymphoma, follicular T-cell lymphoma, nodular peripheral T-cell lymphoma with follicular helper T-cell phenotype, angioimmunoblastic T-cell lymphoma, and subcutaneous panniculitis-like T-cell lymphoma. T-cell lymphoma, cutaneous T-cell lymphoma (not specifically identified), primary cutaneous CD8-positive aggressive epidermotoxic T-cell lymphoma, primary cutaneous acral CD8-positive T-cell lymphoma, anaplastic large cell lymphoma (T-cell and naked cell types), anaplastic large cell lymphoma (not specifically identified), anaplastic large cell lymphoma (ALK-positive), hepatosplenic T-cell lymphoma, intestinal T-cell lymphoma, monomorphic epidermotoxic intestinal T-cell lymphoma, primary mucosal CD30+ T-cell lymphoproliferative disorder, nasal and nasal NK / T-cell lymphoma, gastrointestinal indolent T-cell lymphoproliferative disorder, primary cutaneous CD4-positive small / medium T-cell lymphoproliferative disorder, primary cutaneous CD4-positive small / medium T-cell lymphoma, intravascular large B-cell lymphoma, intravascular large B-cell lymphoma, anaplastic large cell lymphoma ALK-positive, anaplastic large cell lymphoma ALK-negative, breast implant-associated anaplastic large cell lymphoma, primary cutaneous CD30+ T-cell lymphoproliferative disorder, mature T cells Cellular or NK cell tumors, T-cell prolymphocytic leukemia, T-cell large granular lymphocytic leukemia, NK cell chronic lymphocytic dysplasia, aggressive NK cell leukemia, childhood systemic EBV-positive T-cell lymphoma, adult T-cell lymphoma / leukemia associated with human T-cell lymphovirus type 1, extranodal nasal NK / T-cell lymphoma, enteropathy-associated T-cell lymphoma, hepatosplenic T-cell lymphoma, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, and subcutaneous panniculitis-like T-cell lymphoma.

29. The pharmaceutical combination according to any one of claims 1 to 14 or the pharmaceutical composition according to claim 15 or 16, wherein the pharmaceutical combination or the pharmaceutical composition is used to treat cancer; Optionally, the cancers mentioned are selected from the group consisting of: T-cell lymphoma, non-Hodgkin's lymphoma, mature T-cell and NK-cell lymphoma, T-cell tumors, mycosis fungoides, granulomatous skin laxity, Cezari syndrome, mature T-cell lymphoma, lymphoepithelioid lymphoma, follicular T-cell lymphoma, nodular peripheral T-cell lymphoma with follicular helper T-cell phenotype, angioimmunoblastic T-cell lymphoma, and subcutaneous panniculitis-like T-cell lymphoma. T-cell lymphoma, cutaneous T-cell lymphoma (not specifically identified), primary cutaneous CD8-positive aggressive epidermotropic T-cell lymphoma, primary cutaneous acral CD8-positive T-cell lymphoma, anaplastic large cell lymphoma T-cell and naked cell types, anaplastic large cell lymphoma (not specifically identified), anaplastic large cell lymphoma ALK-positive, hepatosplenic T-cell lymphoma, intestinal T-cell lymphoma, monomorphic epidermotropic intestinal T-cell lymphoma, primary mucosal CD30+ T-cell lymphoproliferative disorder, nasal and nasal NK / T-cell lymphoma, gastrointestinal indolent T-cell lymphoproliferative disorder, primary cutaneous CD4-positive small / medium T-cell lymphoproliferative disorder, primary cutaneous CD4-positive small / medium T-cell lymphoma, intravascular large B-cell lymphoma, intravascular large B-cell lymphoma, anaplastic large cell lymphoma ALK-positive, anaplastic large cell lymphoma ALK-negative, breast implant-associated anaplastic large cell lymphoma, primary cutaneous CD30+ T-cell lymphoproliferative disorders, mature T-cell or NK-cell tumors, T-cell prolymphocytic leukemia, T-cell large granular lymphocytic leukemia, NK-cell chronic lymphocytic disorders, aggressive NK-cell leukemia, childhood systemic Epstein-Barr virus-positive T-cell lymphoma, adult T-cell lymphoma / leukemia associated with human T-cell lymphovirus type 1, extranodal nasal NK / T-cell lymphoma, enteropathy-associated T-cell lymphoma, hepatosplenic T-cell lymphoma, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, and subcutaneous panniculitis-like T-cell lymphoma.

30. The EED inhibitor according to any one of claims 1 to 14, wherein the EED inhibitor is used to treat a disease. The diseases mentioned are selected from the following groups: T-cell lymphoma, non-Hodgkin's lymphoma, mature T-cell and NK-cell lymphoma, T-cell tumors, mycosis fungoides, granulomatous skin laxity, Cezari syndrome, mature T-cell lymphoma, lymphoepithelioid lymphoma, follicular T-cell lymphoma, nodular peripheral T-cell lymphoma with follicular helper T-cell phenotype, angioimmunoblastic T-cell lymphoma, and subcutaneous panniculitis-like T-cell lymphoma. T-cell lymphoma, cutaneous T-cell lymphoma (not specifically identified), primary cutaneous CD8-positive aggressive epidermotoxic T-cell lymphoma, primary cutaneous acral CD8-positive T-cell lymphoma, anaplastic large cell lymphoma (T-cell and naked cell types), anaplastic large cell lymphoma (not specifically identified), anaplastic large cell lymphoma (ALK-positive), hepatosplenic T-cell lymphoma, intestinal T-cell lymphoma, monomorphic epidermotoxic intestinal T-cell lymphoma, primary mucosal CD30+ T-cell lymphoproliferative disorder, nasal and nasal NK / T-cell lymphoma, gastrointestinal indolent T-cell lymphoproliferative disorder, primary cutaneous CD4-positive small / medium T-cell lymphoproliferative disorder, primary cutaneous CD4-positive small / medium T-cell lymphoma, intravascular large B-cell lymphoma, intravascular large B-cell lymphoma, anaplastic large cell lymphoma ALK-positive, anaplastic large cell lymphoma ALK-negative, breast implant-associated anaplastic large cell lymphoma, primary cutaneous CD30+ T-cell lymphoproliferative disorder, mature T cells Cellular or NK cell tumors, T-cell prolymphocytic leukemia, T-cell large granular lymphocytic leukemia, NK cell chronic lymphocytic dysplasia, aggressive NK cell leukemia, childhood systemic EBV-positive T-cell lymphoma, adult T-cell lymphoma / leukemia associated with human T-cell lymphovirus type 1, extranodal nasal NK / T-cell lymphoma, enteropathy-associated T-cell lymphoma, hepatosplenic T-cell lymphoma, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, and subcutaneous panniculitis-like T-cell lymphoma.

31. A reagent kit comprising: (a) A first component in a first container, the first component comprising an EED inhibitor according to any one of claims 1 to 14 and optionally a pharmaceutically acceptable carrier; (b) A second component in a second container, the second component comprising an inhibitor selected from the group consisting of HDAC inhibitors (preferably HDAC inhibitors as defined in claim 9), JAK inhibitors (preferably JAK inhibitors as defined in claim 11), and BCL2 / BCL-XL inhibitors (preferably BCL2 / BCL-XL inhibitors as defined in claim 12) and optionally a pharmaceutically acceptable carrier; and (c) Optional instruction manual.

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