Methods for treating cancer using IAP antagonist compounds and combination therapies

Abstract

The present disclosure relates generally to the use of the compound of formula (I), also known as ASTX660, in combination therapy for the treatment of cancer, particularly leukemia. JPEG2025508016000071.jpg35128

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 63 / 316,680, filed March 4, 2022, which is incorporated by reference in its entirety.

[0002] The present application relates to methods of treating cancer with IAP antagonist compounds and combination therapies including IAP antagonist compounds. [Background technology]

[0003] Inhibitors of apoptosis proteins (IAPs) are a family of anti-apoptotic proteins that block cell death (apoptosis) and promote cell cycle progression. Cancer cells overexpress IAPs to promote cancer cell survival and tumor growth. IAP overexpression is a prognostic marker in a variety of solid tumors and hematological malignancies. Eight distinct human IAPs have been characterized: XIAP, hILP-2, c-IAP1, c-IAP2, ML-IAP, NAIP, survivin, and apollon. As IAPs are preferentially expressed in malignant cells, inhibition of IAPs may re-establish apoptotic pathways and induce cancer cell death.

[0004] There is a need for cancer treatments that can overcome certain drawbacks, such as the development of resistance to anticancer drugs. Summary of the Invention

[0005] As resistance to anti-cancer drugs becomes more widespread, targeting IAPs represents a strategy to resensitize refractory cancer cells to existing chemotherapies. In some embodiments, the present disclosure provides a method of treating cancer in a subject, the method comprising administering to a subject in need thereof a compound of formula I [ka] or a pharma- ceutically acceptable salt thereof; and a B cell leukemia / lymphoma-2 (Bcl-2) inhibitor, or a pharma- ceutical acceptable salt thereof.

[0006] In some embodiments, the present disclosure provides a method of treating cancer in a subject, the method comprising administering to a subject in need thereof a compound of formula I, or a pharma- ceutically acceptable salt thereof, and a compound of formula II [ka] or a pharma- ceutically acceptable salt thereof.

[0007] In some embodiments, the present disclosure provides a method of sensitizing a cancer to chemotherapy, when the cancer is refractory to said chemotherapy, comprising administering to a subject in need thereof a compound of formula I [ka] or a pharma- ceutically acceptable salt thereof; and administering said chemotherapy.

[0008] In some embodiments, the present disclosure provides a method of treating dexamethasone-resistant cancer (e.g., leukemia) in a subject in need thereof, the method comprising administering to the subject a compound of formula I [ka] or a pharma- ceutically acceptable salt thereof; and dexamethasone.

[0009] In some embodiments, the present disclosure provides a method of sensitizing a dexamethasone-resistant cancer cell line (e.g., a leukemia cell line) to dexamethasone, the method comprising treating the dexamethasone-resistant leukemia cell line with a compound of Formula I [ka] or a pharma- ceutically acceptable salt thereof.

[0010] In some embodiments, the present disclosure provides a pharmaceutical composition, the pharmaceutical composition comprising a compound of formula I [ka] or a pharma- ceutically acceptable salt thereof, and a B cell leukemia / lymphoma-2 (Bcl-2) inhibitor, or a pharma- ceutically acceptable salt thereof.

[0011] In some embodiments, the present disclosure provides a kit comprising the pharmaceutical composition.

[0012] In some embodiments, the present disclosure provides a pharmaceutical composition for use in the treatment of cancer, the pharmaceutical composition comprising a compound of formula I [ka] or a pharma- ceutically acceptable salt thereof, and a B cell leukemia / lymphoma-2 (Bcl-2) inhibitor, or a pharma- ceutically acceptable salt thereof.

[0013] In some embodiments, the present disclosure provides a pharmaceutical composition for use in the manufacture of a medicament for treating cancer, the pharmaceutical composition comprising a compound of formula I [ka] or a pharma- ceutically acceptable salt thereof, and a B cell leukemia / lymphoma-2 (Bcl-2) inhibitor, or a pharma- ceutically acceptable salt thereof.

[0014] In some embodiments, the present disclosure provides a use of a pharmaceutical composition in the treatment of cancer, the pharmaceutical composition comprising a compound of formula I [ka] or a pharma- ceutically acceptable salt thereof, and a B cell leukemia / lymphoma-2 (Bcl-2) inhibitor, or a pharma- ceutically acceptable salt thereof.

[0015] In some embodiments, the present disclosure provides for the use of a pharmaceutical composition in the manufacture of a medicament for the treatment of cancer, the pharmaceutical composition comprising a compound of formula I [ka] or a pharma- ceutically acceptable salt thereof, and a B cell leukemia / lymphoma-2 (Bcl-2) inhibitor, or a pharma- ceutically acceptable salt thereof. [Brief description of the drawings]

[0016] [Figure 1A] Western blot analysis showing the expression of IAPs and caspases in SUPT11 cells at the indicated time points.

[0017] [Figure 1B] FIG. 1 is a graph showing protein levels normalized to β-actin in Western blots.

[0018] [Figure 2A] FIG. 1 is a graph showing absolute cell counts of T-ALL SUPT11 cells treated with various concentrations of dexamethasone (DEX) and compound I (IAPi), alone and in combination.

[0019] [Figure 2B] 1 is a graph showing the percentage of cell death of T-ALL SUPT11 cells treated with various concentrations of dexamethasone (DEX) and compound I (IAPi), alone and in combination. CI refers to the combination index.

[0020] [Figure 3A]1 is a graph showing absolute cell counts of T-ALL CCRF-CEM cells treated with various concentrations of dexamethasone (DEX) and Compound I (IAPi), alone and in combination.

[0021] [Figure 3B] 1 is a graph showing the percentage of cell death of T-ALL CCRF-CEM cells treated with various concentrations of dexamethasone (DEX) and compound I (IAPi), alone and in combination. CI refers to the combination index.

[0022] [Figure 4A] Graph showing the percentage of cell death of PDX-derived cells (CD45+CD7+CD19-) treated with various concentrations of dexamethasone (DEX) and Compound I (IAPi), alone and in combination.

[0023] [Figure 4B] FIG. 1 is a graph showing the percentage of cell death of leukemic stem cells (LIC, CD45+CD7+CD19-CD34+) treated with various concentrations of dexamethasone (DEX) and Compound I (IAPi), alone and in combination.

[0024] [Figure 5A] FIG. 1 is a graph showing absolute cell numbers of T-ALL LOUCY cells treated with various concentrations of Compound II (ABT199) and Compound I (IAPi), alone and in combination.

[0025] [Figure 5B] 1 is a graph showing absolute cell counts of T-ALL LOUCY cells treated with various concentrations of Compound II (ABT199) and Compound I (IAPi), alone and in combination. CI refers to combination index.

[0026] [Figure 6A]Graph showing the percentage of cell death of PDX-derived cells (CD45+CD7+CD19-) treated with various concentrations of Compound II (ABT199) and Compound I (IAPi), alone and in combination.

[0027] [Figure 6B] FIG. 1 is a graph showing the percentage of cell death of leukemic stem cells (LIC, CD45+CD7+CD19-CD34+) treated with various concentrations of Compound II (ABT199) and Compound I (IAPi), alone and in combination.

[0028] [Figure 7] Western blot analysis showing decreased expression of cIAP2 and poly(ADP-ribose) polymerase (PARP) and increased cleaved caspase-7 in LOUCY cells in response to compound I (IAPi) alone and in combination with compound II (ABT199).

[0029] [Figure 8A] FIG. 1 is a graph showing absolute cell counts of T-ALL CCRF-CEM cells treated with various concentrations of Compound II (ABT199), Compound I (IAPi), and dexamethasone (DEX), alone and in a triple combination.

[0030] [Figure 8B] Figure 1 shows the percentage of cell death of T-ALL CCRF-CEM cells treated with various concentrations of Compound II (ABT199), Compound I (IAPi), and Dexamethasone (DEX), each alone and in a triple combination. CI refers to the combination index.

[0031] [Figure 9A] FIG. 1 is a graph showing absolute cell counts of T-ALL SUPT11 cells treated with various concentrations of Compound II (ABT199), Compound I (IAPi), and Dexamethasone (DEX), alone and in a triple combination.

[0032] [Figure 9B] Figure 1 shows the percentage of cell death of T-ALL SUPT11 cells treated with various concentrations of Compound II (ABT199), Compound I (IAPi), and Dexamethasone (DEX), each alone and in a triple combination. CI refers to the combination index.

[0033] [Figure 10A] 1 is a graph showing absolute cell counts in primary T-ALL patient samples treated with various concentrations of Compound II (ABT199), Compound I (IAPi), and dexamethasone (DEX), alone and in a triple combination.

[0034] [Figure 10B] Figure 1 shows the percentage of cell death in primary T-ALL patient samples treated with various concentrations of Compound II (ABT199), Compound I (IAPi), and dexamethasone (DEX), alone and in triple combination. Cell proliferation and apoptosis were measured in stem / progenitor cells (CD34+ve) by flow cytometry-based bead counting and Annexin V binding assay.

[0035] [Figure 11A-1] Single cell proteomic analysis showing levels of Ki-67, cleaved PARP and cleaved caspase-3 in SUPT11 cells 48 hours after treatment with dexamethasone (DEX) and compound I (IAPi), alone and in combination. [Figure 11A-2] Single cell proteomic analysis showing levels of Ki-67, cleaved PARP and cleaved caspase-3 in SUPT11 cells 48 hours after treatment with dexamethasone (DEX) and compound I (IAPi), alone and in combination.

[0036] [Figure 11B]Single-cell proteomic analysis showing multiple surface and intracellular molecules involved in apoptosis, proliferation and stress response after 48 hours of treatment with dexamethasone (DEX) and compound I (IAPi), alone and in combination. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0037] definition In the following description, exemplary embodiments of the present technology are described, however, it should be recognized that such description is not intended as a limitation on the scope of the present disclosure, but is instead provided as a description of exemplary embodiments.

[0038] As used herein, the following words, phrases and symbols are generally intended to have the meanings indicated below, unless otherwise indicated by the context in which they are used.

[0039] Reference herein to a value or parameter "about" includes (and describes) embodiments directed to that value or parameter itself. In certain embodiments, the term "about" includes the indicated amount ±10%. In other embodiments, the term "about" includes the indicated amount ±5%. In certain other embodiments, the term "about" includes the indicated amount ±1%. Additionally, the term "about X" includes a description of "X." Additionally, the singular forms "a" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "the compound" includes a plurality of such compounds, and reference to "the assay" includes reference to one or more assays and equivalents thereof known to those of skill in the art.

[0040] Pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials that are useful in the preparation of pharmaceutical compositions suitable for veterinary or human medical use.

[0041] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salt" or "physiologically acceptable salt" includes, for example, salts with inorganic acids and salts with organic acids. In addition, when a compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, when the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will recognize various synthetic methodologies that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include, for example, acetic acid, lactic acid (i.e., L-(+)-lactic acid, D-(-)-lactic acid, DL-lactic acid), propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of NH3, or primary, secondary, and tertiary amines, such as salts derived from N-containing heterocycles, N-containing heteroaromatic rings, or salts of the formula N(R N )3 (e.g., HN + (R N )3 or (alkyl)N + (R N ) 3), wherein each R Nare independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more (e.g., 1-5 or 1-3) substituents (e.g., halo, cyano, hydroxy, amino, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, or haloalkoxy), etc. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0042] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to an alkyl group having 1 to 20 carbon atoms (i.e., C 1~20 alkyl), 1 to 8 carbon atoms (i.e., C 1~8 alkyl), 1 to 6 carbon atoms (i.e., C 1~6 alkyl), or 1 to 4 carbon atoms (i.e., C 1~4 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a particular number of carbons is named by a chemical name or identified by a molecular formula, all positional isomers having that number of carbons can be encompassed, thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3), and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0043] "Alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C 2~20 alkenyl), 2 to 8 carbon atoms (i.e., C 2~8 alkenyl), 2 to 6 carbon atoms (i.e., C 2~6 alkenyl), or 2 to 4 carbon atoms (i.e., C 2~4 Examples of alkenyl groups include ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0044] "Alkynyl" refers to an alkynyl group containing at least one carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C 2~20 alkynyl), 2 to 8 carbon atoms (i.e., C 2~8 alkynyl), 2 to 6 carbon atoms (i.e., C 2~6 alkynyl), or 2 to 4 carbon atoms (i.e., C 2~4 The term "alkynyl" also includes groups having one triple bond and one double bond.

[0045] "Alkoxy" refers to the group "alkyl-O-". Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0046] "Haloalkyl" refers to an alkyl group, as defined above, and "haloalkoxy" refers to an alkoxy group, as defined above, where one or more hydrogen atoms of the alkyl or alkoxy group is replaced by a halogen.

[0047] As used herein, the term “amino” refers to a group of the formula —N(R N ) 2 amine, wherein each R Nis independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more (e.g., 1-5 or 1-3) substituents (e.g., halo, cyano, hydroxy, -NH, -NH(alkyl), -N(alkyl), alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, or haloalkoxy).

[0048] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, aryl refers to an aromatic carbocyclic group having 6 to 20 ring carbon atoms (i.e., C 6~20 aryl), 6 to 12 ring carbon atoms (i.e., C 6~12 aryl), or 6 to 10 ring carbon atoms (i.e., C 6~10 aryl). Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. However, aryl does not encompass or overlap in any way with heteroaryl, as defined below. When one or more aryl groups are fused with a heteroaryl, the resulting ring system is a heteroaryl. When one or more aryl groups are fused with a heterocyclyl, the resulting ring system is a heterocyclyl.

[0049] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings, including fused, bridged, and spiro ring systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond). As used herein, cycloalkyl refers to a cyclic group having 3 to 20 ring carbon atoms (i.e., C 3~20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3~12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3~10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3~8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3~6Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0050] "Halogen" or "halo" includes fluoro, chloro, bromo and iodo.

[0051] "Heteroaryl" refers to an aromatic group having a monocyclic, polycyclic, or fused polycyclic rings that contains one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl refers to an aromatic group having 1 to 20 ring carbon atoms (i.e., C 1~20 Heteroaryl), 3 to 12 ring carbon atoms (i.e., C 3~12 heteroaryl), or 3 to 8 ring carbon atoms (i.e., C 3~8 Heteroaryl) and contains 1-5 heteroatoms, 1-4 heteroatoms, 1-3 ring heteroatoms, 1-2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, where the heteroaryl can be attached via any ring of the fused system. Any aromatic ring having a single or multiple fused rings containing at least one heteroatom is considered heteroaryl regardless of the mode of attachment (i.e., via any one of the fused rings) to the remainder of the molecule. Heteroaryl does not encompass or overlap with aryl as defined above.

[0052] "Heterocyclyl" refers to a saturated or unsaturated cyclic alkyl group containing one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclyl" includes heterocycloalkenyl groups (i.e., heterocyclyl groups having at least one double bond), bridged heterocyclyl groups, fused heterocyclyl groups, and spiroheterocyclyl groups. Heterocyclyls may be monocyclic or polycyclic, where the polycyclic rings may be fused, bridged, or spiro. All non-aromatic rings containing at least one heteroatom are considered heterocyclyls, regardless of the mode of attachment (i.e., they may be attached via a carbon atom or a heteroatom). Additionally, the term heterocyclyl is intended to encompass all non-aromatic rings containing at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring, regardless of the mode of attachment to the remainder of the molecule. As used herein, heterocyclyl refers to a heterocyclic ring having 2 to 20 ring carbon atoms (i.e., C 2~20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C 2~12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C 2~10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C 2~8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C 3~12 heterocyclyl), 3 to 8 ring carbon atoms (i.e., C 3~8 heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C 3~6Heterocyclyl) having 1-5 ring heteroatoms, 1-4 ring heteroatoms, 1-3 ring heteroatoms, 1-2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl. As used herein, the term "bridged heterocyclyl" refers to a 4-10 membered ring moiety that is linked at two non-adjacent atoms of the heterocyclyl to one or more (e.g., 1 or 2) 4-10 membered ring moieties having at least one heteroatom, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. As used herein, bridged heterocyclyl includes bicyclic and tricyclic ring systems. Also, as used herein, the term "spiro-heterocyclyl" refers to a ring system in which a 3- to 10-membered heterocyclyl has one or more additional rings, where one or more of the additional rings is a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocyclyl, and an atom of the one or more additional rings is also an atom of the 3- to 10-membered heterocyclyl. Examples of spiro-heterocyclyl rings include bicyclic and tricyclic ring systems such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of fused heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl can be attached via either ring of the fused system.

[0053] Some of the compounds exist as tautomers. The tautomers are in equilibrium with each other. For example, an amide-containing compound may exist in equilibrium with an imidic acid tautomer. Regardless of which tautomer is shown and regardless of the nature of the equilibrium between the tautomers, it is understood by those skilled in the art that the compounds include both amide and imidic acid tautomers. Thus, amide-containing compounds are understood to include their imidic acid tautomers. Similarly, imidic acid-containing compounds are understood to include their amide tautomers.

[0054] All formulas or structures shown herein are also intended to represent unlabeled forms of the compounds as well as isotopically labeled forms. Isotopically labeled compounds have the structure shown by the formula given herein, except that one or more atoms are replaced by an atom having the mass or mass number of the selected atom. Examples of isotopes that can be incorporated into the compounds of the present disclosure include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine. 2 H (deuterium, D), 3 H (tritium), 11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 Various isotopically labeled compounds of the present disclosure include, for example, 3 H and 14 Radioactive isotopes such as C may be incorporated. Such isotopically labeled compounds may be useful in detection or imaging techniques such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT), including metabolic studies, reaction kinetic studies, drug or substrate tissue distribution assays or radiotreatment of patients.

[0055] The present disclosure also includes "deuterated analogs" of formula I or II in which one to n hydrogens attached to a carbon atom are replaced by deuterium, where n is the number of hydrogens in the molecule. Such compounds exhibit enhanced resistance to metabolism and are therefore useful for extending the half-life of compounds of formula I when administered to mammals, particularly humans. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol.Sci., 5(12):524-527 (1984). Such compounds are synthesized by means known in the art, e.g., by using starting materials in which one or more hydrogens have been replaced by deuterium.

[0056] Deuterium labeled or substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetic) properties with respect to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium can provide increased metabolic stability and certain therapeutic advantages, such as increased in vivo half-life or reduced dosage requirements, and / or improved therapeutic index. 18 F-labeled compounds can be useful for PET or SPECT studies.The isotopically labeled compounds and their prodrugs of the present disclosure can generally be prepared by carrying out the procedures disclosed in the schemes or examples and preparations described below, replacing non-isotopically labeled reagents with readily available isotopically labeled reagents.It is understood that deuterium in this context is considered as a substituent in the compound of formula I or II.

[0057] The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotopic enrichment factor. Any atom not specifically designated as a particular isotope in the compounds of the present disclosure is meant to represent any stable isotope of that atom. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen", the position is understood to have hydrogen in its natural abundance isotopic composition. Thus, in the compounds of the present disclosure, all atoms specifically designated as deuterium (D) are meant to represent deuterium.

[0058] As used herein, "Compound I" and "compound of formula I" are used interchangeably. As used herein, "Compound II" and "compound of formula II" are used interchangeably.

[0059] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable additive" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0060] A "solvate" is formed by the interaction of a solvent with a compound. Solvates of the salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0061] compound The compounds of formula I are IAP antagonists and are described in U.S. Patent No. 9,783,538, the disclosure of which is incorporated herein by reference. Compound I is named as follows: 1-(6-(4-fluorobenzyl)-5-(hydroxymethyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)ethan-1-one (alternatively, 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one). The compound of formula I may be referred to herein as "Compound I." [ka]

[0062] The compound of formula II is a Bcl-2 inhibitor and is described in U.S. Patent No. 8,546,399, the disclosure of which is incorporated herein by reference. Compound II is named venetoclax or 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide (or ABT-199). The compound of formula II may be referred to herein as "Compound II." [ka]

[0063] Treatment Methods and Uses "Treatment" or "treating" is an approach to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g., reducing one or more symptoms caused by the disease or condition and / or reducing the severity of the disease or condition), b) slowing or halting the progression of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or slowing the worsening or progression of the disease or condition, and / or preventing or slowing the spread (e.g., metastasis) of the disease or condition), and / or c) relieving the disease, i.e., causing a reduction in clinical symptoms (e.g., improving the disease state, causing partial or complete remission of the disease or condition, enhancing the effect of another drug, slowing the progression of the disease, improving quality of life, and / or prolonging survival).

[0064] "Prevention" or "preventing" refers to any treatment of a disease or condition that does not result in the development of clinical symptoms of the disease or condition. In some embodiments, the compounds can be administered to subjects (including humans) at risk for or who have a family history of a disease or condition.

[0065] "Subject" refers to an animal, such as a mammal (including a human), that has been or is the object of treatment, observation or experiment. The methods described herein may be useful in human treatment and / or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human.

[0066] The term "therapeutically effective amount" or "effective amount" of a compound described herein, or a pharma- ceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, means an amount sufficient to effect therapy when administered to a subject, such that a therapeutic benefit is obtained, such as amelioration of symptoms or delay in progression of a disease. The therapeutically effective amount may vary depending on the subject and disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, the method of administration, and can be readily determined by one of ordinary skill in the art.

[0067] In some embodiments, the disclosure provides a method of treating cancer in a subject, the method comprising administering to a subject in need thereof a compound of formula I [ka] or a pharma- ceutically acceptable salt thereof; and a B cell leukemia / lymphoma-2 (Bcl-2) inhibitor, or a pharma- ceutical acceptable salt thereof.

[0068] In some embodiments, the Bcl-2 inhibitor is selected from venetoclax (ABT-199) and navitoclax (ABT-263). In some embodiments, the Bcl-2 inhibitor is venetoclax (ABT-199) or a pharma- ceutically acceptable salt thereof. In some embodiments, the Bcl-2 inhibitor is selected from obatoclax, subatoclax, malitoclax, navitoclax, gossypol, apogossypol, ABT-737, TW-37, UMI-77, and BDA-366.

[0069] In some embodiments, a method of treating cancer in a subject is provided, the method comprising administering to a subject in need thereof a compound of formula I. [ka] or a pharma- ceutically acceptable salt thereof; Compound of Formula II (Venetoclax) [ka] or a pharma- ceutically acceptable salt thereof.

[0070] In some embodiments, a method for sensitizing a cancer to chemotherapy is provided, where the cancer is refractory to said chemotherapy, the method comprising administering to a subject in need thereof a compound of formula I. [ka] or a pharma- ceutically acceptable salt thereof; and administering said chemotherapy.

[0071] In some embodiments, the cancer is a solid tumor or malignant lymphoma. In some embodiments, the cancer is a blood cancer. In some embodiments, the cancer is a leukemia, malignant lymphoma, or myeloma. In some embodiments, the cancer is a myelodysplastic syndrome. In some embodiments, the cancer is a non-Hodgkin's lymphoma. In some embodiments, the cancer is a recurrent / metastatic head and neck squamous cell carcinoma (HNSCC), relapsed or refractory diffuse large B-cell lymphoma (DLBCL), progressive or relapsed peripheral T-cell lymphoma (PTCL), relapsed or refractory cutaneous T-cell lymphoma (CTCL), or cervical cancer. In some embodiments, the cancer is a leukemia. In some embodiments, the leukemia is acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL). In some embodiments, the leukemia is T-cell acute lymphoblastic leukemia (T-ALL).

[0072] In some embodiments, the cancer is refractory to existing chemotherapy. In some embodiments, the addition of an IAP antagonist (e.g., a compound of Formula I) to the treatment regimen resensitizes the cancer that is refractory to existing chemotherapy.

[0073] In some embodiments, the cancer is resistant to dexamethasone. In some embodiments, the method further comprises administering dexamethasone to the subject. In some such embodiments, the methods described herein sensitize the dexamethasone-resistant cancer to dexamethasone. In some such embodiments, the dexamethasone-resistant cancer is leukemia.

[0074] In some embodiments, a method of treating dexamethasone-resistant leukemia in a subject in need thereof is provided, the method comprising administering to the subject a compound of formula I. [ka] or a pharma- ceutically acceptable salt thereof, and dexamethasone. In some embodiments, bortezomib, melphalan, prednisone can be further administered instead of or in addition to dexamethasone.

[0075] In some embodiments, a method is provided for rendering a dexamethasone-resistant leukemia cell line sensitive to dexamethasone, the method comprising treating the dexamethasone-resistant leukemia cell line with a compound of formula I. [ka] or a pharma- ceutically acceptable salt thereof.

[0076] In some embodiments, a method of treating T-ALL in a subject is provided, the method comprising administering to a subject in need thereof a compound of formula I. [ka] or a pharma- ceutically acceptable salt thereof; Compound of Formula II (Venetoclax) [ka] or a pharma- ceutically acceptable salt thereof.

[0077] In some embodiments, the method further comprises administering dexamethasone to the subject.

[0078] In some embodiments, a method of treating dexamethasone-resistant T-ALL in a subject is provided, the method comprising administering to a subject in need thereof a compound of formula I. [ka] or a pharma- ceutically acceptable salt thereof, and dexamethasone.

[0079] In some embodiments, the method comprises administering to a subject a compound of formula II [ka] or a pharma- ceutically acceptable salt thereof.

[0080] In some embodiments, the compound of formula I is administered once daily for 7 consecutive days every other week of each 28 day cycle.

[0081] Provided herein is the use of a compound of Formula I, or a pharma- ceutically acceptable salt thereof, and a B cell leukemia / lymphoma-2 (Bcl-2) inhibitor, or a pharma- ceutically acceptable salt thereof, in the treatment of cancer.

[0082] Provided herein is the use of a compound of Formula I, or a pharma- ceutically acceptable salt thereof, and a B cell leukemia / lymphoma-2 (Bcl-2) inhibitor, or a pharma- ceutically acceptable salt thereof, in the treatment of cancer, wherein the compound is used in combination with one or more other compounds or therapies.

[0083] Provided are a compound of Formula I, or a pharma- ceutically acceptable salt thereof, and a B cell leukemia / lymphoma-2 (Bcl-2) inhibitor, or a pharma- ceutically acceptable salt thereof, for use in the treatment of cancer.

[0084] Provided is a compound of Formula I, or a pharma- ceutically acceptable salt thereof, for use in combination with a B cell leukemia / lymphoma-2 (Bcl-2) inhibitor, or a pharma- ceutically acceptable salt thereof.

[0085] Provided is a compound of Formula I, or a pharma- ceutically acceptable salt thereof, for use in the treatment of cancer, wherein the compound is used in combination with a B cell leukemia / lymphoma-2 (Bcl-2) inhibitor, or a pharma- ceutically acceptable salt thereof.

[0086] Provided is a compound of formula I, or a pharma- ceutically acceptable salt thereof, for use in combination therapy with a B cell leukemia / lymphoma-2 (Bcl-2) inhibitor, or a pharma- ceutically acceptable salt thereof, wherein compound I is used, optionally in combination with one or more other compounds or therapies.

[0087] There is provided the use of a compound of Formula I, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for use in the treatment of cancer, wherein the compound is used in combination with a B cell leukemia / lymphoma-2 (Bcl-2) inhibitor, or a pharma- ceutically acceptable salt thereof.

[0088] In some embodiments of the methods described herein, dexamethasone and compound I are administered in a dose ratio of 1:1, e.g., as shown in Figures 2A and 2B. In some embodiments of the methods described herein, compound II and compound I are administered in a dose ratio of 1:10 compound II:compound I, e.g., as shown in Figures 5A and 5B, or in other embodiments, a dose ratio of 5:1, 4:1, 3:1, 2:1, 1.5:1, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, or 1:12.5 compound II:compound I. In some embodiments of the methods described herein, compound II, compound I, and dexamethasone are administered in a dose ratio of 1:1:1, e.g., as shown in Figures 8A, 8B, 9A, and 9B. In some embodiments, the drug concentration of dexamethasone ranges from about 300 nM to about 5000 nM, and the drug concentration of compound I ranges from about 300 nM to about 5000 nM. In some embodiments, the drug concentration of compound II ranges from about 6.25 nM to about 100 nM, and the drug concentration of compound I ranges from about 62.5 nM to about 1000 nM. In some embodiments, the drug concentrations of dexamethasone, compound I, and compound II each range from about 300 nM to about 5000 nM.

[0089] In some embodiments of the methods described herein, navitoclax and compound I are administered in a dose ratio of 1:10 navitoclax:compound I, or in other embodiments, in a dose ratio of 5:1, 4:1, 3:1, 2:1, 1.5:1, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, or 1:12.5 navitoclax:compound I. In some embodiments of the methods described herein, navitoclax, compound I, and dexamethasone are administered in a dose ratio of 1:1:1. In some embodiments, the drug concentration of navitoclax ranges from about 6.25 nM to about 100 nM and the drug concentration of compound I ranges from about 62.5 nM to about 1000 nM. In some embodiments, the drug concentrations of each of dexamethasone, Compound I and navitoclax range from about 300 nM to about 5000 nM.

[0090] In some embodiments, the methods described herein may be used in combination with radiation therapy.

[0091] kit The present disclosure provides a kit comprising a compound of Formula I or a pharma- ceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, and suitable packaging. In one embodiment, the kit further comprises a second therapeutic agent selected from a B cell leukemia / lymphoma-2 (Bcl-2) inhibitor described herein. In one embodiment, the kit comprises a pharmaceutical composition described herein. For example, the kit can comprise a pharmaceutical composition comprising a compound of Formula I or a pharma- ceutically acceptable salt thereof and a B cell leukemia / lymphoma-2 (Bcl-2) inhibitor or a pharma- ceutically acceptable salt thereof. In one embodiment, the kit further comprises dexamethasone in addition to the pharmaceutical composition. In one embodiment, the kit further comprises instructions for use. In one aspect, the kit comprises a compound of Formula I, or a pharma- ceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, and a compound of Formula II, or a pharma- ceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, and a label and / or instructions for use of the compounds in treating an indication, including a disease or condition described herein.

[0092] The present disclosure also provides an article of manufacture comprising a compound or a combination of compounds described herein, or a pharma- ceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, in a suitable container, which may be a vial, jar, ampoule, pre-filled syringe, and intravenous bag.

[0093] Pharmaceutical Compositions and Modes of Administration In some embodiments, a pharmaceutical composition is provided, the pharmaceutical composition comprising a compound of formula I [ka] or a pharma- ceutically acceptable salt thereof; and a B cell leukemia / lymphoma-2 (Bcl-2) inhibitor, or a pharma- ceutically acceptable salt thereof.

[0094] In some embodiments, a pharmaceutical composition is provided, the pharmaceutical composition comprising a compound of formula I [ka] or a pharma- ceutically acceptable salt thereof; Compound of Formula II (Venetoclax) [ka] or a pharma- ceutically acceptable salt thereof.

[0095] Any of the pharmaceutical compositions described herein can be used to treat cancer and / or manufacture a medicament for treating cancer. In some embodiments, the cancer is a solid tumor or malignant lymphoma. In some embodiments, the cancer is a hematological cancer. In some embodiments, the cancer is a leukemia, malignant lymphoma, or myeloma. In some embodiments, the cancer is a myelodysplastic syndrome. In some embodiments, the cancer is a non-Hodgkin's lymphoma. In some embodiments, the cancer is a recurrent / metastatic head and neck squamous cell carcinoma (HNSCC), relapsed or refractory diffuse large B-cell lymphoma (DLBCL), progressive or relapsed peripheral T-cell lymphoma (PTCL), relapsed or refractory cutaneous T-cell lymphoma (CTCL), or cervical cancer. In some embodiments, the cancer is a leukemia. In some embodiments, the leukemia is acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL). In some embodiments, the leukemia is T-cell acute lymphoblastic leukemia (T-ALL).

[0096] In some embodiments, the cancer is refractory to existing chemotherapy. In some embodiments, the addition of an IAP antagonist (e.g., a compound of Formula I) to the treatment regimen resensitizes the cancer that is refractory to existing chemotherapy.

[0097] In some embodiments, the cancer is resistant to dexamethasone. In some embodiments, the method further comprises administering dexamethasone to the subject. In some such embodiments, the methods described herein sensitize the dexamethasone-resistant cancer to dexamethasone. In some such embodiments, the dexamethasone-resistant cancer is leukemia.

[0098] The compounds provided herein are usually administered in the form of pharmaceutical compositions. Thus, the present invention also provides pharmaceutical compositions that contain one or more compounds described herein, or their pharma- ceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, prodrugs, or deuterated analogs, and one or more pharma- ceutical acceptable vehicles selected from carriers, adjuvants, and additives. Suitable pharma- ceutical acceptable vehicles can include, for example, inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants. Such compositions are prepared by methods known in the pharmaceutical art. For example, see Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (GS Banker & C.T. Rhodes, Eds.).

[0099] The pharmaceutical compositions may be administered either in a single dose or in multiple doses, hi certain embodiments, the pharmaceutical compositions may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, or orally.

[0100] One mode of administration is parenteral, for example, by injection or intravenous infusion. For example, the form in which the pharmaceutical compositions described herein can be incorporated for administration by injection or intravenous infusion includes sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, aqueous or oily suspensions or emulsions containing mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles.

[0101] Oral administration may be another route of administration of the compounds described herein. Administration may be, for example, via capsules or enteric coated tablets. In the manufacture of pharmaceutical compositions containing at least one compound described herein, or a pharma- ceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, the active ingredient is usually diluted by an additive and / or enclosed within a carrier, which may be in the form of a capsule, sachet, paper, or other container. When an additive serves as a diluent, it may be in the form of a solid, semi-solid, or liquid material, which acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition may be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), for example, an ointment containing up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0102] Some examples of suitable additives include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose.The formulation may further include lubricants such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preserving agents such as methyl and propyl hydroxybenzoates, sweeteners, and flavoring agents.

[0103] To prepare solid compositions such as tablets, the principal active ingredient may be mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogenous mixture of the compounds described herein or a pharma- ceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof. When these preformulation compositions are referred to as homogenous, the active ingredient is uniformly dispersed throughout the composition, such that the composition may be readily subdivided into equally effective unit dosage forms, such as, for example, tablets, pills, and capsules.

[0104] The tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form that provides the advantage of prolonged action or to protect against the acidic conditions of the stomach. For example, the tablet or pill may comprise an inner dosage component and an outer dosage component, the latter being in the form of an outer membrane covering the former. The two components may be separated by an enteric layer that serves to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials may be used for such enteric layers or coatings, including many polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0105] Administration The specific dose level of the compounds of the present application for any particular subject will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combinations, and the severity of the particular disease in the subject being treated. For example, the dosage can be expressed as milligrams of a compound described herein (e.g., dexamethasone, Compound I, Compound II, navitoclax) per kilogram of subject body weight (mg / kg). Doses of about 0.01 to 150 mg / kg may be appropriate. In some embodiments, doses of about 0.03 and 100 mg / kg may be appropriate. In other embodiments, doses of 0.1 to 60 mg / kg may be appropriate. Normalizing according to subject body weight is particularly useful when using drugs in both children and adults, or when adjusting dosages between subjects of widely differing sizes, such as occurs when translating effective doses in non-human subjects, such as dogs, to doses appropriate for human subjects. In other embodiments, the dosage is expressed per body surface area (mg / m 2 ) may also be expressed as:

[0106] A daily dose may also be described as the total amount of a compound described herein (e.g., dexamethasone, Compound I, Compound II, or navitoclax) administered per administration or per day. For example, the daily dose of a compound of formula I, in free form or as a salt, can be about 1 mg to 4,000 mg, about 2,000 to 4,000 mg / day, about 1 to 2,000 mg / day, about 1 to 1,000 mg / day, about 10 to 500 mg / day, about 10 to 300 mg / day, about 10 to 180 mg / day, about 20 to 500 mg / day, about 10 to 180 mg / day, about 50 to 300 mg / day, about 50 to 180 mg / day, about 75 to 200 mg / day, or about 15 to 150 mg / day.

[0107] When administered orally, the total daily dose of a compound described herein (e.g., dexamethasone, Compound I, Compound II, or navitoclax) for a human subject can be 1 mg to 1,000 mg, about 1,000 to 2,000 mg / day, about 10 to 500 mg / day, about 50 to 300 mg / day, about 10 to 180 mg / day, about 75 to 200 mg / day, or about 100 to 150 mg / day.

[0108] In some embodiments, the methods include administering to a subject an initial daily dose of about 1-800 mg of a compound described herein, and gradually increasing the dose until clinical efficacy is achieved. The dose may be increased using increments of about 5, 10, 25, 50, or 100 mg.

[0109] The compounds of the present application (e.g., dexamethasone, Compound I, Compound II, Navitoclax) or compositions thereof can be administered once, twice, three or four times daily using any suitable mode described above. Administration or treatment with the compounds can also continue for several days, for example, treatment generally continues for at least 7 days, 14 days or 28 days during one cycle of treatment. Treatment cycles are known in cancer chemotherapy and are frequently alternated with rest periods of about 1 to 28 days, generally about 7 days or about 14 days, between cycles. In other embodiments, the treatment cycles can also be continuous. The compounds can be administered once or more than once daily. The compounds can be administered continuously (i.e., administered every day without interruption for the duration of the treatment regimen). Alternatively, the compounds can be administered intermittently (i.e., administered continuously for a given period, such as one week, then discontinued for a period, such as one week, then administered continuously for the next period, such as one week, throughout the duration of the treatment regimen). Examples of therapeutic regimens that include intermittent administration include regimens that are one or more cycles, such as 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more cycles of 1 week on and 1 week off, or 2 weeks on and 1 week off, or 3 weeks on and 1 week off, or 2 weeks on and 2 weeks off, or 4 weeks on and 2 weeks off, or 1 week on and 3 weeks off. In some embodiments, the first compound (e.g., Compound I) and the additional therapeutic agent (e.g., a Bcl-2 inhibitor such as Compound II and / or dexamethasone) can be administered together. In some embodiments, the first compound (e.g., Compound I) and the additional therapeutic agent (e.g., a Bcl-2 inhibitor such as Compound II and / or dexamethasone) can be administered sequentially. In some embodiments, the first compound (e.g., Compound I) and the additional therapeutic agent (e.g., a Bcl-2 inhibitor such as Compound II and / or dexamethasone) can be administered using different dosing regimens. For example, dexamethasone is typically administered for 5 consecutive days in a treatment cycle, while Compound I is administered once daily for 7 consecutive days every other week of each 28-day cycle.

[0110] Ultimately, however, the amount of compound administered and the type of composition used will depend on the nature of the disease or physiological condition being treated and will be at the discretion of the physician.

[0111] Embodiment Embodiment 1. A method of treating cancer in a subject, comprising administering to a subject in need thereof a compound of formula I [ka] or a pharma- ceutical acceptable salt thereof, and a B cell leukemia / lymphoma-2 (Bcl-2) inhibitor, or a pharma- ceutical acceptable salt thereof.

[0112] Embodiment 2. The method of embodiment 1, wherein the Bcl-2 inhibitor is venetoclax (ABT-199) or navitoclax (ABT-263).

[0113] Embodiment 3. The method of embodiment 1 or 2, wherein the cancer is a solid tumor or malignant lymphoma.

[0114] Embodiment 4. The method of any of the preceding embodiments, wherein the cancer is recurrent / metastatic head and neck squamous cell carcinoma (HNSCC), relapsed or refractory diffuse large B-cell lymphoma (DLBCL), progressive or recurrent peripheral T-cell lymphoma (PTCL), relapsed or refractory cutaneous T-cell lymphoma (CTCL), or cervical cancer.

[0115] Embodiment 5. The method of embodiment 1 or 2, wherein the cancer is leukemia.

[0116] Embodiment 6. The method of embodiment 5, wherein the leukemia is T-cell acute lymphoblastic leukemia (T-ALL).

[0117] Embodiment 7 The method of any of the preceding embodiments, wherein the cancer is resistant to dexamethasone.

[0118] Embodiment 8 The method of any of the preceding embodiments, further comprising administering dexamethasone to the subject.

[0119] Embodiment 9. A method of treating cancer in a subject, comprising administering to a subject in need thereof a compound of formula I [ka] or a pharma- ceutically acceptable salt thereof, and a compound of formula II (venetoclax): [ka] or a pharma- ceutically acceptable salt thereof.

[0120] Embodiment 10. The method of embodiment 9, wherein the cancer is a solid tumor or a malignant lymphoma.

[0121] Embodiment 11. The method of embodiment 9 or 10, wherein the cancer is recurrent / metastatic head and neck squamous cell carcinoma (HNSCC), relapsed or refractory diffuse large B-cell lymphoma (DLBCL), progressive or recurrent peripheral T-cell lymphoma (PTCL), relapsed or refractory cutaneous T-cell lymphoma (CTCL), or cervical cancer.

[0122] Embodiment 12 The method of embodiment 9, wherein the cancer is leukemia.

[0123] Embodiment 13. The method of embodiment 12, wherein the leukemia is T-cell acute lymphoblastic leukemia (T-ALL).

[0124] Embodiment 14. The method of embodiment 13, wherein the T-ALL is resistant to dexamethasone.

[0125] Embodiment 15. The method of any one of embodiments 9 to 14, further comprising administering dexamethasone to the subject.

[0126] Embodiment 16. A method of sensitizing a cancer to chemotherapy when the cancer is refractory to said chemotherapy, comprising administering to a subject in need thereof a compound of formula I [ka] or a pharma- ceutically acceptable salt thereof, and said chemotherapy.

[0127] Embodiment 17. A method of treating dexamethasone-resistant leukemia in a subject in need thereof, comprising administering to the subject a compound of formula I. [ka] or a pharma- ceutically acceptable salt thereof, and dexamethasone.

[0128] Embodiment 18. A method of rendering a dexamethasone-resistant leukemia cell line sensitive to dexamethasone, comprising treating the dexamethasone-resistant leukemia cell line with a compound of formula I [ka] or a pharma- ceutically acceptable salt thereof.

[0129] Embodiment 19. A method of treating T-ALL in a subject, comprising administering to a subject in need thereof a compound of formula I [ka] or a pharma- ceutically acceptable salt thereof, and a compound of formula II (venetoclax): [ka] or a pharma- ceutically acceptable salt thereof.

[0130] Embodiment 20 The method of embodiment 19, further comprising administering dexamethasone to the subject.

[0131] Embodiment 21. A method of treating dexamethasone-resistant T-ALL in a subject, comprising administering to a subject in need thereof a compound of formula I [ka] or a pharma- ceutically acceptable salt thereof, and dexamethasone.

[0132] Embodiment 22. Compound of Formula II [ka] 22. The method of embodiment 21, further comprising administering

[0133] Embodiment 23. The method of any of the preceding embodiments, wherein the compound of formula I or a pharma- ceutically acceptable salt thereof is administered once daily for 7 consecutive days every other week of each 28-day cycle.

[0134] Embodiment 24. The method of embodiment 23, wherein the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is 10 mg to 180 mg per day.

[0135] Embodiment 25. Compound of Formula I [ka] or a pharma- ceutical acceptable salt thereof, and a B cell leukemia / lymphoma-2 (Bcl-2) inhibitor, or a pharma- ceutical acceptable salt thereof.

[0136] Embodiment 26. The pharmaceutical composition of embodiment 25, wherein the Bcl-2 inhibitor is venetoclax (ABT-199) or navitoclax (ABT-263).

[0137] Embodiment 27. Compound of Formula I [ka] or a pharma- ceutically acceptable salt thereof, and a compound of formula II (venetoclax): [ka] or a pharma- ceutically acceptable salt thereof.

[0138] Embodiment 28. A pharmaceutical composition according to any one of embodiments 25 to 27, further comprising one or more pharma- ceutically acceptable excipients.

[0139] Embodiment 29. A kit comprising the pharmaceutical composition according to any one of embodiments 25 to 28 and dexamethasone.

[0140] Embodiment 30. A pharmaceutical composition for use in the treatment of cancer, comprising a compound of formula I [ka] or a pharma- ceutical acceptable salt thereof, and a B cell leukemia / lymphoma-2 (Bcl-2) inhibitor, or a pharma- ceutical acceptable salt thereof.

[0141] Embodiment 31. A compound of formula I for use in the treatment of cancer [ka] or a pharma- ceutical composition of a medicament for treating leukemia / lymphoma-2 (LCL-2) ...

[0142] Embodiment 32. A pharmaceutical composition for use in the manufacture of a medicament for treating cancer, comprising a compound of formula I [ka] or a pharma- ceutical acceptable salt thereof, and a B cell leukemia / lymphoma-2 (Bcl-2) inhibitor, or a pharma- ceutical acceptable salt thereof.

[0143] Embodiment 33. A compound of formula I for use in the manufacture of a medicament for treating cancer. [ka] or a pharma- ceutical composition of a medicament for treating leukemia / lymphoma-2 (LCL-2) ...

[0144] Embodiment 34. A pharmaceutical composition for use according to embodiments 30 to 33, wherein the Bcl-2 inhibitor is selected from venetoclax (ABT-199) and navitoclax (ABT-263).

[0145] Embodiment 35. A pharmaceutical composition for use according to any one of embodiments 30 to 34, wherein the cancer is a solid tumor or malignant lymphoma.

[0146] Embodiment 36. The pharmaceutical composition for use according to any one of embodiments 30 to 35, wherein the cancer is recurrent / metastatic head and neck squamous cell carcinoma (HNSCC), relapsed or refractory diffuse large B-cell lymphoma (DLBCL), progressive or relapsed peripheral T-cell lymphoma (PTCL), relapsed or refractory cutaneous T-cell lymphoma (CTCL), or cervical cancer.

[0147] Embodiment 37. A pharmaceutical composition for use according to any one of embodiments 30 to 34, wherein the cancer is leukemia.

[0148] Embodiment 38. The pharmaceutical composition for use according to embodiment 37, wherein the leukemia is T-cell acute lymphoblastic leukemia (T-ALL).

[0149] Embodiment 39. A pharmaceutical composition for use according to any one of embodiments 30 to 38, wherein the cancer is resistant to dexamethasone.

[0150] Embodiment 40. Use of a pharmaceutical composition in the treatment of cancer, the pharmaceutical composition comprising a compound of formula I [ka] or a pharma- ceutically acceptable salt thereof, and a B cell leukemia / lymphoma-2 (Bcl-2) inhibitor, or a pharma- ceutically acceptable salt thereof.

[0151] Embodiment 41. Compounds of Formula I in the Treatment of Cancer [ka] or a pharma- ceutical acceptable salt thereof, which is used in combination with a B cell leukemia / lymphoma-2 (Bcl-2) inhibitor, or a pharma- ceutical acceptable salt thereof.

[0152] Embodiment 42. Use of a pharmaceutical composition in the manufacture of a medicament for treating cancer, the pharmaceutical composition comprising a compound of formula I [ka] or a pharma- ceutically acceptable salt thereof, and a B cell leukemia / lymphoma-2 (Bcl-2) inhibitor, or a pharma- ceutically acceptable salt thereof.

[0153] Embodiment 43. A compound of formula I in the manufacture of a medicament for treating cancer. [ka] or a pharma- ceutical acceptable salt thereof, in combination with a B cell leukemia / lymphoma-2 (Bcl-2) inhibitor, or a pharma- ceutical acceptable salt thereof.

[0154] Embodiment 44. A pharmaceutical composition for use according to embodiments 39 to 43, wherein the Bcl-2 inhibitor is selected from venetoclax (ABT-199) and navitoclax (ABT-263).

[0155] Embodiment 45. A pharmaceutical composition for use according to embodiments 39 to 43, wherein the cancer is a solid tumor or malignant lymphoma.

[0156] Embodiment 46. The pharmaceutical composition for use according to any one of embodiments 39 to 43, wherein the cancer is recurrent / metastatic head and neck squamous cell carcinoma (HNSCC), relapsed or refractory diffuse large B-cell lymphoma (DLBCL), progressive or relapsed peripheral T-cell lymphoma (PTCL), relapsed or refractory cutaneous T-cell lymphoma (CTCL), or cervical cancer.

[0157] Embodiment 47. A pharmaceutical composition for use according to embodiments 39 to 43, wherein the cancer is leukemia.

[0158] Embodiment 48. The pharmaceutical composition for use according to embodiment 46, wherein the leukemia is T-cell acute lymphoblastic leukemia (T-ALL).

[0159] Embodiment 49. A pharmaceutical composition for use according to any one of embodiments 40 to 47, wherein the cancer is resistant to dexamethasone.

[0160] Embodiment 50. A kit for use in treating cancer, comprising: 1) a compound of formula I [ka] or a pharma- ceutical composition comprising a B cell leukemia / lymphoma-2 (Bcl-2) inhibitor, or a pharma- ceutical composition comprising a pharma- ceutical composition comprising a B cell leukemia / lymphoma-2 (Bcl-2) inhibitor, or a pharma- ceutical salt thereof.

[0161] Embodiment 51. A pharmaceutical or medicament for use in the treatment of cancer, comprising a compound of formula I [ka] or a pharma- ceutical agent comprising the compound or a pharma- ceutical agent having a medicament for treating leukemia or lymphoma, and a B cell leukemia / lymphoma-2 (Bcl-2) inhibitor, ...

[0162] Embodiment 52. A pharmaceutical or medicament for use in the treatment of cancer, comprising a compound of formula I [ka] or a pharma- ceutical or pharmaceutical agent comprising the compound or a pharma- ceutical agent or a pharma- ceutical agent that is used in combination with a B cell leukemia / lymphoma-2 (Bcl-2) inhibitor, or a pharma- ceutical or pharmaceutical ...

[0163] Embodiment 53. A combination for use in the treatment of T-cell lymphoma, comprising a compound of formula I [ka] or a pharma- ceutically acceptable salt thereof, and a B cell leukemia / lymphoma-2 (Bcl-2) inhibitor, or a pharma- ceutically acceptable salt thereof. EXAMPLES

[0164] The following examples are included to demonstrate specific embodiments of the present disclosure. It should be understood by those skilled in the art that the techniques disclosed in these examples represent techniques that work well in the implementation of the present disclosure and therefore can be considered to constitute specific modes for its implementation. However, those skilled in the art should understand in light of the present disclosure that many changes can be made to the specific embodiments disclosed and still obtain the same or similar results without departing from the spirit and scope of the present disclosure.

[0165] Example 1 The activity of Compound I in combination with Compound II and dexamethasone (DEX) in T-cell acute lymphoblastic leukemia (T-ALL) using patient-derived xenografts (PDX) in vitro and ex vivo was tested as follows.

[0166] Single-agent activity of Compound I was analyzed using a panel of eight human T-ALL cell lines (SUPT11, JURKAT, CCRF-CEM, MOLT4, MOLT16, PF382, LOUCY, ALL-SIL). T-All cells (0.1 × 10 6 1000 mg / ml was incubated with increasing concentrations of compound I for 5 days to determine dose response. Apoptosis was analyzed using flow cytometry (Gallios Flow Cytometer; Beckman Coulter, Fullerton, CA, USA) after staining with Annexin V-APC (Biolegend, USA #640941) and DAPI (Invitrogen, Carlsbad, CA, USA). Cells were resuspended in PBS containing CountBright beads (Invitrogen #C36950) to allow absolute cell counts to be determined. Half-maximal inhibitory concentrations (IC) were calculated using CalcuSyn software (BIOSOFT, Cambridge, UK). 50 The T acute lymphoblastic leukemia cell line Loucy (LOUCY) and Stanford University pediatric T cell line 11 (SUPT11) were the most sensitive (IC 50 = 190 nM and 309 nM). The T lymphoblastoid cell line CCRF-CEM and the human T-ALL cell line (ALL-SIL) showed intermediate sensitivity to compound I, whereas Jurkat, MOLT16, MOLT4 and PF382 were the least sensitive.

[0167] For immunoblotting, T-ALL cells were lysed in RIPA buffer (1% NP-40, 0.5% sodium deoxycholate, 0.1% sodium dodecyl sulfate, 50 mM Tris-Cl, pH 7.5, 150 mM NaCl) in the presence of 1× protease cocktail inhibitors. Soluble lysates were electrophoresed on sodium dodecyl sulfate-polyacrylamide gels and transferred to polyvinylidene difluoride membranes (Bio-Rad, Hercules, CA, USA). Membranes were probed with specific antibodies. Signals were visualized using an Odyssey Infrared Imaging System (LI-COR Biosciences, Lincoln, NE, USA) and quantified using Image Studio Lite software (LI-COR Biosciences). β-actin was used as a loading control. Immunoblots showed decreased levels of cIAP1 and cIAP2 in response to compound I as a single agent, with no change in XIAP.

[0168] Figure 1A shows the effect of Compound I on IAP and caspase expression using Western blot analysis in SUPT11 cells at the indicated time points. Figure 1B shows protein levels in Western blot normalized to β-actin. Table 1 shows the IC of Compound I for each of the T-ALL cell lines. 50 (nM) is indicated. [Table 1]

[0169] Example 2 The effect of the combination of dexamethasone (DEX) and compound I was then tested in T-ALL cell lines using increasing concentrations of dexamethasone (DEX), compound I, or their combination (1:1) by the method described in Example 1. The CCRF-CEM cell line was derived from a relapsed patient and is resistant to DEX. The combination was synergistic against the CCRF-CEM cell line, with 50±4% cell death with a dose ratio of compound I:DEX of 1:1, compared to 20±3% with DEX alone, with a CI of 0.26.

[0170] In SUPT11 cells, strong synergistic effects were observed in terms of both cell loss and induction of apoptosis. Compound I sensitized SUPT11 cells to DEX and reduced the ED of DEX treatment. 50 The ED of the combination was approximately 2 μM, compared with 50 The value was 542 nM.

[0171] Figure 2A shows the dose-response curve of absolute cell number of SUPT11 cells exposed to dexamethasone (DEX) and compound I (IAPi), either alone or in combination. Figure 2B shows the dose-response curve of percentage cell death of SUPT11 cells exposed to dexamethasone (DEX) and compound I (IAPi), either alone or in combination.

[0172] Figure 3A shows the dose-response curves for absolute cell number of CCRF-CEM cells exposed to dexamethasone (DEX) and compound I (IAPi), either alone or in combination. Figure 3B shows the dose-response curves for percent cell death of CCRF-CEM cells exposed to dexamethasone (DEX) and compound I (IAPi), either alone or in combination.

[0173] Absolute cell numbers and apoptosis were determined by flow cytometry-based bead counting and Annexin V binding assays as described in Example 1. Combination Index (CI) and IC 50 was determined using Calcusyn (BIOSOFT, Cambridge, UK).

[0174] Table 2 shows the IC 50 and ED 50 Shows. [Table 2]

[0175] Table 3 shows the IC 50 and ED 50 Shows. [Table 3]

[0176] In the MOLT16 cell line, which harbors a point mutation in p53 and a deletion in CDKN2A, using a 1:1 dose ratio of Compound I:DEX, absolute cell counts were reduced more with the combination compared to either single-agent IAPi or DEX, with a CI of 0.05.

[0177] In PF382 cells harboring mutations in RAS, PTEN, P53, NOTCH1, and CDKN21, a 1:1 dose ratio of Compound I:DEX was synergistic in reducing cell numbers but did not induce apoptosis either alone or in combination.

[0178] The effect of dexamethasone (DEX) in combination with Compound I was also tested in T-ALL PDX cell lines (DFAT-72032, DFAT-28537, CBAT-37614, CBAT-93917, CBAT-44179, 6506870, D115). T-ALL PDX cells were incubated with increasing concentrations of dexamethasone (DEX), Compound I, or their combination (1:1). After 5 days, cells were stained with Annexin V-APC (Biolegend, USA #640941), CD45-PE-Cy7 (Biolegend, USA #304016), CD34-PE (BD Biosciences #348057), CD19-PER-CP (BD Biosciences #347544) and CD7-FITC (BD Biosciences #347483), then washed and stained with DAPI before analysis using flow cytometry with increasing concentrations of dexamethasone (DEX), compound I, or their combination (1:1). Figure 4A shows the effect of dexamethasone (DEX) and compound I (IAPi), alone and in combination, on absolute cell numbers of T-ALL PDX cells. FIG. 4B shows the effect of dexamethasone (DEX) and compound I (IAPi), alone and in combination, on the percentage of cell death in T-ALL PDX cells.

[0179] T-ALL PDX cells were further analyzed by immunoblotting using the method described in Example 1. Figure 11A shows the effect of dexamethasone (DEX) and compound I (IAPi), alone and in combination, on the levels of cleaved PARP and cleaved caspase 3. Figure 11B shows the effect of dexamethasone (DEX) and compound I (IAPi), alone and in combination, on multiple surface and intracellular molecules involved in apoptosis, proliferation and stress response using single cell proteomic analysis 48 hours after treatment.

[0180] As shown in Figures 11A and 11B, treatment with compound I (IAPi) in combination with dexamethasone (DEX) increased the levels of cleaved PARP and cleaved caspase 3, suggesting increased apoptosis. Simultaneous analysis of cell proliferation, stress response and DNA damage using single-cell proteomic analysis showed downregulation of proliferation (Ki-67), stress response (ATF4, LC3B) and increased levels of cleaved PARP and cleaved caspase 3, suggesting increased apoptosis by the combination of compound I (IAPi) and DEX.

[0181] Example 3 The efficacy of the combination of Compound I with the Bcl2 inhibitor venetoclax (ABT-199, Compound II) was tested. The effect of the combination of Compound I with the Bcl2 inhibitor venetoclax (ABT-199, Compound II) was tested in T-ALL cell lines using increasing concentrations of Compound II, Compound I, or their combination (1:10) by the method described in Example 1, and the combination index (CI value) was calculated. The combination of Compound I and Compound II at a dose ratio of Compound II:Compound I of 1:10 was synergistic in LOUCY cell lines, with a combination index (CI) of 0.14. Cell death was increased to 64±3% with the combination compared to 27±0.9% with Compound II alone. Western blotting performed using the same method described in Example 1 showed a decrease in cIAP2 and an increase in the levels of cleaved caspase 7 and cleaved caspase 9 with the combination compared to Compound I or Compound II alone, suggesting an increased induction of apoptosis. The effect of the combination of Compound I and the Bcl2 inhibitor venetoclax (ABT-199, Compound II) in T-ALL PDX cells was tested using increasing concentrations of Compound II, Compound I, or their combination (1:10) by the methods described in Example 2. Ex vivo treatment of patient-derived xenograft cells (PDX-derived cells) with Compound I and Compound II significantly increased CD45+ bulk (46±0.7% vs. 63±6%, p<0.0001) and leukemic stem cells (LICs, CD45 + , CD7 + , CD19 - , CD34 +) (39±3% vs. 54±8%, p=0.003) was more effective than monotherapy in inducing apoptosis in

[0182] Figure 5A shows the effect of compound II (ABT199) and compound I (IAPi), alone and in combination, on the absolute cell number of T-ALL LOUCY cells. Figure 5B shows the effect of compound II (ABT199) and compound I (IAPi), alone and in combination, on the percentage of cell death of T-ALL LOUCY cells. CI refers to the combination index.

[0183] Figure 6A shows the effect of Compound II (ABT199) and Compound I (IAPi), alone and in combination, on the absolute cell number of T-ALL PDX cells. Figure 6B shows the effect of Compound II (ABT199) and Compound I (IAPi), alone and in combination, on the percentage of cell death of T-ALL PDX cells.

[0184] Absolute cell numbers and apoptosis were determined by flow cytometry-based bead counting and Annexin V binding assays as described herein. Combination Coefficients and IC 50 was determined using Calcusyn (BIOSOFT, Cambridge, UK).

[0185] Table 4 shows the IC 50 and ED 50 Shows. [Table 4]

[0186] FIG. 7 shows Western blot analysis demonstrating decreased expression of cIAP2 and PARP and increased cleaved caspase-7 in LOUCY cells in response to compound I (IAPi) alone and in combination with compound II (ABT199).

[0187] In ALL-SIL cells, using a dose ratio of 1:2.5 compound II:compound I, absolute cell counts were reduced to a greater extent with the combination compared to each individual agent alone, with IC 50 Values ​​indicate synergy when using combinations compared to single agents.

[0188] Example 4 The effects of the triple combination of DEX, Compound I and Compound II, and the double combination of DEX + Compound II in a dose ratio of 1:1:1 on T-ALL cell lines and T-ALL PDX cells were analyzed using flow cytometry, and the combination index and IC 50 was determined as described in the previous example. Immunoblotting was also performed as described in the previous example. The triple combination of DEX, Compound I and Compound II at a dose ratio of 1:1:1 increased the apoptotic response by 82.9±1%, compared to the dual combination of DEX+Compound II, which only induced apoptosis by 52.4±2%.

[0189] In SUPT11 cells, synergistic effects were observed in terms of both cell loss and induction of apoptosis. Compound I sensitized SUPT11 cells to DEX, reducing the ED of DEX treatment alone. 50 The ED of the combination was approximately 2 μM, compared with 50 The value was 542 nM. Simultaneous analysis of cell proliferation, stress response and DNA damage using single-cell proteomic analysis showed downregulation of proliferation (Ki-67), stress response (ATF4, LC3B) and elevated levels of cleaved PARP, cleaved caspase 3, suggesting increased apoptosis in response to the combination of Compound I and DEX. Ex vivo treatment of PDX with Compound I enhanced the cytotoxic effect of DEX in CD45+ bulk (58±2% vs. 71±0.1%, p<0.0001) and LIC (62±2% vs. 78±0.9%, p<0.0001).

[0190] Figure 8A shows the effect of compound II (ABT199), compound I (IAPi), and dexamethasone (DEX), alone and in combination, on the absolute cell number of T-ALL CCRF-CEM cells. Figure 8B shows the effect of compound II (ABT199), compound I (IAPi), and dexamethasone (DEX), alone and in combination, on the percentage of cell death of T-ALL CCRF-CEM cells. CI refers to the combination coefficient.

[0191] Figure 9A shows the effect of compound II (ABT199), compound I (IAPi) and dexamethasone (DEX) alone and in combination with the three agents on the absolute cell number of T-ALL SUPT11 cells. Figure 9B shows the effect of compound II (ABT199), compound I (IAPi) and dexamethasone (DEX) alone and in combination with the three agents on the percentage of cell death of T-ALL SUPT11 cells. CI refers to the combination coefficient.

[0192] Absolute cell numbers and apoptosis were determined by flow cytometry-based bead counting and Annexin V binding assays as described herein. Combination indices were determined using Calcusyn (BIOSOFT, Cambridge, UK). Combination indices are for the combination of Compound I (IAPi) versus the dual combination of Compound II (ABT199) and dexamethasone (ABT199+DEX).

[0193] Figure 10A shows the effect of Compound II (ABT199), Compound I (IAPi), and dexamethasone (DEX), alone and in a triple combination, on absolute cell counts in primary T-ALL patient samples. Figure 10B shows the effect of Compound II (ABT199), Compound I (IAPi), and dexamethasone (DEX), alone and in a triple combination, on percent cell death in primary T-ALL patient samples.

[0194] The triple combination of Compound I, Compound II, and DEX was effective in inducing apoptosis. The combination coefficient for the triple combination was less than 0.5, suggesting good synergy. The dual combination of DEX+IAPi (Compound I) was also effective. The dual combination of DEX+ABT199 (Compound II) (data not shown) was moderately effective.

[0195] Compound I was confirmed to synergize with the anti-leukemic activity of compound II and DEX, establishing the therapeutic rationale for IAP antagonists in the treatment of cancer. Data show a decrease in cIAP-2 and an increase in cleaved caspase-7 in response to compound I alone and in combination with ABT199. Furthermore, the triple combination of compound I, ABT199 and DEX significantly reduced leukemic stem cell (LIC, CD45) expression compared to single agent and / or dual agent therapy, as shown in Figures 10A-10B. + , CD7 + , CD19 - , CD34 + ) induced a much greater degree of apoptosis in LICs. Inhibition of IAPs (e.g., with Compound I) in combination with Bcl2 inhibition (e.g., with Compound II) and dexamethasone appears to shift the cytostatic effects of the single agents to cytotoxic effects in T-ALL progenitor cells and increase apoptosis in LICs.

[0196] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0197] The present invention illustratively described herein can be suitably implemented in the absence of any element or limitation not specifically disclosed herein. Thus, for example, the terms "comprising," "including," "containing," etc., are to be read expansively and without limitation. In addition, the terms and expressions used herein are used as terms of description and not of limitation, and in the use of such terms and expressions, there is no intention to exclude any equivalents of the illustrated and described features or portions thereof, but it is recognized that various modifications are possible within the scope of the invention as claimed.

[0198] Thus, while the present invention has been specifically disclosed by preferred embodiments and optional features, it is to be understood that modifications, improvements and variations of the invention embodied in the embodiments disclosed herein may be made by those skilled in the art, and such modifications, improvements and variations are considered to be within the scope of the present invention. The materials, methods, and examples provided herein are representative of preferred embodiments, are illustrative, and are not intended as limitations on the scope of the invention.

[0199] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety to the same extent as if each was individually incorporated by reference. In the case of conflict, the present specification, including definitions, will control.

[0200] While the present disclosure has been described in conjunction with the above embodiments, it should be understood that the foregoing description and examples are intended to illustrate, but not to limit, the scope of the present disclosure. Other aspects, advantages, and modifications within the scope of the present disclosure will be apparent to those skilled in the art to which this disclosure pertains.

Claims

1. Formula I: 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, for use in combination with a B-cell leukemia / lymphoma-2 (Bcl-2) inhibitor or a pharmaceutically acceptable salt thereof.

2. 2. The pharmaceutical composition of claim 1, wherein the Bcl-2 inhibitor is venetoclax (ABT-199) or navitoclax (ABT-263).

3. The pharmaceutical composition according to claim 1, further for use in combination with dexamethasone.

4. 10. The pharmaceutical composition of claim 1, further comprising one or more pharmaceutically acceptable excipients.

5. The pharmaceutical composition of claim 1 , wherein the cancer is a solid tumor or lymphoma.

6. 2. The pharmaceutical composition of claim 1, wherein the cancer is recurrent / metastatic head and neck squamous cell carcinoma (HNSCC), relapsed or refractory diffuse large B-cell lymphoma (DLBCL), advanced or relapsed peripheral T-cell lymphoma (PTCL), relapsed or refractory cutaneous T-cell lymphoma (CTCL), or cervical cancer.

7. The pharmaceutical composition of claim 1 , wherein the cancer is leukemia.

8. The pharmaceutical composition of claim 7, wherein the leukemia is T-cell acute lymphoblastic leukemia (T-ALL).

9. The pharmaceutical composition of claim 7, wherein the cancer is resistant to dexamethasone.

10. Formula I: 【Chemistry 2】 or a pharmaceutically acceptable salt thereof; and B-cell leukemia / lymphoma-2 (Bcl-2) inhibitors or pharmaceutically acceptable salts thereof A kit or combination medicine for treating cancer, comprising:

11. The kit or pharmaceutical combination of claim 10, wherein the Bcl-2 inhibitor is venetoclax (ABT-199) or navitoclax (ABT-263).

12. The kit or combination drug of claim 10, further comprising dexamethasone.

13. 11. The kit or pharmaceutical combination of claim 10, further comprising one or more pharmaceutically acceptable excipients.

14. The kit or combined pharmaceutical composition according to claim 10, wherein the cancer is a solid tumor or lymphoma.

15. The kit or combination pharmaceutical of claim 10, wherein the cancer is recurrent / metastatic head and neck squamous cell carcinoma (HNSCC), relapsed or refractory diffuse large B-cell lymphoma (DLBCL), progressive or relapsed peripheral T-cell lymphoma (PTCL), relapsed or refractory cutaneous T-cell lymphoma (CTCL), or cervical cancer.

16. The kit or pharmaceutical combination according to claim 10, wherein the cancer is leukemia.

17. The kit or combined pharmaceutical of claim 16, wherein the leukemia is T-cell acute lymphoblastic leukemia (T-ALL).

18. The kit or pharmaceutical combination of claim 10, wherein the cancer is resistant to dexamethasone.

19. Formula I: 【Transformation 3】 or a pharmaceutically acceptable salt thereof, wherein the cancer is a cancer that is resistant to the chemotherapeutic agent.

20. 20. The pharmaceutical composition of claim 19, wherein the chemotherapeutic agent is dexamethasone.

21. 20. The pharmaceutical composition of claim 19, further for use in combination with a B-cell leukemia / lymphoma-2 (Bcl-2) inhibitor, or a pharmaceutically acceptable salt thereof.

22. 21. The pharmaceutical composition of claim 20, wherein the cancer that is resistant to the chemotherapeutic agent is dexamethasone-resistant leukemia.

23. The pharmaceutical composition of claim 20, wherein the cancer resistant to the chemotherapeutic agent is dexamethasone-resistant T-ALL.

24. Formula I: 【Chemistry 4】 or a pharmaceutically acceptable salt thereof; and chemotherapy drugs 10. A kit or a combination medicine for treating cancer, comprising:

25. The kit or pharmaceutical combination of claim 24, wherein the chemotherapeutic agent is dexamethasone.

26. The kit or pharmaceutical combination according to claim 24, wherein the cancer resistant to the chemotherapeutic agent is dexamethasone-resistant leukemia.

27. The kit or combined pharmaceutical composition according to claim 24, wherein the cancer resistant to the chemotherapeutic agent is dexamethasone-resistant T-ALL.

28. 25. The pharmaceutical composition of any one of claims 1 to 9 and 19 to 24, wherein the compound or a pharmaceutically acceptable salt thereof is administered once daily for 7 consecutive days every other week of each 28-day cycle.

29. 28. The kit or pharmaceutical combination according to any one of claims 10 to 18 and 25 to 27, wherein the compound or a pharmaceutically acceptable salt thereof is administered once daily for 7 consecutive days every other week of each 28-day cycle.

30. 10. The pharmaceutical composition of any one of claims 1 to 9, wherein the pharmaceutical composition is administered simultaneously or sequentially with the B-cell leukemia / lymphoma-2 (Bcl-2) inhibitor.

31. The pharmaceutical composition according to any one of claims 19 to 24, wherein the pharmaceutical composition is administered simultaneously or sequentially with a chemotherapeutic agent.

32. The kit or pharmaceutical combination of any one of claims 10 to 18, wherein the pharmaceutical composition is administered simultaneously or sequentially with the B-cell leukemia / lymphoma-2 (Bcl-2) inhibitor.

33. The kit or pharmaceutical combination according to any one of claims 25 to 27, wherein the pharmaceutical composition is administered simultaneously or sequentially with a chemotherapeutic agent.

34. Formula I: 【Transformation 5】 or a pharmaceutically acceptable salt thereof, for use in combination with a B-cell leukemia / lymphoma-2 (Bcl-2) inhibitor or a pharmaceutically acceptable salt thereof.

35. 35. The cancer chemotherapy sensitizing agent of claim 34, wherein the Bcl-2 inhibitor is venetoclax (ABT-199) or navitoclax (ABT-263).

36. The chemotherapy sensitizing agent for cancer according to claim 34, further to be used in combination with dexamethasone.

37. 35. The cancer chemotherapy sensitizing agent of claim 34, further comprising one or more pharmaceutically acceptable excipients.

38. The cancer chemotherapy sensitizing agent of claim 34, wherein the cancer is a solid tumor or lymphoma.

39. 35. The chemotherapy sensitizing agent for cancer of claim 34, wherein the cancer is recurrent / metastatic head and neck squamous cell carcinoma (HNSCC), relapsed or refractory diffuse large B-cell lymphoma (DLBCL), progressive or relapsed peripheral T-cell lymphoma (PTCL), relapsed or refractory cutaneous T-cell lymphoma (CTCL), or cervical cancer.

40. 35. The cancer chemotherapy sensitizing agent of claim 34, wherein the cancer is leukemia.

41. 35. The cancer chemotherapy sensitizing agent of claim 34, wherein the leukemia is T-cell acute lymphoblastic leukemia (T-ALL).

42. 35. The cancer chemotherapy sensitizing agent of claim 34, wherein the cancer is resistant to dexamethasone.

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