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WO2025126110A1 - Ent1 inhibitors in combination with bispecific antibodies - Google Patents

Ent1 inhibitors in combination with bispecific antibodies Download PDF

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Publication number
WO2025126110A1
WO2025126110A1 PCT/IB2024/062579 IB2024062579W WO2025126110A1 WO 2025126110 A1 WO2025126110 A1 WO 2025126110A1 IB 2024062579 W IB2024062579 W IB 2024062579W WO 2025126110 A1 WO2025126110 A1 WO 2025126110A1
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WO
WIPO (PCT)
Prior art keywords
diazepana
oxo
benzenacyclotetradecaphane
dimethoxy
dioxa
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PCT/IB2024/062579
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French (fr)
Inventor
Theodore Sanders
Yvonne MCGRATH
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Iteos Belgium SA
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Iteos Belgium SA
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Publication of WO2025126110A1 publication Critical patent/WO2025126110A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/46—Hybrid immunoglobulins
    • C07K16/468—Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
    • C07D273/08—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00 having two nitrogen atoms and more than one oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • BsAb bispecific antibody
  • the BsAb is a bispecific antibody (BsAb) cancer therapy.
  • Non-IgG- like antibodies is the bispecific T-cell engager (BiTE®), which uses a linker to connect two single chain variable fragments (ScFv).
  • BiTE® bispecific T-cell engager
  • One of these targets CD3 and the other is directed to a tumor-associated antigen. This redirects T cells to cancer cells expressing the relevant antigen and promotes targeted killing (Ross et al., 2017, PLoS ONE, 12(8), e0183390, https://doi.org/10.1371/joumal.pone.0183390).
  • BsAbs include recruitment and activation of immune cells, blocking of immune checkpoints, blocking inflammatory factors and blocking of dual signaling pathways (Ma et al., 2021, Frontiers in Immunology, 12, 626616, https://doi.org/10.3389/fimmu.2021.626616).
  • bispecific antibodies (BsAb) in treating cancer has been largely restricted to hematological malignances.
  • BsAb bispecific antibodies
  • T cell and anti-CD3 BsAb only tebentafusp, a natural T-cell receptor (TCR) anti-CD3 bispecific, has succeeded in being licensed for a solid tumor, specifically uveal melanoma (Nathan et al., 2021, N Engl J Med, 385: 1196-1206).
  • Adenosine which can be found in very high levels in solid tumors, can enact widespread immunosuppression on multiple immune cell types. For example, it can prevent T cell activation and proliferation, two critical functions essential to the mechanism of action of T cell BsAbs.
  • the equilibrative nucleoside transporter (ENT) family also known as SLC29, is a group of plasmalemmal transport proteins which transport nucleosides into cells. There are four known ENTs, designated ENT1, ENT2, ENT3, and ENT4.
  • Adenosine is one of the endogenous substrates for ENTs.
  • the intake of extracellular adenosine via ENT1 transporter by lymphocytes has been shown to interfere with pyrimidine biosynthesis and prevent T cell activation and proliferation.
  • ENT inhibitors have been shown to block the intake of extracellular adenosine by blocking the ENT1 transporter. Accordingly, the disclosure herein relates at least in part to the combination of
  • a combination of an ENT1 inhibitor and a bispecific antibody (BsAb) cancer therapy is provided herein.
  • the combination is for use in treating cancer.
  • a method of treating cancer comprising administering to a subject in need thereof an ENT1 inhibitor and a bispecific antibody (BsAb) cancer therapy.
  • BsAb bispecific antibody
  • ENT1 inhibitor and a bispecific antibody (BsAb) cancer therapy for the treatment of cancer.
  • BsAb bispecific antibody
  • the bispecific antibody of the bispecific antibody (BsAb) cancer therapy comprises an antigen-binding domain that binds to an antigen expressed on a T cell, natural killer (NK) cell, macrophages, dendritic cells (DCs), or a combination thereof.
  • NK natural killer
  • DCs dendritic cells
  • the bispecific antibody of the bispecific antibody (BsAb) cancer therapy comprises an antigen-binding domain that binds to an antigen selected from CD3, ⁇ TCR, CD 16, CD47, and a combination thereof.
  • the bispecific antibody of the bispecific antibody (BsAb) cancer therapy comprises an antigen-binding domain that binds to an antigen expressed on a cancer cell.
  • the antigen is selected from BCMA, CD 123, CD33, CD38, CEA, CLEC12A, DLL3, EpCAM, FcRH5, FLT3, GD2, Glypican-3, gpA33, GPRC5D, CD47, CD19, CD20, 4-1BB, HER-2, PD-1, EGFR, EGFRvIII, PD-L1, CD3, MAGE-A4, MUC17, MUC16, NY-ESO-1, p-cadherin, PRAME, PSCA, PSMA, SSTR2, STEAP1, 5T4, CDld, B7H3, GPC3, MSLN, CLDN18.2, B7H4, CDH17, CDH3, CEACAM5, CLDN6, ENPP3, ITGB6, KRASG12V, LY6G6D, MAGE-A3, TMEFF2,
  • TR0P2, WT1 and/or a combination thereof are examples of TR0P2, WT1 and/or a combination thereof.
  • the ENT1 inhibitor is a compound of Formula (I): or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein
  • R 1 is selected from the group consisting of each R 2 is independently selected from the group consisting of absent, halogen, -NHR 3 , -OR 3 , -R 3 , -C(O)R 3 , -CO 2 R 3 , C(O)N(R 3 ) 2 , -CH 2 C(O)N(R 3 ) 2 , - S(O) 2 R 3 , and -CN; or two instances of R 2 are taken together with the atoms on which they are attached to form a heterocyclyl or heteroaryl ring; each R 3 is independently selected from absent, -H, oxo, ALK, phenyl, heterocyclyl, and heteroaryl; R 4 is selected from the group consisting of each U is independently selected from the group consisting of -C(O)-, alkylene, -O-, -N(R 3 )-, -C(O)O-, -C(O)N(R 3 )-, each R
  • Z is C or N, wherein ALK is unsubstituted alkyl or substituted alkyl, or two instances of ALK may be joined together with their intervening atoms to form a cycloalkyl or heterocyclyl ring.
  • the ENT1 inhibitor is a compound of Formula (II): or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein
  • R 1 is selected from the group consisting of ALK, cycloalkyl, heterocyclyl
  • each R 2 is independently selected from the group consisting of absent, halogen, -OR 3 , -R 3 , -CO 2 R 3 , C(O)N(R 3 ) 2 , -CH 2 C(O)N(R 3 ) 2 , -S(O) 2 R 3 , and -CN; or two instances of R 2 are taken together with the atoms on which they are attached to form a heterocyclyl or heteroaryl ring; each R 3 is independently selected from absent, -H, ALK, phenyl, and heteroaryl;
  • X is selected from the group consisting of -CH 2 -, -CHF-, and -CF 2 -; each U is independently selected from the group consisting of -O-, -N(R 3 )-, -
  • the ENT1 inhibitor is a compound of Formula (Ila): or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein X is CH 2 , CHF, or CF 2 .
  • R 1 is [0018] in a compound of Formula (I), (II), or (Ila), R 1 is [0019] in some embodiments, in a compound of Formula (I), (II), or (Ila), R 1 is
  • the compound is a compound of Formula (Ilb): or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
  • R 4 is the U in R 4 is -C(O)O- or -C(O)NR 3 -.
  • the compound is a compound of Formula (Ilal):
  • the ENT1 inhibitor is selected from:
  • (12S)-7 4 -carbamoyl-7 5 -chloro-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
  • alkylsulfoxidealkyl refers to a group -alkyl-SO-alkyl wherein alkyl is as herein defined.
  • alkylene refers to an alkyl group, as defined above, wherein one of the alkyl group's hydrogen atoms has been replaced with a bond. Alkylene groups possess two points of attachment. Non-limiting examples of alkylene groups include — CH 2 — , — CH 2 CH 2 — , — CH 2 CH 2 CH 2 — , — CH 2 CH 2 CH 2 CH 2 — , — CH(CH 3 )CH 2 CH 2 — , —CH(CH 3 ) — and CH 2 CH(CH 3 )CH 2 — . In one embodiment, an alkylene group has from 1 to about 6 carbon atoms.
  • an alkylene group has from about 3 to about 5 carbon atoms. In another embodiment, an alkylene group is branched. In another embodiment, an alkylene group is linear. In one embodiment, an alkylene group is — CH 2 — .
  • At least one hydrogen atom of an alkylene group is substituted by a substituent such as halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, cycloalkoxy, heterocyclooxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, cycloalkylamino, heterocycloamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or aralkyl, alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio, cycloalkylthio, heterocyclothio, alkyl
  • substituent when the substituent is further substituted, it may be substituted with halogen, alkyl, alkoxy, aryl or aralkyl.
  • at least one hydrogen atom of an alkylene group is substituted by -OH, alkoxy, -CF 3 , or - NR 2 .
  • alkyne refers to a class of monovalent unsaturated hydrocarbyl groups, wherein the unsaturation arises from the presence of one or more carbon-carbon triple bonds. Alkynyl groups typically have the same number of carbon atoms as described above in relation to alkyl groups. Non-1imiting examples of alkynyl groups are ethynyl, 2- propynyl, 2- butynyl, 3-butynyl, 2-pentynyl and its isomers, 2-hexynyl and its isomers and the like.
  • alkynealkyl refers to a group -alkyl-alkyne wherein alkyl and alkyne are as herein defined.
  • amino refers to a group -NH 2 .
  • aminoalkyl refers to a group -alkyl-NH 2 wherein alkyl is as herein defined.
  • aminosulfonyl refers to a group -SO 2 -NH 2 .
  • aryl refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring (i.e. phenyl) or multiple aromatic rings fused together (e.g. naphtyl), typically containing 5 to 12 atoms; for example, 5 to 10 atoms.
  • the aryl is a 5- or 6-membered aryl.
  • Non-1imiting examples of aryl include phenyl and naphthal enyl.
  • arylalkyl refers to a group -alkyl-aryl wherein alkyl and aryl are as herein defined.
  • aryloxyalkyl refers to a group -alkyl-O-aryl wherein alkyl and aryl are as herein defined.
  • cycloalkyl refers to a cyclic alkyl group, that is to say, a monovalent, saturated, or unsaturated hydrocarbyl group having 1 or more cyclic structures.
  • Cycloalkyl includes monocyclic or bicyclic hydrocarbyl groups. Cycloalkyl groups may comprise 3 or more carbon atoms in the ring and, in some embodiments, comprise from 3 to 10 carbon atoms, for example from 3 to 8 carbon atoms.
  • cycloalkyl is a 5- or 6- membered cycloalkyl. Examples of cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • cycloalkyloxy refers to a group -O-cycloalkyl wherein cycloalkyl is as herein defined.
  • dialkylamino refers to a group -NR 1 R 2 wherein R 1 and R 2 are both independently alkyl group as herein defined.
  • dialkylaminoalkyl refers to a group -alkyl-NR 1 R 2 wherein R 1 and R 2 are both independently alkyl group, as herein defined.
  • dihydroxyalkyl refers to a group alkyl is as herein defined substituted by two hydroxyl (-OH) groups.
  • halo or halogen refers to fluoro, chloro, bromo, or iodo.
  • haloalkyl refers to an alkyl group in which one or more hydrogen atom is replaced by a halogen atom.
  • haloalkyloxy refers to a group -O-haloalkyl wherein alkyl is as herein defined.
  • heteroaryl refers to an aryl group as herein defined wherein at least one carbon atom is replaced with a heteroatom. In some embodiments, it refers to 5 to 12 carbon-atom aromatic single rings or ring systems containing 2 rings which are fused together, in some instances containing 5 to 6 atoms, in which one or more carbon atoms is replaced by a heteroatom such as an oxygen, nitrogen and/or sulfur atoms where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized.
  • Non-1imiting examples of heteroaryls include: pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • (heterocyclyl)(alkyl)aminoalkyl refers to a group -alkyl-NR x R 2 wherein R 1 is an alkyl group and R 2 is a heterocyclyl group, wherein alkyl and heterocyclyl are as herein defined.
  • heterocyclyloxy refers to a group -O-heterocyclyl wherein heterocyclyl is as herein defined.
  • heterocyclylsulfonyl refers to a group - SO 2 -heterocyclyl wherein heterocyclyl is as herein defined.
  • hydroxy or “hydroxyl” refers to a group -OH.
  • hydroxyalkyl refers to a group -alkyl-OH wherein alkyl is as herein defined.
  • hydroxyalkylaminoalkyl refers to a group -alkyl-NH-alkyl-OH wherein alkyl is as herein defined.
  • sulfonylamino refers to a group -NH-SO 2 .
  • administration means providing the active agent or active ingredient, alone or as part of a pharmaceutically acceptable composition, to the patient in whom/which the condition, symptom, or disease is to be treated or prevented.
  • BsAbs bispecific antibodies
  • chemotherapy refers to a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents) as part of a standardized chemotherapy regimen. Chemotherapy may be given with a curative intent or it may aim to prolong life or to reduce symptoms. Chemotherapeutic agents are for example selected from anticancer alkylating agents, anticancer antimetabolites, anticancer antibiotics, plant-derived anticancer agents, anticancer platinum coordination compounds and any combination thereof.
  • hormone therapy refers to the use of hormones in medical treatment.
  • the hormone therapy is oncologic hormone therapy.
  • the term “patient” refers to a mammal, such as a human, who/which is awaiting the receipt of, or is receiving medical care, or was/is/will be the object of a medical procedure or is monitored for the development or progression of a disease, such as a cancer.
  • pharmaceutically acceptable refers to compounds, salts, compositions, dosage forms, and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” or “excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • the combinations, methods and uses described herein can further comprise an additional therapeutic agent.
  • the additional therapeutic agent is an anti-PD-L1 agent.
  • the anti-PD-L1 agent is as atezolizumab.
  • COMPOUND 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof inhibits adenosine uptake into activated human T cells. In some embodiments, COMPOUND 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof inhibits adenosine uptake into activated human T cells with sub-nanomolar potency. In one embodiment, COMPOUND 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof dose-dependently restores T cell proliferation in the presence of ATP acting as a source of adenosine.
  • any ENT1 inhibitor may be used in the combinations, methods, and uses disclosed herein.
  • the ENT1 inhibitor is a small molecule, a nucleic acid, a peptide, or an antibody.
  • the ENT1 inhibitor is an ENT1 inhibitor such as those disclosed in WO 2021/170797, WO 2021/204896, and WO 2023/059739, the contents of each being incorporated herein by reference in their entirety.
  • R 1 is selected from the group consisting of each R 2 is independently selected from the group consisting of absent, halogen, -NHR 3 , -OR 3 , -R 3 , -C(O)R 3 , -CO 2 R 3 , C(O)N(R 3 ) 2 , -CH 2 C(O)N(R 3 ) 2 , - S(O) 2 R 3 , and -CN; or two instances of R 2 are taken together with the atoms on which they are attached to form a heterocyclyl or heteroaryl ring; each R 3 is independently selected from absent, -H, oxo, ALK, phenyl, heterocyclyl, and heteroaryl; R 4 is selected from the group consisting of each U is independently selected from the group consisting of -C(O)-, alkylene, -O-, -N(R 3 )-, -C(O)O-, -C(O)N(R 3 )-, and each
  • Z is C or N, wherein ALK is unsubstituted alkyl or substituted alkyl, or two instances of ALK may be joined together with their intervening atoms to form a cycloalkyl or heterocyclyl ring.
  • the ENT1 inhibitor is a compound of Formula (II): or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein
  • R 1 is selected from the group consisting of ALK, cycloalkyl, heterocyclyl
  • each R 2 is independently selected from the group consisting of absent, halogen, -OR 3 , -R 3 , -CO 2 R 3 , C(O)N(R 3 ) 2 , -CH 2 C(O)N(R 3 ) 2 , -S(O) 2 R 3 , and -CN; or two instances of R 2 are taken together with the atoms on which they are attached to form a heterocyclyl or heteroaryl ring; each R 3 is independently selected from absent, -H, ALK, phenyl, and heteroaryl;
  • X is selected from the group consisting of -CH 2 -, -CHF-, and -CF 2 -; each U is independently selected from the group consisting of -O-, -N(R 3 )-, -
  • the ENT1 inhibitor is a compound of Formula (Ila): or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein X is CH 2 , CHF, or CF 2 .
  • R 1 is [00140] In some embodiments, in a compound of Formula (I), (II), or (Ila), R 1 is
  • the ENT1 inhibitor is a compound of Formula (Ilb): or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
  • the ENT1 inhibitors can optionally contain or be mixed with other substances that are commonly used in pharmaceutical compositions, such as lubricating agents, wetting agents, emulsifying and suspending agents, dispersing agents, disintegrants, bulking agents, fillers, preserving agents, sweetening agents, flavoring agents, flow regulators, release agents, etc. They may also be formulated so as to provide rapid, sustained or delayed release of the active compound(s) contained therein.
  • Tablets can be prepared by direct compression, by wet granulation, or by dry granulation. Their formulations may incorporate diluents, binders, lubricants and disintegrators as well as the compound. Diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful. Tablet binders may be substances such as starch, gelatin and sugars such as lactose, fructose, glucose and the like. Natural and synthetic gums are also convenient, including acacia, alginates, methylcellulose, polyvinylpyrrolidine and the like. Polyethylene glycol, ethylcellulose and waxes can also serve as binders.
  • Diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sul
  • Solid cancers and non-solid cancers include solid cancers and non-solid cancers, especially benign and malignant solid tumors and benign and malignant non-solid tumors.
  • the cancer may be metastatic or non-metastatic.
  • the cancer may be familial or sporadic.
  • the cancer is a solid-tumor cancer.
  • solid cancer encompasses any cancer (also referred to as malignancy) that forms a discrete tumor mass, as opposed to cancers (or malignancies) that diffusely infiltrate a tissue without forming a mass.
  • the cancer is a non-solid cancer.
  • non-solid tumors include but are not limited to hematological neoplasms.
  • a hematologic neoplasm is a term of art which includes lymphoid disorders, myeloid disorders, and AIDS associated leukemias.
  • Lymphoid disorders include but are not limited to acute lymphocytic leukemia and chronic lymphoproliferative disorders (e.g., lymphomas, myelomas such as multiple myeloma, and chronic lymphoid leukemias). Lymphomas include, for example, Hodgkin’s disease, non-Hodgkin’s lymphoma, follicular lymphoma, mantle cell lymphoma, acute lymphoblastic leukemia, and lymphocytic lymphomas.
  • Chronic lymphoid leukemias include, for example, T cell chronic lymphoid leukemias and B cell chronic lymphoid leukemias.
  • the cancer is characterized by a high concentration of adenosine in the tumor microenvironment (TME).
  • TAE tumor microenvironment
  • the cancer is selected from malignant ascites, acute lymphocytic (ALL) including Philadelphia chromosome-negative precursor B-cell ALL, follicular lymphoma (FL) including relapsed or refractory FL, melanoma including uveal melanoma, multiple myeloma (MM) including relapsed or refractory MM, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), cervical cancer (CC) including relapsed or metastatic CC, acute myeloid leukemia (AML), diffuse large B-cell lymphoma (DLBCL) solid tumors including MUC 17-positive solid tumors, ovarian cancer including recurrent ovarian cancer, neoplasms, neuroendrocrine tumors, prostate cancer, chronic lymphocytic leukemia (CLL), prostate cancer including metastatic castration resistant prostate cancer, non-Hodgkin lymphoma (NHL), and colorectal cancer including micros
  • ALL acute lymphocy
  • the cancer is selected from cervical cancer (CC), colorectal cancer, lung cancer including SCLC and NSCLC, melanoma, ovarian cancer, and prostate cancer.
  • the cancer is breast cancer. In some embodiments, the breast cancer is triple negative breast cancer.
  • the cancer is a solid-tumor cancer.
  • the ENT1 inhibitor is administered prior to, concomitant with, or subsequent to the administration of the bispecific antibody (BsAb) cancer therapy. In some embodiments, the ENT1 inhibitor is administered prior to administration of the bispecific antibody (BsAb) cancer therapy. In some embodiments, the ENT1 inhibitor is administered concomitant with administration of the bispecific antibody (BsAb) cancer therapy. In some embodiments, the ENT1 inhibitor is administered subsequent to administration of the bispecific antibody (BsAb) cancer therapy.
  • the active compound may be administered as a single daily dose, divided over one or more daily doses, or essentially continuously, e.g. using a drip infusion.
  • the subject is receiving or has previously received at least one therapeutic treatment in addition to administration of the ENT1 inhibitor and the bispecific antibody (BsAb) cancer therapy.
  • the therapeutic treatment is selected from chemotherapy, a non-bispecific antibody (BsAb) cancer therapy immunotherapy, radiation therapy, stem cell transplant, hormone therapy, and surgery.
  • the therapeutic treatment is chemotherapy.
  • the chemotherapy is an adenosine receptor antagonist (ARA).
  • the ARA is selected from those disclosed in WO 2018/178338.
  • the ARA is a compound having the following structure: and named 5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfmyl)ethoxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one.
  • the ARA is selected from 5-amino-3-(2-(4-(2,4-difluoro-
  • the ARA is (S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2- (methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
  • the ARA is (S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2- (methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one hydrochloride.
  • Embodiment 1 A combination of an ENT1 inhibitor and a bispecific antibody (BsAb) cancer therapy.
  • BsAb bispecific antibody
  • Embodiment 2 A method of treating cancer comprising administering to a subject in need thereof an ENT1 inhibitor and a bispecific antibody (BsAb) cancer therapy.
  • BsAb bispecific antibody
  • Embodiment 3 A use of an ENT1 inhibitor and a bispecific antibody
  • Embodiment 4 The combination, method or use according to any one of Embodiments 1-3, wherein the bispecific antibody of the bispecific antibody (BsAb) cancer therapy comprises an antigen-binding domain that binds to an antigen expressed on a T cell, natural killer (NK) cell, macrophages, dendritic cells (DCs), or a combination thereof.
  • Embodiment 5. The combination, method or use according to any one of Embodiments 1-3, wherein the bispecific antibody of the bispecific antibody (BsAb) cancer therapy comprises an antigen-binding domain that binds to an antigen selected from CD3, ⁇ TCR, CD 16, CD47, and a combination thereof.
  • Embodiment 6 The combination, method or use according to any one of Embodiments 1-5, wherein the bispecific antibody of the bispecific antibody (BsAb) cancer therapy comprises an antigen-binding domain that binds to an antigen expressed on a cancer cell.
  • the bispecific antibody of the bispecific antibody (BsAb) cancer therapy comprises an antigen-binding domain that binds to an antigen expressed on a cancer cell.
  • Embodiment 7 The combination, method, or use according to Embodiment 6, wherein the bispecific antibody of the bispecific antibody (BsAb) cancer therapy comprises an antigen-binding domain that binds to an antigen selected from BCMA, CD123, CD33, CD38, CEA, CLEC12A, DLL3, DLL4, EpCAM, FcRH5, FLT3, GD2, Glypican-3, gpA33, GPRC5D, CD47, CD19, CD20, 4-1BB, HER-2, HER-3, PD-1, EGFR, EGFRvIII, PD-L1, CD3, MAGE-A4, MUC17, MUC16, NY-ESO-1, p-cadherin, PRAME, PSCA, PSMA, SSTR2, STEAP1, 5T4, CDld, B7H3, GPC3, MSLN, ICOS, CTLA4, LAG3, TIM3, Ang-2, c-MET, LGR5, FAP, DR5, CLDN18
  • Embodiment 8 The combination, method or use according to any one of Embodiments 1-7, wherein the ENT1 inhibitor is a compound of Formula (I): or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 1 is selected from the group consisting of each R 2 is independently selected from the group consisting of absent, halogen, -NHR 3 , -OR 3 , -R 3 , -C(O)R 3 , -CO 2 R 3 , C(O)N(R 3 ) 2 , -CH 2 C(O)N(R 3 ) 2 , - S(O) 2 R 3 , and -CN; or two instances of R 2 are taken together with the atoms on which they are attached to form a heterocyclyl or heteroaryl ring; each R 3 is independently selected from absent, -H, oxo, ALK, phenyl, heterocyclyl, and heteroaryl;
  • R 4 is selected from the group consisting each U is independently selected from the group consisting of -C(O)-, alkylene, -0-, -N(R 3 )-, -C(O)O-, -C(O)N(R 3 )-, and each R x is independently selected from alkylene;

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Abstract

Disclosed herein are combinations, methods, and uses comprising administering an ENT1 inhibitor and a bispecific antibody (BsAb) cancer therapy for the treatment of a disease. In some embodiments, the disease is cancer.

Description

ENT1 INHIBITORS IN COMBINATION WITH BISPECIFIC ANTIBODIES
DESCRIPTION
CROSS REFERENCE TO RELATED APPLICATIONS
[001] This application claims priority to U.S. Provisional Application No. 63/610,714, filed December 15, 2023, the entire contents of which are incorporated by reference herein for all purposes.
FIELD
[002] Disclosed herein are combinations, methods, and uses comprising administering an ENT1 inhibitor and a bispecific antibody (BsAb). In some embodiments, the BsAb is a bispecific antibody (BsAb) cancer therapy.
BACKGROUND
[003] Bispecific antibodies (BsAbs) are antibodies with two binding sites directed at two different antigens or two different epitopes on the same antigen with broad applications for tumor immunotherapy as well as for the treatment of other diseases (Ma et al., 2021, Frontiers in Immunology, 12, 626616, https://doi.org/10.3389/fimmu.2021.626616). Various platforms for generating different types of BsAbs for various uses, have been established, based on the heterologous recombination of heavy chains and matching of light chains. These may be divided broadly into IgG-like and non-IgG-like BsAbs. One example of the non-IgG- like antibodies is the bispecific T-cell engager (BiTE®), which uses a linker to connect two single chain variable fragments (ScFv). One of these targets CD3 and the other is directed to a tumor-associated antigen. This redirects T cells to cancer cells expressing the relevant antigen and promotes targeted killing (Ross et al., 2017, PLoS ONE, 12(8), e0183390, https://doi.org/10.1371/joumal.pone.0183390). Other strategies of BsAbs include recruitment and activation of immune cells, blocking of immune checkpoints, blocking inflammatory factors and blocking of dual signaling pathways (Ma et al., 2021, Frontiers in Immunology, 12, 626616, https://doi.org/10.3389/fimmu.2021.626616).
[004] To date, the success of bispecific antibodies (BsAb) in treating cancer has been largely restricted to hematological malignances. (Wu Y et al., 2021, Exp Hematol Oncol, 10:56, doi: 10.1186/s40164-021-00250-1.) To date, amongst T cell and anti-CD3 BsAb, only tebentafusp, a natural T-cell receptor (TCR) anti-CD3 bispecific, has succeeded in being licensed for a solid tumor, specifically uveal melanoma (Nathan et al., 2021, N Engl J Med, 385: 1196-1206).
[005] There are likely multiple reasons why solid tumor may be more refractory than hematological tumors to cell and BsAbs. One challenge that is shared is the presence of the highly immunosuppressive metabolite adenosine. Adenosine, which can be found in very high levels in solid tumors, can enact widespread immunosuppression on multiple immune cell types. For example, it can prevent T cell activation and proliferation, two critical functions essential to the mechanism of action of T cell BsAbs.
[006] The equilibrative nucleoside transporter (ENT) family, also known as SLC29, is a group of plasmalemmal transport proteins which transport nucleosides into cells. There are four known ENTs, designated ENT1, ENT2, ENT3, and ENT4.
[007] Adenosine is one of the endogenous substrates for ENTs. The intake of extracellular adenosine via ENT1 transporter by lymphocytes has been shown to interfere with pyrimidine biosynthesis and prevent T cell activation and proliferation. ENT inhibitors have been shown to block the intake of extracellular adenosine by blocking the ENT1 transporter. Accordingly, the disclosure herein relates at least in part to the combination of
ENT1 inhibitors and BsAbs for the treatment of diseases, such as cancer. SUMMARY
[008] In some embodiments, provided herein is a combination of an ENT1 inhibitor and a bispecific antibody (BsAb) cancer therapy. In some embodiments, the combination is for use in treating cancer.
[009] In some embodiments, provided herein is a method of treating cancer comprising administering to a subject in need thereof an ENT1 inhibitor and a bispecific antibody (BsAb) cancer therapy.
[0010] In some embodiments, provided herein is a use of an ENT1 inhibitor and a bispecific antibody (BsAb) cancer therapy for the treatment of cancer.
[0011] In some embodiments, the bispecific antibody of the bispecific antibody (BsAb) cancer therapy comprises an antigen-binding domain that binds to an antigen expressed on a T cell, natural killer (NK) cell, macrophages, dendritic cells (DCs), or a combination thereof.
[0012] In some embodiments, the bispecific antibody of the bispecific antibody (BsAb) cancer therapy comprises an antigen-binding domain that binds to an antigen selected from CD3, γδTCR, CD 16, CD47, and a combination thereof.
[0013] In some embodiments, the bispecific antibody of the bispecific antibody (BsAb) cancer therapy comprises an antigen-binding domain that binds to an antigen expressed on a cancer cell.
[0014] In some embodiments, the antigen is selected from BCMA, CD 123, CD33, CD38, CEA, CLEC12A, DLL3, EpCAM, FcRH5, FLT3, GD2, Glypican-3, gpA33, GPRC5D, CD47, CD19, CD20, 4-1BB, HER-2, PD-1, EGFR, EGFRvIII, PD-L1, CD3, MAGE-A4, MUC17, MUC16, NY-ESO-1, p-cadherin, PRAME, PSCA, PSMA, SSTR2, STEAP1, 5T4, CDld, B7H3, GPC3, MSLN, CLDN18.2, B7H4, CDH17, CDH3, CEACAM5, CLDN6, ENPP3, ITGB6, KRASG12V, LY6G6D, MAGE-A3, TMEFF2,
TR0P2, WT1 and/or a combination thereof.
[0015] In some embodiments, the ENT1 inhibitor is a compound of Formula (I):
Figure imgf000005_0001
or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein
R1 is selected from the group consisting of
Figure imgf000005_0002
each R2 is independently selected from the group consisting of absent, halogen, -NHR3, -OR3, -R3, -C(O)R3, -CO2R3, C(O)N(R3)2, -CH2C(O)N(R3)2, - S(O)2R3, and -CN; or two instances of R2 are taken together with the atoms on which they are attached to form a heterocyclyl or heteroaryl ring; each R3 is independently selected from absent, -H, oxo, ALK, phenyl, heterocyclyl, and heteroaryl; R4 is selected from the group consisting of
Figure imgf000006_0001
Figure imgf000006_0002
each U is independently selected from the group consisting of -C(O)-, alkylene, -O-, -N(R3)-, -C(O)O-, -C(O)N(R3)-,
Figure imgf000006_0003
each Rx is independently selected from alkylene; is selected from -C(R3)- and -N-; each V2 is independently selected from -C(R3)=, -N(R3)-, -N=, and -O-;
V3 is selected from -C= and -N-; and
Z is C or N, wherein ALK is unsubstituted alkyl or substituted alkyl, or two instances of ALK may be joined together with their intervening atoms to form a cycloalkyl or heterocyclyl ring.
[0016] In some embodiments, the ENT1 inhibitor is a compound of Formula (II):
Figure imgf000006_0004
or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein
R1 is selected from the group consisting of ALK, cycloalkyl, heterocyclyl,
Figure imgf000007_0001
each R2 is independently selected from the group consisting of absent, halogen, -OR3, -R3, -CO2R3, C(O)N(R3)2, -CH2C(O)N(R3)2, -S(O)2R3, and -CN; or two instances of R2 are taken together with the atoms on which they are attached to form a heterocyclyl or heteroaryl ring; each R3 is independently selected from absent, -H, ALK, phenyl, and heteroaryl;
Figure imgf000007_0002
X is selected from the group consisting of -CH2-, -CHF-, and -CF2-; each U is independently selected from the group consisting of -O-, -N(R3)-, -
C(O)O-, -C(O)N(R3)-, , -C(O)-, -O-N=C(H)- and alkylene;
Figure imgf000007_0003
each Rx is independently selected from alkylene;
V1 is selected from -C(R3)- and -N-; each V2 is independently selected from -C(R3)=, -N(R3)-, -N=, and -O-;
V3 is selected from -C= and -N-; each Z is independently C or N; and n1 is a number of 0 or 1, wherein ALK is unsubstituted alkyl or substituted alkyl, or two instances of ALK may be joined together with their intervening atoms to form a cycloalkyl or heterocyclyl ring.
[0017] In some embodiments, the ENT1 inhibitor is a compound of Formula (Ila):
Figure imgf000008_0001
or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein X is CH2, CHF, or CF2.
[0018] In some embodiments, in a compound of Formula (I), (II), or (Ila), R1 is
Figure imgf000008_0002
[0019] In some embodiments, in a compound of Formula (I), (II), or (Ila), R1 is
Figure imgf000009_0001
[0020] In some embodiments, the compound is a compound of Formula (Ilb):
Figure imgf000009_0002
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
[0021] In some embodiments, in a compound of Formula (I), (II), (Ila), or (Ilb), U is -
C(O)O-.
[0022] In some embodiments, in a compound of Formula (I) or (II), R4 is the U in R4 is -C(O)O- or -C(O)NR3-.
Figure imgf000009_0003
[0023] In some embodiments, the compound is a compound of Formula (Ilal):
Figure imgf000010_0001
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
[0024] In some embodiments, the ENT1 inhibitor is selected from:
(12S)-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
(12R)-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
(12S)-16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
(12R)-16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
N-(74,75)-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl)-3,4,5-trimethoxybenzamide
74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
(12S)-74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate (12R)-74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
74,75-dimethoxy-5-methyl-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
(12S)-74,75-dimethoxy-5-methyl-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
(12R)-74,75-dimethoxy-5-methyl-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
( 11R)-74,75-dimethoxy-6-oxo-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotridecaphane-
11-yl 3,4,5-trimethoxybenzoate
(10S)-14-chloro-2-oxo-11H-3-aza-1(6,1)-indazola-7(1,4)-diazepanacyclotridecaphane-
10-yl 3,4,5-trimethoxybenzoate
(10R)-14-chloro-2-oxo-11H-3-aza-1(6,1)-indazola-7(1,4)-diazepanacyclotridecaphane-
10-yl 3,4,5-trimethoxybenzoate
(12S)-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoate
(12R)-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoate
(12S)-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl benzoate
(12R)-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl benzoate
74,75dichloro-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl
3,4,5 -trimethoxybenzoate (12S)-74,75-dichloro-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
(12R)-74,75-dichloro-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
75-carbamoyl-74-chloro-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
( 11Z, 16E, 10S)- 14-chloro-2-oxo- 12H-3 -aza-1(6,2)-indazola-7(1,4)- diazepanacyclotridecaphane- 10-yl 3,4,5-trimethoxybenzoate
( 11Z, 16E, 10R)- 14-chloro-2-oxo- 12H-3 -aza-1(6,2)-indazola-7(1,4)- diazepanacyclotridecaphane- 10-yl 3,4,5-trimethoxybenzoate
(12S)-74-carbamoyl-75-chloro-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
(12R)- 74-carbamoyl-75-chloro-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
74-bromo-75-chloro-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
75-chloro-74-cyano-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
(12R)-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl benzoate
(12R)-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl benzoate
(12S)-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl benzoate (Z)-benzaldehyde O-(74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl) oxime
12-hydroxy-74,75-dimethoxy-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-hydroxybenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-fluorobenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-isopropoxybenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3-(trifluoromethyl)benzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3-(methylsulfonyl)benzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3-phenoxybenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 2-fluorobenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-bromo-3 -cyanobenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3-methyl-5-(trifluoromethyl)benzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 2-fluoro-4-methoxybenzoate 74,-7d5i-methoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-methoxy-2-(trifluorom ethoxy )benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl picolinate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl nicotinate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl pyrazine-2-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 6-hydroxynicotinate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl quinoline-5-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl oxazole-4-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 1H-1,2,3-triazole-4-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl acetate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl cyclopropanecarboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3-methylbutanoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4,4,4-trifluorobutanoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl cyclohexanecarboxylate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 1-methylpiperidine-4-carboxylate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3, 3 -dimethylcy cl obutane-1 -carboxylate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 2-(oxetan-3-yl)acetate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl (1R,5S,6R)-3-oxabicyclo[3.1.0]hexane-6-carboxylate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 5-oxopyrrolidine-3-carboxylate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 1-benzyl-5-oxopyrrolidine-3-carboxylate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-m ethoxy cyclohexane-1-carboxylate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 2,6-difluorobenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-(trifluorom ethoxy )benzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3 -cyanobenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 2-oxo-1,2,3,4-tetrahydroquinoline-6-carboxylate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3 -(difluorom ethoxy )benzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3,5-dichlorobenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3, 4-di chlorobenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 2,3 -di chlorobenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 2-chloro-6-fluoro-3 -methylbenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3 -fluoro-5 -(trifluoromethyl)benzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-fluoro-3 -(trifluoromethyl)benzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-cyano-3 -fluorobenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-(trifluoromethyl)benzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3,5-difluorobenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3,4-difluorobenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3-cyano-4-fluorobenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-cyanobenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3-chloro-4-fluorobenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 1 -methyl- 1H-benzo[d]imidazole-5-carboxylate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-(oxazol-5-yl)benzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4,5-dichloro-2-fluorobenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3,4,5-triethoxybenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3-methoxypropanoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3 -( 1H-pyrazol-1-yl)propanoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3-cyanopropanoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-cyanobutanoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-acetamidobutanoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3 -( 1H-tetrazol-1-yl)propanoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-(dimethylamino)-4-oxobutanoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3-acetamidopropanoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-(methylamino)-4-oxobutanoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3 -(1H- 1 ,2,4-triazol-1-yl)propanoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-morpholino-4-oxobutanoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3 -(4-fluorophenoxy)propanoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4,4-difluorocyclohexane-1 -carboxylate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-(trifluoromethyl)cyclohexane-1 -carboxylate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3 -(2, 5 -dioxopyrrolidin-1-yl)propanoate
74.75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3 -m ethoxy cy cl ohexane-1 -carboxylate
74.75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl benzoate
(E)-benzaldehyde O-(74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl) oxime (E)-benzaldehyde O-((12R)- 74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-
7(1,3 )-benzenacy clotetradecaphane-12-yl) oxime
(E)-benzaldehyde O-((12S)- 74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl) oxime
12-hydroxy-74,75-dimethoxy-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one
(12R)-12-hydroxy-74,75-dimethoxy-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one
(12S)-12-hydroxy-74,75-dimethoxy-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one
74.75-dimethoxy-12-(5-phenyl-2H-tetrazol-2-yl)-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one
74.75-dimethoxy-12-(4-phenyl-1H-1,2,3-triazol-1-yl)-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one
74.75-dimethoxy-12-(5-phenyl-1H-tetrazol-1-yl)-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one, and pharmaceutically acceptable salts, hydrates, or solvates thereof.
[0025] In some embodiments, the ENT1 inhibitor is selected from (12R)-74,75- dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl
3,4,5-trimethoxybenzoate (i.e., COMPOUND 1, structure below)
Figure imgf000020_0001
and pharmaceutically acceptable salts, hydrates, or solvates thereof. See, e.g., WO
2024/194391 and WO 2024/194392, the contents of which are incorporated herein by reference in their entirety.
[0026] In some embodiments, the ENT1 inhibitor is selected from (COMPOUND 1 and pharmaceutically acceptable salts thereof.
[0027] In some embodiments, the ENT1 inhibitor is selected from hydrogen sulfate salts of COMPOUND 1 and hydrates and solvates thereof. See, e.g., WO 2024/194391.
[0028] In some embodiments, the ENT1 inhibitor is Compound 1 di(hydrogen sulfate) or a hydrate or solvate thereof. In some embodiments, the Compound 1 di(hydrogen sulfate) or a hydrate or solvate thereof is crystalline. In some embodiments, the crystalline Compound 1 di(hydrogen sulfate) or a hydrate or solvate thereof is crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate.
[0029] In some embodiments, the ENT1 inhibitor is administered prior to, concomitant with, or subsequent to the administration of the bispecific antibody (BsAb) cancer therapy.
[0030] In some embodiments, the combinations, methods and uses described herein further comprise an additional therapeutic agent, such as an anti-PD-L1 agent, such as atezolizumab. [0031] In some embodiments, the cancer is characterized by a high concentration of adenosine in the tumor microenvironment (TME).
[0032] In some embodiments, the cancer is selected from breast, carcinoid, cervical, colorectal, endometrial, glioma, head and neck, liver, lung, melanoma, ovarian, pancreatic, prostate, renal, gastric, thyroid and urothelial cancers.
[0033] In some embodiments, the cancer is selected from malignant ascites, acute lymphocytic (ALL) including Philadelphia chromosome-negative precursor B-cell ALL, follicular lymphoma (FL) including relapsed or refractory FL, melanoma including uveal melanoma, multiple myeloma (MM) including relapsed or refractory MM, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), cervical cancer (CC) including relapsed or metastatic CC, acute myeloid leukemia (AML), diffuse large B-cell lymphoma (DLBCL) solid tumors including MUC 17-positive solid tumors, ovarian cancer including recurrent ovarian cancer, neoplasms, neuroendrocrine tumors, prostate cancer, chronic lymphocytic leukemia (CLL), prostate cancer including metastatic castration resistant prostate cancer, non-Hodgkin lymphoma (NHL), and colorectal cancer including microsatellite-stable (MSS) colorectal cancer.
[0034] In some embodiments, the cancer is selected from cervical cancer (CC), colorectal cancer, lung cancer including SCLC and NSCLC, melanoma, ovarian cancer, and prostate cancer.
[0035] In some embodiments, the cancer is breast cancer.
[0036] In some embodiments, the cancer is triple negative breast cancer.
[0037] In some embodiments, the cancer is a solid-tumor cancer.
[0038] Additional objects and advantages will be set forth in part in the description which follows, and in part will be understood from the description, or may be learned by practice. The objects and advantages will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.
[0039] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0040] FIG. 1 shows the effect of CD3 x HER2 bispecific antibodies on SK-OV-3 cells (ovarian cancer cell line) in combination with T cells (2 x T cells per SK-OV-3 cells), as assessed on the first 6 days of co-culture by LDH assay, in vitro. White and black bars indicate the presence and absence of the CD3 x HER2 bispecific antibody, respectively.
[0041] FIG. 2 shows the effect of adenosine at various concentrations on cytotoxicity induction by CD3 x HER2 on SK-OV-3 cells, in vitro.
[0042] FIG. 3 shows the effects of adenosine and ATP at 300 μM on the growth of SK-OV-3 cells, over time, in vitro.
[0043] FIG. 4 shows the kinetics of CD3 x HER2-induced cytotoxicity (cytotoxic activity of CD3 x HER2, T cells, CD3 x HER2 + T cells, and CD3 x HER2 + T cells + COMPOUND 1), on SK-OV-3 cells, over time, in vitro.
[0044] FIG. 5 shows the cytotoxic activity of CD3 x HER2, adenosine, CD3 x HER2 + adenosine, and CD3 x HER2 + adenosine + COMPOUND 1, on SK-OV-3 cells, over time, in vitro.
DESCRIPTION OF THE EMBODIMENTS
I. Definitions
[0045] Unless otherwise defined, all terms of art, notations and other scientific terminology used herein are intended to have the meanings commonly understood by those of skill in the art to which this invention pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and/or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a difference over what is generally understood in the art. The techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodologies by those skilled in the art. Standard techniques may be used for chemical synthesis and chemical analysis. As appropriate, procedures involving the use of commercially available kits and reagents are generally carried out in accordance with manufacturer-defined protocols and conditions unless otherwise noted.
[0046] For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001.
[0047] Unless otherwise indicated, the following terms have the following meanings:
[0048] As used herein, the singular forms “a,” “an,” and “the” include the plural referents unless the context clearly indicates otherwise. The terms “include,” “such as,” and the like are intended to convey inclusion without limitation, unless otherwise specifically indicated. [0049] As used herein, the term “comprising” also specifically includes embodiments “consisting of’ and “consisting essentially of’ the recited elements, unless specifically indicated otherwise.
[0050] The term “about” indicates and encompasses an indicated value and a range above and below that value. In certain embodiments, the term “about” indicates the designated value ± 10%, ± 5%, or ± 1%. In certain embodiments, where applicable, the term “about” indicates the designated value(s) ± one standard deviation of that value(s).
[0051] The term “aldehyde” refers to a group -CHO.
[0052] The term “alkenyl” refers to unsaturated hydrocarbyl group, which may be linear or branched, comprising one or more carbon-carbon double bonds. Suitable alkenyl groups comprise between 2 and 6 carbon atoms, for example between 2 and 4 carbon atoms, such as between 2 and 3 carbon atoms. Examples of alkenyl groups are ethenyl, 2-propenyl, 2- butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers, 2,4-pentadienyl and the like.
[0053] The term “alkenylcarbonyl” refers to a group -(C=O)-alkenyl wherein alkenyl is as herein defined.
[0054] The term “alkenylcarbonylamino” refers to a group -NH-(C=O)-alkenyl wherein alkenyl is as herein defined.
[0055] The term “alkoxy” refers to a group -O-alkyl wherein alkyl is as herein defined. [0056] The term “ALK” or “Aik” or “alk” refers to an alkyl group (hydrocarbyl radical of formula CnH2n+1 wherein n is a number greater than or equal to 1) or an alkyl group substituted by, for example, one to four substituents, such as, halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, cycloalkoxy, heterocyclooxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, cycloalkylamino, heterocycloamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or aralkyl, alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio, cycloalkylthio, heterocyclothio, alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido (e.g. SO2NH2), substituted sulfonamido, nitro, cyano, carboxy, carbamyl (e.g. CONH2), substituted carbamyl (e.g. CONH alkyl, CONH aryl, CONH aralkyl or cases where there are two substituents on the nitrogen selected from alkyl, aryl or aralkyl), alkoxycarbonyl, aryl, substituted aryl, guanidino and heterocyclos, such as, indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like. Where noted above, when the substituent is further substituted, it may be substituted with halogen, alkyl, alkoxy, aryl or aralkyl. In some embodiments, ALK is optionally substituted C1-C8 alkyl.
[0057] In some embodiments, an alkyl group is substituted by OH, alkoxy, CF3, and/or NR2. [0058] Generally, alkyl groups comprise from 1 to 8 carbon atoms, for example, from 1 to 6 carbon atoms. Alkyl groups may be linear or branched. Suitable alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl.
[0059] The term “alkylaminoalkyl” refers to a group -alkyl-NH-alkyl wherein alkyl is as herein defined.
[0060] The term “alkylaminoalkylaminocarbonyl” refers to a group -(C=O)-NH-alkyl-NH- alkyl wherein alkyl is as herein defined.
[0061] The term “(alkylaminoalkyl)(alkyl)aminocarbonyl” refers to a group -(C=O)-NR1R2 wherein R1 is an alkyl group and R2 is a -alkyl-NH-alkyl group, wherein alkyl is as herein defined.
[0062] The term “alkylaminoalkylcarbonyl” refers to a group -(C=O)-alkyl-NH-alkyl wherein alkyl is as herein defined.
[0063] The term “alkylcarbonyl” refers to a group -(C=O)-alkyl wherein alkyl is as herein defined.
[0064] The term “alkylcarbonylamine” refers to a group -NH-(C=O)-alkyl wherein alkyl is as herein defined.
[0065] The term “alkylcarbonyloxyalkyl” refers to a group -alkyl-O-(C=O)-alkyl wherein alkyl is as herein defined. [0066] The term “alkylheteroaryl” refers to any heteroaryl substituted by an alkyl group wherein alkyl is as herein defined.
[0067] The term “alkyloxyalkyl” refers to a group -alkyl-O-alkyl wherein alkyl is as herein defined.
[0068] The term “alkyloxycarbonyl” refers to a group -(C=O)-O-alkyl wherein alkyl is as herein defined.
[0069] The term “alkylsulfonyl” refers to a group -SO2-alkyl wherein alkyl is as herein defined.
[0070] The term “alkylsulfonylaminoalkyl” refers to a group -alkyl-NH-SO2-alkyl wherein alkyl is as herein defined.
[0071] The term “alkyl sulfonealkyl” refers to a group -alkyl-SO2-alkyl wherein alkyl is as herein defined.
[0072] The term “alkylsulfonimidoyl” refers to a group -S(=O)(=NH)-alkyl wherein alkyl is as herein defined.
[0073] The term “alkylsulfoxide” refers to a group -(S=O)-alkyl wherein alkyl is as herein defined.
[0074] The term “alkylsulfoxidealkyl” refers to a group -alkyl-SO-alkyl wherein alkyl is as herein defined.
[0075] The term “alkylene,” as used herein, refers to an alkyl group, as defined above, wherein one of the alkyl group's hydrogen atoms has been replaced with a bond. Alkylene groups possess two points of attachment. Non-limiting examples of alkylene groups include — CH2— , — CH2CH2— , — CH2CH2CH2— , — CH2CH2CH2CH2— , — CH(CH3)CH2CH2— , —CH(CH3) — and CH2CH(CH3)CH2 — . In one embodiment, an alkylene group has from 1 to about 6 carbon atoms. In another embodiment, an alkylene group has from about 3 to about 5 carbon atoms. In another embodiment, an alkylene group is branched. In another embodiment, an alkylene group is linear. In one embodiment, an alkylene group is — CH2 — . In one embodiment, at least one hydrogen atom of an alkylene group is substituted by a substituent such as halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, cycloalkoxy, heterocyclooxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, cycloalkylamino, heterocycloamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or aralkyl, alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio, cycloalkylthio, heterocyclothio, alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido (e.g. SO2NH2), substituted sulfonamido, nitro, cyano, carboxy, carbamyl (e.g. CONH2), substituted carbamyl (e.g. CONH alkyl, CONH aryl, CONH aralkyl or cases where there are two substituents on the nitrogen selected from alkyl, aryl or aralkyl), alkoxycarbonyl, aryl, substituted aryl, guanidino and heterocyclos, such as, indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like. Where noted above, when the substituent is further substituted, it may be substituted with halogen, alkyl, alkoxy, aryl or aralkyl. In another embodiment, at least one hydrogen atom of an alkylene group is substituted by -OH, alkoxy, -CF3, or - NR2.
[0076] The term “alkyne” refers to a class of monovalent unsaturated hydrocarbyl groups, wherein the unsaturation arises from the presence of one or more carbon-carbon triple bonds. Alkynyl groups typically have the same number of carbon atoms as described above in relation to alkyl groups. Non-1imiting examples of alkynyl groups are ethynyl, 2- propynyl, 2- butynyl, 3-butynyl, 2-pentynyl and its isomers, 2-hexynyl and its isomers and the like.
[0077] The term “alkynealkyl” refers to a group -alkyl-alkyne wherein alkyl and alkyne are as herein defined.
[0078] The term “amino” refers to a group -NH2. [0079] The term “aminoalkyl” refers to a group -alkyl-NH2 wherein alkyl is as herein defined.
[0080] The term “aminoalkylaminocarbonyl” refers to a group -(C=O)-NH-alkyl-NH2 wherein alkyl is as herein defined.
[0081] The term “aminoalkylcarbonylamino” refers to a group -NH-(C=O)-alkyl-NH2 wherein alkyl is as herein defined.
[0082] The term “aminocarbonyl” or “aminocarboxy” refers to a group -(C=O)-NH2.
[0083] The term “(aminocarbonylalkyl)(alkyl)amino” refers to a group -N R1R2 wherein R1 is an alkyl group and R2 is a -alkyl-(C=O)-NH2 group, wherein alkyl is as herein defined.
[0084] The term “aminocarbonylalkylamino” refers to a group -NH-alkyl-(C=O)-NH2 wherein alkyl is as herein defined.
[0085] The term “aminosulfonyl” refers to a group -SO2-NH2.
[0086] The term “aryl” refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring (i.e. phenyl) or multiple aromatic rings fused together (e.g. naphtyl), typically containing 5 to 12 atoms; for example, 5 to 10 atoms. In some embodiments, the aryl is a 5- or 6-membered aryl. Non-1imiting examples of aryl include phenyl and naphthal enyl.
[0087] The term “arylalkyl” refers to a group -alkyl-aryl wherein alkyl and aryl are as herein defined.
[0088] The term “aryloxyalkyl” refers to a group -alkyl-O-aryl wherein alkyl and aryl are as herein defined.
[0089] The term “carbonyl” refers to a group -(C=O)-.
[0090] The term “carbonylamino” refers to a group -NH-(C=O)-.
[0091] The term “cycloalkyl” refers to a cyclic alkyl group, that is to say, a monovalent, saturated, or unsaturated hydrocarbyl group having 1 or more cyclic structures. Cycloalkyl includes monocyclic or bicyclic hydrocarbyl groups. Cycloalkyl groups may comprise 3 or more carbon atoms in the ring and, in some embodiments, comprise from 3 to 10 carbon atoms, for example from 3 to 8 carbon atoms. In some embodiments, cycloalkyl is a 5- or 6- membered cycloalkyl. Examples of cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
[0092] The term “cycloalkyloxy” refers to a group -O-cycloalkyl wherein cycloalkyl is as herein defined.
[0093] The term “dialkylamino” refers to a group -NR1R2 wherein R1 and R2 are both independently alkyl group as herein defined.
[0094] The term “dialkylaminoalkyl” refers to a group -alkyl-NR1 R2 wherein R1 and R2 are both independently alkyl group, as herein defined.
[0095] The term “dialkylaminoalkylaminocarbonyl” refers to a group -(C=O)-NH-alkyl- NR1 R2 wherein R1 and R2 are both alkyl group, as herein defined.
[0096] The term “dialkylaminoalkylcarbonyl” refers to a group -(C=O)-alkyl-NR1R2 wherein R1 and R2 are both alkyl group, as herein defined.
[0097] The term “dihydroxyalkyl” refers to a group alkyl is as herein defined substituted by two hydroxyl (-OH) groups.
[0098] The term “halo” or “halogen” refers to fluoro, chloro, bromo, or iodo.
[0099] The term “haloalkyl” refers to an alkyl group in which one or more hydrogen atom is replaced by a halogen atom.
[00100] The term “haloalkyloxy” refers to a group -O-haloalkyl wherein alkyl is as herein defined.
[00101] The term “heteroaryl” refers to an aryl group as herein defined wherein at least one carbon atom is replaced with a heteroatom. In some embodiments, it refers to 5 to 12 carbon-atom aromatic single rings or ring systems containing 2 rings which are fused together, in some instances containing 5 to 6 atoms, in which one or more carbon atoms is replaced by a heteroatom such as an oxygen, nitrogen and/or sulfur atoms where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. Non-1imiting examples of heteroaryls include: pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
[00102] The term “heteroarylalkyl” refers to a group -alkyl-heteroaryl wherein alkyl and heteroaryl are as herein defined.
[00103] The term “heterocyclyl” or “heterocycle” refers to non-aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3 to 7 member monocyclic, 7 to 11 member bicyclic, or containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom-containing ring. In some embodiments, the heterocyclyl is a 5- or 6-membered heterocyclyl. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from, for example, nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows. The rings of multi-ring heterocycles may be fused, bridged and/or joined through one or more spiro atoms. Non limiting exemplary heterocyclic groups include piperidinyl, piperazinyl, azetidinyl, azocanyl, diazepanyl, diazocanyl, morpholin-4-yl, oxazepanyl, pyrrolidinyl, thiomorpholin-4-yl, tetrahydrofuranyl, tetrahydropyranyl, aziridinyl, oxiranyl, thiiranyl, 2-imidazolinyl, pyrazolidinyl imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, succinimidyl, 3H-indolyl, indolinyl, isoindolinyl, 2H-pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, 4H-quinolizinyl, 2- oxopiperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H- pyranyl, 2H- pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, oxetanyl, thietanyl, 3-dioxolanyl, 1,4- dioxanyl, 2,5-dioximidazolidinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, indolinyl, tetrahydrothiophenyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, 1-oxido-1- thiomorpholin-4-yl, 1-dioxido-1-thiomorpholin-4-yl, 1,3-dioxolanyl, 1,4-oxathianyl, 1,4- dithianyl, 1,3,5-trioxanyl, IH-pyrrolizinyl, tetrahydro- 1,1 -di oxothiophenyl, N- formylpiperazinyl, dihydrotriazolopyrazine, dihydroimidazopyrazine, hexahydropyrrolopyrrole, and hexahydropyrrolopyrazine.
[00104] The term “heterocyclylalkyl” refers to a group -alkyl-heterocyclyl wherein alkyl and heterocyclyl are as herein defined.
[00105] The term “heterocyclylalkylaminocarbonyl” refers to a group -(C=0)-NH- alkyl-heterocyclyl, wherein alkyl and heterocyclyl are as herein defined.
[00106] The term “(heterocyclyl)(alkyl)aminoalkyl” refers to a group -alkyl-NRxR2 wherein R1 is an alkyl group and R2 is a heterocyclyl group, wherein alkyl and heterocyclyl are as herein defined.
[00107] The term “heterocyclylalkyloxyalkyl” refers to a group -alkyl-O-alkyl- heterocyclyl wherein alkyl and heterocyclyl are as herein defined.
[00108] The term “heterocyclylcarbonyl” refers to a group -(C=O)-heterocyclyl wherein heterocyclyl is as herein defined.
[00109] The term “heterocyclyloxy” refers to a group -O-heterocyclyl wherein heterocyclyl is as herein defined.
[00110] The term “heterocyclylsulfonyl” refers to a group - SO2-heterocyclyl wherein heterocyclyl is as herein defined.
[00111] The term “hydroxy” or “hydroxyl” refers to a group -OH.
[00112] The term “hydroxyalkyl” refers to a group -alkyl-OH wherein alkyl is as herein defined. [00113] The term “hydroxyalkylaminoalkyl” refers to a group -alkyl-NH-alkyl-OH wherein alkyl is as herein defined.
[00114] The term “hydroxy carbonyl” refers to a group -C(=O)-OH wherein carbonyl is as herein defined. In other words, “hydroxycarbonyl” corresponds to a carboxylic acid group.
[00115] The term “oxo” refers to a =O substituent.
[00116] The term “sulfonylamino” refers to a group -NH-SO2.
[00117] The term “administration”, or a variant thereof (e.g. “administering”), means providing the active agent or active ingredient, alone or as part of a pharmaceutically acceptable composition, to the patient in whom/which the condition, symptom, or disease is to be treated or prevented.
[00118] The term “bispecific antibodies” (BsAbs) refers to antibodies with at least two binding sites directed at at least two different antigens or at least two different epitopes on the same antigen.
[00119] The term “bispecific antibody cancer therapy” refers to cancer treatments that involves a bispecific antibody. For example, a bispecific antibody cancer therapy may comprise a bispecific antibody comprising a first antigen-binding domain that binds to an antigen on an immune cell and a second antigen-binding domain that binds to an antigen on a cancer cell. In another example, a bispecific antibody cancer therapy may comprise a bispecific antibody comprising two antigen-binding domains that bind to an antigen(s) on a cancer cell.
[00120] The term “chemotherapy” refers to a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents) as part of a standardized chemotherapy regimen. Chemotherapy may be given with a curative intent or it may aim to prolong life or to reduce symptoms. Chemotherapeutic agents are for example selected from anticancer alkylating agents, anticancer antimetabolites, anticancer antibiotics, plant-derived anticancer agents, anticancer platinum coordination compounds and any combination thereof.
[00121] The term “hormone therapy” refers to the use of hormones in medical treatment. In one embodiment, the hormone therapy is oncologic hormone therapy.
[00122] The term “radiation therapy” refers to a method of treatment of cancer employing various radiations such as X-ray, gamma-ray, neutron ray, electron beam, proton beam and radiation sources. It is used as part of cancer treatment to control or kill malignant cells. Radiation therapy may be curative in a number of types of cancer if they are localized to one area of the body. It may also be used as part of adjuvant therapy, to prevent tumor recurrence after surgery to remove a primary malignant tumor. The three main divisions of radiation therapy are: external beam radiation therapy (EBRT or XRT); brachytherapy or sealed source radiation therapy; and systemic radioisotope therapy (RIT) or unsealed source radiotherapy.
[00123] The term “immunotherapy” refers to a therapy aiming at inducing and/or enhancing an immune response towards a specific target, for example towards cancer cells. Immunotherapy includes, for example, CAR-T cell therapy, checkpoint inhibitors, checkpoint agonists (also called T-cell agonists), IDO inhibitors, PI3K inhibitors, adenosine receptor inhibitors, adenosine-producing enzymes inhibitors, adoptive transfer, therapeutic vaccines, and combinations thereof.
[00124] The term “patient” refers to a mammal, such as a human, who/which is awaiting the receipt of, or is receiving medical care, or was/is/will be the object of a medical procedure or is monitored for the development or progression of a disease, such as a cancer. [00125] The expression “pharmaceutically acceptable” refers to compounds, salts, compositions, dosage forms, and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use. [00126] The expression “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” or “excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the compositions disclosed herein is contemplated. Additional active ingredients can also be incorporated into the compositions.
[00127] The terms “therapeutically effective amount” or “effective amount” or “therapeutically effective dose” or dose of a compound or a composition refer to that amount of the compound or the composition that results in reduction or inhibition of symptoms or a prolongation of survival in a subject (such as a human patient). The results may require multiple doses of the compound or the composition. A therapeutically effective amount may be administered prior to the onset of a disease or disorder for a prophylactic or preventive action. Alternatively, or additionally, a therapeutically effective amount may be administered after initiation of a disease or disorder for a therapeutic action. In one embodiment, the disease or disorder is cancer.
[00128] The term “subject” refers to a mammal, such as a human. In one embodiment, the subject is diagnosed with cancer. In one embodiment, the subject is a patient, such as a human patient, who/which is awaiting the receipt of, or is receiving, medical care or was/is/will be the subject of a medical procedure or is monitored for the development or progression of a disease, such as a cancer. In one embodiment, the subject is a human patient who is treated and/or monitored for the development or progression of a cancer. In one embodiment, the subject is a male. In another embodiment, the subject is a female. In one embodiment, the subject is an adult. In another embodiment, the subject is a child. [00129] The term “and/or” used herein is to be taken to mean specific disclosure of each of the specified features or components with or without the other. For example, the term
“and/or” as used in a phrase such as “A and/or B” herein is intended to include “A and B,” “A or B,” “A” (alone), and “B” (alone). Likewise, the term “and/or” as used in a phrase such as “A, B, and/or C” is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).
II. Combinations, Methods, and Uses
[00130] Disclosed herein are combinations, methods and uses comprising an ENT1 inhibitor and a bispecific antibody (BsAb) cancer therapy. In some embodiments, the combinations, methods and uses described herein can further comprise an additional therapeutic agent. In some embodiments, the additional therapeutic agent is an anti-PD-L1 agent. In some embodiments, the anti-PD-L1 agent is as atezolizumab.
A. ENT1 Inhibitors
[00131] Applicant observed that activated human T cells took up [3H]adenosine, and this uptake was reduced in the presence of the selective ENT1 inhibitor dilazep, confirming that ENT1 is the dominant transporter involved in adenosine uptake in T cells. These results indicate that T cells increase ENT1 expression upon activation, which could allow uptake of adenosine present in the extracellular environment.
[00132] Applicant engrafted Syngeneic cancer cell lines into wild type (WT) mice and mice in which ENT1 was genetically deleted (ENT 1 -knock-out [KO]). A delay in tumor growth rate was observed for MCA205 (fibrosarcoma), MC38 (colon adenocarcinoma), and Pan02 (pancreatic ductal adenocarcinoma [PDAC]) cells when implanted subcutaneously in ENT1-KO compared to WT mice. Growth of tumors derived from PDAC cells derived from tumors generated in the autochthonous KPC mouse model was also significantly reduced in ENT1-K0 versus WT mice. This suppression of tumor growth was associated with an increased proportion of CD8+ T cells within the tumor microenvironment. Quantitative mass spectrometry imaging reveals adenosine concentrations in human tumors up to the range of 100 μM - levels significantly greater than previously demonstrated and consistent with suppression of T cell responses. Accordingly, deletion of ENT 1 may lead to potent control of tumor growth in syngeneic mouse models including KPC, a poorly immunogenic model of pancreatic ductal adenocarcinoma, and is associated with increased CD8+ T cell frequency, proliferation and cytokine production within tumors. Furthermore, ENT1 expression was observed by flow cytometry on human tumor-infiltrating CD8+ T cells.
[00133] In one embodiment, COMPOUND 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof inhibits adenosine uptake into activated human T cells. In some embodiments, COMPOUND 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof inhibits adenosine uptake into activated human T cells with sub-nanomolar potency. In one embodiment, COMPOUND 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof dose-dependently restores T cell proliferation in the presence of ATP acting as a source of adenosine.
[00134] Any ENT1 inhibitor may be used in the combinations, methods, and uses disclosed herein. In some embodiments, the ENT1 inhibitor is a small molecule, a nucleic acid, a peptide, or an antibody.
[00135] In some embodiments, the ENT1 inhibitor is an ENT1 inhibitor such as those disclosed in WO 2021/170797, WO 2021/204896, and WO 2023/059739, the contents of each being incorporated herein by reference in their entirety.
[00136] In some embodiments, the ENT1 inhibitor is a compound of Formula (I):
Figure imgf000037_0002
or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein
R1 is selected from the group consisting of
Figure imgf000037_0001
each R2 is independently selected from the group consisting of absent, halogen, -NHR3, -OR3, -R3, -C(O)R3, -CO2R3, C(O)N(R3)2, -CH2C(O)N(R3)2, - S(O)2R3, and -CN; or two instances of R2 are taken together with the atoms on which they are attached to form a heterocyclyl or heteroaryl ring; each R3 is independently selected from absent, -H, oxo, ALK, phenyl, heterocyclyl, and heteroaryl; R4 is selected from the group consisting of
Figure imgf000038_0002
Figure imgf000038_0001
each U is independently selected from the group consisting of -C(O)-, alkylene, -O-, -N(R3)-, -C(O)O-, -C(O)N(R3)-, and
Figure imgf000038_0003
each Rx is independently selected from alkylene;
V1 is selected from -C(R3)- and -N-; each V2 is independently selected from -C(R3)=, -N(R3)-, -N=, and -O-;
V3 is selected from -C= and -N-; and
Z is C or N, wherein ALK is unsubstituted alkyl or substituted alkyl, or two instances of ALK may be joined together with their intervening atoms to form a cycloalkyl or heterocyclyl ring.
[00137] In some embodiments, the ENT1 inhibitor is a compound of Formula (II):
Figure imgf000038_0004
or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein
R1 is selected from the group consisting of ALK, cycloalkyl, heterocyclyl,
Figure imgf000039_0001
each R2 is independently selected from the group consisting of absent, halogen, -OR3, -R3, -CO2R3, C(O)N(R3)2, -CH2C(O)N(R3)2, -S(O)2R3, and -CN; or two instances of R2 are taken together with the atoms on which they are attached to form a heterocyclyl or heteroaryl ring; each R3 is independently selected from absent, -H, ALK, phenyl, and heteroaryl;
Figure imgf000039_0002
X is selected from the group consisting of -CH2-, -CHF-, and -CF2-; each U is independently selected from the group consisting of -O-, -N(R3)-, -
C(O)O-, -C(O)N(R3)-, -C(O)-, -O-N=C(H)- and alkylene;
Figure imgf000039_0003
each Rx is independently selected from alkylene;
V1 is selected from -C(R3)- and -N-; each V2 is independently selected from -C(R3)=, -N(R3)-, -N=, and -O-;
V3 is selected from -C= and -N-; each Z is independently C or N; and n1 is a number of 0 or 1, wherein ALK is unsubstituted alkyl or substituted alkyl, or two instances of ALK may be joined together with their intervening atoms to form a cycloalkyl or heterocyclyl ring.
[00138] In some embodiments, the ENT1 inhibitor is a compound of Formula (Ila):
Figure imgf000040_0001
or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein X is CH2, CHF, or CF2.
[00139] In some embodiments, in a compound of Formula (I), (II), or (Ila), R1 is
Figure imgf000040_0002
[00140] In some embodiments, in a compound of Formula (I), (II), or (Ila), R1 is
Figure imgf000041_0003
[00141] In some embodiments, the ENT1 inhibitor is a compound of Formula (Ilb):
Figure imgf000041_0001
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
[00142] In some embodiments, in a compound of Formula (I), (II), (Ila), or (Ilb), U is -
C(O)O-.
[00143] In some embodiments, in a compound of Formula (I) or (II), R4 is the U in R4 is -C(O)O- or -C(O)NR3-. In some embodiments, U in R4 is
Figure imgf000041_0002
-C(O)O-. In some embodiments, U in R4 is -C(O)NR3-. [00144] In some embodiments, the ENT1 inhibitor is a compound of Formula (Ilal):
Figure imgf000042_0001
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
[00145] In some embodiments, the ENT1 inhibitor is selected from (12R)-74,75- dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl
3,4,5-trimethoxybenzoate (also known as COMPOUND 1, structure below) and pharmaceutically acceptable salts, hydrates, or solvates thereof.
Figure imgf000042_0002
COMPOUND 1
[00146]
[00147] In some embodiments, the ENT1 inhibitor is selected from COMPOUND 1 and pharmaceutically acceptable salts thereof.
[00148] In some embodiments, the ENT1 inhibitor is selected from hydrogen sulfate salts of COMPOUND 1 and hydrates and solvates thereof. See, e.g., WO 2024/194391. [00149] In some embodiments, the ENT1 inhibitor is Compound 1 di(hydrogen sulfate) or a hydrate or solvate thereof. In some embodiments, the Compound 1 di(hydrogen sulfate) or a hydrate or solvate thereof is crystalline. In some embodiments, the crystalline Compound 1 di(hydrogen sulfate) or a hydrate or solvate thereof is crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate.
[00150] In some embodiments, the ENT1 inhibitor is selected from one of the compounds in Tables 1 A or IB, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
Table la
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0002
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Table lb
Figure imgf000055_0002
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
[00151] In some embodiments, the ENT1 inhibitors is selected from dilazep, dipyridamole, NBMPR (nitrobenzylthioinosine), draflazine, STI-571 (Gleevec), ticagrelor, soluflazine, mioflazine, decynium-22, lopinavir, quinidine, 8MDP, TC-T 6000, 5- iodotubercidin, cilostazol, and salts thereof and any mixture thereof. In one embodiment, the ENT1 inhibitor is selected from NBMPR, dipyridamole, dilazep, ticagrelor and salts thereof (including dilazep hydrochloride). In another embodiment, the ENT1 inhibitor is selected from dipyridamole, dilazep, ticagrelor and salts thereof (including dilazep hydrochloride). In one embodiment, the ENT1 inhibitor is NBMP or a salt thereof. In one embodiment, the
ENT1 inhibitor is dipyridamole or a salt thereof. In one embodiment, the ENT1 inhibitor is dilazep or a salt thereof (including dilazep hydrochloride). In one embodiment, the ENT1 inhibitor is ticagrelor or a salt thereof.
[00152] In some embodiments, the ENT1 inhibitor is selected from dilazep, dipyridamole, NBMPR (nitrobenzylthioinosine), draflazine, STI-571 (Gleevec), ticagrelor, 8MDP, 5 -iodotuberci din, cilostazol, and salts thereof and any mixture thereof. Examples of selective ENT1 inhibitors include NBMPR, STI-571 (Gleevec), ticagrelor, salts thereof and any mixture thereof.
[00153] By means of non-1imiting examples, the ENT1 inhibitors be in a form suitable for oral administration, for parenteral administration (such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion), for topical administration (including ocular), for administration by inhalation, by a skin patch, by an implant, by a suppository, etc. Such suitable administration forms - which may be solid, semi-solid or liquid, depending on the manner of administration - as well as the methods and carriers, diluents and excipients for use in the preparation thereof, will be clear to the skilled person; reference is made to the latest edition of Remington's Pharmaceutical Sciences.
[00154] In some embodiments, such preparations include tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, cremes, lotions, soft and hard gelatin capsules, suppositories, drops, sterile injectable solutions and sterile packaged powders (which are usually reconstituted prior to use) for administration as a bolus and/or for continuous administration, which may be formulated with carriers, excipients, and diluents that are suitable per se for such formulations, such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, (sterile) water, methylcellulose, methyl- and propyl-hydroxybenzoates, talc, magnesium stearate, edible oils, vegetable oils and mineral oils or suitable mixtures thereof.
[00155] The ENT1 inhibitors can optionally contain or be mixed with other substances that are commonly used in pharmaceutical compositions, such as lubricating agents, wetting agents, emulsifying and suspending agents, dispersing agents, disintegrants, bulking agents, fillers, preserving agents, sweetening agents, flavoring agents, flow regulators, release agents, etc. They may also be formulated so as to provide rapid, sustained or delayed release of the active compound(s) contained therein.
[00156] In general, compositions of ENT1 inhibitors may be prepared according to known methods in pharmaceutical chemistry. Capsules can be prepared by mixing, for example, an ENT1 inhibitor with a suitable carrier or diluent and filling the proper amount of the mixture in capsules. The usual carriers and diluents include, but are not limited to, inert powdered substances such as starch of many different kinds, powdered cellulose, including crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders.
[00157] Tablets can be prepared by direct compression, by wet granulation, or by dry granulation. Their formulations may incorporate diluents, binders, lubricants and disintegrators as well as the compound. Diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful. Tablet binders may be substances such as starch, gelatin and sugars such as lactose, fructose, glucose and the like. Natural and synthetic gums are also convenient, including acacia, alginates, methylcellulose, polyvinylpyrrolidine and the like. Polyethylene glycol, ethylcellulose and waxes can also serve as binders.
[00158] A lubricant might be necessary in a tablet formulation to prevent the tablet and punches from sticking in the dye. The lubricant can be chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils. Tablet disintegrators are substances that swell when wetted to break up the tablet and release the compound. They include starches, clays, celluloses, algins and gums. Corn and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation- exchange resins, alginic acid, guar gum, citrus pulp and carboxymethyl cellulose, for example, can be used as well as sodium lauryl sulfate. Tablets can be coated with sugar as a flavor and sealant, or with film-forming protecting agents to modify the dissolution properties of the tablet. The ENT1 inhibitors can also be formulated as chewable tablets, for example, by using substances such as mannitol in the formulation.
[00159] When it is desired to administer an ENT1 inhibitor as a suppository, a base can be used. Cocoa butter may be used as a suppository base, which can be modified by addition of waxes to raise its melting point slightly. Water-miscible suppository bases comprising, for example, polyethylene glycols of various molecular weights are in wide use. [00160] The effect of the ENT1 inhibitors can be delayed or prolonged by proper formulation. For example, a slowly soluble pellet can be prepared and incorporated in a tablet or capsule, or as a slow-release implantable device. The technique also includes making pellets of several different dissolution rates and filling capsules with a mixture of the pellets. Tablets or capsules can be coated with a film that resists dissolution for a predictable period of time. Even the parenteral preparations can be made long-acting, by dissolving or suspending the compound of the present disclosure in oily or emulsified vehicles that allow it to disperse slowly in the serum. [00161] In some embodiments, the ENT1 inhibitors are in a unit dosage form, and may be suitably packaged, for example in a box, blister, vial, bottle, sachet, ampoule or in any other suitable single-dose or multi-dose holder or container (which may be properly labeled), optionally with one or more leaflets containing product information and/or instructions for use.
[00162] The ENT1 inhibitor can be administered orally. In one embodiment, when administered orally, the ENT1 inhibitor is administered with a meal and water. In another embodiment, the ENT1 inhibitor is dispersed in water or juice (e.g., apple juice or orange juice) or any other liquid and administered orally as a solution or a suspension.
[00163] The ENT1 inhibitor can also be administered intradermally, intramuscularly, intraperitoneally, percutaneously, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, mucosally, by inhalation, or topically to the ears, nose, eyes, or skin. The mode of administration is left to the discretion of the health-care practitioner and can depend in-part upon the site of the medical condition.
B. Bispecific Antibody (BsAb) Cancer Therapies
[00164] Any bispecific antibody (BsAb) cancer therapy may be used in the combinations, methods, and uses disclosed herein.
[00165] In some embodiments, the bispecific antibody of the bispecific antibody (BsAb) cancer therapy is an IgG-based BsAb. In some embodiments, the bispecific antibody of the bispecific antibody (BsAb) cancer therapy is a fragment-based BsAb.
[00166] In some embodiments, the BsAb acts by bridging cells. In some embodiments, the BsAb acts by bridging receptors. In some embodiments, the BsAb acts by bridging cytokines. [00167] In some embodiments, the bispecific antibody of the bispecific antibody
(BsAb) cancer therapy comprises an antigen-binding domain that binds to an antigen expressed on a T cell, natural killer (NK) cell, macrophages, dendritic cells (DCs), or a combination thereof.
[00168] In some embodiments, the bispecific antibody of the bispecific antibody (BsAb) cancer therapy comprises an antigen-binding domain that binds to an antigen expressed on a cancer cell.
[00169] In some embodiments, the bispecific antibody of the bispecific antibody (BsAb) cancer therapy comprises a first antigen-binding domain that binds to an antigen expressed on a T cell, natural killer (NK) cell, macrophages, dendritic cells (DCs), or a combination thereof and a second antigen-binding domain that binds to an antigen expressed on a cancer cell. In some embodiments, the bispecific antibody of the bispecific antibody (BsAb) cancer therapy comprises a first antigen-binding domain that binds to an antigen expressed on a cancer cell and a second antigen-binding domain that binds to an antigen expressed on a cancer cell.
[00170] In some embodiments, the bispecific antibody of the bispecific antibody (BsAb) cancer therapy comprises an antigen-binding domain that binds to an antigen selected from CD3, γδTCR, CD 16, CD47, and a combination thereof.
[00171] In some embodiments, the bispecific antibody of the bispecific antibody (BsAb) cancer therapy comprises an antigen-binding domain that binds to an antigen selected from BCMA, CD123, CD33, CD38, CEA, CLEC12A, DLL3, EpCAM, FcRH5, FLT3, GD2, Glypican-3, gpA33, GPRC5D, CD47, CD19, CD20, 4-1BB, HER-2, PD-1, EGFR, EGFRvIII, PD-L1, CD3, MAGE-A4, MUC17, MUC16, NY-ESO-1, p-cadherin, PRAME, PSCA, PSMA, SSTR2, STEAP1, 5T4, CDld, B7H3, GPC3, MSLN, and a combination thereof. [00172] In some embodiments, the bispecific antibody of the bispecific antibody
(BsAb) cancer therapy comprises an antigen-binding domain that binds to an antigen selected from CD3, EpCAM, CD 19, CD20, gp100, BCMA, EGFR, c-MET, PD-1, CTLA4, and a combination thereof.
[00173] In some embodiments, the BsAb binds to CD3 and an antigen selected from BCMA, CD 123, CD 19, CD20, CD33, CD38, CEA, CLEC12A, DLL3, EGFR, EpCAM, FcRH5, FLT3, GD2, glypican-3, gpA33, GPRC5D, HER-2, MAGE-A4, MUC17, MUC16, NY-ESO-1, p-cadherin, PRAME, PSCA, PSMA, SSTR2, and combinations thereof. In some embodiments, the BsAb binds γδTCR and an antigen on a tumor cell, such as CD 1d, PSMA, and combinations thereof. In some embodiments, the BsAb binds CD16A and an antigen on a tumor cell, such as BCMA, CD30, EGFR, and combinations thereof.
[00174] In some embodiments, the BsAb binds to two antigens selected from CD 19, CD47, CD20, EGFR, c-MET, HER-3, MET, HER-2, IGF-1R, LRP5, LRP6, and PD-L1. In some embodiments, the BsAb binds to two antigens selected from CD40, 4- IBB, CTLA4, 0X40, 4-1BB, PD-1, ICOS, LAG3, and TIM3. In some embodiments, the BsAb binds to two antigens selected from CD40, MSLN, HER-2, 4-1BB, PD-1, PD-L1, 4-1BB, CLTA4, LAG3, TIM3, and CD28.
[00175] In some embodiments, the BsAb binds to two antigens selected from CD73, PD-L1, EGFR, DLL4, PD-1, TGF-β, VEGF, and Ang-2.
[00176] In some embodiments, the BsAb binds to CD3 and an antigen selected from CD19, CD20, CD33, CD38, BCMA, CD123, CLDN18.2, CLEC12A, FcRH5, FLT3, GPRC5D, CEA, EpCAM, PSMA, HER2, P-Cadherin, gpA33, B7H3, DLL3, MUC16, EGFRvIII, GPC3, SSTR2, GD2, MSLN, and combinations thereof. In some embodiments, the BsAb binds to CD3 and HER2. In some embodiments, the BsAb binds to CD3 and CLDN18.2. In some embodiments, the BsAb binds to CD3 and B7H3. [00177] In some embodiments, the BsAb binds to CD 16 and an antigen selected from
CD30, CD33, and combinations thereof.
[00178] In some embodiments, the BsAb binds to CD47 and CD 19.
[00179] In some embodiments, the BsAb binds to PD-1 and an antigen selected from
ICOS, CTLA4, LAG3, TIM3, PD-L1, and combinations thereof.
[00180] In some embodiments, the BsAb binds to PD-L1 and an antigen selected from LAG3, CTLA4, TIM3, and combinations thereof.
[00181] In some embodiments, the BsAb binds to EGFR and an antigen selected from DLL4, Ang-2, c-MET, LGR5, and combinations thereof.
[00182] In some embodiments, the BsAb binds to HER-2 and an antigen selected from HER-3, HER-2, and combinations thereof.
[00183] In some embodiments, the BsAb binds to FAP and DR5.
[00184] The main challenge encountered in the development of BsAbs is that there are two types of chains, heavy and light, that when mismatched may produce a variety of side products. Therefore, several strategies are used to achieve correct matching of heavy and light chains. BsAbs are usually divided into two types: IgG-like and non-IgG-1ike. The relatively large molecular weight of IgG-like BsAbs helps to purify and improve solubility and stability, increase the serum half-life and affinity, and thereby enhance biological activity. Non-IgG-1ike BsAbs only have therapeutic effects through antigen binding because of the lack of Fc fragments. They are easy to produce and have low immunogenicity. More than 30 mature commercial technology platforms have been used to create and develop BsAbs based on the heterologous recombination of heavy chains and matching of light chains. (Ma et al., 2021, Frontiers in Immunology, 12, 626616, https://doi.org/10.3389/fimmu.2021.626616). Examples of bispecific antibody (BsAb) cancer therapies that may be used in accordance with this disclosure include, without being limited to, BsAbs based on the platforms listed in Ma et al., 2021. Specific examples of BsAbs that may be used in accordance with this disclosure include, without being limited to, the BsAbs listed in Ma et al., 2021.
[00185] In some embodiments, the BsAb cancer therapy is administered to the subject via intravenous infusion. In some embodiments, the BsAb cancer therapy is administered in a continuous intravenous (IV) infusion. In some embodiments, the IV infusion is at a constant flow rate with, for example, a portable pump. In some embodiments, the IV infusion is given in repeated cycles.
[00186] In some embodiments, the BsAb cancer therapy is administered daily. In some embodiments, the BsAb cancer therapy is administered every other day, or every 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 , 29, or 30 days, and so on. In some embodiments, the BsAb cancer therapy is administered once per week (which includes every 5-9, 6-9, 7-9, 5-8, 5-7, 6-8, 6-7, 7-8, preferably 7 days). In some embodiments, the BsAb cancer therapy is administered once every two weeks, (which includes every 12-16, 13-16, 14-16, 12-15, 12-14, 13-15, 13-14, 14-15, preferably 14 days) or once every three weeks (which includes every 19-23, 20-23, 21-23, 19-22, 19-21, 20-22, 20- 21, 21-22, preferably 21 days), or once every four weeks (which includes every 26-30, 27-30, 28-30, 26-29, 26-28, 27-29, 27-28, 28-29, preferably 28 days) and so on.
C. Cancers
[00187] Various cancers are known in the art. Cancers that can be treated using the combinations, methods, and uses described herein include solid cancers and non-solid cancers, especially benign and malignant solid tumors and benign and malignant non-solid tumors. The cancer may be metastatic or non-metastatic. The cancer may be familial or sporadic. [00188] In some embodiments, the cancer is a solid-tumor cancer. As used herein, the term “solid cancer” encompasses any cancer (also referred to as malignancy) that forms a discrete tumor mass, as opposed to cancers (or malignancies) that diffusely infiltrate a tissue without forming a mass.
[00189] Examples of solid tumors include, but are not limited to: biliary tract cancer, brain cancer (including glioblastomas and medulloblastomas), breast cancer, carcinoid, cervical cancer, choriocarcinoma, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, glioma, head and neck cancer, intraepithelial neoplasms (including Bowen’s disease and Paget’s disease), liver cancer, lung cancer, neuroblastomas, oral cancer (including squamous cell carcinoma), ovarian cancer (including those arising from epithelial cells, stromal cells, germ cells and mesenchymal cells), pancreatic cancer, prostate cancer, rectal cancer, renal cancer (including adenocarcinoma and Wilms tumor), sarcomas (including leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma and osteosarcoma), skin cancer (including melanoma, Kaposi’s sarcoma, basocellular cancer and squamous cell cancer), testicular cancer including germinal tumors (seminomas, and non- seminomas such as teratomas and choriocarcinomas), stromal tumors, germ cell tumors, thyroid cancer (including thyroid adenocarcinoma and medullary carcinoma) and urothelial cancer.
[00190] In another embodiment, the cancer is a non-solid cancer. Examples of non- solid tumors include but are not limited to hematological neoplasms. As used herein, a hematologic neoplasm is a term of art which includes lymphoid disorders, myeloid disorders, and AIDS associated leukemias.
[00191] Lymphoid disorders include but are not limited to acute lymphocytic leukemia and chronic lymphoproliferative disorders (e.g., lymphomas, myelomas such as multiple myeloma, and chronic lymphoid leukemias). Lymphomas include, for example, Hodgkin’s disease, non-Hodgkin’s lymphoma, follicular lymphoma, mantle cell lymphoma, acute lymphoblastic leukemia, and lymphocytic lymphomas. Chronic lymphoid leukemias include, for example, T cell chronic lymphoid leukemias and B cell chronic lymphoid leukemias.
[00192] In some embodiments, the cancer is characterized by a high concentration of adenosine in the tumor microenvironment (TME).
[00193] In some embodiments, the cancer is selected from breast, carcinoid, cervical, colorectal, endometrial, glioma, head and neck, liver, lung, melanoma, ovarian, pancreatic, prostate, renal, gastric, thyroid and urothelial cancers.
[00194] In some embodiments, the cancer is selected from malignant ascites, acute lymphocytic (ALL) including Philadelphia chromosome-negative precursor B-cell ALL, follicular lymphoma (FL) including relapsed or refractory FL, melanoma including uveal melanoma, multiple myeloma (MM) including relapsed or refractory MM, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), cervical cancer (CC) including relapsed or metastatic CC, acute myeloid leukemia (AML), diffuse large B-cell lymphoma (DLBCL) solid tumors including MUC 17-positive solid tumors, ovarian cancer including recurrent ovarian cancer, neoplasms, neuroendrocrine tumors, prostate cancer, chronic lymphocytic leukemia (CLL), prostate cancer including metastatic castration resistant prostate cancer, non-Hodgkin lymphoma (NHL), and colorectal cancer including microsatellite-stable (MSS) colorectal cancer
[00195] In some embodiments, the cancer is selected from cervical cancer (CC), colorectal cancer, lung cancer including SCLC and NSCLC, melanoma, ovarian cancer, and prostate cancer.
[00196] In some embodiments, the cancer is breast cancer. In some embodiments, the breast cancer is triple negative breast cancer.
[00197] In some embodiments, the cancer is a solid-tumor cancer. [00198] In some embodiments, the ENT1 inhibitor is administered prior to, concomitant with, or subsequent to the administration of the bispecific antibody (BsAb) cancer therapy. In some embodiments, the ENT1 inhibitor is administered prior to administration of the bispecific antibody (BsAb) cancer therapy. In some embodiments, the ENT1 inhibitor is administered concomitant with administration of the bispecific antibody (BsAb) cancer therapy. In some embodiments, the ENT1 inhibitor is administered subsequent to administration of the bispecific antibody (BsAb) cancer therapy.
[00199] Depending on the condition to be treated and the route of administration, the active compound may be administered as a single daily dose, divided over one or more daily doses, or essentially continuously, e.g. using a drip infusion.
[00200] In one embodiment, the subject is receiving or has previously received at least one therapeutic treatment in addition to administration of the ENT1 inhibitor and the bispecific antibody (BsAb) cancer therapy. In one embodiment, the therapeutic treatment is selected from chemotherapy, a non-bispecific antibody (BsAb) cancer therapy immunotherapy, radiation therapy, stem cell transplant, hormone therapy, and surgery.
[00201] In one embodiment, the therapeutic treatment is chemotherapy. In one embodiment, the chemotherapy is an adenosine receptor antagonist (ARA). In one embodiment, the ARA is selected from those disclosed in WO 2018/178338. In one embodiment, the ARA is a compound having the following structure:
Figure imgf000094_0001
and named 5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfmyl)ethoxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one. [00202] In one embodiment, the ARA is selected from 5-amino-3-(2-(4-(2,4-difluoro-
5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one, and pharmaceutically acceptable salt, hydrate, or solvate thereof. In one embodiment, the ARA is (S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2- (methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one or a pharmaceutically acceptable salt, hydrate, or solvate thereof. In one embodiment, the ARA is (S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2- (methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one hydrochloride.
ENUMERATED EMBODIMENTS
[00203] Embodiment 1. A combination of an ENT1 inhibitor and a bispecific antibody (BsAb) cancer therapy.
[00204] Embodiment 2. A method of treating cancer comprising administering to a subject in need thereof an ENT1 inhibitor and a bispecific antibody (BsAb) cancer therapy.
[00205] Embodiment 3. A use of an ENT1 inhibitor and a bispecific antibody
(BsAb) cancer therapy for the treatment of cancer.
[00206] Embodiment 4. The combination, method or use according to any one of Embodiments 1-3, wherein the bispecific antibody of the bispecific antibody (BsAb) cancer therapy comprises an antigen-binding domain that binds to an antigen expressed on a T cell, natural killer (NK) cell, macrophages, dendritic cells (DCs), or a combination thereof. [00207] Embodiment 5. The combination, method or use according to any one of Embodiments 1-3, wherein the bispecific antibody of the bispecific antibody (BsAb) cancer therapy comprises an antigen-binding domain that binds to an antigen selected from CD3, γδTCR, CD 16, CD47, and a combination thereof.
[00208] Embodiment 6. The combination, method or use according to any one of Embodiments 1-5, wherein the bispecific antibody of the bispecific antibody (BsAb) cancer therapy comprises an antigen-binding domain that binds to an antigen expressed on a cancer cell.
[00209] Embodiment 7. The combination, method, or use according to Embodiment 6, wherein the bispecific antibody of the bispecific antibody (BsAb) cancer therapy comprises an antigen-binding domain that binds to an antigen selected from BCMA, CD123, CD33, CD38, CEA, CLEC12A, DLL3, DLL4, EpCAM, FcRH5, FLT3, GD2, Glypican-3, gpA33, GPRC5D, CD47, CD19, CD20, 4-1BB, HER-2, HER-3, PD-1, EGFR, EGFRvIII, PD-L1, CD3, MAGE-A4, MUC17, MUC16, NY-ESO-1, p-cadherin, PRAME, PSCA, PSMA, SSTR2, STEAP1, 5T4, CDld, B7H3, GPC3, MSLN, ICOS, CTLA4, LAG3, TIM3, Ang-2, c-MET, LGR5, FAP, DR5, CLDN18.2, B7H4, CDH17, CDH3, CEACAM5, CLDN6, ENPP3, ITGB6, KRASG12V, LY6G6D, MAGE-A3, TMEFF2, TROP2, WT1, and/or a combination thereof.
[00210] Embodiment 8. The combination, method or use according to any one of Embodiments 1-7, wherein the ENT1 inhibitor is a compound of Formula (I):
Figure imgf000096_0001
or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R1 is selected from the group consisting of
Figure imgf000097_0001
each R2 is independently selected from the group consisting of absent, halogen, -NHR3, -OR3, -R3, -C(O)R3, -CO2R3, C(O)N(R3)2, -CH2C(O)N(R3)2, - S(O)2R3, and -CN; or two instances of R2 are taken together with the atoms on which they are attached to form a heterocyclyl or heteroaryl ring; each R3 is independently selected from absent, -H, oxo, ALK, phenyl, heterocyclyl, and heteroaryl;
R4 is selected from the group consisting
Figure imgf000097_0003
Figure imgf000097_0002
each U is independently selected from the group consisting of -C(O)-, alkylene, -0-, -N(R3)-, -C(O)O-, -C(O)N(R3)-, and
Figure imgf000098_0001
each Rx is independently selected from alkylene;
V1 is selected from -C(R3)- and -N-; each V2 is independently selected from -C(R3)=, -N(R3)-, -N=, and -O-;
V3 is selected from -C= and -N-; and
Z is C or N, wherein ALK is unsubstituted alkyl or substituted alkyl, or two instances of ALK may be joined together with their intervening atoms to form a cycloalkyl or heterocyclyl ring.
[00211] Embodiment 9. The combination, method or use according to any one of Embodiments 1-8, wherein the ENT1 inhibitor is a compound of Formula (II):
Figure imgf000098_0002
or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein
R1 is selected from the group consisting of ALK, cycloalkyl, heterocyclyl,
each R2 is independently selected from the group consisting of absent, halogen, -OR3, -R3, -CO2R3, C(O)N(R3)2, -CH2C(O)N(R3)2, -S(O)2R3, and -CN; or two instances of R2 are taken together with the atoms on which they are attached to form a heterocyclyl or heteroaryl ring; each R3 is independently selected from absent, -H, ALK, phenyl, and heteroaryl;
X is selected from the group consisting of -CH2-, -CHF-, and -CF2-; each U is independently selected from the group consisting of -O-, -N(R3)-, -
C(O)O-, -C(O)N(R3)-, , -C(O)-, -O-N=C(H)- and alkylene; each Rx is independently selected from alkylene;
V1 is selected from -C(R3)- and -N-; each V2 is independently selected from -C(R3)=, -N(R3)-, -N=, and -O-;
V3 is selected from -C= and -N-; each Z is independently C or N; and n1 is a number of 0 or 1, wherein ALK is unsubstituted alkyl or substituted alkyl, or two instances of ALK may be joined together with their intervening atoms to form a cycloalkyl or heterocyclyl ring.
[00212] Embodiment 10. The combination, method or use according to
Embodiment 9, wherein the ENT1 inhibitor is a compound of Formula (Ila):
Figure imgf000100_0001
or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein X is CH2, CHF, or CF2.
[00213] Embodiment 11. The combination, method or use according to any one of Embodiments 8-10, wherein
Figure imgf000100_0002
[00214] Embodiment 12. The combination, method or use according to
Embodiment 11, wherein
Figure imgf000100_0003
[00215] Embodiment 13. The combination, method or use according to any one of Embodiments 8-12, wherein the compound is a compound of Formula (Ilb) :
Figure imgf000101_0001
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
[00216] Embodiment 14. The combination, method or use according to any one of Embodiments 8-13, wherein U is -C(O)O-.
[00217] Embodiment 15. The combination, method or use according to any one of Embodiments 8, 9, 11, and 12, wherein
Figure imgf000101_0002
the U in R4 is -C(O)O- or -C(O)NR3-.
[00218] Embodiment 16. The combination, method or use according to
Embodiment 9, wherein the compound is a compound of Formula (Ilal):
Figure imgf000102_0001
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
[00219] Embodiment 17. The combination, method or use according to any one of Embodiments 1-7, wherein the ENT1 inhibitor is selected from:
(12S)-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
(12R)-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
(12S)-16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
(12R)-16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
N-(74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl)-3,4,5-trimethoxybenzamide
74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate (12S)-74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
(12R)-74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
74,75-dimethoxy-5-methyl-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
(12S)-74,75-dimethoxy-5-methyl-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
(12R)-74,75-dimethoxy-5-methyl-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
( 11R)-74,75-dimethoxy-6-oxo-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotridecaphane-
11-yl 3,4,5-trimethoxybenzoate
(10S)-14-chloro-2-oxo-11H-3-aza-1(6,1)-indazola-7(1,4)-diazepanacyclotridecaphane-
10-yl 3,4,5-trimethoxybenzoate
(10R)-14-chloro-2-oxo-11H-3-aza-1(6,1)-indazola-7(1,4)-diazepanacyclotridecaphane-
10-yl 3,4,5-trimethoxybenzoate
(12S)-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoate
(12R)-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoate
(12S)-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl benzoate
(12R)-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl benzoate 74,75dichloro-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl
3,4,5 -trimethoxybenzoate
(12S)-74,75-dichloro-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
(12R)-74,75-dichloro-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
75-carbamoyl-74-chloro-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
( 11Z, 16E, 10S)- 14-chloro-2-oxo- 12H-3 -aza-1(6,2)-indazola-7(1,4)- diazepanacyclotridecaphane- 10-yl 3,4,5-trimethoxybenzoate
( 11Z, 16E, 10R)- 14-chloro-2-oxo- 12H-3 -aza-1(6,2)-indazola-7(1,4)- diazepanacyclotridecaphane- 10-yl 3,4,5-trimethoxybenzoate
(12S)-74-carbamoyl-75-chloro-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
(12R)- 74-carbamoyl-75-chloro-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
74-bromo-75-chloro-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
75-chloro-74-cyano-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
(12R)-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl benzoate
(12R)-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl benzoate (12S)-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl benzoate
(Z)-benzaldehyde O-(74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl) oxime
12-hydroxy-74,75-dimethoxy-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-hydroxybenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-fluorobenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-isopropoxybenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3-(trifluoromethyl)benzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3-(methylsulfonyl)benzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3-phenoxybenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 2-fluorobenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-bromo-3 -cyanobenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3-methyl-5-(trifluoromethyl)benzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 2-fluoro-4-methoxybenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-methoxy-2-(trifluorom ethoxy )benzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl picolinate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl nicotinate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl pyrazine-2-carboxylate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 6-hydroxynicotinate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl quinoline-5-carboxylate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl oxazole-4-carboxylate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 1H-1,2,3-triazole-4-carboxylate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl acetate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl cyclopropanecarboxylate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3-methylbutanoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4,4,4-trifluorobutanoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl cyclohexanecarboxylate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 1-methylpiperidine-4-carboxylate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3, 3 -dimethylcy cl obutane-1 -carboxylate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 2-(oxetan-3-yl)acetate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl (lR,5S,6R)-3-oxabicyclo[3.1.0]hexane-6-carboxylate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 5-oxopyrrolidine-3-carboxylate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 1-benzyl-5-oxopyrrolidine-3-carboxylate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-m ethoxy cyclohexane-1-carboxylate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 2,6-difluorobenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-(trifluorom ethoxy )benzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3 -cyanobenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 2-oxo-1,2,3,4-tetrahydroquinoline-6-carboxylate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3 -(difluorom ethoxy )benzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3,5-dichlorobenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3, 4-di chlorobenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 2,3 -di chlorobenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 2-chloro-6-fluoro-3 -methylbenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3 -fluoro-5 -(trifluoromethyl)benzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-fluoro-3 -(trifluoromethyl)benzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-cyano-3 -fluorobenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-(trifluoromethyl)benzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3,5-difluorobenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3,4-difluorobenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3-cyano-4-fluorobenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-cyanobenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3-chloro-4-fluorobenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 1 -methyl- 1H-benzo[d]imidazole-5-carboxylate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-(oxazol-5-yl)benzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4,5-dichloro-2-fluorobenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3,4,5-triethoxybenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3-methoxypropanoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3 -( 1H-pyrazol-1-yl)propanoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3-cyanopropanoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-cyanobutanoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-acetamidobutanoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3 -( 1H-tetrazol-1-yl)propanoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-(dimethylamino)-4-oxobutanoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3-acetamidopropanoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-(methylamino)-4-oxobutanoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3 -(1H- 1 ,2,4-triazol-1-yl)propanoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-morpholino-4-oxobutanoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3 -(4-fluorophenoxy)propanoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4,4-difluorocyclohexane-1-carboxylate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-(trifluoromethyl)cyclohexane-1-carboxylate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3 -(2, 5 -dioxopyrrolidin-1-yl)propanoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3 -m ethoxy cy cl ohexane-1 -carboxylate
74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl benzoate (E)-benzaldehyde O-(74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl) oxime
(E)-benzaldehyde O-((12R)- 74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-
7(1,3 )-benzenacy clotetradecaphane-12-yl) oxime
(E)-benzaldehyde O-((12S)- 74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl) oxime
12-hydroxy-74,75-dimethoxy-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one
(12R)-12-hydroxy-74,75-dimethoxy-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one
(12S)-12-hydroxy-74,75-dimethoxy-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one
74.75-dimethoxy-12-(5-phenyl-2H-tetrazol-2-yl)-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one
74.75-dimethoxy-12-(4-phenyl-1H-1,2,3-triazol-1-yl)-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one
74.75-dimethoxy-12-(5-phenyl-1H-tetrazol-1-yl)-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one, and pharmaceutically acceptable salts, hydrates, or solvates thereof.
[00220] Embodiment 18. The combination, method or use according to
Embodiment 17, wherein the
Figure imgf000112_0001
COMPOUND 1 and pharmaceutically acceptable salts, hydrates, or solvates thereof.
[00221] Embodiment 19. The combination, method or use according to
Embodiment 18, wherein the ENT1 inhibitor is a Compound 1 hydrogen sulfate or a hydrate or solvate thereof.
[00222] Embodiment 20. The combination, method or use according to Embodiment 19, wherein the ENT1 inhibitor is a Compound 1 di(hydrogen sulfate) or a hydrate or solvate thereof.
[00223] Embodiment 21. The combination, method or use according to
Embodiment 20, wherein the ENT1 inhibitor is crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate.
[00224] Embodiment 22. The combination, method or use according to any one of Embodiments 1-21, wherein the ENT1 inhibitor is administered prior to, concomitant with, or subsequent to the administration of the bispecific antibody (BsAb) cancer therapy.
[00225] Embodiment 23. The combination, method or use according to any one of Embodiments 1-21, further comprising an additional therapeutic agent, such as an anti-PD- L1 agent, such as atezolizumab. [00226] Embodiment 24. The method or use according to any one of
Embodiments 2-23, wherein the cancer is characterized by a high concentration of adenosine in the tumor microenvironment (TME).
[00227] Embodiment 25. The method or use according to any one of Embodiments 2-23, wherein the cancer is selected from breast, carcinoid, cervical, colorectal, endometrial, glioma, head and neck, liver, lung, melanoma, ovarian, pancreatic, prostate, renal, gastric, thyroid and urothelial cancers.
[00228] Embodiment 26. The method or use according to any one of Embodiments 2-19, wherein the cancer is selected from malignant ascites, acute lymphocytic (ALL) including Philadelphia chromosome-negative precursor B-cell ALL, follicular lymphoma (FL) including relapsed or refractory FL, melanoma including uveal melanoma, multiple myeloma (MM) including relapsed or refractory MM, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), cervical cancer (CC) including relapsed or metastatic CC, acute myeloid leukemia (AML), diffuse large B-cell lymphoma (DLBCL) solid tumors including MUC 17-positive solid tumors, ovarian cancer including recurrent ovarian cancer, neoplasms, neuroendrocrine tumors, prostate cancer, chronic lymphocytic leukemia (CLL), prostate cancer including metastatic castration resistant prostate cancer, non-Hodgkin lymphoma (NHL), and colorectal cancer including microsatellite-stable (MSS) colorectal cancer.
[00229] Embodiment 27. The method or use according to any one of Embodiments 2-23, wherein the cancer is selected from cervical cancer (CC), colorectal cancer, lung cancer including SCLC and NSCLC, melanoma, ovarian cancer, and prostate cancer.
[00230] Embodiment 28. The method or use according to any one of Embodiments 2-23, wherein the cancer is breast cancer. [00231] Embodiment 29. The method or use according to Embodiment 28, wherein the breast cancer is triple negative breast cancer.
[00232] Embodiment 30. The method or use according to Embodiments 2-23, wherein the cancer is a solid-tumor cancer.
[00233] Embodiment 31. The method or use according to Embodiments 2-23, wherein the cancer is ovarian cancer.
[00234] Embodiment 32. The combination, method or use according to any one of Embodiments 1-31, wherein the bispecific antibody of the bispecific antibody (BsAb) cancer therapy comprises an antigen-binding domain that binds to CD3 and an antigen- binding domain that binds to HER2.
EXAMPLES
Example 1. Preparation ENT1 Inhibitors
[00235] ENT1 inhibitors of Formula (I), including COMPOUND 1, can be prepared as described in WO 2021/204896. (See, e.g., Compound 10.)
[00236] A di (hydrogen sulfate) salt of COMPOUND 1 can be prepared as follows. A sample of COMPOUND 1 and 6 vol. of isopropyl alcohol (IPA)/water (75:25% v/v) were added to a 20 mL scintillation vial. 2.05 mole equivalents of sulfuric acid were added as a solution in 2 vol. of IPA/water (75:35% v/v). The solution was stirred for about one hour at 40°C. The temperature was then cycled between 40°C and 5°C with a 0.1 °C/min ramp and a one hour hold between each step. After about 48 hours of cycling, a clear solution was still observed. Up to 6 vol. of anti-solvent (methyl t-butyl ether) was added to 40°C to facilitate precipitation. The experiment (now a slurry) was further temperature cycled for 24 hours.
The solids were then isolated via vacuum filtration and dried under vacuum at about 40°C for 48 hours. The damp and dried solids were subsampled and analyzed by XRPD and shown to be COMPOUND 1 di(hydrogen sulfate) trihydrate. See also, e.g., WO2024/194391.
Example 2. In Vitro Data
[00237] SK-OV-3 cells (ovarian cancer cell line) were cultured in McCoy’s 5 A medium (Capricorn, cat number MCC-A) containing 10% heat-inactivated fetal bovine serum (HI-FBS, Gibco, cat number A5256701). At day -1, SK-OV-3 cells were resuspended in X- VIVO15 (Lonza, cat number 02-060F) with 5% heat-inactivated human serum (HI-HS, Sigma, cat number S4190-100), 1 mM sodium pyruvate (Capricorn, cat number NPY-B) and 1% Pencillin/Streptomycin (Capricorn, cat number PS-B), collectively referred to as “assay medium,” at 5 × 104 cells/mL. 200 μL of cell suspension, representing 1 × 104 cells, was added to a flat bottom 96-well plate (Greiner, cat number 655180) and incubated overnight in a humified incubator at 37°C with 5% CO2.
[00238] HER2 x CD3 bispecific antibody (bsab) solution (Absolute Antibody, cat number bAb0183) was prepared by diluting the bsab to 4 nM in assay medium. At day 0, medium was removed from the cells and 50 μL of either assay medium or HER2 x CD3 bsab solution was added to the appropriate wells. Cells were incubated for 1 hour at 37°C with 5% CO2
[00239] Cryopreserved human CD3+ T cells were thawed and washed twice with RPMI1640 medium (Capricorn, cat number RPMI-STA) containing 10% HI-FBS. Cells were centrifuged at 450 x g for 5 minutes, supernatant was discarded, and cells were resuspended at 4 x 105 cells/mL in assay medium. 50 μL of T cell suspension, representing 2 x 104 cells, was added to the appropriate wells of the 96 well plate. This resulted in a T cell to SK-OV-3 ratio of 2: 1.
[00240] A solution of COMPOUND 1 was prepared in assay medium to give a final concentration of 300 nM when added as 50 μL to a final volume of 200 μL per well. The COMPOUND 1 solution or a concentration-matched DMSO solution was added at 50 μL per well to all relevant wells.
[00241] A solution of adenosine (Sigma, cat number A4036) of 1200 μM was prepared in assay medium such that addition of 50 μL to a final volume of 200 μL resulted in a final concentration of 300 μM.
[00242] IncuCyte Cytotox red dye (Sartorius, cat number 4632) was added to the wells at a final concentration of 250 nM. The assay plate was cultured in an IncuCyte incubator (Sartorius - Zoom40671) at 37°C with 5% CO2 for 4 days. The number of dead cells per well (counted as red objects/well) was used as a measurement of cell death over time.
Results
[00243] CD3 x HER2 (1 nM) was found to induce cytotoxicity of SK-OV-3 cells in combination with T cells (1, 2 and 5 T cells per SK-OV-3 cell), as assessed on day 6 of co- culture by LDH assay. FIG. 1.
[00244] Adenosine at doses > 100 μM was shown to reduce cytotoxicity induction by CD3 x HER2, which appears to be associated with reduction in T cell proliferation and “delayed” upregulation of CD39 expression by CD8+ T cells. FIG. 2.
[00245] Adenosine at 300 μM was shown to not affect growth of SK-OV-3 cells while ATP was shown to slow growth of SK-OV-3 cells. FIG. 3. COMPOUND 1 did not affect cytotoxic activity. FIG. 4.
[00246] CD3 x HER2 demonstrated cytotoxic activity against SK-OV-3 cells in combination with T cells (HER2 x CD3_control). FIG. 5. When adenosine (300 μM) is added to the start of the culture, there is a reduced cytotoxic effect (HER2 x CD3_adenosine; adenosine reduced the ability of CD3 x HER2 to induce cytotoxicity by 50% at day 4 of culture), however adenosine alone did not induce cytotoxicity in SK-OV-3 cells (SK-OV- 3_adenosine). COMPOUND 1 at 300 nM restored the full cytotoxic effect of the CD3 x HER2 antibody despite the presence of the adenosine (Her2 x CD3_adenosine + COMPOUND 1).
[00247] Therefore, adenosine prevents the full potential of the cytotoxic effect of the CD3 x HER2 antibody due to the suppressive effects on T cells, which was restored by inhibiting ENT1 with COMPOUND 1.
EQUIVALENTS
[00248] The foregoing written specification is considered to be sufficient to enable one skilled in the art to practice the embodiments. The foregoing description and Examples detail certain embodiments and describe the best mode contemplated by the inventors. It will be appreciated, however, that no matter how detailed the foregoing may appear in text, the embodiment may be practiced in many ways and should be construed in accordance with the appended claims and any equivalents thereof.
[00249] As used herein, the term about refers to a numeric value, including, for example, whole numbers, fractions, and percentages, whether or not explicitly indicated. The term about generally refers to a range of numerical values (e.g., +/-5- 10% of the recited range) that one of ordinary skill in the art would consider equivalent to the recited value (e.g., having the same function or result). When terms such as at least and about precede a list of numerical values or ranges, the terms modify all of the values or ranges provided in the list. In some instances, the term about may include numerical values that are rounded to the nearest significant figure.

Claims

What is Claimed is:
1. A combination of an ENT1 inhibitor and a bispecific antibody (BsAb) cancer therapy.
2. A method of treating cancer comprising administering to a subject in need thereof an ENT1 inhibitor and a bispecific antibody (BsAb) cancer therapy.
3. A use of an ENT1 inhibitor and a bispecific antibody (BsAb) cancer therapy for the treatment of cancer.
4. The combination, method or use according to any one of claims 1-3, wherein the bispecific antibody of the bispecific antibody (BsAb) cancer therapy comprises an antigen- binding domain that binds to an antigen expressed on a T cell, natural killer (NK) cell, macrophages, dendritic cells (DCs), or a combination thereof.
5. The combination, method or use according to any one of claims 1-3, wherein the bispecific antibody of the bispecific antibody (BsAb) cancer therapy comprises an antigen- binding domain that binds to an antigen selected from CD3, γδTCR, CD16, CD47, and a combination thereof.
6. The combination, method or use according to any one of claims 1-5, wherein the bispecific antibody of the bispecific antibody (BsAb) cancer therapy comprises an antigen- binding domain that binds to an antigen expressed on a cancer cell.
7. The combination, method, or use according to claim 6, wherein the bispecific antibody of the bispecific antibody (BsAb) cancer therapy comprises an antigen-binding domain that binds to an antigen selected from BCMA, CD123, CD33, CD38, CEA, CLEC12A, DLL3, DLL4, EpCAM, FcRH5, FLT3, GD2, Glypican-3, gpA33, GPRC5D, CD47, CD19, CD20, 4-1BB, HER-2, HER-3, PD-1, EGFR, EGFRvIII, PD-L1, CD3, MAGE-A4, MUC17, MUC16, NY-ESO-1, p-cadherin, PRAME, PSCA, PSMA, SSTR2, STEAP1, 5T4, CDld, B7H3, GPC3, MSLN, ICOS, CTLA4, LAG3, TIM3, Ang-2, c-MET, LGR5, FAP, DR5, CLDN18.2, B7H4, CDH17, CDH3, CEACAM5, CLDN6, ENPP3, ITGB6, KRASG12V, LY6G6D, MAGE- A3, TMEFF2, TROP2, WT1, and/or a combination thereof.
8. The combination, method or use according to any one of claims 1-7, wherein the
ENT1 inhibitor is a compound of Formula (I):
Figure imgf000119_0001
or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein
R1 is selected from the group consisting of
Figure imgf000119_0002
each R2 is independently selected from the group consisting of absent, halogen, -NHR3, -OR3, -R3, -C(O)R3, -CO2R3, C(O)N(R3)2, -CH2C(O)N(R3)2, - S(O)2R3, and -CN; or two instances of R2 are taken together with the atoms on which they are attached to form a heterocyclyl or heteroaryl ring; each R3 is independently selected from absent, -H, oxo, ALK, phenyl, heterocyclyl, and heteroaryl;
R4 is selected from the group consisting of
Figure imgf000120_0001
Figure imgf000120_0002
each U is independently selected from the group consisting of -C(O)-, alkylene
, -O-, -N(R3)-, -C(O)O-, -C(O)N(R3)-, and
Figure imgf000120_0003
each Rx is independently selected from alkylene;
V1 is selected from -C(R3)- and -N-; each V2 is independently selected from -C(R3)=, -N(R3)-, -N=, and -O-;
V3 is selected from -C= and -N-; and
Z is C or N, wherein ALK is unsubstituted alkyl or substituted alkyl, or two instances of ALK may be joined together with their intervening atoms to form a cycloalkyl or heterocyclyl ring.
9. The combination, method or use according to any one of claims 1-8, wherein the ENT1 inhibitor is a compound of Formula (II):
Figure imgf000121_0001
or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein
R1 is selected from the group consisting of ALK, cycloalkyl, heterocyclyl,
Figure imgf000121_0002
each R2 is independently selected from the group consisting of absent, halogen, -OR3, -R3, -CO2R3, C(O)N(R3)2, -CH2C(O)N(R3)2, -S(O)2R3, and -CN; or two instances of R2 are taken together with the atoms on which they are attached to form a heterocyclyl or heteroaryl ring; each R3 is independently selected from absent, -H, ALK, phenyl, and heteroaryl;
Figure imgf000121_0003
X is selected from the group consisting of -CH2-, -CHF-, and -CF2-; each U is independently selected from the group consisting of -O-, -N(R3)-, -
C(O)O-, -C(O)N(R3)-, -C(O)-, -O-N=C(H)- and alkylene; each Rx is inde
Figure imgf000122_0001
pendently selected from alkylene;
V1 is selected from -C(R3)- and -N-; each V2 is independently selected from -C(R3)=, -N(R3)-, -N=, and -O-;
V3 is selected from -C= and -N-; each Z is independently C or N; and n1 is a number of 0 or 1, wherein ALK is unsubstituted alkyl or substituted alkyl, or two instances of ALK may be joined together with their intervening atoms to form a cycloalkyl or heterocyclyl ring.
10. The combination, method or use according to claim 9, wherein the ENT1 inhibitor is a compound of Formula (Ila):
Figure imgf000122_0002
or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein X is CH2, CHF, or CF2.
11. The combination, method or use according to any one of claims 8-10, wherein R1 is
Figure imgf000123_0001
12. The combination, method or use according to claim 11, wherein R1 is
Figure imgf000123_0002
13. The combination, method or use according to any one of claims 8-12, wherein the compound is a compound of Formula (Ilb):
Figure imgf000123_0003
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
14. The combination, method or use according to any one of claims 8-13, wherein U is -
C(O)O-.
15. The combination, method or use according to any one of claims 8, 9, 11, and 12, wherein R4 is
Figure imgf000124_0001
the U in R4 is -C(O)O- or -C(O)NR3-.
16. The combination, method or use according to claim 9, wherein the compound is a compound of Formula (Ila1):
Figure imgf000124_0002
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
17. The combination, method or use according to any one of claims 1-7, wherein the ENT1 inhibitor is selected from:
(12S)-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
(12R)-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
(12S)-16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
(12R)-16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate N-(74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl)-3,4,5-trimethoxybenzamide
74.75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
(12S)-74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
(12R)-74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
74.75-dimethoxy-5-methyl-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
(12S)-74,75-dimethoxy-5-methyl-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
(12R)-74,75-dimethoxy-5-methyl-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
(HR)-74,75-dimethoxy-6-oxo-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotridecaphane-
11-yl 3,4,5-trimethoxybenzoate
(10S)-14-chloro-2-oxo-11H-3-aza-1(6,1)-indazola-7(1,4)-diazepanacyclotridecaphane-
10-yl 3,4,5-trimethoxybenzoate
(10R)-14-chloro-2-oxo-11H-3-aza-1(6,1)-indazola-7(1,4)-diazepanacyclotridecaphane-
10-yl 3,4,5-trimethoxybenzoate
(12S)-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoate
(12R)-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoate (12S)-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl benzoate
(12R)-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl benzoate
74,75dichloro-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl
3,4,5 -trimethoxybenzoate
(12S)-74,75-dichloro-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
(12R)-74,75-dichloro-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
75-carbamoyl-74-chloro-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
( 11Z, 16E, 10S)- 14-chloro-2-oxo- 12H-3 -aza-1(6,2)-indazola-7(1,4)- diazepanacyclotridecaphane- 10-yl 3,4,5-trimethoxybenzoate
( 11Z, 16E, 10R)- 14-chloro-2-oxo- 12H-3 -aza-1(6,2)-indazola-7(1,4)- diazepanacyclotridecaphane- 10-yl 3,4,5-trimethoxybenzoate
(12S)-74-carbamoyl-75-chloro-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
(12R)- 74-carbamoyl-75-chloro-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
74-bromo-75-chloro-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
75-chloro-74-cyano-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate (12R)-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl benzoate
(12R)-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl benzoate
(12S)-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl benzoate
(Z)-benzaldehyde O-(74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl) oxime
12-hydroxy-74,75-dimethoxy-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-hydroxybenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-fluorobenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-isopropoxybenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3-(trifluoromethyl)benzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3-(methylsulfonyl)benzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3-phenoxybenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 2-fluorobenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-bromo-3 -cyanobenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3-methyl-5-(trifluoromethyl)benzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 2-fluoro-4-methoxybenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-methoxy-2-(trifluorom ethoxy )benzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl picolinate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl nicotinate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl pyrazine-2-carboxylate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 6-hydroxynicotinate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl quinoline-5-carboxylate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl oxazole-4-carboxylate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 1H-1,2,3-triazole-4-carboxylate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl acetate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl cyclopropanecarboxylate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3-methylbutanoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4,4,4-trifluorobutanoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl cyclohexanecarboxylate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 1-methylpiperidine-4-carboxylate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3, 3 -dimethylcy cl obutane-1 -carboxylate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 2-(oxetan-3-yl)acetate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl (1R,5S,6R)-3-oxabicyclo[3.1.0]hexane-6-carboxylate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 5-oxopyrrolidine-3-carboxylate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 1-benzyl-5-oxopyrrolidine-3-carboxylate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-methoxycyclohexane-1-carboxylate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 2,6-difluorobenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-(trifluorom ethoxy )benzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3 -cyanobenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 2-oxo-1,2,3,4-tetrahydroquinoline-6-carboxylate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3 -(difluorom ethoxy )benzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3,5-dichlorobenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3, 4-di chlorobenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 2,3 -di chlorobenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 2-chloro-6-fluoro-3 -methylbenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3 -fluoro-5 -(trifluoromethyl)benzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-fluoro-3 -(trifluoromethyl)benzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-cyano-3 -fluorobenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-(trifluoromethyl)benzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3,5-difluorobenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3,4-difluorobenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3-cyano-4-fluorobenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-cyanobenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3-chloro-4-fluorobenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 1 -methyl- 1H-benzo[d]imidazole-5-carboxylate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-(oxazol-5-yl)benzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4,5-dichloro-2-fluorobenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3,4,5-triethoxybenzoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3-methoxypropanoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3 -( 1H-pyrazol-1-yl)propanoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3-cyanopropanoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-cyanobutanoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-acetamidobutanoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3 -( 1H-tetrazol-1-yl)propanoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-(dimethylamino)-4-oxobutanoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3-acetamidopropanoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-(methylamino)-4-oxobutanoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3 -(1H- 1 ,2,4-triazol-1-yl)propanoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-morpholino-4-oxobutanoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3 -(4-fluorophenoxy)propanoate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4,4-difluorocyclohexane-1-carboxylate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 4-(trifluoromethyl)cyclohexane-1-carboxylate
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3 -(2, 5 -dioxopyrrolidin-1-yl)propanoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-
12-yl 3-methoxycyclohexane-1-carboxylate
74.75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl benzoate
(E)-benzaldehyde O-(74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl) oxime
(E)-benzaldehyde O-((12R)- 74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-
7(1,3)-benzenacy clotetradecaphane-12-yl) oxime
(E)-benzaldehyde O-((12S)- 74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl) oxime
12-hydroxy-74,75-dimethoxy-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one
(12R)-12-hydroxy-74,75-dimethoxy-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one
(12S)-12-hydroxy-74,75-dimethoxy-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one
74.75-dimethoxy-12-(5-phenyl-2H-tetrazol-2-yl)-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one
74.75-dimethoxy-12-(4-phenyl-1H-1,2,3-triazol-1-yl)-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one
74.75-dimethoxy-12-(5-phenyl-1H-tetrazol-1-yl)-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one, and pharmaceutically acceptable salts, hydrates, or solvates thereof.
18. The combination, method or use according to claim 17, wherein the ENT1 inhibitor is selected from
Figure imgf000134_0001
COMPOUND 1 and pharmaceutically acceptable salts, hydrates, or solvates thereof.
19. The combination, method or use according to claim 18, wherein the ENT1 inhibitor is a Compound 1 hydrogen sulfate or a hydrate or solvate thereof.
20. The combination, method or use according to claim 19, wherein the ENT1 inhibitor is a Compound 1 di(hydrogen sulfate) or a hydrate or solvate thereof.
21. The combination, method or use according to claim 20, wherein the ENT1 inhibitor is crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate.
22. The combination, method or use according to any one of claims 1-21, wherein the ENT1 inhibitor is administered prior to, concomitant with, or subsequent to the administration of the bispecific antibody (BsAb) cancer therapy.
23. The combination, method or use according to any one of claims 1-21, further comprising an additional therapeutic agent, such as an anti-PD-L1 agent, such as atezolizumab.
24. The method or use according to any one of claims 2-23, wherein the cancer is characterized by a high concentration of adenosine in the tumor microenvironment (TME).
25. The method or use according to any one of claims 2-23, wherein the cancer is selected from breast, carcinoid, cervical, colorectal, endometrial, glioma, head and neck, liver, lung, melanoma, ovarian, pancreatic, prostate, renal, gastric, thyroid and urothelial cancers.
26. The method or use according to any one of claims 2-19, wherein the cancer is selected from malignant ascites, acute lymphocytic (ALL) including Philadelphia chromosome- negative precursor B-cell ALL, follicular lymphoma (FL) including relapsed or refractory FL, melanoma including uveal melanoma, multiple myeloma (MM) including relapsed or refractory MM, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), cervical cancer (CC) including relapsed or metastatic CC, acute myeloid leukemia (AML), diffuse large B-cell lymphoma (DLBCL) solid tumors including MUC 17-positive solid tumors, ovarian cancer including recurrent ovarian cancer, neoplasms, neuroendrocrine tumors, prostate cancer, chronic lymphocytic leukemia (CLL), prostate cancer including metastatic castration resistant prostate cancer, non-Hodgkin lymphoma (NHL), and colorectal cancer including microsatellite-stable (MSS) colorectal cancer.
27. The method or use according to any one of claims 2-23, wherein the cancer is selected from cervical cancer (CC), colorectal cancer, lung cancer including SCLC and NSCLC, melanoma, ovarian cancer, and prostate cancer.
28. The method or use according to any one of claims 2-23, wherein the cancer is breast cancer.
29. The method or use according to claim 28, wherein the breast cancer is triple negative breast cancer.
30. The method or use according to claims 2-23, wherein the cancer is a solid-tumor cancer.
31. The method or use according to claims 2-23, wherein the cancer is ovarian cancer.
32. The combination, method or use according to any one of claims 1-31, wherein the bispecific antibody of the bispecific antibody (BsAb) cancer therapy comprises an antigen- binding domain that binds to CD3 and an antigen-binding domain that binds to HER2.
PCT/IB2024/062579 2023-12-15 2024-12-12 Ent1 inhibitors in combination with bispecific antibodies Pending WO2025126110A1 (en)

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