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WO2025163520A1 - Ent1 inhibitors for use in the treatment of diseases with increased adenosine levels - Google Patents

Ent1 inhibitors for use in the treatment of diseases with increased adenosine levels

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Publication number
WO2025163520A1
WO2025163520A1 PCT/IB2025/050979 IB2025050979W WO2025163520A1 WO 2025163520 A1 WO2025163520 A1 WO 2025163520A1 IB 2025050979 W IB2025050979 W IB 2025050979W WO 2025163520 A1 WO2025163520 A1 WO 2025163520A1
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WO
WIPO (PCT)
Prior art keywords
diazepana
oxo
benzenacyclotetradecaphane
dimethoxy
dioxa
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/IB2025/050979
Other languages
French (fr)
Inventor
Reece Gerrad MARILLIER
Hussein SHEHADE
Maura ROSSETTI
Nicolas ROSEWICK
Yvonne MCGRATH
Erica Joke Kateligne Heleen HOUTHUYS
Chiara MARTINOLI
Francesco STROZZI
Sophie DEKONICK
Edmund POON
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Iteos Belgium SA
Original Assignee
Iteos Belgium SA
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Filing date
Publication date
Application filed by Iteos Belgium SA filed Critical Iteos Belgium SA
Publication of WO2025163520A1 publication Critical patent/WO2025163520A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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

Definitions

  • the present disclosure includes treatment of a subject wherein the subject has been identified as having increased levels of adenosine.
  • Compounds of the present disclosure include, but are not limited to ENT1 inhibitors, and are useful as therapeutic compounds, especially in the treatment of cancers.
  • BACKGROUND [0004] Adenosine is a strong immunosuppressive metabolite that is often found elevated in the extracellular tumor microenvironment (TME).
  • adenosine represents a relevant target of interest for cancer immunotherapy.
  • TAE tumor microenvironment
  • adenosine represents a relevant target of interest for cancer immunotherapy.
  • the very short half-life of adenosine makes direct measurement in tumor tissues challenging for high- throughput screening and not practical for routine applications (Mengager et al., AM J Physiol.1989, 256(4 Pt 1):C799-806).
  • the first signature was generated by investigating the effects of adenosine on gene expression prolife in peripheral blood mononuclear cells (PBMC) (Fong et al., Cancer Discov.2020, 10(1): 40-53).
  • PBMC peripheral blood mononuclear cells
  • Adenosine-responsive genes were identified by in vitro stimulation of normal human Attorney Docket No.01330-0108-00PCT PBMCs with the adenosine receptor agonist 5′-N-Ethylcarboxamidoadenosine (NECA).
  • NECA adenosine receptor agonist 5′-N-Ethylcarboxamidoadenosine
  • the second signature was generated using regulatory networks for adenosine signaling pathway derived from the literature (Sidders et al., Clin Cancer Res. 2020, 26(9): 2176-2187).
  • the adenosine signaling pathway was identified focusing on genes that have been reported to be regulated by the adenosine A 2A receptor. Both signatures therefore are dependent on adenosine signaling through adenosine receptors. While they can be instrumental when characterizing human tumors in the context of targeting adenosine receptors, these signatures do not directly measure adenosine content.
  • a disease or disorder such as cancer
  • Embodiment 3. A method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an ENT1 inhibitor, wherein the subject has previously been identified as having increased adenosine.
  • Embodiment 5. The ENT1 inhibitor for use of embodiment 4, wherein the subject was previously identified as having increased adenosine.
  • Embodiment 6. The method or the ENT1 inhibitor for use of any one of embodiments 1-5, wherein the adenosine is increased by comparison to a reference level determined in a sample from a subject not affected and/or diagnosed with the disease or disorder.
  • Attorney Docket No.01330-0108-00PCT Embodiment 7.
  • Embodiment 9 The method or the ENT1 inhibitor for use of any one of embodiments 1-7, wherein the level of adenosine correlates to expression of at least one gene in an adenosine-specific gene signature.
  • Embodiment 9. The method or the ENT1 inhibitor for use of any one of embodiments 1-8, wherein the disease or disorder is characterized by increased or decreased expression of at least one gene in an adenosine-specific gene signature.
  • Embodiment 10 The method or the ENT1 inhibitor for use of embodiment 9, wherein the expression of at least one gene in an adenosine-specific gene signature is increased or decreased by comparison to a reference level determined in a sample from a subject not affected and/or diagnosed with the disease or disorder.
  • adenosine-specific gene signature comprises at least one of the following genes: APOE, CALR, CD63, CD82, CTSB, DMBT1, EIF3G, ENO1, FLNA, FOS, GNAS, HSPA1B, HSPB1, IFITM3, NDUFS5, NPM1, PPDPF, PTP4A2, RPS27A, SLC25A6, SYNGR2, TESC, TPM1, TXNIP, or YBX3.
  • the adenosine-specific gene signature comprises at least one of the following genes: APOE, CALR, CD63, CD82, CTSB, DMBT1, EIF3G, ENO1, FLNA, FOS, GNAS, HSPA1B, HSPB1, IFITM3, NDUFS5, NPM1, PPDPF, PTP4A2, RPS27A, SLC25A6, SYNGR2, TESC, TPM1, TXNIP, or YBX3.
  • adenosine-specific gene signature comprises at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or all 25 genes.
  • the ENT1 inhibitor for use of any one of embodiments 1-12, wherein the ENT1 inhibitor is a compound of Formula (I): Attorney Docket No.01330-0108-00PCT (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
  • Embodiment 14 The method or the ENT1 inhibitor for use of any one of embodiments 1-13, wherein 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, Attorney Docket No.01330-0108-00PCT 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
  • Embodiment 15 The method or the ENT1 inhibitor for use of embodiment 14, wherein the ENT1 inhibitor is a compound of Formula (IIa): (IIa), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein X is CH 2 , CHF, or CF 2 .
  • Embodiment 16. The method or the ENT1 inhibitor for use of any one of embodiments 13- 15, wherein R 1 is .
  • Embodiment 17. The method or the ENT1 inhibitor for use of embodiment 16, wherein R 1 is .
  • Embodiment 19 The method or the ENT1 inhibitor for use of any one of embodiments 13- 18, wherein U is -C(O)O-.
  • Embodiment 20 The method or the ENT1 inhibitor for use of any one of embodiments 113, 14, 15, or 17, wherein R 4 is the U in R 4 is -C(O)O- or -C(O)NR 3 -.
  • Embodiment 21 Embodiment 21.
  • the ENT1 inhibitor is selected from: (12S)-7 4 ,7 5 -dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate (12R)-7 4 ,7 5 -dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate 16,16-difluoro-7 4 ,7 5 -dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate (12S)-16,16-didi
  • Embodiment 23 The method or the ENT1 inhibitor for use of embodiment 22, wherein the ENT1 inhibitor is selected from Attorney Docket No.01330-0108-00PCT COMPOUND 1 and pharmaceutically acceptable salts, hydrates, or solvates thereof.
  • Embodiment 24 The method or the ENT1 inhibitor for use of embodiment 23, wherein the ENT1 inhibitor is a Compound 1 hydrogen sulfate or hydrate or solvate thereof.
  • Embodiment 25. The method or the ENT1 inhibitor for use of embodiment 24, wherein theENT1 inhibitor is a Compound 1 di(hydrogen sulfate) or a hydrate or solvate thereof.
  • Embodiment 26 The method or the ENT1 inhibitor for use of embodiment 22, wherein the ENT1 inhibitor is selected from Attorney Docket No.01330-0108-00PCT COMPOUND 1 and pharmaceutically acceptable salts, hydrates, or solvates thereof.
  • Embodiment 24 The method or the ENT1 inhibitor for use of embodiment 23, wherein the
  • Embodiment 27 The method or the ENT1 inhibitor for use of embodiment 25, wherein the ENT1 inhibitor is crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate.
  • Embodiment 28 The method or the ENT1 inhibitor for use of embodiment 27 wherein the ENT1 inhibitor is administered prior to the additional therapeutic agent.
  • Embodiment 29 The method or the ENT1 inhibitor for use of embodiment 27, wherein the ENT1 inhibitor is administered simultaneously with the additional therapeutic agent.
  • Embodiment 30 The method or the ENT1 inhibitor for use of embodiment 27, wherein the ENT1 inhibitor is administered after the additional therapeutic agent.
  • Embodiment 31 The method or the ENT1 inhibitor for use of embodiment 25, wherein the ENT1 inhibitor is crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate.
  • Embodiment 28 The method or the ENT1 inhibitor for use of embodiment 27 wherein the ENT1 inhibitor is administered prior to the additional therapeutic agent.
  • Embodiment 29 The method or the ENT1 inhibitor for use
  • FIG.1 shows a schematic of the use of quantitative Mass Spectrometry Imaging (qMSI) and Spatial Transcriptomics to derive the quantified adenosine signature (i.e., adenosine-specific gene signature based on quantified adenosine content in human tumors).
  • qMSI quantitative Mass Spectrometry Imaging
  • Spatial Transcriptomics to derive the quantified adenosine signature (i.e., adenosine-specific gene signature based on quantified adenosine content in human tumors).
  • Frozen blocks were sectioned and tumor slides were analyzed by qMSI to determine adenosine levels.
  • Regions of Interest were selected based on their high or low quantified ADO content. Similar ROIs were then selected on adjacent slides and RNA extracted and checked for quality by RNA-scope.
  • FIG.2A-2E demonstrate high adenosine regions are associated with a specific gene expression pattern and contain fewer immune cells compared to low adenosine regions. ROIs with matched adenosine content and gene expression were divided into a training (70%) and a validation (30%) set.
  • FIG 2A shows a schematic of identifying the significantly differentially expressed genes (DEGs) in adenosine high vs adenosine low regions.
  • DEGs significantly differentially expressed genes
  • FIG.2B shows a volcano plot showing the genes upregulated in adenosine high (right) or adenosine low (left) regions.
  • FIG.2C shows a gene ontology enrichment analysis on genes upregulated in adenosine high regions, which revealed associations with protein translation, metabolic processes and immune activation.
  • GO gene ontology.
  • BP biological process.
  • FIG.2D shows a volcano plot displaying the difference (Log2FC) in the abundance of immune cell populations between adenosine high and adenosine low regions.
  • Immune cell signatures were used to deconvolute spatial transcriptomic data.
  • Linear mixed model adjusted for tumor type, patients and PanCK +/- regions was used to compare immune signatures in adenosine high vs low regions.
  • Adenosine high regions are demonstrated to be poor in immune infiltrates compared to adenosine low regions.
  • FIG.2E shows box plots for each immune cell population showing lower expression of the associated gene signature in adenosine high vs adenosine low regions.
  • N 13 paired samples.
  • FIG.3A-3D shows that the quantified adenosine signature predicts adenosine levels in a test set and correlates with another adenosine signaling signature.
  • FIG.3A shows a schematic of Attorney Docket No.01330-0108-00PCT applying a Lasso regression to identify DEGs with the highest predictive power to derive the quantified adenosine signature.
  • FIG.3B shows a box plot showing the difference between adenosine low and adenosine high ROIs in the training set as well as the test set.
  • FIG.3C shows a receiver operating characteristic (ROC) analysis confirming the predictive power of the quantified adenosine signature in the test set.
  • FIG.3D shows a correlation plot showing the relative expression of the quantified adenosine signature (i.e., adenosine-specific signature) and an independent adenosine signaling signature in TCGA dataset.
  • the quantified adenosine signature is shown to correlate with the independent adenosine signaling signature.
  • FIG.4A-4C show that the quantified adenosine signature is enriched in tumor vs healthy tissue and is associated with poor survival in selected cancer types.
  • FIG.4A shows a violin plot showing the expression of the quantified adenosine signature in normal and tumor tissues. The qAdenosine signature is enriched in tumor (TCGA) vs healthy (GTEx) tissue. (Mann-Whitney U test).
  • FIG.4B shows a forest plot depicting the Hazard ratio and 95% confidence for overall survival for each tumor type in TCGA datasets. The quantified adenosine signature is associated with worse survival in several cancer types (Cox regression using adenosine score as continuous variable).
  • FIG.4C shows representative survival curves for a tumor type displaying worse (top) or better (bottom) survival in adenosine high vs adenosine low patients. Patients were stratified according to adenosine content using the quantified adenosine signature and divided in 2 groups based on the median. [0010]
  • FIG.5A-5D demonstrate that the quantified adenosine signature enables tumor type prioritization.
  • FIG.5A shows a box plot showing the relative expression of the quantified adenosine signature in TCGA. The quantified adenosine signature can stratify tumor types by adenosine content.
  • FIG.5B shows actionable patient segments with high adenosine can be identified using TCGA.
  • FIG.5C shows a box plot showing the relative expression of the quantified adenosine signature in WT and KRAS mutated tumor types.
  • FIG.5D shows a box plot showing the relative expression of the quantified adenosine signature in WT and BRAF mutated tumor types.
  • FIG.6A-6B show graphs demonstrating an increase in plasma adenosine in subjects treated with compound 1.
  • FIG.6A shows adenosine ratio to baseline for various cohorts of the subjects at first exposure to compound 1. The adenosine-specific signature was measured by mass spectrometry to give the average values as indicated.
  • FIG.6B shows adenosine ratio to Attorney Docket No.01330-0108-00PCT baseline for Cycle 1 Day 15 group (BID for 15 days) at Day 15 with the trough being right before dosing. *only 1 evaluable patient at 22.5 mg BID upon multiple dosing. DETAILED DESCRIPTION [0011]
  • aldehyde refers to a group –CHO.
  • 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.
  • 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.
  • alkoxy refers to a group –O-alkyl wherein alkyl is as herein defined.
  • ALK alkyl group
  • Alk alkyl radical of formula C n H 2n+1 wherein n is a number greater than or equal to 1
  • 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.
  • alkylaminoalkyl refers to a group –alkyl-NH-alkyl wherein alkyl is as herein defined.
  • alkylheteroaryl refers to any heteroaryl substituted by an alkyl group wherein alkyl is as herein defined.
  • alkyloxyalkyl refers to a group –alkyl-O-alkyl wherein alkyl is as herein defined.
  • Attorney Docket No.01330-0108-00PCT [0031]
  • alkylsulfonyl refers to a group –SO2-alkyl wherein alkyl is as herein defined.
  • alkylsulfonylaminoalkyl refers to a group –alkyl-NH-SO2-alkyl wherein alkyl is as herein defined.
  • alkylsulfonealkyl refers to a group –alkyl–SO 2 -alkyl wherein alkyl is as herein defined.
  • 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 CH2CH(CH3)CH2—.
  • an alkylene group has from 1 to about 6 carbon atoms.
  • an alkylene group has from about 3 to about 5 carbon atoms.
  • an alkylene group is branched.
  • an alkylene group is linear.
  • an alkylene group is —CH2—.
  • 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
  • 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.
  • 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.
  • aminonosulfonyl 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. In some embodiments, the aryl is a 5- or 6-membered aryl. Non-limiting examples of aryl include phenyl and naphthalenyl.
  • arylalkyl refers to a group –alkyl–aryl wherein alkyl and aryl are as herein defined.
  • 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.
  • Attorney Docket No.01330-0108-00PCT 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.
  • heteroaryls include: pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • heteroarylalkyl refers to a group –alkyl–heteroaryl wherein alkyl and heteroaryl are as herein defined.
  • 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-
  • heterocyclylalkyl refers to a group –alkyl–heterocyclyl wherein alkyl and heterocyclyl are as herein defined.
  • heterocyclyl (heterocyclyl)(alkyl)aminoalkyl” refers to a group –alkyl-NR 1 R 2 wherein R 1 is an alkyl group and R 2 is a heterocyclyl group, wherein alkyl and heterocyclyl are as herein defined.
  • heterocyclylalkyloxyalkyl refers to a group –alkyl-O-alkyl–heterocyclyl 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 – SO2-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.
  • 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.
  • inhibitor refers to a natural or synthetic compound that has a biological effect to inhibit or significantly reduce or down-regulate the expression of a gene and/or a protein or that has a biological effect to inhibit or significantly reduce the biological activity of a protein. Consequently, an “ENT inhibitor” or “inhibitor of an ENT family transporter” refers to a compound that has a biological effect to inhibit or significantly reduce or down-regulate the biological activity of ENT family transporter.
  • ENT inhibitor or “inhibitor of an ENT family transporter” refers to a compound that has a biological effect to inhibit or significantly reduce or down-regulate the biological activity of ENT family transporter.
  • the term “combination” means a combined occurrence of the two or more therapeutic agents. In some embodiments, a combination of the present disclosure may occur either as one composition, comprising all the components in one and the same mixture (e.g.
  • 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. In one embodiment, the hormone therapy is oncologic hormone therapy. Attorney Docket No.01330-0108-00PCT [0086]
  • human refers to a subject of both genders and at any stage of development (i.e. neonate, infant, juvenile, adolescent, adult).
  • subject refers to a mammal, preferably a human.
  • the subject is diagnosed with a disease or disorder, such as cancer.
  • the subject is a patient, preferably 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.
  • the subject is a human patient who is treated and/or monitored for the development or progression of a cancer.
  • the subject is a male.
  • the subject is a female.
  • the subject is an adult.
  • the subject is a child.
  • gene signature refers to a specific gene or specific group of genes in a cell or tissue that have characteristic pattern of gene expression and are associated with a particular biological process, cell type, or disease state.
  • a gene signatures may be used to diagnose diseases, such as cancer; plan treatment; assess treatment efficacy; and/or make a prognosis.
  • Each gene in the gene signature is assigned a signature score, which is an overall measure of expression evaluated for each cell. Proteins (e.g.
  • adenosine gene signature or “quantified adenosine signature” refers to a group of genes that positively or negatively correlates to the level of adenosine signaling and/or adenosine levels.
  • immunotherapy refers to a therapy aiming at inducing and/or enhancing an immune response towards a specific target, for example towards cancer cells.
  • Immunotherapy may involve the use of 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.
  • pharmaceutically acceptable refers to the ingredients of a pharmaceutical composition are compatible with each other and not deleterious to the subject to which it is administered.
  • pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant refers to a substance that does not produce an adverse, allergic or other untoward reaction when administered to an animal, preferably a human.
  • inactive substance such as for example solvents, cosolvents, antioxidants, surfactants, stabilizing agents, emulsifying agents, buffering agents, pH modifying agents, preserving agents (or preservating agents), antibacterial and antifungal agents, isotonifiers, granulating agents or binders, lubricants, disintegrants, glidants, diluents or fillers, adsorbents, dispersing agents, suspending agents, coating agents, bulking agents, Attorney Docket No.01330-0108-00PCT release agents, absorption delaying agents, sweetening agents, flavoring agents and the like.
  • solvents for example solvents, cosolvents, antioxidants, surfactants, stabilizing agents, emulsifying agents, buffering agents, pH modifying agents, preserving agents (or preservating agents), antibacterial and antifungal agents, isotonifiers, granulating agents or binders, lubricants, disintegrants, glidants, diluent
  • preparations should meet sterility, pyrogenicity, general safety and purity standards as required by regulatory offices, such as, e.g., FDA Office or EMA.
  • the terms “prevent”, “preventing” and “prevention”, as used herein, refer to a method of delaying or precluding the onset of a condition or disease and/or its attendant symptoms, barring a patient from acquiring a condition or disease, or reducing a patient’s risk of acquiring a condition or disease.
  • 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.
  • 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.
  • terapéuticaally effective amount or “effective amount” or “therapeutically effective dose” refer to the amount or dose of active ingredient that is aimed at, without causing significant negative or adverse side effects to the subject, (1) delaying or preventing the onset of a cancer in the subject; (2) reducing the severity or incidence of a cancer; (3) slowing down or stopping the progression, aggravation, or deterioration of one or more symptoms of a cancer affecting the subject; (4) bringing about ameliorations of the symptoms of a cancer affecting the subject; or (5) curing a cancer affecting the subject.
  • a therapeutically effective amount may be administered prior to the onset of a cancer for a prophylactic or preventive action.
  • a therapeutically effective amount may be administered after initiation of a cancer for a therapeutic action.
  • the terms “treating” or “treatment” refer to therapeutic treatment; wherein the object is to prevent or slow down the targeted pathologic condition or disease.
  • a subject or mammal is successfully “treated” for a disease or affection or condition if, after receiving the treatment according to the present disclosure, the subject or mammal shows observable and/or measurable reduction in or absence of one or more of the following: reduction of the number of cancer cells; and/or relief to some extent, for one or more of the symptoms associated with the specific disease or condition; reduced morbidity and mortality, and improvement in quality of life issues.
  • stem cell transplant refers to a procedure in which a patient receives healthy blood-forming cells (stem cells) to replace their own that have been destroyed by disease or by the radiation or high doses of anticancer drugs that are given as part of the procedure.
  • the healthy stem cells may come from the blood or bone marrow of the patient, from a donor, or from the umbilical cord blood of a newborn baby.
  • a stem cell transplant may be autologous (using a patient’s own stem cells that were collected and saved before treatment), allogeneic (using stem cells donated by someone who is not an identical twin), or syngeneic (using stem cells donated by an identical twin.
  • Detection of Adenosine [0097]
  • the present disclosure provides a method to determine if a subject has an elevated or increased level of adenosine comprising: (a) detecting the level of adenosine in a sample from the subject and (b) comparing the level of the adenosine to a suitable reference level of adenosine.
  • a subject with elevated or increased adenosine is administered a compound or a combination of compounds effective for treatment of a patient having an elevated or increased level of adenosine.
  • a subject with elevated or increased adenosine is selected for treatment with a combination of compounds effective for treatment of a patient having an elevated or increased level of adenosine.
  • the compound or combination of compounds include an ENT1 inhibitor, as further defined below.
  • adenosine may be determined using a suitable in vitro assay.
  • adenosine in a tumor is compared to a control, i.e., a suitable reference standard.
  • control refers to any reference standard suitable to provide a comparison to the expression products in the test sample.
  • the control comprises obtaining a "control sample” from which expression product levels are detected and compared to the expression product levels from the test sample.
  • Such a control sample may comprise any suitable sample, including but not limited to a sample from a control cancer patient (can be stored sample or previous sample measurement) with a known outcome; normal tissue or cells isolated from a subject, such as a normal patient or the cancer patient, cultured primary cells/tissues isolated from a subject such as a normal subject or the cancer patient, adjacent normal cells/tissues obtained from the same organ or body location of the cancer patient, a tissue or cell sample isolated from a normal subject, or a primary cells/tissues obtained from a depository.
  • a sample from a control cancer patient can be stored sample or previous sample measurement
  • normal tissue or cells isolated from a subject such as a normal patient or the cancer patient
  • cultured primary cells/tissues isolated from a subject such as a normal subject or the cancer patient
  • adjacent normal cells/tissues obtained from the same organ or body location of the cancer patient a tissue or cell sample isolated from a normal subject, or a primary cells/tissues obtained from a depository.
  • control may comprise a reference standard expression product level from any suitable source, including but not limited to housekeeping genes, an expression product level range from normal tissue (or other previously analyzed control sample), a previously determined expression product level range Attorney Docket No.01330-0108-00PCT within a test sample from a group of patients, or a set of patients with a certain outcome (for example, survival for one, two, three, four years, etc.) or receiving a certain treatment (for example, standard of care cancer therapy).
  • a certain outcome for example, survival for one, two, three, four years, etc.
  • a certain treatment for example, standard of care cancer therapy
  • control samples and reference standard expression product levels can be used in combination as controls in the methods of the present disclosure.
  • control may comprise normal or non-cancerous cell/tissue sample.
  • control may comprise an expression level for a set of patients, such as a set of cancer patients, or for a set of cancer patients receiving a certain treatment, or for a set of patients with one outcome versus another outcome.
  • the specific expression product level of each patient can be assigned to a percentile level of expression, or expressed as either higher or lower than the mean or average of the reference standard expression level.
  • the control may comprise normal cells, cells from patients treated with combination chemotherapy, and cells from patients having benign cancer.
  • the control may also comprise a measured value for example, average level of expression of a particular gene in a population compared to the level of expression of a housekeeping gene in the same population.
  • control comprises a ratio transformation of expression product levels, including but not limited to determining a ratio of expression product levels of two genes in the test sample and comparing it to any suitable ratio of the same two genes in a reference standard; determining expression product levels of the two or more genes in the test sample and determining a difference in expression product levels in any suitable control; and determining expression product levels of the two or more genes in the test sample, normalizing their expression to expression of housekeeping genes in the test sample, and comparing to any suitable control.
  • control comprises a control sample which is of the same lineage and/or type as the test sample.
  • control may comprise expression product levels grouped as percentiles within or based on a set of patient samples, such as all patients with cancer.
  • a control expression product level is established wherein higher or lower levels of expression product relative to, for instance, a particular percentile, are used as the basis for predicting outcome.
  • a control expression product level is established using expression product levels from cancer control patients with a known outcome, and the expression product levels from the test sample are compared to the control expression product level as the basis for predicting outcome.
  • a suitable control or reference standard is adenosine level in a subject not affected and/or diagnosed with cancer.
  • a suitable reference standard is the mean adenosine level in a population of subjects not affected and/or diagnosed with cancer.
  • a suitable reference standard is adenosine level of a sample from the subject themselves.
  • a suitable reference standard is adenosine level in a non-cancerous cellular sample adjacent to a tumor from the subject themselves.
  • the present disclosure includes determining a level of adenosine in a tumor in a subject comprising obtaining or having obtained a biological sample from the subject; and performing an assay on the biological sample to determine if the tumor has a elevated level of adenosine.
  • the methods of determining a level of adenosine disclosed herein are in vitro methods.
  • the sample is a bodily fluid.
  • the sample is a bodily tissue.
  • the sample is a tumor tissue sample.
  • the tumor tissue sample comprises tumor cells.
  • the tumor tissue sample further comprises tumor infiltrating immune cells.
  • the tumor tissue sample does not comprise tumor infiltrating immune cells.
  • the level of adenosine is considered as “elevated” or “increased” or “higher” when said level is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100% or more higher than the level of adenosine in a control subject or population, e.g., in a subject or a population of subjects not affected and/or diagnosed with cancer, or in a sample such as a non-cancerous sample from the subject themselves.
  • gene expression analysis performed on a sample identifies various genes expressed at different levels in the sample, and the expression levels of the various genes are compared to adenosine content in the sample.
  • the sample is a tumor sample.
  • RNA transcription of genes is compared in inter- and intra- tumor regions of high and low adenosine content.
  • the genes with highest correlation/ predictive power for adenosine content comprises an adenosine-specific gene signature.
  • the adenosine-specific gene signature comprises one or more of 25 genes, which are associated with increased or decreased adenosine expression and/or level.
  • the adenosine-specific gene signature comprises one or more of the following: APOE, CALR, CD63, CD82, CTSB, DMBT1, EIF3G, ENO1, FLNA, FOS, GNAS, HSPA1B, Attorney Docket No.01330-0108-00PCT HSPB1, IFITM3, NDUFS5, NPM1, PPDPF, PTP4A2, RPS27A, SLC25A6, SYNGR2, TESC, TPM1, TXNIP, and/or YBX3.
  • the adenosine-specific signature comprises at least 1, at least 2, at least 3,at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or all 25 genes.
  • the adenosine-specific gene signature comprises 25 genes.
  • the genes are associated with increased adenosine expression and/or level.
  • the genes are upregulated in adenosine-high regions.
  • HGNC ID stable gene ID from the Ensembl database
  • SEQ ID NOs corresponding to DNA sequences of the un-spliced versions of the genes
  • Table 1 HGNC symbol Gene description HGNC ID Gene Stable ID SEQ ID NO: APOE apolipoprotein E HGNC:613 ENSG00000130203 6 CALR calreticulin HGNC:1455 ENSG00000179218 17 CD63 CD63 molecule HGNC:1692 ENSG00000135404 7 CD82 CD82 molecule HGNC:6210 ENSG00000085117 2 CTSB cathepsin B HGNC:2527 ENSG00000285132 28 ENSG00000164733 13 DMBT1 deleted in malignant brain HGNC:2926 ENSG00000187908 26 tumors 1 EIF3G eukaryotic translation HGNC:3274 ENSG00000130811 8 initiation factor 3 subunit G ENO1 enolase 1 HGNC:3350 ENSG00000074800 3 FLNA filamin A HGNC:3754 ENSG00000196924 22 FOS Fos proto-oncogen
  • the adenosine-specific gene signature (as a surrogate for adenosine expression and/or content) allows the characterization of adenosine landscape in human cancers using public datasets and the analysis of patient tumor samples.
  • the gene signature can rank cancer types based on adenosine-specific signature score and characterize the prognostic impact of adenosine on patient survival. Integration of gene expression data with clinical metadata and genomic information can allow the identification of disease segments with the highest adenosine-specific signature scores.
  • the adenosine-specific gene signature represents an important tool for prioritizing patients who would benefit from adenosine-targeting therapies and for understanding the mechanisms of adenosine-mediated immunosuppression. With a similar approach, analysis of the adenosine-specific signature and its relationship with immune cell infiltration could be used to identify potential resistance mechanisms to standard of care or investigational drugs. [0112] In some embodiments the adenosine-specific gene signature correlates to adenosine expression and/or content. In some embodiments, adenosine may be determined by measuring the expression of at least one gene in an adenosine-specific gene signature, at the RNA or protein levels.
  • increased expression of at least one gene in the adenosine-specific gene signature correlates to increased adenosine.
  • the adenosine-specific Attorney Docket No.01330-0108-00PCT gene signature positively correlates to adenosine expression and/or content.
  • the adenosine-specific gene signature negatively correlates to adenosine expression and/or content.
  • An increase in extracellular adenosine may occur when blocking ENT1 with an ENT1 inhibitor, as ENT1 functions to transport adenosine into the cell.
  • an increase in plasma adenosine is evidence of ENT1 inhibitor entry into tumor and/or binding in tumor cells.
  • intracellular adenosine can be more deleterious than the extracellular one, so it would potentially be better to block adenosine out of the cell with an ENT1 inhibitor, even if it results in increased extracellular adenosine. Therefore, increase of plasma adenosine upon exposure to ENT1 inhibitors, indicates that ENT1 inhibitors can get into the tumor and/or bind to tumor cells, and exert its expected proximal effect. Also, the adenosine- specific signature can potentially be used to measure biological effects of ENT1 inhibitors.
  • control refers to any reference standard suitable to provide a comparison to the expression products in the test sample.
  • control comprises obtaining a "control sample” from which expression product levels are detected and compared to the expression product levels from the test sample.
  • Such a control sample may comprise any suitable sample, including but not limited to a sample from a control cancer patient (can be stored sample or previous sample measurement) with a known outcome; normal tissue or cells isolated from a subject, such as a normal patient or the cancer patient, cultured primary cells/tissues isolated from a subject such as a normal subject or the cancer patient, adjacent normal cells/tissues obtained from the same organ or body location of the cancer patient, a tissue or cell sample isolated from a normal subject, or a primary cells/tissues obtained from a depository.
  • a sample from a control cancer patient can be stored sample or previous sample measurement
  • normal tissue or cells isolated from a subject such as a normal patient or the cancer patient
  • cultured primary cells/tissues isolated from a subject such as a normal subject or the cancer patient
  • adjacent normal cells/tissues obtained from the same organ or body location of the cancer patient a tissue or cell sample isolated from a normal subject, or a primary cells/tissues obtained from a depository.
  • control may comprise a reference standard expression product level from any suitable source, including but not limited to housekeeping genes, an expression product level range from normal tissue (or other previously analyzed control sample), a previously determined expression product level range within a test sample from a group of patients, or a set of patients with a certain outcome (for example, survival for one, two, three, four years, etc.) or receiving a certain treatment (for example, standard of care cancer therapy).
  • a certain outcome for example, survival for one, two, three, four years, etc.
  • a certain treatment for example, standard of care cancer therapy
  • control samples and reference standard expression product levels can be used in combination as controls in the methods of the present disclosure.
  • control may comprise normal or non-cancerous cell/tissue sample.
  • control may comprise an expression level for a set of patients, such as a set of cancer patients, or for a set of cancer patients receiving a certain treatment, or for a set of patients with one outcome versus another outcome.
  • the specific expression product level of each patient can be assigned to a percentile level of expression, or expressed as either higher or lower than the mean or average of the reference standard expression level.
  • the control may comprise normal cells, cells from patients treated with combination chemotherapy, and cells from patients having benign cancer.
  • the control may also comprise a measured value for example, average level of expression of a particular gene in a population compared to the level of expression of a housekeeping gene in the same population.
  • control comprises a ratio transformation of expression product levels, including but not limited to determining a ratio of expression product levels of two genes in the test sample and comparing it to any suitable ratio of the same two genes in a reference standard; determining expression product levels of the two or more genes in the test sample and determining a difference in expression product levels in any suitable control; and determining expression product levels of the two or more genes in the test sample, normalizing their expression to expression of housekeeping genes in the test sample, and comparing to any suitable control.
  • control comprises a control sample which is of the same lineage and/or type as the test sample.
  • control may comprise expression product levels grouped as percentiles within or based on a set of patient samples, such as all patients with cancer.
  • a control expression product level is established wherein higher or lower levels of expression product relative to, for instance, a particular percentile, are used as the basis for predicting outcome.
  • a control expression product level is established using expression product levels from cancer control patients with a known outcome, and the expression product levels from the test sample are compared to the control expression product level as the basis for predicting outcome.
  • a suitable control or reference standard is expression level of at least one gene in the adenosine-specific gene signature in a subject not affected and/or diagnosed with cancer.
  • a suitable reference standard is the mean expression level of at least one gene in the adenosine-specific gene signature in a population of subjects not affected and/or diagnosed with cancer.
  • a suitable reference standard is expression level of at least one gene in the adenosine-specific gene signature of a sample from the subject themselves.
  • a suitable reference standard is expression level of at least one gene in the Attorney Docket No.01330-0108-00PCT adenosine-specific gene signature in a non-cancerous cellular sample adjacent to a tumor from the subject themselves.
  • the present disclosure includes determining a level of expression of at least one gene in the adenosine-specific gene signature in a tumor in a subject comprising obtaining or having obtained a biological sample from the subject; and performing an assay on the biological sample to determine if the tumor has an elevated level of expression of at least one gene in the adenosine-specific gene signature.
  • the methods of determining a level of expression of at least one gene in the adenosine-specific gene signature disclosed herein are in vitro methods.
  • the sample is a bodily fluid.
  • the sample is a bodily tissue.
  • the sample is a tumor tissue sample.
  • the tumor tissue sample comprises tumor cells.
  • the tumor tissue sample further comprises tumor infiltrating immune cells.
  • the tumor tissue sample does not comprise tumor infiltrating immune cells.
  • the level of adenosine is considered as “elevated” or “increased” or “higher” when said level is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100% or more higher than the level of adenosine in a control subject or population, e.g., in a subject or a population of subjects not affected and/or diagnosed with cancer, or in a sample such as a non-cancerous sample from the subject themselves.
  • the level of adenosine expression is considered as ‘elevated” or “increased” or “higher” when said level is at least 1.5-fold, at least 2-fold, at least 3-fold, at least 5-fold, at least 8-fold, at least 10-fold, at least 15-fold, at least 20-fold, at least 25-fold, at least 30- fold, at least 35-fold, at least 40-fold, or more higher than the level of adenosine expression in a control subject or population, e.g., in a subject or a population of subjects not affected and/or diagnosed with cancer, or in a sample such as a non-cancerous sample from the subject themselves.
  • the ENT1 inhibitor is an ENT1 inhibitor such as those disclosed in WO 2021/170797, WO 2021/204896, and WO 2023/059739.
  • the ENT1 inhibitor is a compound of Formula (I): Attorney Docket No.01330-0108-00PCT 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 , -CO2R 3 , C(O)N(R 3 )2, -CH2C(O)N(R 3 )2, -S(O)2R 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; Attorney Docket No.01330-0108-00PCT R 4 is selected from the group
  • the ENT1 inhibitor is a compound of Formula (II): or a pharmaceutically acceptable salt, hydrate, or solvate thereof, Attorney Docket No.01330-0108-00PCT 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 , -CO2R 3 , C(O)N(R 3 )2, -CH2C(O)N(R 3 )2, -S(O)2R 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 -CH2-, -CHF-, and -CF2-; each U is independently selected from the group consisting of -
  • the ENT1 inhibitor is a compound of Formula (IIa): or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein X is CH 2 , CHF, or CF 2 .
  • the ENT1 inhibitor in a compound of Formula [0127]
  • the ENT1 inhibitor in a compound of Formula [0128]
  • the ENT1 inhibitor in a compound of Formula [0128]
  • the ENT1 inhibitor in a compound of Formula (IIb): Attorney Docket No.01330-0108-00PCT or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
  • U is -C(O)O-.
  • the U in R 4 is -C(O)O- or -C(O)NR 3 -. In some embodiments, U in R 4 is -C(O)O-. In some embodiments, U in R 4 is -C(O)NR 3 -.
  • the ENT1 inhibitor is a compound of Formula (IIa1): or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
  • the ENT1 inhibitor is selected from (12R)-7 4 ,7 5 -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. See, e.g., WO 2024/194391 and WO 2024/194392, the contents of which are incorporated herein by reference in their entirety.
  • the ENT1 inhibitor is selected from Compound 1 and pharmaceutically acceptable salts thereof.
  • the ENT1 inhibitor is selected from hydrogen sulfate salts of Compound 1 and hydrates and solvates thereof. See, e.g., WO 2024/194391.
  • the ENT1 inhibitor is Compound 1 di(hydrogen sulfate) or a hydrate or solvate thereof.
  • the Compound 1 di(hydrogen sulfate) or a hydrate or solvate thereof is crystalline.
  • the crystalline Compound 1 di(hydrogen sulfate) or a hydrate or solvate thereof is crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate.
  • the ENT1 inhibitor is selected from one of the compounds in Tables 2A or 2B, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
  • Table 2A Compound Structures Chemical Name (12R)-7 4 ,7 5 -dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3) benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
  • 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).
  • the ENT1 inhibitor is ticagrelor or a salt thereof.
  • the ENT1 inhibitor is selected from dilazep, dipyridamole, NBMPR (nitrobenzylthioinosine), draflazine, STI-571 (Gleevec), ticagrelor, 8MDP, 5-iodotubercidin, cilostazol, and salts thereof and any mixture thereof.
  • selective ENT1 inhibitors include NBMPR, STI-571 (Gleevec), ticagrelor, salts thereof and any mixture thereof.
  • the present disclosure includes a method of treating a disease or disorder characterized by increased adenosine in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an ENT1 inhibitor.
  • the present disclosure includes a method of treating cancer characterized by increased adenosine in a tumor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an ENT1 inhibitor.
  • the present disclosure includes an ENT1 inhibitor, for use in the treatment of a disease or disorder in a subject in need thereof, wherein the disease or disorder is characterized by increased adenosine.
  • the disease or disorder is cancer.
  • a subject has previously been identified as having increased adenosine in a tumor microenvironment as compared to a reference.
  • the present disclosure includes a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an ENT inhibitor, wherein the subject has previously been identified as having increased adenosine in a tumor of the subject.
  • the present disclosure includes an ENT1 inhibitor, for use in the treatment of cancer in a subject in need thereof, wherein the cancer is characterized by increased adenosine, and wherein the subject has previously been identified as having increased adenosine in a tumor of the subject.
  • a subject has previously been identified as having increased adenosine in the tumor microenvironment as compared to a reference. In some embodiments, a subject has previously been identified as having increased adenosine in the tumor microenvironment as compared to a reference. [0143] In some embodiments, the present disclosure includes a method of treating cancer in a subject in need thereof, comprising: selecting a subject with cancer having a diagnosis of an increased adenosine in a tumor of the subject; and treating the patient with an ENT1 inhibitor.
  • the present disclosure includes a method of selecting a subject with cancer for treatment with an ENT1 inhibitor, comprising: detecting the level of adenosine in a sample from the subject, such as in a tumor sample from the subject; selecting the subject for treatment with an ENT1 inhibitor based on a comparison of said level with a reference level.
  • the present disclosure includes a method of selecting a subject with cancer for treatment with an ENT1 inhibitor, comprising: detecting the level of adenosine in a sample from the subject, such as in a tumor sample from the subject; selecting the subject for treatment with an ENT1 inhibitor when the level of adenosine is increased.
  • the level of adenosine is increased as compared to a reference.
  • the level of adenosine is increased in the tumor microenvironment as compared to a reference.
  • the level of adenosine correlates to the level of expression of at least one gene in the adenosine-specific signature.
  • the disease or disorder, such as cancer is characterized by an increase or decrease in expression of at least one gene in the adenosine-specific gene signature.
  • the disease or disorder, such as cancer is characterized by an increase or decrease in expression of at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or all 25 genes in the adenosine-specific gene signature.
  • the present disclosure includes a method of treating a disease or disorder characterized by increased or decreased expression of at least one gene in the adenosine- specific gene signature in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an ENT1 inhibitor.
  • the present disclosure includes a method of treating cancer characterized by increased or decreased expression of at least one gene in the adenosine-specific gene signature in a tumor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an ENT1 inhibitor.
  • the disease or disorder such as cancer
  • the present disclosure includes an ENT1 inhibitor, for use in the treatment of a disease or disorder in a subject in need thereof, wherein the disease or disorder is characterized by increased or decreased expression of at least one gene in the adenosine-specific gene signature.
  • the disease or disorder is cancer.
  • the disease or disorder such as cancer
  • a subject has previously been identified as having increased or decreased expression of at least one gene in the adenosine-specific gene signature in a tumor microenvironment as compared to a reference.
  • the subject has previously been identified as having increased or decreased in expression of at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or all 25 genes in the adenosine-specific gene signature.
  • the present disclosure includes a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an ENT1 inhibitor, wherein the subject has previously been identified as having increased or decreased expression of at least one gene in the adenosine-specific gene signature in a tumor of the subject.
  • the present disclosure includes an ENT1 inhibitor, for use in the treatment of cancer in a subject in need thereof, wherein the cancer is characterized by increased or decreased expression of at least one gene in the adenosine-specific gene signature, and wherein the subject has previously been identified as having increased or decreased expression of at least one gene in the adenosine-specific gene signature in a tumor of the subject.
  • a subject has previously been identified as having increased or decreased expression of at least one gene in the adenosine-specific gene signature in the tumor microenvironment as compared to a reference.
  • a subject has previously been identified as having increased or decreased expression of at least one gene in the adenosine-specific gene signature in the tumor microenvironment as compared to a reference.
  • the subject has previously been identified as having, or the disease or disorder, such as cancer, is characterized by an increased or decreased in expression of at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least Attorney Docket No.01330-0108-00PCT 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or all 25 genes in the adenosine-specific gene signature.
  • the present disclosure includes a method of treating cancer in a subject in need thereof, comprising: selecting a subject with cancer having a diagnosis of an increased or decreased expression of at least one gene in the adenosine-specific gene signature in a tumor of the subject; and treating the patient with an ENT1 inhibitor.
  • the subject with can has a diagnosis of increased or decreased expression of at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or all 25 genes in the adenosine-specific gene signature.
  • the present disclosure includes a method of selecting a subject with cancer for treatment with an ENT1 inhibitor, comprising: detecting the level of expression of at least one gene in the adenosine-specific gene signature in a sample from the subject, such as in a tumor sample from the subject; selecting the subject for treatment with an ENT1 inhibitor based on a comparison of said level with a reference level.
  • the present disclosure includes a method of selecting a subject with cancer for treatment with an ENT1 inhibitor, comprising: detecting the level of expression of at least one gene in the adenosine-specific gene signature in a sample from the subject, such as in a tumor sample from the subject; selecting the subject for treatment with an ENT1 inhibitor when the level of expression of at least one gene in the adenosine-specific gene signature is increased or decreased.
  • the level of expression of at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or all 25 genes in the adenosine-specific gene signature is increased or decreased.
  • the level of adenosine is increased as compared to a reference. In some embodiments, the level of adenosine is increased or decreased in the tumor microenvironment as compared to a reference.
  • the subject is to be treated with an ENT1 inhibitor as a first line therapy, i.e., the subject has not received prior anticancer treatment.
  • the subject is to be treated with an ENT1 inhibitor as a second, third or more line therapy, i.e., the subject has received prior anticancer treatment with another anticancer agent.
  • the present disclosure includes a method of treating a disease or disorder characterized by increased adenosine and/or increased expression of at least one gene in the adenosine-specific gene signature in a subject in need thereof, comprising administering to the subject a combination of a therapeutically effective amount of an ENT1 inhibitor and a therapeutically effective amount of an additional therapeutic agent.
  • the disease or disorder is cancer.
  • the additional therapeutic agent is an anticancer agent.
  • the present disclosure includes a combination of a therapeutically effective amount of an ENT1 inhibitor and a therapeutically effective amount of an anticancer agent, for use in the treatment of cancer in a subject in need thereof, wherein the cancer is characterized by increased adenosine and/or increased expression of at least one gene in the adenosine-specific gene signature.
  • the present disclosure includes an ENT1 inhibitor, for use in the treatment of cancer in a subject in need thereof, wherein the cancer is characterized by increased adenosine and/or increased expression of at least one gene in the adenosine-specific gene signature, and wherein the subject is further to be administered with an anticancer agent.
  • an anticancer agent is selected from immunotherapeutic agents, chemotherapeutic agents, antiangiogenic agents, multidrug resistance-associated proteins inhibitors, radiotherapeutic agents, and any combination thereof.
  • a combination comprises a single anticancer agent.
  • a combination comprises a plurality of anticancer agents; i.e., two, three or four anticancer agents as defined below.
  • an anticancer agents may be of the same class of agents or of different classes of agents. For example, a combination of an immunotherapeutic agent and of a chemotherapeutic agent may be used with an ENT inhibitor.
  • administering may occur either simultaneously or timely staggered, either at the same site of administration or at different sites of administration, under similar or different dosage forms as further outlined below.
  • administration of an anticancer agent and an ENT1 inhibitor may occur either simultaneously or timely staggered, either at the same site of administration or at different sites of administration, under similar or different dosage forms as further outlined below.
  • Attorney Docket No.01330-0108-00PCT [0162] In one embodiment, an anticancer agent is administered prior to, concomitant with, or subsequent to administration of an ENT1 inhibitor.
  • an adenosine receptor antagonist and an anticancer agent may be administered separated in time (in a time-staggered manner), i.e. sequentially, and/or are administered at different administration sites.
  • the ENT1 inhibitor may be administrated e.g. prior, concurrent or subsequent to an anticancer agent, or vice versa.
  • an ENT1 inhibitor and an anticancer agent may be administered at different administration sites, or at the same administration site, when administered in a time staggered manner.
  • an ENT1 inhibitor is to be administered prior to and/or concomitantly with an anticancer agent. In one embodiment, an ENT1 inhibitor is to be administered prior to the day or on the same day that an anticancer agent is administered. In another embodiment, an anticancer agent is to be administered prior to and/or concomitantly with an ENT1 inhibitor. In one embodiment, an anticancer agent is to be administered prior to the day or on the same day that an ENT1 inhibitor is administered. In one embodiment, an ENT1 inhibitor is to be administered prior to and/or concomitantly with an anticancer agent and continuously thereafter. In another embodiment, an anticancer agent is to be administered prior to and/or concomitantly with an ENT inhibitor and continuously thereafter.
  • an anticancer agent and the ENT1 inhibitor may be administered as a single daily dose, divided over one or more daily doses.
  • the specific dose for any particular subject will depend upon a variety of factors such as the cancer to be treated; the age, body weight, general health, sex and diet of the patient; and like factors well- known in the medical arts.
  • Diseases and Disorders [0166] In some embodiments, the present disclosure includes the methods of treating proliferative disorders, including cancers.
  • the present disclosure includes a compound for use in the treatment and/or prevention of proliferative disorders, including cancers.
  • the present disclosure provides use of a compound for the manufacture of a medicament for treating and/or preventing cancer.
  • the present disclosure also provides a method of treatment of cancer, which comprises administering to a mammal species in Attorney Docket No.01330-0108-00PCT need thereof a therapeutically effective amount of a compound.
  • the present disclosure also provides for a method for delaying in patient the onset of cancer comprising the administration of a pharmaceutically effective amount of a compound of the disclosure to a patient in need thereof.
  • Various cancers are known in the art.
  • Cancers that can be treated using methods of the disclosure include solid cancers and non-solid cancers, especially benign and malignant solid tumors and benign and malignant non-solid tumors. Cancer may be metastatic or non-metastatic. The cancer may be familial or sporadic. [0169] In some embodiments, cancer is a solid 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.
  • 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 osteosar
  • 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, and chronic lymphoid leukemias). Lymphomas include, for example, Hodgkin’s disease, non-Hodgkin’s lymphoma lymphomas, and lymphocytic lymphomas).
  • cancer is selected from the group consisting of colorectal cancer, stomach cancer, breast cancer, bladder cancer, esophageal cancer, pancreatic cancer, and ovarian cancer.
  • cancer is breast cancer.
  • cancer is colorectal cancer.
  • cancer is bladder cancer.
  • cancer is breast cancer.
  • cancer is esophageal cancer.
  • cancer is stomach cancer.
  • cancer is ovarian cancer. In a specific embodiment, the cancer is pancreatic cancer. [0175] In another embodiment, cancer is selected from the group consisting of: leukemia and multiple myeloma. [0176] In one embodiment, a subject has previously received at least one prior therapeutic treatment, and has progressed subsequent to the administration of at least one prior therapeutic treatment and prior to administration of a therapeutic agent. In one embodiment, a prior therapeutic treatment is selected from the group consisting of chemotherapy, immunotherapy, radiation therapy, stem cell transplant, hormone therapy, and surgery.
  • compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt and solvate thereof, and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant.
  • present disclosure also provides a medicament comprising at least one compound disclosed herein, or a pharmaceutically acceptable salt and solvate thereof, as active ingredient.
  • a compound disclosed herein may be formulated as a pharmaceutical preparation comprising at least one compound disclosed and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant, and optionally one or more further pharmaceutically active compounds. Details regarding the presence of further pharmaceutically active compounds are provided hereafter.
  • such a formulation may 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.
  • parenteral administration such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion
  • topical administration including ocular
  • suitable administration forms – which may be solid, semi-solid or liquid, depending on the manner of administration – as well as methods and carriers, diluents and excipients for use in the preparation Attorney Docket No.01330-0108-00PCT thereof, will be clear to the skilled person; reference is made to the latest edition of Remington’s Pharmaceutical Sciences.
  • 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 prop
  • Formulations can optionally contain other substances that are commonly used in pharmaceutical formulations, such as lubricating agents, wetting agents, emulsifying and suspending agents, dispersing agents, desintegrants, bulking agents, fillers, preserving agents, sweetening agents, flavoring agents, flow regulators, release agents, etc.
  • Compositions may also be formulated so as to provide rapid, sustained or delayed release of the active compound(s) contained therein.
  • the ENT1 inhibitors and compositions herein 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.
  • 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.
  • a lubricant might be necessary in a tablet formulation to prevent the tablet and punches Attorney Docket No.01330-0108-00PCT 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 and compositions can also be formulated as chewable tablets, for example, by using substances such as mannitol in the formulation.
  • a base When it is desired to administer an ENT1 inhibitor or a composition of the present disclosure 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. [0186] The effect of the ENT1 inhibitors and compositions of the present disclosure 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.
  • the ENT1 inhibitors and compositions of the present disclosure 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.
  • the ENT1 inhibitor is administered in a daily dose from about 2.5 mg to about 160 mg.
  • the ENT inhibitor is administered in a daily dose from about 2.5 mg to about 160 mg, from about 2.5 mg to about 155 mg, from about 2.5 mg to about 150 mg, from about 2.5 mg to about 145 mg, from 2.5 mg to about 140 mg, from about 2.5 mg to about 135 mg, from about 2.5 mg to about 130 mg, from about 2.5 mg to about 125 mg, from about 2.5 mg to about 120 mg, from about 2.5 mg to about 115 mg, from 2.5 mg to about 110 mg, from Attorney Docket No.01330-0108-00PCT about 2.5 mg to about 105 mg, about 2.5 mg to about 100 mg, from about 2.5 mg to about 95 mg, from 2.5 mg to about 90 mg, from about 2.5 mg to about 85 mg, from about 2.5 mg to about 80 mg, from about 2.5 mg to about 75 mg, from about 2.5 mg to about 70 mg, from about 2.5 mg to about 65 mg, from about 2.5 mg to about 60 mg, from about 2.5 mg to about 55 mg, from about 2.5 mg to about 50 mg, from about 2.5 mg to about 45 mg, from about 2.5 mg to about 40
  • the ENT inhibitor is administered in a daily dose of about 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg , 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg,
  • the ENT inhibitor is administered in a daily dose of about 2.5 mg. In some embodiments, the ENT inhibitor is administered in a daily dose of about 5 mg. In some embodiments, the ENT inhibitor is administered in a daily dose of about 10 mg. In some embodiments, the ENT inhibitor is administered in a daily dose of about 20 mg. In some embodiments, the ENT inhibitor is administered in a daily dose of about 30 mg. In some embodiments, the ENT inhibitor is administered in a daily dose of about 40 mg. In some embodiments, the ENT inhibitor is administered in a daily dose of about 45 mg. In some embodiments, the ENT inhibitor is administered in a daily dose of about 50 mg. In some embodiments, the ENT inhibitor is administered in a daily dose of about 60 mg.
  • the ENT inhibitor is administered in a daily dose of about 70 mg. In some embodiments, the ENT inhibitor is administered in a daily dose of about 80 mg. In some embodiments, the ENT inhibitor is administered in a daily dose of about 90 mg. In some embodiments, the ENT inhibitor is administered in a daily dose of about 100 mg. In some embodiments, the ENT inhibitor is administered in a daily dose of about 110 mg. In some embodiments, the ENT inhibitor is Attorney Docket No.01330-0108-00PCT administered in a daily dose of about 120 mg. In some embodiments, the ENT inhibitor is administered in a daily dose of about 130 mg. In some embodiments, the ENT inhibitor is administered in a daily dose of about 140 mg.
  • the ENT inhibitor is administered in a daily dose of about 150 mg. In some embodiments, the ENT inhibitor is administered in a daily dose of about 160 mg. [0190] In some embodiments, the ENT1 inhibitor is Compound 1 or a salt, hydrate, or solvate thereof.
  • the Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose (free base) of about 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg , 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg
  • Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 2.5 mg (free base). In some embodiments, Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 5 mg (free base). In some embodiments, Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 10 mg (free base). In some embodiments, Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 20 mg (free base). In some embodiments, Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 30 mg (free base).
  • Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 40 mg (free base). In some embodiments, Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 45 mg (free base). In some embodiments, Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 50 mg (free base). In some embodiments, Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 60 mg (free base). In some embodiments, Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 70 mg (free base).
  • Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 80 mg Attorney Docket No.01330-0108-00PCT (free base). In some embodiments, Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 90 mg (free base). In some embodiments, Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 100 mg (free base). In some embodiments, Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 110 mg (free base).
  • Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 120 mg (free base). In some embodiments, Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 130 mg (free base). In some embodiments, Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 140 mg (free base). In some embodiments, Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 150 mg (free base). In some embodiments, Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 160 mg (free base).
  • the ENT1 inhibitor is a Compound 1 hydrogen sulfate or hydrate or solvate thereof, such as crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate.
  • the Compound 1 hydrogen sulfate or hydrate or solvate thereof for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose (free base) of about 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg , 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg,
  • the Compound 1 hydrogen sulfate or hydrate or solvate thereof for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 2.5 mg (free base). In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 5 mg (free base).
  • the Compound 1 hydrogen sulfate or hydrate or solvate thereof for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 10 mg (free Attorney Docket No.01330-0108-00PCT base). In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 20 mg (free base).
  • the Compound 1 hydrogen sulfate or hydrate or solvate thereof for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 30 mg (free base). In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 40 mg (free base). In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 45 mg (free base).
  • the Compound 1 hydrogen sulfate or hydrate or solvate thereof for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 50 mg (free base). In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 60 mg (free base). In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 70 mg (free base).
  • the Compound 1 hydrogen sulfate or hydrate or solvate thereof for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 80 mg (free base). In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 90 mg (free base). In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 100 mg (free base).
  • the Compound 1 hydrogen sulfate or hydrate or solvate thereof for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 110 mg (free base). In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 120 mg (free base). In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 130 mg (free base).
  • the Compound 1 hydrogen sulfate or hydrate or solvate thereof for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 140 mg (free base). In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, for example crystalline Form 2 Attorney Docket No.01330-0108-00PCT Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 150 mg (free base).
  • the Compound 1 hydrogen sulfate or hydrate or solvate thereof for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 160 mg (free base).
  • the ENT inhibitor is administered once daily during a treatment cycle.
  • the ENT inhibitor is administered twice daily (BID) during a treatment cycle.
  • the treatment comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 treatment cycles.
  • the treatment comprises at least one treatment cycle of 21-28 days.
  • the treatment cycle is 21, 22, 23, 24, 25, 26, 27, or 28 days.
  • the treatment cycle is 21 days.
  • the treatment cycle is 28 days.
  • the ENT inhibitor is administered continuously during the treatment cycle.
  • the ENT inhibitor is administered intermittently during the treatment cycle.
  • the intermittent dosing comprises 5 days of ENT inhibitor treatment and 2 days of no ENT inhibitor treatment in a 21-day cycle.
  • the intermittent dosing comprises 3 weeks of ENT inhibitor treatment and 1 week of no ENT inhibitor treatment in 28-day cycle.
  • the ENT inhibitor is administered at the same dose during the treatment cycle. In some embodiments, the ENT inhibitor is administered at doses of escalating concentration (i.e., increasing doses).
  • a subsequent dose can be increased by a particular increment, or by variable increments, until a maximum dose is reached, at which point administration may cease or may continue at the maximum dose.
  • the ENT inhibitor is administered at about 5 mg for the first week, 10 mg for the second week, etc.
  • the ENT inhibitor is administered orally.
  • the ENT inhibitor is administered as a tablet and/or capsule.
  • the treatment further comprises the administration of an agent capable of treating, preventing, delaying, reducing or attenuating the development or risk of development of the adverse event.
  • the agent may be administered to the patient prior to the initiation of the treatment with the ENT1 inhibitor (e.g., as a prophylaxis in order to prevent or reduce the risk of an adverse event developing) or during or subsequent to treatment with the ENT1 inhibitor (e.g., in response to the development of an adverse event).
  • the adverse event comprises headache, pain, nausea, and/or vomiting.
  • the agent is a medication administered to combat headache, pain, Attorney Docket No.01330-0108-00PCT nausea, and/or vomiting.
  • the agent capable of treating, preventing, delaying, reducing or attenuating the development or risk of development of the adverse event is administered as one or more doses to the patient prior to the initiation of the treatment with the ENT1 inhibitor as a prophylactic treatment for the adverse event.
  • the agent capable of treating, preventing, delaying, reducing or attenuating the development or risk of development of the adverse event is administered to the patient in combination with one or more dose of the ENT1 inhibitor as a prophylactic treatment for the adverse event.
  • the agent may be administered as one or more doses consecutively (before and/or after), and/or concurrently with the ENT1 inhibitor.
  • the agent capable of treating, preventing, delaying, reducing or attenuating the development or risk of development of the adverse event is administered to the patient in the event that the patient develops an adverse event associated with the administration of the ENT1 inhibitor.
  • the treatment comprises administration of the agent at a therapeutic amount, or an amount sufficient to partially or completely alleviate or ameliorate the adverse event (e.g. CRS) or symptoms thereof.
  • agent is administered prior to, concomitant with, and/or subsequent to at least one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, etc. doses of ENT inhibitor.
  • the agent is administered prior to, concomitant with, and/or subsequent to all doses of ENT inhibitor. In some embodiments, the agent is administered at least 30 minutes before and/or after at least one dose of ENT inhibitor. In some embodiments, the agent is administered 30 minutes before at least one dose of ENT inhibitor. [0204] In some embodiments, the agent comprises an antiemetic, analgesic, and/or caffeine.
  • the analgesic comprises a non-steroidal anti-inflammatory drug (NSAID) (e.g., diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, sulindac, tolmetin, celecoxib, rofecoxib, valdecoxib), aspirin, acetaminophen, antidepressive medications (e.g., amitriptyline, duloxetine), antiepileptic medication (e.g., gabapentin, prefabalin), and/or lidocaine.
  • NSAID non-steroidal anti-inflammatory drug
  • the antiemetic comprises anticholinergic agents such as hyoscyamine, methscopolamine, scopolamine; antihistamines, such as cyclizine, dimenhydrinate, doxylamine, hydroxyzine, meclizine, promethazine; cannabinoid receptor agonists, such as dronabinol, nabilone, tetrahydrocannabinol; dopamine receptor antagonists, such as Attorney Docket No.01330-0108-00PCT chlorpromazine, prochlorperazine; serotonin 5-HT3 receptor antagonists, such as alosetron, dolasetron, granisetron, ondansetron, palonosetron; substance P/neurokinin 1 receptor antagonists, such as aprepitant, fosaprepitant, fosnetupitant, rolapitant; or miscellaneous antiemetic agents, such as amisulpride, dexamethas
  • the agent is administered orally. In some embodiments, the agent is administered as a tablet and/or a capsule. In some embodiments, the agent is caffeine. In some embodiments, the caffeine is administered orally as a tablet or capsule. In some embodiments, the caffeine is administered in a beverage or in food.
  • Another object of this disclosure is the use of the combination as a medicament, i.e. for medical use.
  • the disclosure provides the use of the combination of the disclosure for the manufacturing of a medicament.
  • the disclosure provides the use of the combined pharmaceutical composition of the disclosure or the kit of the disclosure for the manufacturing of a medicament.
  • EXAMPLE Example 1 [0209] Adenosine levels in human tumor tissue were assessed using quantitative mass spectrometry imaging (QMSI), and spatial gene expression analysis was performed using GeoMx digital spatial profiler (GeoMx DSP) guided by QMSI.
  • Adenosine quantification on human tumor Tumor blocks were sectioned at -20°C in serial sections. Sections were dried in a desiccator and immediately sprayed with a mixture of 6 inhibitors of adenosine pathway (AOPCP (Adenosine 5′-( ⁇ , ⁇ methylene)diphosphate), EDTA, 5- Iodotubercidin, Dipyridamole, NBMPR (S-(4-Nitrobenzyl)-6-thioinosine), EHNA). Sections were analyzed for adenosine content using quantitative mass spectrometry imaging (QMSI).
  • QMSI quantitative mass spectrometry imaging
  • RNAscope Mild expression model transcript PPIB and low expression model transcript POLR2A were analyzed by RNAscope to evaluate sample’s transcriptome integrity before GeoMx whole transcriptome analysis.
  • transcripts were analyzed by GeoMx DSP using a Whole Transcriptome Atlas (WTA) panel and off the shelf morphological markers CD45, PanCK and DNA counterstain. Transcripts detected from PanCK+ and PanCK- tissues areas were sequenced using a NovaSeq 6000 sequencer and compared between areas enriched in ADO and low in ADO.
  • Bioinformatic analysis ROIs were divided into training (70%) and test (30%) sets. Adenosine high and low regions were defined based on the overall adenosine level median across all ROIs. Immune cell and tertiary lymphoid structure (TLS) signature scores were inferred using GSVA (gene set variation analysis).
  • FIG.2A-2E Gene ontology enrichment analysis was performed on DEGs using g:profiler. Lasso regression was then used to identify DEGs with the highest predictive potential i.e. quantitative adenosine signature.
  • FIG.3A- 3D Quantitative adenosine signature scores were computed using GSVA in an in-house GeoMX dataset, tumor samples from The Cancer Genome Atlas (TCGA), and healthy tissue from the Genotype-Tissue Expression dataset (GTEx).
  • FIG. 4A-4C Quantitative adenosine signature scores were computed using GSVA in an in-house GeoMX dataset, tumor samples from The Cancer Genome Atlas (TCGA), and healthy tissue from the Genotype-Tissue Expression dataset (GTEx).
  • DGE Differential gene expression
  • FIG. 2A and 2B Gene ontology enrichment analysis on genes upregulated in adenosine high regions revealed associations with protein translation, metabolic processes, and immune activation.
  • FIG.2C High adenosine regions are associated with a specific gene expression pattern and contain fewer immune cells compared to low adenosine regions. Adenosine high regions are poor in immune infiltrates compared to adenosine low regions.
  • FIG.3B The area under the curve was 0.972 in the training set, and 0.905 in the validation set.
  • FIG.3C The area under the curve was 0.972 in the training set, and 0.905 in the validation set.
  • FIG.3D The predictive power of the adenosine-specific signature was confirmed in the test set.
  • FIG.3D The 25-gene signature was applied to existing public transcriptomic datasets to characterize the adenosine landscape in human cancer.
  • GTEx Genotype-tissue expression
  • TCGA Cancer Genome Atlas
  • FIG.4B-4C [0217] Analysis of TCGA database also allowed to rank the 33 cancer types based on the adenosine-specific signature score and to characterize the prognostic impact of adenosine on patient survival.
  • FIG.5A-5B Differences were evidenced among the cancer types, but also high degree of heterogeneity were also evidenced within some of the indications.
  • FIG. 5D The adenosine-specific signature can potentially be used for tumor type prioritization for adenosine pathway inhibitors. With a similar approach, analysis of the adenosine-specific signature and its relationship with immune cell infiltration could be used to identify potential resistance mechanisms to standard of care or investigational drugs.
  • the adenosine gene signature was developed based on the spatial quantification of adenosine in human tumors, and demonstrates its potential for indication selection.
  • This new signature derived from 249 differentially expressed genes (DEGs) associated with metabolism and immune activation, showed high predictive power across tumor types.
  • DEGs differentially expressed genes
  • the adenosine signature was higher in tumors compared to healthy tissue and exhibited variable expression and prognostic value across tumor subtypes.
  • Example 2 Patients with solid tumors are treated with crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate in one of the following dosing scheme: (1) a single daily oral dose of 5 mg of Compound 1 (free base); (2) twice a day oral doses of 5 mg of Compound 1 (free base) – i.e., 10 mg of Compound 1 (free base) total per day; (3) twice a day oral doses of 10 mg of Compound 1 (free base) – i.e., 20 mg of Compound 1 (free base) total per day; (4) twice a day oral doses of 15 mg of Compound 1 (free base) – i.e., 30 mg of Compound 1 (free base) total per day; (5) twice a day oral doses of 22.5 mg of Compound 1 (free base) – i.e., 45 mg of Compound 1 (free base) total per day; or (6) twice a day oral doses of 30 mg of Compound 1 (free base) – i.
  • the dosing consists of sequential dose-escalation cohorts with at least 3 and up to 6 dose- limiting toxicity (DLT)-evaluable participants each. There are 5 dose level cohorts.
  • the starting human dose of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate in Cohort 1 (Dose Level 1) is 5 mg (expressed as free-base equivalent) twice daily (BID) oral dosing (PO).
  • the first dose-escalation cohort starts with a single-dose administration of 5 mg (free base) in Cycle 0 followed by the washout period of at least 3 and approximately 7 days before Day 1 of Cycle 1.
  • FIG.6A shows results for various cohorts on first exposure to compound 1, and the adenosine signature is measured by mass spectrometry to give the average value as indicated. A maximum adenosine ratio to baseline was seen at 2 hours, which then generally decreased. A similar trend was seen in FIG.6B for the Cycle 1 Day 15 group (BID for 15 days) at Day 15, with the trough being right before dosing.
  • the data indicates that compound 1 is able to enter tumor and/or bind to tumor cells, and the adenosine-specific signature can be used to measure biological effects of ENT1 inhibitors.

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Abstract

The present disclosure relates to identifying subjects with increased adenosine and treatment of a subject who has been identified with an increased adenosine.

Description

Attorney Docket No.01330-0108-00PCT TREATMENT OF DISEASES WITH INCREASED ADENOSINE LEVELS CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Application No. 63/626,747, filed January 30, 2024, and U.S. Provisional Application No.63/730,101, filed December 10, 2024, the entire contents of which are incorporated by reference herein for all purposes. SEQUENCE LISTING [0002] The present application contains a Sequence Listing which has been submitted electronically in XML format. Said XML copy, created on January 27, 2025, is named “01330- 0108-00PCT.xml” and is 602,050 bytes in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety. FIELD OF THE PRESENT DISCLOSURE [0003] The present disclosure includes treatment of a subject wherein the subject has been identified as having increased levels of adenosine. Compounds of the present disclosure include, but are not limited to ENT1 inhibitors, and are useful as therapeutic compounds, especially in the treatment of cancers. BACKGROUND [0004] Adenosine is a strong immunosuppressive metabolite that is often found elevated in the extracellular tumor microenvironment (TME). This accumulation of adenosine in the tumor microenvironment (TME) mediates immune suppression, causing dysregulation of innate and adaptative immune cell subsets and dampening the antitumor immune response. Therefore, adenosine represents a relevant target of interest for cancer immunotherapy. However, the very short half-life of adenosine makes direct measurement in tumor tissues challenging for high- throughput screening and not practical for routine applications (Möser et al., AM J Physiol.1989, 256(4 Pt 1):C799-806). [0005] Two gene-expression signatures linked to the adenosine pathway have been discovered. The first signature was generated by investigating the effects of adenosine on gene expression prolife in peripheral blood mononuclear cells (PBMC) (Fong et al., Cancer Discov.2020, 10(1): 40-53). Adenosine-responsive genes were identified by in vitro stimulation of normal human Attorney Docket No.01330-0108-00PCT PBMCs with the adenosine receptor agonist 5′-N-Ethylcarboxamidoadenosine (NECA). The second signature was generated using regulatory networks for adenosine signaling pathway derived from the literature (Sidders et al., Clin Cancer Res. 2020, 26(9): 2176-2187). The adenosine signaling pathway was identified focusing on genes that have been reported to be regulated by the adenosine A2A receptor. Both signatures therefore are dependent on adenosine signaling through adenosine receptors. While they can be instrumental when characterizing human tumors in the context of targeting adenosine receptors, these signatures do not directly measure adenosine content. SUMMARY [0006] The present disclosure includes a method of treating a disease or disorder, such as cancer, characterized by increased levels of adenosine in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an ENT1 inhibitor. Embodiment 1. A method of treating a disease or disorder characterized by increased adenosine in a subject in need thereof, comprising administering to the subject with an increased adenosine a therapeutically effective amount of an ENT1 inhibitor. Embodiment 2. The method of embodiment 1, comprising identifying the subject has increased adenosine prior to administration of the ENT1 inhibitor. Embodiment 3. A method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an ENT1 inhibitor, wherein the subject has previously been identified as having increased adenosine. Embodiment 4. An ENT1 inhibitor for use in the treatment of a disease or disorder in a subject in need thereof, wherein the disease or disorder is characterized by increased adenosine. Embodiment 5. The ENT1 inhibitor for use of embodiment 4, wherein the subject was previously identified as having increased adenosine. Embodiment 6. The method or the ENT1 inhibitor for use of any one of embodiments 1-5, wherein the adenosine is increased by comparison to a reference level determined in a sample from a subject not affected and/or diagnosed with the disease or disorder. Attorney Docket No.01330-0108-00PCT Embodiment 7. The method or the ENT1 inhibitor for use of any one of embodiments 1-6, wherein the disease or disorder is cancer. Embodiment 8. The method or the ENT1 inhibitor for use of any one of embodiments 1-7, wherein the level of adenosine correlates to expression of at least one gene in an adenosine-specific gene signature. Embodiment 9. The method or the ENT1 inhibitor for use of any one of embodiments 1-8, wherein the disease or disorder is characterized by increased or decreased expression of at least one gene in an adenosine-specific gene signature. Embodiment 10. The method or the ENT1 inhibitor for use of embodiment 9, wherein the expression of at least one gene in an adenosine-specific gene signature is increased or decreased by comparison to a reference level determined in a sample from a subject not affected and/or diagnosed with the disease or disorder. Embodiment 11. The method or the ENT inhibitor for use of any one of embodiments 8-10, wherein the adenosine-specific gene signature comprises at least one of the following genes: APOE, CALR, CD63, CD82, CTSB, DMBT1, EIF3G, ENO1, FLNA, FOS, GNAS, HSPA1B, HSPB1, IFITM3, NDUFS5, NPM1, PPDPF, PTP4A2, RPS27A, SLC25A6, SYNGR2, TESC, TPM1, TXNIP, or YBX3. Embodiment 12. The method or the ENT inhibitor for use of embodiment 11, wherein the adenosine-specific gene signature comprises at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or all 25 genes. Embodiment 13. The method or the ENT1 inhibitor for use of any one of embodiments 1-12, wherein the ENT1 inhibitor is a compound of Formula (I): Attorney Docket No.01330-0108-00PCT (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R1 is selected from the group consisting of 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 Attorney Docket No.01330-0108-00PCT each U is independently selected from the group consisting of -C(O)-, alkylene , -O-, 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. Embodiment 14. The method or the ENT1 inhibitor for use of any one of embodiments 1-13, wherein the ENT1 inhibitor is a compound of Formula (II): or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R1 is selected from the group consisting of ALK, cycloalkyl, heterocyclyl, Attorney Docket No.01330-0108-00PCT 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-, 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, Attorney Docket No.01330-0108-00PCT 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. Embodiment 15. The method or the ENT1 inhibitor for use of embodiment 14, wherein the ENT1 inhibitor is a compound of Formula (IIa): (IIa), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein X is CH2, CHF, or CF2. Embodiment 16. The method or the ENT1 inhibitor for use of any one of embodiments 13- 15, wherein R1 is . Embodiment 17. The method or the ENT1 inhibitor for use of embodiment 16, wherein R1 is . Attorney Docket No.01330-0108-00PCT Embodiment 18. The method or the ENT1 inhibitor for use of any one of embodiments 13- 17, wherein the compound is a compound of Formula (IIb): or a pharmaceutically acceptable salt, hydrate, or solvate thereof. Embodiment 19. The method or the ENT1 inhibitor for use of any one of embodiments 13- 18, wherein U is -C(O)O-. Embodiment 20. The method or the ENT1 inhibitor for use of any one of embodiments 113, 14, 15, or 17, wherein R4 is the U in R4 is -C(O)O- or -C(O)NR3-. Embodiment 21. The method or the ENT1 inhibitor for use of embodiment 13, wherein the compound is a compound of Formula (IIa1): Attorney Docket No.01330-0108-00PCT (IIa1) or a pharmaceutically acceptable salt, hydrate, or solvate thereof. Embodiment 22. The method or the ENT1 inhibitor according to any one of embodiments 1- 12, 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 Attorney Docket No.01330-0108-00PCT (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 Attorney Docket No.01330-0108-00PCT (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 Attorney Docket No.01330-0108-00PCT 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-(trifluoromethoxy)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 Attorney Docket No.01330-0108-00PCT 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-dimethylcyclobutane-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 Attorney Docket No.01330-0108-00PCT 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-(trifluoromethoxy)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-(difluoromethoxy)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-dichlorobenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 2,3-dichlorobenzoate 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 Attorney Docket No.01330-0108-00PCT 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 Attorney Docket No.01330-0108-00PCT 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 Attorney Docket No.01330-0108-00PCT 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)-benzenacyclotetradecaphane-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. Embodiment 23. The method or the ENT1 inhibitor for use of embodiment 22, wherein the ENT1 inhibitor is selected from Attorney Docket No.01330-0108-00PCT COMPOUND 1 and pharmaceutically acceptable salts, hydrates, or solvates thereof. Embodiment 24. The method or the ENT1 inhibitor for use of embodiment 23, wherein the ENT1 inhibitor is a Compound 1 hydrogen sulfate or hydrate or solvate thereof. Embodiment 25. The method or the ENT1 inhibitor for use of embodiment 24, wherein theENT1 inhibitor is a Compound 1 di(hydrogen sulfate) or a hydrate or solvate thereof. Embodiment 26. The method or the ENT1 inhibitor for use of embodiment 25, wherein the ENT1 inhibitor is crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate. Embodiment 27. The method or the ENT1 inhibitor for use of any one of embodiments 1-26, further comprising administration of an additional therapeutic agent. Embodiment 28. The method or the ENT1 inhibitor for use of embodiment 27 wherein the ENT1 inhibitor is administered prior to the additional therapeutic agent. Embodiment 29. The method or the ENT1 inhibitor for use of embodiment 27, wherein the ENT1 inhibitor is administered simultaneously with the additional therapeutic agent. Embodiment 30. The method or the ENT1 inhibitor for use of embodiment 27, wherein the ENT1 inhibitor is administered after the additional therapeutic agent. Embodiment 31. The method or the ENT1 inhibitor for use of any one of embodiments 1-30, wherein the subject has previously received treatment with an additional therapeutic agent. Attorney Docket No.01330-0108-00PCT Embodiment 32. The method or the ENT1 inhibitor for use of any one of embodiments 7-31, wherein the cancer is selected from the group consisting of bladder cancer, breast cancer, colorectal cancer, esophageal cancer, stomach cancer, ovarian cancer, and pancreatic cancer. BRIEF DESCRIPTION OF THE DRAWINGS [006] FIG.1 shows a schematic of the use of quantitative Mass Spectrometry Imaging (qMSI) and Spatial Transcriptomics to derive the quantified adenosine signature (i.e., adenosine-specific gene signature based on quantified adenosine content in human tumors). Human tumor biopsies (n=13) were collected from six cancer types and flash frozen. Frozen blocks were sectioned and tumor slides were analyzed by qMSI to determine adenosine levels.183 Regions of Interest (ROIs) were selected based on their high or low quantified ADO content. Similar ROIs were then selected on adjacent slides and RNA extracted and checked for quality by RNA-scope. Gene expression was analyzed using spatial transcriptomics (GeoMx). [007] FIG.2A-2E demonstrate high adenosine regions are associated with a specific gene expression pattern and contain fewer immune cells compared to low adenosine regions. ROIs with matched adenosine content and gene expression were divided into a training (70%) and a validation (30%) set. FIG 2A shows a schematic of identifying the significantly differentially expressed genes (DEGs) in adenosine high vs adenosine low regions. A linear mixed model corrected for tumor type and patient was applied to the training set and 249 DEGs were identified in adenosine high vs adenosine low regions (FDR <0.05), most of them over-expressed. FIG.2B shows a volcano plot showing the genes upregulated in adenosine high (right) or adenosine low (left) regions. FIG.2C shows a gene ontology enrichment analysis on genes upregulated in adenosine high regions, which revealed associations with protein translation, metabolic processes and immune activation. GO: gene ontology. BP: biological process. FIG.2D shows a volcano plot displaying the difference (Log2FC) in the abundance of immune cell populations between adenosine high and adenosine low regions. Immune cell signatures were used to deconvolute spatial transcriptomic data. Linear mixed model adjusted for tumor type, patients and PanCK +/- regions was used to compare immune signatures in adenosine high vs low regions. Adenosine high regions are demonstrated to be poor in immune infiltrates compared to adenosine low regions. FIG.2E shows box plots for each immune cell population showing lower expression of the associated gene signature in adenosine high vs adenosine low regions. N = 13 paired samples. [008] FIG.3A-3D shows that the quantified adenosine signature predicts adenosine levels in a test set and correlates with another adenosine signaling signature. FIG.3A shows a schematic of Attorney Docket No.01330-0108-00PCT applying a Lasso regression to identify DEGs with the highest predictive power to derive the quantified adenosine signature. FIG.3B shows a box plot showing the difference between adenosine low and adenosine high ROIs in the training set as well as the test set. The quantified adenosine signature is shown to stratify regions with high and low adenosine content (N=128 Training ROIs; N= 55 Test ROIs; Mann-Witney U test). FIG.3C shows a receiver operating characteristic (ROC) analysis confirming the predictive power of the quantified adenosine signature in the test set. FIG.3D shows a correlation plot showing the relative expression of the quantified adenosine signature (i.e., adenosine-specific signature) and an independent adenosine signaling signature in TCGA dataset. The quantified adenosine signature is shown to correlate with the independent adenosine signaling signature. [009] FIG.4A-4C show that the quantified adenosine signature is enriched in tumor vs healthy tissue and is associated with poor survival in selected cancer types. FIG.4A shows a violin plot showing the expression of the quantified adenosine signature in normal and tumor tissues. The qAdenosine signature is enriched in tumor (TCGA) vs healthy (GTEx) tissue. (Mann-Whitney U test). FIG.4B shows a forest plot depicting the Hazard ratio and 95% confidence for overall survival for each tumor type in TCGA datasets. The quantified adenosine signature is associated with worse survival in several cancer types (Cox regression using adenosine score as continuous variable). FIG.4C shows representative survival curves for a tumor type displaying worse (top) or better (bottom) survival in adenosine high vs adenosine low patients. Patients were stratified according to adenosine content using the quantified adenosine signature and divided in 2 groups based on the median. [0010] FIG.5A-5D demonstrate that the quantified adenosine signature enables tumor type prioritization. FIG.5A shows a box plot showing the relative expression of the quantified adenosine signature in TCGA. The quantified adenosine signature can stratify tumor types by adenosine content. FIG.5B shows actionable patient segments with high adenosine can be identified using TCGA. FIG.5C shows a box plot showing the relative expression of the quantified adenosine signature in WT and KRAS mutated tumor types. FIG.5D shows a box plot showing the relative expression of the quantified adenosine signature in WT and BRAF mutated tumor types. [0011] FIG.6A-6B show graphs demonstrating an increase in plasma adenosine in subjects treated with compound 1. FIG.6A shows adenosine ratio to baseline for various cohorts of the subjects at first exposure to compound 1. The adenosine-specific signature was measured by mass spectrometry to give the average values as indicated. FIG.6B shows adenosine ratio to Attorney Docket No.01330-0108-00PCT baseline for Cycle 1 Day 15 group (BID for 15 days) at Day 15 with the trough being right before dosing. *only 1 evaluable patient at 22.5 mg BID upon multiple dosing. DETAILED DESCRIPTION [0011] 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 invention, as claimed. Herein, the use of the singular includes the plural unless specifically stated otherwise. Furthermore, the use of the term “including” as well as other forms, such as “includes” and “included”, is not limiting. Also, terms such as “element” or “component” encompass both elements and components comprising one unit and elements and components that comprise more than one subunit, unless specifically stated otherwise. [0012] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. Where permitted, all patents, applications, published applications and other publications, gene accession numbers and associated sequence information obtainable through databases such as National Center for Biotechnology Information (NCBI) and other data referred to throughout in the disclosure are incorporated by reference in their entirety for any purpose. Any conflict between the teachings of these patents and publications and this specification shall be resolved in favor of the latter. Definitions [0013] In the present disclosure, the following terms have the following meanings: [0014] The term “aldehyde” refers to a group –CHO. [0015] 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. [0016] The term “alkenylcarbonyl” refers to a group –(C=O)-alkenyl wherein alkenyl is as herein defined. [0017] The term “alkenylcarbonylamino” refers to a group –NH-(C=O)-alkenyl wherein alkenyl is as herein defined. [0018] The term “alkoxy” refers to a group –O-alkyl wherein alkyl is as herein defined. [0019] The term “ALK” or “Alk” 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 Attorney Docket No.01330-0108-00PCT 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. [0020] In some embodiments, an alkyl group is substituted by OH, alkoxy, CF3, and/or NR2. [0021] 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. [0022] The term “alkylaminoalkyl” refers to a group –alkyl-NH-alkyl wherein alkyl is as herein defined. [0023] The term “alkylaminoalkylaminocarbonyl” refers to a group –(C=O)-NH-alkyl-NH-alkyl wherein alkyl is as herein defined. [0024] 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. [0025] The term “alkylaminoalkylcarbonyl” refers to a group –(C=O)-alkyl-NH-alkyl wherein alkyl is as herein defined. [0026] The term “alkylcarbonyl” refers to a group –(C=O)-alkyl wherein alkyl is as herein defined. [0027] The term “alkylcarbonylamine” refers to a group –NH-(C=O)-alkyl wherein alkyl is as herein defined. [0028] The term “alkylcarbonyloxyalkyl” refers to a group –alkyl-O-(C=O)-alkyl wherein alkyl is as herein defined. [0029] The term “alkylheteroaryl” refers to any heteroaryl substituted by an alkyl group wherein alkyl is as herein defined. [0030] The term “alkyloxyalkyl” refers to a group –alkyl-O-alkyl wherein alkyl is as herein defined. Attorney Docket No.01330-0108-00PCT [0031] The term “alkyloxycarbonyl” refers to a group –(C=O)-O-alkyl wherein alkyl is as herein defined. [0032] The term “alkylsulfonyl” refers to a group –SO2-alkyl wherein alkyl is as herein defined. [0033] The term “alkylsulfonylaminoalkyl” refers to a group –alkyl-NH-SO2-alkyl wherein alkyl is as herein defined. [0034] The term “alkylsulfonealkyl” refers to a group –alkyl–SO2-alkyl wherein alkyl is as herein defined. [0035] The term “alkylsulfonimidoyl” refers to a group –S(=O)(=NH)-alkyl wherein alkyl is as herein defined. [0036] The term “alkylsulfoxide” refers to a group –(S=O)-alkyl wherein alkyl is as herein defined. [0037] The term “alkylsulfoxidealkyl” refers to a group –alkyl-SO-alkyl wherein alkyl is as herein defined. [0038] 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. Attorney Docket No.01330-0108-00PCT [0039] 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-limiting 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. [0040] The term “alkynealkyl” refers to a group –alkyl-alkyne wherein alkyl and alkyne are as herein defined. [0041] The term “amino” refers to a group –NH2. [0042] The term “aminoalkyl” refers to a group –alkyl-NH2 wherein alkyl is as herein defined. [0043] The term “aminoalkylaminocarbonyl” refers to a group –(C=O)-NH-alkyl-NH2 wherein alkyl is as herein defined. [0044] The term “aminoalkylcarbonylamino” refers to a group –NH-(C=O)-alkyl-NH2 wherein alkyl is as herein defined. [0045] The term “aminocarbonyl” or “aminocarboxy” refers to a group –(C=O)-NH2. [0046] The term “(aminocarbonylalkyl)(alkyl)amino” refers to a group –NR1R2 wherein R1 is an alkyl group and R2 is a –alkyl-(C=O)-NH2 group, wherein alkyl is as herein defined. [0047] The term “aminocarbonylalkylamino” refers to a group –NH-alkyl-(C=O)-NH2 wherein alkyl is as herein defined. [0048] The term “aminosulfonyl” refers to a group –SO2-NH2. [0049] 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-limiting examples of aryl include phenyl and naphthalenyl. [0050] The term “arylalkyl” refers to a group –alkyl–aryl wherein alkyl and aryl are as herein defined. [0051] The term “aryloxyalkyl” refers to a group –alkyl-O-aryl wherein alkyl and aryl are as herein defined. [0052] The term “carbonyl” refers to a group –(C=O)–. [0053] The term “carbonylamino” refers to a group –NH-(C=O)–. [0054] 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. Attorney Docket No.01330-0108-00PCT Examples of cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. [0055] The term “cycloalkyloxy” refers to a group –O-cycloalkyl wherein cycloalkyl is as herein defined. [0056] The term “dialkylamino” refers to a group –NR1R2 wherein R1 and R2 are both independently alkyl group as herein defined. [0057] The term “dialkylaminoalkyl” refers to a group –alkyl-NR1R2 wherein R1 and R2 are both independently alkyl group, as herein defined. [0058] The term “dialkylaminoalkylaminocarbonyl” refers to a group –(C=O)-NH-alkyl-NR1R2 wherein R1 and R2 are both alkyl group, as herein defined. [0059] The term “dialkylaminoalkylcarbonyl” refers to a group –(C=O)-alkyl-NR1R2 wherein R1 and R2 are both alkyl group, as herein defined. [0060] The term “dihydroxyalkyl” refers to a group alkyl is as herein defined substituted by two hydroxyl (–OH) groups. [0061] The term “halo” or “halogen” refers to fluoro, chloro, bromo, or iodo. [0062] The term “haloalkyl” refers to an alkyl group in which one or more hydrogen atom is replaced by a halogen atom. [0063] The term “haloalkyloxy” refers to a group –O-haloalkyl wherein alkyl is as herein defined. [0064] 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-limiting examples of heteroaryls include: pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl. [0065] The term “heteroarylalkyl” refers to a group –alkyl–heteroaryl wherein alkyl and heteroaryl are as herein defined. [0066] 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 Attorney Docket No.01330-0108-00PCT 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, 1H-pyrrolizinyl, tetrahydro-1,1-dioxothiophenyl, N-formylpiperazinyl, dihydrotriazolopyrazine, dihydroimidazopyrazine, hexahydropyrrolopyrrole, and hexahydropyrrolopyrazine. [0067] The term “heterocyclylalkyl” refers to a group –alkyl–heterocyclyl wherein alkyl and heterocyclyl are as herein defined. [0068] The term “heterocyclylalkylaminocarbonyl” refers to a group –(C=O)-NH-alkyl- heterocyclyl, wherein alkyl and heterocyclyl are as herein defined. [0069] The term “(heterocyclyl)(alkyl)aminoalkyl” refers to a group –alkyl-NR1R2 wherein R1 is an alkyl group and R2 is a heterocyclyl group, wherein alkyl and heterocyclyl are as herein defined. [0070] The term “heterocyclylalkyloxyalkyl” refers to a group –alkyl-O-alkyl–heterocyclyl wherein alkyl and heterocyclyl are as herein defined. [0071] The term “heterocyclylcarbonyl” refers to a group –(C=O)-heterocyclyl wherein heterocyclyl is as herein defined. [0072] The term “heterocyclyloxy” refers to a group –O-heterocyclyl wherein heterocyclyl is as herein defined. [0073] The term “heterocyclylsulfonyl” refers to a group – SO2-heterocyclyl wherein heterocyclyl is as herein defined. [0074] The term “hydroxy” or “hydroxyl” refers to a group –OH. [0075] The term “hydroxyalkyl” refers to a group –alkyl-OH wherein alkyl is as herein defined. [0076] The term “hydroxyalkylaminoalkyl” refers to a group –alkyl-NH-alkyl-OH wherein alkyl Attorney Docket No.01330-0108-00PCT is as herein defined. [0077] The term “hydroxycarbonyl” refers to a group –C(=O)-OH wherein carbonyl is as herein defined. In other words, “hydroxycarbonyl” corresponds to a carboxylic acid group. [0078] The term “oxo” refers to a =O substituent. [0079] The term “sulfonylamino” refers to a group –NH-SO2. [0080] The term “about”, preceding a figure encompasses plus or minus 10%, or less, of the value of said figure. It is to be understood that the value to which the term “about” refers is itself also specifically, and preferably, disclosed. [0081] 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. [0082] The term “inhibitor” refers to a natural or synthetic compound that has a biological effect to inhibit or significantly reduce or down-regulate the expression of a gene and/or a protein or that has a biological effect to inhibit or significantly reduce the biological activity of a protein. Consequently, an “ENT inhibitor” or “inhibitor of an ENT family transporter” refers to a compound that has a biological effect to inhibit or significantly reduce or down-regulate the biological activity of ENT family transporter. [0083] As used herein, the term “combination” means a combined occurrence of the two or more therapeutic agents. In some embodiments, a combination of the present disclosure may occur either as one composition, comprising all the components in one and the same mixture (e.g. a pharmaceutical composition), or may occur as a kit of parts, wherein the different components form different parts of such a kit of parts. Administration of each compound of a combination of the present disclosure may occur either simultaneously or timely staggered, with similar or different timing of administration (i.e. similar or different numbers of administration of each component), either at the same site of administration or at different sites of administration, under similar of different dosage form. [0084] 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. [0085] The term "hormone therapy" refers to the use of hormones in medical treatment. In one embodiment, the hormone therapy is oncologic hormone therapy. Attorney Docket No.01330-0108-00PCT [0086] The term “human” refers to a subject of both genders and at any stage of development (i.e. neonate, infant, juvenile, adolescent, adult). [0087] The term “subject” refers to a mammal, preferably a human. In one embodiment, the subject is diagnosed with a disease or disorder, such as cancer. In one embodiment, the subject is a patient, preferably 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. [0088] The term “gene signature” refers to a specific gene or specific group of genes in a cell or tissue that have characteristic pattern of gene expression and are associated with a particular biological process, cell type, or disease state. A gene signatures may be used to diagnose diseases, such as cancer; plan treatment; assess treatment efficacy; and/or make a prognosis. Each gene in the gene signature is assigned a signature score, which is an overall measure of expression evaluated for each cell. Proteins (e.g. differentially expressed proteins) may fall within the definition of “gene signature.” The term “adenosine gene signature” or “quantified adenosine signature” refers to a group of genes that positively or negatively correlates to the level of adenosine signaling and/or adenosine levels. [0089] 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 may involve the use of 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. [0090] The expression "pharmaceutically acceptable" refers to the ingredients of a pharmaceutical composition are compatible with each other and not deleterious to the subject to which it is administered. [0091] The expression “pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant” refers to a substance that does not produce an adverse, allergic or other untoward reaction when administered to an animal, preferably a human. It includes any and all inactive substance such as for example solvents, cosolvents, antioxidants, surfactants, stabilizing agents, emulsifying agents, buffering agents, pH modifying agents, preserving agents (or preservating agents), antibacterial and antifungal agents, isotonifiers, granulating agents or binders, lubricants, disintegrants, glidants, diluents or fillers, adsorbents, dispersing agents, suspending agents, coating agents, bulking agents, Attorney Docket No.01330-0108-00PCT release agents, absorption delaying agents, sweetening agents, flavoring agents and the like. For human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by regulatory offices, such as, e.g., FDA Office or EMA. [0092] The terms “prevent”, “preventing” and “prevention”, as used herein, refer to a method of delaying or precluding the onset of a condition or disease and/or its attendant symptoms, barring a patient from acquiring a condition or disease, or reducing a patient’s risk of acquiring a condition or disease. [0093] 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. [0094] The terms “therapeutically effective amount” or “effective amount” or “therapeutically effective dose” refer to the amount or dose of active ingredient that is aimed at, without causing significant negative or adverse side effects to the subject, (1) delaying or preventing the onset of a cancer in the subject; (2) reducing the severity or incidence of a cancer; (3) slowing down or stopping the progression, aggravation, or deterioration of one or more symptoms of a cancer affecting the subject; (4) bringing about ameliorations of the symptoms of a cancer affecting the subject; or (5) curing a cancer affecting the subject. A therapeutically effective amount may be administered prior to the onset of a cancer for a prophylactic or preventive action. Alternatively, or additionally, a therapeutically effective amount may be administered after initiation of a cancer for a therapeutic action. [0095] The terms “treating” or “treatment” refer to therapeutic treatment; wherein the object is to prevent or slow down the targeted pathologic condition or disease. A subject or mammal is successfully “treated” for a disease or affection or condition if, after receiving the treatment according to the present disclosure, the subject or mammal shows observable and/or measurable reduction in or absence of one or more of the following: reduction of the number of cancer cells; and/or relief to some extent, for one or more of the symptoms associated with the specific disease or condition; reduced morbidity and mortality, and improvement in quality of life issues. The above parameters for assessing successful treatment and improvement in the disease are readily measurable by routine procedures familiar to a physician. Attorney Docket No.01330-0108-00PCT [0096] The term “stem cell transplant” refers to a procedure in which a patient receives healthy blood-forming cells (stem cells) to replace their own that have been destroyed by disease or by the radiation or high doses of anticancer drugs that are given as part of the procedure. The healthy stem cells may come from the blood or bone marrow of the patient, from a donor, or from the umbilical cord blood of a newborn baby. A stem cell transplant may be autologous (using a patient’s own stem cells that were collected and saved before treatment), allogeneic (using stem cells donated by someone who is not an identical twin), or syngeneic (using stem cells donated by an identical twin. Detection of Adenosine [0097] In some embodiments, the present disclosure provides a method to determine if a subject has an elevated or increased level of adenosine comprising: (a) detecting the level of adenosine in a sample from the subject and (b) comparing the level of the adenosine to a suitable reference level of adenosine. In some embodiments, a subject with elevated or increased adenosine is administered a compound or a combination of compounds effective for treatment of a patient having an elevated or increased level of adenosine. In some embodiments, a subject with elevated or increased adenosine is selected for treatment with a combination of compounds effective for treatment of a patient having an elevated or increased level of adenosine. In some embodiments, the compound or combination of compounds include an ENT1 inhibitor, as further defined below. [0098] In some embodiments, adenosine may be determined using a suitable in vitro assay. [0099] In some embodiments, adenosine in a tumor is compared to a control, i.e., a suitable reference standard. [0100] The term "control" refers to any reference standard suitable to provide a comparison to the expression products in the test sample. In one embodiment, the control comprises obtaining a "control sample" from which expression product levels are detected and compared to the expression product levels from the test sample. Such a control sample may comprise any suitable sample, including but not limited to a sample from a control cancer patient (can be stored sample or previous sample measurement) with a known outcome; normal tissue or cells isolated from a subject, such as a normal patient or the cancer patient, cultured primary cells/tissues isolated from a subject such as a normal subject or the cancer patient, adjacent normal cells/tissues obtained from the same organ or body location of the cancer patient, a tissue or cell sample isolated from a normal subject, or a primary cells/tissues obtained from a depository. In another embodiment, the control may comprise a reference standard expression product level from any suitable source, including but not limited to housekeeping genes, an expression product level range from normal tissue (or other previously analyzed control sample), a previously determined expression product level range Attorney Docket No.01330-0108-00PCT within a test sample from a group of patients, or a set of patients with a certain outcome (for example, survival for one, two, three, four years, etc.) or receiving a certain treatment (for example, standard of care cancer therapy). It will be understood by those of skill in the art that such control samples and reference standard expression product levels can be used in combination as controls in the methods of the present disclosure. In one embodiment, the control may comprise normal or non-cancerous cell/tissue sample. In another embodiment, the control may comprise an expression level for a set of patients, such as a set of cancer patients, or for a set of cancer patients receiving a certain treatment, or for a set of patients with one outcome versus another outcome. In the former case, the specific expression product level of each patient can be assigned to a percentile level of expression, or expressed as either higher or lower than the mean or average of the reference standard expression level. In another embodiment, the control may comprise normal cells, cells from patients treated with combination chemotherapy, and cells from patients having benign cancer. In another embodiment, the control may also comprise a measured value for example, average level of expression of a particular gene in a population compared to the level of expression of a housekeeping gene in the same population. Such a population may comprise normal subjects, cancer patients who have not undergone any treatment (i.e., treatment naive), cancer patients undergoing standard of care therapy, or patients having benign cancer. In another embodiment, the control comprises a ratio transformation of expression product levels, including but not limited to determining a ratio of expression product levels of two genes in the test sample and comparing it to any suitable ratio of the same two genes in a reference standard; determining expression product levels of the two or more genes in the test sample and determining a difference in expression product levels in any suitable control; and determining expression product levels of the two or more genes in the test sample, normalizing their expression to expression of housekeeping genes in the test sample, and comparing to any suitable control. In particularly embodiments, the control comprises a control sample which is of the same lineage and/or type as the test sample. In another embodiment, the control may comprise expression product levels grouped as percentiles within or based on a set of patient samples, such as all patients with cancer. In one embodiment a control expression product level is established wherein higher or lower levels of expression product relative to, for instance, a particular percentile, are used as the basis for predicting outcome. In another embodiment, a control expression product level is established using expression product levels from cancer control patients with a known outcome, and the expression product levels from the test sample are compared to the control expression product level as the basis for predicting outcome. As demonstrated by the data below, the methods of the disclosure are not limited to use of a specific cut-point in comparing the level of expression product in the test sample to the control. Attorney Docket No.01330-0108-00PCT [0101] In some embodiments, a suitable control or reference standard is adenosine level in a subject not affected and/or diagnosed with cancer. In some embodiments, a suitable reference standard is the mean adenosine level in a population of subjects not affected and/or diagnosed with cancer. In some embodiments, a suitable reference standard is adenosine level of a sample from the subject themselves. In some embodiments, a suitable reference standard is adenosine level in a non-cancerous cellular sample adjacent to a tumor from the subject themselves. [0102] In some embodiments, the present disclosure includes determining a level of adenosine in a tumor in a subject comprising obtaining or having obtained a biological sample from the subject; and performing an assay on the biological sample to determine if the tumor has a elevated level of adenosine. [0103] In some embodiments, the methods of determining a level of adenosine disclosed herein are in vitro methods. [0104] In some embodiments, the sample is a bodily fluid. In some embodiments, the sample is a bodily tissue. In some embodiments, the sample is a tumor tissue sample. In some embodiments, the tumor tissue sample comprises tumor cells. In some embodiments, the tumor tissue sample further comprises tumor infiltrating immune cells. In some embodiments, the tumor tissue sample does not comprise tumor infiltrating immune cells. [0105] In some embodiments, the level of adenosine is considered as “elevated” or “increased” or “higher” when said level is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100% or more higher than the level of adenosine in a control subject or population, e.g., in a subject or a population of subjects not affected and/or diagnosed with cancer, or in a sample such as a non-cancerous sample from the subject themselves. Adenosine-Specific Gene Signature [0106] In some embodiments, gene expression analysis performed on a sample identifies various genes expressed at different levels in the sample, and the expression levels of the various genes are compared to adenosine content in the sample. In some embodiments, the sample is a tumor sample. In some embodiments, RNA transcription of genes is compared in inter- and intra- tumor regions of high and low adenosine content. In some embodiments, the genes with highest correlation/ predictive power for adenosine content comprises an adenosine-specific gene signature. [0107] In some embodiments, the adenosine-specific gene signature comprises one or more of 25 genes, which are associated with increased or decreased adenosine expression and/or level. In some embodiments, the adenosine-specific gene signature comprises one or more of the following: APOE, CALR, CD63, CD82, CTSB, DMBT1, EIF3G, ENO1, FLNA, FOS, GNAS, HSPA1B, Attorney Docket No.01330-0108-00PCT HSPB1, IFITM3, NDUFS5, NPM1, PPDPF, PTP4A2, RPS27A, SLC25A6, SYNGR2, TESC, TPM1, TXNIP, and/or YBX3. In some embodiments, the adenosine-specific signature comprises at least 1, at least 2, at least 3,at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or all 25 genes. In some embodiments, the adenosine-specific gene signature comprises 25 genes. In some embodiments, the genes are associated with increased adenosine expression and/or level. In some embodiments, the genes are upregulated in adenosine-high regions. [0108] The HGNC ID, stable gene ID from the Ensembl database, and the SEQ ID NOs (corresponding to DNA sequences of the un-spliced versions of the genes) for the 25 genes are set forth in Table 1. Certain genes have multiple stable ID’s since they are present in multiple copies across the genome. [0109] Table 1: HGNC symbol Gene description HGNC ID Gene Stable ID SEQ ID NO: APOE apolipoprotein E HGNC:613 ENSG00000130203 6 CALR calreticulin HGNC:1455 ENSG00000179218 17 CD63 CD63 molecule HGNC:1692 ENSG00000135404 7 CD82 CD82 molecule HGNC:6210 ENSG00000085117 2 CTSB cathepsin B HGNC:2527 ENSG00000285132 28 ENSG00000164733 13 DMBT1 deleted in malignant brain HGNC:2926 ENSG00000187908 26 tumors 1 EIF3G eukaryotic translation HGNC:3274 ENSG00000130811 8 initiation factor 3 subunit G ENO1 enolase 1 HGNC:3350 ENSG00000074800 3 FLNA filamin A HGNC:3754 ENSG00000196924 22 FOS Fos proto-oncogene, AP-1 HGNC:3796 ENSG00000170345 18 transcription factor subunit GNAS GNAS complex locus HGNC:4392 ENSG00000087460 4 HSPA1B heat shock protein family A HGNC:5233 ENSG00000232804 23 (Hsp70) member 1B ENSG00000231555 30 ENSG00000224501 29 ENSG00000212866 27 ENSG00000204388 25 HSPB1 heat shock protein family B HGNC:5246 ENSG00000106211 5 (small) member 1 IFITM3 interferon induced HGNC:5414 ENSG00000142089 15 transmembrane protein 3 Attorney Docket No.01330-0108-00PCT NDUFS5 NADH:ubiquinone HGNC:7712 ENSG00000168653 19 oxidoreductase subunit S5 NPM1 nucleophosmin 1 HGNC:7910 ENSG00000181163 14 PPDPF pancreatic progenitor cell HGNC:16142 ENSG00000125534 9 differentiation and proliferation factor PTP4A2 protein tyrosine HGNC:9635 ENSG00000184007 12 phosphatase 4A2 RPS27A ribosomal protein S27a HGNC:10417 ENSG00000143947 16 SLC25A6 solute carrier family 25 HGNC:10992 ENSG00000292334 31 member 6 ENSG00000169100 21 SYNGR2 synaptogyrin 2 HGNC:11499 ENSG00000108639 11 TESC tescalcin HGNC:26065 ENSG00000088992 10 TPM1 tropomyosin 1 HGNC:12010 ENSG00000140416 20 TXNIP thioredoxin interacting HGNC:16952 ENSG00000265972 24 protein YBX3 Y-box binding protein 3 HGNC:2428 ENSG00000060138 1 [0110] In some embodiments, adenosine expression and/or level may be determined by measuring the expression of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 genes in an adenosine-specific gene signature. [0111] In some embodiments, the adenosine-specific gene signature (as a surrogate for adenosine expression and/or content) allows the characterization of adenosine landscape in human cancers using public datasets and the analysis of patient tumor samples. For example, the gene signature can rank cancer types based on adenosine-specific signature score and characterize the prognostic impact of adenosine on patient survival. Integration of gene expression data with clinical metadata and genomic information can allow the identification of disease segments with the highest adenosine-specific signature scores. The adenosine-specific gene signature represents an important tool for prioritizing patients who would benefit from adenosine-targeting therapies and for understanding the mechanisms of adenosine-mediated immunosuppression. With a similar approach, analysis of the adenosine-specific signature and its relationship with immune cell infiltration could be used to identify potential resistance mechanisms to standard of care or investigational drugs. [0112] In some embodiments the adenosine-specific gene signature correlates to adenosine expression and/or content. In some embodiments, adenosine may be determined by measuring the expression of at least one gene in an adenosine-specific gene signature, at the RNA or protein levels. In some embodiments, increased expression of at least one gene in the adenosine-specific gene signature correlates to increased adenosine. In some embodiments the adenosine-specific Attorney Docket No.01330-0108-00PCT gene signature positively correlates to adenosine expression and/or content. In some embodiments the adenosine-specific gene signature negatively correlates to adenosine expression and/or content. [0113] An increase in extracellular adenosine may occur when blocking ENT1 with an ENT1 inhibitor, as ENT1 functions to transport adenosine into the cell. In some embodiments, an increase in plasma adenosine is evidence of ENT1 inhibitor entry into tumor and/or binding in tumor cells. Without being bound by theory, intracellular adenosine can be more deleterious than the extracellular one, so it would potentially be better to block adenosine out of the cell with an ENT1 inhibitor, even if it results in increased extracellular adenosine. Therefore, increase of plasma adenosine upon exposure to ENT1 inhibitors, indicates that ENT1 inhibitors can get into the tumor and/or bind to tumor cells, and exert its expected proximal effect. Also, the adenosine- specific signature can potentially be used to measure biological effects of ENT1 inhibitors. [0114] In some embodiments, expression of at least one gene in the adenosine-specific gene signature in a tumor is compared to a control, i.e., a suitable reference standard. [0115] The term "control" refers to any reference standard suitable to provide a comparison to the expression products in the test sample. In one embodiment, the control comprises obtaining a "control sample" from which expression product levels are detected and compared to the expression product levels from the test sample. Such a control sample may comprise any suitable sample, including but not limited to a sample from a control cancer patient (can be stored sample or previous sample measurement) with a known outcome; normal tissue or cells isolated from a subject, such as a normal patient or the cancer patient, cultured primary cells/tissues isolated from a subject such as a normal subject or the cancer patient, adjacent normal cells/tissues obtained from the same organ or body location of the cancer patient, a tissue or cell sample isolated from a normal subject, or a primary cells/tissues obtained from a depository. In another embodiment, the control may comprise a reference standard expression product level from any suitable source, including but not limited to housekeeping genes, an expression product level range from normal tissue (or other previously analyzed control sample), a previously determined expression product level range within a test sample from a group of patients, or a set of patients with a certain outcome (for example, survival for one, two, three, four years, etc.) or receiving a certain treatment (for example, standard of care cancer therapy). It will be understood by those of skill in the art that such control samples and reference standard expression product levels can be used in combination as controls in the methods of the present disclosure. In one embodiment, the control may comprise normal or non-cancerous cell/tissue sample. In another embodiment, the control may comprise an expression level for a set of patients, such as a set of cancer patients, or for a set of cancer patients receiving a certain treatment, or for a set of patients with one outcome versus another outcome. In the former Attorney Docket No.01330-0108-00PCT case, the specific expression product level of each patient can be assigned to a percentile level of expression, or expressed as either higher or lower than the mean or average of the reference standard expression level. In another embodiment, the control may comprise normal cells, cells from patients treated with combination chemotherapy, and cells from patients having benign cancer. In another embodiment, the control may also comprise a measured value for example, average level of expression of a particular gene in a population compared to the level of expression of a housekeeping gene in the same population. Such a population may comprise normal subjects, cancer patients who have not undergone any treatment (i.e., treatment naive), cancer patients undergoing standard of care therapy, or patients having benign cancer. In another embodiment, the control comprises a ratio transformation of expression product levels, including but not limited to determining a ratio of expression product levels of two genes in the test sample and comparing it to any suitable ratio of the same two genes in a reference standard; determining expression product levels of the two or more genes in the test sample and determining a difference in expression product levels in any suitable control; and determining expression product levels of the two or more genes in the test sample, normalizing their expression to expression of housekeeping genes in the test sample, and comparing to any suitable control. In some embodiments, the control comprises a control sample which is of the same lineage and/or type as the test sample. In another embodiment, the control may comprise expression product levels grouped as percentiles within or based on a set of patient samples, such as all patients with cancer. In one embodiment a control expression product level is established wherein higher or lower levels of expression product relative to, for instance, a particular percentile, are used as the basis for predicting outcome. In another embodiment, a control expression product level is established using expression product levels from cancer control patients with a known outcome, and the expression product levels from the test sample are compared to the control expression product level as the basis for predicting outcome. As demonstrated by the data below, the methods of the disclosure are not limited to use of a specific cut-point in comparing the level of expression product in the test sample to the control. [0116] In some embodiments, a suitable control or reference standard is expression level of at least one gene in the adenosine-specific gene signature in a subject not affected and/or diagnosed with cancer. In some embodiments, a suitable reference standard is the mean expression level of at least one gene in the adenosine-specific gene signature in a population of subjects not affected and/or diagnosed with cancer. In some embodiments, a suitable reference standard is expression level of at least one gene in the adenosine-specific gene signature of a sample from the subject themselves. In some embodiments, a suitable reference standard is expression level of at least one gene in the Attorney Docket No.01330-0108-00PCT adenosine-specific gene signature in a non-cancerous cellular sample adjacent to a tumor from the subject themselves. [0117] In some embodiments, the present disclosure includes determining a level of expression of at least one gene in the adenosine-specific gene signature in a tumor in a subject comprising obtaining or having obtained a biological sample from the subject; and performing an assay on the biological sample to determine if the tumor has an elevated level of expression of at least one gene in the adenosine-specific gene signature. [0118] In some embodiments, the methods of determining a level of expression of at least one gene in the adenosine-specific gene signature disclosed herein are in vitro methods. [0119] In some embodiments, the sample is a bodily fluid. In some embodiments, the sample is a bodily tissue. In some embodiments, the sample is a tumor tissue sample. In some embodiments, the tumor tissue sample comprises tumor cells. In some embodiments, the tumor tissue sample further comprises tumor infiltrating immune cells. In some embodiments, the tumor tissue sample does not comprise tumor infiltrating immune cells. [0120] In some embodiments, the level of adenosine is considered as “elevated” or “increased” or “higher” when said level is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100% or more higher than the level of adenosine in a control subject or population, e.g., in a subject or a population of subjects not affected and/or diagnosed with cancer, or in a sample such as a non-cancerous sample from the subject themselves. [0121] In some embodiments, the level of adenosine expression is considered as ‘elevated” or “increased” or “higher” when said level is at least 1.5-fold, at least 2-fold, at least 3-fold, at least 5-fold, at least 8-fold, at least 10-fold, at least 15-fold, at least 20-fold, at least 25-fold, at least 30- fold, at least 35-fold, at least 40-fold, or more higher than the level of adenosine expression in a control subject or population, e.g., in a subject or a population of subjects not affected and/or diagnosed with cancer, or in a sample such as a non-cancerous sample from the subject themselves. ENT1 Inhibitors and Methods of Use Thereof [0122] 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. [0123] In some embodiments, the ENT1 inhibitor is a compound of Formula (I): Attorney Docket No.01330-0108-00PCT or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R1 is selected from the group consisting of 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; Attorney Docket No.01330-0108-00PCT R4 is selected from the group consisting each U is independently selected from the group consisting of -C(O)-, alkylene, - each Rx is independently selected from alkylene; 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. [0124] In some embodiments, the ENT1 inhibitor is a compound of Formula (II): or a pharmaceutically acceptable salt, hydrate, or solvate thereof, Attorney Docket No.01330-0108-00PCT 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)-, - 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-; Attorney Docket No.01330-0108-00PCT 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. [0125] In some embodiments, the ENT1 inhibitor is a compound of Formula (IIa): or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein X is CH2, CHF, or CF2. [0126] In some embodiments, in a compound of Formula [0127] In some embodiments, in a compound of Formula [0128] In some embodiments, the ENT1 inhibitor is a compound of Formula (IIb): Attorney Docket No.01330-0108-00PCT or a pharmaceutically acceptable salt, hydrate, or solvate thereof. [0129] In some embodiments, in a compound of Formula (I), (II), (IIa), or (IIb), U is -C(O)O-. [0130] In some embodiments, in a compound of Formula the U in R4 is -C(O)O- or -C(O)NR3-. In some embodiments, U in R4 is -C(O)O-. In some embodiments, U in R4 is -C(O)NR3-. [0131] In some embodiments, the ENT1 inhibitor is a compound of Formula (IIa1): or a pharmaceutically acceptable salt, hydrate, or solvate thereof. [0132] 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. See, e.g., WO 2024/194391 and WO 2024/194392, the contents of which are incorporated herein by reference in their entirety. Attorney Docket No.01330-0108-00PCT COMPOUND 1 [0133] In some embodiments, the ENT1 inhibitor is selected from Compound 1 and pharmaceutically acceptable salts thereof. [0134] 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. [0135] 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. [0136] In some embodiments, the ENT1 inhibitor is selected from one of the compounds in Tables 2A or 2B, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. Table 2A Compound Structures Chemical Name (12R)-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3) benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
Attorney Docket No.01330-0108-00PCT Compound Structures Chemical Name (12S)- 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl 3-ethoxy-4,5- dimethoxybenzoate; 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl 3-(2-amino- 2-oxoethyl)-4,5-dimethoxybenzoate; 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5 trimethoxybenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl 4-chloro-3- methoxybenzoate Attorney Docket No.01330-0108-00PCT Compound Structures Chemical Name O 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- O O 7(1,3)-benzenacyclotetradecaphane-12-yl 4-fluoro-3- O O methoxybenzoate N N O F O O 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl 1-(3,4,5- trimethoxybenzyl)-1H-indazole-6-carboxylate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl 2,6- dimethylisonicotinate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl 3,5-dichloro- 4-methoxybenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl 2-benzyl-4- chloro-2H-indazole-6-carboxylate Attorney Docket No.01330-0108-00PCT Compound Structures Chemical Name 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl 4-chloro-1- methyl-1H-indazole-6-carboxylate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl 1-benzyl-4- chloro-1H-indazole-6-carboxylate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- O O O 7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5- O O trifluorobenzoate N F N O F O F 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl 3-carbamoyl- 4,5-dimethoxybenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl 3- (benzyloxy)-4,5-dimethoxybenzoate Attorney Docket No.01330-0108-00PCT Compound Structures Chemical Name 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl 7-methoxy- 1,3-dimethyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazole-5-carboxylate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl 1-methyl-6- oxo-1,6-dihydropyridine-3-carboxylate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl 6- cyanonicotinate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl 4- acetylbenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl 4- (trifluoromethyl)benzoate Attorney Docket No.01330-0108-00PCT Compound Structures Chemical Name 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl 6- (trifluoromethyl)nicotinate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl 6- methylnicotinate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl 3,4- dichlorobenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl 4-chloro-3- fluorobenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl 4- chlorobenzoate Attorney Docket No.01330-0108-00PCT Compound Structures Chemical Name O 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- O O 7(1,3)-benzenacyclotetradecaphane-12-yl 3-chloro-4- O O fluorobenzoate N N O F O Cl 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- morpholinobenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl 4- (trifluoromethoxy)benzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl 2-chloro-3,4- dimethoxybenzoate Attorney Docket No.01330-0108-00PCT Compound Structures Chemical Name 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl 4- (methylsulfonyl)benzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl 2,3- dihydrobenzo[b][1,4]dioxine-6-carboxylate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl 1-methyl-1H- indazole-6-carboxylate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl 1-benzyl-1H- indazole-6-carboxylate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl benzo[d]thiazole-6-carboxylate Attorney Docket No.01330-0108-00PCT Compound Structures Chemical Name 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl [1,2,4]triazolo[4,3-a]pyridine-6-carboxylate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl 2- (trifluoromethyl)isonicotinate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl 5,6- dichloronicotinate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl 6-chloro-5- fluoronicotinate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl 2- aminopyrimidine-5-carboxylate Attorney Docket No.01330-0108-00PCT Compound Structures Chemical Name 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl 5- chloronicotinate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl 4- methoxybenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl 4-methoxy-3- (trifluoromethyl)benzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl 3-chloro-4- methoxybenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl 3,4- dimethoxybenzoate
Attorney Docket No.01330-0108-00PCT Compound Structures Chemical Name 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl 6- methoxynicotinate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl 5- methoxynicotinate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl 2- methoxypyrimidine-5-carboxylate 16-fluoro-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
Attorney Docket No.01330-0108-00PCT Compound Structures Chemical Name N-(74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl)-3,4,5- trimethoxybenzamide N-(74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl)-3,4,5- trimethoxy-N-methylbenzamide N-(16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa- 1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane- 12-yl)-3,4,5-trimethoxybenzamide N-(16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa- 1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane- 12-yl)-3,4,5-trimethoxy-N-methylbenzamide N-((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- trimethoxybenzamide Attorney Docket No. 01330-0108-00PCT Compound Structures Chemical Name N-((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-trimethoxy- N-methylbenzamide N-((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- trimethoxybenzamide N-((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-trimethoxy- N-methylbenzamide Table 2B STRUCTURE Name (12R)- 74,75-dimethoxy-6-oxo-5,8- dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate Attorney Docket No. 01330-0108-00PCT STRUCTURE Name (12S)- 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 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 74,75-dimethoxy-6-oxo-8-oxa-5-aza- 1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate Attorney Docket No. 01330-0108-00PCT STRUCTURE Name (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 Attorney Docket No. 01330-0108-00PCT STRUCTURE Name (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 Attorney Docket No. 01330-0108-00PCT STRUCTURE Name (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 74,75-dichloro-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 Attorney Docket No. 01330-0108-00PCT STRUCTURE Name (12R)- 74,75-dichloro-6-oxo-5,8- dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa- 1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4-dichlorobenzoate (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 74,75-dimethoxy-6-oxo-5,8-dioxa- 1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3-chloro-4-fluorobenzoate Attorney Docket No. 01330-0108-00PCT STRUCTURE Name (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 74,75-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-(trifluoromethoxy)benzoate (12R)- 74,75-dimethoxy-6-oxo-5,8- dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl benzoate
Attorney Docket No. 01330-0108-00PCT STRUCTURE Name (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 (R)- 74,75-dimethoxy-6-oxo-5,8- dioxa-1(4,1)-piperidina-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate (R)-15,16-dimethoxy-9,12- dimethyl-17-oxo-2,16-dioxa-9,12- diaza-1(1,3)- benzenacycloheptadecaphane-6-yl benzoate Attorney Docket No. 01330-0108-00PCT STRUCTURE Name (R)-15,16-dimethoxy-9,12- dimethyl-17-oxo-2,16-dioxa-9,12- diaza-1(1,3)- benzenacycloheptadecaphane-6-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 (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 Attorney Docket No. 01330-0108-00PCT STRUCTURE Name 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-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
Attorney Docket No. 01330-0108-00PCT STRUCTURE Name 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 Attorney Docket No. 01330-0108-00PCT STRUCTURE Name 74,75-dimethoxy-6-oxo-5,8-dioxa- 1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 4-methoxy-2- (trifluoromethoxy)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 Attorney Docket No. 01330-0108-00PCT STRUCTURE Name 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 Attorney Docket No. 01330-0108-00PCT STRUCTURE Name 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 Attorney Docket No. 01330-0108-00PCT STRUCTURE Name 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-dimethylcyclobutane-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 Attorney Docket No. 01330-0108-00PCT STRUCTURE Name 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
Attorney Docket No. 01330-0108-00PCT STRUCTURE Name 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-(difluoromethoxy)benzoate 74,75-dimethoxy-6-oxo-5,8-dioxa- 1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,5-dichlorobenzoate
Attorney Docket No. 01330-0108-00PCT STRUCTURE Name 74,75-dimethoxy-6-oxo-5,8-dioxa- 1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 2,3-dichlorobenzoate 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
Attorney Docket No. 01330-0108-00PCT STRUCTURE Name 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
Attorney Docket No. 01330-0108-00PCT STRUCTURE Name 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 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
Attorney Docket No. 01330-0108-00PCT STRUCTURE Name 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
Attorney Docket No. 01330-0108-00PCT STRUCTURE Name 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 Attorney Docket No. 01330-0108-00PCT STRUCTURE Name 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 Attorney Docket No. 01330-0108-00PCT STRUCTURE Name 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-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
Attorney Docket No. 01330-0108-00PCT STRUCTURE Name 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 Attorney Docket No. 01330-0108-00PCT STRUCTURE Name (E)-benzaldehyde O-((12R)- 74,75- dimethoxy-6-oxo-8-oxa-5-aza- 1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-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 74,75-dimethoxy-12-(5-phenyl-1H- tetrazol-1-yl)-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphan-6-one
Attorney Docket No. 01330-0108-00PCT STRUCTURE Name (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 75-carbamoyl-74-chloro-6-oxo-5,8- dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-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 74-bromo-75-chloro-6-oxo-8-oxa-5- aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate
Attorney Docket No. 01330-0108-00PCT STRUCTURE Name 75-chloro-74-cyano-6-oxo-8-oxa-5- aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate 74,75-dimethoxy-12-(5-phenyl-1H- tetrazol-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 [0137] 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 Attorney Docket No.01330-0108-00PCT one embodiment, the ENT1 inhibitor is ticagrelor or a salt thereof. [0138] In some embodiments, the ENT1 inhibitor is selected from dilazep, dipyridamole, NBMPR (nitrobenzylthioinosine), draflazine, STI-571 (Gleevec), ticagrelor, 8MDP, 5-iodotubercidin, 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. Methods [0139] In some embodiments, the present disclosure includes a method of treating a disease or disorder characterized by increased adenosine in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an ENT1 inhibitor. In some embodiments, the present disclosure includes a method of treating cancer characterized by increased adenosine in a tumor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an ENT1 inhibitor. [0140] In some embodiments, the present disclosure includes an ENT1 inhibitor, for use in the treatment of a disease or disorder in a subject in need thereof, wherein the disease or disorder is characterized by increased adenosine. In some embodiments, the disease or disorder is cancer. [0141] In some embodiments, a subject has previously been identified as having increased adenosine in a tumor microenvironment as compared to a reference. [0142] In some embodiments, the present disclosure includes a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an ENT inhibitor, wherein the subject has previously been identified as having increased adenosine in a tumor of the subject. In some embodiments, the present disclosure includes an ENT1 inhibitor, for use in the treatment of cancer in a subject in need thereof, wherein the cancer is characterized by increased adenosine, and wherein the subject has previously been identified as having increased adenosine in a tumor of the subject. In some embodiments, a subject has previously been identified as having increased adenosine in the tumor microenvironment as compared to a reference. In some embodiments, a subject has previously been identified as having increased adenosine in the tumor microenvironment as compared to a reference. [0143] In some embodiments, the present disclosure includes a method of treating cancer in a subject in need thereof, comprising: selecting a subject with cancer having a diagnosis of an increased adenosine in a tumor of the subject; and treating the patient with an ENT1 inhibitor. Attorney Docket No.01330-0108-00PCT [0144] In some embodiments, the present disclosure includes a method of selecting a subject with cancer for treatment with an ENT1 inhibitor, comprising: detecting the level of adenosine in a sample from the subject, such as in a tumor sample from the subject; selecting the subject for treatment with an ENT1 inhibitor based on a comparison of said level with a reference level. [0145] In some embodiments, the present disclosure includes a method of selecting a subject with cancer for treatment with an ENT1 inhibitor, comprising: detecting the level of adenosine in a sample from the subject, such as in a tumor sample from the subject; selecting the subject for treatment with an ENT1 inhibitor when the level of adenosine is increased. [0146] In some embodiments, the level of adenosine is increased as compared to a reference. In some embodiments, the level of adenosine is increased in the tumor microenvironment as compared to a reference. [0147] In some embodiments, the level of adenosine correlates to the level of expression of at least one gene in the adenosine-specific signature. In some embodiments, the disease or disorder, such as cancer, is characterized by an increase or decrease in expression of at least one gene in the adenosine-specific gene signature. In some embodiments, the disease or disorder, such as cancer, is characterized by an increase or decrease in expression of at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or all 25 genes in the adenosine-specific gene signature. [0148] In some embodiments, the present disclosure includes a method of treating a disease or disorder characterized by increased or decreased expression of at least one gene in the adenosine- specific gene signature in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an ENT1 inhibitor. In some embodiments, the present disclosure includes a method of treating cancer characterized by increased or decreased expression of at least one gene in the adenosine-specific gene signature in a tumor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an ENT1 inhibitor. In some embodiments, the disease or disorder, such as cancer, is characterized by an increase or decrease in expression of at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or all 25 genes in the adenosine-specific gene signature. Attorney Docket No.01330-0108-00PCT [0149] In some embodiments, the present disclosure includes an ENT1 inhibitor, for use in the treatment of a disease or disorder in a subject in need thereof, wherein the disease or disorder is characterized by increased or decreased expression of at least one gene in the adenosine-specific gene signature. In some embodiments, the disease or disorder is cancer. In some embodiments, the disease or disorder, such as cancer, is characterized by an increase or decrease in expression of at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or all 25 genes in the adenosine-specific gene signature. [0150] In some embodiments, a subject has previously been identified as having increased or decreased expression of at least one gene in the adenosine-specific gene signature in a tumor microenvironment as compared to a reference. In some embodiments, the subject has previously been identified as having increased or decreased in expression of at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or all 25 genes in the adenosine-specific gene signature. [0151] In some embodiments, the present disclosure includes a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an ENT1 inhibitor, wherein the subject has previously been identified as having increased or decreased expression of at least one gene in the adenosine-specific gene signature in a tumor of the subject. In some embodiments, the present disclosure includes an ENT1 inhibitor, for use in the treatment of cancer in a subject in need thereof, wherein the cancer is characterized by increased or decreased expression of at least one gene in the adenosine-specific gene signature, and wherein the subject has previously been identified as having increased or decreased expression of at least one gene in the adenosine-specific gene signature in a tumor of the subject. In some embodiments, a subject has previously been identified as having increased or decreased expression of at least one gene in the adenosine-specific gene signature in the tumor microenvironment as compared to a reference. In some embodiments, a subject has previously been identified as having increased or decreased expression of at least one gene in the adenosine-specific gene signature in the tumor microenvironment as compared to a reference. In some embodiments, the subject has previously been identified as having, or the disease or disorder, such as cancer, is characterized by an increased or decreased in expression of at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least Attorney Docket No.01330-0108-00PCT 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or all 25 genes in the adenosine-specific gene signature. [0152] In some embodiments, the present disclosure includes a method of treating cancer in a subject in need thereof, comprising: selecting a subject with cancer having a diagnosis of an increased or decreased expression of at least one gene in the adenosine-specific gene signature in a tumor of the subject; and treating the patient with an ENT1 inhibitor. In some embodiments, the subject with can has a diagnosis of increased or decreased expression of at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or all 25 genes in the adenosine-specific gene signature. [0153] In some embodiments, the present disclosure includes a method of selecting a subject with cancer for treatment with an ENT1 inhibitor, comprising: detecting the level of expression of at least one gene in the adenosine-specific gene signature in a sample from the subject, such as in a tumor sample from the subject; selecting the subject for treatment with an ENT1 inhibitor based on a comparison of said level with a reference level. [0154] In some embodiments, the present disclosure includes a method of selecting a subject with cancer for treatment with an ENT1 inhibitor, comprising: detecting the level of expression of at least one gene in the adenosine-specific gene signature in a sample from the subject, such as in a tumor sample from the subject; selecting the subject for treatment with an ENT1 inhibitor when the level of expression of at least one gene in the adenosine-specific gene signature is increased or decreased. In some embodiments, the level of expression of at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or all 25 genes in the adenosine-specific gene signature is increased or decreased. [0155] In some embodiments, the level of adenosine is increased as compared to a reference. In some embodiments, the level of adenosine is increased or decreased in the tumor microenvironment as compared to a reference. [0156] In some embodiments, the subject is to be treated with an ENT1 inhibitor as a first line therapy, i.e., the subject has not received prior anticancer treatment. In some embodiments, the subject is to be treated with an ENT1 inhibitor as a second, third or more line therapy, i.e., the subject has received prior anticancer treatment with another anticancer agent. Attorney Docket No.01330-0108-00PCT Combinations [0157] In some embodiments, the present disclosure includes a method of treating a disease or disorder characterized by increased adenosine and/or increased expression of at least one gene in the adenosine-specific gene signature in a subject in need thereof, comprising administering to the subject a combination of a therapeutically effective amount of an ENT1 inhibitor and a therapeutically effective amount of an additional therapeutic agent. In some embodiments, the disease or disorder is cancer. In some embodiments, the additional therapeutic agent is an anticancer agent. In some embodiments, the present disclosure includes a combination of a therapeutically effective amount of an ENT1 inhibitor and a therapeutically effective amount of an anticancer agent, for use in the treatment of cancer in a subject in need thereof, wherein the cancer is characterized by increased adenosine and/or increased expression of at least one gene in the adenosine-specific gene signature. In some embodiments, the present disclosure includes an ENT1 inhibitor, for use in the treatment of cancer in a subject in need thereof, wherein the cancer is characterized by increased adenosine and/or increased expression of at least one gene in the adenosine-specific gene signature, and wherein the subject is further to be administered with an anticancer agent. [0158] In one embodiment, an anticancer agent is selected from immunotherapeutic agents, chemotherapeutic agents, antiangiogenic agents, multidrug resistance-associated proteins inhibitors, radiotherapeutic agents, and any combination thereof. [0159] In one embodiment, a combination comprises a single anticancer agent. In another embodiment, a combination comprises a plurality of anticancer agents; i.e., two, three or four anticancer agents as defined below. In case of use of a combination of anticancer agents in a combination, an anticancer agents may be of the same class of agents or of different classes of agents. For example, a combination of an immunotherapeutic agent and of a chemotherapeutic agent may be used with an ENT inhibitor. [0160] In the context of the present disclosure, administration of an anticancer agent and an ENT1 inhibitor may occur either simultaneously or timely staggered, either at the same site of administration or at different sites of administration, under similar or different dosage forms as further outlined below. [0161] In the context of the present disclosure, administration of an anticancer agent and an ENT1 inhibitor may occur either simultaneously or timely staggered, either at the same site of administration or at different sites of administration, under similar or different dosage forms as further outlined below. Attorney Docket No.01330-0108-00PCT [0162] In one embodiment, an anticancer agent is administered prior to, concomitant with, or subsequent to administration of an ENT1 inhibitor. To ensure that the separate mechanisms elicited by an anticancer agent and an ENT1 inhibitor are not negatively influenced by each other, an adenosine receptor antagonist and an anticancer agent may be administered separated in time (in a time-staggered manner), i.e. sequentially, and/or are administered at different administration sites. This means that the ENT1 inhibitor may be administrated e.g. prior, concurrent or subsequent to an anticancer agent, or vice versa. Alternatively or additionally, an ENT1 inhibitor and an anticancer agent may be administered at different administration sites, or at the same administration site, when administered in a time staggered manner. [0163] In one embodiment, an ENT1 inhibitor is to be administered prior to and/or concomitantly with an anticancer agent. In one embodiment, an ENT1 inhibitor is to be administered prior to the day or on the same day that an anticancer agent is administered. In another embodiment, an anticancer agent is to be administered prior to and/or concomitantly with an ENT1 inhibitor. In one embodiment, an anticancer agent is to be administered prior to the day or on the same day that an ENT1 inhibitor is administered. In one embodiment, an ENT1 inhibitor is to be administered prior to and/or concomitantly with an anticancer agent and continuously thereafter. In another embodiment, an anticancer agent is to be administered prior to and/or concomitantly with an ENT inhibitor and continuously thereafter. [0164] Depending on the condition to be prevented or treated and the form of administration, an anticancer agent and the ENT1 inhibitor may be administered as a single daily dose, divided over one or more daily doses. [0165] It will be understood that the total daily usage of an ENT1 inhibitor and anticancer agent will be decided by the attending physician within the scope of sound medical judgment. The specific dose for any particular subject will depend upon a variety of factors such as the cancer to be treated; the age, body weight, general health, sex and diet of the patient; and like factors well- known in the medical arts. Diseases and Disorders [0166] In some embodiments, the present disclosure includes the methods of treating proliferative disorders, including cancers. In some embodiments, the present disclosure includes a compound for use in the treatment and/or prevention of proliferative disorders, including cancers. Thus, in one embodiment, the present disclosure provides use of a compound for the manufacture of a medicament for treating and/or preventing cancer. The present disclosure also provides a method of treatment of cancer, which comprises administering to a mammal species in Attorney Docket No.01330-0108-00PCT need thereof a therapeutically effective amount of a compound. [0167] The present disclosure also provides for a method for delaying in patient the onset of cancer comprising the administration of a pharmaceutically effective amount of a compound of the disclosure to a patient in need thereof. [0168] Various cancers are known in the art. Cancers that can be treated using methods of the disclosure include solid cancers and non-solid cancers, especially benign and malignant solid tumors and benign and malignant non-solid tumors. Cancer may be metastatic or non-metastatic. The cancer may be familial or sporadic. [0169] In some embodiments, cancer is a solid 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. [0170] 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. [0171] In another embodiment, 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. [0172] Lymphoid disorders include but are not limited to acute lymphocytic leukemia and chronic lymphoproliferative disorders (e.g., lymphomas, myelomas, and chronic lymphoid leukemias). Lymphomas include, for example, Hodgkin’s disease, non-Hodgkin’s lymphoma lymphomas, and lymphocytic lymphomas). Chronic lymphoid leukemias include, for example, T cell chronic lymphoid leukemias and B cell chronic lymphoid Attorney Docket No.01330-0108-00PCT leukemias. [0173] In some embodiments, cancer is selected from the group consisting of colorectal cancer, stomach cancer, breast cancer, bladder cancer, esophageal cancer, pancreatic cancer, and ovarian cancer. [0174] In a specific embodiment, cancer is breast cancer. In a specific embodiment, cancer is colorectal cancer. In a specific embodiment, cancer is bladder cancer. In a specific embodiment, cancer is breast cancer. In a specific embodiment, cancer is esophageal cancer. In a specific embodiment, cancer is stomach cancer. In a specific embodiment, cancer is ovarian cancer. In a specific embodiment, the cancer is pancreatic cancer. [0175] In another embodiment, cancer is selected from the group consisting of: leukemia and multiple myeloma. [0176] In one embodiment, a subject has previously received at least one prior therapeutic treatment, and has progressed subsequent to the administration of at least one prior therapeutic treatment and prior to administration of a therapeutic agent. In one embodiment, a prior therapeutic treatment is selected from the group consisting of chemotherapy, immunotherapy, radiation therapy, stem cell transplant, hormone therapy, and surgery. Formulations [0177] The present disclosure also provides pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt and solvate thereof, and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant. [0178] The present disclosure also provides a medicament comprising at least one compound disclosed herein, or a pharmaceutically acceptable salt and solvate thereof, as active ingredient. [0179] Generally, for pharmaceutical use, a compound disclosed herein may be formulated as a pharmaceutical preparation comprising at least one compound disclosed and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant, and optionally one or more further pharmaceutically active compounds. Details regarding the presence of further pharmaceutically active compounds are provided hereafter. [0180] By means of non-limiting examples, such a formulation may 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 methods and carriers, diluents and excipients for use in the preparation Attorney Docket No.01330-0108-00PCT thereof, will be clear to the skilled person; reference is made to the latest edition of Remington’s Pharmaceutical Sciences. [0181] Some non-limiting examples of 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 propylhydroxybenzoates, talc, magnesium stearate, edible oils, vegetable oils and mineral oils or suitable mixtures thereof. Formulations can optionally contain other substances that are commonly used in pharmaceutical formulations, such as lubricating agents, wetting agents, emulsifying and suspending agents, dispersing agents, desintegrants, bulking agents, fillers, preserving agents, sweetening agents, flavoring agents, flow regulators, release agents, etc. Compositions may also be formulated so as to provide rapid, sustained or delayed release of the active compound(s) contained therein. [0182] In general, the ENT1 inhibitors and compositions herein 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. [0183] 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. [0184] A lubricant might be necessary in a tablet formulation to prevent the tablet and punches Attorney Docket No.01330-0108-00PCT 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 and compositions can also be formulated as chewable tablets, for example, by using substances such as mannitol in the formulation. [0185] When it is desired to administer an ENT1 inhibitor or a composition of the present disclosure 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. [0186] The effect of the ENT1 inhibitors and compositions of the present disclosure 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. [0187] In some embodiments, the ENT1 inhibitors and compositions of the present disclosure 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. [0188] In some embodiments, the ENT1 inhibitor is administered in a daily dose from about 2.5 mg to about 160 mg. In some embodiments, the ENT inhibitor is administered in a daily dose from about 2.5 mg to about 160 mg, from about 2.5 mg to about 155 mg, from about 2.5 mg to about 150 mg, from about 2.5 mg to about 145 mg, from 2.5 mg to about 140 mg, from about 2.5 mg to about 135 mg, from about 2.5 mg to about 130 mg, from about 2.5 mg to about 125 mg, from about 2.5 mg to about 120 mg, from about 2.5 mg to about 115 mg, from 2.5 mg to about 110 mg, from Attorney Docket No.01330-0108-00PCT about 2.5 mg to about 105 mg, about 2.5 mg to about 100 mg, from about 2.5 mg to about 95 mg, from 2.5 mg to about 90 mg, from about 2.5 mg to about 85 mg, from about 2.5 mg to about 80 mg, from about 2.5 mg to about 75 mg, from about 2.5 mg to about 70 mg, from about 2.5 mg to about 65 mg, from about 2.5 mg to about 60 mg, from about 2.5 mg to about 55 mg, from about 2.5 mg to about 50 mg, from about 2.5 mg to about 45 mg, from about 2.5 mg to about 40 mg, from about 2.5 mg to about 35 mg, from about 2.5 mg to about 30 mg, from about 2.5 mg to about 25 mg, from about 2.5 mg to about 20 mg, from about 2.5 mg to about 15 mg, from about 2.5 mg to about 10 mg, or from about 2.5 mg to about 5 mg. [0189] In some embodiments, the ENT inhibitor is administered in a daily dose of about 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg , 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, 100 mg, 101 mg, 102 mg, 103 mg, 104 mg, 105 mg, 106 mg, 107 mg, 108 mg, 109 mg, 110 mg, 111 mg, 112 mg, 113 mg, 114 mg, 115 mg, 116 mg, 117 mg, 118 mg, 119 mg, 120 mg, 121 mg, 122 mg, 123 mg, 124 mg, 125 mg, 126 mg, 127 mg, 128 mg, 129 mg, 130 mg, 131 mg, 132 mg, 133 mg, 134 mg, 135 mg, 136 mg, 137 mg, 138 mg, 139 mg, 140 mg, 145 mg, 150 mg, 155 mg, or 160 mg. In some embodiments, the ENT inhibitor is administered in a daily dose of about 2.5 mg. In some embodiments, the ENT inhibitor is administered in a daily dose of about 5 mg. In some embodiments, the ENT inhibitor is administered in a daily dose of about 10 mg. In some embodiments, the ENT inhibitor is administered in a daily dose of about 20 mg. In some embodiments, the ENT inhibitor is administered in a daily dose of about 30 mg. In some embodiments, the ENT inhibitor is administered in a daily dose of about 40 mg. In some embodiments, the ENT inhibitor is administered in a daily dose of about 45 mg. In some embodiments, the ENT inhibitor is administered in a daily dose of about 50 mg. In some embodiments, the ENT inhibitor is administered in a daily dose of about 60 mg. In some embodiments, the ENT inhibitor is administered in a daily dose of about 70 mg. In some embodiments, the ENT inhibitor is administered in a daily dose of about 80 mg. In some embodiments, the ENT inhibitor is administered in a daily dose of about 90 mg. In some embodiments, the ENT inhibitor is administered in a daily dose of about 100 mg. In some embodiments, the ENT inhibitor is administered in a daily dose of about 110 mg. In some embodiments, the ENT inhibitor is Attorney Docket No.01330-0108-00PCT administered in a daily dose of about 120 mg. In some embodiments, the ENT inhibitor is administered in a daily dose of about 130 mg. In some embodiments, the ENT inhibitor is administered in a daily dose of about 140 mg. In some embodiments, the ENT inhibitor is administered in a daily dose of about 150 mg. In some embodiments, the ENT inhibitor is administered in a daily dose of about 160 mg. [0190] In some embodiments, the ENT1 inhibitor is Compound 1 or a salt, hydrate, or solvate thereof. In some embodiments, the Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose (free base) of about 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg , 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, 100 mg, 101 mg, 102 mg, 103 mg, 104 mg, 105 mg, 106 mg, 107 mg, 108 mg, 109 mg, 110 mg, 111 mg, 112 mg, 113 mg, 114 mg, 115 mg, 116 mg, 117 mg, 118 mg, 119 mg, 120 mg, 121 mg, 122 mg, 123 mg, 124 mg, 125 mg, 126 mg, 127 mg, 128 mg, 129 mg, 130 mg, 131 mg, 132 mg, 133 mg, 134 mg, 135 mg, 136 mg, 137 mg, 138 mg, 139 mg, 140 mg, 145 mg, 150 mg, 155 mg, or 160 mg. [0191] In some embodiments, Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 2.5 mg (free base). In some embodiments, Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 5 mg (free base). In some embodiments, Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 10 mg (free base). In some embodiments, Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 20 mg (free base). In some embodiments, Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 30 mg (free base). In some embodiments, Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 40 mg (free base). In some embodiments, Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 45 mg (free base). In some embodiments, Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 50 mg (free base). In some embodiments, Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 60 mg (free base). In some embodiments, Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 70 mg (free base). In some embodiments, Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 80 mg Attorney Docket No.01330-0108-00PCT (free base). In some embodiments, Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 90 mg (free base). In some embodiments, Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 100 mg (free base). In some embodiments, Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 110 mg (free base). In some embodiments, Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 120 mg (free base). In some embodiments, Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 130 mg (free base). In some embodiments, Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 140 mg (free base). In some embodiments, Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 150 mg (free base). In some embodiments, Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 160 mg (free base). [0192] In some embodiments, the ENT1 inhibitor is a Compound 1 hydrogen sulfate or hydrate or solvate thereof, such as crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate. In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose (free base) of about 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg , 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, 100 mg, 101 mg, 102 mg, 103 mg, 104 mg, 105 mg, 106 mg, 107 mg, 108 mg, 109 mg, 110 mg, 111 mg, 112 mg, 113 mg, 114 mg, 115 mg, 116 mg, 117 mg, 118 mg, 119 mg, 120 mg, 121 mg, 122 mg, 123 mg, 124 mg, 125 mg, 126 mg, 127 mg, 128 mg, 129 mg, 130 mg, 131 mg, 132 mg, 133 mg, 134 mg, 135 mg, 136 mg, 137 mg, 138 mg, 139 mg, 140 mg, 145 mg, 150 mg, 155 mg, or 160 mg. [0193] In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 2.5 mg (free base). In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 5 mg (free base). In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 10 mg (free Attorney Docket No.01330-0108-00PCT base). In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 20 mg (free base). In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 30 mg (free base). In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 40 mg (free base). In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 45 mg (free base). In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 50 mg (free base). In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 60 mg (free base). In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 70 mg (free base). In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 80 mg (free base). In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 90 mg (free base). In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 100 mg (free base). In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 110 mg (free base). In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 120 mg (free base). In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 130 mg (free base). In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 140 mg (free base). In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, for example crystalline Form 2 Attorney Docket No.01330-0108-00PCT Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 150 mg (free base). In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 160 mg (free base). [0194] In some embodiments, the ENT inhibitor is administered once daily during a treatment cycle. In some embodiments, the ENT inhibitor is administered twice daily (BID) during a treatment cycle. [0195] In some embodiments, the treatment comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 treatment cycles. In some embodiments, the treatment comprises at least one treatment cycle of 21-28 days. In some embodiments, the treatment cycle is 21, 22, 23, 24, 25, 26, 27, or 28 days. In some embodiments, the treatment cycle is 21 days. In some embodiments, the treatment cycle is 28 days. [0196] In some embodiments, the ENT inhibitor is administered continuously during the treatment cycle. In some embodiments, the ENT inhibitor is administered intermittently during the treatment cycle. In some embodiments, the intermittent dosing comprises 5 days of ENT inhibitor treatment and 2 days of no ENT inhibitor treatment in a 21-day cycle. In some embodiments, the intermittent dosing comprises 3 weeks of ENT inhibitor treatment and 1 week of no ENT inhibitor treatment in 28-day cycle. [0197] In some embodiments, the ENT inhibitor is administered at the same dose during the treatment cycle. In some embodiments, the ENT inhibitor is administered at doses of escalating concentration (i.e., increasing doses). In this case, a subsequent dose can be increased by a particular increment, or by variable increments, until a maximum dose is reached, at which point administration may cease or may continue at the maximum dose. In some embodiments, the ENT inhibitor is administered at about 5 mg for the first week, 10 mg for the second week, etc. [0198] In some embodiments, the ENT inhibitor is administered orally. In some embodiments, the ENT inhibitor is administered as a tablet and/or capsule. [0199] In some embodiments, in the event that the patient develops, or is at risk of developing, an adverse event associated with the administration of the ENT1 inhibitor, the treatment further comprises the administration of an agent capable of treating, preventing, delaying, reducing or attenuating the development or risk of development of the adverse event. The agent may be administered to the patient prior to the initiation of the treatment with the ENT1 inhibitor (e.g., as a prophylaxis in order to prevent or reduce the risk of an adverse event developing) or during or subsequent to treatment with the ENT1 inhibitor (e.g., in response to the development of an adverse event). In some embodiments, the adverse event comprises headache, pain, nausea, and/or vomiting. In some embodiments, the agent is a medication administered to combat headache, pain, Attorney Docket No.01330-0108-00PCT nausea, and/or vomiting. [0200] In some embodiments, the agent capable of treating, preventing, delaying, reducing or attenuating the development or risk of development of the adverse event is administered as one or more doses to the patient prior to the initiation of the treatment with the ENT1 inhibitor as a prophylactic treatment for the adverse event. [0201] In some embodiments, the agent capable of treating, preventing, delaying, reducing or attenuating the development or risk of development of the adverse event is administered to the patient in combination with one or more dose of the ENT1 inhibitor as a prophylactic treatment for the adverse event. The agent may be administered as one or more doses consecutively (before and/or after), and/or concurrently with the ENT1 inhibitor. [0202] In some embodiments, the agent capable of treating, preventing, delaying, reducing or attenuating the development or risk of development of the adverse event is administered to the patient in the event that the patient develops an adverse event associated with the administration of the ENT1 inhibitor. In some embodiments, the treatment comprises administration of the agent at a therapeutic amount, or an amount sufficient to partially or completely alleviate or ameliorate the adverse event (e.g. CRS) or symptoms thereof. [0203] In some embodiments, agent is administered prior to, concomitant with, and/or subsequent to at least one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, etc. doses of ENT inhibitor. In some embodiments, the agent is administered prior to, concomitant with, and/or subsequent to all doses of ENT inhibitor. In some embodiments, the agent is administered at least 30 minutes before and/or after at least one dose of ENT inhibitor. In some embodiments, the agent is administered 30 minutes before at least one dose of ENT inhibitor. [0204] In some embodiments, the agent comprises an antiemetic, analgesic, and/or caffeine. [0205] In some embodiments, the analgesic comprises a non-steroidal anti-inflammatory drug (NSAID) (e.g., diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, sulindac, tolmetin, celecoxib, rofecoxib, valdecoxib), aspirin, acetaminophen, antidepressive medications (e.g., amitriptyline, duloxetine), antiepileptic medication (e.g., gabapentin, prefabalin), and/or lidocaine. [0206] In some embodiments the antiemetic comprises anticholinergic agents such as hyoscyamine, methscopolamine, scopolamine; antihistamines, such as cyclizine, dimenhydrinate, doxylamine, hydroxyzine, meclizine, promethazine; cannabinoid receptor agonists, such as dronabinol, nabilone, tetrahydrocannabinol; dopamine receptor antagonists, such as Attorney Docket No.01330-0108-00PCT chlorpromazine, prochlorperazine; serotonin 5-HT3 receptor antagonists, such as alosetron, dolasetron, granisetron, ondansetron, palonosetron; substance P/neurokinin 1 receptor antagonists, such as aprepitant, fosaprepitant, fosnetupitant, rolapitant; or miscellaneous antiemetic agents, such as amisulpride, dexamethasone, metoclopramide, trimethobenzamide. [0207] In some embodiments, the agent is administered orally. In some embodiments, the agent is administered as a tablet and/or a capsule. In some embodiments, the agent is caffeine. In some embodiments, the caffeine is administered orally as a tablet or capsule. In some embodiments, the caffeine is administered in a beverage or in food. [0208] Another object of this disclosure is the use of the combination as a medicament, i.e. for medical use. Thus, in one embodiment, the disclosure provides the use of the combination of the disclosure for the manufacturing of a medicament. Especially, the disclosure provides the use of the combined pharmaceutical composition of the disclosure or the kit of the disclosure for the manufacturing of a medicament. EXAMPLE Example 1: [0209] Adenosine levels in human tumor tissue were assessed using quantitative mass spectrometry imaging (QMSI), and spatial gene expression analysis was performed using GeoMx digital spatial profiler (GeoMx DSP) guided by QMSI. FIG.1. [0210] Human tumor collection: Serial sections were cut from snap-frozen tumor tissue (tissue were snap frozen on dry ice and stored at -80°C) collected from 14 donors. The tumor content was confirmed in 13 samples from 11 donors affected by bladder (N=2), breast (N=2), colorectal (N=1), esophageal (N=1), stomach (N=3) and pancreatic (N=2) cancer. Tumor, stroma and normal tissue areas were identified by pathologist evaluation of HE stained sections. [0211] Adenosine quantification on human tumor: Tumor blocks were sectioned at -20°C in serial sections. Sections were dried in a desiccator and immediately sprayed with a mixture of 6 inhibitors of adenosine pathway (AOPCP (Adenosine 5′-(α,β methylene)diphosphate), EDTA, 5- Iodotubercidin, Dipyridamole, NBMPR (S-(4-Nitrobenzyl)-6-thioinosine), EHNA). Sections were analyzed for adenosine content using quantitative mass spectrometry imaging (QMSI). The adenosine content and distribution across the tissue was quantified using QMSI on one consecutive section. 183 Regions of interest (ROIs) (based on adenosine content (high vs. low)) for GeoMx analysis were selected based on QMSI data, and 4-14 ROIs encompassing different adenosine levels and histological features were defined within each tissue. Similar ROIs were then selected on adjacent slides and RNA extracted and checked for quality by RNAscope. After verification of Attorney Docket No.01330-0108-00PCT RNA integrity, gene expression analysis was performed on one consecutive section using spatial transcriptomics (GeoMx) DSP. A segmented profiling strategy using Pancytokeratin (PanCK) staining was applied to allow expression profiling of tumor cells and surrounding microenvironment within each ROI. - qMSI: All the biological sections were analyzed by 7T MALDI-FTICR with following methods: CASI negative mode m/z 267 Da with an isolation window of 30Da at 90 µm spatial resolution for the tissue sections and 200 µm for the calibrants on tissue. - RNAscope: Mild expression model transcript PPIB and low expression model transcript POLR2A were analyzed by RNAscope to evaluate sample’s transcriptome integrity before GeoMx whole transcriptome analysis. - WTA: transcripts were analyzed by GeoMx DSP using a Whole Transcriptome Atlas (WTA) panel and off the shelf morphological markers CD45, PanCK and DNA counterstain. Transcripts detected from PanCK+ and PanCK- tissues areas were sequenced using a NovaSeq 6000 sequencer and compared between areas enriched in ADO and low in ADO. [0212] Bioinformatic analysis: ROIs were divided into training (70%) and test (30%) sets. Adenosine high and low regions were defined based on the overall adenosine level median across all ROIs. Immune cell and tertiary lymphoid structure (TLS) signature scores were inferred using GSVA (gene set variation analysis). A linear mixed model adjusted for tumor type and patient was applied to the training set to identify differentially immune cell signatures and expressed genes (DEGs) in adenosine high versus adenosine low regions (FDR <0.05). FIG.2A-2E. Gene ontology enrichment analysis was performed on DEGs using g:profiler. Lasso regression was then used to identify DEGs with the highest predictive potential i.e. quantitative adenosine signature. FIG.3A- 3D. Quantitative adenosine signature scores were computed using GSVA in an in-house GeoMX dataset, tumor samples from The Cancer Genome Atlas (TCGA), and healthy tissue from the Genotype-Tissue Expression dataset (GTEx). FIG. 4A-4C. The predictive power of the resulting gene signature was evaluated in the test set using the Area Under the Receiver Operating Characteristics (AUROC). Mann-Whitney U test was used for all pairwise comparisons of quantitative adenosine signature scores. An adjusted p-value of 0.05 was defined as significative. All analysis was performed using R 4.4.0. [0213] Differential gene expression (DGE) analysis was used to identify which genes were expressed at different levels in segments with high (i.e. above the median overall adenosine levels measured across the 13 samples) or low (i.e. below the median) adenosine content. After adjusting for tumor type, patient and PanCK positivity, 249 genes remained significantly differentially Attorney Docket No.01330-0108-00PCT expressed (FDR < 0.05 and abs(log2FC) > 0.5) in adenosine high or low conditions, most of them overexpressed. FIG. 2A and 2B. Gene ontology enrichment analysis on genes upregulated in adenosine high regions revealed associations with protein translation, metabolic processes, and immune activation. FIG.2C. High adenosine regions are associated with a specific gene expression pattern and contain fewer immune cells compared to low adenosine regions. Adenosine high regions are poor in immune infiltrates compared to adenosine low regions. FIG.2D. Immune cell populations showed significantly lower expression of the associated gene signature in adenosine high versus adenosine low regions (N = 13 paired samples). FIG.2E. [0214] Lasso regression with 10-fold cross-validation was applied to select the 25 genes with the highest predictive power for adenosine content. FIG.3A. The 25-gene adenosine-specific signature was then trained on 70% ROIs and validated on the remaining 30% of regions (N= 128 training ROIs (2.4e-06); N = 55 test ROIs (5.1e-05); Mann Whitney U test). FIG.3B. The area under the curve was 0.972 in the training set, and 0.905 in the validation set. FIG.3C. The predictive power of the adenosine-specific signature was confirmed in the test set. The adenosine-specific signature was also found to correlate with an independent adenosine signaling signature in the TCGA dataset (R = 0.52, p < 2.2e-16). FIG.3D. [0215] The 25-gene signature was applied to existing public transcriptomic datasets to characterize the adenosine landscape in human cancer. [0216] Analysis of Genotype-tissue expression (GTEx) and The Cancer Genome Atlas (TCGA) data allowed to compare adenosine-specific signature scores in 5,551 normal tissue samples of healthy individuals, and 11,350 tumor samples from 33 cancer types. FIG. 4A. Scores were significantly higher in tumor tissue (TCGA) compared to normal tissue (GTEx) (p < 2.22e-16). The adenosine-specific signature was also associated with worse survival in several cancer types (Cox regression using adenosine score as continuous variable). FIG.4B-4C. [0217] Analysis of TCGA database also allowed to rank the 33 cancer types based on the adenosine-specific signature score and to characterize the prognostic impact of adenosine on patient survival. FIG.5A-5B. Differences were evidenced among the cancer types, but also high degree of heterogeneity were also evidenced within some of the indications. Integration of gene expression data with clinical metadata and genomic information allowed the identification of disease segments (and actionable patient segments) with the highest adenosine-specific signature scores. For example, subjects with KRAS mutations/ KRAS mutated tumor types were found to have a high adenosine-specific signature score (N = 9450 wild type (WT); N = 737 mutated (MUT); Mann-Whitney U test) (p < 2.22e-16). FIG. 5C. Subjects with BRAF mutations/ BRAF mutated tumor types were found to have a high adenosine-specific signature score (N = 10561 wild Attorney Docket No.01330-0108-00PCT type (WT); N = 618 mutated (MUT); Mann-Whitney U test) (p < 2.22e-16). FIG. 5D. The adenosine-specific signature can potentially be used for tumor type prioritization for adenosine pathway inhibitors. With a similar approach, analysis of the adenosine-specific signature and its relationship with immune cell infiltration could be used to identify potential resistance mechanisms to standard of care or investigational drugs. [0218] Therefore, the adenosine gene signature was developed based on the spatial quantification of adenosine in human tumors, and demonstrates its potential for indication selection. This new signature, derived from 249 differentially expressed genes (DEGs) associated with metabolism and immune activation, showed high predictive power across tumor types. Furthermore, the adenosine signature was higher in tumors compared to healthy tissue and exhibited variable expression and prognostic value across tumor subtypes. These findings suggest that the adenosine signature represents an important tool for prioritizing patients who would benefit from adenosine-targeting therapies and for understanding the mechanisms of adenosine-mediated immunosuppression. Example 2: [0219] Patients with solid tumors are treated with crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate in one of the following dosing scheme: (1) a single daily oral dose of 5 mg of Compound 1 (free base); (2) twice a day oral doses of 5 mg of Compound 1 (free base) – i.e., 10 mg of Compound 1 (free base) total per day; (3) twice a day oral doses of 10 mg of Compound 1 (free base) – i.e., 20 mg of Compound 1 (free base) total per day; (4) twice a day oral doses of 15 mg of Compound 1 (free base) – i.e., 30 mg of Compound 1 (free base) total per day; (5) twice a day oral doses of 22.5 mg of Compound 1 (free base) – i.e., 45 mg of Compound 1 (free base) total per day; or (6) twice a day oral doses of 30 mg of Compound 1 (free base) – i.e., 60 mg of Compound 1 (free base) total per day. [0220] The dosing consists of sequential dose-escalation cohorts with at least 3 and up to 6 dose- limiting toxicity (DLT)-evaluable participants each. There are 5 dose level cohorts. The starting human dose of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate in Cohort 1 (Dose Level 1) is 5 mg (expressed as free-base equivalent) twice daily (BID) oral dosing (PO). The first dose-escalation cohort (Cohort 1) starts with a single-dose administration of 5 mg (free base) in Cycle 0 followed by the washout period of at least 3 and approximately 7 days before Day 1 of Cycle 1. On Day 1 of Cycle 1, participants in Cohort 1 starts taking crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate at 5 mg (free base) BID continuously for 21 days of each 21-day cycle. Subsequent dose-escalation cohorts may also include the single-dose Cycle 0 until sufficient PK/PD information is collected to support the prediction of PK and PD at higher BID dose levels. Attorney Docket No.01330-0108-00PCT [0221] The initial dosing schedule is BID (every 12 hours ± 2 hours) orally continuously for 21 days of each 21-day treatment cycle. The dosing schedule may be modified at any time at the Sponsor’s discretion and with the Safety Review Committee (SRC) approval in response to emerging data. Further, intermittent dosing (e.g., 5 days on and 2 days off in 21-day cycles, or 3 weeks on and 1 week off in 28-day cycles) may be used if treatment holiday is deemed necessary to manage the incidence or severity of treatment-emergent adverse events (TEAEs). Results: [0222] An increase in extracellular adenosine may occur when blocking ENT1 with an ENT1 inhibitor, as ENT1 functions to transport adenosine into the cell. The results indicate an initial increase in plasma adenosine for various doses of compound 1. FIG.6A and 6B. Plasma adenosine increased at all doses at Cmax and at doses ≥ 10 mg BID at trough. FIG. 6A shows results for various cohorts on first exposure to compound 1, and the adenosine signature is measured by mass spectrometry to give the average value as indicated. A maximum adenosine ratio to baseline was seen at 2 hours, which then generally decreased. A similar trend was seen in FIG.6B for the Cycle 1 Day 15 group (BID for 15 days) at Day 15, with the trough being right before dosing. [0223] The data indicates that compound 1 is able to enter tumor and/or bind to tumor cells, and the adenosine-specific signature can be used to measure biological effects of ENT1 inhibitors.

Claims

Attorney Docket No.01330-0108-00PCT CLAIMS We claim: 1. A method of treating a disease or disorder characterized by increased adenosine in a subject in need thereof, comprising administering to the subject with an increased adenosine a therapeutically effective amount of an ENT1 inhibitor. 2. The method of claim 1, comprising identifying the subject has increased adenosine prior to administration of the ENT1 inhibitor. 3. A method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an ENT1 inhibitor, wherein the subject has previously been identified as having increased adenosine. 4. An ENT1 inhibitor for use in the treatment of a disease or disorder in a subject in need thereof, wherein the disease or disorder is characterized by increased adenosine. 5. The ENT1 inhibitor for use of claim 4, wherein the subject was previously identified as having increased adenosine. 6. The method or the ENT1 inhibitor for use of any one of claims 1-5, wherein the adenosine is increased by comparison to a reference level determined in a sample from a subject not affected and/or diagnosed with the disease or disorder. 7. The method or the ENT1 inhibitor for use of any one of claims 1-6, wherein the disease or disorder is cancer. 8. The method or the ENT1 inhibitor for use of any one of claims 1-7, wherein the level of adenosine correlates to expression of at least one gene in an adenosine-specific gene signature. 9. The method or the ENT1 inhibitor for use of any one of claims 1-8, wherein the disease or disorder is characterized by increased or decreased expression of at least one gene in an adenosine-specific gene signature. 10. The method or the ENT1 inhibitor for use of claim 9, wherein the expression of at least one gene in an adenosine-specific gene signature is increased or decreased by comparison to a reference level determined in a sample from a subject not affected and/or diagnosed with the disease or disorder. 11. The method or the ENT inhibitor for use of any one of claims 8-10, wherein the adenosine-specific gene signature comprises at least one of following genes: APOE, CALR, CD63, CD82, CTSB, DMBT1, EIF3G, ENO1, FLNA, FOS, GNAS, Attorney Docket No.01330-0108-00PCT HSPA1B, HSPB1, IFITM3, NDUFS5, NPM1, PPDPF, PTP4A2, RPS27A, SLC25A6, SYNGR2, TESC, TPM1, TXNIP, or YBX3. 12. The method or the ENT inhibitor for use of claim 11, wherein the adenosine-specific gene signature comprises at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or all 25 genes. 13. The method or the ENT1 inhibitor for use of any one of claims 1-12, wherein the ENT1 inhibitor is a compound of Formula (I): or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R1 is selected from the group consisting of 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; Attorney Docket No.01330-0108-00PCT 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 each U is independently selected from the group consisting of -C(O)-, alkylene , -O-, 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. 14. The method or the ENT1 inhibitor for use of any one of claims 1-13, wherein the ENT1 inhibitor is a compound of Formula (II): Attorney Docket No.01330-0108-00PCT 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-; Attorney Docket No.01330-0108-00PCT each U is independently selected from the group consisting of -O-, -N(R3)-, -C(O)O-, 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. 15. The method or the ENT1 inhibitor for use of claim 14, wherein the ENT1 inhibitor is a compound of Formula (IIa): (IIa), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein X is CH2, CHF, or CF2. Attorney Docket No.01330-0108-00PCT 16. The method or the ENT1 inhibitor for use of any one of claims 13-15, wherein R1 is . 17. The method or the ENT1 inhibitor for use of claim 16, wherein R1 is . 18. The method or the ENT1 inhibitor for use of any one of claims 13-17, wherein the compound is a compound of Formula (IIb): or a pharmaceutically acceptable salt, hydrate, or solvate thereof. 19. The method or the ENT1 inhibitor for use of any one of claims 13-18, wherein U is - C(O)O-. 20. The method or the ENT1 inhibitor for use of any one of claims 13, 14, 15, or 17, wherein R4 is Attorney Docket No.01330-0108-00PCT the U in R4 is -C(O)O- or -C(O)NR3-. 21. The method or the ENT1 inhibitor for use of claim 13, wherein the compound is a compound of Formula (IIa1): or a pharmaceutically acceptable salt, hydrate, or solvate thereof. 22. The method or the ENT1 inhibitor according to any one of claims 1-12, 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 Attorney Docket No.01330-0108-00PCT 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 Attorney Docket No.01330-0108-00PCT (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 Attorney Docket No.01330-0108-00PCT (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 Attorney Docket No.01330-0108-00PCT 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 4-methoxy-2-(trifluoromethoxy)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 Attorney Docket No.01330-0108-00PCT 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-dimethylcyclobutane-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-(trifluoromethoxy)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-(difluoromethoxy)benzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,5-dichlorobenzoate Attorney Docket No.01330-0108-00PCT 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4-dichlorobenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 2,3-dichlorobenzoate 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 Attorney Docket No.01330-0108-00PCT 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 Attorney Docket No.01330-0108-00PCT 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)-benzenacyclotetradecaphane-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 Attorney Docket No.01330-0108-00PCT 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. 23. The method or the ENT1 inhibitor for use of claim 22, wherein the ENT1 inhibitor is selected from COMPOUND 1 and pharmaceutically acceptable salts, hydrates, or solvates thereof. 24. The method or the ENT1 inhibitor for use of claim 23, wherein the ENT1 inhibitor is a Compound 1 hydrogen sulfate or a hydrate or solvate thereof. 25. The method or the ENT1 inhibitor for use of claim 24, wherein the ENT1 inhibitor is a Compound 1 di(hydrogen sulfate) or a hydrate or solvate thereof. 26. The method or the ENT1 inhibitor for use of claim 25, wherein the ENT1 inhibitor is a crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate. 27. The method or the ENT1 inhibitor for use of any one of claims 1-26, further comprising administration of an additional therapeutic agent. 28. The method or the ENT1 inhibitor for use of claim 27, wherein the ENT1 inhibitor is administered prior to the additional therapeutic agent. Attorney Docket No.01330-0108-00PCT 29. The method or the ENT1 inhibitor for use of claim 27, wherein the ENT1 inhibitor is administered simultaneously with the additional therapeutic agent. 30. The method or the ENT1 inhibitor for use of claim 27, wherein the ENT1 inhibitor is administered after the additional therapeutic agent. 31. The method or the ENT1 inhibitor for use of any one of claims 1-30, wherein the subject has previously received treatment with an additional therapeutic agent. 32. The method or the ENT1 inhibitor for use of any one of claims 7-31, wherein the cancer is selected from the group consisting of bladder cancer, breast cancer, colorectal cancer, esophageal cancer, stomach cancer, ovarian cancer, and pancreatic cancer.
PCT/IB2025/050979 2024-01-30 2025-01-29 Ent1 inhibitors for use in the treatment of diseases with increased adenosine levels Pending WO2025163520A1 (en)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020065036A1 (en) * 2018-09-27 2020-04-02 Iteos Therapeutics S.A. Use of an inhibitor of an ent family transporter in the treatment of cancer and combination thereof with an adenosine receptor antagonist
WO2021170797A1 (en) 2020-02-26 2021-09-02 iTeos Belgium SA PYRIMIDO[5,4-d]PYRIMIDINE DERIVATIVES AS ENT INHIBITORS FOR THE TREATMENT OF CANCERS, AND COMBINATION THEREOF WITH ADENOSINE RECEPTOR ANTAGONISTS
WO2021204896A1 (en) 2020-04-07 2021-10-14 iTeos Belgium SA Macrocyclic diamine derivatives as ent inhibitors for the treatment of cancers, and combination thereof with adenosine receptor antagonists
WO2023059739A1 (en) 2021-10-06 2023-04-13 iTeos Belgium SA Macrocyclic compounds having ent1 inhibiting activity
WO2023056910A1 (en) * 2021-10-06 2023-04-13 iTeos Belgium SA Processes for preparing a macrocyclic compound having ent1 inhibiting activity
WO2024194392A1 (en) 2023-03-22 2024-09-26 iTeos Belgium SA Multicomponent complexes, including salts and crystalline complexes, of ent1 inhibitors

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020065036A1 (en) * 2018-09-27 2020-04-02 Iteos Therapeutics S.A. Use of an inhibitor of an ent family transporter in the treatment of cancer and combination thereof with an adenosine receptor antagonist
WO2021170797A1 (en) 2020-02-26 2021-09-02 iTeos Belgium SA PYRIMIDO[5,4-d]PYRIMIDINE DERIVATIVES AS ENT INHIBITORS FOR THE TREATMENT OF CANCERS, AND COMBINATION THEREOF WITH ADENOSINE RECEPTOR ANTAGONISTS
WO2021204896A1 (en) 2020-04-07 2021-10-14 iTeos Belgium SA Macrocyclic diamine derivatives as ent inhibitors for the treatment of cancers, and combination thereof with adenosine receptor antagonists
WO2023059739A1 (en) 2021-10-06 2023-04-13 iTeos Belgium SA Macrocyclic compounds having ent1 inhibiting activity
WO2023056910A1 (en) * 2021-10-06 2023-04-13 iTeos Belgium SA Processes for preparing a macrocyclic compound having ent1 inhibiting activity
WO2024194392A1 (en) 2023-03-22 2024-09-26 iTeos Belgium SA Multicomponent complexes, including salts and crystalline complexes, of ent1 inhibitors
WO2024194391A1 (en) 2023-03-22 2024-09-26 iTeos Belgium SA Hydrogen sulfate complexes, including salts, crystalline forms, and hydrates and solvates of ent1 inhibitors

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
FONG ET AL., CANCER DISCOV., vol. 10, no. 1, 2020, pages 40 - 53
MOSER ET AL., AM J PHYSIOL., 1989
SIDDERS ET AL., CLIN CANCER RES., vol. 26, no. 9, 2020, pages 2176 - 2187

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