ENT1 inhibitors in combination with car-t cell therapy

Abstract

Disclosed herein are combinations, methods, and uses comprising administering an ENT1 inhibitor and a CAR-T cell therapy for the treatment of a disease. In some embodiments, the disease is cancer.

Description

Attorney Docket No: 01330-0106-00PCTENT1 INHIBITORS IN COMBINATION WITH CAR-T CELL THERAPYCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Application No. 63 / 736,131, filed December 19, 2024, the entire contents of which are incorporated by reference herein for all purposes.DESCRIPTIONFIELD

[0002] Disclosed herein are combinations, methods, and uses comprising administering an ENT1 inhibitor and a CAR-T cell therapy for the treatment of a disease. In some embodiments, the disease is cancer.BACKGROUND

[0003] T cells are part of the immune system and play a key role in the defense against pathogens that enter the body as well as host cells that have undergone oncogenic transformation. They do so by binding to specific peptide fragments of proteins (called antigens) that are presented in association with major histocompatibility complexes at the cell surface. This triggers T cell activation which can lead to direct killing of the target cell and / or activation or recruitment of additional immune cells which drive the immune response.

[0004] Chimeric antigen receptor (CAR)-T cells are T cells that have been genetically engineered to express a CAR - a combination of antigen-binding domains, most commonly a single-chain variable fragment (scFv) derived from the variable domains of antibodies, with the signaling domains of the TCR^ chain and additional costimulatory domains from receptors such as, but not limited to, CD28, 0X40, and CD137 (June et al., Science, 2018, 359(6382), 1361-1365). The CAR enables major histocompatibility (MHC)-independent target recognition by T cells - enabling the circumvention of loss of MHC-associated antigen presentation as a mechanism of tumor immune escape. Engagement of the CAR-T cell with its antigen leads to T cell activation and ‘serial killing’ of tumor cells (Davenport et al., Cancer Immunology Research, 2015, 3(5), 483-494). Further developments in this field include the ectopic expression of cytokines such as IL- 15 that promote survival, proliferation and effector function of CAR-T cells as well as the presence of inducible ‘suicide’ mechanisms (e.g. expression of caspase 9 upon treatment with a particular small molecule) that allow CAR-T cell numbers to be therapeutically modulated in case of toxicity (Hoyos et al., Leukemia, 2010, 24(6), 1160-1170).Attorney Docket No: 01330-0106-00PCT

[0005] CAR-T cell therapy is a promising treatment for cancer. However, the immunosuppressive nature of tumor microenvironment (TME) is considered to be one of the key factors limiting CAR-T cell efficacy in solid tumor treatment.

[0006] Adenosine is also a potent immunosuppressive metabolite that is often found elevated in the extracellular tumor microenvironment (TME) (Blay J et al., Cancer Res, 1997, 57, 2602-2605). Extracellular adenosine is generated mainly by the conversion of ATP by the ectonucleotidases CD39 and CD73 (Stagg J and Smyth MJ, Oncogene, 2010, 2, 5346- 5358). Adenosine activates four G-protein-coupled receptor subtypes (Al, A2A, A2B, and A3). A2A receptor is believed to be a key driver of CAR-T cell suppression leading to suppression of antitumor responses (Giuffrida et al., Nature Communications, 2021, 12, article no. 3236; Ohta and Sitkovsky, Nature, 2001, 414, 916-920; Stagg and Smyth, Oncogene, 2010, 2, 5346-5358; Antonioli L et al., Nature Reviews Cancer, 2013, 13, 842- 857; Cekic C and Linden J, Nature Reviews, Immunology, 2016, 16, 177-192; Allard B et al., Curr Op Pharmacol, 2016, 29, 7-16; Vijayan D et al., Nature Reviews Cancer, 2017, 17, 709-724).

[0007] The equilibrative nucleoside transporter (ENT) family, also known as SLC29, is a group of plasmalemmal transport proteins which transport nucleosides into cells. There are four known ENTs, designated ENT1, ENT2, ENT3, and ENT4.

[0008] One of the endogenous substrates for ENTs is adenosine, a potent physiological and pharmacological regulator of numerous functions. Cellular signaling by adenosine occurs through four known G-protein-coupled adenosine receptors Al, A2A, A2B, and A3. By influencing the concentration of adenosine available to these receptors, ENTs fulfill important regulatory roles in different physiological processes, such as modulation of coronary blood flow, inflammation, and neurotransmission (Griffith DA and Jarvis SM, Biochim Biophys Acta, 1996, 1286, 153-181; Shryock JC and Belardinelli L, Am J Cardiol, 1997, 79(12A), 2-10; Anderson CM et al., JNeurochem, 1999, 73, 867-873).

[0009] Applicant previously showed that adenosine as well as ATP profoundly suppressed T cell proliferation and cytokine secretion (IL-2), and strongly reduced T cell viability. See WO 2020 / 065036. Adenosine- and ATP-mediated suppression of T cell viability and proliferation were successfully restored using ENT inhibitors. Moreover, the use of an ENT inhibitors with an adenosine receptor antagonist restored not only adenosine- and ATP-mediated suppression of T cell viability and proliferation, but also restored T cellAttorney Docket No: 01330-0106-00PCT cytokine secretion. These results show that ENT inhibitors, either alone or in combination with an adenosine receptor antagonist, may be useful for the treatment of cancer.

[0010] Accordingly, the disclosure herein relates at least in part to the combination of ENT1 inhibitors and CAR-T cell therapies for the treatment of cancer.SUMMARY

[0011] In some embodiments, provided herein is a combination of an ENT1 inhibitor and a CAR-T cell therapy. In some embodiments, the combination is for use in treating cancer.

[0012] In some embodiments, provided herein is a method of treating cancer comprising administering to a subject in need thereof an ENT1 inhibitor and a CAR-T cell therapy.

[0013] In some embodiments, provided herein is a use of an ENT1 inhibitor and a CAR-T cell therapy for the treatment of cancer.

[0014] In some embodiments, the CAR-T cell therapy targets CD19, BCMA, TAG72, B7H3, MUC1, MUC16, or a combination thereof.

[0015] In some embodiments, the ENT1 inhibitor is a compound of Formula (I):or a pharmaceutically acceptable salt, hydrate, or solvate thereof, whereinR1is selected from the group consisting ofAttorney Docket No: 01330-0106-00PCTeach R2is 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 R2are taken together with the atoms on which they are attached to form a heterocyclyl or heteroaryl ring; each R3is independently selected from absent, -H, oxo, ALK, phenyl, heterocyclyl, and heteroaryl;R4is selected from the group consistingeach U is independently selected from the group consisting of -C(O)-, alkylene, -each Rxis independently selected from alkylene;V1is selected from -C(R3)- and -N-; each V2is independently selected from -C(R3)=, -N(R3)-, -N=, and -O-;V3is selected from -C= and -N-; andAttorney Docket No: 01330-0106-00PCTZ is C or N, wherein ALK is unsubstituted alkyl or substituted alkyl, or two instances of ALK may be joined together with their intervening atoms to form a cycloalkyl or heterocyclyl ring.

[0016] In some embodiments, the ENT1 inhibitor is a compound of Formula (II):or a pharmaceutically acceptable salt, hydrate, or solvate thereof, whereinR1is selected from the group consisting of ALK, cycloalkyl, heterocyclyl,each R2is 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 R2are taken together with the atoms on which they are attached to form a heterocyclyl or heteroaryl ring; each R3is independently selected from absent, -H, ALK, phenyl, and heteroaryl;Attorney Docket No: 01330-0106-00PCTX 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 Rxis independently selected from alkylene;V1is selected from -C(R3)- and -N-; each V2is independently selected from -C(R3)=, -N(R3)-, -N=, and -O-;V3is selected from -C= and -N-; each Z is independently C or N; and n1is a number of 0 or 1, wherein ALK is unsubstituted alkyl or substituted alkyl, or two instances of ALK may be joined together with their intervening atoms to form a cycloalkyl or heterocyclyl ring.

[0017] In some embodiments, the ENT1 inhibitor is a compound of Formula (Ila):(Ila), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein X is CH2, CHF, or CF2.

[0018] In some embodiments, in a compound of Formula (I), (II), or (Ila), R1isAttorney Docket No: 01330-0106-00PCT

[0019] In some embodiments, in a compound of Formula (I), (II), or (Ila), R1is

[0020] In some embodiments, the compound is a compound of Formula (lib):or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0021] In some embodiments, in a compound of Formula (I), (II), (Ila), or (lib), U is -C(O)O-.

[0022] In some embodiments, in a compound of Formula (I) or (II), R4isthe U in R4is -C(O)O- or -C(O)NR3-.

[0023] In some embodiments, the compound is a compound of Formula (Ilal):or a pharmaceutically acceptable salt, hydrate, or solvate thereof.Attorney Docket No: 01330-0106-00PCT

[0024] In some embodiments, the ENT1 inhibitor is selected from:(12S)-74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate(12R)-74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate(12S)-16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate(12R)-16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoateN-(74,75)-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane-12-yl)-3,4,5-trimethoxybenzamide74.75-dimethoxy-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate(12S)-74,75-dimethoxy-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate(12R)-74,75-dimethoxy-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate74.75-dimethoxy-5-methyl-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate(12S)-74,75-dimethoxy-5-methyl-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate(12R)-74,75-dimethoxy-5-methyl-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate(HR)-74,75-dimethoxy-6-oxo-5-aza-l(l,4)-diazepana-7(l,3)-benzenacyclotridecaphane-11-yl 3,4,5-trimethoxybenzoate(10S)-14-chloro-2-oxo-l lH-3-aza-l(6,l)-indazola-7(l,4)-diazepanacyclotridecaphane-10-yl 3,4,5-trimethoxybenzoate(10R)-14-chloro-2-oxo-l lH-3-aza-l(6,l)-indazola-7(l,4)-diazepanacyclotridecaphane-10-yl 3,4,5-trimethoxybenzoate(12S)-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoateAttorney Docket No: 01330-0106-00PCT(12R)-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoate(12S)-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl benzoate(12R)-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl benzoate74,75dichloro-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl3,4,5 -trimethoxybenzoate(12S)-74,75-dichloro-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate(12R)-74,75-dichloro-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate75-carbamoyl-74-chloro-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate( 11Z, 16E, 1 OS)- 14-chloro-2-oxo- 12H-3 -aza- 1 (6,2)-indazola-7( 1 ,4)- diazepanacyclotridecaphane- 10-yl 3,4,5-trimethoxybenzoate( 11Z, 16E, 1 OR)- 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-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate(12R)- 74-carbamoyl-75-chloro-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate74-bromo-75-chloro-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate75-chloro-74-cyano-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate(12R)-74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl benzoate(12R)-74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl benzoate(12S)-74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl benzoateAttorney Docket No: 01330-0106-00PCT(Z)-benzaldehyde O-(74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl) oxime12-hydroxy-74,75-dimethoxy-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphan-6-one74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4-hydroxybenzoate74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane- 12-yl 4-fluorobenzoate74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane- 12-yl 4-isopropoxybenzoate74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane- 12-yl 3-(trifluoromethyl)benzoate74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane- 12-yl 3-(methylsulfonyl)benzoate74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3-phenoxybenzoate74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane- 12-yl 2-fluorobenzoate74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane- 12-yl 4-bromo-3 -cyanobenzoate74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane- 12-yl 3-methyl-5-(trifluoromethyl)benzoate74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane- 12-yl 2-fluoro-4-methoxybenzoate74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane- 12-yl 4-methoxy-2-(trifluorom ethoxy )benzoate74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane- 12-yl picolinate74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane- 12-yl nicotinate74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane- 12-yl pyrazine-2-carboxylateAttorney Docket No: 01330-0106-00PCT ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 6-hydroxynicotinate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl quinoline-5-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl oxazole-4-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl lH-l,2,3-triazole-4-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl acetate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl cyclopropanecarboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3-methylbutanoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4,4,4-trifluorobutanoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl cyclohexanecarboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl l-methylpiperidine-4-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3, 3 -dimethylcy cl obutane-1 -carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 2-(oxetan-3-yl)acetate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl (lR,5S,6R)-3-oxabicyclo[3.1.0]hexane-6-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 5-oxopyrrolidine-3-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl l-benzyl-5-oxopyrrolidine-3-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4-m ethoxy cyclohexane- 1 -carboxylateAttorney Docket No: 01330-0106-00PCT ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane- 12-yl 2,6-difluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane- 12-yl 4-(trifluorom ethoxy )benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3 -cyanobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 2-oxo-l,2,3,4-tetrahydroquinoline-6-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3 -(difluorom ethoxy )benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3,5-dichlorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3, 4-di chlorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 2,3 -di chlorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane- 12-yl 2-chloro-6-fluoro-3 -methylbenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3 -fluoro-5 -(trifluoromethyl)benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane- 12-yl 4-fluoro-3 -(trifluoromethyl)benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4-cyano-3 -fluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4-(trifluoromethyl)benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3,5-difluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3,4-difluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3-cyano-4-fluorobenzoateAttorney Docket No: 01330-0106-00PCT ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4-cyanobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3-chloro-4-fluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 1 -methyl- lH-benzo[d]imidazole-5-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4-(oxazol-5-yl)benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4,5-dichloro-2-fluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3,4,5-triethoxybenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3-methoxypropanoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane- 12-yl 3 -( 1 H-pyrazol- 1 -yl)propanoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3-cyanopropanoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4-cyanobutanoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4-acetamidobutanoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane- 12-yl 3 -( 1 H-tetrazol- 1 -yl)propanoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4-(dimethylamino)-4-oxobutanoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3-acetamidopropanoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4-(methylamino)-4-oxobutanoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane- 12-yl 3 -(1H- 1 ,2,4-triazol- 1 -yl)propanoateAttorney Docket No: 01330-0106-00PCT74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4-morpholino-4-oxobutanoate74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3 -(4-fluorophenoxy)propanoate74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4,4-difluorocyclohexane-l -carboxylate74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4-(trifluoromethyl)cyclohexane-l -carboxylate74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3 -(2, 5 -dioxopyrrolidin- 1 -yl)propanoate74.75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3 -m ethoxy cy cl ohexane-1 -carboxylate74.75-dimethoxy-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl benzoate(E)-benzaldehyde O-(74,75-dimethoxy-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl) oxime(E)-benzaldehyde O-((12R)- 74,75-dimethoxy-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(1 ,3 )-benzenacy clotetradecaphane- 12-yl) oxime(E)-benzaldehyde O-((12S)- 74,75-dimethoxy-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl) oxime12-hydroxy-74,75-dimethoxy-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphan-6-one(12R)-12-hydroxy-74,75-dimethoxy-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphan-6-one(12S)-12-hydroxy-74,75-dimethoxy-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphan-6-one74.75-dimethoxy-12-(5-phenyl-2H-tetrazol-2-yl)-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphan-6-one74.75-dimethoxy-12-(4-phenyl-lH-l,2,3-triazol-l-yl)-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphan-6-one74.75-dimethoxy-12-(5-phenyl-lH-tetrazol-l-yl)-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphan-6-one, and pharmaceutically acceptable salts, hydrates, or solvates thereof.Attorney Docket No: 01330-0106-00PCT

[0025] In some embodiments, the compound is selected from (12R)-74,75-dimethoxy- 6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoate (i.e., COMPOUND 1, structure below)COMPOUND 1 and pharmaceutically acceptable salts, hydrates, or solvates thereof. See, e.g., WO 2024 / 194391 and WO 2024 / 194392, the contents of which are incorporated herein by reference in their entirety.

[0026] In some embodiments, the compound is selected from COMPOUND 1 and pharmaceutically acceptable salts thereof.

[0027] In some embodiments, the compound is selected from hydrogen sulfate salts of COMPOUND 1 and hydrates and solvates thereof. See, e.g., WO 2024 / 194391.

[0028] In some embodiments, the compound is Compound 1 di(hydrogen sulfate) or a hydrate or solvate thereof. In some embodiments, the Compound 1 di(hydrogen sulfate) or a hydrate or solvate thereof is crystalline. In some embodiments, the crystalline Compound 1 di(hydrogen sulfate) or a hydrate or solvate thereof is crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate.

[0029] In some embodiments, the ENT1 inhibitor is administered prior to, concomitant with, or subsequent to the administration of the CAR-T cell therapy.

[0030] In some embodiments, the cancer is characterized by a high concentration of adenosine in the tumor microenvironment (TME).

[0031] In some embodiments, the cancer is selected from breast, carcinoid, cervical, colorectal, endometrial, glioma, head and neck, liver, lung, melanoma, ovarian, pancreatic, prostate, renal, gastric, thyroid and urothelial cancers.

[0032] In some embodiments, the cancer is selected from multiple myeloma, lymphoma, leukemia, follicular lymphoma (FL), Non-Hodgkin’s lymphoma (NEIL), diffuseAttorney Docket No: 01330-0106-00PCT large B cell lymphoma (DLBCL), acute lymphocytic (ALL), CD20 positive malignancies, acute myeloid (AML), CD 19 positive cancers, chronic lymphocytic (CLL), and small lymphocytic leukaemia (SLL).

[0033] In some embodiments, the cancer is selected from EGFRvIII positive cancer, neuroblastoma, glioma, mesothelioma, lung cancer, ovarian cancer, breast cancer, hepatocellular carcinoma, HER2 positive cancer, sarcoma including Ewing sarcoma, glioblastoma, mesothelioma, pancreatic cancer, non-small cell lung cancer (NSCLC), MUC1 positive solid tumors, prostate cancer, and PD-L1 positive cancers.

[0034] In some embodiments, the cancer is selected from breast, glioma, lung, ovarian, pancreatic, and prostate.

[0035] In some embodiments, the cancer is breast cancer.

[0036] In some embodiments, the cancer is triple negative breast cancer.

[0037] In some embodiments, the cancer is a solid-tumor cancer.

[0038] Additional objects and advantages will be set forth in part in the description which follows, and in part will be understood from the description, or may be learned by practice. The objects and advantages will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.

[0039] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the claims.DESCRIPTION OF THE EMBODIMENTSI. Definitions

[0040] Unless otherwise defined, all terms of art, notations and other scientific terminology used herein are intended to have the meanings commonly understood by those of skill in the art to which this invention pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a difference over what is generally understood in the art. The techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodologies by those skilled in the art. Standard techniques may be used for chemical synthesis and chemical analysis. As appropriate, procedures involving the use of commercially available kits andAttorney Docket No: 01330-0106-00PCT reagents are generally carried out in accordance with manufacturer-defined protocols and conditions unless otherwise noted.

[0041] For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001.

[0042] Unless otherwise indicated, the following terms have the following meanings:

[0043] As used herein, the singular forms “a,” “an,” and “the” include the plural referents unless the context clearly indicates otherwise. The terms “include,” “such as,” and the like are intended to convey inclusion without limitation, unless otherwise specifically indicated.

[0044] As used herein, the term “comprising” also specifically includes embodiments “consisting of’ and “consisting essentially of’ the recited elements, unless specifically indicated otherwise.

[0045] The term “about” indicates and encompasses an indicated value and a range above and below that value. In certain embodiments, the term “about” indicates the designated value ± 10%, ± 5%, or ± 1%. In certain embodiments, where applicable, the term “about” indicates the designated value(s) ± one standard deviation of that value(s).

[0046] The term “aldehyde” refers to a group -CHO.

[0047] 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.

[0048] The term “alkenylcarbonyl” refers to a group -(C=O)-alkenyl wherein alkenyl is as herein defined.

[0049] The term “alkenylcarbonylamino” refers to a group -NH-(C=O)-alkenyl wherein alkenyl is as herein defined.

[0050] The term “alkoxy” refers to a group -O-alkyl wherein alkyl is as herein defined.

[0051] The term “ALK” or “Aik” or “alk” refers to an alkyl group (hydrocarbyl radical of formula CnH2n+i wherein n is a number greater than or equal to 1) or an alkyl groupAttorney Docket No: 01330-0106-00PCT substituted by, for example, one to four substituents, such as, halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, cycloalkoxy, heterocyclooxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, cycloalkylamino, heterocycloamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or aralkyl, alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio, cycloalkylthio, heterocyclothio, alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido (e.g. SO2NH2), substituted sulfonamido, nitro, cyano, carboxy, carbamyl (e.g. CONH2), substituted carbamyl (e.g. CONH alkyl, CONH aryl, CONH aralkyl or cases where there are two substituents on the nitrogen selected from alkyl, aryl or aralkyl), alkoxycarbonyl, aryl, substituted aryl, guanidino and heterocyclos, such as, indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like. Where noted above, when the substituent is further substituted, it may be substituted with halogen, alkyl, alkoxy, aryl or aralkyl. In some embodiments, ALK is optionally substituted Ci-Cs alkyl.

[0052] In some embodiments, an alkyl group is substituted by OH, alkoxy, CF3, and / or NR2.

[0053] 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.

[0054] The term “alkylaminoalkyl” refers to a group -alkyl-NH-alkyl wherein alkyl is as herein defined.

[0055] The term “alkylaminoalkylaminocarbonyl” refers to a group -(C=O)-NH-alkyl-NH- alkyl wherein alkyl is as herein defined.

[0056] The term “(alkylaminoalkyl)(alkyl)aminocarbonyl” refers to a group -(C=O)-NR1R2wherein R1is an alkyl group and R2is a -alkyl-NH-alkyl group, wherein alkyl is as herein defined.

[0057] The term “alkylaminoalkylcarbonyl” refers to a group -(C=O)-alkyl-NH-alkyl wherein alkyl is as herein defined.

[0058] The term “alkylcarbonyl” refers to a group -(C=O)-alkyl wherein alkyl is as herein defined.

[0059] The term “alkylcarbonylamine” refers to a group -NH-(C=O)-alkyl wherein alkyl is as herein defined.Attorney Docket No: 01330-0106-00PCT

[0060] The term “alkylcarbonyloxyalkyl” refers to a group -alkyl-O-(C=O)-alkyl wherein alkyl is as herein defined.

[0061] The term “alkylheteroaryl” refers to any heteroaryl substituted by an alkyl group wherein alkyl is as herein defined.

[0062] The term “alkyloxyalkyl” refers to a group -alkyl-O-alkyl wherein alkyl is as herein defined.

[0063] The term “alkyloxycarbonyl” refers to a group -(C=O)-O-alkyl wherein alkyl is as herein defined.

[0064] The term “alkylsulfonyl” refers to a group -SCh-alkyl wherein alkyl is as herein defined.

[0065] The term “alkylsulfonylaminoalkyl” refers to a group -alkyl-NH-SCh-alkyl wherein alkyl is as herein defined.

[0066] The term “alkyl sulfonealkyl” refers to a group -alkyl-SCh-alkyl wherein alkyl is as herein defined.

[0067] The term “alkylsulfonimidoyl” refers to a group -S(=O)(=NH)-alkyl wherein alkyl is as herein defined.

[0068] The term “alkylsulfoxide” refers to a group -(S=O)-alkyl wherein alkyl is as herein defined.

[0069] The term “alkylsulfoxidealkyl” refers to a group -alkyl-SO-alkyl wherein alkyl is as herein defined.

[0070] 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— , — CHfCHs) — 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,Attorney Docket No: 01330-0106-00PCT 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.

[0071] 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.

[0072] The term “alkynealkyl” refers to a group -alkyl-alkyne wherein alkyl and alkyne are as herein defined.

[0073] The term “amino” refers to a group -NH2.

[0074] The term “aminoalkyl” refers to a group -alkyl-NH2 wherein alkyl is as herein defined.

[0075] The term “aminoalkylaminocarbonyl” refers to a group -(C=O)-NH-alkyl-NH2 wherein alkyl is as herein defined.

[0076] The term “aminoalkylcarbonylamino” refers to a group -NH-(C=O)-alkyl-NH2 wherein alkyl is as herein defined.

[0077] The term “aminocarbonyl” or “aminocarboxy” refers to a group -(C=O)-NH2.

[0078] The term “(aminocarbonylalkyl)(alkyl)amino” refers to a group -NRXR2wherein R1is an alkyl group and R2is a -alkyl-(C=O)-NH2 group, wherein alkyl is as herein defined.

[0079] The term “aminocarbonylalkylamino” refers to a group -NH-alkyl-(C=O)-NH2 wherein alkyl is as herein defined.

[0080] The term “aminosulfonyl” refers to a group -SO2-NH2.

[0081] 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), typicallyAttorney Docket No: 01330-0106-00PCT 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 naphthal enyl.

[0082] The term “arylalkyl” refers to a group -alkyl-aryl wherein alkyl and aryl are as herein defined.

[0083] The term “aryloxyalkyl” refers to a group -alkyl-O-aryl wherein alkyl and aryl are as herein defined.

[0084] The term “carbonyl” refers to a group -(C=O)-.

[0085] The term “carbonylamino” refers to a group -NH-(C=O)-.

[0086] The term “cycloalkyl” refers to a cyclic alkyl group, that is to say, a monovalent, saturated, or unsaturated hydrocarbyl group having 1 or more cyclic structures. Cycloalkyl includes monocyclic or bicyclic hydrocarbyl groups. Cycloalkyl groups may comprise 3 or more carbon atoms in the ring and, in some embodiments, comprise from 3 to 10 carbon atoms, for example from 3 to 8 carbon atoms. In some embodiments, cycloalkyl is a 5- or 6- membered cycloalkyl. Examples of cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0087] The term “cycloalkyloxy” refers to a group -O-cycloalkyl wherein cycloalkyl is as herein defined.

[0088] The term “dialkylamino” refers to a group -NRXR2wherein R1and R2are both independently alkyl group as herein defined.

[0089] The term “dialkylaminoalkyl” refers to a group -alkyl-NR1R2wherein R1and R2are both independently alkyl group, as herein defined.

[0090] The term “dialkylaminoalkylaminocarbonyl” refers to a group -(C=O)-NH-alkyl- NR1R2wherein R1and R2are both alkyl group, as herein defined.

[0091] The term “dialkylaminoalkylcarbonyl” refers to a group -(C=O)-alkyl-NR1R2wherein R1and R2are both alkyl group, as herein defined.

[0092] The term “dihydroxyalkyl” refers to a group alkyl is as herein defined substituted by two hydroxyl (-OH) groups.

[0093] The term “halo” or “halogen” refers to fluoro, chloro, bromo, or iodo.

[0094] The term “haloalkyl” refers to an alkyl group in which one or more hydrogen atom is replaced by a halogen atom.

[0095] The term “haloalkyloxy” refers to a group -O-haloalkyl wherein alkyl is as herein defined.Attorney Docket No: 01330-0106-00PCT

[0096] 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.

[0097] The term “heteroarylalkyl” refers to a group -alkyl-heteroaryl wherein alkyl and heteroaryl are as herein defined.

[0098] The term “heterocyclyl” or “heterocycle” refers to non-aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3 to 7 member monocyclic, 7 to 11 member bicyclic, or containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom-containing ring. In some embodiments, the heterocyclyl is a 5- or 6- membered heterocyclyl. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from, for example, nitrogen atoms, oxygen atoms and / or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows. The rings of multi-ring heterocycles may be fused, bridged and / or joined through one or more spiro atoms. Non limiting exemplary heterocyclic groups include piperidinyl, piperazinyl, azetidinyl, azocanyl, diazepanyl, diazocanyl, morpholin-4-yl, oxazepanyl, pyrrolidinyl, thiomorpholin-4-yl, tetrahydrofuranyl, tetrahydropyranyl, aziridinyl, oxiranyl, thiiranyl, 2- imidazolinyl, pyrazolidinyl imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, succinimidyl, 3H-indolyl, indolinyl, isoindolinyl, 2H-pyrrolyl,1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, 4H-quinolizinyl, 2-oxopiperazinyl, homopiperazinyl,2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H- pyranyl, 2H-pyranyl, 4H-pyranyl, 3,4-dihydro- 2H-pyranyl, oxetanyl, thietanyl, 3-dioxolanyl, 1,4-dioxanyl, 2,5-dioximidazolidinyl, 2- oxopiperidinyl, 2-oxopyrrolodinyl, indolinyl, tetrahydrothiophenyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, l-oxido-l-thiomorpholin-4-yl, l-dioxido-l-thiomorpholin-4-yl, 1,3- dioxolanyl, 1,4-oxathianyl, 1,4-dithianyl, 1,3,5-trioxanyl, IH-pyrrolizinyl, tetrahydro- 1,1-Attorney Docket No: 01330-0106-00PCT di oxothiophenyl, N-formylpiperazinyl, dihydrotriazolopyrazine, dihydroimidazopyrazine, hexahydropyrrolopyrrole, and hexahydropyrrolopyrazine.

[0099] The term “heterocyclylalkyl” refers to a group -alkyl-heterocyclyl wherein alkyl and heterocyclyl are as herein defined.

[0100] The term “heterocyclylalkylaminocarbonyl” refers to a group -(C=O)-NH- alkyl-heterocyclyl, wherein alkyl and heterocyclyl are as herein defined.

[0101] The term “(heterocyclyl)(alkyl)aminoalkyl” refers to a group -alkyl-NRxR2wherein R1is an alkyl group and R2is a heterocyclyl group, wherein alkyl and heterocyclyl are as herein defined.

[0102] The term “heterocyclylalkyloxyalkyl” refers to a group -alkyl-O-alkyl- heterocyclyl wherein alkyl and heterocyclyl are as herein defined.

[0103] The term “heterocyclylcarbonyl” refers to a group -(C=O)-heterocyclyl wherein heterocyclyl is as herein defined.

[0104] The term “heterocyclyloxy” refers to a group -O-heterocyclyl wherein heterocyclyl is as herein defined.

[0105] The term “heterocyclylsulfonyl” refers to a group - SCh-heterocyclyl wherein heterocyclyl is as herein defined.

[0106] The term “hydroxy” or “hydroxyl” refers to a group -OH.

[0107] The term “hydroxyalkyl” refers to a group -alkyl-OH wherein alkyl is as herein defined.

[0108] The term “hydroxyalkylaminoalkyl” refers to a group -alkyl-NH-alkyl-OH wherein alkyl is as herein defined.

[0109] The term “hydroxy carbonyl” refers to a group -C(=O)-OH wherein carbonyl is as herein defined. In other words, “hydroxycarbonyl” corresponds to a carboxylic acid group.

[0110] The term “oxo” refers to a =0 substituent.

[0111] The term “sulfonylamino” refers to a group -NH-SO2.

[0112] 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.

[0113] 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 chemotherapyAttorney Docket No: 01330-0106-00PCT 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.

[0114] The term “hormone therapy” refers to the use of hormones in medical treatment. In one embodiment, the hormone therapy is oncologic hormone therapy.

[0115] 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.

[0116] The term “immunotherapy” refers to a therapy aiming at inducing and / or enhancing an immune response towards a specific target, for example towards cancer cells. Immunotherapy includes, for example, CAR-T cell therapy, checkpoint inhibitors, checkpoint agonists (also called T-cell agonists), IDO inhibitors, PI3K inhibitors, adenosine receptor inhibitors, adenosine-producing enzymes inhibitors, adoptive transfer, therapeutic vaccines, and combinations thereof.

[0117] The term “CAR” (also known as chimeric antigen receptor, chimeric immunoreceptors, chimeric T cell receptors, and artificial T cell receptors) are recombinant receptors for antigens which redirect the specificity and function of T lymphocytes and / or other immune cells. A CAR is a fusion protein comprising antigen recognition moieties and cell-activation elements.

[0118] The term “CAR-T cell therapy” refers to a type of cancer immunotherapy treatment in which the genes inside a T cell(s) are altered to enable the expression of a chimeric antigen receptor (CAR). The therapy generally involves collecting T cells from a patient or donor, adding a gene for a specific CAR to create a CAR-T cell, growing and multiplying the CAR-T cells, and then administering the CAR-T cells to the patient.Attorney Docket No: 01330-0106-00PCT

[0119] The term “patient” refers to a mammal, such as a human, who / which is awaiting the receipt of, or is receiving medical care, or was / is / will be the object of a medical procedure or is monitored for the development or progression of a disease, such as a cancer.

[0120] The expression “pharmaceutically acceptable” refers to compounds, salts, compositions, dosage forms, and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.

[0121] The expression “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” or “excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the compositions disclosed herein is contemplated. Additional active ingredients can also be incorporated into the compositions.

[0122] The terms “therapeutically effective amount” or “effective amount” or “therapeutically effective dose” or dose of a compound or a composition refer to that amount of the compound or the composition that results in reduction or inhibition of symptoms or a prolongation of survival in a subject (such as a human patient). The results may require multiple doses of the compound or the composition. A therapeutically effective amount may be administered prior to the onset of a disease or disorder for a prophylactic or preventive action. Alternatively, or additionally, a therapeutically effective amount may be administered after initiation of a disease or disorder for a therapeutic action. In one embodiment, the disease or disorder is cancer.

[0123] The term “subject” refers to a mammal, such as a human. In one embodiment, the subject is diagnosed with cancer. In one embodiment, the subject is a patient, such as a human patient, who / which is awaiting the receipt of, or is receiving, medical care or was / is / will be the subject of a medical procedure or is monitored for the development or progression of a disease, such as a cancer. In one embodiment, the subject is a human patient who is treated and / or monitored for the development or progression of a cancer. In one embodiment, the subject is a male. In another embodiment, the subject is a female. In one embodiment, the subject is an adult. In another embodiment, the subject is a child.

[0124] The term “and / or” used herein is to be taken to mean specific disclosure of each of the specified features or components with or without the other. For example, the term “and / or” as used in a phrase such as “A and / or B” herein is intended to include “A and B,”Attorney Docket No: 01330-0106-00PCT“A or B,” “A” (alone), and “B” (alone). Likewise, the term “and / or” as used in a phrase such as “A, B, and / or C” is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).II. Combinations, Methods, and Uses

[0125] Disclosed herein are combinations, methods and uses comprising an ENT1 inhibitor and a CAR-T cell therapy.A. ENT1 Inhibitors

[0126] Applicant observed that activated human T cells took up [3H]adenosine, and this uptake was reduced in the presence of the selective ENT1 inhibitor dilazep, confirming that ENT1 is the dominant transporter involved in adenosine uptake in T cells. These results indicate that T cells increase ENT1 expression upon activation, which could allow uptake of adenosine present in the extracellular environment.

[0127] Applicant engrafted Syngeneic cancer cell lines into wild type (WT) mice and mice in which ENT1 was genetically deleted (ENT 1 -knock-out [KO]). A delay in tumor growth rate was observed for MCA205 (fibrosarcoma), MC38 (colon adenocarcinoma), and Pan02 (pancreatic ductal adenocarcinoma [PDAC]) cells when implanted subcutaneously in ENT1-KO compared to WT mice. Growth of tumors derived from PDAC cells derived from tumors generated in the autochthonous KPC mouse model was also significantly reduced in ENT1-KO versus WT mice. This suppression of tumor growth was associated with an increased proportion of CD8+ T cells within the tumor microenvironment. Quantitative mass spectrometry imaging reveals adenosine concentrations in human tumors up to the range of 100 pM - levels significantly greater than previously demonstrated and consistent with suppression of T cell responses. Accordingly, deletion of ENT 1 may lead to potent control of tumor growth in syngeneic mouse models including KPC, a poorly immunogenic model of pancreatic ductal adenocarcinoma, and is associated with increased CD8+ T cell frequency, proliferation and cytokine production within tumors. Furthermore, ENT1 expression was observed by flow cytometry on human tumor-infiltrating CD8+ T cells.

[0128] In one embodiment, COMPOUND 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof inhibits adenosine uptake into activated human T cells. In some embodiments, COMPOUND 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof inhibits adenosine uptake into activated human T cells with sub-nanomolar potency. In one embodiment, COMPOUND 1 or a pharmaceutically acceptable salt, hydrate, orAttorney Docket No: 01330-0106-00PCT solvate thereof dose-dependently restores CAR-T cell proliferation in the presence of ATP acting as a source of adenosine.

[0129] Any ENT1 inhibitor may be used in the combinations, methods, and uses disclosed herein. In some embodiments, the ENT1 inhibitor is a small molecule, a nucleic acid, a peptide, or an antibody.

[0130] In some embodiments, the ENT1 inhibitor is an ENT1 inhibitor such as those disclosed in WO 2021 / 170797, WO 2021 / 204896, and WO 2023 / 059739, the contents of each being incorporated herein by reference in their entirety.

[0131] In some embodiments, the ENT1 inhibitor is a compound of Formula (I):or a pharmaceutically acceptable salt, hydrate, or solvate thereof, whereinR1is selected from the group consisting ofeach R2is 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 R2are taken together with the atoms on which they are attached to form a heterocyclyl or heteroaryl ring;Attorney Docket No: 01330-0106-00PCT each R3is independently selected from absent, -H, oxo, ALK, phenyl, heterocyclyl, and heteroaryl;R4is selected from the group consistingeach U is independently selected from the group consisting of -C(O)-, alkylene, -each Rxis independently selected from alkylene;V1is selected from -C(R3)- and -N-; each V2is independently selected from -C(R3)=, -N(R3)-, -N=, and -O-;V3is selected from -C= and -N-; andZ 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.

[0132] In some embodiments, the ENT1 inhibitor is a compound of Formula (II):or a pharmaceutically acceptable salt, hydrate, or solvate thereof, whereinR1is selected from the group consisting of ALK, cycloalkyl, heterocyclyl,Attorney Docket No: 01330-0106-00PCTeach R2is 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 R2are taken together with the atoms on which they are attached to form a heterocyclyl or heteroaryl ring; each R3is 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 Rxis independently selected from alkylene;V1is selected from -C(R3)- and -N-; each V2is independently selected from -C(R3)=, -N(R3)-, -N=, and -O-;V3is selected from -C= and -N-; each Z is independently C or N; and n1is 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.Attorney Docket No: 01330-0106-00PCT

[0133] In some embodiments, the ENT1 inhibitor is a compound of Formula (Ila):or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein X is CH2, CHF, or CF2.

[0134] In some embodiments, in a compound of Formula (I), (II), or (Ila), R1is[ n some embodiments, in a compound of Formula (I), (II), or (Ila), R1is

[0136] In some embodiments, the ENT1 inhibitor is a compound of Formula (lib):or a pharmaceutically acceptable salt, hydrate, or solvate thereof.Attorney Docket No: 01330-0106-00PCT

[0137] In some embodiments, in a compound of Formula (I), (II), (Ila), or (lib), U is - C(O)O-.

[0138] In some embodiments, in a compound of Formula (I) or (II), R4isthe U in R4is -C(O)O- or -C(O)NR3-. In some embodiments, U in R4is -C(O)O-. In some embodiments, U in R4is -C(O)NR3-.

[0139] In some embodiments, the ENT1 inhibitor is a compound of Formula (Ilal):or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0140] In some embodiments, the ENT1 inhibitor is selected from (12R)-74,75- dimethoxy-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate (also known as COMPOUND 1, structure below) and pharmaceutically acceptable salts, hydrates, or solvates thereof.COMPOUND 1

[0141] In some embodiments, the ENT1 inhibitor is selected from COMPOUND 1 and pharmaceutically acceptable salts thereof.Attorney Docket No: 01330-0106-00PCT

[0142] 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.

[0143] 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.

[0144] In some embodiments, the ENT1 inhibitor is selected from one of the compounds in Tables 1 A or IB, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.Table laAttorney Docket No: 01330-0106-00PCTAttorney Docket No: 01330-0106-00PCTAttorney Docket No: 01330-0106-00PCTAttorney Docket No: 01330-0106-00PCTAttorney Docket No: 01330-0106-00PCTAttorney Docket No: 01330-0106-00PCTAttorney Docket No: 01330-0106-00PCTAttorney Docket No: 01330-0106-00PCTAttorney Docket No: 01330-0106-00PCTAttorney Docket No: 01330-0106-00PCTAttorney Docket No: 01330-0106-00PCTTable lbAttorney Docket No: 01330-0106-00PCTAttorney Docket No: 01330-0106-00PCTAttorney Docket No: 01330-0106-00PCTAttorney Docket No: 01330-0106-00PCTAttorney Docket No: 01330-0106-00PCTAttorney Docket No: 01330-0106-00PCTAttorney Docket No: 01330-0106-00PCTAttorney Docket No: 01330-0106-00PCTAttorney Docket No: 01330-0106-00PCTAttorney Docket No: 01330-0106-00PCTAttorney Docket No: 01330-0106-00PCTAttorney Docket No: 01330-0106-00PCTAttorney Docket No: 01330-0106-00PCTAttorney Docket No: 01330-0106-00PCTAttorney Docket No: 01330-0106-00PCTAttorney Docket No: 01330-0106-00PCTAttorney Docket No: 01330-0106-00PCTAttorney Docket No: 01330-0106-00PCTAttorney Docket No: 01330-0106-00PCTAttorney Docket No: 01330-0106-00PCTAttorney Docket No: 01330-0106-00PCTAttorney Docket No: 01330-0106-00PCTAttorney Docket No: 01330-0106-00PCTAttorney Docket No: 01330-0106-00PCTAttorney Docket No: 01330-0106-00PCTAttorney Docket No: 01330-0106-00PCT

[0145] 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 isAttorney Docket No: 01330-0106-00PCT dilazep or a salt thereof (including dilazep hydrochloride). In one embodiment, the ENT1 inhibitor is ticagrelor or a salt thereof.

[0146] In some embodiments, the ENT1 inhibitor is selected from dilazep, dipyridamole, NBMPR (nitrobenzylthioinosine), draflazine, STI-571 (Gleevec), ticagrelor, 8MDP, 5 -iodotuberci din, cilostazol, and salts thereof and any mixture thereof. Examples of selective ENT1 inhibitors include NBMPR, STI-571 (Gleevec), ticagrelor, salts thereof and any mixture thereof.

[0147] By means of non-limiting examples, the ENT1 inhibitors be in a form suitable for oral administration, for parenteral administration (such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion), for topical administration (including ocular), for administration by inhalation, by a skin patch, by an implant, by a suppository, etc. Such suitable administration forms - which may be solid, semi-solid or liquid, depending on the manner of administration - as well as the methods and carriers, diluents and excipients for use in the preparation thereof, will be clear to the skilled person; reference is made to the latest edition of Remington's Pharmaceutical Sciences.

[0148] In some embodiments, such preparations include tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, cremes, lotions, soft and hard gelatin capsules, suppositories, drops, sterile injectable solutions and sterile packaged powders (which are usually reconstituted prior to use) for administration as a bolus and / or for continuous administration, which may be formulated with carriers, excipients, and diluents that are suitable per se for such formulations, such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, (sterile) water, methylcellulose, methyl- and propyl-hydroxybenzoates, talc, magnesium stearate, edible oils, vegetable oils and mineral oils or suitable mixtures thereof.

[0149] The ENT1 inhibitors can optionally contain or be mixed with other substances that are commonly used in pharmaceutical compositions, such as lubricating agents, wetting agents, emulsifying and suspending agents, dispersing agents, disintegrants, bulking agents, fillers, preserving agents, sweetening agents, flavoring agents, flow regulators, release agents, etc. They may also be formulated so as to provide rapid, sustained or delayed release of the active compound(s) contained therein.Attorney Docket No: 01330-0106-00PCT

[0150] In general, compositions of ENT1 inhibitors may be prepared according to known methods in pharmaceutical chemistry. Capsules can be prepared by mixing, for example, an ENT1 inhibitor with a suitable carrier or diluent and filling the proper amount of the mixture in capsules. The usual carriers and diluents include, but are not limited to, inert powdered substances such as starch of many different kinds, powdered cellulose, including crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders.

[0151] 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.

[0152] A lubricant might be necessary in a tablet formulation to prevent the tablet and punches from sticking in the dye. The lubricant can be chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils. Tablet disintegrators are substances that swell when wetted to break up the tablet and release the compound. They include starches, clays, celluloses, algins and gums. Com and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cationexchange resins, alginic acid, guar gum, citrus pulp and carboxymethyl cellulose, for example, can be used as well as sodium lauryl sulfate. Tablets can be coated with sugar as a flavor and sealant, or with film-forming protecting agents to modify the dissolution properties of the tablet. The ENT1 inhibitors can also be formulated as chewable tablets, for example, by using substances such as mannitol in the formulation.

[0153] When it is desired to administer an ENT1 inhibitor as a suppository, a base can be used. Cocoa butter may be used as a suppository base, which can be modified by addition of waxes to raise its melting point slightly. Water-miscible suppository bases comprising, for example, polyethylene glycols of various molecular weights are in wide use.

[0154] The effect of the ENT1 inhibitors can be delayed or prolonged by proper formulation. For example, a slowly soluble pellet can be prepared and incorporated in aAttorney Docket No: 01330-0106-00PCT 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.

[0155] In some embodiments, the ENT1 inhibitors are in a unit dosage form, and may be suitably packaged, for example in a box, blister, vial, bottle, sachet, ampoule or in any other suitable single-dose or multi-dose holder or container (which may be properly labeled), optionally with one or more leaflets containing product information and / or instructions for use.

[0156] The ENT1 inhibitor can be administered orally. In one embodiment, when administered orally, the ENT1 inhibitor is administered with a meal and water. In another embodiment, the ENT1 inhibitor is dispersed in water or juice (e.g., apple juice or orange juice) or any other liquid and administered orally as a solution or a suspension.

[0157] The ENT1 inhibitor can also be administered intradermally, intramuscularly, intraperitoneally, percutaneously, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, mucosally, by inhalation, or topically to the ears, nose, eyes, or skin. The mode of administration is left to the discretion of the health-care practitioner and can depend in-part upon the site of the medical condition.B. CAR-T Cell Therapies

[0158] Any CAR-T cell therapy may be used in the combinations, methods, and uses disclosed herein.

[0159] In some embodiments, the CAR-T cell therapy targets CD 19, BCMA, CD22, CD20, CD 138, CD33, CD 123, CD 19, PSMA, FITC-CD19 Ab, IgK, LeY, ROR1, biotin, CD171, EGFRvIII, FAP, FR, Glypican-3, HER2, MUC1, IL13Ra2, mesothelin, NKG2D, PD1, or a combination thereof. In some embodiments, the CAR-T cell therapy targets CD 19, BCMA, TAG72, B7H3, MUC1, MUC16, or a combination thereof. In some embodiments, the CAR-T cell therapy targets CD 19, BCMA, or a combination thereof.

[0160] Examples of CAR-T cell therapies that may be used in accordance with this disclosure include, without being limited to, CAR-T cell therapies with the following targets and CAR structures:Attorney Docket No: 01330-0106-00PCTTable 2: Exemplary CAR-T cell targets for treatment of certain hematological tumorsTable 3: Exemplary CAR-T cell targets for treatment of certain solid tumorsAttorney Docket No: 01330-0106-00PCT

[0161] In some embodiments, the CAR-T cells are administered to the subject via intravenous infusion. In some embodiments, the target dose is 2 x 106cells / kg.Attorney Docket No: 01330-0106-00PCTC. Cancers

[0162] Various cancers are known in the art. Cancers that can be treated using the combinations, methods, and uses described herein include solid cancers and non-solid cancers, especially benign and malignant solid tumors and benign and malignant non-solid tumors. The cancer may be metastatic or non-metastatic. The cancer may be familial or sporadic.

[0163] In some embodiments, the cancer is a solid-tumor cancer. As used herein, the term “solid cancer” encompasses any cancer (also referred to as malignancy) that forms a discrete tumor mass, as opposed to cancers (or malignancies) that diffusely infiltrate a tissue without forming a mass.

[0164] 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 nonseminomas such as teratomas and choriocarcinomas), stromal tumors, germ cell tumors, thyroid cancer (including thyroid adenocarcinoma and medullary carcinoma) and urothelial cancer.

[0165] In another embodiment, the cancer is a non-solid cancer. Examples of non- solid tumors include but are not limited to hematological neoplasms. As used herein, a hematologic neoplasm is a term of art which includes lymphoid disorders, myeloid disorders, and AIDS associated leukemias.

[0166] Lymphoid disorders include but are not limited to acute lymphocytic leukemia and chronic lymphoproliferative disorders (e.g., lymphomas, myelomas such as multiple myeloma, and chronic lymphoid leukemias). Lymphomas include, for example, Hodgkin’s disease, non-Hodgkin’s lymphoma, follicular lymphoma, mantle cell lymphoma, acuteAttorney Docket No: 01330-0106-00PCT lymphoblastic leukemia, and lymphocytic lymphomas. Chronic lymphoid leukemias include, for example, T cell chronic lymphoid leukemias and B cell chronic lymphoid leukemias.

[0167] In some embodiments, the cancer is characterized by a high concentration of adenosine in the tumor microenvironment (TME).

[0168] In some embodiments, the cancer is selected from breast, carcinoid, cervical, colorectal, endometrial, glioma, head and neck, liver, lung, melanoma, ovarian, pancreatic, prostate, renal, gastric, thyroid and urothelial cancers. In some embodiments, the cancer is breast cancer. In some embodiments, the breast cancer is triple negative breast cancer.

[0169] In some embodiments, the ENT1 inhibitor is administered prior to, concomitant with, or subsequent to the administration of the CAR-T cell therapy. In some embodiments, the ENT1 inhibitor is administered prior to administration of the CAR-T cell therapy. In some embodiments, the ENT1 inhibitor is administered concomitant with administration of the CAR-T cell therapy. In some embodiments, the ENT1 inhibitor is administered subsequent to administration of the CAR-T cell therapy.

[0170] Depending on the condition to be treated and the route of administration, the active compound may be administered as a single daily dose, divided over one or more daily doses, or essentially continuously, e.g. using a drip infusion.

[0171] In one embodiment, the subject is receiving or has previously received at least one therapeutic treatment prior to administration of the ENT1 inhibitor and the CAR-T cell therapy. In one embodiment, the therapeutic treatment is selected from chemotherapy, a non- CAR-T cell therapy immunotherapy, radiation therapy, stem cell transplant, hormone therapy, and surgery.

[0172] In one embodiment, the therapeutic treatment is chemotherapy. In one embodiment, the chemotherapy is selected from fludarabine, cyclophosphamide, and a combination thereof.

[0173] In one embodiment, the chemotherapy is an adenosine receptor antagonist (ARA). In one embodiment, the ARA is selected from those disclosed in WO 2018 / 178338. In one embodiment, the ARA is a compound having the following structure:Attorney Docket No: 01330-0106-00PCT and named 5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfmyl)ethoxy)phenyl)piperazin-l- yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e] [ 1 , 2, 4]tri azolof 1 ,5-c]pyrimidin-2(3H)-one.

[0174] In one embodiment, the ARA is selected from 5-amino-3-(2-(4-(2,4-difluoro- 5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-l-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e][l,2,4]triazolo[l,5-c]pyrimidin-2(3H)-one, and pharmaceutically acceptable salt, hydrate, or solvate thereof. In one embodiment, the ARA is (S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2- (methylsulfinyl)ethoxy)phenyl)piperazin-l-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e][l,2,4]triazolo[l,5-c]pyrimidin-2(3H)-one or a pharmaceutically acceptable salt, hydrate, or solvate thereof. In one embodiment, the ARA is (S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2- (methylsulfinyl)ethoxy)phenyl)piperazin-l-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e][l,2,4]triazolo[l,5-c]pyrimidin-2(3H)-one hydrochloride.ENUMERATED EMBODIMENTS

[0175] Embodiment 1. A combination of an ENT1 inhibitor and a CAR-T cell therapy.

[0176] Embodiment 2. A method of treating cancer comprising administering to a subject in need thereof an ENT1 inhibitor and a CAR-T cell therapy.

[0177] Embodiment 3. A use of an ENT1 inhibitor and a CAR-T cell therapy for the treatment of cancer.

[0178] Embodiment 4. The combination, method or use according to any one of Embodiments 1-3, wherein the CAR-T cell therapy targets CD19, BCMA, TAG72, B7H3, MUC1, MUC16, or a combination thereof.

[0179] Embodiment 5. The combination, method or use according to any one of Embodiments 1-4, wherein the ENT1 inhibitor is a compound of Formula (I):or a pharmaceutically acceptable salt, hydrate, or solvate thereof, whereinR1is selected from the group consisting ofAttorney Docket No: 01330-0106-00PCTeach R2is 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 R2are taken together with the atoms on which they are attached to form a heterocyclyl or heteroaryl ring; each R3is independently selected from absent, -H, oxo, ALK, phenyl, heterocyclyl, and heteroaryl;R4is selected from the group consistingeach U is independently selected from the group consisting of -C(O)-, alkylene, -each Rxis independently selected from alkylene;V1is selected from -C(R3)- and -N-; each V2is independently selected from -C(R3)=, -N(R3)-, -N=, and -O-;V3is selected from -C= and -N-; andAttorney Docket No: 01330-0106-00PCTZ 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.

[0180] Embodiment 6. The combination, method or use according to any one of Embodiments 1-5, wherein the ENT1 inhibitor is a compound of Formula (II):or a pharmaceutically acceptable salt, hydrate, or solvate thereof, whereinR1is selected from the group consisting of ALK, cycloalkyl, heterocyclyl,each R2is 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 R2are taken together with the atoms on which they are attached to form a heterocyclyl or heteroaryl ring; each R3is independently selected from absent, -H, ALK, phenyl, and heteroaryl;Attorney Docket No: 01330-0106-00PCTX 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 Rxis independently selected from alkylene;V1is selected from -C(R3)- and -N-; each V2is independently selected from -C(R3)=, -N(R3)-, -N=, and -O-;V3is selected from -C= and -N-; each Z is independently C or N; and n1is 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.

[0181] Embodiment 7. The combination, method or use according toEmbodiment 6, wherein the ENT1 inhibitor is a compound of Formula (Ila):or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein X is CEE, CHF, or CF2.

[0182] Embodiment 8. The combination, method or use according to any one of Embodiments 5-7, whereinAttorney Docket No: 01330-0106-00PCT

[0183] Embodiment 9. The combination, method or use according to

[0184] Embodiment 10. The combination, method or use according to any one of Embodiments 5-9, wherein the compound is a compound of Formula (lib) :or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0185] Embodiment 11. The combination, method or use according to any one of Embodiments 5-10, wherein U is -C(O)O-.

[0186] Embodiment 12. The combination, method or use according to any one of Embodiments 5, 6, 8, and 9, whereinthe U in R4is -C(O)O- or -C(O)NR3-.

[0187] Embodiment 13. The combination, method or use according toEmbodiment 6, wherein the compound is a compound of Formula (Ilal):Attorney Docket No: 01330-0106-00PCTor a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0188] Embodiment 14. The combination, method or use according to any one of Embodiments 1-5, wherein the ENT1 inhibitor is selected from:(12S)-74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate(12R)-74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate(12S)-16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate(12R)-16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoateN-(74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane-12-yl)-3,4,5-trimethoxybenzamide74.75-dimethoxy-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate(12S)-74,75-dimethoxy-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate(12R)-74,75-dimethoxy-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate74.75-dimethoxy-5-methyl-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate(12S)-74,75-dimethoxy-5-methyl-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoateAttorney Docket No: 01330-0106-00PCT(12R)-74,75-dimethoxy-5-methyl-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate(HR)-74,75-dimethoxy-6-oxo-5-aza-l(l,4)-diazepana-7(l,3)-benzenacyclotridecaphane-11-yl 3,4,5-trimethoxybenzoate(10S)-14-chloro-2-oxo-l lH-3-aza-l(6,l)-indazola-7(l,4)-diazepanacyclotridecaphane-10-yl 3,4,5-trimethoxybenzoate(10R)-14-chloro-2-oxo-l lH-3-aza-l(6,l)-indazola-7(l,4)-diazepanacyclotridecaphane-10-yl 3,4,5-trimethoxybenzoate(12S)-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoate(12R)-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoate(12S)-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl benzoate(12R)-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl benzoate74,75dichloro-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl3,4,5 -trimethoxybenzoate(12S)-74,75-dichloro-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate(12R)-74,75-dichloro-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate75-carbamoyl-74-chloro-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate( 11Z, 16E, 1 OS)- 14-chloro-2-oxo- 12H-3 -aza- 1 (6,2)-indazola-7( 1 ,4)- diazepanacyclotridecaphane- 10-yl 3,4,5-trimethoxybenzoate( 11Z, 16E, 1 OR)- 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-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate(12R)- 74-carbamoyl-75-chloro-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoateAttorney Docket No: 01330-0106-00PCT74-bromo-75-chloro-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate75-chloro-74-cyano-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate(12R)-74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl benzoate(12R)-74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl benzoate(12S)-74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl benzoate(Z)-benzaldehyde O-(74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl) oxime12-hydroxy-74,75-dimethoxy-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphan-6-one74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4-hydroxybenzoate74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4-fluorobenzoate74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4-isopropoxybenzoate74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3-(trifluoromethyl)benzoate74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3-(methylsulfonyl)benzoate74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3-phenoxybenzoate74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 2-fluorobenzoate74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4-bromo-3 -cyanobenzoate74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3-methyl-5-(trifluoromethyl)benzoateAttorney Docket No: 01330-0106-00PCT ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane- 12-yl 2-fluoro-4-methoxybenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane- 12-yl 4-methoxy-2-(trifluorom ethoxy )benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl picolinate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl nicotinate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl pyrazine-2-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 6-hydroxynicotinate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl quinoline-5-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl oxazole-4-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl lH-l,2,3-triazole-4-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl acetate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl cyclopropanecarboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3-methylbutanoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4,4,4-trifluorobutanoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl cyclohexanecarboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl l-methylpiperidine-4-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3, 3 -dimethylcy cl obutane-1 -carboxylateAttorney Docket No: 01330-0106-00PCT ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 2-(oxetan-3-yl)acetate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl (lR,5S,6R)-3-oxabicyclo[3.1.0]hexane-6-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 5-oxopyrrolidine-3-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl l-benzyl-5-oxopyrrolidine-3-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane- 12-yl 4-m ethoxy cyclohexane- 1 -carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 2,6-difluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane- 12-yl 4-(trifluorom ethoxy )benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3 -cyanobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 2-oxo-l,2,3,4-tetrahydroquinoline-6-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3 -(difluorom ethoxy )benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3,5-dichlorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3, 4-di chlorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 2,3 -di chlorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 2-chloro-6-fluoro-3 -methylbenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3 -fluoro-5 -(trifluoromethyl)benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane- 12-yl 4-fluoro-3 -(trifluoromethyl)benzoateAttorney Docket No: 01330-0106-00PCT ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4-cyano-3 -fluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4-(trifluoromethyl)benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3,5-difluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3,4-difluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3-cyano-4-fluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4-cyanobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3-chloro-4-fluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 1 -methyl- lH-benzo[d]imidazole-5-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4-(oxazol-5-yl)benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4,5-dichloro-2-fluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3,4,5-triethoxybenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3-methoxypropanoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane- 12-yl 3 -( 1 H-pyrazol- 1 -yl)propanoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3-cyanopropanoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4-cyanobutanoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4-acetamidobutanoateAttorney Docket No: 01330-0106-00PCT74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3 -( 1 H-tetrazol- 1 -yl)propanoate74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4-(dimethylamino)-4-oxobutanoate74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3-acetamidopropanoate74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4-(methylamino)-4-oxobutanoate74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3 -(1H- 1 ,2,4-triazol- 1 -yl)propanoate74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4-morpholino-4-oxobutanoate74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3 -(4-fluorophenoxy)propanoate74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4,4-difluorocyclohexane-l -carboxylate74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4-(trifluoromethyl)cyclohexane-l -carboxylate74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3 -(2, 5 -dioxopyrrolidin- 1 -yl)propanoate74.75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3 -m ethoxy cy cl ohexane-1 -carboxylate74.75-dimethoxy-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl benzoate(E)-benzaldehyde O-(74,75-dimethoxy-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl) oxime(E)-benzaldehyde O-((12R)- 74,75-dimethoxy-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(1 ,3 )-benzenacy clotetradecaphane- 12-yl) oxime(E)-benzaldehyde O-((12S)- 74,75-dimethoxy-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl) oxime12-hydroxy-74,75-dimethoxy-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphan-6-oneAttorney Docket No: 01330-0106-00PCT(12R)-12-hydroxy-74,75-dimethoxy-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphan-6-one(12S)-12-hydroxy-74,75-dimethoxy-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphan-6-one74.75-dimethoxy-12-(5-phenyl-2H-tetrazol-2-yl)-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphan-6-one74.75-dimethoxy-12-(4-phenyl-lH-l,2,3-triazol-l-yl)-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphan-6-one74.75-dimethoxy-12-(5-phenyl-lH-tetrazol-l-yl)-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphan-6-one, and pharmaceutically acceptable salts, hydrates, or solvates thereof.Embodiment 15. The combination, method or use according to Embodiment 14, wherein the compound is selected fromCOMPOUND 1 and pharmaceutically acceptable salts, hydrates, or solvates thereof.

[0189] Embodiment 16. The combination, method or use according to Embodiment 14, wherein the compound is a COMPOUND 1 hydrogen sulfate or a hydrate or solvate thereof.

[0190] Embodiment 17. The combination, method or use according to Embodiment 16, wherein the compound is a COMPOUND 1 di(hydrogen sulfate) or a hydrate or solvate thereof.

[0191] Embodiment 18. The combination, method or use according to Embodiment 17, wherein the compound is crystalline Form 2 COMPOUND 1 di(hydrogen sulfate) trihydrate.Attorney Docket No: 01330-0106-00PCT

[0192] Embodiment 19. The combination, method or use according to any one of Embodiments 1-18, wherein the ENT1 inhibitor is administered prior to, concomitant with, or subsequent to the administration of the CAR-T cell therapy.

[0193] Embodiment 20. The method or use according to any one of Embodiments 2-19, wherein the cancer is characterized by a high concentration of adenosine in the tumor microenvironment (TME).

[0194] Embodiment 21. The method or use according to any one of Embodiments 2-19, wherein the cancer is selected from breast, carcinoid, cervical, colorectal, endometrial, glioma, head and neck, liver, lung, melanoma, ovarian, pancreatic, prostate, renal, gastric, thyroid and urothelial cancers.

[0195] Embodiment 22. The method or use according to any one of Embodiments 2-19, wherein the cancer is selected from multiple myeloma, lymphoma, leukemia, follicular lymphoma (FL), Non-Hodgkin’s lymphoma (NHL), diffuse large B cell lymphoma (DLBCL), acute lymphocytic (ALL), CD20 positive malignancies, acute myeloid (AML), CD 19 positive cancers, chronic lymphocytic (CLL), and small lymphocytic leukaemia (SLL).

[0196] Embodiment 23. The method or use according to any one of Embodiments 2-19, wherein the cancer is selected from EGFRvIII positive cancer, neuroblastoma, glioma, mesothelioma, lung cancer, ovarian cancer, breast cancer, hepatocellular carcinoma, HER2 positive cancer, sarcoma including Ewing sarcoma, glioblastoma, mesothelioma, pancreatic cancer, non-small cell lung cancer (NSCLC), MUC1 positive solid tumors, prostate cancer, and PD-L1 positive cancers.

[0197] Embodiment 24. The method or use according to any one of Embodiments 2-19, wherein the cancer is selected from breast, glioma, lung, ovarian, pancreatic, and prostate.

[0198] Embodiment 25. The method or use according to any one of Embodiments 2-19, wherein the cancer is breast cancer.

[0199] Embodiment 26. The method or use according to Embodiment 25, wherein the breast cancer is triple negative breast cancer.

[0200] Embodiment 27. The method or use according to Embodiments 2-19, wherein the cancer is a solid-tumor cancer.Attorney Docket No: 01330-0106-00PCTEXAMPLESExample 1. Preparation ENT1 Inhibitors

[0201] ENT1 inhibitors of Formula (I), including COMPOUND 1, can be prepared as described in WO 2021 / 204896. (See, e.g., Compound 10.)

[0202] A di(hydrogen sulfate) salt of COMPOUND 1 can be prepared as follows. A sample of COMPOUND 1 and 6 vol. of isopropyl alcohol (IPA) / water (75:25% v / v) were added to a 20 mL scintillation vial. 2.05 mole equivalents of sulfuric acid were added as a solution in 2 vol. of IPA / water (75:35% v / v). The solution was stirred for about one hour at 40°C. The temperature was then cycled between 40°C and 5°C with a 0.1 °C / min ramp and a one hour hold between each step. After about 48 hours of cycling, a clear solution was still observed. Up to 6 vol. of anti-solvent (methyl t-butyl ether) was added to 40°C to facilitate precipitation. The experiment (now a slurry) was further temperature cycled for 24 hours.The solids were then isolated via vacuum filtration and dried under vacuum at about 40°C for 48 hours. The damp and dried solids were subsampled and analyzed by XRPD and shown to be COMPOUND 1 di(hydrogen sulfate) trihydrate. See also, e.g., WO2024 / 194391.EQUIVALENTS

[0203] The foregoing written specification is considered to be sufficient to enable one skilled in the art to practice the embodiments. The foregoing description and Examples detail certain embodiments and describe the best mode contemplated by the inventors. It will be appreciated, however, that no matter how detailed the foregoing may appear in text, the embodiment may be practiced in many ways and should be construed in accordance with the appended claims and any equivalents thereof.

[0204] As used herein, the term about refers to a numeric value, including, for example, whole numbers, fractions, and percentages, whether or not explicitly indicated. The term about generally refers to a range of numerical values (e.g., + / -5- 10% of the recited range) that one of ordinary skill in the art would consider equivalent to the recited value (e.g., having the same function or result). When terms such as at least and about precede a list of numerical values or ranges, the terms modify all of the values or ranges provided in the list. In some instances, the term about may include numerical values that are rounded to the nearest significant figure.

Claims

Attorney Docket No: 01330-0106-00PCTWhat is Claimed is:

1. A combination of an ENT1 inhibitor and a CAR-T cell therapy.

2. A method of treating cancer comprising administering to a subject in need thereof an ENT1 inhibitor and a CAR-T cell therapy.

3. A use of an ENT1 inhibitor and a CAR-T cell therapy for the treatment of cancer.

4. The combination, method or use according to any one of claims 1-3, wherein the CAR-T cell therapy targets CD19, BCMA, TAG72, B7H3, MUC1, MUC16, or a combination thereof.

5. The combination, method or use according to any one of claims 1-4, wherein the ENT1 inhibitor is a compound of Formula (I):or a pharmaceutically acceptable salt, hydrate, or solvate thereof, whereinR1is selected from the group consisting ofeach R2is 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 R2are taken together with the atoms on which they are attached to form a heterocyclyl or heteroaryl ring;Attorney Docket No: 01330-0106-00PCT each R3is independently selected from absent, -H, oxo, ALK, phenyl, heterocyclyl, and heteroaryl;R4is selected from the group consistingeach U is independently selected from the group consisting of -C(O)-, alkylene, -each Rxis independently selected from alkylene;V1is selected from -C(R3)- and -N-; each V2is independently selected from -C(R3)=, -N(R3)-, -N=, and -O-;V3is selected from -C= and -N-; andZ 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.

6. The combination, method or use according to any one of claims 1-5, wherein the ENT1 inhibitor is a compound of Formula (II):or a pharmaceutically acceptable salt, hydrate, or solvate thereof,Attorney Docket No: 01330-0106-00PCT whereinR1is selected from the group consisting of ALK, cycloalkyl, heterocyclyl,each R2is 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 R2are taken together with the atoms on which they are attached to form a heterocyclyl or heteroaryl ring; each R3is 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 Rxis independently selected from alkylene;V1is selected from -C(R3)- and -N-; each V2is independently selected from -C(R3)=, -N(R3)-, -N=, and -O-;V3is selected from -C= and -N-; each Z is independently C or N; and n1is a number of 0 or 1,Attorney Docket No: 01330-0106-00PCT 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.

7. The combination, method or use according to claim 6, wherein the ENT1 inhibitor is a compound of Formula (Ila):or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein X is CH2, CHF, or CF2.

8. The combination, method or use according to any one of claims 5-7, wherein R1is9. The combination, method or use according to claim 8, wherein R1is10. The combination, method or use according to any one of claims 5-9, wherein the compound is a compound of Formula (lib):Attorney Docket No: 01330-0106-00PCTor a pharmaceutically acceptable salt, hydrate, or solvate thereof.

11. The combination, method or use according to any one of claims 5-10, wherein U is -C(O)O-.

12. The combination, method or use according to any one of claims 5, 6, 8, and 9, wherein R4isthe U in R4is -C(O)O- or -C(O)NR3-.

13. The combination, method or use according to claim 6, wherein the compound is a compound of Formula (Ilal):or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

14. The combination, method or use according to any one of claims 1-5, wherein the ENT1 inhibitor is selected from:(12S)-74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoateAttorney Docket No: 01330-0106-00PCT(12R)-74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate(12S)-16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate(12R)-16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoateN-(74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane-12-yl)-3,4,5-trimethoxybenzamide74.75-dimethoxy-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate(12S)-74,75-dimethoxy-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate(12R)-74,75-dimethoxy-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate74.75-dimethoxy-5-methyl-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate(12S)-74,75-dimethoxy-5-methyl-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate(12R)-74,75-dimethoxy-5-methyl-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate(HR)-74,75-dimethoxy-6-oxo-5-aza-l(l,4)-diazepana-7(l,3)-benzenacyclotridecaphane-11-yl 3,4,5-trimethoxybenzoate(10S)-14-chloro-2-oxo-l lH-3-aza-l(6,l)-indazola-7(l,4)-diazepanacyclotridecaphane-10-yl 3,4,5-trimethoxybenzoate(10R)-14-chloro-2-oxo-l lH-3-aza-l(6,l)-indazola-7(l,4)-diazepanacyclotridecaphane-10-yl 3,4,5-trimethoxybenzoate(12S)-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoate(12R)-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoateAttorney Docket No: 01330-0106-00PCT(12S)-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl benzoate(12R)-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl benzoate74,75dichloro-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl3,4,5 -trimethoxybenzoate(12S)-74,75-dichloro-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate(12R)-74,75-dichloro-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate75-carbamoyl-74-chloro-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate( 11Z, 16E, 1 OS)- 14-chloro-2-oxo- 12H-3 -aza- 1 (6,2)-indazola-7( 1 ,4)- diazepanacyclotridecaphane- 10-yl 3,4,5-trimethoxybenzoate( 11Z, 16E, 1 OR)- 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-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate(12R)- 74-carbamoyl-75-chloro-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate74-bromo-75-chloro-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate75-chloro-74-cyano-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate(12R)-74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl benzoate(12R)-74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl benzoate(12S)-74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl benzoate(Z)-benzaldehyde O-(74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl) oximeAttorney Docket No: 01330-0106-00PCT -hydroxy-74,75-dimethoxy-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphan-6-one ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4-hydroxybenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4-fluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4-isopropoxybenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3-(trifluoromethyl)benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3-(methylsulfonyl)benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3-phenoxybenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 2-fluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4-bromo-3 -cyanobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3-methyl-5-(trifluoromethyl)benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 2-fluoro-4-methoxybenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane- 12-yl 4-methoxy-2-(trifluorom ethoxy )benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl picolinate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl nicotinate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl pyrazine-2-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 6-hydroxynicotinateAttorney Docket No: 01330-0106-00PCT ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl quinoline-5-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl oxazole-4-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl lH-l,2,3-triazole-4-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl acetate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl cyclopropanecarboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3-methylbutanoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4,4,4-trifluorobutanoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl cyclohexanecarboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl l-methylpiperidine-4-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3, 3 -dimethylcy cl obutane-1 -carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 2-(oxetan-3-yl)acetate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl (lR,5S,6R)-3-oxabicyclo[3.1.0]hexane-6-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 5-oxopyrrolidine-3-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl l-benzyl-5-oxopyrrolidine-3-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4-m ethoxy cyclohexane- 1 -carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 2,6-difluorobenzoateAttorney Docket No: 01330-0106-00PCT ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane- 12-yl 4-(trifluorom ethoxy )benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane- 12-yl 3 -cyanobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane- 12-yl 2-oxo-l,2,3,4-tetrahydroquinoline-6-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane- 12-yl 3 -(difluorom ethoxy )benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3,5-dichlorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3, 4-di chlorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane- 12-yl 2,3 -di chlorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane- 12-yl 2-chloro-6-fluoro-3 -methylbenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane- 12-yl 3 -fluoro-5 -(trifluoromethyl)benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane- 12-yl 4-fluoro-3 -(trifluoromethyl)benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane- 12-yl 4-cyano-3 -fluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane- 12-yl 4-(trifluoromethyl)benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3,5-difluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane- 12-yl 3,4-difluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane- 12-yl 3-cyano-4-fluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane- 12-yl 4-cyanobenzoateAttorney Docket No: 01330-0106-00PCT ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3-chloro-4-fluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 1 -methyl- lH-benzo[d]imidazole-5-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4-(oxazol-5-yl)benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4,5-dichloro-2-fluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3,4,5-triethoxybenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3-methoxypropanoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane- 12-yl 3 -( 1 H-pyrazol- 1 -yl)propanoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3-cyanopropanoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4-cyanobutanoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4-acetamidobutanoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane- 12-yl 3 -( 1 H-tetrazol- 1 -yl)propanoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4-(dimethylamino)-4-oxobutanoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3-acetamidopropanoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4-(methylamino)-4-oxobutanoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane- 12-yl 3 -(1H- 1 ,2,4-triazol- 1 -yl)propanoate ,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4-morpholino-4-oxobutanoateAttorney Docket No: 01330-0106-00PCT74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3 -(4-fluorophenoxy)propanoate74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4,4-difluorocyclohexane-l -carboxylate74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 4-(trifluoromethyl)cyclohexane-l -carboxylate74,75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3 -(2, 5 -dioxopyrrolidin- 1 -yl)propanoate74.75-dimethoxy-6-oxo-5,8-dioxa-l(l,4)-diazepana-7(l,3)-benzenacyclotetradecaphane-12-yl 3 -m ethoxy cy cl ohexane-1 -carboxylate74.75-dimethoxy-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl benzoate(E)-benzaldehyde O-(74,75-dimethoxy-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl) oxime(E)-benzaldehyde O-((12R)- 74,75-dimethoxy-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(1 ,3 )-benzenacy clotetradecaphane- 12-yl) oxime(E)-benzaldehyde O-((12S)- 74,75-dimethoxy-6-oxo-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphane- 12-yl) oxime12-hydroxy-74,75-dimethoxy-8-oxa-5-aza-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphan-6-one(12R)-12-hydroxy-74,75-dimethoxy-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphan-6-one(12S)-12-hydroxy-74,75-dimethoxy-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphan-6-one74.75-dimethoxy-12-(5-phenyl-2H-tetrazol-2-yl)-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphan-6-one74.75-dimethoxy-12-(4-phenyl-lH-l,2,3-triazol-l-yl)-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphan-6-one74.75-dimethoxy-12-(5-phenyl-lH-tetrazol-l-yl)-5,8-dioxa-l(l,4)-diazepana-7(l,3)- benzenacyclotetradecaphan-6-one, and pharmaceutically acceptable salts, hydrates, or solvates thereof.

15. The combination, method or use according to claim 14, wherein the compound is selectedAttorney Docket No: 01330-0106-00PCTCOMPOUND 1 and pharmaceutically acceptable salts, hydrates, or solvates thereof.

16. The combination, method or use according to claim 14, wherein the compound is a COMPOUND 1 hydrogen sulfate or a hydrate or solvate thereof.

17. The combination, method or use according to claim 16, wherein the compound is a COMPOUND 1 di(hydrogen sulfate) or a hydrate or solvate thereof.

18. The combination, method or use according to claim 17, wherein the compound is crystalline Form 2 COMPOUND 1 di(hydrogen sulfate) trihydrate.

19. The combination, method or use according to any one of claims 1-18, wherein the ENT1 inhibitor is administered prior to, concomitant with, or subsequent to the administration of the CAR-T cell therapy.

20. The method or use according to any one of claims 2-19, wherein the cancer is characterized by a high concentration of adenosine in the tumor microenvironment (TME).

21. The method or use according to any one of claims 2-19, wherein the cancer is selected from breast, carcinoid, cervical, colorectal, endometrial, glioma, head and neck, liver, lung, melanoma, ovarian, pancreatic, prostate, renal, gastric, thyroid and urothelial cancers.

22. The method or use according to any one of claims 2-19, wherein the cancer is selected from multiple myeloma, lymphoma, leukemia, follicular lymphoma (FL), Non-Hodgkin’s lymphoma (NI4L), diffuse large B cell lymphoma (DLBCL), acute lymphocytic (ALL), CD20 positive malignancies, acute myeloid (AML), CD 19 positive cancers, chronic lymphocytic (CLL), and small lymphocytic leukaemia (SLL).

23. The method or use according to any one of claims 2-19, wherein the cancer is selected from EGFRvIII positive cancer, neuroblastoma, glioma, mesothelioma, lung cancer, ovarian cancer, breast cancer, hepatocellular carcinoma, HER2 positive cancer, sarcoma includingAttorney Docket No: 01330-0106-00PCTEwing sarcoma, glioblastoma, mesothelioma, pancreatic cancer, non-small cell lung cancer (NSCLC), MUC1 positive solid tumors, prostate cancer, and PD-L1 positive cancers.

24. The method or use according to any one of claims 2-19, wherein the cancer is selected from breast, glioma, lung, ovarian, pancreatic, and prostate.

25. The method or use according to any one of claims 2-19, wherein the cancer is breast cancer.

26. The method or use according to claim 25, wherein the breast cancer is triple negative breast cancer.

27. The method or use according to claims 2-19, wherein the cancer is a solid-tumor cancer.

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