ENT1 inhibitors in combination with oncolytic viruses and their use in the treatment of cancer

Abstract

Disclosed herein are combinations, compositions, and kits comprising an ENT1 inhibitor and an oncolytic virus. In some embodiments, the ENT1 inhibitor is a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof. Also disclosed herein are methods comprising administering an ENT1 inhibitor and an oncolytic virus as well as uses of an ENT1 inhibitor and an oncolytic virus in the manufacture of a medicament. (I)

Description

Attorney Docket No: 01330-0112-00PCT ENT1 INHIBITORS IN COMBINATION WITH ONCOLYTIC VIRUSES DESCRIPTION CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No.63 / 569,451, filed March 25, 2024, the entire contents of which is incorporated by reference herein for all purposes. FIELD

[0002] Disclosed herein are combinations, compositions, and kits comprising an ENT1 inhibitor and an oncolytic virus. Also disclosed herein are methods comprising administering an ENT1 inhibitor and an oncolytic virus as well as uses of an ENT1 inhibitor and an oncolytic virus in the manufacture of a medicament.

[0003] In some embodiments, the method is a method of treating cancer. In some embodiments, the use is in the manufacture of a medicament for the treatment of cancer. BACKGROUND

[0004] Viruses are particles that infect or enter a cell and then use the cell’s genetic machinery to make copies of themselves, which subsequently spread to surrounding uninfected cells. Viruses can be used to target and attack tumors and activate a robust immune system. These viruses, known as oncolytic viruses, can be naturally occurring or genetically modified. Oncolytic viruses can be engineered to give them advantageous properties, including decreasing their ability to infect healthy cells as well as granting them the ability to deliver therapeutic payloads specifically to tumors and produce immune-boosting molecules once they infect tumor cells. After infection, these oncolytic viruses can cause cancer cells to “burst”—killing the cancer cells and releasing cancer antigens. These antigens can then stimulate immune responses that can seek out and eliminate any remaining tumor cells nearby and potentially anywhere else in the body.

[0005] 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.

[0006] 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,Attorney Docket No: 01330-0112-00PCT 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., J Neurochem, 1999, 73, 867-873).

[0007] Adenosine is 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). In particular, activation of the A2A receptor is believed to be the main driver of innate and adaptive immune cell suppression leading to suppression of antitumor immune responses (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).

[0008] 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 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 cell cytokine secretion. These results show that ENT inhibitors may be useful for the treatment of cancer.

[0009] Passer et al., Cancer Res (2010) 70 (10): 3890–3895, discusses the combination of two specific ENT1 inhibitors (dilazep and dipyridamole) and one specific oncolytic virus (HSV G47Δ) for use against tumor cells, the entire content of which is incorporated herein by reference.

[0010] The disclosure herein shows the combination of ENT1 antagonists and oncolytic viruses for the treatment of cancer. SUMMARY

[0011] In some embodiments, provided herein is a combination of an ENT1 inhibitor and an oncolytic virus.

[0012] In some embodiments, provided herein is a pharmaceutical composition comprising an ENT1 inhibitor and an oncolytic virus.

[0013] In some embodiments, provided herein is a kit of parts comprising an ENT1 inhibitor and an oncolytic virus.Attorney Docket No: 01330-0112-00PCT

[0014] In some embodiments, provided herein is a method of treating cancer comprising administering to a subject in need thereof an ENT1 inhibitor and an oncolytic virus. In some embodiments, provided herein is a use of an ENT1 inhibitor and an oncolytic virus in the manufacture of a medicament for the treatment of cancer.

[0015] In some embodiments, the ENT1 inhibitor is not dilazep, dipyridamole, or a salt thereof.

[0016] In some embodiments, the oncolytic virus is an adenovirus, a vaccinia virus, a reovirus, a coxsackievirus, or a herpes simplex virus.

[0017] In some embodiments, the oncolytic virus is chosen from talimogene laherparepvec (T-VEC, Imlygic®), Oncorine (H101), Reolysin (Reovirus), pexastimogene devacirepvec (JX-594, Pexa-Vec), CG0070, pelareorep (Reolysin®), ONYX-015, coxsackievirus A21 (CVA21, CavatakTM), and JX-963.

[0018] In some embodiments, the ENT1 inhibitor is a compound of Formula (I):or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R1is selected from the group consisting of ,, ; each 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: 01330-0112-00PCT each R3is independently selected from absent, -H, oxo, ALK, phenyl, heterocyclyl, and heteroaryl; R4is selected from the group consisting ,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-; and Z is C or N, wherein ALK is unsubstituted alkyl or substituted alkyl, or two instances of ALK may be joined together with their intervening atoms to form a cycloalkyl or heterocyclyl ring.

[0019] In some embodiments, the ENT1 inhibitor is a compound of Formula (II):or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R1is selected from the group consisting of ALK, cycloalkyl, heterocyclyl,Attorney Docket No: 01330-0112-00PCThalogen, - 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)-, - C, , , , 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.

[0020] In some embodiments, the ENT1 inhibitor is a compound of Formula (IIa):Attorney Docket No: 01330-0112-00PCTor a or solvate thereof, wherein X is CH2, CHF, or CF2.

[0021] In some embodiments, in a compound of Formula (I), (II), or (IIa), R1is some embodiments, in a compound of Formula (I), (II), or (IIa), R1is.

[0023] In some embodiments, the compound is a compound of Formula (IIb):or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0024] In some embodiments, in a compound of Formula (I), (II), (IIa), or (IIb), U is - C(O)O-.Attorney Docket No: 01330-0112-00PCT

[0025] In some embodiments, in a compound of Formula (I) or (II), R4is U in R4is -C(O)O- or -C(O)NR3-.embodiments, the compound is a compound of Formula (IIa1):or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0027] In some embodiments, the compound is selected from: (12S)-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate (12R)-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate 16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate (12S)-16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate (12R)-16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate N-(74,75)-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane- 12-yl)-3,4,5-trimethoxybenzamide 74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate (12S)-74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate (12R)-74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoateAttorney Docket No: 01330-0112-00PCT 74,75-dimethoxy-5-methyl-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate (12S)-74,75-dimethoxy-5-methyl-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate (12R)-74,75-dimethoxy-5-methyl-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate (11R)-74,75-dimethoxy-6-oxo-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotridecaphane-11- yl 3,4,5-trimethoxybenzoate (10S)-14-chloro-2-oxo-11H-3-aza-1(6,1)-indazola-7(1,4)-diazepanacyclotridecaphane-10-yl 3,4,5-trimethoxybenzoate (10R)-14-chloro-2-oxo-11H-3-aza-1(6,1)-indazola-7(1,4)-diazepanacyclotridecaphane-10-yl 3,4,5-trimethoxybenzoate (12S)-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoate (12R)-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoate (12S)-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl benzoate (12R)-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl benzoate 74,75dichloro-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate (12S)-74,75-dichloro-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate (12R)-74,75-dichloro-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate 75-carbamoyl-74-chloro-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate (11Z,16E,10S)-14-chloro-2-oxo-12H-3-aza-1(6,2)-indazola-7(1,4)- diazepanacyclotridecaphane-10-yl 3,4,5-trimethoxybenzoate (11Z,16E,10R)-14-chloro-2-oxo-12H-3-aza-1(6,2)-indazola-7(1,4)- diazepanacyclotridecaphane-10-yl 3,4,5-trimethoxybenzoate (12S)-74-carbamoyl-75-chloro-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoateAttorney Docket No: 01330-0112-00PCT (12R)- 74-carbamoyl-75-chloro-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate 74-bromo-75-chloro-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate 75-chloro-74-cyano-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate (12R)-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl benzoate (12R)-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl benzoate (12S)-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl benzoate (Z)-benzaldehyde O-(74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl) oxime 12-hydroxy-74,75-dimethoxy-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphan- 6-one 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-hydroxybenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-fluorobenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-isopropoxybenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-(trifluoromethyl)benzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-(methylsulfonyl)benzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-phenoxybenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 2-fluorobenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-bromo-3-cyanobenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-methyl-5-(trifluoromethyl)benzoateAttorney Docket No: 01330-0112-00PCT,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 2-fluoro-4-methoxybenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-methoxy-2-(trifluoromethoxy)benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl picolinate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl nicotinate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl pyrazine-2-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 6-hydroxynicotinate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl quinoline-5-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl oxazole-4-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 1H-1,2,3-triazole-4-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl acetate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl cyclopropanecarboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-methylbutanoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4,4,4-trifluorobutanoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl cyclohexanecarboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 1-methylpiperidine-4-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,3-dimethylcyclobutane-1-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 2-(oxetan-3-yl)acetateAttorney Docket No: 01330-0112-00PCT,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl (1R,5S,6R)-3-oxabicyclo[3.1.0]hexane-6-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 5-oxopyrrolidine-3-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 1-benzyl-5-oxopyrrolidine-3-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-methoxycyclohexane-1-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 2,6-difluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-(trifluoromethoxy)benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-cyanobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 2-oxo-1,2,3,4-tetrahydroquinoline-6-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-(difluoromethoxy)benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,5-dichlorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4-dichlorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 2,3-dichlorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 2-chloro-6-fluoro-3-methylbenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-fluoro-5-(trifluoromethyl)benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-fluoro-3-(trifluoromethyl)benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-cyano-3-fluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-(trifluoromethyl)benzoateAttorney Docket No: 01330-0112-00PCT,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,5-difluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4-difluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-cyano-4-fluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-cyanobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-chloro-4-fluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 1-methyl-1H-benzo[d]imidazole-5-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-(oxazol-5-yl)benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4,5-dichloro-2-fluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5-triethoxybenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-methoxypropanoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-(1H-pyrazol-1-yl)propanoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-cyanopropanoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-cyanobutanoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-acetamidobutanoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-(1H-tetrazol-1-yl)propanoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-(dimethylamino)-4-oxobutanoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-acetamidopropanoateAttorney Docket No: 01330-0112-00PCT 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-(methylamino)-4-oxobutanoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-(1H-1,2,4-triazol-1-yl)propanoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-morpholino-4-oxobutanoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-(4-fluorophenoxy)propanoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4,4-difluorocyclohexane-1-carboxylate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-(trifluoromethyl)cyclohexane-1-carboxylate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-(2,5-dioxopyrrolidin-1-yl)propanoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-methoxycyclohexane-1-carboxylate 74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane- 12-yl benzoate (E)-benzaldehyde O-(74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl) oxime (E)-benzaldehyde O-((12R)- 74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl) oxime (E)-benzaldehyde O-((12S)- 74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl) oxime 12-hydroxy-74,75-dimethoxy-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one (12R)-12-hydroxy-74,75-dimethoxy-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one (12S)-12-hydroxy-74,75-dimethoxy-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one 74,75-dimethoxy-12-(5-phenyl-2H-tetrazol-2-yl)-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one 74,75-dimethoxy-12-(4-phenyl-1H-1,2,3-triazol-1-yl)-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-oneAttorney Docket No: 01330-0112-00PCT 74,75-dimethoxy-12-(5-phenyl-1H-tetrazol-1-yl)-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one, and pharmaceutically acceptable salts, hydrates, or solvates thereof.

[0028] In some embodiments, the ENT1 inhibitor is selected from (12R)-74,75- dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoate (i.e., Compound 1, structure below)Compound 1 and pharmaceutically acceptable salts, hydrates, and solvates thereof.

[0029] In some embodiments, the ENT1 inhibitor is selected from Compound 1 and pharmaceutically acceptable salts thereof.

[0030] In some embodiments, the ENT1 inhibitor is Compound 1 hydrogen sulfate or a hydrate or solvate thereof.

[0031] 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.

[0032] In some embodiments, the ENT1 inhibitor is administered prior to, concomitant with, or subsequent to the administration of the oncolytic virus.

[0033] In some embodiments, the cancer is characterized by a high concentration of adenosine in the tumor microenvironment (TME).

[0034] In some embodiments, the cancer is selected from breast, carcinoid, cervical, colorectal, endometrial, glioma, glioblastoma, head and neck, liver, espohageal, lung, melanoma, ovarian, pancreatic, prostate, renal, gastric, thyroid and urothelial cancers.

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

[0036] In some embodiments, the cancer is a solid-tumor cancer.Attorney Docket No: 01330-0112-00PCT

[0037] In some embodiments, the cancer is selected from melanoma, prostate cancer, glioblastoma, and esophageal carcinoma.

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

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

[0040] Figure 1A shows an XRPD pattern of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate.

[0041] Figure 1B shows a peak picked XRPD pattern of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate.

[0042] Figure 2 shows XRPD patterns of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate as prepared in Example 1 – damp and dried samples – compared to an exemplary pattern for crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate.

[0043] Figure 3 shows TG / DSC results of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate prepared in Example 1.

[0044] Figure 4 shows a DSC thermogram of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate prepared in Example 1.

[0045] Figure 5 shows a1H-NMR spectrum of dissolved crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate prepared in Example 1, compared to an exemplary spectrum of dissolved Compound 1 (free base).

[0046] Figure 6 shows a DVS isothermal plot for crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate prepared in Example 1.

[0047] Figure 7 shows a DVS kinetic plot for crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate prepared in Example 1.

[0048] Figure 8 shows an XRPD patterns of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate prepared according to Example 2, compared to an exemplary pattern of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate.

[0049] Figure 9 shows a Raman Spectrum of a sample of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate prepared according to Example 2.Attorney Docket No: 01330-0112-00PCT

[0050] Figure 10 shows XRPD patterns of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate prepared according to Example 3 - damp, dried, and after moisture equilibration samples - compared to an exemplary XRPD pattern and an exemplary simulated single crystal XRPD of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate.

[0051] Figure 11 shows PLM images of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate samples prepared according to Example 3 - damp, dried, and after moisture equilibration.

[0052] Figure 12 shows an overlay of Particle Size Distributions of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate prepared according to Example 3 at 4.33% and 6.07% water contents.

[0053] Figure 13 shows TG / DSC data of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate prepared according to Example 3.

[0054] Figure 14 shows a DSC thermogram of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate prepared according to Example 3.

[0055] Figure 15 shows a1H-NMR spectrum of dissolved crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate prepared according to Example 3.

[0056] Figure 16 shows an FT-Infrared spectrum of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate prepared according to Example 3.

[0057] Figure 17 shows a Single Crystal Structure Drawing of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate at 100 K – orientation 1.

[0058] Figure 18 shows Single Crystal Structure Drawing of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate at 100 K – orientation 2.

[0059] Figure 19 shows simulated XRPD patterns for crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate from crystallographic data obtained at 100 K and 295 K.

[0060] Figure 20 shows stacked plots of simulated XRPD patterns from crystallographic data obtained at 100 K and 295 K (bottom two patterns) along with the experimental XRPD for crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate at 298 K (top pattern).

[0061] Figure 21 shows XRPD patterns taken during the experiments relating to crystalline Compound 1 as described in Example 5, compared to exemplary patterns of Compound 1 Form 1 and Compound 1 Form 2.

[0062] Figure 22 shows an XRPD pattern of crystalline Form 1 Compound 1, as prepared in Example 5.

[0063] Figure 23 shows an XRPD pattern of crystalline Form 2 Compound 1, as prepared in Example 5.Attorney Docket No: 01330-0112-00PCT

[0064] Figure 24 shows XRPD patterns of the results of the DVS experiment described in Example 5 on crystalline Form 1 Compound 1 compared to the input material.

[0065] Figure 25 an XRPD pattern of amorphous Compound 1 di(hydrogen sulfate) prepared according to Example 6B. DESCRIPTION OF THE EMBODIMENTS I. Definitions

[0066] Unless otherwise defined, all terms of art, notations and other scientific terminology used herein are intended to have the meanings commonly understood by those of skill in the art to which this invention pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a difference over what is generally understood in the art. The techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodologies by those skilled in the art. Standard techniques may be used for chemical synthesis and chemical analysis. As appropriate, procedures involving the use of commercially available kits and reagents are generally carried out in accordance with manufacturer-defined protocols and conditions unless otherwise noted.

[0067] 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, Μ. B. and March, J., John Wiley & Sons, New York: 2001.

[0068] Unless otherwise indicated, the following terms have the following meanings:

[0069] 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.

[0070] As used herein, the term “comprising” also specifically includes embodiments “consisting of” and “consisting essentially of” the recited elements, unless specifically indicated otherwise.

[0071] 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).

[0072] The term “aldehyde” refers to a group –CHO.Attorney Docket No: 01330-0112-00PCT

[0073] 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.

[0074] The term “alkenylcarbonyl” refers to a group –(C=O)-alkenyl wherein alkenyl is as herein defined.

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

[0076] The term “alkoxy” refers to a group –O-alkyl wherein alkyl is as herein defined.

[0077] The term “ALK” or “Alk” or “alk” refers to an alkyl group (hydrocarbyl radical of formula CnH2n+1 wherein n is a number greater than or equal to 1) or an alkyl group substituted by, for example, one to four substituents, such as, halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, cycloalkoxy, heterocyclooxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, cycloalkylamino, heterocycloamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or aralkyl, alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio, cycloalkylthio, heterocyclothio, alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido (e.g. SO2NH2), substituted sulfonamido, nitro, cyano, carboxy, carbamyl (e.g. CONH2), substituted carbamyl (e.g. CONH alkyl, CONH aryl, CONH aralkyl or cases where there are two substituents on the nitrogen selected from alkyl, aryl or aralkyl), alkoxycarbonyl, aryl, substituted aryl, guanidino and heterocyclos, such as, indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like. Where noted above, when the substituent is further substituted, it may be substituted with halogen, alkyl, alkoxy, aryl or aralkyl. In some embodiments, ALK is optionally substituted C1-C8 alkyl.

[0078] In some embodiments, an alkyl group is substituted by OH, alkoxy, CF3, and / or NR2.

[0079] 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.

[0080] The term “alkylaminoalkyl” refers to a group –alkyl-NH-alkyl wherein alkyl is as herein defined.

[0081] The term “alkylaminoalkylaminocarbonyl” refers to a group –(C=O)-NH-alkyl-NH-alkyl wherein alkyl is as herein defined.Attorney Docket No: 01330-0112-00PCT

[0082] 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.

[0083] The term “alkylaminoalkylcarbonyl” refers to a group –(C=O)-alkyl-NH-alkyl wherein alkyl is as herein defined.

[0084] The term “alkylcarbonyl” refers to a group –(C=O)-alkyl wherein alkyl is as herein defined.

[0085] The term “alkylcarbonylamine” refers to a group –NH-(C=O)-alkyl wherein alkyl is as herein defined.

[0086] The term “alkylcarbonyloxyalkyl” refers to a group –alkyl-O-(C=O)-alkyl wherein alkyl is as herein defined.

[0087] The term “alkylheteroaryl” refers to any heteroaryl substituted by an alkyl group wherein alkyl is as herein defined.

[0088] The term “alkyloxyalkyl” refers to a group –alkyl-O-alkyl wherein alkyl is as herein defined.

[0089] The term “alkyloxycarbonyl” refers to a group –(C=O)-O-alkyl wherein alkyl is as herein defined.

[0090] The term “alkylsulfonyl” refers to a group –SO2-alkyl wherein alkyl is as herein defined.

[0091] The term “alkylsulfonylaminoalkyl” refers to a group –alkyl-NH-SO2-alkyl wherein alkyl is as herein defined.

[0092] The term “alkylsulfonealkyl” refers to a group –alkyl–SO2-alkyl wherein alkyl is as herein defined.

[0093] The term “alkylsulfonimidoyl” refers to a group –S(=O)(=NH)-alkyl wherein alkyl is as herein defined.

[0094] The term “alkylsulfoxide” refers to a group –(S=O)-alkyl wherein alkyl is as herein defined.

[0095] The term “alkylsulfoxidealkyl” refers to a group –alkyl-SO-alkyl wherein alkyl is as herein defined.

[0096] The term “alkylene,” as used herein, refers to an alkyl group, as defined above, wherein one of the alkyl group's hydrogen atoms has been replaced with a bond. Alkylene groups possess two points of attachment. Non-limiting examples of alkylene groups include —CH2—, — CH2CH2—, —CH2CH2CH2—, —CH2CH2CH2CH2—, —CH(CH3)CH2CH2—, —CH(CH3)— and CH2CH(CH3)CH2—. In one embodiment, an alkylene group has from 1 to about 6 carbon atoms. In another embodiment, an alkylene group has from about 3 to about 5 carbon atoms. In another embodiment, an alkylene group is branched. In another embodiment, an alkylene groupAttorney Docket No: 01330-0112-00PCT is linear. In one embodiment, an alkylene group is —CH2—. In one embodiment, at least one hydrogen atom of an alkylene group is substituted by a substituent such as halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, cycloalkoxy, heterocyclooxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, cycloalkylamino, heterocycloamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or aralkyl, alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio, cycloalkylthio, heterocyclothio, alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido (e.g. SO2NH2), substituted sulfonamido, nitro, cyano, carboxy, carbamyl (e.g. CONH2), substituted carbamyl (e.g. CONH alkyl, CONH aryl, CONH aralkyl or cases where there are two substituents on the nitrogen selected from alkyl, aryl or aralkyl), alkoxycarbonyl, aryl, substituted aryl, guanidino and heterocyclos, such as, indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like. Where noted above, when the substituent is further substituted, it may be substituted with halogen, alkyl, alkoxy, aryl or aralkyl. In another embodiment, at least one hydrogen atom of an alkylene group is substituted by -OH, alkoxy, -CF3, or -NR2.

[0097] 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.

[0098] The term “alkynealkyl” refers to a group –alkyl-alkyne wherein alkyl and alkyne are as herein defined.

[0099] The term “amino” refers to a group –NH2.

[0100] The term “aminoalkyl” refers to a group –alkyl-NH2 wherein alkyl is as herein defined.

[0101] The term “aminoalkylaminocarbonyl” refers to a group –(C=O)-NH-alkyl-NH2wherein alkyl is as herein defined.

[0102] The term “aminoalkylcarbonylamino” refers to a group –NH-(C=O)-alkyl-NH2 wherein alkyl is as herein defined.

[0103] The term “aminocarbonyl” or “aminocarboxy” refers to a group –(C=O)-NH2.

[0104] The term “(aminocarbonylalkyl)(alkyl)amino” refers to a group –NR1R2wherein R1is an alkyl group and R2is a –alkyl-(C=O)-NH2 group, wherein alkyl is as herein defined.

[0105] The term “aminocarbonylalkylamino” refers to a group –NH-alkyl-(C=O)-NH2wherein alkyl is as herein defined.Attorney Docket No: 01330-0112-00PCT

[0106] The term “aminosulfonyl” refers to a group –SO2-NH2.

[0107] The term “aryl” refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring (i.e. phenyl) or multiple aromatic rings fused together (e.g. naphtyl), typically containing 5 to 12 atoms; for example, 5 to 10 atoms. In some embodiments, the aryl is a 5- or 6-membered aryl. Non-limiting examples of aryl include phenyl and naphthalenyl.

[0108] The term “arylalkyl” refers to a group –alkyl–aryl wherein alkyl and aryl are as herein defined.

[0109] The term “aryloxyalkyl” refers to a group –alkyl-O-aryl wherein alkyl and aryl are as herein defined.

[0110] The term “carbonyl” refers to a group –(C=O)–.

[0111] The term “carbonylamino” refers to a group –NH-(C=O)–.

[0112] 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.

[0113] The term “cycloalkyloxy” refers to a group –O-cycloalkyl wherein cycloalkyl is as herein defined.

[0114] The term “dialkylamino” refers to a group –NR1R2wherein R1and R2are both independently alkyl group as herein defined.

[0115] The term “dialkylaminoalkyl” refers to a group –alkyl-NR1R2wherein R1and R2are both independently alkyl group, as herein defined.

[0116] The term “dialkylaminoalkylaminocarbonyl” refers to a group –(C=O)-NH-alkyl- NR1R2wherein R1and R2are both alkyl group, as herein defined.

[0117] The term “dialkylaminoalkylcarbonyl” refers to a group –(C=O)-alkyl-NR1R2wherein R1and R2are both alkyl group, as herein defined.

[0118] The term “dihydroxyalkyl” refers to a group alkyl is as herein defined substituted by two hydroxyl (–OH) groups.

[0119] The term “halo” or “halogen” refers to fluoro, chloro, bromo, or iodo.

[0120] The term “haloalkyl” refers to an alkyl group in which one or more hydrogen atom is replaced by a halogen atom.

[0121] The term “haloalkyloxy” refers to a group –O-haloalkyl wherein alkyl is as herein defined.Attorney Docket No: 01330-0112-00PCT

[0122] 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.

[0123] The term “heteroarylalkyl” refers to a group –alkyl–heteroaryl wherein alkyl and heteroaryl are as herein defined.

[0124] The term “heterocyclyl” or “heterocycle” refers to non-aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3 to 7 member monocyclic, 7 to 11 member bicyclic, or containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom-containing ring. In some embodiments, the heterocyclyl is a 5- or 6- membered heterocyclyl. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from, for example, nitrogen atoms, oxygen atoms and / or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows. The rings of multi- ring heterocycles may be fused, bridged and / or joined through one or more spiro atoms. Non limiting exemplary heterocyclic groups include piperidinyl, piperazinyl, azetidinyl, azocanyl, diazepanyl, diazocanyl, morpholin-4-yl, oxazepanyl, pyrrolidinyl, thiomorpholin-4-yl, tetrahydrofuranyl, tetrahydropyranyl,aziridinyl, oxiranyl, thiiranyl, 2-imidazolinyl, pyrazolidinyl imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, succinimidyl, 3H-indolyl, indolinyl, isoindolinyl, 2H-pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3- pyrrolinyl, 4H-quinolizinyl, 2-oxopiperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H- pyranyl, 2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, oxetanyl, thietanyl, 3- dioxolanyl, 1,4-dioxanyl, 2,5-dioximidazolidinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, indolinyl, tetrahydrothiophenyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, 1-oxido-1-thiomorpholin-4- yl, 1-dioxido-1-thiomorpholin-4-yl, 1,3-dioxolanyl, 1,4-oxathianyl, 1,4-dithianyl, 1,3,5- trioxanyl, 1H-pyrrolizinyl, tetrahydro-1,1-dioxothiophenyl, N-formylpiperazinyl, dihydrotriazolopyrazine, dihydroimidazopyrazine, hexahydropyrrolopyrrole, and hexahydropyrrolopyrazine.Attorney Docket No: 01330-0112-00PCT

[0125] The term “heterocyclylalkyl” refers to a group –alkyl–heterocyclyl wherein alkyl and heterocyclyl are as herein defined.

[0126] The term “heterocyclylalkylaminocarbonyl” refers to a group –(C=O)-NH-alkyl- heterocyclyl, wherein alkyl and heterocyclyl are as herein defined.

[0127] The term “(heterocyclyl)(alkyl)aminoalkyl” refers to a group –alkyl-NR1R2wherein R1is an alkyl group and R2is a heterocyclyl group, wherein alkyl and heterocyclyl are as herein defined.

[0128] The term “heterocyclylalkyloxyalkyl” refers to a group –alkyl-O-alkyl– heterocyclyl wherein alkyl and heterocyclyl are as herein defined.

[0129] The term “heterocyclylcarbonyl” refers to a group –(C=O)-heterocyclyl wherein heterocyclyl is as herein defined.

[0130] The term “heterocyclyloxy” refers to a group –O-heterocyclyl wherein heterocyclyl is as herein defined.

[0131] The term “heterocyclylsulfonyl” refers to a group – SO2-heterocyclyl wherein heterocyclyl is as herein defined.

[0132] The term “hydroxy” or “hydroxyl” refers to a group –OH.

[0133] The term “hydroxyalkyl” refers to a group –alkyl-OH wherein alkyl is as herein defined.

[0134] The term “hydroxyalkylaminoalkyl” refers to a group –alkyl-NH-alkyl-OH wherein alkyl is as herein defined.

[0135] The term “hydroxycarbonyl” refers to a group –C(=O)-OH wherein carbonyl is as herein defined. In other words, “hydroxycarbonyl” corresponds to a carboxylic acid group.

[0136] The term “oxo” refers to a =O substituent.

[0137] The term “sulfonylamino” refers to a group –NH-SO2.

[0138] 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.

[0139] The term “oncolytic virus” refers to a virus that replicates selectively in a proliferative cell (such as a cancer cell), with the aim of slowing the growth and / or lysing the proliferative cell. These include viruses that naturally preferentially replicate and accumulate in such cells as well as viruses that have been engineered to do so.

[0140] The term “chemotherapy” refers to a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents) as part of a standardized chemotherapy regimen. Chemotherapy may be given with a curative intent or it may aim to prolong life or toAttorney Docket No: 01330-0112-00PCT 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.

[0141] The term “hormone therapy” refers to the use of hormones in medical treatment. In one embodiment, the hormone therapy is oncologic hormone therapy.

[0142] 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.

[0143] The term “immunotherapy” refers to a therapy aiming at inducing and / or enhancing an immune response towards a specific target, for example towards cancer cells. Immunotherapy may involve the use of 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.

[0144] 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.

[0145] 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.

[0146] 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.

[0147] 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 aAttorney Docket No: 01330-0112-00PCT 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.

[0148] 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.

[0149] The term “and / or” used herein is to be taken to mean specific disclosure of each of the specified features or components with or without the other. For example, the term “and / or” as used in a phrase such as “A and / or B” herein is intended to include “A and B,” “A or B,” “A” (alone), and “B” (alone). Likewise, the term “and / or” as used in a phrase such as “A, B, and / or C” is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone). II. Combinations, Compositions, Kits, Methods and Uses

[0150] Disclosed herein are combinations, compositions, and kits comprising an ENT1 inhibitor and an oncolytic virus. Disclosed herein are methods and uses comprising an ENT1 inhibitor and an oncolytic virus. Disclosed herein are methods and uses comprising a combination, composition, or kit as described herein. A. ENT1 Inhibitors

[0151] Any ENT1 inhibitor may be used in the combinations, compositions, kits, methods, and uses disclosed herein. In some embodiments, the ENT1 inhibitor is a small molecule, a nucleic acid, a peptide, or an antibody.

[0152] In some embodiments, the ENT1 inhibitor is not dilazep, dipyridamole, or a salt thereof.

[0153] 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.Attorney Docket No: 01330-0112-00PCT

[0154] In some embodiments, the ENT1 inhibitor is a compound of Formula (I): or asolvate thereof, wherein R1is selected from the group consisting of ,each 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; 4R the group consisting , ,and ;Attorney Docket No: 01330-0112-00PCT each U is independently selected from the group consisting of -C(O)-, 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-; and Z is C or N, wherein ALK is unsubstituted alkyl or substituted alkyl, or two instances of ALK may be joined together with their intervening atoms to form a cycloalkyl or heterocyclyl ring.

[0155] In some embodiments, the ENT1 inhibitor is a compound of Formula (II):or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R1is 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;Attorney Docket No: 01330-0112-00PCT each R3is independently selected from absent, -H, ALK, phenyl, and heteroaryl; ;, , ; each U is independently selected from the group consisting of -O-, -N(R3)-, - C 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.

[0156] In some embodiments, the ENT1 inhibitor is a compound of Formula (IIa):, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein X is CH2, CHF, or CF2.Attorney Docket No: 01330-0112-00PCT

[0157] In some embodiments, in a compound of Formula (I), (II), or (IIa), R1is some embodiments, in a compound of Formula (I), (II), or (IIa), R1is

[0159] In some embodiments, the ENT1 inhibitor is a compound of Formula (IIb):or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0160] In some embodiments, in a compound of Formula (I), (II), (IIa), or (IIb), U is - C(O)O-.

[0161] In some embodiments, in a compound of Formula (I) or (II), R4isU 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-.Attorney Docket No: 01330-0112-00PCT

[0162] In some embodiments, the ENT1 inhibitor is a compound of Formula (IIa1):or a pharmaceutically

[0163] In some embodiments, the ENT1 inhibitor is selected from (12R)-74,75- dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoate (also known as Compound 1, structure below) and pharmaceutically acceptable salts, hydrates, or solvates thereof.Compound 1

[0164] In some embodiments, the ENT1 inhibitor is selected from (12R)-74,75- dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoate (Compound 1) and pharmaceutically acceptable salts, hydrates, or solvates thereof.

[0165] In some embodiments, the ENT1 inhibitor is a hydrogen sulfate of Compound 1 (“Compound 1 hydrogen sulfate”) or a hydrate or solvate thereof. See, e.g., WO 2024 / 194381. In some embodiments, the hydrogen sulfate of Compound 1 or a hydrate or solvate thereof is a hydrate. In some embodiments, the hydrogen sulfate of Compound 1 or a hydrate or solvate thereof is a di(hydrogen sulfate) (“Compound 1 di(hydrogen sulfate)”) or a hydrate or solvate thereof, and in some embodiments, the hydrogen sulfate of Compound 1 di(hydrogen sulfate) or a hydrate or solvate thereof is a trihydrate.Attorney Docket No: 01330-0112-00PCT

[0166] In some embodiments, the Compound 1 hydrogen sulfate or a hydrate or solvate thereof is a crystalline hydrogen sulfate such as a crystalline mono(hydrogen sulfate) or a crystalline di(hydrogen sulfate) or a hydrate or solvate thereof.

[0167] In some embodiments, the ENT1 inhibitor is a Compound 1 hydrogen sulfate or a hydrate or solvate thereof, including crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, having an X-ray powder diffraction pattern comprising a peak at about 4.9° 2θ. In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, including crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern comprising peaks at about 4.9° 2θ and about 9.9° 2θ. In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, including crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern comprising peaks at about 4.9° 2θ and about 11.7° 2θ. In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, including crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern comprising peaks at about 4.9° 2θ and about 15.0° 2θ. In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, including crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern comprising peaks at about 4.9° 2θ, about 11.7° 2θ, and about 15.0° 2θ.

[0168] In some embodiments, the ENT1 inhibitor is a Compound 1 hydrogen sulfate or hydrate or solvate thereof, including crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, having an X-ray powder diffraction pattern comprising one or more peaks chosen from about 4.9° 2θ, about 9.9° 2θ about 10.2° 2θ, about 11.7° 2θ, about 12.7° 2θ, about 14.4° 2θ, about 15.0° 2θ, about 15.7° 2θ, about 19.0° 2θ, and about 19.6° 2θ.

[0169] In some embodiments, the ENT1 inhibitor is a Compound 1 hydrogen sulfate or hydrate or solvate thereof, including crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, having an X-ray powder diffraction pattern comprising a peak at about 4.9° 2θ and one or more peaks chosen from peaks at about 10.2° 2θ and about 15.0° 2θ. In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate, including crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern substantially the same as that of Figure 1A.

[0170] In some embodiments, the ENT1 inhibitor is crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate. Crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate can be prepared in a number of different ways. The XRPD diffraction patterns of Figures 1A and 1B are, as with the other XRPD patterns of crystalline Form 2 Compound 1 di(hydrogenAttorney Docket No: 01330-0112-00PCT sulfate) trihydrate disclosed herein, exemplary patterns of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate.

[0171] In some embodiments, the ENT1 inhibitor is a Compound 1 hydrogen sulfate or hydrate or solvate thereof, including crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, having an FT-IR spectrum substantially the same as that of Figure 16 (bottom or top spectrum). In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, including crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has a melting onset as measured by DSC in a sealed aluminum pan with a pierced lid of about 144°C. In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, including crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has a DSC thermogram substantially the same as that of Figure 4.

[0172] In some embodiments, the ENT1 inhibitor is a Compound 1 hydrogen sulfate or hydrate or solvate thereof, including crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, exhibiting a mass loss of between about 5% wt and about 9% wt upon heating from about 20°C to about 130°C. In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, including crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, exhibits a weight loss of about 6% wt upon heating from about 20°C to about 130°C. In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, including crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, exhibits a weight loss of about 7% wt upon heating from about 20°C to about 130°C. In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, including crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has a TGA thermogram substantially the same as in Figure 3.

[0173] In some embodiments, the ENT1 inhibitor is a Compound 1 hydrogen sulfate or hydrate or solvate thereof, including crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, exhibiting a moisture uptake of between about 5% and about 7% between about 0% RH and about 10% RH. In some embodiments, the moisture uptake is between about 6% and about 6.5% between about 0% RH and about 10% RH. In some embodiments, the moisture uptake is about 6% between about 0 % RH and about 10% RH. In some embodiments, the moisture uptake is about 7% between about 0 % RH and about 10% RH. In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, including crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an isotherm plot substantially the same as in Figure 6.

[0174] In some embodiments, the ENT1 inhibitor is a Compound 1 hydrogen sulfate or hydrate or solvate thereof, including crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, having a water content of between about 4% and about 7%. In some embodiments,Attorney Docket No: 01330-0112-00PCT the water content is between about 6% and about 7%. In some embodiments, the water content is about 4%. In some embodiments, the water content is about 6%. In some embodiments, the water content is about 7%.

[0175] In some embodiments, the ENT1 inhibitor is a Compound 1 hydrogen sulfate or hydrate or solvate thereof, including crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, having a chemical purity of about 95%. In some embodiments, the chemical purity is about 97%. In some embodiments, the chemical purity is 99%. In some embodiments, the chemical purity is greater than 99%.

[0176] In some embodiments, the ENT1 inhibitor is crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate having an X-ray powder diffraction pattern comprising one or more peaks chosen from the peak list in Table 1 below (all peaks that can be or have been chosen from Table 1 are rounded to the nearest 0.1° 2θ). In some embodiments, the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate has an X-ray powder diffraction pattern comprising two or more peaks chosen from the peak list in Table 1 below (all peaks that can be or have been chosen from Table 1 are rounded to the nearest 0.1° 2θ). In some embodiments, the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate has an X-ray powder diffraction pattern comprising three or more peaks chosen from the peak list in Table 1 below (all peaks that can be or have been chosen from Table 1 are rounded to the nearest 0.1° 2θ). Table 1: Peak list for crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate No. Pos. [° 2θ] d-spacing [Å] Height [cts] Rel. Int. [%] 1 3.2145 27.4858 144.12 16.34 2 4.8584 18.18883 503.65 57.11 3 9.8661 8.96524 282.03 31.98 4 10.2164 8.65865 784.06 88.9 5 11.6994 7.56419 119.98 13.6 6 12.6578 6.99355 140.57 15.94 7 14.3558 6.16994 159.37 18.07 8 15.0008 5.90607 803.41 91.1 9 15.6918 5.64753 424.18 48.1 10 16.2234 5.46363 127.56 14.46 11 18.0641 4.91085 105.13 11.92 12 19.0052 4.66973 225.18 25.53 13 19.5999 4.52935 237.59 26.94Attorney Docket No: 01330-0112-00PCT 14 20.019 4.43548 142.38 16.14 15 20.3701 4.35981 881.93 100 16 21.4304 4.14645 352.47 39.97 17 21.7663 4.08321 585.79 66.42 18 22.0553 4.03035 135.37 15.35 19 22.6211 3.93081 160.73 18.23 20 23.3558 3.8088 120.51 13.66 21 23.7449 3.74726 454.73 51.56 22 24.2988 3.66308 159.23 18.05 23 25.0687 3.55229 188.58 21.38 24 25.3332 3.51581 306.82 34.79 25 25.5499 3.48647 253.82 28.78 26 26.2676 3.39282 56.63 6.42 27 26.5834 3.35323 95.33 10.81 28 27.4053 3.2545 94.49 10.71 29 29.7707 3.00109 50.92 5.77 30 33.0781 2.70819 33 3.74

[0177] Below is the peak list and parameters used for a simulated XRPD diffractogram that was calculated for crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate from the crystallographic analysis conducted at 295 K. Accordingly, in some embodiments, the ENT1 inhibitor is a Compound 1 hydrogen sulfate or a hydrate or solvate thereof, including crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, having an X-ray powder diffraction pattern comprising a peak at about 4.9° 2θ. In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, including crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern comprising peaks at about 4.9° 2θ and about 9.9° 2θ. In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, including crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern comprising peaks at about 4.9° 2θ and about 11.8° 2θ. In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, including crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern comprising peaks at about 4.9° 2θ and about 15.1° 2θ. In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, including crystalline Form 2 Compound 1 di(hydrogenAttorney Docket No: 01330-0112-00PCT sulfate) trihydrate, has an X-ray powder diffraction pattern comprising peaks at about 4.9° 2θ, about 11.8° 2θ, and about 15.1° 2θ.

[0178] In some embodiments, the ENT1 inhibitor is a Compound 1 hydrogen sulfate or hydrate or solvate thereof, including crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, having an X-ray powder diffraction pattern comprising one or more peaks chosen from about 4.9° 2θ, about 9.9° 2θ, about 10.3° 2θ, about 11.8° 2θ, about 12.7° 2θ, about 14.4° 2θ, about 15.1° 2θ, about 15.7° 2θ, about 19.1° 2θ, and about 19.7° 2θ.

[0179] In some embodiments, the ENT1 inhibitor is a Compound 1 hydrogen sulfate or hydrate or solvate thereof, including crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, having an X-ray powder diffraction pattern comprising a peak at about 4.9° 2θ and one or more peaks chosen from peaks at about 10.3° 2θ and about 15.1° 2θ.

[0180] In some embodiments, the ENT1 inhibitor is a Compound 1 hydrogen sulfate or hydrate or solvate, including crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, having an X-ray powder diffraction pattern substantially the same as the bottom pattern of Figure 19 (Simulated at 295 K).

[0181] In some embodiments, the ENT1 inhibitor is crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate having an X-ray powder diffraction pattern comprising one or more peaks chosen from the peak list in Table 3 or 4 below (all peaks that can be or have been chosen from Table 3 or 4 are rounded to the nearest 0.1° 2θ). In some embodiments, the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate has an X-ray powder diffraction pattern comprising two or more peaks chosen from the peak list in Table 3 or 4 below (all peaks that can be or have been chosen from Table 3 or 4 are rounded to the nearest 0.1° 2θ). In some embodiments, the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate has an X-ray powder diffraction pattern comprising three or more peaks chosen from the peak list in Table 3 or 4 below (all peaks that can be or have been chosen from Table 3 or 4 are rounded to the nearest 0.1° 2θ). Table 2. Crystallographic parameters and refinement indicators of Crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate (295 K) C33H55N3O19S2Empirical *the calculated formula differs from the reported formula by two formula hydrogen atoms and one oxygen atom that were not located Formula weight 858.89 g / mol Temperature / K 295 Crystal system TriclinicAttorney Docket No: 01330-0112-00PCT Space group P1 a / Å 9.669(2) b / Å 12.439(3) c / Å 18.717(4) α / ° 102.143(13) β / ° 94.505(14) γ / ° 110.746(12) Volume / Å32029.0(8) Z , Z` 2, 2 ρcalcg / cm31.406 μ / mm-11.896 F(000) 910.0 Crystal size / mm30.26 × 0.18 × 0.1 Radiation CuKα (λ = 1.54184) 2Θ range for data 4.898 to 133.718 collection / ° Index ranges -11 ≤ h ≤ 11, -14 ≤ k ≤ 14, -22 ≤ l ≤ 22 Reflections 59429 collected Independent 13898 [Rint = 0.0790, Rsigma = 0.0782] reflections Data / restraints / 13898 / 9 / 1037 parameters S 1.141 Final R indexes R1 = 0.0835, wR2 = 0.2430 [F2> 2σ (F2)] Final R indexes R1 = 0.1304, wR2 = 0.2767 [all data] Δρmax , Δρmin / - 0.75 / -0.72 e Å3Flack parameter 0.016(16) R1= (Σ |Fo| – |Fc| ) / Σ |Fo|) ; wR2= {Σ [w(Fo2– Fc2)2] / Σ [w(Fo2)2]}½; S = {Σ [w(Fo2– Fc2)2] / (n-p)}½.Attorney Docket No: 01330-0112-00PCT Table 3. Simulated XRPD 2θ diffractogram of Crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate (295 K) (to 35° 2θ). No. Pos. [° 2θ] d-spacing [Å] Height [cts] Rel. Int. [%] 1 4.8946 18.03960 6042.30 59.50 2 7.8547 11.24670 556.77 5.48 3 8.1269 10.87055 210.73 2.08 4 9.9142 8.91452 3372.58 33.21 5 10.2843 8.59445 8325.80 81.99 6 11.0213 8.02136 246.99 2.43 7 11.3260 7.80626 124.83 1.23 8 11.7769 7.50836 1449.36 14.27 9 12.7288 6.94891 946.25 9.32 10 13.7978 6.41286 208.45 2.05 11 14.0557 6.29576 175.68 1.73 12 14.4212 6.13703 1381.48 13.60 13 14.8161 5.97431 798.24 7.86 14 15.0866 5.86780 8503.98 83.74 15 15.7472 5.62311 4635.76 45.65 16 16.3067 5.43141 950.60 9.36 17 16.5804 5.34236 396.22 3.90 18 16.7518 5.28810 732.42 7.21 19 17.6648 5.01677 1162.56 11.45 20 18.1455 4.88495 977.39 9.63 21 18.7007 4.74114 895.86 8.82 22 19.1179 4.63861 2593.46 25.54 23 19.3951 4.57295 1135.31 11.18 24 19.6844 4.50638 3525.96 34.72 25 20.1541 4.40241 1482.37 14.60 26 20.5087 4.32709 10154.64 100.00 27 20.6883 4.28991 3063.49 30.17 28 21.5353 4.12307 4158.59 40.95 29 21.8691 4.06089 5594.20 55.09 30 22.1724 4.00602 2019.79 19.89 31 22.7572 3.90438 1932.14 19.03Attorney Docket No: 01330-0112-00PCT No. Pos. [° 2θ] d-spacing [Å] Height [cts] Rel. Int. [%] 32 23.2319 3.82567 774.16 7.62 33 23.4414 3.79193 1503.00 14.80 34 23.8808 3.72316 4836.63 47.63 35 24.0983 3.69005 976.79 9.62 36 24.4603 3.63624 1794.58 17.67 37 25.1790 3.53406 2515.82 24.78 38 25.4667 3.49479 3482.27 34.29 39 25.6807 3.46614 2622.15 25.82 40 25.8405 3.44507 1042.79 10.27 41 26.0935 3.41223 282.03 2.78 42 26.4560 3.36630 534.53 5.26 43 26.7225 3.33333 988.58 9.74 44 26.8890 3.31307 537.29 5.29 45 27.5852 3.23101 1124.78 11.08 46 27.8048 3.20599 721.02 7.10 47 28.0213 3.18171 737.19 7.26 48 28.1626 3.16606 700.32 6.90 49 28.3719 3.14318 450.70 4.44 50 28.7104 3.10689 799.44 7.87 51 28.9146 3.08541 359.05 3.54 52 29.0906 3.06714 581.41 5.73 53 29.4930 3.02620 888.83 8.75 54 29.6586 3.00969 595.93 5.87 55 29.9076 2.98519 897.31 8.84 56 30.1441 2.96231 360.12 3.55 57 30.5331 2.92544 448.44 4.42 58 30.9066 2.89094 637.94 6.28 59 31.2138 2.86318 500.03 4.92 60 31.7259 2.81813 403.18 3.97 61 31.9896 2.79550 180.41 1.78 62 32.3740 2.76318 292.01 2.88 63 32.7117 2.73542 173.43 1.71 64 32.9971 2.71240 310.93 3.06Attorney Docket No: 01330-0112-00PCT No. Pos. [° 2θ] d-spacing [Å] Height [cts] Rel. Int. [%] 65 33.3364 2.68557 441.08 4.34 66 33.9267 2.64018 201.06 1.98 67 34.1530 2.62320 165.81 1.63 68 34.6331 2.58793 175.24 1.73 Table 4. Simulated XRPD 2θ diffractogram of Crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate (295 K) (20 most intense peaks). No. Pos. [° 2θ] d-spacing [Å] Height [cts] Rel. Int. [%] 1 20.5087 4.32709 10154.64 100.00 2 15.0866 5.86780 8503.98 83.74 3 10.2843 8.59445 8325.80 81.99 4 4.8946 18.03960 6042.30 59.50 5 21.8691 4.06089 5594.20 55.09 6 23.8808 3.72316 4836.63 47.63 7 15.7472 5.62311 4635.76 45.65 8 21.5353 4.12307 4158.59 40.95 9 19.6844 4.50638 3525.96 34.72 10 25.4667 3.49479 3482.27 34.29 11 9.9142 8.91452 3372.58 33.21 12 20.6883 4.28991 3063.49 30.17 13 25.6807 3.46614 2622.15 25.82 14 19.1179 4.63861 2593.46 25.54 15 25.1790 3.53406 2515.82 24.78 16 22.1724 4.00602 2019.79 19.89 17 22.7572 3.90438 1932.14 19.03 18 24.4603 3.63624 1794.58 17.67 19 23.4414 3.79193 1503.00 14.80 20 20.1541 4.40241 1482.37 14.60

[0182] Below is the peak list and parameters used for a simulated XRPD diffractogram that was calculated for crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate at 100 K. Accordingly, in some embodiments, the ENT1 inhibitor is crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate having an X-ray powder diffraction pattern comprising one orAttorney Docket No: 01330-0112-00PCT more peaks chosen from the peak list in Table 6 or 7 below (all peaks that can be or have been chosen from Table 6 or 7 are rounded to the nearest 0.1° 2θ). In some embodiments, the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate has an X-ray powder diffraction pattern comprising two or more peaks chosen from the peak list in Table 6 or 7 below (all peaks that can be or have been chosen from Table 6 or 7 are rounded to the nearest 0.1° 2θ). In some embodiments, the crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate has an X-ray powder diffraction pattern comprising three or more peaks chosen from the peak list in Table 6 or 7 below (all peaks that can be or have been chosen from Table 6 or 7 are rounded to the nearest 0.1° 2θ). In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate, including crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, has an X-ray powder diffraction pattern substantially the same as the top pattern of Figure 19 (Simulated at 100 K). Table 5. Crystallographic parameters and refinement indicators of Crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate (100 K) Empirical formula C33H57N3O20S2 Formula weight 879.93 g / mol Temperature / K 100 Crystal system Triclinic Space group P1 a / Å 9.6794(2) b / Å 12.3886(2) c / Å 18.4016(4) α / ° 101.6708(8) β / ° 94.7448(8) γ / ° 110.7514(8) Volume / Å31991.88(7) Z , Z` 2, 2 ρcalcg / cm31.467 μ / mm-11.962 F(000) 936.0 Crystal size / mm30.38 × 0.24 × 0.12 Radiation CuKα (λ = 1.54178) 2Θ range for data collection / ° 4.974 to 144.29 Index ranges -10 ≤ h ≤ 11, -15 ≤ k ≤ 15, -22 ≤ l ≤ 2 Reflections collected 97841Attorney Docket No: 01330-0112-00PCT Independent reflections 15198 [Rint = 0.0299, Rsigma = 0.0202] Data / restraints / parameters 15198 / 33 / 1139 S 1.029 Final R indexes [F2> 2σ (F2)] R1= 0.0586, wR2 = 0.1588 Final R indexes [all data] R1= 0.0592, wR2= 0.1597 Δρmax , Δρmin / e Å-30.63 / -1.17 Flack parameter -0.008(5) R1= (Σ |Fo| – |Fc| ) / Σ |Fo|) ; wR2= {Σ [w(Fo2– Fc2)2] / Σ [w(Fo2)2]}½; S = {Σ [w(Fo2– Fc2)2] / (n-p)}½.Table 6. Simulated XRPD 2θ diffractogram of Crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate (100 K) (to 35° 2θ). No. Pos. [° 2θ] d-spacing [Å] Height [cts] Rel. Int. [%] 1 4.9708 17.76340 5692.39 57.05 2 7.8721 11.22177 192.87 1.93 3 8.2012 10.77221 118.89 1.19 4 9.9051 8.92269 2513.16 25.19 5 10.3093 8.57375 6074.58 60.88 6 11.0697 7.98639 381.20 3.82 7 11.8171 7.48292 506.02 5.07 8 12.8134 6.90323 597.90 5.99 9 13.9479 6.34418 211.75 2.12 10 14.1586 6.25023 346.39 3.47 11 14.4510 6.12442 967.78 9.70 12 15.2031 5.82311 7129.03 71.45 13 15.7809 5.61116 4079.65 40.89 14 16.4745 5.37646 794.87 7.97 15 16.7852 5.27763 453.42 4.54 16 17.7061 5.00516 847.97 8.50 17 18.3200 4.83881 709.84 7.11 18 18.6841 4.74533 393.29 3.94 19 19.3213 4.59023 3032.46 30.39 20 19.6644 4.51092 3526.60 35.34 21 19.8463 4.46998 1072.98 10.75Attorney Docket No: 01330-0112-00PCT No. Pos. [° 2θ] d-spacing [Å] Height [cts] Rel. Int. [%] 22 20.1614 4.40082 1610.14 16.14 23 20.7696 4.27331 9978.21 100.00 24 21.5995 4.11096 759.84 7.61 25 21.8102 4.07171 3594.54 36.02 26 22.2082 3.99964 5614.95 56.27 27 22.3481 3.97491 1892.70 18.97 28 22.7901 3.89882 1412.77 14.16 29 23.2451 3.82351 1120.21 11.23 30 23.4845 3.78508 1365.48 13.68 31 23.7730 3.73979 884.41 8.86 32 24.0898 3.69132 1251.47 12.54 33 24.3072 3.65880 5161.43 51.73 34 24.5353 3.62530 1465.70 14.69 35 24.7824 3.58971 996.51 9.99 36 25.4465 3.49751 2461.31 24.67 37 25.8398 3.44517 3425.07 34.33 38 26.1214 3.40866 2704.76 27.11 39 26.7881 3.32531 828.92 8.31 40 26.9212 3.30917 1036.14 10.38 41 27.3278 3.26086 516.98 5.18 42 27.5109 3.23957 527.00 5.28 43 27.7881 3.20787 1169.38 11.72 44 28.1012 3.17284 937.34 9.39 45 28.3241 3.14838 1081.95 10.84 46 28.5401 3.12505 773.11 7.75 47 28.7454 3.10318 1024.38 10.27 48 29.1078 3.06537 964.03 9.66 49 29.4874 3.02676 857.33 8.59 50 29.9255 2.98345 806.76 8.09 51 30.1457 2.96215 1038.18 10.40 52 30.4145 2.93659 577.92 5.79 53 30.7961 2.90106 714.10 7.16 54 30.9877 2.88356 724.52 7.26Attorney Docket No: 01330-0112-00PCT No. Pos. [° 2θ] d-spacing [Å] Height [cts] Rel. Int. [%] 55 31.2722 2.85797 663.29 6.65 56 31.7460 2.81639 339.03 3.40 57 32.0668 2.78894 523.95 5.25 58 32.3819 2.76252 429.15 4.30 59 32.6774 2.73821 209.40 2.10 60 33.3433 2.68503 859.27 8.61 61 33.9170 2.64091 408.11 4.09 62 34.1856 2.62078 272.79 2.73 63 34.6088 2.58969 110.44 1.11 64 34.8394 2.57308 228.50 2.29 Table 7. Simulated XRPD 2θ diffractogram of Crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate (100 K) (20 most intense peaks). No. Pos. [° 2θ] d-spacing [Å] Height [cts] Rel. Int. [%] 1 20.7696 4.27331 9978.21 100.00 2 15.2031 5.82311 7129.03 71.45 3 10.3093 8.57375 6074.58 60.88 4 4.9708 17.76340 5692.39 57.05 5 22.2082 3.99964 5614.95 56.27 6 24.3072 3.65880 5161.43 51.73 7 15.7809 5.61116 4079.65 40.89 8 21.8102 4.07171 3594.54 36.02 9 19.6644 4.51092 3526.60 35.34 10 25.8398 3.44517 3425.07 34.33 11 19.3213 4.59023 3032.46 30.39 12 26.1214 3.40866 2704.76 27.11 13 9.9051 8.92269 2513.16 25.19 14 25.4465 3.49751 2461.31 24.67 15 22.3481 3.97491 1892.70 18.97 16 20.1614 4.40082 1610.14 16.14 17 24.5353 3.62530 1465.70 14.69 18 22.7901 3.89882 1412.77 14.16 19 23.4845 3.78508 1365.48 13.68Attorney Docket No: 01330-0112-00PCT No. Pos. [° 2θ] d-spacing [Å] Height [cts] Rel. Int. [%] 20 24.0898 3.69132 1251.47 12.54

[0183] In some embodiments, the ENT1 inhibitor is crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate. Crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate contains one stereogenic center and is a single enantiomer with the R-configuration, as shown in Table 8. It contains three molecules of water, as shown in Table 8, and thus is a trihydrate. Table 8 Chemical Structure x 2 H2SO4 x 3 H2O Molecular formula C33H47N3O9, 2 H2SO4, 3 H2O (C33H51N3O17S2, 3 H2O) Relative molecular 629.75 (free base); 879.94 (salt: di(hydrogen sulfate) trihydrate) mass (MW)

[0184] Crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate has a single Compound 1 cation and at least one hydrogen sulfate anion and where the other sulfate moiety may be in the form of a second hydrogen sulfate anion or sulfuric acid (which would be neutral).

[0185] In some embodiments, the ENT1 inhibitor is selected from one of the compounds in Tables 9 or 10, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.Attorney Docket No: 01330-0112-00PCT Table 9 Compound Structures Chemical Name (12R)-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3) benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoate (12S)- 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3-ethoxy-4,5- dimethoxybenzoate; 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3-(2-amino-2-oxoethyl)- 4,5-dimethoxybenzoate; 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5 trimethoxybenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 4-chloro-3- methoxybenzoateAttorney Docket No: 01330-0112-00PCT Compound Structures Chemical Name O O 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- O O benzenacyclotetradecaphane-12-yl 4-fluoro-3- O N methoxybenzoate N O F O O 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 1-(3,4,5- trimethoxybenzyl)-1H-indazole-6-carboxylate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 2,6-dimethylisonicotinate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,5-dichloro-4- methoxybenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 2-benzyl-4-chloro-2H- indazole-6-carboxylate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 4-chloro-1-methyl-1H- indazole-6-carboxylateAttorney Docket No: 01330-0112-00PCT Compound Structures Chemical Name 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 1-benzyl-4-chloro-1H- indazole-6-carboxylate O O 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- O O benzenacyclotetradecaphane-12-yl 3,4,5-trifluorobenzoate O N F N O F O F 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3-carbamoyl-4,5- dimethoxybenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3-(benzyloxy)-4,5- dimethoxybenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 7-methoxy-1,3-dimethyl- 2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylateAttorney Docket No: 01330-0112-00PCT Compound Structures Chemical Name 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 1-methyl-6-oxo-1,6- dihydropyridine-3-carboxylate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 6-cyanonicotinate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 4-acetylbenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 4- (trifluoromethyl)benzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 6- (trifluoromethyl)nicotinate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 6-methylnicotinateAttorney Docket No: 01330-0112-00PCT Compound Structures Chemical Name 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4-dichlorobenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 4-chloro-3- fluorobenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 4-chlorobenzoate O O 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- O O benzenacyclotetradecaphane-12-yl 3-chloro-4- O N fluorobenzoate N O F O Cl 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 4-fluorobenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 4-morpholinobenzoateAttorney Docket No: 01330-0112-00PCT Compound Structures Chemical Name 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 4- (trifluoromethoxy)benzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 2-chloro-3,4- dimethoxybenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 4- (methylsulfonyl)benzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 2,3- dihydrobenzo[b][1,4]dioxine-6-carboxylate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 1-methyl-1H-indazole-6- carboxylate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 1-benzyl-1H-indazole-6- carboxylateAttorney Docket No: 01330-0112-00PCT Compound Structures Chemical Name 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl benzo[d]thiazole-6- carboxylate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl [1,2,4]triazolo[4,3- a]pyridine-6-carboxylate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 2- (trifluoromethyl)isonicotinate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 5,6-dichloronicotinate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 6-chloro-5- fluoronicotinate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 2-aminopyrimidine-5- carboxylateAttorney Docket No: 01330-0112-00PCT Compound Structures Chemical Name 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 5-chloronicotinate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 4-methoxybenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 4-methoxy-3- (trifluoromethyl)benzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3-chloro-4- methoxybenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4-dimethoxybenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 6-methoxynicotinate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 5-methoxynicotinateAttorney Docket No: 01330-0112-00PCT Compound Structures Chemical Name 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 2-methoxypyrimidine-5- carboxylate 16-fluoro-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoate 16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoate N-(74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl)-3,4,5- trimethoxybenzamide N-(74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl)-3,4,5-trimethoxy- N-methylbenzamide N-(16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl)-3,4,5- trimethoxybenzamideAttorney Docket No: 01330-0112-00PCT Compound Structures Chemical Name N-(16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl)-3,4,5- trimethoxy-N-methylbenzamide N-((12R)-16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa- 1(1,4)-diazepana-7(1,3) benzenacyclotetradecaphane-12-yl)- 3,4,5-trimethoxybenzamide N-((12R)-16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa- 1(1,4)-diazepana-7(1,3) benzenacyclotetradecaphane-12-yl)- 3,4,5-trimethoxy-N-methylbenzamide N-((12S)-16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa- 1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl)- 3,4,5-trimethoxybenzamide N-((12S)-16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa- 1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl)- 3,4,5-trimethoxy-N-methylbenzamideAttorney Docket No: 01330-0112-00PCT Table 10 STRUCTURE Name (12R)- 74,75-dimethoxy-6-oxo-5,8-dioxa- 1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoate (12S)- 74,75-dimethoxy-6-oxo-5,8-dioxa- 1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoate N-(74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl)-3,4,5- trimethoxybenzamide 16,16-difluoro-74,75-dimethoxy-6-oxo-5,8- dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoate (12R)-16,16-difluoro-74,75-dimethoxy-6- oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoateAttorney Docket No: 01330-0112-00PCT STRUCTURE Name 74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoate (12S)- 74,75-dimethoxy-6-oxo-8-oxa-5-aza- 1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoate (12R)- 74,75-dimethoxy-6-oxo-8-oxa-5-aza- 1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoate 74,75-dimethoxy-5-methyl-6-oxo-8-oxa-5- aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoate (12S)- 74,75-dimethoxy-5-methyl-6-oxo-8- oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoateAttorney Docket No: 01330-0112-00PCT STRUCTURE Name (12R)- 74,75-dimethoxy-5-methyl-6-oxo-8- oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoate (11R)- 74,75-dimethoxy-6-oxo-5-aza-1(1,4)- diazepana-7(1,3)-benzenacyclotridecaphane- 11-yl 3,4,5-trimethoxybenzoate (10S)-14-chloro-2-oxo-11H-3-aza-1(6,1)- indazola-7(1,4)- diazepanacyclotridecaphane-10-yl 3,4,5- trimethoxybenzoate (10R)-14-chloro-2-oxo-11H-3-aza-1(6,1)- indazola-7(1,4)- diazepanacyclotridecaphane-10-yl 3,4,5- trimethoxybenzoateAttorney Docket No: 01330-0112-00PCT STRUCTURE Name (12S)-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate (12R)-6-oxo-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate (12S)-6-oxo-8-oxa-5-aza-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl benzoate (12R)-6-oxo-8-oxa-5-aza-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphane-12-yl benzoate 74,75-dichloro-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoateAttorney Docket No: 01330-0112-00PCT STRUCTURE Name (12S)- 74,75-dichloro-6-oxo-5,8-dioxa- 1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoate (12R)- 74,75-dichloro-6-oxo-5,8-dioxa- 1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4- dichlorobenzoate (11Z,16E,10S)-14-chloro-2-oxo-12H-3-aza- 1(6,2)-indazola-7(1,4)- diazepanacyclotridecaphane-10-yl 3,4,5- trimethoxybenzoate (11Z,16E,10R)-14-chloro-2-oxo-12H-3-aza- 1(6,2)-indazola-7(1,4)- diazepanacyclotridecaphane-10-yl 3,4,5- trimethoxybenzoateAttorney Docket No: 01330-0112-00PCT STRUCTURE Name 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3-chloro- 4-fluorobenzoate (12R)-74-carbamoyl-75-chloro-6-oxo-8-oxa- 5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 4- fluorobenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 4- (trifluoromethoxy)benzoate (12R)- 74,75-dimethoxy-6-oxo-5,8-dioxa- 1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl benzoateAttorney Docket No: 01330-0112-00PCT STRUCTURE Name (12R)- 74,75-dimethoxy-6-oxo-5,8-dioxa- 1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl benzoate (12S)- 74,75-dimethoxy-6-oxo-5,8-dioxa- 1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl benzoate (R)- 74,75-dimethoxy-6-oxo-5,8-dioxa- 1(4,1)-piperidina-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoate (R)-15,16-dimethoxy-9,12-dimethyl-17-oxo- 2,16-dioxa-9,12-diaza-1(1,3)- benzenacycloheptadecaphane-6-yl benzoateAttorney Docket No: 01330-0112-00PCT STRUCTURE Name (R)-15,16-dimethoxy-9,12-dimethyl-17-oxo- 2,16-dioxa-9,12-diaza-1(1,3)- benzenacycloheptadecaphane-6-yl benzoate (Z)-benzaldehyde O-(74,75-dimethoxy-6- oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl) oxime 12-hydroxy-74,75-dimethoxy-5,8-dioxa- 1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one (12R)-12-hydroxy-74,75-dimethoxy-5,8- dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one (12S)-12-hydroxy-74,75-dimethoxy-5,8- dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 4- hydroxybenzoateAttorney Docket No: 01330-0112-00PCT STRUCTURE Name 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 4- isopropoxybenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3- (trifluoromethyl)benzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3- (methylsulfonyl)benzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3- phenoxybenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 2- fluorobenzoateAttorney Docket No: 01330-0112-00PCT STRUCTURE Name 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 4-bromo- 3-cyanobenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3- methyl-5-(trifluoromethyl)benzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 2-fluoro- 4-methoxybenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 4- methoxy-2-(trifluoromethoxy)benzoateAttorney Docket No: 01330-0112-00PCT STRUCTURE Name 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl picolinate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl nicotinate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl pyrazine- 2-carboxylate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 6- hydroxynicotinateAttorney Docket No: 01330-0112-00PCT STRUCTURE Name 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl quinoline-5-carboxylate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl oxazole- 4-carboxylate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 1H-1,2,3- triazole-4-carboxylate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl acetateAttorney Docket No: 01330-0112-00PCT STRUCTURE Name 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl cyclopropanecarboxylate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3- methylbutanoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 4,4,4- trifluorobutanoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl cyclohexanecarboxylate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 1- methylpiperidine-4-carboxylateAttorney Docket No: 01330-0112-00PCT STRUCTURE Name 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,3- dimethylcyclobutane-1-carboxylate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 2- (oxetan-3-yl)acetate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl (1R,5S,6r)-3-oxabicyclo[3.1.0]hexane-6- carboxylate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 5- oxopyrrolidine-3-carboxylate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 1-benzyl- 5-oxopyrrolidine-3-carboxylateAttorney Docket No: 01330-0112-00PCT STRUCTURE Name 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 4- methoxycyclohexane-1-carboxylate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 2,6- difluorobenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3- cyanobenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 2-oxo- 1,2,3,4-tetrahydroquinoline-6-carboxylate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3- (difluoromethoxy)benzoateAttorney Docket No: 01330-0112-00PCT STRUCTURE Name 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,5- dichlorobenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 2,3- dichlorobenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 2-chloro- 6-fluoro-3-methylbenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3-fluoro- 5-(trifluoromethyl)benzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 4-fluoro- 3-(trifluoromethyl)benzoateAttorney Docket No: 01330-0112-00PCT STRUCTURE Name 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 4-cyano- 3-fluorobenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 4- (trifluoromethyl)benzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,5- difluorobenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4- difluorobenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3-cyano- 4-fluorobenzoateAttorney Docket No: 01330-0112-00PCT STRUCTURE Name 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 4- cyanobenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 1- methyl-1H-benzo[d]imidazole-5-carboxylate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 4- (oxazol-5-yl)benzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 4,5- dichloro-2-fluorobenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5- triethoxybenzoateAttorney Docket No: 01330-0112-00PCT STRUCTURE Name 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3- methoxypropanoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3-(1H- pyrazol-1-yl)propanoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3- cyanopropanoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 4- cyanobutanoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 4- acetamidobutanoateAttorney Docket No: 01330-0112-00PCT STRUCTURE Name 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3-(1H- tetrazol-1-yl)propanoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 4- (dimethylamino)-4-oxobutanoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3- acetamidopropanoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 4- (methylamino)-4-oxobutanoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3-(1H- 1,2,4-triazol-1-yl)propanoateAttorney Docket No: 01330-0112-00PCT STRUCTURE Name 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 4- morpholino-4-oxobutanoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3-(4- fluorophenoxy)propanoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 4,4- difluorocyclohexane-1-carboxylate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 4- (trifluoromethyl)cyclohexane-1-carboxylate 74,75-dimethoxy-12-(5-phenyl-2H-tetrazol- 2-yl)-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-oneAttorney Docket No: 01330-0112-00PCT STRUCTURE Name 74,75-dimethoxy-12-(4-phenyl-1H-1,2,3- triazol-1-yl)-5,8-dioxa-1(1,4)-diazepana- 7(1,3)-benzenacyclotetradecaphan-6-one 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3-(2,5- dioxopyrrolidin-1-yl)propanoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3- methoxycyclohexane-1-carboxylate 74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl benzoate (E)-benzaldehyde O-(74,75-dimethoxy-6- oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl) oximeAttorney Docket No: 01330-0112-00PCT STRUCTURE Name (E)-benzaldehyde O-((12R)- 74,75- dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl) oxime (E)-benzaldehyde O-((12S)- 74,75- dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)- diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl) oxime 12-hydroxy-74,75-dimethoxy-8-oxa-5-aza- 1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one 74,75-dimethoxy-12-(5-phenyl-1H-tetrazol- 1-yl)-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one (12S)-16,16-difluoro-74,75-dimethoxy-6- oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoateAttorney Docket No: 01330-0112-00PCT STRUCTURE Name 75-carbamoyl-74-chloro-6-oxo-5,8-dioxa- 1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoate (12S)-74-carbamoyl-75-chloro-6-oxo-8-oxa- 5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoate 74-bromo-75-chloro-6-oxo-8-oxa-5-aza- 1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoate 75-chloro-74-cyano-6-oxo-8-oxa-5-aza- 1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoateAttorney Docket No: 01330-0112-00PCT STRUCTURE Name 74,75-dimethoxy-12-(5-phenyl-1H-tetrazol- 1-yl)-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one 74,75-dimethoxy-12-(5-phenyl-1H-tetrazol- 1-yl)-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one

[0186] In some embodiments, the ENT1 inhibitors is selected from 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, ticagrelor and salts thereof. In another embodiment, the ENT1 inhibitor is selected from ticagrelor and salts thereof. In one embodiment, the ENT1 inhibitor is NBMP or a salt thereof.

[0187] In some embodiments, the ENT1 inhibitor is selected from NBMPR (nitrobenzylthioinosine), draflazine, STI-571 (Gleevec), ticagrelor, 8MDP, 5-iodotubercidin, cilostazol, and salts thereof and any mixture thereof. Examples of selective ENT1 inhibitors include NBMPR, STI-571 (Gleevec), ticagrelor, salts thereof and any mixture thereof. B. Oncolytic Viruses

[0188] Any oncolytic virus may be used in the combinations, compositions, kits, methods, and uses disclosed herein.

[0189] Examples of oncolytic viruses include, without being limited to: − DNA virus such as adenovirus, herpes virus such as herpes simplex virus (HSV), parvovirus, and poxvirus such as vaccinia virus (VACV) and myxoma virus (MYXV).Attorney Docket No: 01330-0112-00PCT − RNA virus, such as Coxsackie virus, Maraba virus, measles virus (MV), Newcastle disease virus (NDV), poliovirus (PV), reovirus, retrovirus, Seneca Valley virus (SVV), Semliki Forest virus (SFV), Vesicular stomatitis virus (VSV), and Sindbis virus (SBV).

[0190] In one embodiment, the oncolytic virus is selected from RNA virus or DNA virus.

[0191] In one embodiment, the oncolytic virus is selected from adenovirus, herpes virus such as herpes simplex virus (HSV), rhabdovirus, letivirus, adeno-associated virus, papillomavirus, picomavirus, parvovirus, and poxvirus such as vaccinia virus (VACV) and myxoma virus (MYXV), Coxsackie virus, Maraba virus, measles virus (MV), Newcastle disease virus (NDV), poliovirus (PV), reovirus, retrovirus, Seneca Valley virus (SVV), Semliki Forest virus (SFV), Vesicular stomatitis virus (VSV), Sindbis virus (SBV), and any mixtures thereof.

[0192] In some embodiments, the oncolytic virus is an adenovirus, a vaccinia virus, a reovirus, a coxsackievirus, and a herpes simplex virus.

[0193] In some embodiments, the oncolytic virus is chosen from talimogene laherparepvec (T-VEC, Imlygic®), Oncorine (H101), Reolysin (Reovirus), pexastimogene devacirepvec (JX-594, Pexa-Vec), CG0070, pelareorep (Reolysin®), ONYX-015, coxsackievirus A21 (CVA21, CavatakTM), and JX-963. C. Combinations, Compositions, and Kits

[0194] In some embodiments, disclosed herein are combinations and compositions comprising an ENT1 inhibitor and an oncolytic virus. In some embodiments, the combinations and compositions further comprise a pharmaceutically acceptable excipient.

[0195] By means of non-limiting examples, the ENT1 inhibitors, oncolytic virus, combinations and compositions disclosed herein may each independently 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.

[0196] 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, andAttorney Docket No: 01330-0112-00PCT 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.

[0197] The ENT1 inhibitors, oncolytic virus, combinations, and compositions described herein 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.

[0198] In general, the ENT1 inhibitors, oncolytic virus, combinations, and compositions herein may be prepared according to known methods in pharmaceutical chemistry. Capsules can be prepared by mixing, for example, an ENT1 inhibitor with a suitable carrier or diluent and filling the proper amount of the mixture in capsules. The usual carriers and diluents include, but are not limited to, inert powdered substances such as starch of many different kinds, powdered cellulose, including crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders.

[0199] 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.

[0200] A lubricant might be necessary in a tablet formulation to prevent the tablet and punches from sticking in the dye. The lubricant can be chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils. Tablet disintegrators are substances that swell when wetted to break up the tablet and release the compound. They include starches, clays, celluloses, algins and gums. Corn and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation-exchange resins, alginic acid, guar gum, citrus pulp and carboxymethyl cellulose, for example, can be usedAttorney Docket No: 01330-0112-00PCT 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, oncolytic viruses, combinations, and compositions can also be formulated as chewable tablets, for example, by using substances such as mannitol in the formulation.

[0201] When it is desired to administer an ENT1 inhibitor, an oncolytic virus, a combination, or a composition of the present disclosure as a suppository, a base can be used. Cocoa butter may be used as a suppository base, which can be modified by addition of waxes to raise its melting point slightly. Water-miscible suppository bases comprising, for example, polyethylene glycols of various molecular weights are in wide use.

[0202] The effect of the ENT1 inhibitors, oncolytic viruses, combinations, and compositions of the present disclosure can be delayed or prolonged by proper formulation. For example, a slowly soluble pellet can be prepared and incorporated in a tablet or capsule, or as a slow-release implantable device. The technique also includes making pellets of several different dissolution rates and filling capsules with a mixture of the pellets. Tablets or capsules can be coated with a film that resists dissolution for a predictable period of time. Even the parenteral preparations can be made long-acting, by dissolving or suspending the compound of the present disclosure in oily or emulsified vehicles that allow it to disperse slowly in the serum.

[0203] In some embodiments, the ENT1 inhibitors, oncolytic viruses, combinations, and compositions of the present disclosure are in a unit dosage form, and may be suitably packaged, for example in a box, blister, vial, bottle, sachet, ampoule or in any other suitable single-dose or multi-dose holder or container (which may be properly labeled), optionally with one or more leaflets containing product information and / or instructions for use.

[0204] In some embodiments, the ENT1 inhibitor is administered in a daily dose from about 2.5 mg to about 100 mg. In some embodiments, the ENT inhibitor is administered in a daily dose from about 2.5 mg to about 60 mg, from about 2.5 mg to about 45 mg, from about 2.5 mg to about 30 mg, from about 2.5 mg to about 20 mg, from about 2.5 mg to about 10 mg. In some embodiments, the ENT inhibitor is administered in a daily dose of about 2.5 mg. In some embodiments, the ENT inhibitor is administered in a daily dose of about 5 mg. In some embodiments, the ENT inhibitor is administered in a daily dose of about 10 mg. In some embodiments, the ENT inhibitor is administered in a daily dose of about 20 mg. In some embodiments, the ENT inhibitor is administered in a daily dose of about 30 mg. In some embodiments, the ENT inhibitor is administered in a daily dose of about 40 mg. In some embodiments, the ENT inhibitor is administered in a daily dose of about 45 mg. In some embodiments, the ENT inhibitor is administered in a daily dose of about 60 mg.Attorney Docket No: 01330-0112-00PCT

[0205] In some embodiments, the ENT1 inhibitor is Compound 1 or a salt, hydrate, or solvate thereof. In some embodiments, Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 2.5 mg (free base). In some embodiments, Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 5 mg (free base). In some embodiments, Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 10 mg (free base). In some embodiments, Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 20 mg (free base). In some embodiments, Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 30 mg (free base). In some embodiments, Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 40 mg (free base). In some embodiments, Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 45 mg (free base). In some embodiments, Compound 1 or a salt, hydrate, or solvate thereof is administered in a daily dose of about 60 mg (free base).

[0206] In some embodiments, the ENT1 inhibitor is a Compound 1 hydrogen sulfate or hydrate or solvate thereof, such as crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate. In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 2.5 mg (free base). In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 5 mg (free base). In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 10 mg (free base). In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 20 mg (free base). In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 30 mg (free base). In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 40 mg (free base). In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 45 mg (free base). In some embodiments, the Compound 1 hydrogen sulfate or hydrate or solvate thereof, for example crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, is administered in a daily dose of about 60 mg (free base).Attorney Docket No: 01330-0112-00PCT

[0207] In some embodiments, the ENT inhibitor is administered once daily. In some embodiments, the ENT inhibitor is administered twice daily (BID).

[0208] In some embodiments, the oncolytic virus may be administered via intertumoral route, intravenous route, intraperitoneal route, or intrathecal route. It can be administered, for example, into cutaneous, subcutaneous, and / or into nodal lesson.

[0209] In some embodiments, the oncolytic virus is administered in a daily dose of from about 106(1 million) plaque-forming units (PFU) per mL to about 109(1 billion) PFUs. In some embodiments, the oncolytic virus is administered daily, weekly, every two weeks, every three weeks, or every four weeks. In some embodiment, the oncolytic virus is administered every three weeks.

[0210] In some embodiments, disclosed herein is a kit of parts comprising an ENT1 inhibitor and an oncolytic virus. In some embodiments, the kit of parts further comprises a product insert. In some embodiments, the insert instructs one to administer the ENT1 inhibitor prior to, concomitant with, or subsequent to the administration of the oncolytic virus.

[0211] In one embodiment, the disclosure provides for a kit of parts as described herein for use in any method described herein. In some embodiments, the kit of parts is for use in the treatment of cancer. The disclosure further provides for a use of the kit of parts as described herein for the manufacture of a medicament for treating cancer. The disclosure further provides a method of treating cancer, which comprises administering to a patient in need thereof an ENT1 inhibitor and an oncolytic virus contained within a kit of parts as described herein. D. Methods and Uses

[0212] In some embodiments, disclosed herein is a method of treating cancer comprising administering to a subject in need thereof an ENT1 inhibitor and an oncolytic virus. In some embodiments, disclosed herein is a use of an ENT1 inhibitor and an oncolytic virus in the manufacture of a medicament for the treatment of cancer. As described earlier, in some embodiments, the ENT1 inhibitor used in the methods and uses herein is selected from (12R)- 74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate (Compound 1) and pharmaceutically acceptable salts, hydrates, or solvates thereof. In some embodiments, the ENT1 inhibitor is a hydrogen sulfate of Compound 1 (“Compound 1 hydrogen sulfate”) or a hydrate or solvate thereof. In some embodiments, the hydrogen sulfate of Compound 1 or a hydrate or solvate thereof is a hydrate. In some embodiments, the hydrogen sulfate of Compound 1 or a hydrate or solvate thereof is a di(hydrogen sulfate) (“Compound 1 di(hydrogen sulfate)”) or a hydrate or solvate thereof, and in some embodiments, the hydrogen sulfate of Compound 1 di(hydrogen sulfate) or a hydrate or solvate thereof is a trihydrate. In some embodiments, the Compound 1 hydrogen sulfate or aAttorney Docket No: 01330-0112-00PCT hydrate or solvate thereof is a crystalline hydrogen sulfate such as a crystalline mono(hydrogen sulfate) or a crystalline di(hydrogen sulfate) or a hydrate or solvate thereof. In some embodiments, the ENT1 inhibitor used in the methods and uses herein is a Compound 1 hydrogen sulfate or a hydrate or solvate thereof, such as crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate.

[0213] Various cancers are known in the art. Cancers that can be treated using the methods 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.

[0214] 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.

[0215] Examples of solid tumors include, but are not limited to: biliary tract cancer, brain cancer (including glioblastomas and medulloblastomas), breast cancer, carcinoid, cervical cancer, choriocarcinoma, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, glioma, head and neck cancer, intraepithelial neoplasms (including Bowen’s disease and Paget’s disease), liver cancer, lung cancer, neuroblastomas, oral cancer (including squamous cell carcinoma), ovarian cancer (including those arising from epithelial cells, stromal cells, germ cells and mesenchymal cells), pancreatic cancer, prostate cancer, rectal cancer, renal cancer (including adenocarcinoma and Wilms tumor), sarcomas (including leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma and osteosarcoma), skin cancer (including melanoma, Kaposi’s sarcoma, basocellular cancer and squamous cell cancer), testicular cancer including germinal tumors (seminomas, and non-seminomas such as teratomas and choriocarcinomas), stromal tumors, germ cell tumors, thyroid cancer (including thyroid adenocarcinoma and medullary carcinoma) and urothelial cancer.

[0216] In some embodiments, the cancer is glioblastoma and the ENT1 inhibitor selected from (12R)-74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate (Compound 1) and pharmaceutically acceptable salts, hydrates, or solvates thereof, such as crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate.

[0217] 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.Attorney Docket No: 01330-0112-00PCT

[0218] Lymphoid disorders include but are not limited to acute lymphocytic leukemia and chronic lymphoproliferative disorders (e.g., lymphomas, myelomas, and chronic lymphoid leukemias). Lymphomas include, for example, Hodgkin’s disease, non-Hodgkin’s lymphoma lymphomas, and lymphocytic lymphomas. Chronic lymphoid leukemias include, for example, T cell chronic lymphoid leukemias and B cell chronic lymphoid leukemias.

[0219] In some embodiments, the cancer is characterized by a high concentration of adenosine in the tumor microenvironment (TME). 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 selected from melanoma, prostate cancer, glioblastoma, and esophageal carcinoma. In some embodiments, the cancer is breast cancer. In some embodiments, the breast cancer is triple negative breast cancer.

[0220] In some embodiments, the ENT1 inhibitor is administered prior to, concomitant with, or subsequent to the administration of the oncolytic virus. In some embodiments, the ENT1 inhibitor is administered prior to administration of the oncolytic virus. In some embodiments, the ENT1 inhibitor is administered concomitant with administration of the oncolytic virus. In some embodiments, the ENT1 inhibitor is administered subsequent to administration of the oncolytic virus.

[0221] Depending on the condition to be treated and the route of administration, the active compounds may be administered as a single daily dose, divided over one or more daily doses, or essentially continuously, e.g. using a drip infusion.

[0222] The ENT1 inhibitor, oncolytic virus, combination or composition of the present disclosure can be administered orally. For example, in some embodiments, the ENT inhibitor is administered orally. In one embodiment, when administered orally, the combination or composition of the present disclosure is administered without food. In one embodiment, when administered orally, the combination or composition of the present disclosure is administered with a meal and / or water. In another embodiment, the combination or composition of the present disclosure 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.

[0223] The ENT1 inhibitor, oncolytic virus, combination or composition disclosed herein may 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. For example, in some embodiments, the oncolytic virus is administered byAttorney Docket No: 01330-0112-00PCT injection into cutaneous, subcutaneous, and / or nodal lesions. 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.

[0224] In one embodiment, the subject has previously received at least one prior therapeutic treatment prior to administration of the ENT1 inhibitor and oncolytic virus. In one embodiment, the subject has previously received at least one prior therapeutic treatment and has progressed subsequent to the administration of the at least one prior therapeutic treatment and prior to administration of the ENT1 inhibitor and oncolytic virus. In one embodiment, the prior therapeutic treatment is selected from the group consisting of chemotherapy, immunotherapy, radiation therapy, stem cell transplant, hormone therapy, and surgery. ENUMERATED EMBODIMENTS

[0225] Embodiment 1. A combination of an ENT1 inhibitor and an oncolytic virus.

[0226] Embodiment 2. A pharmaceutical composition comprising an ENT1 inhibitor and an oncolytic virus.

[0227] Embodiment 3. A kit of parts comprising an ENT1 inhibitor and an oncolytic virus.

[0228] Embodiment 4. A method of treating cancer comprising administering to a subject in need thereof an ENT1 inhibitor and an oncolytic virus.

[0229] Embodiment 5. A use of an ENT1 inhibitor and an oncolytic virus in the manufacture of a medicament for the treatment of cancer.

[0230] Embodiment 6. The combination, composition, kit, method or use according to any one of Embodiments 1-5, wherein the oncolytic virus is a DNA virus.

[0231] Embodiment 7. The combination, composition, kit, method or use according to any one of Embodiments 1-5, wherein the oncolytic virus is an RNA virus.

[0232] Embodiment 8. The combination, composition, kit, method or use according to any one of Embodiments 1-5, wherein the oncolytic virus is an adenovirus, a vaccinia virus, a reovirus, a coxsackievirus, or a herpes simplex virus.

[0233] Embodiment 9. The combination, composition, kit, method or use according to any one of Embodiments 1-5, wherein the oncolytic virus is selected from talimogene laherparepvec (T-VEC, Imlygic®), Oncorine (H101), Reolysin (Reovirus), pexastimogene devacirepvec (JX-594, Pexa-Vec), CG0070, pelareorep (Reolysin®), ONYX- 015, coxsackievirus A21 (CVA21, CavatakTM), and JX-963.Attorney Docket No: 01330-0112-00PCT

[0234] Embodiment 10. The combination, composition, kit, method or use according to any one of Embodiments 1-9, wherein the ENT1 inhibitor is not dilazep, dipyridamole, or a salt thereof.

[0235] Embodiment 11. The combination, composition, kit, method or use according to any one of Embodiments 1-9, wherein the ENT1 inhibitor is a compound of Formula (I):or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R1is selected from the group consisting of ,, each 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;Attorney Docket No: 01330-0112-00PCT R4is selected from the group consisting ,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-; and Z is C or N, wherein ALK is unsubstituted alkyl or substituted alkyl, or two instances of ALK may be joined together with their intervening atoms to form a cycloalkyl or heterocyclyl ring.

[0236] Embodiment 12. The combination, composition, kit, method or use according to any one of Embodiments 1-9, wherein the ENT1 inhibitor is a compound of Formula (II):or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R1is selected from the group consisting of ALK, cycloalkyl, heterocyclyl,Attorney Docket No: 01330-0112-00PCThalogen, - 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)-, - C, , , , 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.

[0237] Embodiment 13. The combination, composition, kit, method or use according to Embodiment 12, wherein the ENT1 inhibitor is a compound of Formula (IIa):Attorney Docket No: 01330-0112-00PCTor a or solvate thereof, wherein X is CH2, CHF, or CF2.

[0238] Embodiment 14. The combination, composition, kit, method or use according to any one of Embodiments 11-13, wherein.

[0239] Embodiment 15. The combination, composition, kit, method or use according to Embodiment 14, wherein.

[0240] Embodiment 16. The combination, composition, kit, method or use according to any one of Embodiments 12-15, wherein the compound is a compound of Formula (IIb):(IIb) or a pharmaceutically acceptable salt, hydrate, or solvate thereof.Attorney Docket No: 01330-0112-00PCT

[0241] Embodiment 17. The combination, composition, kit, method or use according to any one of Embodiments 11-16, wherein U is -C(O)O-.

[0242] Embodiment 18. The combination, composition, kit, method or use according to any one of Embodiments 11, 12, 14, and 15, the 43U in R is -C(O)O- or -C(O)NR -.

[0243] Embodiment 19. The combination, composition, kit, method or use according to Embodiment 12, wherein the compound is a compound of Formula (IIa1):or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0244] Embodiment 20. The combination, composition, kit, method or use according to any one of Embodiments 1-12, wherein the ENT1 inhibitor is selected from: (12S)-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate (12R)-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate 16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate (12S)-16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate (12R)-16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate N-(74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane- 12-yl)-3,4,5-trimethoxybenzamide 74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoateAttorney Docket No: 01330-0112-00PCT (12S)-74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate (12R)-74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate 74,75-dimethoxy-5-methyl-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate (12S)-74,75-dimethoxy-5-methyl-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate (12R)-74,75-dimethoxy-5-methyl-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate (11R)-74,75-dimethoxy-6-oxo-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotridecaphane-11- yl 3,4,5-trimethoxybenzoate (10S)-14-chloro-2-oxo-11H-3-aza-1(6,1)-indazola-7(1,4)-diazepanacyclotridecaphane-10-yl 3,4,5-trimethoxybenzoate (10R)-14-chloro-2-oxo-11H-3-aza-1(6,1)-indazola-7(1,4)-diazepanacyclotridecaphane-10-yl 3,4,5-trimethoxybenzoate (12S)-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoate (12R)-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoate (12S)-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl benzoate (12R)-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl benzoate 74,75dichloro-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate (12S)-74,75-dichloro-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate (12R)-74,75-dichloro-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate 75-carbamoyl-74-chloro-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate (11Z,16E,10S)-14-chloro-2-oxo-12H-3-aza-1(6,2)-indazola-7(1,4)- diazepanacyclotridecaphane-10-yl 3,4,5-trimethoxybenzoateAttorney Docket No: 01330-0112-00PCT (11Z,16E,10R)-14-chloro-2-oxo-12H-3-aza-1(6,2)-indazola-7(1,4)- diazepanacyclotridecaphane-10-yl 3,4,5-trimethoxybenzoate (12S)-74-carbamoyl-75-chloro-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate (12R)- 74-carbamoyl-75-chloro-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate 74-bromo-75-chloro-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate 75-chloro-74-cyano-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate (12R)-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl benzoate (12R)-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl benzoate (12S)-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl benzoate (Z)-benzaldehyde O-(74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl) oxime 12-hydroxy-74,75-dimethoxy-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphan- 6-one 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-hydroxybenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-fluorobenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-isopropoxybenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-(trifluoromethyl)benzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-(methylsulfonyl)benzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-phenoxybenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 2-fluorobenzoateAttorney Docket No: 01330-0112-00PCT,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-bromo-3-cyanobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-methyl-5-(trifluoromethyl)benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 2-fluoro-4-methoxybenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-methoxy-2-(trifluoromethoxy)benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl picolinate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl nicotinate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl pyrazine-2-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 6-hydroxynicotinate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl quinoline-5-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl oxazole-4-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 1H-1,2,3-triazole-4-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl acetate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl cyclopropanecarboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-methylbutanoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4,4,4-trifluorobutanoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl cyclohexanecarboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 1-methylpiperidine-4-carboxylateAttorney Docket No: 01330-0112-00PCT,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,3-dimethylcyclobutane-1-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 2-(oxetan-3-yl)acetate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl (1R,5S,6R)-3-oxabicyclo[3.1.0]hexane-6-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 5-oxopyrrolidine-3-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 1-benzyl-5-oxopyrrolidine-3-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-methoxycyclohexane-1-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 2,6-difluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-(trifluoromethoxy)benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-cyanobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 2-oxo-1,2,3,4-tetrahydroquinoline-6-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-(difluoromethoxy)benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,5-dichlorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4-dichlorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 2,3-dichlorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 2-chloro-6-fluoro-3-methylbenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-fluoro-5-(trifluoromethyl)benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-fluoro-3-(trifluoromethyl)benzoateAttorney Docket No: 01330-0112-00PCT,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-cyano-3-fluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-(trifluoromethyl)benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,5-difluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4-difluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-cyano-4-fluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-cyanobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-chloro-4-fluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 1-methyl-1H-benzo[d]imidazole-5-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-(oxazol-5-yl)benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4,5-dichloro-2-fluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5-triethoxybenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-methoxypropanoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-(1H-pyrazol-1-yl)propanoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-cyanopropanoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-cyanobutanoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-acetamidobutanoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-(1H-tetrazol-1-yl)propanoateAttorney Docket No: 01330-0112-00PCT 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-(dimethylamino)-4-oxobutanoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-acetamidopropanoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-(methylamino)-4-oxobutanoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-(1H-1,2,4-triazol-1-yl)propanoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-morpholino-4-oxobutanoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-(4-fluorophenoxy)propanoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4,4-difluorocyclohexane-1-carboxylate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-(trifluoromethyl)cyclohexane-1-carboxylate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-(2,5-dioxopyrrolidin-1-yl)propanoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-methoxycyclohexane-1-carboxylate 74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane- 12-yl benzoate (E)-benzaldehyde O-(74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl) oxime (E)-benzaldehyde O-((12R)- 74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl) oxime (E)-benzaldehyde O-((12S)- 74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl) oxime 12-hydroxy-74,75-dimethoxy-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one (12R)-12-hydroxy-74,75-dimethoxy-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one (12S)-12-hydroxy-74,75-dimethoxy-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-oneAttorney Docket No: 01330-0112-00PCT 74,75-dimethoxy-12-(5-phenyl-2H-tetrazol-2-yl)-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one 74,75-dimethoxy-12-(4-phenyl-1H-1,2,3-triazol-1-yl)-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one 74,75-dimethoxy-12-(5-phenyl-1H-tetrazol-1-yl)-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one, and pharmaceutically acceptable salts, hydrates, or solvates thereof.

[0245] Embodiment 21. The combination, composition, kit, method or use according to any one of Embodiments 1-12, wherein the ENT1 inhibitor is selected from Compound 1Compound 1 and pharmaceutically acceptable salts, hydrates, and solvates thereof.

[0246] Embodiment 22. The combination, composition, kit, method or use according to any one of Embodiments 1-12, wherein the ENT1 inhibitor is selected from Compound 1Compound 1 and pharmaceutically acceptable salts thereof.

[0247] Embodiment 23. The combination, composition, kit, method or use according to Embodiment 21, wherein the ENT1 inhibitor is a Compound 1 hydrogen sulfate or a hydrate or solvate thereof.Attorney Docket No: 01330-0112-00PCT

[0248] Embodiment 24. The combination, composition, kit, method or use according to Embodiment 23, wherein the ENT1 inhibitor is a Compound 1 di(hydrogen sulfate) or a hydrate or solvate thereof.

[0249] Embodiment 25. The combination, composition, kit, method or use according to Embodiment 24, wherein the Compound 1 di(hydrogen sulfate) or a hydrate or solvate thereof is crystalline.

[0250] Embodiment 26. The combination, composition, kit, method or use according to Embodiment 25, wherein the crystalline Compound 1 di(hydrogen sulfate) or a hydrate or solvate thereof is crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate.

[0251] Embodiment 27. The method or use according to any one of Embodiments 4-26, wherein the ENT1 inhibitor is administered prior to, concomitant with, or subsequent to the administration of the oncolytic virus.

[0252] Embodiment 28. The method or use according to any one of Embodiments 4-27, wherein the cancer is characterized by a high concentration of adenosine in the tumor microenvironment (TME).

[0253] Embodiment 29. The method or use according to any one of Embodiments 4-28, 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.

[0254] Embodiment 30. The method or use according to any one of Embodiments 4-29, wherein the cancer is breast cancer.

[0255] Embodiment 31. The method or use according to Embodiment 34, wherein the breast cancer is triple negative breast cancer.

[0256] Embodiment 32. The method or use according to Embodiments 4-30, wherein the cancer is a solid-tumor cancer.

[0257] Embodiment 33. The method or use according to Embodiments 4-29, wherein the cancer is melanoma, prostate cancer, glioblastoma, or esophageal carcinoma. EXAMPLES PREPARATION OF CERTAIN ENT1 INHIBITORS Analytical Methods.

[0258] (1) X-ray Powder Diffraction (XRPD)

[0259] In the examples below, unless otherwise stated, XRPD analysis was carried out on a PANalytical X’pert pro with PIXcel detector (128 channels), scanning the samples between 3 and 35° 2θ. The material was gently ground (where required) to release anyAttorney Docket No: 01330-0112-00PCT agglomerates and loaded onto a multi-well plate with Mylar polymer film to support the sample. The multi-well plate was then placed into the diffractometer and analyzed using Cu K radiation (α1 λ = 1.54060 Å; α2 = 1.54443 Å; β = 1.39225 Å; α1 : α2 ratio = 0.5; most, if not all, β radiation is removed from the beam using an X-ray mirror) running in transmission mode (step size 0.0130° 2θ, step time 18.87s) using 40 kV / 40 mA generator settings. Data were visualized and images generated using the HighScore Plus 4.7 desktop application (PANalytical, 2017).

[0260] (2) Single Crystal X-ray Diffraction (SCXRD)

[0261] In Example 4, a suitable crystal was selected and mounted in a nylon loop while protected in a protective layer of paratone oil. Two data sets were collected at temperatures: 295K and 100K. In both cases, data were collected using a Bruker D8 Venture diffractometer equipped with a Photon III detector operating in shutterless mode with Cu-Kα radiation (1.54178 Å). All nonhydrogen atoms were located in the Fourier map and their positions refined prior to describing the thermal movement of all non-hydrogen atoms anisotropically.

[0262] The structures were solved in the Olex2 software package with the ShelXT (intrinsic phasing) structure solution program and refined with the ShelXL refinement package using Least Squares minimization. See Dolomanov, O.V. et al, J. Appl. Cryst., 2009, 42, 339-341; Sheldrick, G.M., Acta Cryst., 2015, A71, 3-8; and Sheldrick, G.M., Acta Cryst., 2015, C71, 3-8. Data was collected, solved, and refined in triclinic space-group P1.

[0263] A series of restraints were applied to the final refinement. All CH and CH2groups were refined with fixed Uiso of 1.2 times, and all CH3groups with fixed Uiso of 1.5 times. The anions were disordered in the structure collected at 100K and they were modelled as follows: - S4 was disordered over two positions and modelled at 0.44 occupancy; O300, O302 and O303 were disordered over two positions and modelled at 0.55 occupancy.

[0264] For the structure collected at 295 K, the highest residual Fourier peak was found to be 0.75 e.Å-3approx.2.43 Å from O302 and the deepest Fourier hole was found to be - 0.72 e.Å-3approx.0.62 Å from S2.

[0265] For the structure collected at 100 K, the highest residual Fourier peak was found to be 0.63 e.Å-3approx.0.51 Å from H4WA and the deepest Fourier hole was found to be -1.17 e.Å-3approx.0.61 Å from S2.

[0266] Crystal data for the structure at 295K was obtained with the following parameters: C33H55N3O19S2* (M = 858.89 g / mol): triclinic, space group P1 (no.1), a = 9.669(2) Å, b = 12.439(3) Å, c = 18.717(4) Å, α = 102.143(13)°, β = 94.505(14)°, γ = 110.746(12)°, V = 2029.0(8) Å3, Z = 2 T = 295(2) K, μ(CuKα) = 1.896 mm-1, Dcalc = 1.406 g / cm3, 59429 reflections measured (4.898 ≤ 2Θ ≤ 133.718), 13898 unique (Rint = 0.0790, Rsigma = 0.0782)Attorney Docket No: 01330-0112-00PCT which were used in all calculations. The final R1was 0.0835 (>2σ(I)) and wR2 was 0.2767 (all data). *the calculated formula differs from the reported formula by two hydrogen atoms and one oxygen atom that were not located

[0267] Crystal data for the structure at 100K was obtained with the following parameters: C33H57N3O20S2 (M = 879.93 g / mol): triclinic, space group P1 (no.1), a = 9.6794(2) Å, b = 12.3886(2) Å, c = 18.4016(4) Å, α = 101.6708(8)°, β = 94.7448(8)°, γ = 110.7514(8)°, V = 1991.88(7) Å3, Z = 2, T = 100.0 K, μ(CuKα) = 1.962 mm-1, Dcalc = 1.467 g / cm3, 97841 reflections measured (4.974° ≤ 2Θ ≤ 144.29°), 15198 unique (Rint = 0.0299, Rsigma = 0.0202) which were used in all calculations. The final R1 was 0.0586 (I > 2σ(I)) and wR2 was 0.1597 (all data).

[0268] (3) Thermogravimetric Analysis / Differential Scanning Calorimetry (TGA / DSC), a.k.a. Thermogravimetric / Differential Scanning Calorimetry (TG / DSC)

[0269] In the examples below, to measure TGA / DSC, 2 – 10 mg of material was added into a pre-tared open aluminum pan and loaded into a TA Instruments Discovery SDT 650 Auto - Simultaneous DSC and held at room temperature. The sample was then heated at a rate of 10 °C / min from 30°C to 400°C during which time the change in sample weight was recorded along with the heat flow response (DSC). Nitrogen was used as the sample purge gas, at a flow rate of 200 cm3 / min.

[0270] (4) Differential Scanning Calorimetry (DSC)

[0271] METHOD A: In Example 1, 1 – 5 mg of material was weighed into an aluminum DSC pan and sealed non-hermetically with a pierced aluminum lid. The sample pan was then loaded into a TA DSC2500 and held at 20°C. Once a stable heat-flow response was obtained, the sample and reference were heated to an upper temperature of 200°C at a scan rate of 10°C / min and the resulting heat flow response monitored. The sample was held at the upper temperature for 3 minutes, before it was cooled at 10°C / min to 20°C, reheated to the upper temperature at 10°C / min, and then cooled again to 20°C at the same rate. Nitrogen was used as the purge gas, at a flow rate of 50 cm3 / min.

[0272] METHOD B: In Example 3, 1 – 5 mg of a sample were weighed into an aluminum DSC pan and sealed non-hermetically with an aluminum lid. The sample pan was then loaded into a TA Instruments Discovery DSC 2500 differential scanning calorimeter equipped with a RC90 cooler. The sample and reference were heated to 190°C at a scan rate of 10°C / min and the resulting heat flow response monitored. The sample was re-cooled to -80°C and then reheated again to 190°C all at 10 °C / min. Nitrogen was used as the purge gas, at a flow rate of 50 cm3 / min.Attorney Docket No: 01330-0112-00PCT

[0273] (5) Nuclear Magnetic Resonance Spectroscopy (NMR)

[0274] METHOD A: In Examples 1,1H NMR experiments were performed on a Bruker AV500 (frequency: 500 MHz for protons). Experiments were performed in d4-methanol and samples were prepared to ca.5 mM concentration.

[0275] METHOD B: In Example 3, NMR experiments were performed on a Bruker AVIIIHD spectrometer equipped with a DCH cryoprobe operating at 500.12MHz for protons. Experiments were performed in d4-methanol and each sample was prepared to ca.10 mM concentration. Quantitative NMR analysis was carried out using 1,3,5-trimethoxybenzene as the external standard; experiments were carried out in d4-methanol for Compound 1, which is a free base, samples and in DMSO-d6for the di(hydrogen sulfate) samples.

[0276] (6) Infrared spectroscopy (IR)

[0277] In the examples below, Infrared spectroscopy was carried out on a Bruker ALPHA P spectrometer. Sufficient material was placed onto the center of the plate of the spectrometer and the spectra were obtained using the following parameters: Resolution: 4 cm-1Background Scan Time: 16 scans Sample Scan Time: 16 scans Data Collection: 4000 to 400 cm-1Result Spectrum: Transmittance

[0278] Software: OPUS version 6

[0279] (7) Polarized Light Microscopy (PLM)

[0280] In Example 3, the presence of crystallinity (birefringence) was determined using an Olympus BX50 microscope, equipped with cross-polarizing lenses and a Motic camera. Images were captured using Motic Images Plus 2.0. All images were recorded using the 20× objective, unless otherwise stated.

[0281] (8) Hot Stage Light Microscopy (HSM)

[0282] In Example 5, thermal events were monitored visually using a calibrated Linkam THM600 hotstage with connected controller unit coupled to an Olympus BH2 microscope equipped with a Motic camera and image capture software (Motic Images Plus 3.0). Approximately 0.5 mg of material was placed onto a microscope coverslip and heated at a rate of 10 °C / min with images taken at routine intervals to document any thermal transitions. All images were recorded using the 20 × objective, unless otherwise stated.

[0283] (9) Karl Fischer Coulometric Titration (KF)

[0284] In the examples below, KF titration was measured using either an In Motion KF Autosampler or Direct Addition Method. The In Motion KF Autosampler wasAttorney Docket No: 01330-0112-00PCT carried out via the following procedure.15 –20 mg of solid was weighed into a 10 mL glass vial and tightly sealed with a screw cap. Samples were analyzed using a Mettler Toledo C30SX and an InMotion KFOven Autosampler at 130°C. Samples were analyzed in duplicate and an average moisture content reported. See table below for further details. Oven Temperature / °C 130 Source for Drift Determination Max. Start Drift / µg / min 10 Carrier Gas Flow Rate / 80 mL / min Blank Transfer Tube Heating No Mix Time / s 60 Stir Speed / % 45 Drift Termination / s 10 (Delay Time) Max. Titration Time / s 600 Oven Temperature / °C 130 Source for Drift Determination Max. Start Drift / µg / min 10 Carrier Gas Flow Rate / 80 Sample mL / min Mix Time / s 60 Stir Speed / % 45 Drift Termination / s 10 (Delay Time) Max. Titration Time / s 600

[0285] The Direct Addition Method was carried out via the following procedure. 15 - 20 mg of solid material was accurately weighed into a vial. The solid was then manually introduced into the titration cell of a Mettler Toledo C30 Compact Titrator. The vial was back- weighed after the addition of the solid and the weight of the added solid entered on the instrument. Titration was initiated once the sample had fully dissolved in the cell. The water content was calculated automatically by the instrument as a percentage and the data printed.

[0286] (10) Dynamic Vapor Sorption (DVS)

[0287] METHOD A: In Example 5, approximately 5-15 mg of sample was placed into a mesh vapor sorption balance pan and loaded into either a DVS Intrinsic or DVS Advantage dynamic vapor sorption balance by Surface Measurement Systems. The sample wasAttorney Docket No: 01330-0112-00PCT subjected to a ramping profile from 40–90% relative humidity (RH) at 10% increments, maintaining the sample at each step until a stable weight had been achieved (dm / dt 0.004%, minimum step length 30 minutes, maximum step length 500 minutes) at 25°C. After completion of the sorption cycle, the sample was dried using the same procedure to 0% RH and then a second sorption cycle back to 40% RH was carried out. Two cycles were performed. The weight change during the sorption / desorption cycles were plotted, allowing the hygroscopic nature of the sample to be determined. XRPD analysis was then carried out on the residual solid.

[0288] METHOD B: In Examples 1, approximately 10 – 20 mg of sample was placed into a mesh vapor sorption balance pan and loaded into either a DVS Intrinsic or DVS Advantage dynamic vapor sorption balance by Surface Measurement Systems. The sample was subjected to a ramping profile from 40–90% relative humidity (RH) at 10% increments, maintaining the sample at each step until a stable weight had been achieved (dm / dt 0.004%, minimum step length 30 minutes, maximum step length 500 minutes) at 25°C. After completion of the sorption cycle, the sample was dried using the same procedure to 0% RH and then a second sorption cycle back to 40% RH was carried out. Two cycles were performed. The weight change during the sorption / desorption cycles were plotted, allowing the hygroscopic nature of the sample to be determined.

[0289] (11) High Performance Liquid Chromatography-Ultraviolet Detection (HPLC-UV)

[0290] Unless otherwise indicated in the examples below, HPLC-UV was performed with the follow experimental parameters and conditions: Column: Waters XSelect CSH Fluoro-Phenyl 150 × 4.6 mm, 2.5 μm Mobile Phase A: 0.1% TFA in water Mobile Phase B: 0.1% TFA in acetonitrile Diluent: Methanol Autosampler Temperature: 5°C Flow Rate: 1.0 mL / min Runtime: 30 minutes Column Temperature: 30°C (± 1°C) Column Pressure: 110 bar (at start of run) Injection Volume: 5 μL Sample Concentration: 0.5 mg / mL Detection: 266 nm Sampling Rate: 50 Hz Gradient Program:Attorney Docket No: 01330-0112-00PCT Time (min) Mobile Phase A (%) Mobile Phase B (%) 0.0 95 5 5.0 75 25 18.0 65 35 20.0 50 50 22.0 5 95 25.0 5 95 25.1 95 5 30.0 95 5

[0291] (12) Gas Chromatography (GC)

[0292] In Example 3, gas chromatography was conducted using a Thermo Trace 1300 GC equipped with a Tri-Plus 300 Headspace sampler. The following parameters were used: Column: Agilent J&W DB-62430 m × 0.32 mm, 1.8 μm d.f. or equivalent Oven Temperature: 35 °C (hold 0.5 min) to 45 °C @ 16.5 °C / min to 70 °C @ 5.0 °C / min to 220 °C@ 30.0 °C / min Flow Rate: 2.2 mL / min (constant flow) Carrier Gas: Hydrogen Diluent: DMA Injection Mode: Split Injection Temperature: 225 °C Injection Split Ratio: 20:1 Detector Temperature: 250 °C Detector Hydrogen: 30.0 mL / min Detector Air: 400 mL / min Make-up Flow: 40.0 mL / min Make-up Gas: Nitrogen The following Headspace Parameters were used: Oven Temperature: 100 °C Loop Temperature: 110 °C Transfer Line Temperature: 150 °C Vial Equilibration Time: 10.0 min Pressurization Mode: Pressure Auxiliary Pressure: 100 kPa (Nitrogen) Pressurization Time: 0.2 minAttorney Docket No: 01330-0112-00PCT Loop Fill Mode: Pressure Loop Pressure: 50 kPa Loop Equilibration Time: 0.2 min Loop Volume: 1 mL Inject Time: 0.5 min Vial Shaking: High GC Cycle Time: 21 min.

[0293] (13) Raman Spectroscopy

[0294] In Example 2, Raman spectroscopy was carried out using a Wasatch 785 nm spectrometer and a BlazeMetrics 900 probe. The material to be analyzed was brought in contact with the probe window and measurements were taken with the following parameters: Wavenumber: ca.2021 – 218 cm-1Accumulations: 2 Integration time: 2000 ms Care was taken to protect the sample from external light sources.

[0295] (14) Particle Size Distribution

[0296] In Example 3, the particle size distribution of solids was measured using a Mastersizer 2000 instrument and the method is detailed below. Dispersant 0.05% w / v span 85 in Heptane Concentration 100mg in 10mL dispersant Stirrer Speed 2000 rpm Sonication time 30 seconds Pre-measurement delay 1 minute Measurement time 10 seconds Background measurement time 10 seconds Measurement cycles 3 Obscuration 5-20% Analysis model General model Sensitivity Normal Dispersant Refractive Index 1.39 Material size absorption 0.01 Material R.I. 1.58Attorney Docket No: 01330-0112-00PCT Example 1. Preparation ENT inhibitors of Formula (I), including Crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate

[0297] ENT1 inhibitors that can be used in the combinations, compositions, kits, methods, and uses described herein WO 2021 / 170797, WO 2021 / 204896, WO 2023 / 059739, WO 2024 / 19439, and WO 2024 / 194392, the contents of each being incorporated herein by reference in their entirety.

[0298] Crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate can be prepared as described in WO 2024 / 194391 and as described below.

[0299] In this first method of preparing Crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate, a sample of Compound 1 (which is a free base) and 6 vol. of 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 (tBME) 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 crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate as shown in Figure 2. TG / DSC data show a mass loss of 7.3% corresponding to an endothermic event with an onset of 67°C which is likely due to water loss (approximating 3.6 mole equivalents of water) (Figure 3). DSC shows an endotherm at an onset of 144°C, which is consistent with a melting event (Figure 4) whereas a small melting event was observed in the TG / DSC data with an onset of 130°C.

[0300] KF analysis shows a water content of 6.74%.1H-NMR is consistent with the Compound 1 (free base) structure with peak shifts indicating salt formation (Figure 5). A DVS experiment (Figure 6 and Figure 7) shows a moisture uptake of about 6.3% between 0 and 10% RH with a more gradual uptake of 1.7% as RH is raised to 80% from 10%.Attorney Docket No: 01330-0112-00PCT Example 2. Second Preparation of Crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate

[0301] Approximately 1.5 g of Compound 1 was added to three 20 mL scintillation vials. 5 mL of 2-propanol:water (75:25 % v / v) was added to each vial, and the samples were stirred at 40°C. 2.05 mole equiv. of H2SO4 was added to each sample as solutions in 5 mL of propanol:water (75:25 % v / v). Clear solutions were observed in all samples. Stirring continued at 40°C for about 1.5 hours after addition of H2SO4. tBME was then added to each sample, also at 40°C, as an anti-solvent in 1 mL aliquots until the solutions turned cloudy. The samples were then temperature-cycled between 40°C and 5°C for about 20 hours with 0.1 °C / min ramp and a 1 hour hold between steps. The resultant slurries were subsampled, and solids isolated via centrifugation. The isolated solids were analyzed by XRPD. The remainder of the slurries were vacuum filtered as one sample using a Buchner funnel. The filter cake was dried under vacuum at 40°C for 48 hours. 4.87 g of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate was obtained; isolated yield = 81 %. An XRPD pattern was collected confirming crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate (Figure 8). A Raman spectrum was also collected (Figure 9). Example 3. Third Preparation of Crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate

[0302] 253.75 g of a mixture of crystalline Form 1 Compound 1 (free base) and crystalline Form 2 Compound 1 (free base) (see Example 5 below) was added to a 5 L temperature-controlled reactor. 1.10 L of 1-propanol:water (80:20 %v / v) was added to the reactor, followed by stirring at 50°C at 100 RPM. 2.5 equivalents of sulfuric acid (95 %wt.) were added to the reactor as a solution in 0.17 L of the solvent system, achieving a concentration of about 200 mg / mL. The experiment was equilibrated at 50°C, cooled to 40°C and seeded with 1% crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate. The seed crystal can be prepared methods such as those disclosed herein. Post-seeding, equilibration of ca.6 hr was applied. The stirring speed was increased to 120 RPM during the equilibration period. The experiment was cooled to 20°C at 0.2 °C / min and equilibrated at 20°C for 1 hour. At 20°C, anti- solvent addition with 1-propanol was carried out at 0.25 L / hr. 2.96 L of 1-propanol was added to reach a final ratio of 94:6 %v / v. The stirring speed was increased to 190 RPM during the addition. Equilibration at 20°C for about 1 hour was applied post-addition followed by cooling to 5°C at 0.2 °C / min and stirring at 5°C for about 20 hours. The resulting slurry was vacuum filtered and the resulting isolated cake was washed with 0.5 L of the precooled resulting solvent system. The filter cake was dried under vacuum at 40°C for 4 days. The dried solids were exposed to ambient conditions for about 20 hours to allow time for moisture equilibration. TheAttorney Docket No: 01330-0112-00PCT moisture content of the solids after about 20 hours exposure to ambient condition was measured as 4.33 %w / w. The solids were then re-exposed to ambient conditions for 2 days to allow time for further moisture uptake and equilibration during which time the solids were manually mixed intermittently.

[0303] The resulting solids were shown to be crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate by XRPD. Figure 10 shows the material before drying, after drying, and after drying and moisture equilibration. All diffractograms are that of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate. An isolated yield of 80.4% was obtained, with the theoretical yield estimated as 80.3% (based on the concentrations of the extracted mother liquor and wash). The purity of the dried solids was determined as >99.99 % area by HPLC and GC indicated about 0.12% by weight residual 1-propanol.

[0304] PLM showed the particle to be birefringent after anti-solvent addition at 20°C, as damp solids, after drying, and after moisture equilibration (Figure 11). By Karl Fischer measurements, a water content on average of 4.33% w / w was measured after about 21 hours of re-exposure to ambient conditions, which increased to 6.07% after another 48 hours. A water content of 6.14% is the theoretical content for a trihydrate.

[0305] Particle size-measurements were taken before and after complete equilibration (moisture content of 4.33% and then later 6.07%). Figure 12 is an overlay of the two measurements showing the difference in particle size distributions. The data are summarized in Table 11 below: Table 11: Particle Size Measurements after Equilibration Before complete equilibration; After complete equilibration; 24 hr post-drying 3 days post-drying (moisture content = 4.33%) (moisture content = 6.07%) D10 17.596 µm 6.32 µm D5046.785 µm 32.90 µm D90109.799 µm 84.73 µm

[0306] These data show that the average particle size decreased with longer equilibration times and higher water contents.

[0307] TG / DSC thermograms are presented in Figure 13 of a fully equilibrated sample of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate. The data reveal a mass loss of about 6.4% between about 20°C and 130°C, which corresponded with an endothermic event at about 61°C, both of which are likely due to solvent / water loss. A small endothermic event with a peak onset of about 150°C may be due to melting and the thermal events above 200°C areAttorney Docket No: 01330-0112-00PCT likely due to degradation. A DSC thermogram is provided in Figure 14 showing thermal events at onsets of about 89°C and about 148°C. The lower one is likely dehydration whereas the higher one is a melting event.

[0308] 1H-NMR spectra were collected on crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate and the spectrum was consistent with the di(hydrogen sulfate) structure (Figure 15).

[0309] An FT-IR spectrum of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate is shown in Figure 16. Example 4. Single Crystal Study of Crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate

[0310] A single crystal of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate was prepared in the following manner. Approximately 10 mg of amorphous Compound 1 di(hydrogen sulfate) (prepared as described in Example 6B). was added to a 2 mL vial, into which 100 µL of 2-ethoxyethanol was added. Complete dissolution was observed at ambient temperature (ca.20°C). The solvent was then allowed to evaporate at ambient conditions for 3 days. Post-evaporation, the residual solid was observed to be clear block-like particles, which were analyzed by single crystal X-ray diffraction. Figures 17 and 18 show a single crystal structure drawing of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate at 100K in two different orientations. Simulated XRPD diffractograms were calculated for structures collected at 295 K and 100 K, respectively (Figure 19), and compared to an experimental (room temperature) diffractogram (Figure 20) with detailed peak list in Table 3 and Table 6 and the 20 most intense peaks listed in Table 4 and Table 7. The simulated diffractogram showed good correlation with the experimental diffractogram indicating that the structure presented in this data is representative of the bulk material. Example 5. Preparation of Crystalline Form 1 Compound 1 (free base) and Crystalline Form 2 Compound 1 (free base)

[0311] Approximately 100 mg of amorphous Compound 1 (free base) (see Example 6A) was weighed into a 1.5 mL screw-cap vial. Acetonitrile was added in 100 μL aliquots while stirring at 40°C until the material dissolved (500 μL). The solution was stirred at 40°C for 0.25 hr and then cooled to 5°C at 0.1°C / min. A thick slurry (poorly mixed) was obtained at ca.30°C and so 200 μL of tBME was added as anti-solvent, but the slurry dissolved. After 11 hr at 5°C, a slurry was obtained. A portion of the slurry was isolated by centrifugation (0.22 μm nylon filter) and analyzed by XRPD. The isolated solids were consistent with a mixture of crystalline Form 1 Compound 1 (free base) and crystalline Form 2 Compound 1 (free base), which dried to crystalline Form 1 Compound 1 (free base).Attorney Docket No: 01330-0112-00PCT

[0312] Further aliquots of tBME were added to the remaining slurry (total of 600 μL), but dissolution was observed. Aliquots of heptane (3 × 100 μL) were added, but solution remained. Material was recovered by rotary evaporation and re-slurried in acetonitrile, then isolated by centrifugation (0.22 μm nylon filter) and analyzed by XRPD and found to be crystalline Form 1 Compound 1 (free base).

[0313] All liquors were evaporated to recover material. Solids were dried under vacuum at 35°C for ca.21 hr and then re-analyzed by XRPD. The solids were found to be crystalline Form 2 Compound 1 (free base), which dried to crystalline Form 1 Compound 1 (free base) with some loss of crystallinity. Figure 21 is a stackplot of XRPD patterns taken during this experiment including crystalline Form 1 Compound 1 (free base) and crystalline Form 2 Compound 1 (free base) reference patterns. Figure 22 is a separate XRPD pattern of crystalline Form 1 Compound 1 (free base) and Figure 23 is a separate XRPD Pattern of crystalline Form 2 Compound 1 (free base) each prepared separately.

[0314] Hot stage microscopy showed that crystalline Form 1 Compound 1 (free base) started to melt at 65°C, with melting complete at 80°C. DVS analysis indicated that crystalline Form 1 Compound 1 (free base) was slightly hygroscopic with water uptake of 0.9% between 40-80% RH in the first sorption cycle. A further uptake of 3.8% between 80-90% RH likely resulted in formation of amorphous material, which was then moderately hygroscopic (uptake of 3.3% at 80% RH) in the second sorption cycle. Post-DVS XRPD analysis indicated that predominantly amorphous material was recovered (traces of crystalline Form 1 Compound 1 (free base)) as shown in Figure 24. Example 6. Preparation of Amorphous Compound 1 (free base) and Amorphous Compound 1 di(hydrogen sulfate)

[0315] (A) Amorphous Compound 1 (free base) was used to prepare different crystalline forms. Compound 1 (free base) can be prepared as described by, for example, WO 2021 / 204896 or as described by WO 2023 / 056910, for example, as well.

[0316] (B) Amorphous Compound 1 di(hydrogen sulfate) was used to prepare the single crystal that was used in the Single Crystal Study (see Example 4 above). The amorphous Compound 1 di(hydrogen sulfate) was prepared as follows. Approximately 2.5 g of crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate (see, e.g., Example 4) was added to a 250 mL conical flask. 100 mL of methanol was added to the flask to dissolve the solid at ambient temperature. When complete dissolution was observed, the solvent was removed under vacuum via rotary evaporation. An amorphous solid resulted as determined by XRPD (Figure 25).1H- NMR analysis of a solution of the compound prepared from the solid material was consistent with the1H-NMR spectrum of Compound 1.Attorney Docket No: 01330-0112-00PCT Example 7.

[0317] The oncolytic virus preparation is thawed on the day of surgery and diluted to the required viral titer and volume based on the size of the tumor to be treated and administered within 5 hours.

[0318] In the context of glioblastoma, depending on the tumor stage and characteristics, the oncolytic virus is administered to glioblastoma patients, through one of three main delivery routes: (i) systemic IV administration; (ii) direct intratumoral injection; (iii) intracerebral delivery (e.g., through convection-enhanced delivery (CED)). Intracerebral delivery utilizes a pressure gradient generated by a pump-catheter system put during surgery that enables the delivery of the oncolytic virus to both targeted and adjacent tissues. In some instances, the oncolytic virus is administered to glioblastoma patients under general anesthetic on day 0 in an intraoperative magnetic resonance imaging (MRI) with a stepped needle over a period of 5 minutes using a specialized cannula. Further intraoperative MRI is used to confirm the presence of the injected material in the correct location.

[0319] In other solid cancers where the tumors are accessible (e.g. cutaneous melanoma lesions or certain head and neck cancers), the oncolytic virus is also administered by intratumoral injection, without a requirement for guidance by MRI.

[0320] In some cases, the oncolytic virus is administered by intravenous injection (e.g. in the treatment of multiple tumors or metastases not easily accessible for direct injection).

[0321] For cancers within body cavities, such as ovarian cancer or mesothelioma, the oncolytic virus is administered directly into the cavity (e.g., intraperitoneal injection for the abdominal cavity or intrapleural injection for the pleural cavity). This method aims to saturate the tumor environment with the virus while limiting systemic spread.

[0322] In the specific case of bladder cancer, the oncolytic virus is introduced directly into the bladder through the urethra (intravesical administration). The virus is retained in the bladder for a period to allow it to contact and infect the tumor cells.

[0323] In addition to receiving the oncolytic virus through one of the aforementioned routes, patients are administered tablets comprising crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate orally once or twice daily. EQUIVALENTS

[0324] 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, theAttorney Docket No: 01330-0112-00PCT embodiment may be practiced in many ways and should be construed in accordance with the appended claims and any equivalents thereof.

[0325] 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: 01330-0112-00PCT What is Claimed is:

1. A combination of an ENT1 inhibitor and an oncolytic virus.

2. A pharmaceutical composition comprising an ENT1 inhibitor and an oncolytic virus.

3. A kit of parts comprising an ENT1 inhibitor and an oncolytic virus.

4. A method of treating cancer comprising administering to a subject in need thereof an ENT1 inhibitor and an oncolytic virus.

5. A use of an ENT1 inhibitor and an oncolytic virus in the manufacture of a medicament for the treatment of cancer.

6. The combination, composition, kit, method or use according to any one of claims 1-5, wherein the oncolytic virus is a DNA virus.

7. The combination, composition, kit, method or use according to any one of claims 1-5, wherein the oncolytic virus is an RNA virus.

8. The combination, composition, kit, method or use according to any one of claims 1-5, wherein the oncolytic virus is an adenovirus, a vaccinia virus, a reovirus, a coxsackievirus, or a herpes simplex virus.

9. The combination, composition, kit, method or use according to any one of claims 1-5 and 11, wherein the oncolytic virus is selected from talimogene laherparepvec (T-VEC, Imlygic®), Oncorine (H101), Reolysin (Reovirus), pexastimogene devacirepvec (JX-594, Pexa-Vec), CG0070, pelareorep (Reolysin®), ONYX-015, coxsackievirus A21 (CVA21, CavatakTM), and JX-963.

10. The combination, composition, kit, method or use according to any one of claims 1-9, wherein the ENT1 inhibitor is not dilazep, dipyridamole, or a salt thereof.

11. The combination, composition, kit, method or use according to any one of claims 1-9, wherein the ENT1 inhibitor is a compound of Formula (I):or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R1is selected from the group consisting ofAttorney Docket No: 01330-0112-00PCT ,group - 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 consisting,each 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-; and Z is C or N,Attorney Docket No: 01330-0112-00PCT 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.

12. The combination, composition, kit, method or use according to any one of claims 1-9, wherein the ENT1 inhibitor is a compound of Formula (II):or a pharmaceutically or thereof, wherein R1is 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 selected from absent, -H, ALK, and heteroaryl;R4is , or ; X is selected from the group consisting of -CH2-, -CHF-, and -CF2-;Attorney Docket No: 01330-0112-00PCT each U is independently selected from the group consisting of -O-, -N(R3)-, - C 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.

13. The combination, composition, kit, method or use according to claim 12, wherein the ENT1 inhibitor is a compound of Formula (IIa):(IIa), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein X is CH2, CHF, or CF2.

14. The combination, composition, kit, method or use according to any one of claims 11-13, R1is.

15. The combination, composition, kit, method or use according to claim 14, wherein R1isAttorney Docket No: 01330-0112-00PCTcomposition, kit, method or use according to any one of claims 12-15, wherein the compound is a compound of Formula (IIb):or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

17. The combination, composition, kit, method or use according to any one of claims 11-16, wherein U is -C(O)O-.

18. The combination, composition, kit, method or use according to any one of claims 11, 12, 14, and 15, wherein R4isU in R4is -C(O)O- or -C(O)NR3-.

19. The combination, composition, kit, method or use according to claim 12, wherein the compound is a compound of Formula :(IIa1) or a pharmaceutically acceptable salt, hydrate, or solvate thereof.Attorney Docket No: 01330-0112-00PCT 20. The combination, composition, kit, method or use according to any one of claims 1-12, wherein the ENT1 inhibitor is selected from: (12S)-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate (12R)-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate 16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate (12S)-16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate (12R)-16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate N-(74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane- 12-yl)-3,4,5-trimethoxybenzamide 74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate (12S)-74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate (12R)-74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate 74,75-dimethoxy-5-methyl-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate (12S)-74,75-dimethoxy-5-methyl-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate (12R)-74,75-dimethoxy-5-methyl-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate (11R)-74,75-dimethoxy-6-oxo-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotridecaphane-11- yl 3,4,5-trimethoxybenzoate (10S)-14-chloro-2-oxo-11H-3-aza-1(6,1)-indazola-7(1,4)-diazepanacyclotridecaphane-10-yl 3,4,5-trimethoxybenzoate (10R)-14-chloro-2-oxo-11H-3-aza-1(6,1)-indazola-7(1,4)-diazepanacyclotridecaphane-10-yl 3,4,5-trimethoxybenzoate (12S)-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoateAttorney Docket No: 01330-0112-00PCT (12R)-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5- trimethoxybenzoate (12S)-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl benzoate (12R)-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl benzoate 74,75dichloro-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate (12S)-74,75-dichloro-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate (12R)-74,75-dichloro-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate 75-carbamoyl-74-chloro-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate (11Z,16E,10S)-14-chloro-2-oxo-12H-3-aza-1(6,2)-indazola-7(1,4)- diazepanacyclotridecaphane-10-yl 3,4,5-trimethoxybenzoate (11Z,16E,10R)-14-chloro-2-oxo-12H-3-aza-1(6,2)-indazola-7(1,4)- diazepanacyclotridecaphane-10-yl 3,4,5-trimethoxybenzoate (12S)-74-carbamoyl-75-chloro-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate (12R)- 74-carbamoyl-75-chloro-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate 74-bromo-75-chloro-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate 75-chloro-74-cyano-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane- 12-yl 3,4,5-trimethoxybenzoate (12R)-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl benzoate (12R)-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl benzoate (12S)-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl benzoate (Z)-benzaldehyde O-(74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl) oximeAttorney Docket No: 01330-0112-00PCT-hydroxy-74,75-dimethoxy-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphan- 6-one ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-hydroxybenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-fluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-isopropoxybenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-(trifluoromethyl)benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-(methylsulfonyl)benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-phenoxybenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 2-fluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-bromo-3-cyanobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-methyl-5-(trifluoromethyl)benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 2-fluoro-4-methoxybenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-methoxy-2-(trifluoromethoxy)benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl picolinate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl nicotinate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl pyrazine-2-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 6-hydroxynicotinate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl quinoline-5-carboxylateAttorney Docket No: 01330-0112-00PCT,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl oxazole-4-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 1H-1,2,3-triazole-4-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl acetate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl cyclopropanecarboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-methylbutanoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4,4,4-trifluorobutanoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl cyclohexanecarboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 1-methylpiperidine-4-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,3-dimethylcyclobutane-1-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 2-(oxetan-3-yl)acetate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl (1R,5S,6R)-3-oxabicyclo[3.1.0]hexane-6-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 5-oxopyrrolidine-3-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 1-benzyl-5-oxopyrrolidine-3-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-methoxycyclohexane-1-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 2,6-difluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-(trifluoromethoxy)benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-cyanobenzoateAttorney Docket No: 01330-0112-00PCT,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 2-oxo-1,2,3,4-tetrahydroquinoline-6-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-(difluoromethoxy)benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,5-dichlorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4-dichlorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 2,3-dichlorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 2-chloro-6-fluoro-3-methylbenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-fluoro-5-(trifluoromethyl)benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-fluoro-3-(trifluoromethyl)benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-cyano-3-fluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-(trifluoromethyl)benzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,5-difluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4-difluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-cyano-4-fluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-cyanobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-chloro-4-fluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 1-methyl-1H-benzo[d]imidazole-5-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-(oxazol-5-yl)benzoateAttorney Docket No: 01330-0112-00PCT,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4,5-dichloro-2-fluorobenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5-triethoxybenzoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-methoxypropanoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-(1H-pyrazol-1-yl)propanoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-cyanopropanoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-cyanobutanoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-acetamidobutanoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-(1H-tetrazol-1-yl)propanoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-(dimethylamino)-4-oxobutanoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-acetamidopropanoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-(methylamino)-4-oxobutanoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-(1H-1,2,4-triazol-1-yl)propanoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-morpholino-4-oxobutanoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-(4-fluorophenoxy)propanoate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4,4-difluorocyclohexane-1-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-(trifluoromethyl)cyclohexane-1-carboxylate ,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-(2,5-dioxopyrrolidin-1-yl)propanoateAttorney Docket No: 01330-0112-00PCT 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-methoxycyclohexane-1-carboxylate 74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane- 12-yl benzoate (E)-benzaldehyde O-(74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl) oxime (E)-benzaldehyde O-((12R)- 74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl) oxime (E)-benzaldehyde O-((12S)- 74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphane-12-yl) oxime 12-hydroxy-74,75-dimethoxy-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one (12R)-12-hydroxy-74,75-dimethoxy-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one (12S)-12-hydroxy-74,75-dimethoxy-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one 74,75-dimethoxy-12-(5-phenyl-2H-tetrazol-2-yl)-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one 74,75-dimethoxy-12-(4-phenyl-1H-1,2,3-triazol-1-yl)-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one 74,75-dimethoxy-12-(5-phenyl-1H-tetrazol-1-yl)-5,8-dioxa-1(1,4)-diazepana-7(1,3)- benzenacyclotetradecaphan-6-one, and pharmaceutically acceptable salts, hydrates, or solvates thereof.

21. The combination, composition, kit, method or use according to any one of claims 1-12, wherein the ENT1 inhibitor is selected from Compound 1Compound 1Attorney Docket No: 01330-0112-00PCT and pharmaceutically acceptable salts, hydrates, and solvates thereof.

22. The combination, composition, kit, method or use according to any one of claims 1-12, wherein the ENT1 inhibitor is selected from Compound 1Compound 1 and pharmaceutically acceptable salts thereof.

23. The combination, composition, kit, method or use according to claim 21, wherein the ENT1 inhibitor is a Compound 1 hydrogen sulfate or a hydrate or solvate thereof.

24. The combination, composition, kit, method or use according to claim 23, wherein the ENT1 inhibitor is a Compound 1 di(hydrogen sulfate) or a hydrate or solvate thereof.

25. The combination, composition, kit, method or use according to claim 24, wherein the Compound 1 di(hydrogen sulfate) or a hydrate or solvate thereof is crystalline.

26. The combination, composition, kit, method or use according to claim 25, wherein the crystalline Compound 1 di(hydrogen sulfate) or a hydrate or solvate thereof is crystalline Form 2 Compound 1 di(hydrogen sulfate) trihydrate.

27. The method or use according to any one of claims 4-26, wherein the ENT1 inhibitor is administered prior to, concomitant with, or subsequent to the administration of the oncolytic virus.

28. The method or use according to any one of claims 4-27, wherein the cancer is characterized by a high concentration of adenosine in the tumor microenvironment (TME).

29. The method or use according to any one of claims 4-28, 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.

30. The method or use according to any one of claims 4-29, wherein the cancer is breast cancer.

31. The method or use according to claim 30, wherein the breast cancer is triple negative breast cancer.

32. The method or use according to claims 4-30, wherein the cancer is a solid-tumor cancer.

33. The method or use according to claims 4-29, wherein the cancer is melanoma, prostate cancer, glioblastoma, or esophageal carcinoma.

Images