The combination of pool and PARP inhibitors to treat cancer

Abstract

Provided herein are combinations of polymerase theta (Polθ) helicase inhibitors and second therapeutic agents and methods comprising administering to a subject in need thereof such combinations for the treatment of cancer.

Description

Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)COMBINATION OF POLYMERASE THETA INHIBITORS AND METHODS OF USING THE SAMERELATED APPLICATIONS

[0001] This application claims priority to, and the benefit of, U.S. Provisional Application No. 63 / 702,493, filed October 2, 2024; U.S. Provisional Application No. 63 / 772,354, filed March 14, 2025; U.S. Provisional Application No. 63 / 775,575, filed March 21, 2025; U.S. Provisional Application No. 63 / 794,898, filed April 25, 2025; and U.S. Provisional Application No. 63 / 821,829, filed June 11, 2025, the entire contents of which are incorporated herein by reference.BACKGROUND

[0002] The present disclosure relates to the combination of small molecule inhibitors of DNA polymerase theta (I’olG) with poly(adenosine diphosphate [ADP] -ribose) polymerase (PARI’) inhibitors for the treatment of cancer.

[0003] PolO is a cellular protein that functions to repair DNA double-strand breaks (DSBs) that occur during DNA replication or as the result of genotoxic stress. PolO consists of an N-terminal DNA helicase domain and a C-terminal DNA polymerase domain that coordinately repair DSBs via a process known as theta-mediated end-joining (TMEJ). In normal cells, PolG activity is largely dispensable, as DSB repair is performed by the primary pathways of nonhomologous end-joining (NHEJ) and homoglous recombination (HR). In contrast, PolO activity is essential in cancer cells in which mutations have disabled these primary' repair pathways. For example, HR-deficient proteins including breast cancer gene 1 (BRCA1), breast cancer gene 2 (BRCA2), partner and localizer of BRCA2 (PALB2), and paralogs of radiation-sensitive protein 51 (RAD51) are prevalent in many types of cancer, creating a dependence on PolO DNA repair activity .

[0004] PARI’ inhibitors are a class of cancer therapeutics that block the repair of DNA breaks which may be useful for the treatment of various cancers. While PolO helicase inhibitors and PARP inhibitors can individually disrupt the repairing of DSBs, the combination of the two inhibitors may provide new therapeutic potential.

[0005] This disclosure arises from the need to provide a combination therapy for the treatment of cancer, e.g., a combination therapy comprising a polymerase theta (PolG) helicase inhibitor and a PARP inhibitor.1316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)SUMMARY

[0006] In some aspects, the present disclosure provides a combination therapy comprising:(a) a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a second therapeutic agent.

[0007] In some aspects, the present disclosure provides a combination therapy comprising:(a) a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a poly(adenosine diphosphate [ADP]-ribose) polymerase (PARI5) inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0008] In some aspects, the present disclosure provides a combination therapy comprising:(a) a polymerase theta (Pol0) helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a poly(adenosine diphosphate [ADP] -ribose) polymerase (PARP) inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof,

[0009] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent, for use in combination for treating or preventing cancer in a subject.

[0010] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, for use in combination for treating or preventing cancer in a subject.

[0011] In some aspects, the present disclosure provides a polymerase theta (Pol0) helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, for use in combination for treating or preventing cancer in a subject.

[0012] In some aspects, the present disclosure provides a method of treating or preventing cancer, comprising administering to a subject:(a) a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and318259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)(b) a second therapeutic agent.

[0013] In some aspects, the present disclosure provides a method of treating or preventing cancer, comprising administering to a subject:(a) a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0014] In some aspects, the present disclosure provides a method of treating or preventing cancer, comprising administering to a subject:(a) a polymerase theta helicase (PolO) inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0015] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of cancer in a subject.

[0016] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of cancer in a subject.

[0017] In some aspects, the present disclosure provides a polymerase theta helicase (PolO) inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of cancer in a subject.

[0018] In some aspects, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with a second therapeutic agent, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of cancer in a subject.3316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0019] In some aspects, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of cancer in a subject.

[0020] In some aspects, the present disclosure provides use of a polymerase theta helicase (Pol0) inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of cancer in a subject.

[0021] In some aspects, the present disclosure provides kit comprising:(a) a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a second therapeutic agent.

[0022] In some aspects, the present disclosure provides kit comprising:(a) a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0023] In some aspects, the present disclosure provides kit comprising:(a) a polymerase theta helicase (PolO) inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and(b) a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0024] In some aspects, the present disclosure provides a pharmaceutical package comprising:(a) a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a second therapeutic agent.

[0025] In some aspects, the present disclosure provides a pharmaceutical package comprising:(a) a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and4316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)(b) a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0026] In some aspects, the present disclosure provides a pharmaceutical package comprising:(a) a polymerase theta helicase (Pol9) inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0027] In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is a polymerase theta helicase (Pol0) inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0028] In some aspects, the polymerase theta (Pol0) helicase inhibitor is a compound of Formula I:or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein:Ralis H, oxo, halo, cyano, -OH, -NH?., -NH(CI-C6 alkyl), -N(CI-C6 alkyl)?, -C(O)(Ci-C6 alkyl), -C(0)(C3-Cio cycloalkyl), Ci-Ce alkyl, Cz-CA alkenyl, Cz-Ce alkynyl, Ci-Cs haloalkyl, Ci- Cs alkoxy, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10- membered heteroaryl, wherein the -C(0)(C3-Cto cycloalkyl), Ci-Ce alkyl, Cz-Ce alkenyl, C?-Ce alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more Ra2; each Ra2independently is oxo, halo, cyano, -OH, -NHz, -NH(Ci-Ce alkyl), -N(CJ-C6 alkyl)?, Ci-Ce alkyl optionally substituted with Ci-Ce alkoxy or -OH, C3-C10 cycloalkyl, Ci-Ce haloalkoxy, Ci-Ce haloalkyl, Ci-Ce alkoxy, 3- to 10-membered heterocycloalkyl optionally substituted with oxo, or 5- to 10-membered heteroaryl;R3ais halo, cyano, -OH, -NH?, Ci-Ce alkyl, Cz-Ce alkenyl, Cz-Q alkynyl, Ci-Ce haloalkyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the Ci-Q alkyl, Cz-Q alkenyl, C2-C0 alkynyl, Ci-Ce haloalkyl, C3-C105316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO) cycloalkyl, 3- to 10-membered heterocycloalkyl, Cs-Cio aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R3al; and each R3a3independently is oxo, halo, cyano, -OH, -C(O)(Ci-C6 alkyl), -C(O)(O-(Ci-Q alkyl)), Ci-Co alkyl optionally substituted with C3-C10 cycloalkyl, Cj-Ce alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce haloalkoxy, Ci-Cs alkoxy, -OfCi-Ce haloalkyl),C3-Cio cycloalkyl, Cs-Cto aryl, or 5- to 10-membered heteroaryl.

[0029] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting. In the case of conflict between the chemical structures and names of the compounds disclosed herein, the chemical structures will control.

[0030] Other features and advantages of the disclosure will be apparent from the following detailed description and claims.BRIEF DESCRIPTION OF THE FIGURES

[0031] This patent or application file contains at least one figure executed in color. Copies of this patent or patent application with color figure(s) will be provided by the Office upon request and payment of the necessary fee.

[0032] FIG. 1 shows (A) the dose- response curve and (B) the Loewe Excess Matrix for Compound 15 in combination with 0.75, 2.9. 11.7, 46.9, 188, 750, or 3000 nM olaparib for DoTc24510 cells. Error bars represent the standard deviation of the mean. Regions of mathematical synergy are shaded in proportion to the synergistic benefit.

[0033] FIG. 2 show's the dose-response curves for Compound 15 in combination with olaparib for the (A) DLD1-BRCA2-KO cells (0.41, 1.2, 3.7, 11.1, 33.3, 100, or 300 nM olaparib) and (B)6316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)Capan-1 cells (0,8, 3.1, 12.5, 50, or 200 nM olaparib). Error bars represent the standard deviation of the mean.

[0034] FIG. 3 shows the time-dependent induction of (A) DNA damage and (B) apoptosis in DoTc24510 cells in response to treatment with Compound 15 (30 nM), olaparib (300 nM), saruparib (5 nM) as single-agents, or Compound 15 (30 nM) in combination with olaparib (300 nM) or saruparib (5 nM).

[0035] FIG. 4 shows (A) the mean tumor volume vs. time; (B) the mean percent change in body weight from day 0 vs. time; and (C) Compound 15 concentration versus time for mice harboring DLD1-BRCA2-KO tumor xenografts treated with the vehicle, olaparib as a single-agent (100 mg / kg QD), Compound 15 as a single-agent (10 mg / kg BID), and Compound 15 (0.3, 1, 3, or 10 mg / kg BID) in combination with olaparib (100 mg / kg QD) against DLD1-BRCA2-KO tumor xenografts. Error bars represent the standard deviation of the mean. ** P value < 0.01, *** P value < 0.001, **** p value < 0.0001.

[0036] FIG. 5 shows tumor volume over time against DLD1-BRCA2-KO tumor xenografts in mice treated with Compound 15 and olaparib as single agents and in combination, with variations in the olaparib dose level (A) and combination dosing schedule (B).

[0037] FIG. 6 shows tumor volume over time against PDX models from different tissues with HRD genotypes following administration with vehicle, olaparib as a single-agent. Compound 15 as a single-agent, and Compound 15 in combination with olaparib, including (A), (D), & (E) pancreatic, (B) ovarian, and (C) breast PDX models. PDX #2 and PDX #1 of FIGs. 6A and 6E, respectively, correspond to two PDX models with different inactivating mutations in BRCA2.

[0038] FIG. 7 shows tumor volume over time in HR-deficient Capanl pancreatic tumor xenografts in mice treated with vehicle, olaparib as a single-agent, Compound 15 as a single-agent, and Compound 15 in combination with olaparib.

[0039] FIG. 8 shows (A) the dose- response curve and (B) the Loewe Excess Matrix for Compound 15 m combination with 0.02, 0.09, 0.39, 1.56, 6.25, 25, or 100 nM Compound 1064 for DoTc24510 cells. Error bars represent the standard deviation of the mean. Regions of mathematical synergy are shaded in proportion to the synergistic benefit.

[0040] FIG. 9 shows (A) the mean tumor volume vs. time; (B) the mean percent change in body weight from day 0 vs. time; and (C) Compound 18 concentration versus time for mice harboring DLD1-BRCA2-KO tumor xenografts treated with vehicle, olaparib as a single-agent (100 mg / kgAttorney Docket No.: 43705-02087, AVO (MOMA-010 / 001 WO)QD), Compound 18 as a single-agent (100 mg / kg BID), and Compound 18 (10, 30, or 100 mg / kg BID) in combination with olaparib (100 mg / kg QD). Error bars represent the standard deviation of the mean.

[0041] FIG. 10 shows (A) the mean tumor volume vs. time; and (B) the mean percent change in body weight from day 0 vs. time for mice harboring DLD1-BRCA2-KO tumor xenografts treated with vehicle, Compound 1064 as a single-agent (1 mg / kg QD), Compound 15 as a single-agent (0.3 and 10 mg / kg BID), and Compound 15 (0.3 or 10 mg / kg BID) in combination with Compound 1064 (1 mg / kg QD). Error bars represent the standard deviation of the mean. Asterisks indicate statistical significance with respect to Compound 1064 single-agent treatment as follows: **** P < 0.0001.

[0042] FIG. 11 shows (A) the mean tumor volume vs. time; and (B) the mean percent change in body weight from day 0 vs. time for mice harboring Capan-1 BRCA2muttumor xenografts treated with vehicle, Compound 1064 as a single-agent (0.3 and 10 mg / kg QD), Compound 15 as a singleagent (30 mg / kg BID), and Compound 15 (30 mg / kg BID) in combination with Compound 1064 (0.3 and 10 mg / kg QD). Error bars represent the standard deviation of the mean. Asterisks indicate statistical significance with respect to Compound 1064 single-agent treatment as follows: *** P < 0.001, 0.0001.DETAILED DESCRIPTIONDefinitions

[0043] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0044] Without wishing to be limited by this statement, it is understood that, while various options for variables are described herein, the disclosure intends to encompass operable embodiments having combinations of the options. The disclosure may be interpreted as excluding the non- operable embodiments caused by certain combinations of the options. For example, while various options for variables Ra!, Ra2, R3a, and R3alare described herein, the disclosure may be interpreted as excluding structures for non-operable compound caused by certain combinations of variables Ra!, Ra2, R3a, and R3ai.

[0045] As used herein, “alkyl”, “Ci, C2, C3, C4, Cs or Ce alkyl” or “Ci-C e alkyl” is intended to include Ci, C?, C3, Ch, Cs or Ce straight chain (linear) saturated aliphatic hydrocarbon groups and8316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)CJ, C4, Cs or Q branched saturated aliphatic hydrocarbon groups. For example, CpCg alkyl includes C1;C2, C3, C4, C5and C6alkyl groups. Examples of alkyl include, moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl. In some embodiments, a straight chain or branched alkyl has six or fewer carbon atoms (e.g., Ci-Ce for straight chain, Cs-Ce for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms.

[0046] As used herein, the term ‘'‘optionally substituted alkyl” refers to unsubstituted alkyl or alkyl having designated substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkydarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety7.

[0047] As used herein, the term “alkenyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond. For example, the term “alkenyl” includes straight chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched alkenyl groups. In certain embodiments, a straight chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term “C2-C6” includes alkenyl groups containing two to six carbon atoms. The term “C3-C6” includes alkenyl groups containing three to six carbon atoms.

[0048] As used herein, the term “optionally substituted alkenyl” refers to unsubstituted alkenyl or alkenyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxy carbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, aAttorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO) phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0049] As used herein, the term “alkynyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, “alkynyl” includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyi, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), and branched alkynyl groups. In certain embodiments, a straight chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g., Cz-Cs for straight chain, Cs-Ce for branched chain). The term “Cz-Ce” includes alkynyl groups containing two to six carbon atoms. The term “Cs-Cs” includes alkynyl groups containing three to six carbon atoms. As used herein, “C2-C6 alkenylene linker” or “C2-C0 alkynylene linker” is intended to include C2, C3, C4, C5 or Ce chain (linear or branched) divalent unsaturated aliphatic hydrocarbon groups. For example, C2-C6alkenylene linker is intended to include C2, C3, C4, C5 and Ce alkenylene linker groups.

[0050] As used herein, the term “optionally substituted alkynyl” refers to unsubstituted alkynyl or alkynyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxy carbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinate, ammo (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0051] Other optionally substituted nioieties (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both the unsubstituted moieties and the moieties having one or more of the designated substituents. For example, substituted heterocycloalkyl10316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO) includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl- 1 ,2,3 ,6-tetrahydropyridinyl.

[0052] .As used herein, the term “cycloalkyl” refers to a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spiro rings) system having 3 to 30 carbon atoms (e.g., C3-C12, C3-C10, or Cs-Cs). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1 ,2,3,4-tetrahydronaphthalenyl, and adamantyl. In the case of polycyclic cycloalkyl, only one of the rings in the cycloalkyl needs to be non-aromatic.

[0053] As used herein, the term “heterocycloalkyl” or “heterocyclyl” refers to a saturated or partially unsaturated 3-8 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spiro rings), or 11 - 14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms (such as O, N, S, P, or Se), e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g.s1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur, unless specified otherwise. Examples of heterocycloalkyl groups include, but are not limited to, pipendinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazol idinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1 ,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5- azabicyclo[2.2.1 ]heptanyl, 2,5-diazabicyclo[2.2.1 ]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6- diazaspiro[3.3]heptanyl, 1 ,4-dioxa-8-azaspiro[4.5]decanyl, 1 ,4-di oxaspiro [4.5]decanyl, 1 - oxaspiro[4.5]decanyl, 1 -azaspiro[4.5]decanyl, 3'H-spiro[cyclohexane- 1 , 1 '-isobenzofuran]-yl, 7'H- spiro[cyclohexane-l,5'-furo[3,4-b]pyridin]-yl, 3U-spiro[cyc1ohexane-l,r-furo[3,4-c]pyridin]-yl, 3-azabicyclo[3. 1.0]hexanyl, 3-azabicyclo[3.1 ,0]hexan-3-yl, 1 ,4,5,6-tetrahydropyrrolo[3,4- c]pyrazolyl, 3,4,5,6,7,8-hexahydropyndo[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-lH-pyrazolo[3,4- c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2- azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2-azaspiro[3.5]nonanyl, 2- azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa-azaspiro[3.4]octanyl, 2-oxa- azaspiro[3.4]octan-6-yl, 5,6-dihydro-4H-cyclopenta[b]thiophenyl, and the like. In the case of multicyclic heterocycloalkyl, only one of the rings in the heterocycloalkyl needs to be nonaromatic (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).11316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0054] It is understood that when a vanable has two attachments to the rest of the formula of the compound, the two atachments could be at the same atom or different atoms of the variable. For example, when a variable (e.g., variable X) is cycloalkyl or heterocycloalkyl, and has two attachments to the rest of the formula of the compound, the two attachments could be at the same atom or different atoms of the cycloalkyl or heterocycloalkyl.

[0055] As used herein, the term “aryl” includes groups with aromaticity, including “conjugated,” or multicychc systems with one or more aromatic rings and do not contain any heteroatom in the ring structure. The term aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like.

[0056] As used herein, the term “heteroaryl” is intended to include a stable 5-, 6-, or 7-membered monocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromatic heterocyclic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g.t1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or other substituents, as defined). The nitrogen and sulfur heteroatoms may optionally be oxidised (i.e., N(R)0 and S(O)P, where p = 1 or 2). It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, isothiazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like. Heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0057] Furthermore, the terms “aryl” and “heteroaryl” include multicychc aryl and heteroaryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, quinoline, isoquinoline, naphthrydine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine.

[0058] When a ring is denoted with a circle and all ring members are carbon atoms (e.g.,), the ring is an aryl ring. When a ring is denoted with a circle and comprises at least one ring12316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO) member that is a heteroatom (e.g,the ring is a heteroaryl ring. Multicyclic aryl

[0059] The cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring can be substituted at one or more ring positions (e.g., the ring-forming carbon or heteroatom such as N) with such substituents as described above, for example, aikyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxy carbonyl oxy, aryloxy carbonyl oxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkyl carbonyl, alkenylcarbonyl, alkoxy carbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinate, ammo (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkyl carbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl and heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., tetralin, methylenedioxyphenyl such as benzo[d][l,3]dioxole-5-yl).

[0060] As used herein, the term “about” refers to a recited amount, value, or duration ± 10 % or less of said amount, value, or duration. In some embodiments, “about” refers to a recited amount, value, or duration ± 10 %, ± 8 %, ± 6 %, ± 5 %, ± 4 %, ± 2 %, ± 1 %, or ± 0.5 %. In other embodiments, “about” refers to a recited amount, value, or duration ± 10 %, ± 8 %, ± 6 %, ± 5 %, ± 4 %, or ± 2 %. In other embodiments, “about” refers to a recited amount, value, or duration ± 5 %. In some embodiments, “about” refers to a listed amount, value, or duration ± 2 % or ± 1 %. For example, in some embodiments, when the term “about” is used when reciting a temperature or temperature range, these terms refer to the recited temperature or temperature range ± 5 °C, ± 2 °C, or ± 1 °C. In other embodiments, the term “about” refers to the recited temperature or temperature range ± 2CC.

[0061] As used herein, the term “substituted,” means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated groups, provided that the13316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO) designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is oxo or keto (i.e., =0), then 2 hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moieties. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, (>=N or N:;=N). “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0062] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such formula. Combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0063] When any variable (e.g, R) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R moieties, then the group may optionally be substituted with up to two R moieties and R at each occurrence is selected independently from the definition of R. Also, combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0064] As used herein, the term “hydroxy” or “hydroxyl” includes groups with an -OH or -O'.

[0065] As used herein, the term “halo” or “halogen” refers to fluoro, chloro, bromo and iodo.

[0066] The term “haloalkyl” or “haloalkoxyl” refers to an alkyl or alkoxyl substituted with one or more halogen atoms.

[0067] As used herein, the term “optionally substituted haloalky l” refers to unsubstituted haloalky l having designated substituents replacing one or more hy drogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxy carbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinate, ammo (including alkylamino, dialkylamino, arylamino, diarylamino and alkydarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino,14316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO) sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0068] As used herein, the term “alkoxy” or “alkoxyl” includes substituted and unsubstituted alkyl, alkenyl and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaniinocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, di chloromethoxy and trichloromethoxy.

[0069] As used herein, the expressions “one or more of A, B, or C,” “one or more A, B, or C,” “one or more of A, B, and C,” “one or more A, B, and C,” “selected from the group consisting of A, B, and C”, “selected from A, B, and C”, and the like are used interchangeably and all refer to a selection from a group consisting of A, B, and / or C, be., one or more As, one or more Bs, one or more Cs, or any combination thereof, unless indicated otherwise.

[0070] It is to be understood that, throughout the description, where compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.15316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0071] It is to be understood that compounds of the present disclosure can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, M. B., March, J., March 's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5thedition, John Wiley & Sons: New' York, 2001; Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rdedition, John Wiley & Sons: New' York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser s Reagents for organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.. Encyclopedia of Reagents for organic Synthesis, John Wiley and Sons (1995), incorporated by reference herein, are useful and recognized reference textbooks of organic synthesis known to those in the art.

[0072] It is to be understood that, unless otherwise stated, any description of a method of treatment or prevention includes use of the compounds to provide such treatment or prevention as is described herein. It is to be further understood, unless otherwise stated, any description of a method of treatment or prevention includes use of the compounds to prepare a medicament to treat or prevent such condition. The treatment or prevention includes treatment or prevention of human or non-hurnan animals including rodents and other disease models.

[0073] It is to be understood that, unless otherwise stated, any description of a method of treatment includes use of the compounds to provide such treatment as is described herein. It is to be further understood, unless otherwise stated, any description of a method of treatment includes use of the compounds to prepare a medicament to treat such condition. The treatment includes treatment of human or non-human animals including rodents and other disease models.

[0074] As used herein, the term “subject” includes human and non-human animals, as well as cell lines, cell cultures, tissues, and organs. In some embodiments, the subject is a mammal. The mammal can be e.g., a human or appropriate non-human mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig. The subject can also be a bird or fowl. In some embodiments, the subject is a human.16316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0075] As used herein, the term “subject in need thereof’ refers to a subject having a disease or having an increased risk of developing the disease. A subject in need thereof can be one who has been previously diagnosed or identified as having a disease or disorder disclosed herein. A subject in need thereof can also be one who is suffering from a disease or disorder disclosed herein. Alternatively, a subject in need thereof can be one who has an increased risk of developing such disease or disorder relative to the population at large (i.e., a subject who is predisposed to developing such disorder relative to the population at large). A subject in need thereof can have a refractor}' or resistant a disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond or has not yet responded to treatment). The subject may be resistant at start of treatment or may become resistant during treatment. In some embodiments, the subject in need thereof received and failed all known effective therapies for a disease or disorder disclosed herein. In some embodiments, the subject in need thereof received at least one prior therapy.

[0076] As used herein, the term “treating” or “treat” describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder. The term “treat” can also include treatment of a cell in vitro or an animal model. It is to be appreciated that references to “treating” or “treatment” include the alleviation of established symptoms of a condition. “Treating” or “treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclmical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

[0077] It is to be understood that a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hy drate, or prodrug thereof, can or may also be used to prevent a relevant disease, condition or disorder, or used to identify suitable candidates for such purposes.17316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0078] As used herein, the term “preventing,” “prevent,” or “protecting against” describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder.

[0079] It is to be understood that one skilled in the art may refer to general reference texts for detailed descriptions of known techniques discussed herein or equivalent techniques. These texts include Ausubel etal., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook el al.. Molecular Cloning, A Laboratory Manual (3rdedition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al.. Current Protocols in Immunology, John Wiley & Sons, N.Y.; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, N.Y.; Fingl et al.. The Pharmacological Basis of Therapeutics (1975), Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18thedition (1990). These texts can, of course, also be referred to in making or using an aspect of the disclosure.

[0080] It is to be understood that the present disclosure also provides pharmaceutical compositions comprising any compound described herein in combination with at least one pharmaceutically acceptable excipient or carrier,

[0081] As used herein, the term “pharmaceutical composition” is a formulation containing the compounds of the present disclosure in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial. The quantity of active ingredient (e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved. One skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for the topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, diluent,18316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO) adjuvant, excipient, or a combination thereof, and with any preservatives, buffers, or propellants that are required.

[0082] As used herein, the term “pharmaceutically acceptable” refers to those compounds, anions, cations, materials, compositions, carriers, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0083] As used herein, the term “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use. A “pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient.

[0084] It is to be understood that a pharmaceutical composition of the disclosure is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediarninetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

[0085] It is to be understood that a compound or pharmaceutical composition of the disclosure can be administered to a subject in many of the well-known methods currently used for chemotherapeutic treatment. For example, a compound of the disclosure may be injected into the blood stream or body cavities or taken orally or applied through the skin with patches. The dose chosen should be sufficient to constitute effective treatment but not so high as to cause unacceptable side effects. The state of the disease condition (e.g., a disease or disorder disclosed19316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO) herein) and the health of the patient should preferably be closely monitored during and for a reasonable period after treatment.

[0086] .As used herein, the term “therapeutically effective amount,” refers to an amount of a pharmaceutical agent to treat, ameliorate, and / or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration.

[0087] The pharmaceutical compositions containing active compounds of the present disclosure may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes. Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and / or auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Of course, the appropriate formulation is dependent upon the route of admini strati on chosen.

[0088] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor ELO (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), cyclodextrins and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol and sorbitol, and sodium20316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO) chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum nionostearate and gelatin.

[0089] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile filtered solution thereof.

[0090] Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier, diluent, adjuvant, excipient, or a combination thereof. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, capsules or sachets. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid earner is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch, a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, orange flavoring.

[0091] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

[0092] Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.21316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)Transmucosal administration can be accomplished through the use of nasal sprays, powders or suppositories. For transdermai administration, the active compounds are formulated into ointments, salves, geis, or creams as generally known in the art.

[0093] The active compounds can be prepared with pharmaceutically acceptable carrier, diluent, adjuvant, excipient, or a combination thereof that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polygly colic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[0094] It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary' dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the disclosure are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved.

[0095] In therapeutic applications, the dosages of the pharmaceutical compositions used in accordance with the disclosure vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage. Generally, the dose should be sufficient to result in slowing, and preferably regressing, the symptoms of the disease or disorder disclosed herein and also preferably causing complete regression of the disease or disorder.

[0096] It is to be understood that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.22316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0097] It is to be understood that, for the compounds of the present disclosure being capable of further forming salts, all of these forms are also contemplated within the scope of the claimed disclosure.

[0098] As used herein, the term “pharmaceutically acceptable salts” refer to derivatives of the compounds of the present disclosure wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral organic acid salts of basic residues such as amines, alkali organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary’ ammonium salts of the parent compound formed, for example, from non-toxic inorganic organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, 1,2-ethane sulfonic, fumaric, glucohept onic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcmic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobi onic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluene sulfonic, and the commonly occurring amine acids, e.g., glycine, alanine, phenylalanine, arginine, etc.

[0099] In some embodiments, the pharmaceutically acceptable salt is a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a diethylamine salt, a choline salt, a meglumine salt, a benzathine salt, a tromethamine salt, an ammonia salt, an arginine salt, or a lysine salt.

[0100] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4- chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphor sulfonic acid, 4-methylbicyclO“[2.2.2]-oct-2-ene-l-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. In the salt form, it is understood that the ratio of23316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO) the compound to the cation or anion of the salt can be 1:1, or any ratio other than 1 : 1, e.g., 3: 1 , 2: 1, 1 :2, or 1:3.

[0101] The compounds, or pharmaceutically acceptable salts thereof, are administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally. In one embodiment, the compound is administered orally. One skilled in the art will recognise the advantages of certain routes of administration.

[0102] The dosage regimen utilizing the compounds is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.

[0103] Techniques for formulation and administration of the disclosed compounds of the disclosure can be found in Remington: the Science and Practice of Pharmacy, 19toedition, Mack Publishing Co., Easton, PA (1995). In an embodiment, the compounds described herein, and the pharmaceutically acceptable salts thereof, are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier, diluent, adjuvant, excipient, or a combination thereof. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous organic solutions. The compounds will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein.

[0104] All percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present disclosure are apparent from the different examples. The provided examples illustrate different components and methodology useful in practicing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure the skilled artisan can identify and employ other components and methodology useful for practicing the present disclosure.

[0105] All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor does it constitute any admission as to the contents or date of the same. The invention having now been described by way of written description, those of skill in the art will recognize that the invention can be practiced in a variety' of embodiments and that the24316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO) foregoing description and examples below are for purposes of illustration and not limitation of the claims that follow.

[0106] .As use herein, the phrase “compound of the disclosure” refers to those compounds which are disclosed herein, both generically and specifically.

[0107] “Combination therapy” or “combination treatment” refers to the use of two or more drugs or agents in treatment. For example, the use of a compound of Formula (I), (I-a), ( I-b), (I-a’), (I- b’), (I-c), or ( I -c ’ ) of the present disclosure together with at least one additional agent useful to treat cancer (e.g, a PARP inhibitor), or a symptom of cancer, is a combination therapy. Administration in “combination” refers to the administration of two agents (e.g, a compound of Formula (I), (I-a), (I-b), (I-a’), (I-b’), (I-c), or (I-c’) of the present disclosure, and at least one additional agent) in any manner in which the pharmacological effects of both manifest in the subject. Thus, administration in combination does not require that a single pharmaceutical composition, the same dosage form, or even the same route of administration be used for administration of both agents or that the two agents be administered at precisely the same time. Both agents can also be formulated in a single pharmaceutically acceptable composition. In some embodiments, the each agent may be administered in temporal proximity, sequentially, or in alternation.Combinations

[0108] In some aspects, the present disclosure provides a combination therapy comprising:(a) a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a second therapeutic agent.

[0109] In some aspects, the present disclosure provides a combination therapy comprising:(a) a polymerase theta ( PolO) helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a second therapeutic agent.

[0110] In some aspects, the present disclosure provides a combination therapy comprising:(a) Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a second therapeutic agent.25316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0111] In some aspects, the present disclosure provides a combination therapy comprising:(a) Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a second therapeutic agent.

[0112] In some aspects, the present disclosure provides a combination therapy comprising:(a) a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a poly(adenosine diphosphate [ADP]-ribose) polymerase (PARI5) inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0113] In some aspects, the present disclosure provides a combination therapy comprising:(a) a polymerase theta (Pol0) helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a poly(adenosine diphosphate [ADP] -ribose) polymerase (PARP) inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof,

[0114] In some aspects, the present disclosure provides a combination therapy comprising:(a) Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0115] In some aspects, the present disclosure provides a combination therapy comprising:(a) Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and(b) a poly (adenosine diphosphate [ADP] -ribose) polymerase (PARP) inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0116] In some aspects, the present disclosure provides a combination therapy comprising:(a) a polymerase theta (Pol0) helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) olaparib.

[0117] In some aspects, the present disclosure provides a combination therapy comprising:(a) Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and26316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)(b) olaparib.

[0118] In some aspects, the present disclosure provides a combination therapy comprising:(a) Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) olaparib.

[0119] In some aspects, the present disclosure provides a combination therapy comprising:(a) a polymerase theta (PolO) helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1064, or a pharmaceutically acceptable salt thereof.

[0120] In some aspects, the present disclosure provides a combination therapy comprising:(a) a polymerase theta (PolO) helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1056, or a pharmaceutically acceptable salt thereof.

[0121] In some aspects, the present disclosure provides a combination therapy comprising:(a) a polymerase theta (PolO) helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1056a, or a pharmaceutically acceptable salt thereof.

[0122] In some aspects, the present disclosure provides a combination therapy comprising:(a) a polymerase theta (PolO) helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and(b) Compound 1056b, or a pharmaceutically acceptable salt thereof.

[0123] In some aspects, the present disclosure provides a combination therapy comprising:(a) Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1064, or a pharmaceutically acceptable salt thereof.

[0124] In some aspects, the present disclosure provides a combination therapy comprising:(a) Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1064, or a pharmaceutically acceptable salt thereof.

[0125] In some aspects, the present disclosure provides a combination therapy comprising:27316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)(a) Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1056, or a pharmaceutically acceptable salt thereof.

[0126] In some aspects, the present disclosure provides a combination therapy comprising:(a) Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1056, or a pharmaceutically acceptable salt thereof.

[0127] In some aspects, the present disclosure provides a combination therapy comprising:(a) Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1056a, or a pharmaceutically acceptable salt thereof.

[0128] In some aspects, the present disclosure provides a combination therapy comprising:(a) Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1056a, or a pharmaceutically acceptable salt thereof.

[0129] In some aspects, the present disclosure provides a combination therapy comprising:(a) Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1056b, or a pharmaceutically acceptable salt thereof.

[0130] In some aspects, the present disclosure provides a combination therapy comprising:(a) Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and(b) Compound 1056b, or a pharmaceutically acceptable salt thereof.

[0131] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent, for use in combination for treating or preventing cancer in a subject.

[0132] In some aspects, the present disclosure provides a PolO helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent, for use in combination for treating or preventing cancer in a subject.28316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0133] In some aspects, the present disclosure provides Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent, for use in combination for treating or preventing cancer in a subject.

[0134] In some aspects, the present disclosure provides Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent, for use in combination for treating or preventing cancer in a subject.

[0135] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a PARI’ inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, for use in combination for treating or preventing cancer in a subject.

[0136] In some aspects, the present disclosure provides a PolO helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, for use in combination for treating or preventing cancer in a subject.

[0137] In some aspects, the present disclosure provides Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, for use in combination for treating or preventing cancer in a subject.

[0138] In some aspects, the present disclosure provides Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, for use in combination for treating or preventing cancer in a subject.

[0139] In some aspects, the present disclosure provides a Poll) helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and olaparib, for use in combination for treating or preventing cancer in a subject.

[0140] In some aspects, the present disclosure provides Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and olaparib for use in combination for treating or preventing cancer in a subject.

[0141] In some aspects, the present disclosure provides Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and olaparib for use in combination for treating or preventing cancer in a subject.29316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0142] In some aspects, the present disclosure provides a PolO helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1064, or a pharmaceutically acceptable salt thereof, for use in combination for treating or preventing cancer in a subject.

[0143] In some aspects, the present disclosure provides a PolO helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1056, or a pharmaceutically acceptable salt thereof, for use in combination for treating or preventing cancer in a subject.

[0144] In some aspects, the present disclosure provides a PolO helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1056a, or a pharmaceutically acceptable salt thereof, for use in combination for treating or preventing cancer in a subject.

[0145] In some aspects, the present disclosure provides a PolO helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1056b, or a pharmaceutically acceptable salt thereof, for use in combination for treating or preventing cancer in a subject.

[0146] In some aspects, the present disclosure provides Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1064, or a pharmaceutically acceptable salt thereof, for use in combination for treating or preventing cancer in a subject.

[0147] In some aspects, the present disclosure provides Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1064, or a pharmaceutically acceptable salt thereof, for use in combination for treating or preventing cancer in a subject.

[0148] In some aspects, the present disclosure provides Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1056, or a pharmaceutically acceptable salt thereof, for use in combination for treating or preventing cancer in a subject.

[0149] In some aspects, the present disclosure provides Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1056, or a pharmaceutically acceptable salt thereof, for use in combination for treating or preventing cancer in a subject.

[0150] In some aspects, the present disclosure provides Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1056a, or a pharmaceutically acceptable salt thereof, for use in combination for treating or preventing cancer in a subject.30316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0151] In some aspects, the present disclosure provides Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1056a, or a pharmaceutically acceptable salt thereof, for use in combination for treating or preventing cancer in a subject.

[0152] In some aspects, the present disclosure provides Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1056b, or a pharmaceutically acceptable salt thereof, for use in combination for treating or preventing cancer in a subject.

[0153] In some aspects, the present disclosure provides Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1056b, or a pharmaceutically acceptable salt thereof, for use in combination for treating or preventing cancer in a subject.

[0154] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent, for use in combination for treating cancer in a subject.

[0155] In some aspects, the present disclosure provides a PolO helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent, for use in combination for treating cancer in a subject.

[0156] In some aspects, the present disclosure provides Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent, for use in combination for treating cancer in a subject.

[0157] In some aspects, the present disclosure provides Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent, for use in combination for treating cancer in a subject.

[0158] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, for use in combination for treating cancer in a subject.

[0159] In some aspects, the present disclosure provides a Pol0 helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, for use in combination for treating cancer in a subject.

[0160] In some aspects, the present disclosure provides Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a PARP inhibitor, or a pharmaceutically31316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO) acceptable salt, solvate, hydrate, or prodrug thereof, for use in combination for treating cancer in a subject.

[0161] In some aspects, the present disclosure provides Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a PARI’ inhibitor, or a pharmaceutically acceptable salt, solvate, hy drate, or prodrug thereof, for use in combination for treating cancer in a subject.

[0162] In some aspects, the present disclosure provides a Pol0 helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and olaparib, for use in combination for treating cancer in a subject.

[0163] In some aspects, the present disclosure provides Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and olaparib for use in combination for treating cancer in a subject.

[0164] In some aspects, the present disclosure provides Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and olaparib for use in combination for treating cancer in a subject.

[0165] In some aspects, the present disclosure provides a Pol0 helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 106-4, or a pharmaceutically acceptable salt thereof, for use in combination for treating cancer in a subject.

[0166] In some aspects, the present disclosure provides a Po10 helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1056, or a pharmaceutically acceptable salt thereof, for use in combination for treating cancer in a subject.

[0167] In some aspects, the present disclosure provides a Pol0 helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1056a, or a pharmaceutically acceptable salt thereof, for use in combination for treating cancer in a subject.

[0168] In some aspects, the present disclosure provides a Pol0 helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1056b, or a pharmaceutically acceptable salt thereof, for use in combination for treating cancer in a subject.

[0169] In some aspects, the present disclosure provides Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1064, or a pharmaceutically acceptable salt thereof, for use in combination for treating cancer in a subject.32316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0170] In some aspects, the present disclosure provides Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1064, or a pharmaceutically acceptable salt thereof, for use in combination for treating cancer in a subject.

[0171] In some aspects, the present disclosure provides Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1056, or a pharmaceutically acceptable salt thereof, for use in combination for treating cancer in a subject.

[0172] In some aspects, the present disclosure provides Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1056, or a pharmaceutically acceptable salt thereof, for use in combination for treating cancer in a subject.

[0173] In some aspects, the present disclosure provides Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1056a, or a pharmaceutically acceptable salt thereof, for use in combination for treating cancer in a subject.

[0174] In some aspects, the present disclosure provides Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1056a, or a pharmaceutically acceptable salt thereof, for use in combination for treating cancer in a subject,

[0175] In some aspects, the present disclosure provides Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1056b, or a pharmaceutically acceptable salt thereof, for use in combination for treating cancer in a subject.

[0176] In some aspects, the present disclosure provides Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1056b, or a pharmaceutically acceptable salt thereof, for use in combination for treating cancer in a subject.

[0177] In some aspects, the present disclosure provides a method of treating or preventing cancer, comprising administering to a subject:(a) a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a second therapeutic agent.

[0178] In some aspects, the present disclosure provides a method of treating or preventing cancer, comprising administering to a subject:(a) a Pol0 helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a second therapeutic agent.33316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0179] In some aspects, the present disclosure provides a method of treating or preventing cancer, comprising administering to a subject:(a) Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a second therapeutic agent.

[0180] In some aspects, the present disclosure provides a method of treating or preventing cancer, comprising administering to a subject:(a) Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a second therapeutic agent.

[0181] In some aspects, the present disclosure provides a method of treating or preventing cancer, comprising administering to a subject:(a) a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0182] In some aspects, the present disclosure provides a method of treating or preventing cancer, comprising administering to a subject:(a) a PolO helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0183] In some aspects, the present disclosure provides a method of treating or preventing cancer, comprising administering to a subject:(a) Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0184] In some aspects, the present disclosure provides a method of treating or preventing cancer, comprising administering to a subject:34316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)(a) Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a PARI’ inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0185] In some aspects, the present disclosure provides a method of treating or preventing cancer, comprising administering to a subject:(a) a PolO helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) olaparib.

[0186] In some aspects, the present disclosure provides a method of treating or preventing cancer, comprising administering to a subject:(a) Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) olaparib.

[0187] In some aspects, the present disclosure provides a method of treating or preventing cancer, comprising administering to a subject:(a) Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) olaparib.

[0188] In some aspects, the present disclosure provides a method of treating or preventing cancer, comprising administering to a subject:(a) a PolO helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1064, or a pharmaceutically acceptable salt thereof.

[0189] In some aspects, the present disclosure provides a method of treating or preventing cancer, comprising administering to a subject:(a) a PolO helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1056, or a pharmaceutically acceptable salt thereof.

[0190] In some aspects, the present disclosure provides a method of treating or preventing cancer, comprising administering to a subject:35316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)(a) a Po10 helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1056a, or a pharmaceutically acceptable salt thereof.

[0191] In some aspects, the present disclosure provides a method of treating or preventing cancer, comprising administering to a subject:(a) a Pol0 helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1056b, or a pharmaceutically acceptable salt thereof.

[0192] In some aspects, the present disclosure provides a method of treating or preventing cancer, comprising administering to a subject:(a) Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1064, or a pharmaceutically acceptable salt thereof.

[0193] In some aspects, the present disclosure provides a method of treating or preventing cancer, comprising administering to a subject:(a) Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1064, or a pharmaceutically acceptable salt thereof.

[0194] In some aspects, the present disclosure provides a method of treating or preventing cancer, comprising administering to a subject:(a) Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and(b) Compound 1056, or a pharmaceutically acceptable salt thereof.10195 ] In some aspects, the present disclosure provides a method of treating or preventing cancer, comprising administering to a subject:(a) Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1056, or a pharmaceutically acceptable salt thereof.

[0196] In some aspects, the present disclosure provides a method of treating or preventing cancer, comprising administering to a subject:36316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)(a) Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1056a, or a pharmaceutically acceptable salt thereof.

[0197] In some aspects, the present disclosure provides a method of treating or preventing cancer, comprising administering to a subject:(a) Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1056a, or a pharmaceutically acceptable salt thereof.

[0198] In some aspects, the present disclosure provides a method of treating or preventing cancer, comprising administering to a subject:(a) Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1056b, or a pharmaceutically acceptable salt thereof.

[0199] In some aspects, the present disclosure provides a method of treating or preventing cancer, comprising administering to a subject:(a) Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1056b, or a pharmaceutically acceptable salt thereof.

[0200] In some aspects, the present disclosure provides a method of treating cancer, comprising administering to a subject:(a) a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a second therapeutic agent.

[0201] In some aspects, the present disclosure provides a method of treating cancer, comprising administering to a subject:(a) a PolO helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a second therapeutic agent.

[0202] In some aspects, the present disclosure provides a method of treating cancer, comprising administering to a subject:37316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)(a) Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a second therapeutic agent.

[0203] In some aspects, the present disclosure provides a method of treating cancer, comprising administering to a subject:(a) Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a second therapeutic agent.

[0204] In some aspects, the present disclosure provides a method of treating cancer, comprising administering to a subject:(a) a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a PARI5inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0205] In some aspects, the present disclosure provides a method of treating cancer, comprising administering to a subject:(a) a Pol0 helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0206] In some aspects, the present disclosure provides a method of treating cancer, comprising administering to a subject:(a) Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0207] In some aspects, the present disclosure provides a method of treating cancer, comprising administering to a subject:(a) Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and38316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)(b) a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0208] In some aspects, the present disclosure provides a method of treating cancer, comprising administering to a subject:(a) a Pol0 helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) olaparib.

[0209] In some aspects, the present disclosure provides a method of treating cancer, comprising administering to a subject:(a) Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) olaparib.

[0210] In some aspects, the present disclosure provides a method of treating cancer, comprising administering to a subject:(a) Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) olaparib.

[0211] In some aspects, the present disclosure provides a method of treating cancer, comprising administering to a subject:(a) a Po10 helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1064, or a pharmaceutically acceptable salt thereof.

[0212] In some aspects, the present disclosure provides a method of treating cancer, comprising administering to a subject:(a) a Pol0 helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1056, or a pharmaceutically acceptable salt thereof.

[0213] In some aspects, the present disclosure provides a method of treating cancer, comprising administering to a subject:(a) a PolO helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and39316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)(b) Compound 1056a, or a pharmaceutically acceptable salt thereof.

[0214] In some aspects, the present disclosure provides a method of treating cancer, comprising administering to a subject:(a) a Pol0 helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1056b, or a pharmaceutically acceptable salt thereof.

[0215] In some aspects, the present disclosure provides a method of treating cancer, comprising administering to a subject:(a) Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1064, or a pharmaceutically acceptable salt thereof.

[0216] In some aspects, the present disclosure provides a method of treating cancer, comprising administering to a subject:(a) Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1064, or a pharmaceutically acceptable salt thereof.

[0217] In some aspects, the present disclosure provides a method of treating cancer, comprising administering to a subject:(a) Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and(b) Compound 1056, or a pharmaceutically acceptable salt thereof.

[0218] In some aspects, the present disclosure provides a method of treating cancer, comprising administering to a subject:(a) Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1056, or a pharmaceutically acceptable salt thereof.

[0219] In some aspects, the present disclosure provides a method of treating cancer, comprising administering to a subject:(a) Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1056a, or a pharmaceutically acceptable salt thereof.40316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0220] In some aspects, the present disclosure provides a method of treating cancer, comprising administering to a subject:(a) Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1056a, or a pharmaceutically acceptable salt thereof.

[0221] In some aspects, the present disclosure provides a method of treating cancer, comprising administering to a subject:(a) Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1056b, or a pharmaceutically acceptable salt thereof.

[0222] In some aspects, the present disclosure provides a method of treating cancer, comprising administering to a subject:(a) Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1056b, or a pharmaceutically acceptable salt thereof.

[0223] In some aspects, the present disclosure provides a compound of the present disclsoure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of cancer in a subject.

[0224] In some aspects, the present disclosure provides a PolO helicase inhibitor, or a. pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of cancer in a. subject.

[0225] In some aspects, the present disclosure provides Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of cancer in a subject.

[0226] In some aspects, the present disclosure provides Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of cancer in a subject.41316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0227] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of cancer in a subject.

[0228] In some aspects, the present disclosure provides a Pol0 helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hy drate, or prodrug thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of cancer in a subject.

[0229] In some aspects, the present disclosure provides Compound 15, or a pharmaceutically acceptable sait, solvate, hydrate, or prodrug thereof, and a PARP inhibitor, or a pharmaceutically acceptable sait, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of cancer in a subject.

[0230] In some aspects, the present disclosure provides Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of cancer in a subject.

[0231] In some aspects, the present disclosure provides a Pol© helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and olaparib in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of cancer in a subject.

[0232] In some aspects, the present disclosure provides Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and olaparib in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of cancer in a subject.

[0233] In some aspects, the present disclosure provides Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and olaparib in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of cancer in a subject.

[0234] In some aspects, the present disclosure provides a PolO helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1064, or a42316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO) pharmaceutically acceptable salt thereof; in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of cancer in a subject.

[0235] In some aspects, the present disclosure provides a Pol0 helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1056, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of cancer in a subject.

[0236] In some aspects, the present disclosure provides a Pol0 helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1056a, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of cancer in a subject.

[0237] In some aspects, the present disclosure provides a Pol0 helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1056b, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of cancer in a subject.

[0238] In some aspects, the present disclosure provides Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 106-4, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of cancer in a subject.

[0239] In some aspects, the present disclosure provides Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1064, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of cancer in a subject.

[0240] In some aspects, the present disclosure provides Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1056, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of cancer in a subject.

[0241] In some aspects, the present disclosure provides Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1056, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of cancer in a subject.43316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0242] In some aspects, the present disclosure provides Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1056a, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of cancer in a subject.

[0243] In some aspects, the present disclosure provides Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1056a, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of cancer in a subject.

[0244] In some aspects, the present disclosure provides Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1056b, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of cancer in a subject.

[0245] In some aspects, the present disclosure provides Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1056b, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of cancer in a subject.

[0246] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent, in the manufacture of a medicament for a combinatorial therapy for the treatment of cancer in a subject.

[0247] In some aspects, the present disclosure provides a Pol9 helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent, in the manufacture of a medicament for a combinatorial therapy for the treatment of cancer in a subject.

[0248] In some aspects, the present disclosure provides Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent, in the manufacture of a medicament for a combinatorial therapy for the treatment of cancer in a subject.

[0249] In some aspects, the present disclosure provides Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a second therapeutic agent, in the manufacture of a medicament for a combinatorial therapy for the treatment of cancer in a subject.44316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0250] In some aspects, the present disclosure provides a compound of the present disclsoure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment of cancer in a subject.

[0251] In some aspects, the present disclosure provides a Pol0 helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hy drate, or prodrug thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment of cancer in a subject.

[0252] In some aspects, the present disclosure provides Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment of cancer in a subject.

[0253] In some aspects, the present disclosure provides Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment of cancer in a subject.

[0254] In some aspects, the present disclosure provides a Pol© helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and olaparib in the manufacture of a medicament for a combinatorial therapy for the treatment of cancer in a subject.

[0255] In some aspects, the present disclosure provides Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and olaparib in the manufacture of a medicament for a combinatorial therapy for the treatment of cancer in a subject.

[0256] In some aspects, the present disclosure provides Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and olaparib in the manufacture of a medicament for a combinatorial therapy for the treatment of cancer in a subject.

[0257] In some aspects, the present disclosure provides a Pol0 helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1064, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment of cancer in a subject.

[0258] In some aspects, the present disclosure provides a Pol0 helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1056, or a45316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO) pharmaceutically acceptable salt thereof; in the manufacture of a medicament for a combinatorial therapy for the treatment of cancer in a subject.

[0259] In some aspects, the present disclosure provides a Pol0 helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1056a, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment of cancer in a subject.

[0260] In some aspects, the present disclosure provides a PolO helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1056b, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment of cancer in a subject.

[0261] In some aspects, the present disclosure provides Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1064, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment of cancer in a subject.

[0262] In some aspects, the present disclosure provides Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1064, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment of cancer in a subject.

[0263] In some aspects, the present disclosure provides Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1056, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment of cancer in a subject.

[0264] In some aspects, the present disclosure provides Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1056, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment of cancer in a subject.

[0265] In some aspects, the present disclosure provides Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1056a, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment of cancer in a subject.46316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0266] In some aspects, the present disclosure provides Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1056a, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment of cancer in a subject.

[0267] In some aspects, the present disclosure provides Compound 15, or a pharmaceutically acceptable salt, solvate, hy drate, or prodrug thereof, and Compound 1056b, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment of cancer in a subject.

[0268] In some aspects, the present disclosure provides Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and Compound 1056b, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment of cancer in a subject.

[0269] In some aspects, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with a second therapeutic agent, in the manufacture of a medicament for the treatment or prevention of cancer in a subject.

[0270] In some aspects, the present disclosure provides use of a PolO helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with a second therapeutic agent, in the manufacture of a medicament for the treatment or prevention of cancer in a subject.

[0271] In some aspects, the present disclosure provides use of Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with a second therapeutic agent, in the manufacture of a medicament for the treatment or prevention of cancer in a subject.

[0272] In some aspects, the present disclosure provides use of Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with a second therapeutic agent, in the manufacture of a medicament for the treatment or prevention of cancer in a subject.

[0273] In some aspects, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or47316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO) prodrug thereof in the manufacture of a medicament for the treatment or prevention of cancer in a subject.

[0274] In some aspects, the present disclosure provides use of a Pol0 helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for the treatment or prevention of cancer in a subject.

[0275] In some aspects, the present disclosure provides use of Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for the treatment or prevention of cancer in a subject.

[0276] In some aspects, the present disclosure provides use of Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for the treatment or prevention of cancer in a subject.

[0277] In some aspects, the present disclosure provides use of a Pol 6 helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with olaparib in the manufacture of a medicament for the treatment or prevention of cancer in a subject.

[0278] In some aspects, the present disclosure provides use of Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with olaparib in the manufacture of a medicament for the treatment or prevention of cancer in a subject.

[0279] In some aspects, the present disclosure provides use of Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with olaparib in the manufacture of a medicament for the treatment or prevention of cancer in a subject.

[0280] In some aspects, the present disclosure provides use of a Pol0 helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with Compound 1064, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of cancer in a subject.10281] In some aspects, the present disclosure provides use of a Pol0 helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with Compound 1056, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of cancer in a subject.48316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0282] In some aspects, the present disclosure provides use of a PolO helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with Compound 1056a, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of cancer in a subject.

[0283] In some aspects, the present disclosure provides use of a PolO helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with Compound 1056b, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of cancer in a subject.

[0284] In some aspects, the present disclosure provides use of Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with Compound 1064, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of cancer in a subject.

[0285] In some aspects, the present disclosure provides use of Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with Compound 1064, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of cancer in a subject.

[0286] In some aspects, the present disclosure provides use of Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with Compound 1056, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of cancer in a subject.

[0287] In some aspects, the present disclosure provides use of Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with Compound 1056, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of cancer in a subject.

[0288] In some aspects, the present disclosure provides use of Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with Compound 1056a, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of cancer in a subject.

[0289] In some aspects, the present disclosure provides use of Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with49316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)Compound 1056a, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of cancer in a subject.

[0290] In some aspects, the present disclosure provides use of Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with Compound 1056b, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of cancer in a subject.

[0291] In some aspects, the present disclosure provides use of Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with Compound 1056b, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of cancer in a subject.

[0292] In some aspects, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with a second therapeutic agent, in the manufacture of a medicament for the treatment of cancer in a subject.

[0293] In some aspects, the present disclosure provides use of a PolO helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with a second therapeutic agent, in the manufacture of a medicament for the treatment of cancer in a subject.

[0294] In some aspects, the present disclosure provides use of Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with a second therapeutic agent, in the manufacture of a medicament for the treatment of cancer in a subject.

[0295] In some aspects, the present disclosure provides use of Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with a second therapeutic agent, in the manufacture of a medicament for the treatment of cancer in a subject.

[0296] In some aspects, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for the treatment of cancer in a subject.50316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0297] In some aspects, the present disclosure provides use of a PolO helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for the treatment of cancer in a subject.

[0298] In some aspects, the present disclosure provides use of Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for the treatment of cancer in a subject.

[0299] In some aspects, the present disclosure provides use of Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for the treatment of cancer in a subject.

[0300] In some aspects, the present disclosure provides use of a PolO helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with olaparib in the manufacture of a medicament for the treatment of cancer in a subject.

[0301] In some aspects, the present disclosure provides use of Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with olaparib in the manufacture of a medicament for the treatment of cancer in a subject.

[0302] In some aspects, the present disclosure provides use of Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with olaparib in the manufacture of a medicament for the treatment of cancer in a subject.

[0303] In some aspects, the present disclosure provides use of a PolO helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with Compound 1064, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer in a subject.

[0304] In some aspects, the present disclosure provides use of a PolO helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with Compound 1056, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer in a subject.

[0305] In some aspects, the present disclosure provides use of a PolO helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with51316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)Compound 1056a, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer in a subject.

[0306] In some aspects, the present disclosure provides use of a Pol0 helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with Compound 1056b, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer in a subject.

[0307] In some aspects, the present disclosure provides use of Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with Compound 1064, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer in a subject.

[0308] In some aspects, the present disclosure provides use of Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with Compound 1064, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer in a subject.

[0309] In some aspects, the present disclosure provides use of Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with Compound 1056, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer in a subject.

[0310] In some aspects, the present disclosure provides use of Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with Compound 1056, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer in a subject.

[0311] In some aspects, the present disclosure provides use of Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with Compound 1056a, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer in a subject.

[0312] In some aspects, the present disclosure provides use of Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with Compound 1056a, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer in a subject.52316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0313] In some aspects, the present disclosure provides use of Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with Compound 1056b, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer in a subject.

[0314] In some aspects, the present disclosure provides use of Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with Compound 1056b, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer in a subject.

[0315] In some aspects, the present disclosure provides a kit comprising:(a) a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a second therapeutic agent.

[0316] In some aspects, the present disclosure provides a kit comprising:(a) a PolO helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a second therapeutic agent.

[0317] In some aspects, the present disclosure provides a kit comprising:(a) Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a second therapeutic agent.

[0318] In some aspects, the present disclosure provides a kit comprising:(a) Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a second therapeutic agent.

[0319] In some aspects, the present disclosure provides a kit comprising:(a) a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a PARI’ inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0320] In some aspects, the present disclosure provides a kit comprising:53316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)(a) a PolO helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a PARI’ inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0321] In some aspects, the present disclosure provides a kit comprising:(a) Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0322] In some aspects, the present disclosure provides a kit comprising:(a) Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a PARI5inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0323] In some aspects, the present disclosure provides a kit comprising:(a) a PolO helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) olaparib.

[0324] In some aspects, the present disclosure provides a kit comprising:(a) Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) olaparib.

[0325] In some aspects, the present disclosure provides a kit comprising:(a) Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) olaparib.

[0326] In some aspects, the present disclosure provides a kit comprising:(a) a PolO helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1064, or a pharmaceutically acceptable salt thereof.

[0327] In some aspects, the present disclosure provides a kit comprising:54316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)(a) a PolO helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1056, or a pharmaceutically acceptable salt thereof.

[0328] In some aspects, the present disclosure provides a kit comprising:(a) a PolO helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1056a, or a pharmaceutically acceptable salt thereof.

[0329] In some aspects, the present disclosure provides a kit comprising:(a) a PolO helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1056b, or a pharmaceutically acceptable salt thereof.

[0330] In some aspects, the present disclosure provides a kit comprising:(a) Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1064, or a pharmaceutically acceptable salt thereof.

[0331] In some aspects, the present disclosure provides a kit comprising:(a) Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1064, or a pharmaceutically acceptable salt thereof.

[0332] In some aspects, the present disclosure provides a kit comprising:(a) Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and(b) Compound 1056, or a pharmaceutically acceptable salt thereof.

[0333] In some aspects, the present disclosure provides a kit comprising:(a) Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1056, or a pharmaceutically acceptable salt thereof.

[0334] In some aspects, the present disclosure provides a kit comprising:(a) Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1056a, or a pharmaceutically acceptable salt thereof.55318259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0335] In some aspects, the present disclosure provides a kit comprising:(a) Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1056a, or a pharmaceutically acceptable salt thereof.

[0336] In some aspects, the present disclosure provides a kit comprising:(a) Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1056b, or a pharmaceutically acceptable salt thereof.

[0337] In some aspects, the present disclosure provides a kit comprising:(a) Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1056b, or a pharmaceutically acceptable salt thereof.

[0338] In some aspects, the present disclosure provides a pharmaceutical package comprising:(a) a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a second therapeutic agent.

[0339] In some aspects, the present disclosure provides a pharmaceutical package comprising:(a) a PolO helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a second therapeutic agent.

[0340] In some aspects, the present disclosure provides a pharmaceutical package comprising:(a) Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a second therapeutic agent.

[0341] In some aspects, the present disclosure provides a pharmaceutical package comprising:(a) Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a second therapeutic agent.

[0342] In some aspects, the present disclosure provides a pharmaceutical package comprising:(a) a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and56316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)(b) a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0343] In some aspects, the present disclosure provides a pharmaceutical package comprising:(a) a PolO helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0344] In some aspects, the present disclosure provides a pharmaceutical package comprising:(a) Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a PARI5inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0345] In some aspects, the present disclosure provides a pharmaceutical package comprising:(a) Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0346] In some aspects, the present disclosure provides a pharmaceutical package comprising:(a) a Pol9 helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) olaparib.

[0347] In some aspects, the present disclosure provides a pharmaceutical package comprising:(a) Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) olaparib.

[0348] In some aspects, the present disclosure provides a pharmaceutical package comprising:(a) Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) olaparib.

[0349] In some aspects, the present disclosure provides a pharmaceutical package comprising:57316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)(a) a PolO helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1064, or a pharmaceutically acceptable salt thereof.

[0350] In some aspects, the present disclosure provides a pharmaceutical package comprising:(a) a PolO helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1056, or a pharmaceutically acceptable salt thereof.

[0351] In some aspects, the present disclosure provides a pharmaceutical package comprising:(a) a PolO helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1056a, or a pharmaceutically acceptable salt thereof.

[0352] In some aspects, the present disclosure provides a pharmaceutical package comprising:(a) a PolO helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1056b, or a pharmaceutically acceptable salt thereof.

[0353] In some aspects, the present disclosure provides a pharmaceutical package comprising:(a) Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1064, or a pharmaceutically acceptable salt thereof.

[0354] In some aspects, the present disclosure provides a pharmaceutical package comprising:(a) Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and(b) Compound 1064, or a pharmaceutically acceptable salt thereof.

[0355] In some aspects, the present disclosure provides a pharmaceutical package comprising:(a) Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1056, or a pharmaceutically acceptable salt thereof.

[0356] In some aspects, the present disclosure provides a pharmaceutical package comprising:(a) Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1056, or a pharmaceutically acceptable salt thereof.58316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0357] In some aspects, the present disclosure provides a pharmaceutical package comprising:(a) Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1056a, or a pharmaceutically acceptable salt thereof.

[0358] In some aspects, the present disclosure provides a pharmaceutical package comprising:(a) Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1056a, or a pharmaceutically acceptable salt thereof.

[0359] In some aspects, the present disclosure provides a pharmaceutical package comprising:(a) Compound 15, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1056b, or a pharmaceutically acceptable salt thereof.

[0360] In some aspects, the present disclosure provides a pharmaceutical package comprising:(a) Compound 18, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) Compound 1056b, or a pharmaceutically acceptable salt thereof.

[0361] In some embodiments, the kit or pharmaceutical package further comprises instructions for use.

[0362] In some embodiments, the kit further comprises instructions for use.

[0363] In some embodiments, the pharmaceutical package further comprises instructions for use.

[0364] In some embodiments, the second therapeutic agent is not a PolO helicase inhibitor.

[0365] In some embodiments, the cancer is an advanced tumor.

[0366] In some embodiments, the cancer is a solid tumor.

[0367] In some embodiments, the cancer is an advanced solid tumor.

[0368] In some embodiments, the tumor is advanced because the tumor is large.

[0369] In some embodiments, the tumor is advanced because the tumor is complex.

[0370] In some embodiments, the tumor is advanced because the tumor is aggressive.

[0371] In some embodiments, the cancer is metastatic.

[0372] In some embodiments, the cancer is HR-deficient. In some embodiments, the cancer is not HR-proficient.59316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0373] In some embodiments, the cancer is carcinoma, sarcoma, lymphoma, leukemia, or melanoma.

[0374] In some embodiments, the carcinoma is adenocarcinoma, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriforni carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatmiforni carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, premvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, Schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signetring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, or carcinoma villosum.60316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0375] In some embodiments, the sarcoma is chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernethy’s sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma.

[0376] In some embodiments, the leukemia is acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphoma, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.

[0377] In some embodiments, the melanoma is acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual melanoma, and superficial spreading melanoma.

[0378] In some embodiments, the cancer is prostate cancer, breast cancer, ovarian cancer, multiple myeloma, brain cancer, glioma, lung cancer, salivary cancer, stomach cancer, thymic epithelial cancer, thyroid cancer, leukemia, melanoma, lymphoma, gastric cancer, pancreatic cancer, kidney cancer, bladder cancer, colon cancer, and liver cancer.61316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0379] In some embodiments, the cancer is selected from prostate cancer, pancreatic cancer, breast cancer, lung cancer, and ovarian cancer.

[0380] In some embodiments, the cancer is selected from prostate cancer, pancreatic cancer, breast cancer, and ovarian cancer.

[0381] In some embodiments, the cancer is prostate cancer.

[0382] In some embodiments, the cancer is pancreatic cancer.

[0383] In some embodiments, the cancer is breast cancer.

[0384] In some embodiments, the cancer is lung cancer.

[0385] In some embodiments, the lung cancer is non-small cell lung cancer.

[0386] In some embodiments, the cancer is ovarian cancer.

[0387] In some embodiments, the cancer is a castrate-resistant prostate cancer or pancreatic adenocarcinoma.

[0388] In some embodiments, the cancer is a castrate-resistant prostate cancer.

[0389] In some embodiments, the cancer is pancreatic adenocarcinoma,

[0390] In some embodiments, the cancer comprises a BRCA2 mutation, a PALB2 gene mutation, or a RAD51 gene mutation.

[0391] In some emboidments, the cancer comprsies a gene mutation selected from: BRCA1, BRCA2, CDK12, PALB2, RAD51B, RAD51C, and RADS ID.

[0392] In some emboidments, the cancer comprsies a BRCA1 mutation.

[0393] In some embodiments, the cancer comprises a BRCA2 mutation.

[0394] In some embodiments, the cancer comprises a CDK12 mutation.

[0395] In some embodiments, the cancer comprises a PALB2 gene mutation.

[0396] In some embodiments, the cancer comprises a RAD51 gene mutation.

[0397] In some embodiments, the cancer comprises a RAD51B, RAD51C, or RAD51D mutation.

[0398] In some embodiments, the cancer comprises a RADS IB mutation.

[0399] In some embodiments, the cancer comprises a RAD51C mutation.

[0400] In some embodiments, the cancer comprises a RADS ID mutation.

[0401] In some embodiments, the cancer has a deficiency in a DNA damage repair process.

[0402] In some embodiments, the cancer is sensitive to POL0 inhibition.

[0403] In some embodiments, the cancer has evidence of elevated POL© activity.

[0404] In some embodiments, the cancer has elevated expression of POL© mRNA or protein.62316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0405] In some embodiments, the cancer has elevated expression of POL0 mRNA.

[0406] In some embodiments, the cancer has elevated expression of POLO protein.

[0407] In some embodiments, the cancer is classified by a genotype.

[0408] In some embodiments, the genotype has a modulated function.

[0409] In some embodiments, the modulated function is an inactivating mutation, deletion, or other genomic alteration.

[0410] In some embodiments, the genotype is loss of mRNA or protein expression.

[0411] In some embodiments, the cancer has modulated function of at least one gene.

[0412] In some embodiments, the gene is selected from ATM, BARD1, BRIP1, CDK12, CHE, KI , CHEK2, FANCL, PALB2, RADS IB, RAD51C, RADS ID, and RAD54L.

[0413] In some embodiments, the cancer comprises a homologous recombination deficiency (HRD).

[0414] In some embodiments, the cancer is a homologous recombination deficient (HRD) cancer.

[0415] In some embodiments, the cancer is classified as an HRD cancer because the tumor is unable to accurately repair double-strand breaks in DNA via homologous recombination.

[0416] In some embodiments, the mutation is a gene that, when lost, causes HRD.

[0417] In some embodiments, the cancer has a compromised homologous recombination (HR) or non-homologous DNA end joining (NHEJ) repair pathway.

[0418] In some embodiments, the cancer with a compromised HR is dependent on Pol© activity.

[0419] In some embodiments, the cancer with a compromised NHEJ is dependent on Pol© activity.

[0420] In some embodiments, the subject is a human.

[0421] In some embodiments, the PolO helicase inhibitor and PARP inhibitor are administered in temporal proximity, sequentially, or in alternation.

[0422] In some embodiments, the PolO helicase inhibitor and PARP inhibitor are administered in temporal proximity.

[0423] In some embodiments, the PolO helicase inhibitor and PARP inhibitor are administered sequentially,

[0424] In some embodiments, the Pol0 helicase inhibitor and PARP inhibitor are administered in alternation.63316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0425] In some embodiments, the PolO helicase inhibitor and PARP inhibitor are administered as separate formulations.

[0426] In some embodiments, each of the PolO helicase inhibitor and PARI’ inhibitor are administered once daily

[0427] In some embodiments, the PolO helicase inhibitor is administered once daily.

[0428] In some embodiments, the PARP inhibitor is administered once daily.

[0429] In some embodiments, each of the PolO helicase inhibitor and PARI’ inhibitor are administered twice daily.

[0430] In some embodiments, the PolO helicase inhibitor is administered twice daily.

[0431] In some embodiments, the PARP inhibitor is administered twice daily.

[0432] In some embodiments, each of the PolO helicase inhibitor and PARI’ inhibitor are administered for at least 7 days, at least 14 days, at least 28 days, or at least 35 days.

[0433] In some embodiments, each of the PolO helicase inhibitor and PARI’ inhibitor are administered for at least about 7 days.

[0434] In some embodiments, each of the PolO helicase inhibitor and PARP inhibitor are administered for at least about 14 days.

[0435] In some embodiments, each of the PolO helicase inhibitor and PARP inhibitor are administered for at least about 28 days.

[0436] In some embodiments, each of the PolO helicase inhibitor and PARP inhibitor are administered for at least about 35 days.

[0437] In some embodiments, each of the PolO helicase inhibitor and PARP inhibitor are administered for 7 days.

[0438] In some embodiments. each of the PolO helicase inhibitor and PARP inhibitor are administered for 14 days.

[0439] In some embodiments, each of the PolO helicase inhibitorPARP inhibitor are administered for 28 days.

[0440] In some embodiments, each of the PolO helicase inhibitor and PARP inhibitor are administered for 35 days.

[0441] In some embodiments, each of the PolO helicase inhibitor and PARP inhibitor are administered for at least about one month, at least about two months, at least about three months. at least about four months, at least about five months, or at least about six months.64316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0442] In some embodiments, each of the Pol0 helicase inhibitor and PARP inhibitor are administered for at least about one month.

[0443] In some embodiments, each of the Pol0 helicase inhibitor and PARI’ inhibitor are administered for at least about two months.

[0444] In some embodiments, each of the Pol0 helicase inhibitor and PARI’ inhibitor are administered for at least about three months.

[0445] In some embodiments, each of the Pol0 helicase inhibitor and PARI’ inhibitor are administered for at least about four months.

[0446] In some embodiments, each of the Pol0 helicase inhibitor and PARI’ inhibitor are administered for at least about five months.

[0447] In some embodiments, each of the Pol0 helicase inhibitor and PARI’ inhibitor are administered for at least about six months.

[0448] In some embodiments, each of the Pol0 helicase inhibitor and PARI’ inhibitor are administered for about one year, about two years, about three years, about four years, about five years, or about six years.

[0449] In some embodiments, each of the Pol0 helicase inhibitor and PARP inhibitor are administered for about one year.

[0450] In some embodiments, each of the Pol0 helicase inhibitor and PARP inhibitor are administered for about two years.

[0451] In some embodiments, each of the Pol0 helicase inhibitor and PARP inhibitor are administered for about three years.

[0452] In some embodiments, each of the Pol0 helicase inhibitor and PARP inhibitor are administered for about four years.

[0453] In some embodiments, each of the Pol0 helicase inhibitor and PARI’ inhibitor are administered for about five years.

[0454] In some embodiments, each of the Pol0 helicase inhibitor and PARI’ inhibitor are administered for about six years.

[0455] In some embodiments, the Pol0 helicase inhibitor is administered orally.

[0456] In some embodiments, the PARP inhibitor is administered orally.65316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)Compounds of the Present Disclosure

[0457] In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is a polymerase theta (Pol0) helicase inhibitor.

[0458] In some embodiments, a polymerase theta (Pol0) helicase mhbitior can be used in accordance with the combinations and / or methods described herein.

[0459] In some embodiments, the Pol0 helicase inhibitor is a compound of Formula I:or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein:Ralis H, oxo, halo, cyano, -OH, -XH . -NH(Ci-Ce alkyl), -N(Ci-Cs alkyl)?, -C(O)(Ci-C6alkyl), -C(0)(C3-Cio cycloalkyl), Ci-Co alkyl, C2-Ce alkenyl, Cz-Ce alkynyl, (';-( ■• haloalkyl, Ci- Cg alkoxy, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10- membered heteroaryl, wherein the -C(0)(Cs-Cio cycloalkyl), Ci-Ce alkyl, Cz-Ce alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more Ra2; each Ra2independently is oxo, halo, cyano, -OH, -NHz, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)?., Ci-Ce alkyl optionally substituted with Ci-Ce alkoxy or -OH, C3-C10 cycloalkyl, Ci-Ce haloalkoxy, Ci-Ce haloalkyl, Ci-Ce alkoxy, 3- to 10-membered heterocycloalkyl optionally substituted with oxo, or 5- to 10-membered heteroaryl;R3ais halo, cyano, -OH, -NHz, Ci-Ce alkyl, C2-C6 alkenyl, Cz-Ce alkynyl, Ci-Ce haloalkyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the Ci-Ce alkyl, Cz-Ce alkenyl, Cz-Ce alkynyl, Ci-Ce haloalkyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Cw aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R3al; and each R3alindependently is oxo, halo, cyano, -OH, -C(O)(Ci-Ce alkyl), -C(O)(O-(Ci-Ce alkyl)), Ci-Ce alkyl optionally substituted with C3-C10 cycloalkyl, Cz-Ce alkenyl, Cz-Ce alkynyl, Ci-Ce haloalkyl, Ci-Ce haloalkoxy, Ci-Ce alkoxy, -O(Ci-Ce haloalkyl), C3-C10 cycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl.66316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0460] In some embodiments, the PolO helicase inhibitor is a compound is of Formula (I-a) or Formula (I-b):or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof.

[0461] In some embodiments, the PolO helicase inhibitor is a compound is of Formula (I-a’) or Formula (I-b’):or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof.

[0462] In some embodiments, the PolO helicase inhibitor is a compound is of Formula (I-c):67316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof.

[0463] In some embodiments, the Poi0 helicase inhibitor is a compound is of Formula (I-c’ ):or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof.

[0464] It is understood that, for a compound of the present disclosure, variables Ral, Ra2, and R3a, and Raalcan each be, where applicable, selected from the groups described herein, and any group described herein for any of variables Ral, Ra2, Rda, and Rja!can be combined, where applicable, with any group described herein for one or more of the remainder of variables RaI, Ra2, R3a, and R3a!.

[0465] In some embodiments, Ra!is H, oxo, halo, cyano, -OH, -NHz, -NH / Ci-Ce alkyl), -N / Ci-Ce alkyl)z, -C(O)(Ci-Cs alkyl), -C(0)(C3-Cio cycloalkyl), Ci-Ce alkyl, Cz-Cs alkenyl, Cz-Q alkynyl, Ci-Cs haloalkyl, Ci-Co alkoxy, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the -C(0)(C3-Cio cycloalkyl), Ci-Cg alkyl, Cz-Ce alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C1-C0 alkoxy, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, Cs-Cio aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more Ra2.

[0466] In some embodiments, Ra!is H, oxo, halo, cyano, -OH, -NHz, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)z, -C(O)(Ci-C6 alkyl), -C(0)(C3-Cio cycloalkyl), Ci-CN alkyl, Cz-Ce alkenyl, Cz-Ce alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the -C(0)(C’3-Cio cycloalkyl), Ci-Ce alkyl, Cz-Co68316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO) alkenyl, Cz-Ce alkynyl, Ci-Cs haloalkyl, Ci-Cs alkoxy, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl is substituted with one or more Ra2.

[0467] In some embodiments, Ra-!is H, oxo, halo, cyano, -OH, -NHz, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)?,, -C(O)(Ci-C6 alkyl), -C(0)(C3-Cio cycloalkyl), C1-C6 alkyl, C2-C6 alkenyl, Cz-Ce alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl.

[0468] In some embodiments, Ralis oxo, halo, cyano, -OH, -NHz, -NH(Ci-C6 alkyl), -NfCt-Ce alkyi)2, -C(O)(Ci-Ce alkyl), -C(O)(C3-Cw cycloalkyl), Ci-Ce alkyl, Cz-Ce alkenyl, Cz-Ce alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the -C(0)(C3-Cio cycloalkyl), Ci-Ce alkyl, Cz-Ce alkenyl, Cz-Ce alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Cw aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more Ra2

[0469] In some embodiments, Ralis oxo, halo, cyano, -OH, -NHz, -NH(Ci-Ce alkyl), -N(Ci-Cs alkyl).’, -('(())((':-( k alkyl), -C(0)(C3-Cio cycloalkyl), Ci-Ce alkyl,5 alkenyl, Cz-Ce alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, C.3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the -C(0)(Cj-Cio cycloalkyl), Ci-Ce alkyl, C2-C0 alkenyl, Cz-Ce alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl is substituted with one or more Ra2

[0470] In some embodiments, Ralis oxo, halo, cyano, -OH, -NHz, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)z, -C(O)(Ci-Ce alkyl), -C(0)(C3-Cio cycloalkyl), Ci-Ce alkyl, C2-C0 alkenyl, Cz-Ce alkynyl, Ci-Ce haloalkyl, C1-G5 alkoxy, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl.

[0471] In some embodiments, Ralis H.

[0472] In some embodiments, Ralis oxo.

[0473] In some embodiments, Ralis halo.

[0474] In some embodiments, Ra lis F, Cl, Br, or I. In some embodiments, Ralis F, Cl, or Br. In some embodiments, Ra lis F or Cl.

[0475] In some embodiments, Ralis F. In some embodiments, Ra!is Cl. In some embodiments, Raiis Br. In some embodiments, Ralis I.

[0476] In some embodiments, Ra!is cyano.69316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0477] In some embodiments, Ralis -OH.

[0478] In some embodiments, Ralis -NEb.

[0479] In some embodiments, Ralis -NH(Ci -Ce alkyl).

[0480] In some embodiments, Ralis “N(Ci-C6 alkyl)?..

[0481] In some embodiments, Ralis -C(O)(Ci-C6 alkyl).

[0482] In some embodiments, Ralis -C(0)(C3-Cio cycloalkyl).

[0483] In some embodiments, Ralis -C(0)(C3-Cio cycloalkyl) optionally substituted with one or more Ra2.

[0484] In some embodiments, Raiis -C(O)(C3-Cw cycloalkyl) substituted with one or more Raz

[0485] In some embodiments, Ra!is Ci-Ce alkyl.

[0486] In some embodiments, Raiis Ci-Cs alkyl optionally substituted with one or more Ra2.

[0487] In some embodiments, Ralis Ci-Ce alkyl substituted with one or more Ra2.

[0488] In some embodiments, RaIis methyl. In some embodiments, Ralis ethyl. In some embodiments, Ralis propyl. In some embodiments, Ralis butyl. In some embodiments, Ralis pentyl. In some embodiments, Ralis hexyl. In some embodiments, RaIis isopropyl. In some embodiments, Ralis isobutyl. In some embodiments, Ralis isopentyl. In some embodiments, Ra!is isohexyl. In some embodiments, Ralis secbutyl. In some embodiments, Ralis secpentyl. In some embodiments, Ralis sechexyl. In some embodiments, Ralis tertbutyl.

[0489] In some embodiments, Ralis C2-C6 alkenyl.

[0490] In some embodiments, Ralis C2-C6 alkenyl optionally substituted with one or more Ra2.

[0491] In some embodiments, Ralis C2-C6 alkenyl substituted with one or more Raz

[0492] In some embodiments, Ralis C2-C6 alkynyl.

[0493] In some embodiments, Ralis C2-C6 alkynyl optionally substituted with one or more Ra2.

[0494] In some embodiments, Ralis C2-C6 alkynyl substituted with one or more Ra2.

[0495] In some embodiments, Ralis Ci-Ce haloalkyl.

[0496] In some embodiments, Ralis Ci-Cs haloalkyl optionally substituted with one or more Ra2.

[0497] In some embodiments, Ralis Ci-Ce haloalkyl substituted with one or more Ra2.

[0498] In some embodiments, Ra lis halomethyl. In some embodiments, Ra lis haloethyl. In some embodiments, Ralis halopropyl. In some embodiments, Ralis halobutyl. In some embodiments, Raiis halopentyl. In some embodiments, Ra!is halohexyl.

[0499] In some embodiments, Ra!is Ci-Ce alkoxy.70316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0500] In some embodiments, Ralis alkoxy optionally substituted with one or more Ra2.

[0501] In some embodiments, Ralis Ci-Ce alkoxy substituted with one or more Ra2.

[0502] In some embodiments, Ralis C3-C10 cycloalkyl.

[0503] In some embodiments, Ra!is C3-C10 cycloalkyl optionally substituted with one or more R82.

[0504] In some embodiments, Ralis C3-C10 cycloalkyl substituted with one or more Ra2.

[0505] In some embodiments, Ralis C3-C7 cycloalkyl.

[0506] In some embodiments, Ra’!is C3-C7 cycloalkyl optionally substituted with one or more Ra2.

[0507] In some embodiments, Ra!is C3-C7 cycloalkyl substituted with one or more Raz

[0508] In some embodiments, Rai3- to 10-membered heterocycloalkyl.

[0509] In some embodiments, Raiis 3- to 10-membered heterocycloalkyl optionally substituted with one or more Ra2.

[0510] In some embodiments, Ralis 3- to 10-membered heterocycloalkyl substituted with one or more Ra2.

[0511] In some embodiments, Ral3- to 7-membered heterocycloalkyl.

[0512] In some embodiments, Ralis 3- to 7-membered heterocycloalkyl optionally substituted with one or more Ra2.

[0513] In some embodiments, Ralis 3- to 7-membered heterocycloal kyl substituted with one or more Raz,

[0514] In some embodiments, Ralis Ce-Cio aryl.

[0515] In some embodiments, Ralis Cs-Cio aryl optionally substituted with one or more Ra2.

[0516] In some embodiments, Ralis Ce-Cio aryl substituted with one or more Ra2.

[0517] In some embodiments, Ralis Cs aryl.

[0518] In some embodiments, Ralis Ce aryl optionally substituted with one or more Ra2.

[0519] In some embodiments, Ralis Co aryl substituted with one or more Ra2.

[0520] In some embodiments, Ralis 5- to 10-membered heteroaryL

[0521] In some embodiments, Ralis 5- to 10-membered heteroaryl optionally substituted with one or more Ra2.

[0522] In some embodiments, Ra!is 5- to 10-membered heteroaryl substituted with one or more Ra2.

[0523] In some embodiments, Raiis 5- to 6~niembered heteroaryl.71316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0524] In some embodiments, Ralis 5- to 6-membered heteroaryl optionally substituted with one or more Ra2.

[0525] In some embodiments, Ri,;is 5- to 6-membered heteroaryl substituted with one or more Ra2.

[0526] In some embodiments, Ralis pyridinyl .

[0527] In some embodiments, Ralis pyridinyl optionally substituted with one or more Ra2.

[0528] In some embodiments, Raiis pyridinyl substituted with one or more Ra2.

[0529] In some embodiments, Ralis:72316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)73316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)74316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)75316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0530] In some embodiments, each Rzzindependently is oxo, halo, cyano, -OH, -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)?,, Ci-Cs alkyl, C3-C10 cycloalkyl, Ci-Ce haloalkoxy, Ci-Co haloalkyl, Ci-Ck alkoxy, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl.

[0531] In some embodiments, each Ra2independently is oxo, halo, cyano, -OH, -NH?, -NH(CI -C6 alkyl), -N(Ci-Cs alkyl)?, Ci-C-6 alkyl optionally substituted with Ci-C-6 alkoxy or -OH, C3-C10 cycloalkyl, Ci-Ce haloalkoxy, Ci-Ce haloalkyl, Ct-Ce alkoxy, 3- to 10-membered heterocycloalkyl optionally substituted with oxo, or 5- to 10-membered heteroaryl.

[0532] In some embodiments, each Ra2independently is oxo, halo, cyano, -OH, -NH?, -NH(Ci -C& alkyl), -N(Ci-Ce alkyl)?, Ci-Cs alkyl substituted with Ci-Ck alkoxy or -OH, C3-C10 cycloalkyl, Ci- Cs haloalkoxy, Ci-Ce haloalkyl, Ci-Ce alkoxy, 3- to 10-membered heterocycloalkyl optionally substituted with oxo, or 5- to 10-membered heteroaryl.

[0533] In some embodiments, each Ra2independently is oxo, halo, cyano, -OH, -NH?, -NH(CJ -C& alkyl), -N(Ci-Ce alkyl)?, Ci-Ce alkyl optionally substituted with Ci-Ce alkoxy or -OH, C3-C10 cycloalkyl, C1-C0 haloalkoxy, Ci-Cs haloalkyl, Ci-Ce alkoxy, 3- to 10-membered heterocycloalkyl substituted with oxo, or 5- to 10-membered heteroaryl.

[0534] In some embodiments, each Ra2independently is oxo.

[0535] In some embodiments, each Ra2independently is halo.

[0536] In some embodiments, each Ra2independently is F, Cl, Br, or I. In some embodiments, each Ra2independently is F, Cl, or Br. In some embodiments, each Ra2independently is F or Cl.

[0537] In some embodiments, each R;’2independently is F. In some embodiments, each R!lzindependently is Cl. In some embodiments, each Ra2independently is Br. In some embodiments, each Ra2independently is I.

[0538] In some embodiments, each Razindependently is cyano.

[0539] In some embodiments, each Ra2independently is -OH.

[0540] In some embodiments, each Ra2independently is -NH2.

[0541] In some embodiments, each Ra2independently is -NH(CI-C6 alkyl).

[0542] In some embodiments, each Ra2independently is -N(CI-C6 alkyl)?.

[0543] In some embodiments, each Ra2independently is Ci-Ck alkyl.

[0544] In some embodiments, each Ra2independently is Ci-Ce alkyl optionally substituted with Ci -Cfi alkoxy or -OH.76316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0545] In some embodiments, each Ra2independently is Ci-Cs alkyl substituted with Ci-Ce alkoxy or -OH.

[0546] In some embodiments, each Ra2independently is Ci-Ce alkyl optionally substituted with Ci-Cs alkoxy.

[0547] In some embodiments, each Ra2independently is Ci-Ce alkyl substituted with Ci-Ce alkoxy.

[0548] In some embodiments, each Ra2independently is Ci-Ce alkyl optionally substituted with - OH.

[0549] In some embodiments, each Ra2independently is Ci-Cs alkyl substituted with -OH.

[0550] In some embodiments, each Razindependently is methyl. In some embodiments, each Razindependently is ethyl. In some embodiments, each Ra2independently is propyl. In some embodiments, each R!iZindependently is butyl. In some embodiments, each R!iZindependently is pentyl. In some embodiments, each Ra2independently is hexyl. In some embodiments, each Ra2independently is isopropyl. In some embodiments, each Razindependently is isobutyl. In some embodiments, each R®2independently is isopentyl. In some embodiments, each Ra2independently is isohexyl. In some embodiments, each Ra2independently is secbutyl. In some embodiments, each Ra2independently is secpentyl. In some embodiments, eachRa2independently is sechexyl. In some embodiments, each Ra2independently is tertbutyl ,

[0551] In some embodiments, each Ra2independently is C3-C10 cycloalkyl.

[0552] In some embodiments, each R®2independently is C3-C7 cycloalkyl.

[0553] In some embodiments, each Ra2independently is Ci-Ce haloalkoxy.

[0554] In some embodiments, each R®2independently is Ci-Cs haloalkyl.

[0555] In some embodiments, each Razindependently is Ci-Ce alkoxy.

[0556] In some embodiments, each R®2independently is 3- to 10-membered heterocycloalkyl.

[0557] In some embodiments, each Ra2independently is 3- to 10-membered heterocycloalkyl optionally substituted with oxo.

[0558] In some embodiments, each Ra2independently is 3- to 10-membered heterocycloalkyl substituted with oxo.

[0559] In some embodiments, each Ra2independently is 3- to 7-membered heterocycloalkyl.

[0560] In some embodiments, each Ra2independently is 3- to 7-membered heterocycloalkyl optionally substituted with oxo.77316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0561] In some embodiments, each Ra2independently is 3- to 7-membered heterocycloalkyl substituted with oxo.

[0562] In some embodiments, each Ra2independently is 5- to 10-membered heteroaryl.

[0563] In some embodiments, each Ra2independently is 5- to 6-membered heteroaryl.

[0564] In some embodiments, each Ra2independently is Ci-Ce alkyl, Ci-Cs haloalkyl, or Ct-Ce alkoxy.

[0565] In some embodiments, each Ra2independently is Ci-Cs haloalkyl or Ci-Ce alkoxy.

[0566] In some embodiments, each Ra2independently is CFs or -OCH3.

[0567] In some embodiments, each Ra2independently is oxo, -CH3, -CH2CH3, -CH(CHs)2, -Cl, - F, -CN, -CHF2, -OCH3, -CF3, -OCHF2, -OH, -CH2CHF2, -CH2CF3, -CH2OH, -CH2OCH3, -OCF3,

[0569] In some embodiments, R5ais halo, cyano, -OH, -NHz, Ci-Q alkyl, C2-C6 alkenyl, C2-C0 alkynyl, Ci-Cs haloalkyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, Cs-Cio aryl, or 5- to 10-membered heteroaryl, wherein the Ci-Cs alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Cs haloalkyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more R'ai.

[0570] In some embodiments, R3ais halo, cyano, -OH, -NHz, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the Ci-Cfi alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10- membered heteroaryl is substituted with one or more R3al.

[0571] In some embodiments, Rjais halo, cyano, -OH, -NH2, Ci-Cs alkyl, C2-Q alkenyl, C2-C6 alkynyl, Ci-Ct. haloalkyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, Cs-Cio aryl, or 5- to 10-membered heteroaryl.

[0572] In some embodiments, R3ais halo.78316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0573] In some embodiments, R3ais F, Cl, Br, or I. In some embodiments, R3ais F, Cl, or Br. In some embodiments, R3ais F or Cl.

[0574] In some embodiments, R’ais F. In some embodiments, R3ais Cl. In some embodiments, R‘,ais Br. In some embodiments, R3ais I.

[0575] In some embodiments, R3ais cyano.

[0576] In some embodiments, R3aR3ais -OH.

[0577] In some embodiments, R3ais -NH2.

[0578] In some embodiments, RJais Ci-Cs alkyl.

[0579] In some embodiments, R3ais Ci-Ce alkyl optionally substituted with one or more RJa!.

[0580] In some embodiments, RJais Ci-Cs alkyl substituted with one or more R3al.

[0581] In some embodiments, R3ais methyl. In some embodiments, R3ais ethyl. In some embodiments, R3ais propyl. In some embodiments, R3ais butyl. In some embodiments, R3ais pentyl. In some embodiments, R3ais hexyl. In some embodiments, R3ais isopropyl. In some embodiments, Raais isobutyl. In some embodiments, Rjais isopentyl. In some embodiments, Rjais isohexyl. In some embodiments, Rjais secbutyl. In some embodiments, Rjais secpentyl. In some embodiments, R3ais sechexyl. In some embodiments, R3ais tertbutyl.

[0582] In some embodiments, R3ais C2-C6 alkenyl,

[0583] In some embodiments, Rjais C2-C6 alkenyl optionally substituted with one or more Rjai.

[0584] In some embodiments, R3ais C2-C6 alkenyl substituted with one or more R3al.

[0585] In some embodiments, Rjais C2-C6 alkynyl.

[0586] In some embodiments, R3ais C2-C6 alkynyl optionally substituted with one or more Rjal.

[0587] In some embodiments, Rjais C2-C6 alkynyl substituted with one or more R3al.

[0588] In some embodiments, R3ais Ci-Cg haloalkyl.

[0589] In some embodiments, R3ais C1-C6 haloalkyl optionally substituted with one or more R‘,a’!.

[0590] In some embodiments, R3ais Ci-Cs haloalkyl substituted with one or more R3al.

[0591] In some embodiments, R3ais halomethyl. In some embodiments, R3ais haloethyl. In some embodiments, R3ais halopropyl. In some embodiments, R3ais halobutyl. In some embodiments, R’ais halopentyl. In some embodiments, R3ais halohexyl.

[0592] In some embodiments, RJais C3-C10 cycloalkyl.

[0593] In some embodiments, R3ais C3-C10 cycloalkyl optionally substituted with one or more R3a’!.79316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0594] In some embodiments, R3ais C3-C10 cycloalkyl substituted with one or more R3al.

[0595] In some embodiments, R3ais C3-C7 cycloalkyl.

[0596] In some embodiments, R’ais C3-C7 cycloalkyl optionally substituted with one or more R5al.

[0597] In some embodiments, R3ais C3-C7 cycloalkyl substituted with one or more R3aI.

[0598] In some embodiments, R3ais 3- to 10-membered heterocycloalkyl.

[0599] In some embodiments, R3ais 3- to 10-membered heterocycloalkyl optionally substituted with one or more R3al.

[0600] In some embodiments, R3ais 3- to 10-membered heterocycloalkyl substituted with one or more R3al.

[0601] In some embodiments, RJais 3- to 7-membered heterocycloalkyl.

[0602] In some embodiments, R3ais 3- to 7-membered heterocycloalkyl optionally substituted with one or more R3al.

[0603] In some embodiments, R3ais 3- to 7-membered heterocycloalkyl substituted with one or more Rja!,

[0604] In some embodiments, R3ais Ce-Cio aryl.

[0605] In some embodiments, Raais Cs-Cio aryl optionally substituted with one or more R3al.

[0606] In some embodiments, R3ais Ce-Cio aryl substituted with one or more Rja!,

[0607] In some embodiments, Rjais Cs aryl ,

[0608] In some embodiments, R3ais Ce aryl optionally substituted with one or more Rjal.

[0609] In some embodiments, Rjais Ce ary! substituted with one or more R3al.

[0610] In some embodiments, R3ais 5- to 10-membered heteroaryl.

[0611] In some embodiments, R3ais 5- to 10-membered heteroaryl optionally substituted with one or more R’aJ.

[0612] In some embodiments, R3ais 5- to 10-membered heteroaryl substituted with one or more R3al.

[0613] In some embodiments, R3ais 5- to 6-membered heteroaryl.

[0614] In some embodiments, R3ais 5- to 6-membered heteroaryl optionally substituted with one or more R3al.

[0615] In some embodiments, R3ais 5- to 6-membered heteroaryl substituted with one or more R3<

[0616] In some embodiments, RJais pyridinyl.80316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0617] In some embodiments, R3ais pyridinyl optionally substituted with one or more R3al.

[0618] In some embodiments, R3ais pyridinyl substituted with one or more R3al.81316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0621] In some embodiments,

[0622] In some embodiments, each R3a!independently is oxo, halo, cyano, -OH, -C(O)(Ci-Ce alkyl), -C(O)(O-(Ci-C6 alkyl)), Ci -Ce alkyl optionally substituted with C3-C10 cycloalkyl, C2-C0 alkenyl, Cj-Ce alkynyl, Ci-C-6 haloalkyl, Ci-Cs haloalkoxy, Ci-Ce alkoxy, -O(Ci-Cs haloalkyl), C3- C10 cycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl.

[0623] In some embodiments, each R3alindependently is oxo, halo, cyano, -OH, -C(O)(Ci-Ce alkyl), -C(O)(O-(Ci-Ce alkyl)), Ci-Ce alkyl substituted with C3-C10 cycloalkyl, C2-C6 alkenyl, C2- Ce alkynyl, Ci-Ce haloalkyl, Ci-Ce haloalkoxy, Ci-Ce alkoxy, -O(Ci-Ce haloalkyl), Cs-Cw cycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl.

[0624] In some embodiments, each R3alindependently is oxo, halo, cyano, -OH, -C(O)(Ci-Ce alkyl), -C(O)(O-(Ci-Cs alkyl)), Ci-Ce alkyl, C2-C0 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce haloalkoxy, Ci-Ce alkoxy, -O(Ci-Cs haloalkyl), C3-C10 cycloalkyl, Ce-Cio aryl, or 5- to 10- membered heteroaryl.

[0625] In some embodiments, each Rja!independently is oxo.

[0626] In some embodiments, each R3®1independently is halo,

[0627] In some embodiments, each R3aiindependently is F, Cl, Br, or I. In some embodiments, each R3alindependently is F, Cl, or Br. In some embodiments, each R3aiindependently is F or Cl.

[0628] In some embodiments, each R3alindependently is F. In some embodiments, each R3aiindependently is Cl. In some embodiments, each R3aiindependently is Br. In some embodiments, each Rjalindependently is I.

[0629] In some embodiments, each R3independently is cyano.

[0630] In some embodiments, each R’ independently is -OH.

[0631] In some embodiments, each R3independently is -C(O)(Ci-Ce alkyl).

[0632] In some embodiments, each R’a lindependently is -C(O)(O-(Ci-Ce alkyl)).

[0633] In some embodiments, each R3a’!independently is Ci-Ce alkyl.

[0634] In some embodiments, each R3alindependently is Ci-Ce alkyl optionally substituted with C3-C10 cycloalky 1.

[0635] In some embodiments, each R3alindependently is Ci-Ce alkyl substituted with C3-C10 cycloalkyl.82316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0636] In some embodiments, each R3a!independently is methyl. In some embodiments, each R’alindependently is ethyl. In some embodiments, each R’alindependently is propyl. In some embodiments, each R3alindependently is butyl. In some embodiments, each R3a-!independently is pentyl. In some embodiments, each R3alindependently is hexyl. In some embodiments, each R’,a;independently is isopropyl. In some embodiments, each R3a!independently is isobutyl. In some embodiments, each R3alindependently is isopentyl. In some embodiments, eachindependently is isohexyl. In some embodiments, each R'aiindependently is secbutyl. In some embodiments, each R3aiindependently is secpentyl. In some embodiments, each R'aiindependently is sechexyl. In some embodiments, each R3alindependently is tertbutyl.

[0637] In some embodiments, each R3aiindependently is C2-C6 alkenyl.

[0638] In some embodiments, each R'aiindependently is C2-C0 alkynyl.

[0639] In some embodiments, each R3®1independently is Ci-Ce haloalkyl.

[0640] In some embodiments, each R3alindependently is halomethyl. In some embodiments, each Rja!independently is haloethyl. In some embodiments, each Rja!independently is halopropyl. In some embodiments, each R3alindependently is halobutyl. In some embodiments, each R3aIindependently is halopentyl. In some embodiments, each R3aIindependently is halohexyl.

[0641] In some embodiments, each Rja!independently is Ci-Ce haloalkoxy.

[0642] In some embodiments, each R3aiindependently is Ci-Ce alkoxy.

[0643] In some embodiments, each Rjaiindependently is -O(Ci-C6 haloalkyl).

[0644] In some embodiments, each R3aiindependently is C3-C10 cycloalkyl.

[0645] In some embodiments, each Rjaiindependently is C3-C7 cycloalkyl.

[0646] In some embodiments, each R3aiindependently is Cg-Cio aryl.

[0647] In some embodiments, each R’a lindependently is Ce aryl.

[0648] In some embodiments, each R’,a3independently is 5- to 10-membered heteroaryl.

[0649] In some embodiments, each R’a lindependently is 5- to 6-membered heteroaryL

[0650] In some embodiments, each R3a!independently is oxo, methyl, -CF2H, cyano, -F, -Cl, - OH, -OCF2H, or -OCH 3.

[0651] In some embodiments, each R’,a3independently is halo or Ci-Ce alkoxy.

[0652] In some embodiments, each R3aiindependently is -Cl or -OCII3.83316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0653] In some embodiments,

[0654] In some embodiments, the PolO helicase inhbitor is a compound of Formula I, wherein:Ralis a 5- to 10-membered heteroaryl optionally substituted with one or more Ra2; each Ra2independently is (';-( ■• alkyl, Ci-Co haloalkyl, or Ci-Ce alkoxy;R3ais 5- to 10-membered heteroaryl optionally substituted with one or more R3al; and each Rjaiindependently is halo, Ci-Cg alkyl, C2-C6 alkenyl, (T-Cealkynyl, Ci-Ce haloalkyl, Ci-Ce haloalkoxy,alkoxy.

[0655] In some embodiments, the PolO helicase inhbitor is a compound selected from Table 1 or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0656] In some embodiments, the PolO helicase inhbitor is a prodrug of a compound selected from Table 1 or a pharmaceutically acceptable salt thereof

[0657] In some embodiments, the PolO helicase inhbitor is a compound selected from Table 1 or a pharmaceutically acceptable salt thereof.

[0658] In some embodiments, the PolO helicase inhbitor is a compound selected from Table 1.

[0659] In some embodiments, the PolO helicase inhbitor is a pharmaceutically acceptable salt of a compound selected from Table 1.

[0660] In some embodiments, the PolO helicase inhbitor is a prodrug of a compound selected from Table 1.

[0661] In some embodiments, the PolO helicase inhbitor is a solvate of a compound selected from Table 1 .

[0662] In some embodiments, the PolO helicase inhbitor is a hydrate of a compound selected from Table 1 .84316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)85316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)86316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)87316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)88316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)89316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)90316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)91316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)92316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)93316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)94316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)95316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)96316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)97316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)98316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)99316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)100316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)101316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)102316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)103316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)104316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)105316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)106316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)107316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)108316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)109316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)110316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)111316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)318259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)113316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)114316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)115316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)116316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)117316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)118316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)119316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)120316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)121316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)318259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)123316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)124316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)126316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)318259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)128316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)318259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)130316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)131316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)318259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)133316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)134316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)135316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)136316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)137316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)138316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)139316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)140316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)141316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)142316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)143316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)144316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)145316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)146316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)147316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)148316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)149316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)150316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)151316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)318259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)153316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)154316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)318259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)156316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)157318259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)158316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)150318259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)160316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)161316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)318259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)163316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)164316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)165316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)166316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)167316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)168316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)169316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)170316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)171316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)318259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)173316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)174316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)175318259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)176316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)318259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)178316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0663] In some embodiments, the Pol0 helicase inhbitor is Compound 15:(Compound 15), or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0664] In some embodiments, the Pol0 helicase inhbitor is Compound 15:or a pharmaceutically acceptable salt thereof.

[0665] In some embodiments, the Pol0 helicase inhbitor is Compound 15:Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)(Compound 15).

[0666] In some embodiments, the PoI0 helicase inhbitor is Compound 18:(Compound 18), or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0667] In some embodiments, the Pol0 helicase inhbitor is Compound 18:(Compound 18), or a pharmaceutically acceptable salt thereof.

[0668] In some embodiments, the Pol0 helicase inhbitor is Compound 18:

[0669] In some aspects, the present disclosure provides a Pol0 helicase inhbitor that is an isotopic derivative (e.g., isotopically labeled compound) of any one of the compounds of the Formulae disclosed herein.

[0670] In some embodiments, the Pol0 helicase inhbitor is an isotopic derivative of any one of the compounds described in Table 1, or pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0671] In some embodiments, the Pol0 helicase inhbitor is an isotopic derivative of any one of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof.

[0672] In some embodiments, the Pol0 helicase inhbitor is an isotopic derivative of any one of the compounds described in Table 1.

[0673] In some embodiments, the Pol0 helicase inhbitor is an isotopic derivative of any one of the prodrugs of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof.180316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0674] In some embodiments, the PolO helicase inhbitor is an isotopic derivative of any one of the prodrugs of the compounds described in Table I .

[0675] In some embodiments, the PolO helicase inhbitor is an isotopic derivative of any one of the solvates of the compounds described in Table 1.

[0676] In some embodiments, the PolO helicase inhbitor is an isotopic derivative of any one of the hydrates of the compounds described in Table 1.

[0677] It is understood that the isotopic derivative can be prepared using any of a variety of art- recognized techniques. For example, the isotopic derivative can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples described in PCT / US2024 / 023445, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0678] For the avoidance of doubt it is to be understood that, where in this specification a group is qualified by “described herein,” the said group encompasses the first occurring and broadest definition as well as each and all of the particular definitions for that group.

[0679] It will be understood that while compounds disclosed herein may be presented in one particular configuration. Such particular configuration is not to be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers or stereoisomers. In some embodiments, the presentation of a compound herein in a particular configuration intends to encompass, and to refer to, each of the available isomers, tautomers, regioisomers, and stereoisomers of the compound, or any mixture thereof; while the presentation further intends to refer to the specific configuration of the compound.

[0680] It will be understood that while compounds disclosed herein may be presented without specified configuration (e.g., without specified stereochemistry). Such presentation intends to encompass all available isomers, tautomers, regioisomers, and stereoisomers of the compound. In some embodiments, the presentation of a compound herein without specified configuration intends to refer to each of the available isomers, tautomers, regioisomers, and stereoisomers of the compound, or any mixture thereof.

[0681] As used herein, the term “isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.”181316259781Attorney Docket No.: 43705-02087, AVO (MOMA-010 / 001 WO)Stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture.”

[0682] As used herein, the term “chiral center” refers to a carbon atom bonded to four nonidentical substituents.

[0683] As used herein, the term “chiral isomer” means a compound with at least one chiral center. Compounds with more than one chiral center may exist either as an individual diastereomer or as a mixture of diastereomers, termed “dia stereomeric mixture.” When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511 ; Cahn etal., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0684] As used herein, the term “geometric isomer” means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., 1,3-cyclobutyl), These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.

[0685] It is to be understood that the compounds of the present disclosure may be depicted as different chiral isomers or geometric isomers. It is also to be understood that when compounds have chiral isomeric or geometric isomeric forms, all isomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any isomeric forms, it being understood that not all isomers may have the same level of activity.It is to be understood that the structures and other compounds discussed in this disclosure include all atropic isomers thereof. It is also to be understood that not all atropic isomers may have the same level of activity.

[0686] As used herein, the term “atropic isomers” are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers182316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO) typically exist as a mixture, however as a result of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases.

[0687] .As used herein, the term “tautomer” is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers wall be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertible by tautomerisations is called tautomerism. Of the various types of tautomerism that are possible, tw?o are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose.

[0688] It is to be understood that the compounds of the present disclosure may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any tautomer form. It will be understood that certain tautomers may have a higher level of activity than others.

[0689] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are nonsuperimposable mirror images of each other are termed “enantiomers.” When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterised by the absolute configuration of its asymmetric center and is described by the R and S sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory’ (?.e., as (+) or (-)isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture.”183316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0690] The compounds of this disclosure may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R) or (S) stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry,” 4th edition J. March, John Wiley and Sons, New7York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form. Some of the compounds of the disclosure may have geometric isomeric centers (E and Z isomers). It is to be understood that the present disclosure encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess PolO helicase inhibitory activity.

[0691] The present disclosure also encompasses compounds of the disclosure as defined herein which comprise one or more isotopic substitutions.

[0692] It is to be understood that the compounds of any Formula described herein include the compounds themselves, as well as their salts, and their solvates, if applicable. A salt, for example, can be formed between an anion and a positively charged group (e.g, ammo) on a substituted compound disclosed herein. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g, trifluoroacetate).

[0693] As used herein, the term “pharmaceutically acceptable anion” refers to an anion suitable for forming a pharmaceutically acceptable salt. Likewise, a salt can also be formed between a cation and a negatively charged group (e.g, carboxylate) on a substituted compound disclosed herein. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion or diethylamine ion. The substituted compounds disclosed herein also include those salts containing quaternary nitrogen atoms.

[0694] It is to be understood that the compounds of the present disclosure, for example, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Nonlimiting examples of hydrates include monohydrates, dihydrates, etc. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.184316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0695] As used herein, the term “solvate” means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H?.O.

[0696] As used herein, the term “analog” refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group). Thus, an analog is a compound that is similar or comparable in function and appearance, but not in structure origin to the reference compound.

[0697] As used herein, the term “derivative” refers to compounds that have a common core structure and are substituted with various groups as described herein.

[0698] As used herein, the term “bioisostere” refers to a compound resulting from the exchange of an atom or of a group of atoms with another, broadly similar, atom or group of atoms. The objective of a bioisosteric replacement is to create a new compound with similar biological properties to the parent compound. The bioisosteric replacement may be physicochemically or topologically based. Examples of carboxylic acid bioisosteres include, but are not limited to, acyl sulfonamides, tetrazoles, sulfonates and phosphorates. See, e.g., Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0699] It is also to be understood that certain compounds of any one of the Formulae disclosed herein may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. A suitable pharmaceutically acceptable solvate is, for example, a hydrate such as hemi -hydrate, a mono-hydrate, a di-hydrate or a tri-hydrate. It is to be understood that the disclosure encompasses all such solvated forms that possess Pol0 helicase inhibitory activity.

[0700] It is also to be understood that certain compounds of any one of the Formulae disclosed herein may exhibit polymorphism, and that the disclosure encompasses all such forms, or mixtures thereof, which possess Pol0 helicase inhibitory activity. It is generally known that crystalline materials may be analysed using conventional techniques such as X-Ray Powder Diffraction analysis, Differential Scanning Calorimetry, Thermal Gravimetric Analysis, Diffuse Reflectance Infrared Fourier Transform (DRIFT) spectroscopy, Near Infrared (NIR) spectroscopy, solution185316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO) and / or solid state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials may be determined by Karl Fischer analysis.

[0701] Compounds of any one of the Formulae disclosed herein may exist in a number of different tautomeric forms and references to compounds of Formula (I) include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by Formula (I). Examples of tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, aniide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro.keto enol enolate

[0702] Compounds of any one of the Formulae disclosed herein containing an amine function may also form N-oxides. A reference herein to a compound of Formula (1) that contains an amine function also includes the N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. N- oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., a peroxy carboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with meta-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.

[0703] The compounds of any one of the Formulae disclosed herein may be administered in the form of a prodrug which is broken down in the human or animal body to release a compound of the disclosure. A prodrug may be used to alter the physical properties and / or the pharmacokinetic properties of a compound of the disclosure. A prodrug can be formed when the compound of the disclosure contains a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include derivatives containing in vivo cleavable alkyl or acyl substituents at the ester or amide group in any one of the Formulae disclosed herein. The in vivo effects of a compound of any one of the Formulae disclosed herein may be exerted in part by one186316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO) or more metabolites that are formed within the human or animal body after administration of a compound of any one of the Formulae disclosed herein. As stated hereinbefore, the in vivo effects of a compound of any one of the Formulae disclosed herein may also be exerted by way of metabolism of a precursor compound (a prodrug).

[0704] Suitably, the present disclosure excludes any individual compounds not possessing the biological activity defined herein.

[0705] A compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, (e.g., a polymerase theta (Pol0) helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof) may be prepared in accordance with the disclosure of PCT / US2024 / 023445 (incorporated herein by reference).PARP Inhibitor

[0706] In some embodiments, the PARI’ inhibitor that can be used in accordance with the combinations and / or methods described herein may be an inhibitor of more than one PARP.

[0707] In some embodiments, the PARP inhibitor is a dual inhibitor (e.g, inhibiting PARP! and PARP2).

[0708] In some embodiments, the PARP inhibitor inhibits, at least, PARP1.

[0709] In some embodiments, the PARP inhibitor is selected from Table 2A.

[0710] In some embodiments, the PARP inhibitor is selected from Table 2B.

[0711] In some embodiments, the PARP inhibitor is selected from Table 2C.

[0712] In some embodiments, the PARP inhibitor is selected from Table 2D.

[0713] In some embodiments, the PARP inhibitor is selected from Table 2D, or a pharmaceutically acceptable salt thereof.

[0714] In some embodiments, the PARP inhibitor is fuzuloparib, niraparib, olaparib, pamiparib, rucaparib, or talazoparib.

[0715] In some embodiments, the PARI1inhibitor is saruparib, AZD9574, XIN6301, XIN5104, or XIN5789.

[0716] In some embodiments, the PARP inhibitor is olaparib.

[0717] In some embodiments, the PARI’ inhibitor is a compound of Formula (II), or a pharmaceutically acceptable salt thereof:187316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)0)wherein:Y1is (). CH 2, or CRY1RY2; each RY 1and RY 2is independently deuterium, halogen, or an unsubstituted Ci-4 alkyl;Ring A is pyrrole, thiophene, pyridine, or phenyl, wherein the pyrrole, thiophene, pyridine or phenyl is optionally substituted with one or more deuterium, halogen, Ct-4 alkyl, Ci-4 alkoxy, Ci-4 haloalkyl, or Ci-4 haloalkoxy;Ring B is 6-membered monocyclic nitrogen-containing heterocyclyl, 7 -membered bicyclic nitrogen-containing heterocyclyl, or 8-membered bicyclic nitrogen-containing heterocyclyl;Ring C is pyrrole, thiophene, thiazole, pyridine, pyridazine, pyrimidine, pyrazine, or phenyl;Rlais hydrogen, deuterium, Ci-4 alkyl, C2-4 alkenyl, Ci-4 haloalkyl, C1-4 hydroxyalkyl, monocyclic C3-6 cycloalkyl, bicyclic Cs-8 cycloalkyl, monocyclic C3-6 cycloalkyl(Ci -4 alkyl), or monocyclic C3-6 cycloalkyl(C2-4 alkenyl), wherein the alkyl is optionally substituted with one or more deuterium, and wherein the monocyclic C3-6 cycloalkyl, bicyclic C5-8 cycloalkyl, monocyclic C3-6 cycloalkyl(Ci-4 alkyl), or monocyclic C3-6 cycloalkyl(C2-4 alkenyl) is independently optionally substituted with one or more deuterium or halogen;Rlbis hydrogen, Ci-4 alkyl, or C1-4 haloalkyl, or Rlaand Rlb, together with the atoms to which they are attached, form a monocyclic 3- 4-membered cycloalkyl or monocyclic 4-5 membered heterocyclyl, wherein the monocyclic 3-4- membered cycloalkyl or monocyclic 4-5 membered heterocyclyl is optionally substituted with one or more halogen, C1-3 alkyl, or C1-3 haloalkyl; provided that when Rlbis hydrogen, then Rlais deuterium, Ci-4 alkyl, C2-4 alkenyl, Ci-4 haloalkyl, Ct-4 hydroxyalkyl, monocyclic C3-6 cycloalkyl, bicyclic C5-8 cycloalkyl, bicyclic C5-8 cycloalkyl, monocyclic C3-6 cycloalkyl(Ci-4 alkyl), or monocyclic C3-6 cycloalkyl(C2-4 alkenyl), wherein the Ci-4 alkyl is optionally substitued with one or more deuterium, and wherein the monocyclic C3-6 cycloalkyl, bicyclic C5-8 cycloalkyl, monocyclic C3-6 cycloalkyl(Ci-4 alkyl), or188316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO) monocyclic C3-6 cycloa1kyl(C2-4 alkenyl) is optionally substituted with one or more deuterium or halogen; each R2and R3independently is hydrogen, deuterium, or Ci-4 alkyl, or R2and R3, together with the atoms to which they are attached, form a monocyclic C3-6 cycloalkyl; m is 0, 1 or 2; n is 0, 1 or 2; each R3ais independently deuterium, halogen, Ci-4 alkyl optionally substituted with cyano, Ci -4 haloalky 1, or monocyclic C3-6 cycloalkyl; each R3bis independently deuterium, halogen, Ci-4 alkyl optionally substituted with one or more deuterium, C2-4 alkenyl, Ci-4 haloalkyl, monocyclic C3-6 cycloalkyl, or monocyclic C3-6 cycloalkyl(Ci-4 alkyl);R4is — -C(=O)NR5R6;R5is hydrogen or Ci-4 alkyl; andR° is hydrogen, C1-4 alkyl, monocyclic C3-6 cycloalkyl, bicyclic Cs-s cycloalkyl, monocyclic C3-6 cycloaIkyl(Ci-4 alkyl), or bicyclic C5-8 cycloalkyl(Ci-4 alkyl), wherein the C1-4 alkyl is optionally substituted by one or more deuterium.

[0718] In some embodiments, the PARP inhibitor is Compound 1064 or a pharmacuetically acceptable salt thereof.

[0719] In some embodiments, the PARP inhibitor is Compound 1056 or a pharmacuetically acceptable salt thereof.

[0720] In some embodiments, the PARP inhibitor is Compound 1056a or a pharmacuetically acceptable salt thereof.

[0721] In some embodiments, the PARP inhibitor is Compound 1056b or a pharmacuetically acceptable salt thereof.

[0722] In some embodiments, the PARI’ inhibitor is Compound 1064.

[0723] In some embodiments, the PARP inhibitor is Compound 1056.

[0724] In some embodiments, the PARI’ inhibitor is Compound 1056a.

[0725] In some embodiments, the PARP inhibitor is Compound 1056b.189316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)Table 2ATable 2BTable 2C190316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)Table 2D191316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)192318259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)193316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)194316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)195318259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)196316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)197318259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)198316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)318259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)200316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)201316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)202316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)203316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)204316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)205316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)318259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0726] A compound of Table 2D, or a pharmaceutically acceptable salt, may be prepared in accordance with the disclosure of WO2023 / 178035 (incorporated herein by reference).Second Therapeutic Agent

[0727] In some embodiments, the second therapeutic agent that can be used in accordance with the combinations and / or methods described herein may be an inhibitor of more than one therapeutic target (e.g., PARP1 , PARP2, PARP3, tankyrase, TNKS1, TNKS2, Trop2, Her2, Her3, Cl.) 19. PSMA, SSTR2, or EGFR / cMET).

[0728] In some embodiments, the second therapeutic agent is a platinum-based chemotherapy.

[0729] In some embodiments, the platinum-based chemotherapy is cisplatin, carboplatin, or oxaliplatin.

[0730] In some embodiments, the platinum-based chemotherapy is cisplatin.

[0731] In some embodiments, the platinum-based chemotherapy is carboplatin.Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0732] In some embodiments, the platinum-based chemotherapy is oxaliplatin.

[0733] In some embodiments, the second therapeutic agent is a DNA damage response-conjugated antibody-drug conjugate (DDR-conjugated ADC).

[0734] In some embodiments, the DDR-conjugated ADC is Trodelvy, Enhertu, Zynlonta, datopotamab deruxtecan, sacituzumab tirumotecan, patritumab deruxtecan, TRX-920, or HS- 20105.

[0735] In some embodiments, the DDR-conjugated ADC is Trodelvy.

[0736] In some embodiments, the DDR-conjugated ADC is Enhertu.

[0737] In some embodiments, the DDR-conjugated ADC is Zynlonta.

[0738] In some embodiments, the DDR-conjugated ADC is datopotamab deruxtecan.

[0739] In some embodiments, the DDR-conjugated ADC is sacituzumab tirumotecan.

[0740] In some embodiments, the DDR- conjugated ADC is patritumab deruxtecan.

[0741] In some embodiments, the DDR-conjugated ADC is TRX-920.

[0742] In some embodiments, the DDR-conjugated ADC is HS-20105.

[0743] In some embodiments, the second therapeutic agent is a radioligand therapeutic.

[0744] In some embodiments, the radioligand therapeutic is Pluvicto, Lutathera, FPI-2265, FPI- 2068, Tozaride, BAY-2701439, BAY-2315497, 177Lu-rhPSMA-10.1, CTT-1403, lopofosine, SAR-BBN, SAR-bisPSMA, S ART ATE, 177Lu-PSMA-I&T, FPI-2059, FPI-1434, FPI-1966, 161Tb-PSMA-I&T, ITM31 , JNJ-69086420, Zevalm, Actimab-A, lomab-B, Lutitium-177- DOTAGA-PEG-IAC, TLX592, TLX66, TLX250, TLX101 , Azedra, or PPMX-T002.

[0745] In some embodiments, the radioligand therapeutic is Pluvicto.

[0746] In some embodiments, the radioligand therapeutic is Lutathera.

[0747] In some embodiments, the radioligand therapeutic is FPI-2265.

[0748] In some embodiments, the radioligand therapeutic is FPI-2068.

[0749] In some embodiments, the radioligand therapeutic is Tozaride.

[0750] In some embodiments, the radioligand therapeutic is BAY-2701439.

[0751] In some embodiments, the radioligand therapeutic is BAY-2315497.

[0752] In some embodiments, the radioligand therapeutic is I77Lu-rhPSMA-10.1.

[0753] In some embodiments, the radioligand therapeutic is CTT-1403.

[0754] In some embodiments, the radioligand therapeutic is lopofosine.

[0755] In some embodiments, the radioligand therapeutic is SAR-BBN.208316259781Attorney Docket No.: 43705-02087, / WO (MOMA-010 / 001 WO)

[0756] In some embodiments, the radioligand therapeutic is SAR-bisPSMA.

[0757] In some embodiments, the radioligand therapeutic is SARTATE.

[0758] In some embodiments, the radioligand therapeutic is 177Lu-PSMA-I&T.

[0759] In some embodiments, the radioligand therapeutic is FPI-2059.

[0760] In some embodiments, the radioligand therapeutic is FPL 1434.

[0761] In some embodiments, the radioligand therapeutic is FPI-1966.

[0762] In some embodiments, the radioligand therapeutic is 16ITb-PSMA-I&T.

[0763] In some embodiments, the radioligand therapeutic is ITM31.

[0764] In some embodiments, the radioligand therapeutic is JNJ-69086420.

[0765] In some embodiments, the radioligand therapeutic is Zevalm.

[0766] In some embodiments, the radioligand therapeutic is Actimab-A.

[0767] In some embodiments, the radioligand therapeutic is Iomab~B.

[0768] In some embodiments, the radioligand therapeutic is Lutitium-177-DOTAGA-PEG-IAC.

[0769] In some embodiments, the radioligand therapeutic is TLX592.

[0770] In some embodiments, the radioligand therapeutic is TL.X66.

[0771] In some embodiments, the radioligand therapeutic is TLX250.

[0772] In some embodiments, the radioligand therapeutic is TL.X101.

[0773] In some embodiments, the radioligand therapeutic is Azedra.

[0774] In some embodiments, the radioligand therapeutic is PPMX-T002.

[0775] In some embodiments, the second therapeutic agent is a Weel inhibitor.

[0776] In some embodiments, the Weel inhibitor is azenosertib, adavosertib, APR- 1051 , or Debio 0123.

[0777] In some embodiments, the Weel inhibitor is azenosertib.

[0778] In some embodiments, the Weel inhibitor is adavosertib.

[0779] In some embodiments, the Weel inhibitor is APR- 1051.

[0780] In some embodiments, the Weel inhibitor is Debio 0123.

[0781] In some embodiments, the second therapeutic agent is a PKMYT1 inhibitor.

[0782] In some embodiments, the PKMYT1 inhibitor is lunresertib.

[0783] In some embodiments, the second therapeutic agent is a Weel / PKMYTl dual inhibitor.

[0784] In some embodiments, the Weel / PKMYTl dual inhibitor is SGR-3515 or ACR-2316.

[0785] In some embodiments, the Weel / PKMYTl dual inhibitor is SGR-3515.Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0786] In some embodiments, the Weel / PKMYTl dual inhibitor is ACR-2316.

[0787] In some embodiments, the second therapeutic agent is an ATR inhibitor.

[0788] In some embodiments, ATR inhibitor is ART0380, ATG-018, ATRN-119, berzosertib, camonsertib, ceralasertib, elimusertib, HRS2398, IMP9064, SC0245, tuvusertib, or TCC1727.

[0789] In some embodiments, ATR inhibitor is ART0380.

[0790] In some embodiments, ATR inhibitor is ATG-018.

[0791] In some embodiments, ATR inhibitor is ATRN-119.

[0792] In some embodiments, ATR inhibitor is berzosertib.

[0793] In some embodiments, ATR inhibitor is camonsertib.

[0794] In some embodiments, ATR inhibitor is ceralasertib.

[0795] In some embodiments, ATR inhibitor is elimusertib.

[0796] In some embodiments, ATR inhibitor is HRS2398.

[0797] In some embodiments, ATR inhibitor is IMP9064.

[0798] In some embodiments, ATR inhibitor is SC0245.

[0799] In some embodiments, ATR inhibitor is tuvusertib.

[0800] In some embodiments, ATR inhibitor is TCC1727.

[0801] In some embodiments, the second therapeutic agent is an DNA-dependent protein kinase (DNA-PK) inhibitor.

[0802] In some embodiments, the DNA-PK inhibitor is avadomide, BRI 01801 , CC-115, LY3023414, M9831, peposertib, XRD-0394, ZSTK474, or AZD7648.

[0803] In some embodiments, the DNA-PK inhibitor is avadomide.

[0804] In some embodiments, the DNA-PK inhibitor is BRI 01801 .

[0805] In some embodiments, the DNA-PK inhibitor is CC-115.

[0806] In some embodiments, the DNA-PK inhibitor is LY3023414.

[0807] In some embodiments, the DNA-PK inhibitor is M9831.

[0808] In some embodiments, the DNA-PK inhibitor is peposertib.

[0809] In some embodiments, the DNA-PK inhibitor is XRD-0394.

[0810] In some embodiments, the DNA-PK inhibitor is ZSTK474.

[0811] In some embodiments, the DNA-PK inhibitor is AZD7648.Pharmaceutical Compositions210316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0812] In some aspects, composition or pharmaceutic compositions are disclosed herein.

[0813] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound of each of the formulae described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carrier, diluent, adjuvant, excipient, or a combination thereof. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound described in Table 1. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 1. In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound 15. In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound 18. In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, adjuvant, excipient, or a combination thereof.

[0814] As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0815] The compounds of present disclosure can be formulated for oral administration m forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. The compounds of present disclosure on can also be formulated for intravenous (bolus or in-fusion), intraperitoneal, topical, subcutaneous, intramuscular or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.

[0816] The formulation of the present disclosure may be in the form of an aqueous solution comprising an aqueous vehicle. The aqueous vehicle component may comprise water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of a solubility enhancing agent, chelating agent, preservative, tonicityagent, viscosity / suspendmg agent, buffer, and pH modifying agent, and a mixture thereof.

[0817] Any? suitable solubility enhancing agent can be used. Examples of a solubility enhancing agent include cyclodextrin, such as those selected from the group consisting of hydroxypropyl-P-Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO) cyclodextrin, methyl-|3-cyclodextrin, randomly methylated-P-cyclodextrm, ethylated-p- cyclodextrin, triacetyl-p-cyclodextrm, peracetylated-P-cyclodextrm, carboxymethyl-P- cyclodextrin, hydroxyethyl-P-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl“p“ cyclodextrin, glucosyl-p-cyclodextrin, sulfated p-cyclodextrin (S-p-CD), maltosyl-P-cyclodextrin, P-cyclodextrin sulfobutyl ether, branched-P-cyclodextrin, hydroxypropyl-y-cyclodextrin, randomly methylated-y-cyclodextrin, and trimethyl-y-cyclodextrm, and mixtures thereof.

[0818] Any suitable chelating agent can be used. Examples of a suitable chelating agent include those selected from the group consisting of ethylenediaminetetraacetic acid and metal salts thereof, disodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof.

[0819] Any suitable preservative can be used. Examples of a preservative include those selected from the group consisting of quaternary’ ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmer cury acetate, phenylmercury neodecanoate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl- p-hydroxybenzoate, and sorbic acid, and mixtures thereof.

[0820] The aqueous vehicle may also include a tonicity agent to adjust the tonicity (osmotic pressure). The tonicity agent can be selected from the group consisting of a glycol (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof.

[0821] The aqueous vehicle may also contain a viscosity / suspending agent. Suitable viscosity / suspending agents include those selected from the group consisting of cellulose derivatives, such as methyl cellulose, ethyl cellulose, hydroxyethylcellulose, polyethylene glycols (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropylmethyl cellulose, and cross-linked acrylic acid polymers (carbomers), such as polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol (Carbopols - such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P), and a mixture thereof.

[0822] In order to adjust the formulation to an acceptable pH (ty pically a pH range of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7. 1 to about 7.9, or about 7.5 to about 8.0), the formulation9] ?Attorney Docket No.: 43705-02087, / WO (MOMA-010 / 001 WO) may contain a pH modifying agent. The pH modifying agent is typically a mineral acid or metal hydroxide base, selected from the group of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, and preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or basic pH modifying agents are added to adjust the formulation to the target acceptable pH range. Hence it may not be necessary to use both acid and base - depending on the formulation, the addition of one of the acid or base may be sufficient to bring the mixture to the desired pH range.

[0823] The aqueous vehicle may also contain a buffering agent to stabilize the pH. When used, the buffer is selected from the group consisting of a phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), a borate buffer (such as boric acid, or salts thereof including disodium tetraborate), a citrate buffer (such as citric acid, or salts thereof including sodium citrate), and s-ammocaproic acid, and mixtures thereof.

[0824] The formulation may further comprise a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oils, poly oxy ethylenated sorbitan esters (polysorbates), polymers of oxyethylated octyl phenol (Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty esters, and polyoxyethylene fatty esters, and mixtures thereof.

[0825] Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier, diluent, adjuvant, excipient, or a combination thereof. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0826] According to a further aspect of the disclosure there is provided a pharmaceutical composition which comprises a compound of the disclosure as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.

[0827] The compositions of the disclosure may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).

[0828] An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent a Pol0 helicase related condition referred to herein, slow its progression and / or reduce the symptoms associated with the condition.

[0829] An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat a Pol0 helicase related condition referred to herein, slow' its progression and / or reduce the symptoms associated with the condition,

[0830] The size of the dose for therapeutic or prophylactic purposes of a compound of Formula (I) will naturally vary according to, for example, the nature and severity of the condi tions, and the age and sex of the animal or patient.

[0831] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a Po10 helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof (e.g., Formula (I), (I -a), (I-b), (I -a’), (I-b’), (I-c), or (I-c’ )), a PARP inhibitor, and a pharmaceutically acceptable carrier, diluent, adjuvant, excipient, or a combination thereof.

[0832] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a Pol0 helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof (e.g., a compound of Formula (I), (I-a), (I-b), (I-a ’), (I-b’), (I-c), or (I-c’), or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof), a PARI’ inhibitor (e.g., a compound selected from Table 2A, Table 2B, Table 2C, or Table 2D, or a pharmaceutically214316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO) acceptable salt thereof), and a pharmaceutically acceptable carrier, diluent, adjuvant, excipient, or a combination thereof.

[0833] In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound 15, olaparib, and a pharmaceutically acceptable carrier, diluent, adjuvant, excipient, or a combination thereof.

[0834] In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound 18, olaparib, and a pharmaceutically acceptable carrier, diluent, adjuvant, excipient, or a combination thereof.

[0835] In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound 15, Compound 1064, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, adjuvant, excipient, or a combination thereof.

[0836] In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound 18, Compound 1064, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, adjuvant, excipient, or a combination thereof.

[0837] In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound 15, Compound 1056, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, adjuvant, excipient, or a combination thereof,

[0838] In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound 18, Compound 1056, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, adjuvant, excipient, or a combination thereof.

[0839] In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound 15, Compound 1056a, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, adjuvant, excipient, or a combination thereof.]0840] In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound 18, Compound 1056a, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, adjuvant, excipient, or a combination thereof.

[0841] In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound 15, Compound 1056b, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, adjuvant, excipient, or a combination thereof.215316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0842] In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound 18, Compound 1056b, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, adjuvant, excipient, or a combination thereof.Exemplary Embodiments

[0843] Exemplary Embodiment No. I . A combination therapy comprising:(a) a polymerase theta (Pol0) helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a poly(adenosine diphosphate [ADP] -ribose) polymerase (PARP) inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0844] Exemplary Embodiment No. 2. A polymerase theta (Pol0) helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, for use in combination for treating or preventing cancer in a subject.

[0845] Exemplary Embodiment No. 3. A method of treating or preventing cancer, comprising administering to a subject:(a) a polymerase theta helicase (Pol0) inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0846] Exemplary Embodiment No. 4. A polymerase theta helicase (Pol0) inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of cancer in a subject.

[0847] Exemplary Embodiment No. 5. Use of a polymerase theta helicase (PolG) inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with a PARI’ inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of cancer in a subject.

[0848] Exemplary Embodiment No. 6. A kit comprising:216316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)(a) a polymerase theta helicase (Pol0) inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a PARI’ inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0849] Exemplary Embodiment No. 7. A pharmaceutical package comprising:(a) a polymerase theta helicase (Pol0) inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0850] Exemplary Embodiment No. 8. The combination, use, method, pharmaceutical package, or kit of any one of the preceding Exemplar}' Embodiments, wherein the PolO helicase inhibitor is a compound of Formula I:or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein:RaSis H, oxo, halo, cyano, -OH, -NH2, -NH(Ci-Cs alkyl), -N(CI-C6 alkyl)2, -C(O)(Ci-Co alkyl), -C(0)(C3-Cio cycloalkyl), Ci-Ce alkyl, C.-G-. alkenyl, C2-C6alkynyl, Ci-Cs haloalkyl, Ci- Ct. alkoxy, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, Cs-Cio aryl, or 5- to 10- membered heteroaryl, wherein the -C(0)(C3-Cio cycloalkyl), Ci-Ct. alkyl, Cz-Ct. alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more Ra2, each R82independently is oxo, halo, cyano, -OH, -NH2, -NH(CI-C6 alkyl), -N(Ci-Ce alkyl)2, Ci-Ce alkyl optionally substituted with Ci-Cs alkoxy or -OH, C3-C10 cycloalkyl, Ci-Cs haloalkoxy, Ci-Ce haloalkyl, Ci-Cs alkoxy, 3- to 1 O-membered heterocycloalkyl optionally substituted with oxo, or 5- to 10-membered heteroaryl;R3ais halo, cyano, -OH, -NHz, Ci-Ce alkyl, Cz-Ce alkenyl, Cz-Cs alkynyl, Ci-Cs haloalkyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10- membered heteroaryl, wherein the Ci-Ce alkyl, Cz-Ce alkenyl, Cz-Cs alkynyl, Ci-Cs haloalkyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R3al; and7] 7Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO) each R3alindependently is oxo, halo, cyano, -OH, -C(O)(Ci-C6 alkyl), -C(O)(O-(Ci-Cs alkyl)), Ct-Cs alkyl optionally substituted with C3-C10 cycloalkyl, C2-C6 alkenyl, Cb-Cs alkynyl, Ci-Ce haloalkyl, Ci-Co haloalkoxy, Ci-Ce alkoxy, -O(Ci-Ce haloalky I), C3-C10 cycloalkyl, Cs-Cto aryl, or 5- to 10-membered heteroaryl.

[0851] Exemplary Embodiment No. 9. The combination, use, method, pharmaceutical package, or kit of Exemplary Embodiment 8, wherein the compound is of Formula (I -a) or Formula (I-b):or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof.

[0852] Exemplary' Embodiment No. 10. The combination, use, method, pharmaceutical package, or kit of Exemplary Embodiment 8 or 9, wherein the compound is of Formula (I -a’) or Formula(I-lf):or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof.

[0853] Exemplary' Embodiment No. 11. The combination, use, method, pharmaceutical package, or kit of Exemplary Embodiment 8 or 9, wherein the compound is of Formula (I-c) :or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof.

[0854] Exemplary Embodiment No. 12. The combination, use, method, pharmaceutical package, or kit of any one of Exemplary Embodiments 9-11, wherein the compound is of Formula (I-c’):316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof.

[0855] Exemplary Embodiment No. 13. The combination, use, method, pharmaceutical package, or kit of any one of Exemplary Embodiments 8-10, wherein:Rslis a 5- to 10-membered heteroaryl optionally substituted with one or more Ra2; each Ra2independently is Ci-Cs alkyl, Ci-Ce haloalky 1, or Ci-Ce alkoxy;R3ais 5- to 10-membered heteroaryl optionally substituted with one or more Rjal, and each Rjalindependently is halo, Ci-Cs alkyl, Cb-Cs alkenyl, C2-C6 alkynyl, Ci-Cs haloalkyl, C1-C0 haloalkoxy, or Ci-Cs alkoxy.

[0856] Exemplary Embodiment No. 14. The combination, use, method, pharmaceutical package, or kit of any one of Exemplary Embodiments 8-10 or 13, wherein Ralis a 5- to 10-membered heteroaryl substituted with one or more Ra2.

[0857] Exemplary Embodiment No. 15. The combination, use, method, pharmaceutical package, or kit of any one of Exemplary Embodiments 8-10 or 13-14, wherein Ralis pyridinyl substituted with one or more Ra2.

[0858] Exemplary Embodiment No. 16. The combination, use, method, pharmaceutical package, or kit of any one of Exemplary Embodiments 8-15, wherein each Ra2independently is C-i-Q haloalkyl or Ci-Ce alkoxy.

[0859] Exemplary Embodiment No. 17. The combination, use, method, pharmaceutical package, or kit of any one of Exemplary Embodiments 8-16, wherein each Ra2independently is -CF3 or - OCH3.

[0860] Exemplary Embodiment No. 18. The combination, use, method, pharmaceutical package, or kit of any one of Exemplary Embodiments 8-15, wherein219316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0861] Exemplary Embodiment No. 19. The combination, use, method, pharmaceutical package, or kit of any one of Exemplary Embodiments 8-10 or 13, wherein R3ais 5- to 10-membered heteroaryl substituted with one or more R3al.

[0862] Exemplary Embodiment No. 20. The combination, use, method, pharmaceutical package, or kit of any one of Exemplary Embodiments 8-10, 13, or 19, wherein R3ais pyridinyl substituted with one or more R3a!.

[0863] Exemplary Embodiment No. 21. The combination, use, method, pharmaceutical package, or kit of any one of Exemplary Embodiments 8-13 or 19-20, wherein each R 'aiindependently is halo or Ci-Ce alkoxy.

[0864] Exemplary Embodiment No. 22. The combination, use, method, pharmaceutical package, or kit of any one of Exemplary Embodiments 8-13 or 19-21, wherein each R3a{independently is chloro or -OCEE.

[0865] Exemplary Embodiment No. 23. The combination, use, method, pharmaceutical package, or kit of any one of Exemplary Embodiments 8-13 or 19-20, wherein R3ais

[0866] Exemplary Embodiment No. 24. The combination, use, method, pharmaceutical package, or kit of Exemplary Embodiment 8, wherein the compound of Formula I is selected from Table I .

[0867] Exemplary Embodiment No. 25. The combination, use, method, pharmaceutical package, or kit of any one of Exemplary Embodiments 8-24, wherein the compound is:or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof.

[0868] Exemplary Embodiment No. 26. The combination, use, method, pharmaceutical package, or kit of any one of the preceding Exemplary Embodiments, wherein the PARI5inhibitor is olaparib, talazoparib, rucaparib, veliparib, mraparib, saruparib, fuzuloparib, panliparib, AMXI-316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)5001, Basroparib, CK-102, CVL218, HTMC0435, HWH340, nesuparib, RP12146, SC ! 0914, senaparib, simmiparib, stenoparib, TQB3823, TSL1502, venadaparib, AZD9574, NMS-293, HS- 10502, EIK1003, EIK1004, GS-0201, DSB2455, SNV-001, XIN6301, XIN5104, XIN5789, Ol’AL-OOOl, or ACE-86225106.

[0869] Exemplary Embodiment No. 27. The combination, use, method, pharmaceutical package, or kit of any one of the preceding Exemplary Embodiments, wherein the PARI’ inhibitor is olaparib.

[0870] Exemplary Embodiment No. 28. The combination, use, method, pharmaceutical package, or kit of any one of the preceding Exemplar}' Embodiments, wherein the PARP inhibitor is Compound 1064.

[0871] Exemplary Embodiment No. 29. The combination, use, method, pharmaceutical package, or kit of any one of the preceding Exemplary Embodiments, wherein the PARI’ inhibitor is Compound 1056.

[0872] Exemplary Embodiment No. 30. The combination, use, method, pharmaceutical package, or kit of any one of the preceding Exemplary Embodiments, wherein the PARP inhibitor is Compound 1056a.

[0873] Exemplary Embodiment No. 31. The combination, use, method, pharmaceutical package, or kit of any one of the preceding Exemplars' Embodiments, wherein the PARP inhibitor is Compound 1056b.

[0874] Exemplary Embodiment No. 32, The combination, use, method, pharmaceutical package, or kit of Exemplar}'’ Embodiment 24, wherein the compound is:or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof.

[0875] Exemplary Embodiment No. 33. The combination, use, method, pharmaceutical package, or kit of Exemplary Embodiment 32, wherein the PARP inhibitor is olaparib, talazoparib, rucaparib, veliparib, niraparib, saruparib, fuzulopanb, pamiparib, AMXI-500I, Basroparib, CK- 102, CVL218, HTMC0435, HWH340, nesuparib, RP12146, SCT0914, senaparib, simmiparib, stenoparib, TQB3823, TSL1502, venadaparib, AZD9574, NMS-293, HS- 10502, EIK1003,99]318259783Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)EIK1004, GS-0201 , DSB2455, SNV-001, XIN6301, XIN5104, XIN5789, OPAL-OOOl, or ACE- 86225106.

[0876] Exemplary Embodiment No. 34. The combination, use, method, pharmaceutical package, or kit of Exemplary Embodiment 32, wherein the PARI’ inhibitor is olaparib.

[0877] Exemplary Embodiment No. 35. The kit or pharmaceutical package of any one of Exemplary Embodiments 6-34 further comprising instructions for use.

[0878] Exemplary Embodiment No. 36. The combination, use, method, pharmaceutical package, or kit of any one of the preceding Exemplary Embodiments, wherein the Pol0 helicase inhibitor is administered once daily.

[0879] Exemplary Embodiment No. 37. The combination, use, method, pharmaceutical package, or kit of any one of the preceding Exemplary Embodiments, wherein the Pol0 helicase inhibitor is administered twice daily.

[0880] Exemplary Embodiment No. 38. The combination, use, method, pharmaceutical package, or kit of any one of the preceding Exemplary' Embodiments, wherein the PARP inhibitor is administered once daily.

[0881] Exemplary Embodiment No. 39. The combination, use, method, pharmaceutical package, or kit of any one of the preceding Exemplary Embodiments, wherein the PARP inhibitor is administered twice daily.

[0882] Exemplary' Embodiment No. 40. The combination, use, method, pharmaceutical package, or kit of any one of the preceding Exemplary Embodiments, wherein each of the PolO helicase inhibitor and PARP inhibitor is administered once or twice daily for at least 28 days.

[0883] Exemplary Embodiment No. 41. The combination, use, method, pharmaceutical package, or kit of any one of the preceding Exemplary' Embodiments, wherein the PolO helicase inhibitor is administered orally.

[0884] Exemplary Embodiment No. 42. The combination, use, method, pharmaceutical package, or kit of any one of the preceding Exemplar}' Embodiments, wherein the PARP inhibitor is administered orally.

[0885] Exemplary Embodiment No. 43. The combination, use, method, pharmaceutical package, or kit of any one of the preceding Exemplary Embodiments, wherein the Pol0 helicase inhibitor and PARP inhibitor are administered on the same day. ooo318259783Attorney Docket No.: 43705-02087, AVO (MOMA-010 / 001 WO)

[0886] Exemplary Embodiment No. 44. The combination, use, method, pharmaceutical package, or kit of any one of the preceding Exemplary Embodiments, wherein the cancer is a solid tumor.

[0887] Exemplary Embodiment No. 45. The combination, use, method, pharmaceutical package, or kit of any one of the preceding Exemplary Embodiments, wherein the cancer is an advanced solid tumor.

[0888] Exemplary Embodiment No. 46. The combination, use, method, pharmaceutical package, or kit of any one of the preceding Exemplary Embodiments, wherein the cancer is metastatic.

[0889] Exemplary Embodiment No. 47. The combination, use, method, pharmaceutical package, or kit of any one of the preceding Exemplary Embodiments, wherein the cancer is selected from prostate cancer, pancreatic cancer, breast cancer, lung cancer, and ovarian cancer.

[0890] Exemplary Embodiment No. 48. The combination, use, method, pharmaceutical package, or kit of any one of the preceding Exemplary Embodiments, wherein the cancer is a castrateresistant prostate cancer or pancreatic adenocarcinoma.

[0891] Exemplary Embodiment No. 49. The combination, use, method, pharmaceutical package, or kit of any one of the preceding Exemplary Embodiments, wherein the cancer is a non-small cell lung cancer.

[0892] Exemplary Embodiment No. 50. The combination, use, method, pharmaceutical package, or kit of any one of the preceding Exemplary Embodiments, wherein the cancer comprises a BRCA1 mutation, a BRCA2 mutation, a PALB2 gene mutation, a CDK12 gene mutation, a RAD51B gene mutation, a RAD51C gene mutation, or a RAD51D gene mutation.

[0893] Exemplary' Embodiment No. 51. The combination, use, method, pharmaceutical package, or kit of any one of the preceding Exemplary Embodiments, wherein the cancer comprises a homologous recombination deficiency.

[0894] Exemplary Embodiment No. 52. The combination, use, method, pharmaceutical package, or kit of any one of the preceding Exemplary Embodiments, wherein the Pol0 helicase inhibitor and PARP inhibitor are administered in temporal proximity, sequentially, or in alternation.

[0895] Exemplary Embodiment No. 53. The combination, use, method, pharmaceutical package, or kit of any one of the preceding Exemplary Embodiments, wherein the Pol0 helicase inhibitor and PARP inhibitor are administered as separate formulations.

[0896] Exemplary Embodiment No. 54. The combination, use, or method of any one of the preceding Exemplary Embodiments, wherein the subject is a human.223316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0897] Exemplary Embodiment No. 55. A combination therapy comprising:(a) Compound 15, and(b) olaparib.

[0898] Exemplary Embodiment No. 56. A combination therapy comprising:(a) Compound 15, and(b) Compound 1064.

[0899] Exemplary Embodiment No. 57. A combination therapy comprising:(a) Compound 15, and(b) Compound 1056.

[0900] Exemplary Embodiment No. 58. A combination therapy comprising:(a) Compound 15, and(b) Compound 1056a.

[0901] Exemplary Embodiment No. 59. A combination therapy comprising:(a) Compound 15, and(b) Compound 1056b.

[0902] Exemplary Embodiment No. 60. A combination therapy comprising:(a) Compound 18, and(b) olaparib.EXAMPLES

[0903] The combination treatment provided herein can be tested by administering the combination of the agents to a well-known mouse model and evaluating the results. Methods of such testing can be adapted from those known.Example 1: Cellular efficacy of Compound 15 in combination with a panel of PARP inhibitors against DoTc24510 cells

[0904] The in vitro cellular efficacy of Compound 15 in combination with a panel of PARP inhibitors (olaparib, rucaparib, niraparib, vehparib, talazoparib, and saruparib) was assessed in the BRCA2-mutant cervical cancer cell line, DoTc24510. For each PARP inhibitor, DoTc24510 cells were seeded in 384- well culture plates and treated with a 9 x 7 drug matrix using a nine-point, three-fold dilution of Compound 15 ranging from 0.38 nMto 2,500 nM, and a seven-point dilutionAttorney Docket No.: 43705-02087, AVO (MOMA-010 / 001 WO) of the PARP inhibitor. Concentration ranges for the PARP inhibitors are shown in Table A. After seven days of treatment with the compound matrix, ceil viability in each well was measured using the CellTiter-Glo assay. Compound synergy was calculated using the Loewe Additivity reference synergy niodei. The dose-response curves and the corresponding Loewe excess volume matrix for Compound 15 in combination with olaparib are shown in FIG. 1 A and FIG. IB, respectively. The Loewe synergy score for Compound 15 in combination with each PARI’ inhibitor is reported in Table A, with scores for the PARP inhibitor combinations ranging from 9.1 to 14.2. These data demonstrate that Compound 15 synergizes with each PARI’ inhibitor tested in in vitro cellular efficacy assays against BRCA2-mutant DoTc24510 cells.Table AExample 2: Cellular efficacy of Compound 15 in combination with olaparib against DLD1- BRCA2-KO and Capan-1 cells

[0905] The in vitro cellular efficacy of Compound 15 was assessed in combination with the representative PARI’ inhibitor olaparib against two additional BRCA2-deficient cancer cell lines. The colorectal cancer cell line DLD1 with the BRCA2 gene deleted (DLD1-BRCA2-KO cells) was seeded in 384- well culture plates and treated with a 10 x 7 drug matrix. Compound 15 was dosed as a ten-point, three-fold dilution series ranging from 0.005 nM to 100 nM, while olaparib was dosed as a seven-point, three-fold dilution series ranging from 0.41 nMto 300 nM. After seven days of treatment with the compound matrix, cell viability in each well was measured using the CellTiter-Glo assay. The BRCA2-mutant pancreatic cancer cell line, Capan-1, was seeded in 96- well culture plates and treated with a 9 x 5 drug matrix. For Capan-1 cells, Compound 15 was dosed as a nine-point, four-fold dilution series ranging from 0.006 nM to 400 nM, while olaparib was dosed as a five-point, four-fold dilution series ranging from 0.78 nM to 200 nM. The compound matrix was refreshed after seven days, and cell viability in each well was measured using the CellTiter-Glo assay after a total of 14 days of treatment with the compound matrix.316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)Compound synergy was calculated using the Loewe Additivity reference synergy model. Doseresponse curves for the DLD1-BRCA2-K0 and Capan-1 cell lines treated with Compound 15 in combination with olaparib are shown in FIG. 2A and FIG. 2B, respectively. The Loewe synergy score for Compound 15 in combination with olaparib is reported in Table B. The data demonstrate that Compound 15 synergizes with olaparib in in vitro cellular efficacy assays against two additional BRCA2-deficient cell lines, DLD1-BRCA2-K0 and Capan-1.Table BExample 3: Induction of DNA damage and apoptosis by Compound 15 in combination with olaparib and saruparib

[0906] The ability of Compound 15 in combination with the PARI’ inhibitors olaparib and saruparib to induce DNA damage and apoptosis was assessed in BRCA2-mutant DoTc24510 cells. DoTc25410 cells were seeded in six-well plates and treated with Compound 15 (30 nM), olaparib (300 nM), saruparib (5 nM), or a combination of Compound 15 (30 nM) and either olaparib (300 nM) or saruparib (5 nM). Single-cell suspensions were harvested from each treatment condition after 48, 72, 96 and 120 hours of treatment. The cell suspensions were stained with antibodies against yH2AX (a marker of DNA double-strand breaks) and cleaved caspase-3 (a marker of cellular apoptosis), and the induction of DNA damage and apoptosis was quantified using flow cytometry. At each time point, the combination of Compound 15 with either olaparib or saruparib increased the strength of ?H2AX and cleaved caspase-3 induction relative to each single-agent treatment, as shown in FIG. 3A and FIG. 3B, respectively. Thus, these data indicate that Compound 15 in combination with olaparib or saruparib accentuates the induction of DN A damage and apoptosis in BRCA2-mutant DoTc24510 cells.Example 4; In vivo efficacy of Compound 15 in combination with olaparib against DLD1- BRCA2-KO tumor xenografts

[0907] The anti-tumor efficacy of Compound 15 in combination with olaparib was assessed in vivo against tumor xenografts derived from DLD1-BRCA2-KO cells. DLD1-BRCA2-KO cells were inoculated in the flank of female Balb / c nude mice. Tumor-bearing mice were randomizedAttorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO) into efficacy groups of eight to ten mice per group when tumors reached an average volume of over 100 mm5. Tumor bearing mice were dosed orally twice daily (BID) for 25 days with Compound 15 or vehicle and once daily (QD) with olaparib or vehicle at the doses indicated in Table C. Neither olaparib (100 mg / kg QD) nor Compound 15 (10 mg / kg BID) produced strong antitumor efficacy as single-agents, generating modest and nonsignificant tumor growth inhibition (TGI) of 25% and 41%, respectively (Table C). In contrast to the single-agent arms, the combination of Compound 15 (0.3, 1 , 3, or 10 mg / kg BID) with olaparib (100 mg / kg QD) produced substantial dose-dependent antitumor activity. In the combination regimen, treatment with Compound 15 dosed at 0.3 and 1 mg / kg BID produced a TGI of 82% and 96%, respectively, while Compound 15 dosed at 3 and 10 mg / kg BID induced regressions from the initial tumor volume (TGI > 100%). All four dose levels of Compound 15 m combination with olaparib demonstrated antitumor responses that were statistically distinct from vehicle treatment and from both singleagent groups, as demonstrated in FIG. 4A. Ail doses of Compound 15 and olaparib were well- tolerated, having no impact on body weight relative to vehicle- treated mice throughout the course of the study, as demonstrated in FIG. 4B. Compound 15 concetration over time is shown in FIG. 4C.

[0908] To assess the impact of dosing schedule on the antitumor activity of Compound 15 in combination with olaparib, mice bearing DLD1-BRCA2- / - tumor xenografts were treated with Compound 15 (10 mg / kg BID) in combination with olaparib (100 mg / kg QD). Single agent treatment with each agent was performed to control for single-agent anti- tumor activity.

[0909] To determine the impact of reducing to once daily dosing of Compound 15 on anti-tumor efficacy, study groups were treated with Compound 15 administered at either 10 mg / kg QD or 30 mg / kg QD in combination with olaparib (100 mg / kg QD).

[0910] To assess continuous daily dosing to achieve anti-tumor efficacy, additional combination treatment study groups were included for administration of Compound 15 at 10 mg / kg BID in combination with olaparib at 100 mg / kg QD, wherein one or both treatments v / ere interrupted. The dosing schedule for the interrupted agent(s) was as follows: (1) one cycle of 5 days on / 2 days off followed by (2) 3 cycles of 5 days on / 4 days off and (3) a final cycle of 3 days on.

[0911] The anti-tumor efficacy of all schedule modifications was compared to the efficacy of the reference group: continuous dosing of Compound 15 (10 mg / kg BID) in combination with olaparib (100 mg / kg QD). Plasma sampling for pharmacokinetic analysis was conducted for all efficacy318259783Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO) groups on the first day of dosing, and from all continuous treatment groups on the final day of dosing.

[0912] The combination of Compound 15 and olaparib was seen to be efficacious at a reduced olaparib dose or with treatment interruptions (FIG. 5A and FIG. 5B). Statistically significant tumor growth inhibition with combination treatment relative to single-agent olaparib treatment is indicated as follows: **P<0.01; ****P<0.0001. All combination groups also displayed statistically significant tumor growth inhibition relative to vehicle treatment.

[0913] Thus, the combination of Compound 15 with olaparib was well tolerated and produced strong antitumor responses in a BRCA2-deficient xenograft model that showed limited responses to either Compound 15 or olaparib as single-agents.Table CExample 5; Efficacy of Compound 15 in combination with oUparib against tumor models

[0914] The anti-tumor efficacy of Compound 15 in combination with olaparib was assessed against tumor PDX models with mutations in either BRCA1 or BRCA2. The combination of Compound 15 with olaparib was well tolerated and produced strong antitumor responses against BRCAl-mutant and BRCA2-mutant tumor models of pancreatic cancer (FIGs. 6A, 61), and 6E), ovarian cancer (FIG. 6B), and breast cancer (FIG. 6C).316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)

[0915] The anti-tumor efficacy of Compound 15 in combination with olaparib was also assessed against the BRCA2-mutant pancreatic CDX model Capan-1. The combination of Compound 15 with olaparib was well tolerated and produced strong antitumor responses (FIG. 7).

[0916] Statistically significant tumor growth inhibition of combination treatment relative to single-agent olaparib treatment is indicated as follows: *P<0.05; **P<0.01 ; ***P<0.001. All combination groups also displayed statistically significant tumor growth inhibition relative to vehicle treatment.Example 6: Cellular efficacy of Compound 15 in combination with Compound 1064 against DoTc24510 ceils

[0917] The in vitro cellular efficacy of Compound 15 in combination with Compound 1064 is assessed in the BRCA2-mutant cervical cancer cell line, DoTc24510. DoTc24510 cells are seeded in 384- well culture plates and treated with a 9 x 7 drug matrix using a nine-point, three-fold dilution of Compound 15 ranging from 0.38 nM to 2,500 nM, and a seven-point dilution of Compound 1064. After seven days of treatment with the compound matrix, cell viability in each well is measured using the CellTiter-Glo assay. Compound synergy is calculated using the Loewe Additivity reference synergy model. The dose-response curves and the corresponding Loewe excess volume matrix for Compound 15 in combination with Compound 1064 are shown in FIG. 8A and FIG. 8B, respectively.Example 7; In vivo efficacy of Compound 18 in combination with olaparib against DLD1- BRCA2-KO tumor xenografts

[0918] The anti-tumor efficacy of Compound 18 in combination with olaparib was assessed in vivo against tumor xenografts derived from DLD1-BRCA2-KO cells. DLD1-BRCA2-KO cells were inoculated in the flank of female Balb / c nude mice. Tumor-bearing mice were randomized into efficacy groups of eight to ten mice per group when tumors reached an average volume of over 100 mm5. Tumor bearing mice were dosed orally twice daily (BID) for 25 days with Compound 18 (10, 30, or 100 mg / kg BID) or vehicle and once daily (QD) with olaparib (100 mg / kg QD) or vehicle. Neither olaparib (100 mg / kg QD) nor Compound 18 (100 mg / kg BID) produced strong antitumor efficacy as single-agents. In contrast to the single-agent arms, the229316259781Attorney Docket No.: 43705-02087, AVO (MOMA-010 / 001 WO) combination of Compound 18 (10, 30, or 100 mg / kg BID) with olaparib (100 mg / kg QD) produced substantial dose-dependent antitumor activity.

[0919] All three dose levels of Compound 18 in combination with olaparib demonstrated antitumor responses that were distinct from vehicle treatment and from both single-agent groups, as demonstrated in FIG. 9A. Statistically significant tumor growth inhibition with combination treatment relative to single-agent olaparib treatment is indicated as follows: ***P<0.001; **** / ?<0.0001. All combination groups also displayed statistically significant tumor growth inhibition relative to vehicle treatment. All doses of Compound 18 and olaparib were w-ell- tolerated, having no impact on body weight relative to vehicle-treated mice throughout the course of the study, as demonstrated in FIG. 9B. Compound 18 concetration over time is shown in FIG. 9C.Example 8.° In vivo efficacy of Compound 15 in combination with Compound 1064 against DIJ)1-BRCA2-KO tumor xenografts

[0920] The anti -tumor efficacy of Compound 15 in combination with Compound 1064 was assessed in vivo against tumor xenografts derived from DLD1-BRCA2-KO cells. DLD1-BRCA2- KO cells were inoculated in the flank of female Balb / c nude mice. Tumor-bearing mice were randomized into efficacy groups of eight mice per group when tumors reached an average volume of over 100-150 mnr. Tumor bearing mice were dosed orally twice daily (BID) for 25 days with Compound 15 or vehicle and once daily (QD) with Compound 1064 or vehicle at the doses indicated in Table D. The two doses of Compound 15 (0.3 mg / kg and 10 mg / kg BID) showed antitumor efficacy, achieving tumor growth inhibition (TGI) rates of 41% and 42%, respectively. Compound 1064 single agent demonstrated dose-dependent antitumor activity, with TGI rates of 56% at I mg / kg QD and tumor regressions (TGI >100%) at 10 mg / kg QD. Compound 15 (0.3 and 10 mg / kg BID) with Compound 1064 (1 mg / kg QD) showed a synergistic combination benefit resulting in substantial tumor regressions, achieving TGI rates exceeding 100% for all the groups as demonstrated in FIG. 10A.

[0921] The combination groups were statistically significant over vehicle and Compound 1064 monotherapy. Compound 15 and Compound 1064 were well -tolerated as single agents and in combination at all dose levels, having no impact on body weight relative to vehicle-treated mice throughout the course of the study as shown in FIG. 10B.Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)Table DExample 9. Ira vivo efficacy of Compound 15 in combination with Compound 1064 against Capan-1 BRCA2m!rttumor xenografts

[0922] The anti -tumor efficacy of Compound 15 in combination with Compound 1064 was assessed in vivo against tumor xenografts derived from Capan-1 cells. Capan-1 cells were inoculated in the flank of female Balb / c nude mice. Tumor-bearing mice were randomized into efficacy groups of ten mice per group when tumors reached an average volume of over 100-150 num. Tumor bearing mice were dosed orally twice daily (BID) for 33 days with Compound 15 or vehicle and once daily (QD) with Compound 1064 or vehicle at the doses indicated in Table E. Compound 15 dosed at 30mg / kg BID did not show' anti-tumor efficacy with tumor growth inhibition (TGI) rates of 31%. Compound 1064 demonstrated dose-dependent antitumor activity (0.3 and 10 mg / kg QD) with TGI rates of 36% and 87% respectively. Combination of Compound 15 dosed at 30 mg / kg BID with Compound 1064 (0.3 and 10 mg / kg QD) resulted in strong combination efficacy with TGI of 68% and tumor regressions with TGI>100%, respectively, as shown in FIG, 11 A.

[0923] Combination effect of Compound 15 with both the dose levels of Compound 1064 was statistically significant from vehicle and Compound 1064 alone at corresponding doses. Compound 15 and Compound 1064 were well-tolerated as single agents and in combination at ad the dose levels, having no impact on body weight relative to vehicle-treated mice throughout the course of the study as shown in FIG. 11B.31316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)Table EEQUIVALENTS

[0924] All publications, including patents, patent applications, and scientific articles, mentioned in this specification are herein incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, including patent, patent application, or scientific article, were specifically and individually indicated to be incorporated by reference.

[0925] .Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is apparent to those skilled in the art that certain minor changes and modifications will be practiced in light of the above teaching. Therefore, the description and examples should not be construed as limiting the scope of the invention.316259781

Claims

1. Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)CLAIMS1. A combination therapy comprising:(a) a polymerase theta (PolO) helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a polyf adenosme diphosphate [ADP] -ribose) polymerase (PARI’) inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

2. A polymerase theta (PolO) helicase inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a PARI’ inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, for use in combination for treating or preventing cancer in a subject.

3. A method of treating or preventing cancer, comprising administering to a subject:(a) a polymerase theta helicase (PolO) inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

4. A polymerase theta helicase (PolO) inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of cancer in a subject.

5. Use of a polymerase theta helicase (PolO) inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hy drate, or prodrug thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of cancer in a subject.

6. A kit comprising:(a) a polymerase theta helicase (PolO) inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; andAttorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)(b) a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

7. A pharmaceutical package comprising:(a) a polymerase theta helicase (PolO) inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a PARI’ inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

8. The combination, use, method, pharmaceutical package, or kit of any one of the preceding claims, wherein the Pol0 helicase inhibitor is a compound of Formula I:or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein:RS1is H, oxo, halo, cyano, -OH, -NH2, -NH(Ci-Cs alkyl), ~N(Ci-Ce alkyl)2, -C(0)(Ci-C6 alkyl), -C(0)(C3-Cio cycloalkyl), Ci-Cs alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci- C,6 alkoxy, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10- membered heteroaryl, wherein the -C(0)(C3-Cio cycloalkyl), Ci-Q alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, Cs-Cio aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R82; each Ra2independently is oxo, halo, cyano, -OH, -M l . -NH / Ci-Ce alkyl), -N(CI-C6 alkyl)2, alkyl optionally substituted with Ci-Ce alkoxy or -OH, C3-C10 cycloalkyl, C1-C0 haloalkoxy, Ci-Cs haloalkyl, Ci-Ce alkoxy, 3- to 10-membered heterocycloalkyl optionally substituted with oxo, or 5- to 10-membered heteroaryl;R3ais halo, cyano, -OH, -NI-I2, Ci-Cs alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C-6-Cio aryl, or 5- to 10- membered heteroaryl, wherein the Ci-Co alkyl, C2-C0 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, Cs-Cto aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R3al; and316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO) each R3alindependently is oxo, halo, cyano, -OH, -C(O)(Ci-C6 alkyl), -C(O)(O-(Ci-Cs alkyl)), Ct-Cs alkyl optionally substituted with C3-C10 cycloalkyl, C2-C6 alkenyl, Cb-Cs alkynyl, Ci-Ce haloalkyl, Ci-Cs haloalkoxy, Ci-Ce alkoxy, -O(Ci-Ce haloalky I), C3-C10 cycloalkyl, Cs-Cto aryl, or 5- to 10-membered heteroaryl.

9. The combination, use, method, pharmaceutical package, or kit of claim 8, wherein the compound is of Formula (I-a) or Formula (I-b):or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof.

10. The combination, use, method, pharmaceutical package, or kit of claim 8 or 9, wherein the compound is of Formula (I-a’) or Formula (I-b’):or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof.1 1. The combination, use, method, pharmaceutical package, or kit of claim 8 or 9, wherein the compound is of Formula (I-c):or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof.Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)12. The combination, use, method, pharmaceutical package, or kit of any one of claims 9-11 , wherein the compound is of Formula ( I -c ’ ):or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof.

13. The combination, use, method, pharmaceutical package, or kit of any one of claims 8-10, wherein :Ralis a 5- to 10-membered heteroaryl optionally substituted with one or more Ra2; each Ra2independently is Ci-Cs alkyl, Ci-Co haloalkyl, or Ci-Ce alkoxy;R3ais 5- to 10-membered heteroary! optionally substituted with one or more R3al; and each R3aiindependently is halo, Ci-Ce alkyl, C2-C0 alkenyl, C2-C6 alkynyl, Ci-Cs haloalkyl, Ci-Cs haloalkoxy, or Ci-Ce alkoxy.

14. The combination, use, method, pharmaceutical package, or kit of any one of claims 8-10 or 13, wherein Ralis a 5- to 10-membered heteroaryl substituted with one or more Ra2.

15. The combination, use, method, pharmaceutical package, or kit of any one of claims 8-10 or 13-14, wherein Raiis pyridinyl substituted with one or more Ra2.

16. The combination, use, method, pharmaceutical package, or kit of any one of claims 8-15, wherein each Ra2independently is Ci-Ce haloalkyl or Ci-Ce alkoxy.

17. The combination, use, method, pharmaceutical package, or kit of any one of claims 8-16, wherein each Ra2independently is -CFs or -OCHs.316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)18. The combination, use, method, pharmaceutical package, or kit of any one of claims 8-15, wherein19. The combination, use, method, pharmaceutical package, or kit of any one of claims 8-10 or 13, wherein R3ais 5- to 10-membered heteroaryl substituted with one or more R3al.

20. The combination, use, method, pharmaceutical package, or kit of any one of claims 8-10,13, or 19, wherein Rjais pyridinyl substituted with one or more R3al.

21. The combination, use, method, pharmaceutical package, or kit of any one of claims 8-13 or 19-20, wherein each Rjaiindependently is halo or Ci-Cs alkoxy.

22. The combination, use, method, pharmaceutical package, or kit of any one of claims 8-13 or 19-21, wherein each R‘,alindependently is chloro or -OCH3.

23. The combination, use, method, pharmaceutical package, or kit of any one of claims 8-13 or 19-20, wherein R3ais24. The combination, use, method, pharmaceutical package, or kit of claim 8, wherein the compound of Formula I is selected from Table 1.

25. The combination, use, method, pharmaceutical package, or kit of any one of claims 8-24, wherein the compound is:316259781Attorney Docket No.: 43705-02087, AVO (MOMA-010 / 001 WO)or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof.

26. The combination, use, method, pharmaceutical package, or kit of any one of the preceding claims, wherein the PARP inhibitor is olaparib, talazoparib, rucaparib, veliparib, niraparib, saruparib, fuzuloparib, pamiparib, AMXI-500I, Basroparib, CK-102, CVL218, HTMC0435, HWH340, nesuparib, RP12146, SC10914, senaparib, simmiparib, stenoparib, TQB3823, TSL1502, venadaparib, AZD9574, NMS-293, HS-10502, EIK1003, EIK1004, GS- 0201, DSB2455, SNV-001, XIN6301, XIN5104, XIN5789, OPAL-0001, or ACE-86225106.

27. The combination, use, method, pharmaceutical package, or kit of any one of the preceding claims, wherein the PARP inhibitor is olaparib.

28. The combination, use, method, pharmaceutical package, or kit of any one of the preceding claims, wherein the PARI5inhibitor is Compound 1064.

29. The combination, use, method, pharmaceutical package, or kit of any one of the preceding claims, wherein the PARP inhibitor is Compound 1056.

30. The combination, use, method, pharmaceutical package, or kit of any one of the preceding claims, wherein the PARP inhibitor is Compound 1056a.

31. The combination, use, method, pharmaceutical package, or kit of any one of the preceding claims, wherein the PARP inhibitor is Compound 1056b.

32. The combination, use, method, pharmaceutical package, or kit of claim 24, wherein the compound is:238316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof.

33. The combination, use, method, pharmaceutical package, or kit of claim 32, wherein the PARP inhibitor is olaparib, talazoparib, rucaparib, veliparib, niraparib, saruparib, fuzuloparib, parnipanb, AMXI-500I, Basroparib, CK-102, CVL218, HTMC0435, HWH340, nesuparib, RP12146, SCI 0914, senaparib, simmiparib, stenoparib, TQB3823, TSL1502, venadaparib, AZD9574, NMS-293, HS-10502, EIK1003, EIK1004, GS-0201, DSB2455, SNV-001 , XIN6301 , XIN5104, XIN5789, OPAL-0001, or ACE-86225106.

34. The combination, use, method, pharmaceutical package, or kit of claim 32, wherein the PARP inhibitor is olaparib.

35. The kit or pharmaceutical package of any one of claims 6-34 further comprising instructions for use.

36. The combination, use, method, pharmaceutical package, or kit of any one of the preceding claims, wherein the PolO helicase inhibitor is administered once daily.

37. The combination, use, method, pharmaceutical package, or kit of any one of the preceding claims, wherein the Pol0 helicase inhibitor is administered twice daily.

38. The combination, use, method, pharmaceutical package, or kit of any one of the preceding claims, wherein the PARP inhibitor is administered once daily.

39. The combination, use, method, pharmaceutical package, or kit of any one of the preceding claims, wherein the PARP inhibitor is administered twice daily.316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)40. The combination, use, method, pharmaceutical package, or kit of any one of the preceding claims, wherein each of the Pol0 helicase inhibitor and PARP inhibitor is administered once or twice daily for at least 28 days.

41. The combination, use, method, pharmaceutical package, or kit of any one of the preceding claims, wherein the Pol0 helicase inhibitor is administered orally.

42. The combination, use, method, pharmaceutical package, or kit of any one of the preceding claims, wherein the PARP inhibitor is administered orally.

43. The combination, use, method, pharmaceutical package, or kit of any one of the preceding claims, wherein the Pol0 helicase inhibitor and PARP inhibitor are administered on the same day.

44. The combination, use, method, pharmaceutical package, or kit of any one of the preceding claims, wherein the cancer is a solid tumor.

45. The combination, use, method, pharmaceutical package, or kit of any one of the preceding claims, wherein the cancer is an advanced solid tumor.

46. The combination, use, method, pharmaceutical package, or kit of any one of the preceding claims, wherein the cancer is metastatic.

47. The combination, use, method, pharmaceutical package, or kit of any one of the preceding claims, wherein the cancer is selected from prostate cancer, pancreatic cancer, breast cancer, lung cancer, and ovarian cancer.

48. The combination, use, method, pharmaceutical package, or kit of any one of the preceding claims, wherein the cancer is a castrate-resistant prostate cancer or pancreatic adenocarcinoma.240316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)49. The combination, use, method, pharmaceutical package, or kit of any one of the preceding claims, wherein the cancer is a non-small cell lung cancer.

50. The combination, use, method, pharmaceutical package, or kit of any one of the preceding claims, wherein the cancer comprises a BRCA1 mutation, a BRCA2 mutation, a PALB2 gene mutation, a CDKI 2 gene mutation, a RAD51 B gene mutation, a RAD51C gene mutation, or a RAD51D gene mutation.

51. The combination, use, method, pharmaceutical package, or kit of any one of the preceding claims, wherein the cancer comprises a homologous recombination deficiency.

52. The combination, use, method, pharmaceutical package, or kit of any one of the preceding claims, wherein the Poi0 helicase inhibitor and PARP inhibitor are administered in temporal proximity, sequentially, or in alternation.

53. The combination, use, method, pharmaceutical package, or kit of any one of the preceding claims, wherein the Pol0 helicase inhibitor and PAiRP inhibitor are administered as separate formulations.

54. The combination, use, or method of any one of the preceding claims, wherein the subject is a human.

55. A combination therapy comprising:(a) Compound 15, and(b) olapanb.

56. A combination therapy comprising:(a) Compound 15, and(b) Compound 1064.

57. A combination therapy comprising:241316259781Attorney Docket No.: 43705-02087AVO (MOMA-010 / 001 WO)(a) Compound 15, and(b) Compound 1056.

58. A combination therapy comprising:(a) Compound 15, and(b) Compound 1056a.

59. A combination therapy comprising:(a) Compound 15, and(b) Compound 1056b.

60. A combination therapy comprising:(a) Compound 18, and(b) olaparib.316259781

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