PARP inhibitor combination therapy with deoxyuridine triphosphatase inhibitors

Abstract

Provided herein are methods of treating cancer in a subject in need thereof, the methods comprising administering to the subject a poly (ADP-ribose) polymerase (PARP) inhibitor, a deoxyuridine triphosphatase (dUTPase) inhibitor, and an inhibitor of thymidylate biosynthesis.

Description

Atty. Dkt. No. 109290-0190PARP INHIBITOR COMBINATION THERAPY WITH DEOXYURIDINE TRIPHOSPHATASE INHIBITORSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims priority to U.S. Provisional Patent Application No.63 / 745,965 under 35 U.S.C. 119(e), filed on January 16, 2025, which is hereby expressly incorporated by reference herein in its entirety.FIELD OF DISCLOSURE

[0002] The present disclosure is, in some aspects, in the field of combination therapy of deoxyuridine triphosphatase inhibitors with other active agents for the treatment of cancer.SUMMARY

[0003] In one aspect, presented herein are methods of treating cancer in a subject in need thereof, the methods comprising, or consisting essentially of, or consisting of, administering to the subject a poly (ADP-ribose) polymerase (PARP) inhibitor, a deoxyuridine triphosphatase (dUTPase) inhibitor, and an inhibitor of thymidylate biosynthesis.

[0004] In another aspect, presented herein are methods of inhibiting growth of a cancer cell comprising, or consisting essentially of, or consisting of, contacting the cell with a poly (ADP-ribose) polymerase (PARP) inhibitor, a deoxyuridine triphosphatase (dUTPase) inhibitor, and an inhibitor of thymidylate biosynthesis.BRIEF DESCRIPTION OF DRAWINGS

[0005] Figures 1A-1C depict line graphs demonstrating cytotoxicity as a percentage of untreated control as determined by growth inhibition assay (GIA) following 72H and 120H incubation of HCT116 (Figure 1A), A549 (Figure IB), and MDA-MB-231 (Figure 1C) cells with increasing doses of talazoparib (denoted as “PARPi”) as a single agent or with a fixed dose of Compound A, FUdR, or Compound A + FUdR (also denoted as “combination”). Horizontal dashed line represents the activity of Compound A + FUdR.

[0006] Figures 2A-2C depict bar graphs demonstrating cell survival as a percentage of untreated control as determined by colony formation assay following 48-hour incubation of HCT116 (Figure 2A), A549 (Figure 2B), and MDA-MB-231 (Figure 2C) cells with a fixed dose of Compound A, FUdR, or Compound A + FUdR (“combination”), with or without the14927-6853-2615.1Atty. Dkt. No. 109290-0190addition of increasing doses of olaparib. All data points are expressed as mean ± SEM.Figure 2D depicts the results of Two-Way ANOVA statistical analysis and subsequent post-hoc analysis using Tukey’s Multiple comparisons test (MCT) of HCT116, A549 and MDA-MB-231 cell lines following 48-hour incubation with a fixed dose of Compound A, FUdR, or Compound A + FUdR, with and without the addition of increasing doses of olaparib.

[0007] Figures 3A-3C depict bar graphs demonstrating cell survival as a percentage of untreated control as determined by colony formation assay following 48-hour incubation of HCT116 (Figure 3A), A549 (Figure 3B), and MDA-MB-231 (Figure 3C) cells with a fixed dose of Compound A, FUdR, or Compound A + FUdR (“combination”), with and without the addition of increasing doses of rucaparib. All data points are expressed as mean ± SEM. Figure 3D depicts the results of Two-Way ANOVA statistical analysis and subsequent post-hoc analysis using Tukey’s Multiple comparisons test (MCT) of HCT116, A549 and MDA-MB-231 cell lines following 48-hour incubation with a fixed dose of Compound A, FUdR, or Compound A + FUdR, with and without the addition of increasing doses of rucaparib.

[0008] Figures 4A-4C depict bar graphs demonstrating cell survival as a percentage of untreated control as determined by colony formation assay following 48-hour incubation of HCT116 (Figure 4A), A549 (Figure 4B), and MDA-MB-231 (Figure 4C) cells with a fixed dose of Compound A, FUdR, or Compound A + FUdR (“combination”), with or without the addition of increasing doses of niraparib. All data points are expressed as mean ± SEM. Figure 4D depicts the results of Two-Way ANOVA statistical analysis and subsequent post-hoc analysis using Tukey’s Multiple comparisons test (MCT) of HCT116, A549 and MDA-MB-231 cell lines following 48-hour incubation with a fixed dose of Compound A, FUdR, or Compound A + FUdR, with and without the addition of increasing doses of niraparib.

[0009] Figures 5A-5C depict bar graphs demonstrating cell survival as a percentage of untreated control as determined by colony formation assay following 48-hour incubation of HCT116 (Figure 5A), A549 (Figure 5B), and MDA-MB-231 (Figure 5C) cells with a fixed dose of Compound A, FUdR, or Compound A + FUdR (“combination”), with or without the addition of increasing doses of talazoparib. All data points are expressed as mean ± SEM. Figure 5D depicts the results of Two-Way ANOVA statistical analysis and subsequent post-hoc analysis using Tukey’s Multiple comparisons test (MCT) of HCT116, A549 and MDA-MB-231 cell lines following 48-hour incubation with a fixed dose of Compound A, FUdR, or Compound A + FUdR, with and without the addition of increasing doses of talazoparib.24927-6853-2615.1Atty. Dkt. No. 109290-0190

[0010] Figures 6A-6C depict bar graphs demonstrating cell survival as a percentage of untreated control as determined by colony formation assay following 48-hour incubation of HCT116 (Figure 6A), A549 (Figure 6B), and MDA-MB-231 (Figure 6C) cells with Compound A (at concentrations ranging from 1.56 pM - 6.25 pM), FUdR (fixed dose of 0.5 pM), or Compound A (at concentrations ranging from 1.56 pM - 6.25 pM) + FUdR (fixed dose of 0.5 pM) (“combination”), with or without the addition of a fixed dose of olaparib (1 pM). All data points are expressed as mean ± SEM. Figure 6D depicts the results of Two-Way ANOVA statistical analysis and subsequent post-hoc analysis using Tukey’s Multiple comparisons test (MCT) of HCT116, A549 and MDA-MB-231 cell lines following 48-hour incubation with Compound A, FUdR, or Compound A + FUdR, with and without the addition of a fixed dose of olaparib (1 pM).

[0011] Figures 7A-7C depict bar graphs demonstrating cell survival as a percentage of untreated control as determined by colony formation assay following 48-hour incubation of HCT116 (Figure 7A), A549 (Figure 7B), and MDA-MB-231 (Figure 7C) cells with Compound A (at concentrations ranging from 1.56 pM - 6.25 pM), FUdR (fixed dose of 0.5 pM), or Compound A (at concentrations ranging from 1.56 pM - 6.25 pM) + FUdR (fixed dose of 0.5 pM) (“combination”), with or without the addition of a fixed dose of rucaparib (1 pM). All data points are expressed as mean ± SEM. Figure 7D depicts the results of Two-Way ANOVA statistical analysis and subsequent post-hoc analysis using Tukey’s Multiple comparisons test (MCT) of HCT116, A549 and MDA-MB-231 cell lines following 48-hour incubation with Compound A, FUdR, or Compound A + FUdR, with and without the addition of a fixed dose of rucaparib (1 pM).

[0012] Figures 8A-8C depict bar graphs demonstrating cell survival as a percentage of untreated control as determined by colony formation assay following 48-hour incubation of HCT116 (Figure 8A), A549 (Figure 8B), and MDA-MB-231 (Figure 8C) cells with Compound A (at concentrations ranging from 1.56 pM - 6.25 pM), FUdR (fixed dose of 0.5 pM), or Compound A (at concentrations ranging from 1.56 pM - 6.25 pM) + FUdR (fixed dose of 0.5 pM) (“combination”), with or without the addition of a fixed dose of niraparib (0.5 pM). All data points are expressed as mean± SEM. Figure 8D depicts the results of Two-Way ANOVA statistical analysis and subsequent post-hoc analysis using Tukey’s Multiple comparisons test (MCT) of HCT116, A549 and MDA-MB-231 cell lines following 48-hour incubation with Compound A, FUdR, or Compound A + FUdR, with and without the addition of a fixed dose of niraparib (0.5 pM).34927-6853-2615.1Atty. Dkt. No. 109290-0190

[0013] Figures 9A-9C depict bar graphs demonstrating cell survival as a percentage of untreated control as determined by colony formation assay following 48-hour incubation of HCT116 (Figure 9A), A549 (Figure 9B), and MDA-MB-231 (Figure 9C) cells with Compound A (at concentrations ranging from 1.56 pM - 6.25 pM), FUdR (fixed dose of 0.5 pM), or Compound A (at concentrations ranging from 1.56 pM - 6.25 pM) + FUdR (fixed dose of 0.5 pM) (“combination”), with or without the addition of a fixed dose of talazoparib (0.005 pM). All data points are expressed as mean ± SEM. Figure 9D depicts the results of Two-Way ANOVA statistical analysis and subsequent post-hoc analysis using Tukey’s Multiple comparisons test (MCT) of HCT116, A549 and MDA-MB-231 cell lines following 48-hour incubation with Compound A, FUdR, or Compound A + FUdR, with and without the addition of a fixed dose of talazoparib (0.005 pM).

[0014] Figure 10A depicts bar graph demonstrating cell survival as a percentage of untreated control as determined by colony formation assay following 48-hour incubation of HCT116 cells with Compound B, FUdR, or Compound B + FUdR (“combination”), with and without the addition of a fixed dose of olaparib (1 pM). All data points are expressed as mean± SEM. Figure 10B depicts results of Two-Way ANOVA statistical analysis and subsequent post-hoc analysis using Tukey’s Multiple comparisons test (MCT) of the HCT116 cell line following 48-hour incubation with Compound B, FUdR, or Compound B + FUdR, with and without the addition of a fixed dose of olaparib (1 pM).

[0015] Figure 11A depicts bar graph demonstrating cell survival as a percentage of untreated control as determined by colony formation assay following 48-hour incubation of HCT116 cells with Compound B, FUdR, or Compound B + FUdR (“combination”), with and without the addition of a fixed dose of rucaparib (1 pM). All data points are expressed as mean ± SEM. Figure 11B depicts results of Two-Way ANOVA statistical analysis and subsequent post-hoc analysis using Tukey’s Multiple comparisons test (MCT) of the HCT116 cell line following 48-hour incubation with Compound B, FUdR, or Compound B + FUdR, with and without the addition of a fixed dose of rucaparib (1 pM).

[0016] Figure 12A depicts bar graph demonstrating cell survival as a percentage of untreated control as determined by colony formation assay following 48-hour incubation of HCT116 cells with Compound B, FUdR, or Compound B + FUdR (“combination”), with and without the addition of a fixed dose of niraparib (0.5 pM). All data points are expressed as mean± SEM. Figure 12B depicts results of Two-Way ANOVA statistical analysis and subsequent post-hoc analysis using Tukey’s Multiple comparisons test (MCT) of the HCT11644927-6853-2615.1Atty. Dkt. No. 109290-0190cell line following 48-hour incubation with Compound B, FUdR, or Compound B + FUdR, with and without the addition of a fixed dose of niraparib (0.5 pM).

[0017] Figure 13A depicts bar graph demonstrating cell survival as a percentage of untreated control as determined by colony formation assay following 48-hour incubation of HCT116 cells with Compound B, FUdR, or Compound B + FUdR (“combination”), with and without the addition of a fixed dose of talazoparib (0.005 pM). All data points are expressed as mean± SEM. Figure 13B depicts results of Two-Way ANOVA statistical analysis and subsequent post-hoc analysis using Tukey’s Multiple comparisons test (MCT) of the HCT116 cell line following 48-hour incubation with Compound B, FUdR, or Compound B + FUdR, with and without the addition of a fixed dose of talazoparib (0.005 pM).DETAILED DESCRIPTIONDefinitions

[0018] Throughout this disclosure, various publications, patents and published patent specifications are referenced by an identifying citation. The disclosures of these publications, patents and published patent specifications are hereby incorporated by reference into the present disclosure in their entirety to more fully describe the state of the art to which this invention pertains.

[0019] The practice of the present technology will employ, unless otherwise indicated, conventional techniques of organic chemistry, pharmacology, immunology, molecular biology, microbiology, cell biology and recombinant DNA, which are within the skill of the art. See, e.g., Sambrook, Fritsch and Maniatis, Molecular Cloning: A Laboratory Manual, 2ndedition (1989); Current Protocols In Molecular Biology (F. M. Ausubel, et al. eds., (1987)); the series Methods in Enzymology (Academic Press); PCR 2: A Practical Approach (M. J. MacPherson, B.D. Hames and G.R. Taylor eds., (1995)); Antibodies, a Laboratory Manual, and Animal Cell Culture (R.I. Freshney, ed. (1987)).

[0020] As used in the specification and claims, the singular form “a,” “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a cell” includes a plurality of cells, including mixtures thereof.

[0021] As used herein, the term “comprising” is intended to mean that the compounds, compositions and methods include the recited elements, but not exclude others. “Consisting essentially of’ when used to define compounds, compositions and methods, shall mean54927-6853-2615.1Atty. Dkt. No. 109290-0190excluding other elements of any essential significance to the combination. Thus, a composition consisting essentially of the elements as defined herein would not exclude trace contaminants, e.g., from the isolation and purification method and pharmaceutically acceptable carriers, preservatives, and the like. “Consisting of’ shall mean excluding more than trace elements of other ingredients. Embodiments defined by each of these transition terms are within the scope of this technology.

[0022] As used herein, “about” will be understood by persons of ordinary skill in the art and will vary to some extent depending upon the context in which it is used. If there are uses of the term which are not clear to persons of ordinary skill in the art, given the context in which it is used, “about” will mean up to plus or minus 10% of the particular term. It also is to be understood, although not always explicitly stated, that the reagents described herein are merely exemplary and that equivalents of such are known in the art.

[0023] “Alkyl” refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and preferably 1 to 6 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), t-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-).

[0024] “Alkenyl” refers to monovalent straight or branched hydrocarbyl groups having from 2 to 10 carbon atoms and preferably 2 to 6 carbon atoms or preferably 2 to 4 carbon atoms and having at least 1 and preferably from 1 to 2 sites of vinyl (>C=C<) unsaturation. Such groups are exemplified, for example, by vinyl, allyl, and but-3-en-l-yl. Included within this term are the cis and trans isomers or mixtures of these isomers.

[0025] “ Alkynyl” refers to straight or branched monovalent hydrocarbyl groups having from 2 to 10 carbon atoms and preferably 2 to 6 carbon atoms or preferably 2 to 3 carbon atoms and having at least 1 and preferably from 1 to 2 sites of acetylenic (-C=C-) unsaturation. Examples of such alkynyl groups include acetylenyl (-C=CH), and propargyl (-CH2OCH).

[0026] “ Substituted alkyl” refers to an alkyl group having from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy,64927-6853-2615.1Atty. Dkt. No. 109290-0190aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are as defined herein.

[0027] “Heteroalkyl” refers to an alkyl group one or more carbons is replaced with -O-, -S-, SO2, a P containing moiety as provided herein, -NRQ-,moieties where RQis H or Ci-Ce alkyl. Substituted heteroalkyl refers to a heteroalkyl group having from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryl oxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are as defined herein.4927-6853-2615.1Atty. Dkt. No. 109290-0190

[0028] “ Substituted alkenyl” refers to alkenyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are as defined herein and with the proviso that any hydroxyl or thiol substitution is not attached to a vinyl (unsaturated) carbon atom.

[0029] “Heteroalkenyl” refers to an alkenyl group one or more carbons is replaced with -O-, -S-, SO2, a P containing moiety as provided herein, -NRQ-,moieties where RQis H or Ci-Ce alkyl. Substituted heteroalkenyl refers to a heteroalkenyl group having from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl,84927-6853-2615.1Atty. Dkt. No. 109290-0190heteroaryl oxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are as defined herein.

[0030] “ Substituted alkynyl” refers to alkynyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are as defined herein and with the proviso that any hydroxyl or thiol substitution is not attached to an acetylenic carbon atom.

[0031] “Heteroalkynyl” refers to an alkynyl group one or more carbons is replaced with -O-, -S-, SO2, a P containing moiety as provided herein, -NRQ-,moieties where RQis H or Ci-Ce alkyl. Substituted heteroalkynyl refers to a heteroalkynyl group having from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio,94927-6853-2615.1Atty. Dkt. No. 109290-0190substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryl oxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are as defined herein.

[0032] “Alkylene” refers to divalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms, preferably having from 1 to 6 and more preferably 1 to 3 carbon atoms that are either straight-chained or branched. This term is exemplified by groups such as methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), iso-propylene (-CH2CH(CH3)- or -CH(CH3)CH2-), butylene (-CH2CH2CH2CH2-), isobutylene(-CH2CH(CH3)CH2-), sec-butylene (-CH2CH2(CH3)CH-), and the like. Similarly, “alkenylene” and “alkynylene” refer to an alkylene moiety containing respective 1 or 2 carbon carbon double bonds or a carbon carbon triple bond.

[0033] “ Substituted alkylene” refers to an alkylene group having from 1 to 3 hydrogens replaced with substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl, carboxyl ester, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and oxo wherein said substituents are defined herein. In some embodiments, the alkylene has 1 to 2 of the aforementioned groups, or having from 1-3 carbon atoms replaced with -O-, -S-, or -NRQ- moieties where RQis H or Ci-Ce alkyl. It is to be noted that when the alkylene is substituted by an oxo group, 2 hydrogens attached to the same carbon of the alkylene group are replaced by “=O”. “Substituted alkenylene” and “ substituted alkynylene” refer to alkenylene and substituted alkynylene moieties substituted with substituents as described for substituted alkylene.

[0034] “Alkynylene” refers to straight or branched divalent hydrocarbyl groups having from 2 to 10 carbon atoms and preferably 2 to 6 carbon atoms or preferably 2 to 3 carbon104927-6853-2615.1Atty. Dkt. No. 109290-0190atoms and having at least 1 and preferably from 1 to 2 sites of acetylenic (-C=C-) unsaturation. Examples of such alkynylene groups include -C=C- and -CH2OC-.

[0035] “ Substituted alkynylene” refers to alkynylene groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are as defined herein and with the proviso that any hydroxyl or thiol substitution is not attached to an acetylenic carbon atom.

[0036] “Heteroalkylene” refers to an alkylene group wherein one or more carbons is replaced with -O-, -S-, SO2, a P containing moiety as provided herein, -NRQ-,moieties where RQis H or Ci-Ce alkyl. “Substituted heteroalkylene” refers to heteroalkynylene groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the substituents disclosed for substituted alkylene.

[0037] “Heteroalkenylene” refers to an alkenylene group wherein one or more carbons is replaced with -O-, -S-, SO2, a P containing moiety as provided herein, -NRQ-,114927-6853-2615.1Atty. Dkt. No. 109290-0190moieties where RQis H or Ci-Ce alkyl. “Substituted heteroalkenylene” refers to heteroalkynylene groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the substituents disclosed for substituted alkenylene.

[0038] “Heteroalkynylene” refers to an alkynylene group wherein one or more carbons is replaced with -O-, -S-, SO2, a P containing moiety as provided herein, -NRQ-,moieties where RQis H or Ci-Ce alkyl. “Substituted heteroalkynylene” refers to heteroalkynylene groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the substituents disclosed for substituted alkynylene.

[0039] “Alkoxy” refers to the group -O-alkyl wherein alkyl is defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy.

[0040] “ Substituted alkoxy” refers to the group -O-(substituted alkyl) wherein substituted alkyl is defined herein.

[0041] “Acyl” refers to the groups H-C(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclic-C(O)-, and substituted heterocyclic-C(O)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Acyl includes the “acetyl” group CH3C(O)-.

[0042] “Acylamino” refers to the groups -NR47C(O)alkyl, -NR47C(O)substituted alkyl, -NR47C(O)cycloalkyl, -NR47C(O)substituted cycloalkyl, -NR47C(O)cycloalkenyl,4927-6853-2615.1Atty. Dkt. No. 109290-0190-NR47C(O)substituted cycloalkenyl, -NR47C(O)alkenyl, -NR47C(O)substituted alkenyl, -NR47C(O)alkynyl, -NR47C(O)substituted alkynyl, -NR47C(O)aryl, -NR47C(O)substituted aryl, -NR47C(O)heteroaryl, -NR47C(O)substituted heteroaryl, -NR47C(O)heterocyclic, and -NR47C(O) substituted heterocyclic wherein R47is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0043] “Acyloxy” refers to the groups alkyl-C(O)O-, substituted alkyl-C(O)O-, alkenyl-C(O)O-, substituted alkenyl-C(O)O-, alkynyl-C(O)O-, substituted alkynyl-C(O)O-, aryl-C(O)O-, substituted aryl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, cycloalkenyl-C(O)O-, substituted cycloalkenyl-C(O)O-, heteroaryl-C(O)O-, substituted heteroaryl-C(O)O-, heterocyclic-C(O)O-, and substituted heterocyclic-C(O)O- wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0044] An animal, subject or patient for diagnosis or treatment refers to an animal such as a mammal, or a human, ovine, bovine, feline, canine, equine, simian, etc. Non-human animals subject to diagnosis or treatment include, for example, simians, murine, such as, rat, mice, canine, leporid, livestock, sport animals, and pets.

[0045] “Amino” refers to the group -NH2.

[0046] “ Substituted amino” refers to the group -NR48R49where R48and R49are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -SCh-alkyl, -SO2- substitutedalkyl, -SCh-alkenyl, -SCh-substituted alkenyl, -SCh-cycloalkyl, -SO2- substituted cylcoalkyl, -SCh-cycloalkenyl, -SCh-substituted cylcoalkenyl, -SCh-aryl, -SCh-substituted aryl, -SCh-heteroaryl, -SCh-substituted heteroaryl, -SCh-heterocyclic, and -SCh-substituted heterocyclic and wherein R48and R49are optionally joined, together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, provided that R48and R49are134927-6853-2615.1Atty. Dkt. No. 109290-0190both not hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. When R48is hydrogen and R49is alkyl, the substituted amino group is sometimes referred to herein as alkylamino. When R48and R49are alkyl, the substituted amino group is sometimes referred to herein as dialkylamino. When referring to a monosubstituted amino, it is meant that either R48or R49is hydrogen but not both. When referring to a disubstituted amino, it is meant that neither R48nor R49are hydrogen.

[0047] “Aminocarbonyl” refers to the group -C(O)NR50R51where R50and R51are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R50and R51are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0048] “Aminothiocarbonyl” refers to the group -C(S)NR50R51where R50and R51are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R50and R51are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0049] “Aminocarbonylamino” refers to the group -NR47C(O)NR50R51where R47is hydrogen or alkyl and R50and R51are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic,144927-6853-2615.1Atty. Dkt. No. 109290-0190and where R50and R51are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0050] “Aminothiocarbonylamino” refers to the group -NR47C(S)NR50R51where R47is hydrogen or alkyl and R50and R51are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R50and R51are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0051] “Aminocarbonyloxy” refers to the group -O-C(O)NR50R51where R50and R51are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R50and R51are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0052] “Aminosulfonyl” refers to the group -SC>2NR50R51where R50and R51are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R50and R51are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,154927-6853-2615.1Atty. Dkt. No. 109290-0190aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0053] “Aminosulfonyloxy” refers to the group -O-SO2NR50R51where R50and R51are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R50and R51are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0054] “Aminosulfonylamino” refers to the group -NR47SO2NR50R51where R47is hydrogen or alkyl and R50and R51are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R50and R51are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0055] “Amidino” refers to the group -C(=NR52)NR50R51where R50, R51, and R52are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R50and R51are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.164927-6853-2615.1Atty. Dkt. No. 109290-0190

[0056] “Aryl” or “Ar” refers to a monovalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-l,4-benzoxazin-3(4H)-one-7-yl, and the like) provided that the point of attachment is at an aromatic carbon atom. Preferred aryl groups include phenyl and naphthyl.

[0057] “ Substituted aryl” refers to aryl groups which are substituted with 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are as defined herein.

[0058] “Arylene” refers to a divalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring or multiple condensed rings. “Substituted arylene” refers to an arylene having from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents as defined for aryl groups.

[0059] "Heteroarylene" refers to a divalent aromatic group of from 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur within the ring. "Substituted heteroarylene" refers to heteroarylene groups that are substituted with from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of the same group of substituents defined for substituted aryl.

[0060] “Aryloxy” refers to the group -O-aryl, where aryl is as defined herein, that includes, by way of example, phenoxy and naphthoxy.174927-6853-2615.1Atty. Dkt. No. 109290-0190

[0061] “ Substituted aryloxy” refers to the group -©-(substituted aryl) where substituted aryl is as defined herein.

[0062] “Arylthio” refers to the group -S-aryl, where aryl is as defined herein.

[0063] “ Substituted arylthio” refers to the group -S-(substituted aryl), where substituted aryl is as defined herein.

[0064] “Carbonyl” refers to the divalent group -C(O)- which is equivalent to -C(=O)-.

[0065] “Carboxyl” or “carboxy” refers to -COOH or salts thereof.

[0066] “Carboxyl ester” or “carboxy ester” refers to the group -C(O)(O)-alkyl, -C(O)(O)-substituted alkyl, -C(O)O-alkenyl, -C(O)(O)-substituted alkenyl, -C(O)(O)-alkynyl, -C(O)(O)-substituted alkynyl, -C(O)(O)-aryl, -C(O)(O)-substituted-aryl, -C(O)(O)-cycloalkyl, -C(O)(O)-substituted cycloalkyl, -C(O)(O)-cycloalkenyl, -C(O)(O)-substituted cycloalkenyl, -C(O)(O)-heteroaryl, -C(O)(O)-substituted heteroaryl, -C(O)(O)-heterocyclic, and -C(O)(O)-substituted heterocyclic wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0067] “(Carboxyl ester)amino refers to the group -NR47C(O)(O)-alkyl, -NR47C(O)(O)-substituted alkyl, -NR47C(O)O-alkenyl, -NR47C(O)(O)-substituted alkenyl, -NR47C(O)(O)-alkynyl, -NR47C(O)(O)-substituted alkynyl, -NR47C(O)(O)-aryl, -NR47C(O)(O)-substituted-aryl, -NR47C(O)(O)-cycloalkyl, -NR47C(O)(O)-substituted cycloalkyl, -NR47C(O)(O)-cycloalkenyl, -NR47C(O)(O)-substituted cycloalkenyl, -NR47C(O)(O)-heteroaryl, -NR47C(O)(O)-substituted heteroaryl, -NR47C(O)(O)-heterocyclic, and -NR47C(O)(O)-substituted heterocyclic wherein R47is alkyl or hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0068] “(Carboxyl ester)oxy refers to the group -O-C(O)O-alkyl, -O-C(O)O-substituted alkyl, -O-C(O)O-alkenyl, -O-C(O)O-substituted alkenyl, -O-C(O)O-alkynyl, -O-C(O)(O)-substituted alkynyl, -O-C(O)O-aryl, -O-C(O)O-substituted-aryl, -O-C(O)O-cycloalkyl, -O-C(O)O-substituted cycloalkyl, -O-C(O)O-cycloalkenyl, -O-C(O)O-substituted cycloalkenyl, -O-C(O)O-heteroaryl, -O-C(O)O-substitutedheteroaryl, -O-C(O)O-heterocyclic, and -O-C(O)O-substituted heterocyclic wherein alkyl,184927-6853-2615.1Atty. Dkt. No. 109290-0190substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0069] A “composition” as used herein, refers to an active agent, such as a compound as disclosed herein and a carrier, inert or active. The carrier can be, without limitation, solid such as a bead or resin, or liquid, such as phosphate buffered saline.

[0070] Administration or treatment in “combination” refers to administering two or more agents such that their pharmacological effects are manifest at the same time. Combination does not require administration at the same time or substantially the same time, although combination can include such administrations.

[0071] “Cyano” refers to the group -CN.

[0072] “Cycloalkyl” refers to cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings including fused, bridged, and spiro ring systems. The fused ring can be an aryl ring provided that the non aryl part is joined to the rest of the molecule. Examples of suitable cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl.

[0073] “Cycloalkenyl” refers to non-aromatic cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings and having at least one >C=C< ring unsaturation and preferably from 1 to 2 sites of >C=C< ring unsaturation.

[0074] “ Substituted cycloalkyl” and “substituted cycloalkenyl” refers to a cycloalkyl or cycloalkenyl group having from 1 to 5 or preferably 1 to 3 substituents selected from the group consisting of oxo, thioxo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl esterjamino, (carboxyl esterjoxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted 194927-6853-2615.1Atty. Dkt. No. 109290-0190heteroaryl oxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are as defined herein.

[0075] “Cyclopropane” refers to:

[0076] “Cyclobutano” refers to:

[0077] “Cycloalkyloxy” refers to -O-cycloalkyl.

[0078] “ Substituted cycloalkyloxy refers to -©-(substituted cycloalkyl).

[0079] “Cycloalkylthio” refers to -S-cycloalkyl.

[0080] “ Substituted cycloalkylthio” refers to -S-(substituted cycloalkyl).

[0081] “Cycloalkenyloxy” refers to -O-cycloalkenyl.

[0082] “ Substituted cycloalkenyloxy” refers to -©-(substituted cycloalkenyl).

[0083] “Cycloalkenylthio” refers to -S-cycloalkenyl.

[0084] “ Substituted cycloalkenylthio” refers to -S-(substituted cycloalkenyl).

[0085] “Guanidino” refers to the group -NHC(=NH)NH2.

[0086] “Substituted guanidino” refers to -NR53C(=NR53)N(R53)2 where each R53is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclic, and substituted heterocyclic and two R53groups attached to a common guanidino nitrogen atom are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, provided that at least one R53is not hydrogen, and wherein said substituents are as defined herein.

[0087] “Halo” or “halogen” refers to fluoro, chloro, bromo and iodo.4927-6853-2615.1Atty. Dkt. No. 109290-0190

[0088] “Hydroxy” or “hydroxyl” refers to the group -OH.

[0089] “Heteroaryl” refers to an aromatic group of from 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur within the ring. Such heteroaryl groups can have a single ring (e.g., pyridinyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl) wherein the condensed rings may or may not be aromatic and / or contain a heteroatom provided that the point of attachment is through an atom of the aromatic heteroaryl group. In one embodiment, the nitrogen and / or the sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N— >0), sulfinyl, or sulfonyl moieties. Certain non-limiting examples include pyridinyl, pyrrolyl, indolyl, thiophenyl, oxazolyl, thiazolyl, and furanyl.

[0090] “ Substituted heteroaryl” refers to heteroaryl groups that are substituted with from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of the same group of substituents defined for substituted aryl.

[0091] “Heteroaryloxy” refers to -O-heteroaryl.

[0092] “ Substituted heteroaryl oxy” refers to the group -©-(substituted heteroaryl).

[0093] “Heteroarylthio” refers to the group -S -heteroaryl.

[0094] “ Substituted heteroarylthio” refers to the group -S-(substituted heteroaryl).

[0095] “Heterocycle” or “heterocyclic” or “heterocycloalkyl” or “heterocyclyl” refers to a saturated or partially saturated, but not aromatic, group having from 1 to 10 ring carbon atoms and from 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen. Heterocycle encompasses single ring or multiple condensed rings, including fused bridged and spiro ring systems. In fused ring systems, one or more the rings can be cycloalkyl, aryl, or heteroaryl provided that the point of attachment is through a non-aromatic ring. In one embodiment, the nitrogen and / or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, sulfinyl, or sulfonyl moieties.

[0096] “ Substituted heterocyclic” or “substituted heterocycloalkyl” or “substituted heterocyclyl” refers to heterocyclyl groups that are substituted with from 1 to 5 or preferably 1 to 3 of the same substituents as defined for substituted cycloalkyl.

[0097] “Heterocyclyloxy” refers to the group -O-heterocycyl.

[0098] “ Substituted heterocyclyloxy” refers to the group -©-(substituted heterocycyl).214927-6853-2615.1Atty. Dkt. No. 109290-0190

[0099] “Heterocyclylthio” refers to the group -S-heterocycyl.

[0100] “ Substituted heterocyclylthio” refers to the group -S-(substituted heterocycyl).

[0101] Examples of heterocycle and heteroaryls include, but are not limited to, azetidine, pyrrole, furan, thiophene, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo [b]thiophene, morpholinyl, thiomorpholinyl (also referred to as thiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine, and tetrahydrofuranyl .

[0102] “Nitro” refers to the group -NO2.

[0103] “ Oxo” refers to the atom (=0).

[0104] Phenylene refers to a divalent aryl ring, where the ring contains 6 carbon atoms.

[0105] Substituted phenylene refers to phenylenes which are substituted with 1 to 4, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are as defined herein.224927-6853-2615.1Atty. Dkt. No. 109290-0190

[0106] “Spirocycloalkyl” and “spiro ring systems” refers to divalent cyclic groups from 3 to 10 carbon atoms having a cycloalkyl or heterocycloalkyl ring with a spiro union (the union formed by a single atom which is the only common member of the rings) as exemplified by the following structure:

[0107] “Sulfonyl” refers to the divalent group -S(O)2-.

[0108] “ Substituted sulfonyl” refers to the group -SCh-alkyl, -SCh-substitutedalkyl, -SCh-alkenyl, -SCh-substituted alkenyl, -SCh-cycloalkyl, -SO2- substituted cylcoalkyl, -SCh-cycloalkenyl, -SCh-substituted cylcoalkenyl, -SCh-aryl, -SCh-substituted aryl, -SCh-heteroaryl, -SCh-substituted heteroaryl, -SCh-heterocyclic, -SO2- substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Substituted sulfonyl includes groups such as methyl-SCh-, phenyl-SCh-, and 4-methylphenyl-SC>2-.

[0109] “ Substituted sulfonyloxy” refers to the group -OSCh-alkyl, -OSCh-substituted alkyl, -OSCh-alkenyl, -OSCh-substituted alkenyl, -OSCh-cycloalkyl, -OSCh-substituted cylcoalkyl, -OSCh-cycloalkenyl, -OSCh-substituted cylcoalkenyl, -OSCh-aryl,-OSCh-substituted aryl, -OSCh-heteroaryl, -OSCh-substituted heteroaryl,-OSCh-heterocyclic, -OSCh-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0110] “Thioacyl” refers to the groups H-C(S)-, alkyl-C(S)-, substituted alkyl-C(S)-, alkenyl-C(S)-, substituted alkenyl-C(S)-, alkynyl-C(S)-, substituted alkynyl-C(S)-, cycloalkyl-C(S)-, substituted cycloalkyl-C(S)-, cycloalkenyl-C(S)-, substituted cycloalkenyl-C(S)-, aryl-C(S)-, substituted aryl-C(S)-, heteroaryl-C(S)-, substituted heteroaryl-C(S)-, heterocyclic-C(S)-, and substituted heterocyclic-C(S)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,4927-6853-2615.1Atty. Dkt. No. 109290-0190substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0111] “ Thiol” refers to the group -SH.

[0112] “Thiocarbonyl” refers to the divalent group -C(S)- which is equivalent to -C(=S)-.

[0113] “ Thioxo” refers to the atom (=S).

[0114] “Alkylthio” refers to the group -S-alkyl wherein alkyl is as defined herein.

[0115] “ Substituted alkylthio” refers to the group -S-(substituted alkyl) wherein substituted alkyl is as defined herein.

[0116] A substituted ring can be substituted with one or more fused and / or spiro cycles. Such fused cycles include a fused cycloalkyl, a fused heterocyclyl, a fused aryl, a fused heteroaryl ring, each of which rings can be unsubstituted or substituted. Such spiro cycles include a fused cycloalkyl and a fused heterocyclyl, each of which rings can be unsubstituted or substituted.

[0117] “Optionally substituted” refers to a group selected from that group and a substituted form of that group. Substituents are such as those defined hereinabove. In one embodiment, substituents are selected from Ci-Cio or Ci-Ce alkyl, substituted Ci-Cio or Ci-Ce alkyl, C2-Ce alkenyl, C2-C6 alkynyl, Ce-Cio aryl, Cs-Cs cycloalkyl, C2-C10 heterocyclyl, C1-C10 heteroaryl, substituted C2-C6 alkenyl, substituted C2-C6 alkynyl, substituted Ce-Cio aryl, substituted Cs-Cs cycloalkyl, substituted C2-C10 heterocyclyl, substituted C1-C10 heteroaryl, halo, nitro, cyano, -CO2H or a Ci-Ce alkyl ester thereof.

[0118] Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment. For example, the substituent “alkoxycarbonylalkyl” refers to the group (alkoxy)-C(O)-(alkyl)-.

[0119] It is understood that in all substituted groups defined above, polymers arrived at by defining substituents with further substituents to themselves (e.g., substituted aryl having a substituted aryl group as a substituent which is itself substituted with a substituted aryl group, etc.) are not intended for inclusion herein. In such cases, the maximum number of such substituents is three. That is to say that each of the above definitions is constrained by a244927-6853-2615.1Atty. Dkt. No. 109290-0190limitation that, for example, substituted aryl groups are limited to -substituted aryl-(substituted aryl)-substituted aryl.

[0120] It is understood that the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluoro groups). Such impermissible substitution patterns are well known to the skilled artisan.

[0121] “ Tautomer” refer to alternate forms of a compound that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups containing a ring atom attached to both a ring -NH- moiety and a ring =N- moiety such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.

[0122] As used herein, the term stereochemically pure denotes a compound which has 80% or greater by weight of the indicated stereoisomer and 20% or less by weight of other stereoisomers. In a further embodiment, the compound of Formula (I) has 90% or greater by weight of the stated stereoisomer and 10% or less by weight of other stereoisomers. In a yet further embodiment, the compound of Formula (I) has 95% or greater by weight of the stated stereoisomer and 5% or less by weight of other stereoisomers. In a still further embodiment, the compound of Formula (I) has 97% or greater by weight of the stated stereoisomer and 3% or less by weight of other stereoisomers.

[0123] “Pharmaceutically acceptable salt” refers to salts of a compound, which salts are suitable for pharmaceutical use and are derived from a variety of organic and inorganic counter ions well known in the art and include, when the compound contains an acidic functionality, by way of example only, sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, and oxalate (see Stahl and Wermuth, eds., “Handbook of Pharmaceutically Acceptable Salts,” (2002), Verlag Helvetica Chimica Acta, Zurich, Switzerland), for a discussion of pharmaceutical salts, their selection, preparation, and use.

[0124] Generally, pharmaceutically acceptable salts are those salts that retain substantially one or more of the desired pharmacological activities of the parent compound and which are suitable for in vivo administration. Pharmaceutically acceptable salts include acid addition salts formed with inorganic acids or organic acids. Inorganic acids suitable for forming pharmaceutically acceptable acid addition salts include, by way of example and not254927-6853-2615.1Atty. Dkt. No. 109290-0190limitation, hydrohalide acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, etc.), sulfuric acid, nitric acid, phosphoric acid, and the like.

[0125] Organic acids suitable for forming pharmaceutically acceptable acid addition salts include, by way of example and not limitation, acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, oxalic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, palmitic acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, alkylsulfonic acids (e.g., methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxy ethanesulfonic acid, etc.), arylsulfonic acids (e.g., benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, etc.), glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like.

[0126] Pharmaceutically acceptable salts also include salts formed when an acidic proton present in the parent compound is either replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion) or by an ammonium ion (e.g., an ammonium ion derived from an organic base, such as, ethanolamine, diethanolamine, triethanolamine, morpholine, piperidine, dimethylamine, diethylamine, triethylamine, and ammonia).

[0127] An “effective amount” is an amount sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications or dosages. Such delivery is dependent on a number of variables including the time period for which the individual dosage unit is to be used, the bioavailability of the therapeutic agent, the route of administration, etc. It is understood, however, that specific dose levels of the therapeutic agents disclosed herein for any particular subject depends upon a variety of factors including the activity of the specific compound employed, bioavailability of the compound, the route of administration, the age of the animal and its body weight, general health, sex, the diet of the animal, the time of administration, the rate of excretion, the drug combination, and the severity of the particular disorder being treated and form of administration. In general, one will desire to administer an amount of the compound that is effective to achieve a serum level commensurate with the concentrations found to be effective in vivo. These considerations, as well as effective formulations and administration procedures are well known in the art and are described in standard textbooks.264927-6853-2615.1Atty. Dkt. No. 109290-0190

[0128] “Therapeutically effective amount” of a drug or an agent refers to an amount of the drug or the agent that is an amount sufficient to obtain a pharmacological response such as inhibiting a biological target (e.g., dUTPase); or alternatively, is an amount of the drug or agent that, when administered to a patient with a specified disorder or disease, is sufficient to have the intended effect, e.g., treatment, alleviation, amelioration, palliation or elimination of one or more manifestations of the specified disorder or disease in the patient. A therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations.

[0129] As used herein, “treating” or “treatment” of a disease in a subject refers to (1) preventing the symptoms or disease from occurring in a subject that is predisposed or does not yet display symptoms of the disease; (2) inhibiting the disease or arresting its development; or (3) ameliorating or causing regression of the disease or the symptoms of the disease. As understood in the art, “treatment” is an approach for obtaining beneficial or desired results, including clinical results. For the purposes of this technology, beneficial or desired results can include one or more, but are not limited to, alleviation or amelioration of one or more symptoms, diminishment of extent of a condition (including a disease), stabilized (i.e., not worsening) state of a condition (including disease), delay or slowing of condition (including disease), progression, amelioration or palliation of the condition (including disease), states and remission (whether partial or total), whether detectable or undetectable. In one aspect, treatment excludes prophylaxis.

[0130] When the disease is cancer, the following clinical endpoints are non-limiting examples of treatment: (1) elimination of a cancer in a subject or in a tissue / organ of the subject or in a cancer loci; (2) reduction in tumor burden (such as number of cancer cells, number of cancer foci, number of cancer cells in a foci, size of a solid cancer, concentrate of a liquid cancer in the body fluid, and / or amount of cancer in the body); (3) stabilizing or delay or slowing or inhibition of cancer growth and / or development, including but not limited to, cancer cell growth and / or division, size growth of a solid tumor or a cancer loci, cancer progression, and / or metastasis (such as time to form a new metastasis, number of total metastases, size of a metastasis, as well as variety of the tissues / organs to house metastatic cells); (4) less risk of having a cancer growth and / or development; (5) inducing an immune response of the patient to the cancer, such as higher number of tumor-infiltrating immune cell or higher number of activated immune cells; (6) higher probability of survival and / or274927-6853-2615.1Atty. Dkt. No. 109290-0190increased duration of survival, such as increased overall survival (OS, which may be shown as 1-year, 2-year, 5-year, 10-year, or 20-year survival rate), increased progression free survival (PFS), increased disease free survival (DFS), increased time to tumor recurrence (TTR) and increased time to tumor progression (TTP). In some embodiments, the subject after treatment experiences one or more endpoints selected from tumor response, reduction in tumor size, reduction in tumor burden, increase in overall survival, increase in progression free survival, inhibiting metastasis, improvement of quality of life, minimization of drug-related toxicity, and avoidance of side-effects (e.g., decreased treatment emergent adverse events). In some embodiments, improvement of quality of life includes resolution or improvement of cancer-specific symptoms, such as but not limited to fatigue, pain, nausea / vomiting, lack of appetite, and constipation; improvement or maintenance of psychological well-being (e.g., degree of irritability, depression, memory loss, tension, and anxiety); improvement or maintenance of social well-being (e.g., decreased requirement for assistance with eating, dressing, or using the restroom; improvement or maintenance of ability to perform normal leisure activities, hobbies, or social activities; improvement or maintenance of relationships with family). In some embodiments, improved patient quality of life that is measured qualitatively through patient narratives or quantitatively using validated quality of life tools known to those skilled in the art, or a combination thereof. Additional non-limiting examples of endpoints include reduced hospital admissions, reduced drug use to treat side effects, longer periods off-treatment, and earlier return to work or caring responsibilities. In one aspect, prevention or prophylaxis is excluded from treatment.

[0131] The term “subject,” “host,” “individual,” and “patient” are as used interchangeably herein to refer to animals, typically mammalian animals. Any suitable mammal can be treated by a method described herein. Non-limiting examples of mammals include humans, nonhuman primates (e.g., apes, gibbons, chimpanzees, orangutans, monkeys, macaques, and the like), domestic animals (e.g., dogs and cats), farm animals (e.g., horses, cows, goats, sheep, pigs) and experimental animals (e.g., mouse, rat, rabbit, guinea pig). In some embodiments, a mammal is a human. A mammal can be any age or at any stage of development (e.g., an adult, teen, child, infant, or a mammal in utero). A mammal can be male or female. In some embodiments, a subject is a human. In some embodiments, a subject has or is diagnosed of having or is suspected of having a cancer.

[0132] In certain embodiments, the terms “disease” “disorder” and “condition” are used interchangeably herein, referring to a cancer, a status of being diagnosed with a cancer, or a 284927-6853-2615.1Atty. Dkt. No. 109290-0190status of being suspect of having a cancer. “Cancer”, which is also referred to herein as “tumor”, is a known medically as an uncontrolled division of abnormal cells in a part of the body, benign or malignant. In one embodiment, cancer refers to a malignant neoplasm, a broad group of diseases involving unregulated cell division and growth, and invasion to nearby parts of the body. Non-limiting examples of cancers include carcinomas, sarcomas, leukemia and lymphoma, e.g., colon cancer, colorectal cancer, rectal cancer, gastric cancer, esophageal cancer, head and neck cancer, breast cancer, brain cancer, lung cancer, stomach cancer, liver cancer, gall bladder cancer, or pancreatic cancer. In one embodiment, the term “cancer” refers to a solid tumor, which is an abnormal mass of tissue that usually does not contain cysts or liquid areas, including but not limited to, sarcomas, carcinomas, and certain lymphomas (such as Non-Hodgkin's lymphoma). In another embodiment, the term “cancer” refers to a liquid cancer, which is a cancer presenting in body fluids (such as, the blood and bone marrow), for example, leukemias (cancers of the blood) and certain lymphomas.

[0133] Additionally or alternatively, a cancer may refer to a local cancer (which is an invasive malignant cancer confined entirely to the organ or tissue where the cancer began), a metastatic cancer (referring to a cancer that spreads from its site of origin to another part of the body), a non-metastatic cancer, a primary cancer (a term used describing an initial cancer a subject experiences), a secondary cancer (referring to a metastasis from primary cancer or second cancer unrelated to the original cancer), an advanced cancer, an unresectable cancer, or a recurrent cancer. As used herein, an advanced cancer refers to a cancer that had progressed after receiving one or more of: the first line therapy, the second line therapy, or the third line therapy.

[0134] The term “contacting” means direct or indirect binding or interaction between two or more. A particular example of direct interaction is binding. A particular example of an indirect interaction is where one entity acts upon an intermediary molecule, which in turn acts upon the second referenced entity. Contacting as used herein includes in solution, in solid phase, in vitro, ex vivo, in a cell and in vivo. Contacting in vivo can be referred to as administering, or administration.

[0135] As used herein, the term “administration” and “administering” are used to mean introducing an agent into a subject. Routes of administration include, but are not limited to, oral (such as a tablet, capsule or suspension), topical, transdermal, intranasal, vaginal, rectal, subcutaneous intravenous, intravenous, intraarterial, intramuscular, intraosseous,294927-6853-2615.1Atty. Dkt. No. 109290-0190intraperitoneal, intraocular, subconjunctival, sub-Tenon’s, intravitreal, retrobulbar, intracam eral, intratumoral, epidural and intrathecal.

[0136] The term “cell” as used herein may refer to either a prokaryotic or an eukaryotic cell, optionally obtained from a subject or a commercially available source.

[0137] “ An inhibitor of thymidylate biosynthesis” means an inhibitor which directly or indirectly impacts the thymidylate biosynthesis pathway. Non-limiting examples of an inhibitor of thymidylate biosynthesis include thymidylate synthase inhibitors and inhibitors of folate-mediated one-carbon metabolism. Non-limiting examples include the fluoropyrimidines (e.g., 5-fluorouracil (5-FU) or 5-FU based adjuvant therapy, S-l, and capecitabine (Xeloda®)); and antifolates (e.g., pemetrexed (Alimta®) and methotrexate). Additional non-limiting examples include prodrug derivatives of inhibitors of thymidylate biosynthesis as well as formulations of inhibitors of thymidylate biosynthesis with modulatory co-factors.

[0138] “ dUTPase” means any of the following, which are considered to be synonymous, "deoxyuridine triphosphate nucleotidohydrolase", "deoxyuridine triphosphate pyrophosphatase", "dUTP nucleotidohydrolase", "dUTP pyrophosphatase", and other equivalent nomenclature for the dUTPase enzyme. In one aspect, dUTPase intends DUT-N and DUT-M. In other aspects, it is DUT-N only, or alternatively, DUT-M only. The amino acid and coding sequences for dUTPase are known in the art and disclosed in U.S. Patent No.5,962,246. Methods for expressing and screening for expression level of the enzyme are disclosed in U.S. Patent No. 5,962,246 and Ladner et al. (US Patent Publ. No.2011 / 0212467A1).

[0139] “DUT-N” means the nuclear form of dUTPase.

[0140] “DUT-M” means the mitochondrial or cytoplasmic form of dUTPase.

[0141] 5 -Fluorouracil (5-FU) belongs to the family of therapy drugs called pyrimidine based anti-metabolites. It is a pyrimidine analog, which is transformed into different cytotoxic metabolites that are then incorporated into DNA and RNA thereby inducing cell cycle arrest and apoptosis. Chemical equivalents are pyrimidine analogs which result in disruption of DNA replication. Chemical equivalents inhibit cell cycle progression at S phase resulting in the disruption of cell cycle and consequently apoptosis. Equivalents to 5-FU include prodrugs, analogs and derivative thereof such as 5'-deoxy-5-fluorouridine (doxifluoroidine), floxuridine (FUdR), l-tetrahydrofuranyl-5-fluorouracil (ftorafur),304927-6853-2615.1Atty. Dkt. No. 109290-0190capecitabine (Xeloda®), S-l (MBMS-247616, consisting of tegafur and two modulators, a 5-chloro-2,4-dihydroxypyridine and potassium oxonate), ralititrexed (tomudex), nolatrexed (Thymitaq, AG337), LY231514 and ZD9331, as described for example in Papamichael (1999) The Oncologist 4:478-487.

[0142] “5 -FU based adjuvant therapy” refers to 5-FU alone or alternatively the combination of 5-FU with one or more other treatments, that include, but are not limited to radiation, methyl-CCNU, leucovorin, a platinum agent (such as oxaliplatin, cisplatin, or carboplatin), irinotecan, mitomycin, cytarabine, doxorubicin, cyclophosphamide, and levamisole, as well as an immunotherapy. Specific treatment adjuvant regimens are known in the art such as weekly Fluorouracil / Leucovorin, weekly Fluorouracil / Leucovorin + Bevacizumab, FOLFOX, FOLFOX-4, FOLFOX6, modified FOLFOX6 (mFOLFOX6), FOLFOX6 with bevacizumab, mFOLFOX6 + Cetuximab, mFOLFOX6 + Panitumumab, modified FOLFOX7 (mFOLFOX7), FOLFIRI, FOLFIRI with Bevacizumab, FOLFIRI + Ziv-aflibercept, FOLFIRI with Cetuximab, FOLFIRI + Panitumumab, FOLFIRI + Ramucirumab, FOLFOXIRI, FOLFIRI with FOLFOX6, FOLFOXIRI + Bevacizumab, FOLFOXIRI + Cetuximab, FOLFOXIRI + Panitumumab, Roswell Park Fluorouracil / Leucovorin, Roswell Park Fluorouracil / Leucovorin + Bevacizumab, Simplified Biweekly Infusional Fluorouracil / Leucovorin, Simplified Biweekly Infusional Fluorouracil / Leucovorin + Bevacizumab, and MOF (semustine (methyl-CCNU), vincrisine (Oncovin®) and 5-FU). For a review of these therapies see Beaven and Goldberg (2006) Oncology 20(5):461-470 as well as www.cancertherapyadvisor.com / home / cancer-topics / gastrointestinal-cancers / gastrointestinal-cancers-treatment-regimens / colon-cancer-treatment-regimens / .Other chemotherapeutics can be added, e.g., oxaliplatin or irinotecan.

[0143] Capecitabine is a prodrug of (5-FU) that is converted to its active form by the tumor-specific enzyme PynPase following a pathway of three enzymatic steps and two intermediary metabolites, 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-deoxy-5-fluorouridine (5'-DFUR). Capecitabine is marketed by Roche under the trade name Xeloda®.

[0144] Leucovorin (Folinic acid) is an adjuvant used in cancer therapy. It is used in synergistic combination with 5-FU to improve efficacy of the chemotherapeutic agent.Without being bound by theory, addition of Leucovorin is believed to enhance efficacy of 5-FU by inhibiting thymidylate synthase. It has been used as an antidote to protect normal cells from high doses of the anticancer drug methotrexate and to increase the antitumor effects of fluorouracil (5-FU) and tegafur-uracil. It is also known as citrovorum factor and Wellcovorin.314927-6853-2615.1Atty. Dkt. No. 109290-0190This compound has the chemical designation of L-Glutamic acid N-[4-[[(2-amino-5-formyl-l,4,5,6,7,8-hexahydro-4-oxo-6-pteridinyl)methyl]amino]benzoyl], calcium salt (1:1).

[0145] “Oxaliplatin” (Eloxatin) is a platinum-based chemotherapy drug in the same family as cisplatin and carboplatin. It is typically administered in combination with fluorouracil and leucovorin in a combination known as FOLFOX for the treatment of colorectal cancer.Compared to cisplatin, the two amine groups are replaced by cyclohexyldiamine for improved antitumor activity. The chlorine ligands are replaced by the oxalato bidentate derived from oxalic acid in order to improve water solubility. Equivalents to Oxaliplatin are known in the art and include, but are not limited to cisplatin, carboplatin, aroplatin, lobaplatin, nedaplatin, and JM-216 (see McKeage et al. (1997) J. Clin. Oncol. 201:1232-1237 and in general, Chemotherapy for Gynecological Neoplasm, Curr. Therapy and Novel Approaches, in the Series Basic and Clinical Oncology, Angioli et al. Eds., 2004).

[0146] “FOLFOX” is an abbreviation for a type of combination therapy that is used to treat cancer. This therapy includes leucovorin ("FOL"), 5-FU ("F"), and oxaliplatin ("OX") and encompasses various regimens, such as FOLFOX-4, FOLFOX-6, modified FOLOX-6, and FOLFOX-7, which vary in doses and ways in which each of the three drugs are administered. "FOLFIRI" is an abbreviation for a type of combination therapy that is used treat cancer and comprises, or alternatively consists essentially of, or yet further consists of 5-FU, leucovorin, and irinotecan. Information regarding these treatments are available on the National Cancer Institute's web site, cancer.gov, last accessed on May 30, 2020 as well as www.cancertherapyadvisor.com / home / cancer-topics / gastrointestinal-cancers / gastrointestinal-cancers-treatment-regimens / colon-cancer-treatment-regimens / , last accessed on May 30, 2020.

[0147] Irinotecan (CPT-11) is sold under the trade name of Camptosar. It is a semisynthetic analogue of the alkaloid camptothecin, which is activated by hydrolysis to SN-38 and targets topoisomerase I. Chemical equivalents are those that inhibit the interaction of topoisomerase I and DNA to form a catalytically active topoisomerase LDNA complex. Chemical equivalents inhibit cell cycle progression at G2-M phase resulting in the disruption of cell proliferation.

[0148] S-l consists of three agents (at a molar ratio of 1:0.4:1): tegafur, 5-chloro-2-4-dihydroxypyridine, and potassium oxonate.324927-6853-2615.1Atty. Dkt. No. 109290-0190

[0149] The term “adjuvant” therapy refers to administration of a therapy or chemotherapeutic regimen to a patient in addition to the primary or initial treatment, such as after removal of a tumor by surgery. Adjuvant therapy is typically given to minimize or prevent a possible cancer reoccurrence. Alternatively, “neoadjuvant” therapy refers to administration of therapy or chemotherapeutic regimen before surgery, typically in an attempt to shrink the tumor prior to a surgical procedure to minimize the extent of tissue removed during the procedure. Additionally or alternatively, such adjuvant therapy potentials (i.e., sensitizes the subject to the original therapy) the subject may help reach one or more of clinical end points of the cancer treatment.

[0150] The phrase “first line” or “second line” or “third line” etc., refers to the order of treatment received by a patient. First line therapy regimens are treatments given first, whereas second or third line therapy are given after the first line therapy or after the second line therapy, respectively. The National Cancer Institute defines first line therapy as “the first treatment for a disease or condition. In patients with cancer, primary treatment can be surgery, chemotherapy, radiation therapy, or a combination of these therapies. First line therapy is also referred to those skilled in the art as primary therapy and primary treatment." See National Cancer Institute website as www.cancer.gov, last visited on May 1, 2008.Typically, a patient is given a subsequent chemotherapy regimen because the patient did not shown a positive clinical or sub-clinical response to the first line therapy or the first line therapy has stopped.

[0151] As used herein, the term “antifolate” intends a drug or biologic that impairs the function of folic acids, e.g., an antimetabolite agent that inhibits the use of a metabolite, i.e. another chemical that is part of normal metabolism. In cancer treatment, antimetabolites interfere with DNA production, thus cell division and growth of the tumor. Non-limiting examples of these agents are dihydrofolate reductase inhibitors, such as methotrexate, Aminopterin, and Pemetrexed; thymidylate synthase inhibitors, such as Raltitrexed or Pemetrexed; purine based, i.e. an adenosine deaminase inhibitor, such as Pentostatin, a thiopurine, such as Thioguanine and Mercaptopurine, a halogenated / ribonucleotide reductase inhibitor, such as Cladribine, Clofarabine, Fludarabine, or a guanine / guanosine: thiopurine, such as Thioguanine; or Pyrimidine based, i.e. cytosine / cytidine: hypomethylating agent, such as Azacitidine and Decitabine, a DNA polymerase inhibitor, such as Cytarabine, a ribonucleotide reductase inhibitor, such as Gemcitabine, or a thymine / thymidine: thymidylate synthase inhibitor, such as a Fluorouracil (5-FU).334927-6853-2615.1Atty. Dkt. No. 109290-0190

[0152] In one aspect, the term "chemical equivalent" means the ability of the chemical to selectively interact with its target protein, DNA, RNA or fragment thereof as measured by the inactivation of the target protein, incorporation of the chemical into the DNA or RNA or other suitable methods. Chemical equivalents include, but are not limited to, those agents with the same or similar biological activity and include, without limitation a pharmaceutically acceptable salt or mixtures thereof that interact with and / or inactivate the same target protein, DNA, or RNA as the reference chemical.

[0153] When a genetic marker, e.g., over-expression of dUTPase, is used as a basis for selecting a patient for a treatment described herein, the genetic marker is measured before and / or during treatment, and the values obtained are used by a clinician in assessing any of the following: (a) probable or likely suitability of an individual to initially receive treatment s); (b) probable or likely unsuitability of an individual to initially receive treatment(s); (c) responsiveness to treatment; (d) probable or likely suitability of an individual to continue to receive treatment(s); (e) probable or likely unsuitability of an individual to continue to receive treatment(s); (f) adjusting dosage; (g) predicting likelihood of clinical benefits; or (h) toxicity. As would be well understood by one in the art, measurement of the genetic marker in a clinical setting is a clear indication that this parameter was used as a basis for initiating, continuing, adjusting and / or ceasing administration of the treatments described herein.Poly (ADP-ribose) polymerase (PARP)

[0154] Poly (ADP-ribose) polymerases are involved in various cellular processes, including stress response, chromatin remodeling, DNA repair, and apoptosis. Because PARP inhibitors prevent PARP-associated DNA repair (e.g., single-strand break repair), cancers with existing DNA repair defects (e.g., HR-deficiency or BRCA 1 / 2 mutations) are susceptible to treatment with PARP inhibition. Such cancers include certain types of ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, fallopian tube cancer, and primary peritoneal cancer. However, PARP inhibitors are poorly effective against cancers without existing HR-deficiency or BRCA 1 / 2 DNA repair defects (such as, but limited to, colorectal adenocarcinoma, non-small cell lung cancer (NSCLC), gastric adenocarcinoma / gastroesophageal junction cancer and esophageal carcinoma).

[0155] The inventors of the present technology surprisingly discovered methods to treat cancer, regardless of existing DNA repair defects, by combining administration of a PARP344927-6853-2615.1Atty. Dkt. No. 109290-0190inhibitor with a deoxyuridine triphosphatase (dUTPase) inhibitor, and an inhibitor of thymidylate biosynthesis.Methods

[0156] In one aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject a poly (ADP-ribose) polymerase (PARP) inhibitor, a deoxyuridine triphosphatase (dUTPase) inhibitor, and an inhibitor of thymidylate biosynthesis.

[0157] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject an effective amount of a poly (ADP-ribose) polymerase (PARP) inhibitor, an effective amount of a deoxyuridine triphosphatase (dUTPase) inhibitor, and an effective amount of an inhibitor of thymidylate biosynthesis. In some embodiments, each of the effective amounts is a therapeutically effective amount.

[0158] In another aspect, provided herein is a poly (ADP-ribose) polymerase (PARP) inhibitor, a deoxyuridine triphosphatase (dUTPase) inhibitor, and an inhibitor of thymidylate biosynthesis for use in treating cancer. In another aspect, provided herein is a combination of a poly (ADP-ribose) polymerase (PARP) inhibitor, a deoxyuridine triphosphatase (dUTPase) inhibitor, and an inhibitor of thymidylate biosynthesis for use in treating cancer.

[0159] In another aspect, provided herein is a use of a poly (ADP-ribose) polymerase (PARP) inhibitor, a deoxyuridine triphosphatase (dUTPase) inhibitor, and an inhibitor of thymidylate biosynthesis in the manufacture of a medicament for the treatment of cancer. In another aspect, provided herein is a use of a combination of a poly (ADP-ribose) polymerase (PARP) inhibitor, a deoxyuridine triphosphatase (dUTPase) inhibitor, and an inhibitor of thymidylate biosynthesis in the manufacture of a medicament for the treatment of cancer.

[0160] In some embodiments, the subject after treatment experiences one or more clinical endpoints as disclosed herein. In some embodiments, the endpoints are selected from tumor response, reduction in tumor size, reduction in tumor burden, increase in overall survival, increase in progression free survival, and inhibiting metastasis.

[0161] In some embodiments, the cancer is selected from cancers of the: circulatory system, for example, heart (sarcoma [angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma], myxoma, rhabdomyoma, fibroma, lipoma and teratoma), mediastinum and pleura, and other intrathoracic organs, vascular tumors and tumor-associated vascular tissue; respiratory tract,354927-6853-2615.1Atty. Dkt. No. 109290-0190for example, nasal cavity and middle ear, accessory sinuses, larynx, trachea, bronchus and lung such as small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal system, for example, esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), gastric, pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); gastrointestinal stromal tumors and neuroendocrine tumors arising at any site; genitourinary tract, for example, kidney (adenocarcinoma, Wilm's tumor [nephroblastoma], lymphoma, leukemia), bladder and / or urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); liver, for example, hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, pancreatic endocrine tumors (such as pheochromocytoma, insulinoma, vasoactive intestinal peptide tumor, islet cell tumor and glucagonoma); bone, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; nervous system, for example, neoplasms of the central nervous system (CNS), primary CNS lymphoma, skull cancer (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); reproductive system, for example, gynecological, uterus (endometrial carcinoma), cervix (cervical carcinoma, pre- tumor cervical dysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,364927-6853-2615.1Atty. Dkt. No. 109290-0190intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma) and other sites associated with female genital organs; placenta, penis, prostate, testis, and other sites associated with male genital organs; hematologic system, for example, blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; oral cavity, for example, lip, tongue, gum, floor of mouth, palate, and other parts of mouth, parotid gland, and other parts of the salivary glands, tonsil, oropharynx, nasopharynx, pyriform sinus, hypopharynx, and other sites in the lip, oral cavity and pharynx; skin, for example, malignant melanoma, cutaneous melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, and keloids; and other tissues comprising connective and soft tissue, retroperitoneum and peritoneum, eye, intraocular melanoma, and adnexa, breast, head or / and neck, anal region, thyroid, parathyroid, adrenal gland and other endocrine glands and related structures, secondary and unspecified malignant neoplasm of lymph nodes, secondary malignant neoplasm of respiratory and digestive systems and secondary malignant neoplasm of other sites. In some embodiments, the cancer is selected from the group of cancers: a cancer of the circulatory system; a cancer of the respiratory system; a cancer of the gastrointestinal system; a cancer of the genitourinary system; a liver cancer; a cancer of the bone; a cancer of the nervous system; a cancer of the hematologic system; a cancer of skin or tissues comprising connective or soft tissue; a cancer of the retroperitoneum or peritoneum; an eye cancer; a breast cancer; a cancer of the head or / and neck; a thyroid cancer; a parathyroid cancer; a cancer of the adrenal gland; a cancer of the endocrine glands; and a cancer of the lymph nodes. In some embodiments, the cancer is colon cancer, gastric cancer, breast cancer, lung cancer, pancreatic cancer, head and / or neck cancer, or esophageal cancer. Additionally or alternatively, the cancer is a solid tumor or a liquid cancer. In some embodiments, the cancer is a primary cancer. In another embodiment, the cancer is a metastasis.

[0162] In some embodiments, the cancer comprises, consists essentially of, or consists of a carcinoma, a sarcoma, a myeloma, a leukemia, or a lymphoma. In some embodiments, the cancer comprises, consists essentially of, or consists of a carcinoma. In some embodiments, the cancer comprises, consists essentially of, or consists of a sarcoma. In some embodiments,374927-6853-2615.1Atty. Dkt. No. 109290-0190the cancer comprises, consists essentially of, or consists of a myeloma. In some embodiments, the cancer comprises, consists essentially of, or consists of a leukemia. In some embodiments, the cancer comprises, consists essentially of, or consists of a lymphoma.

[0163] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject talazoparib, olaparib, niraparib, or rucaparib; Compound A or Compound B; and FUdR. In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject an effective amount of talazoparib, olaparib, niraparib, or rucaparib; an effective amount of Compound A or Compound B; and an effective amount of FUdR. In some embodiments, the cancer is colorectal cancer, lung cancer, or breast cancer. In some embodiments, each of the effective amounts is a therapeutically effective amount.

[0164] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject talazoparib; Compound A or Compound B; and FUdR. In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject an effective amount of talazoparib, an effective amount of Compound A or Compound B, and an effective amount of FUdR. In some embodiments, the cancer is colorectal cancer, lung cancer, or breast cancer. In some embodiments, each of the effective amounts is a therapeutically effective amount.

[0165] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject olaparib; Compound A or Compound B; and FUdR. In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject an effective amount of olaparib, an effective amount of Compound A or Compound B, and an effective amount of FUdR. In some embodiments, the cancer is colorectal cancer, lung cancer, or breast cancer. In some embodiments, each of the effective amounts is a therapeutically effective amount.

[0166] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject niraparib; Compound A or Compound B; and FUdR. In another aspect, provided384927-6853-2615.1Atty. Dkt. No. 109290-0190herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject an effective amount of niraparib, an effective amount of Compound A or Compound B, and an effective amount of FUdR. In some embodiments, the cancer is colorectal cancer, lung cancer, or breast cancer. In some embodiments, each of the effective amounts is a therapeutically effective amount.

[0167] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject rucaparib; Compound A or Compound B; and FUdR. In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject an effective amount of rucaparib, an effective amount of Compound A or Compound B, and an effective amount of FUdR. In some embodiments, the cancer is colorectal cancer, lung cancer, or breast cancer. In some embodiments, each of the effective amounts is a therapeutically effective amount.

[0168] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject talazoparib, olaparib, niraparib, or rucaparib; Compound A or Compound B; and 5-FU. In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject an effective amount of talazoparib, olaparib, niraparib, or rucaparib; an effective amount of Compound A or Compound B; and an effective amount of 5-FU. In some embodiments, the cancer is colorectal cancer, lung cancer, or breast cancer. In some embodiments, each of the effective amounts is a therapeutically effective amount.

[0169] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject talazoparib; Compound A or Compound B; and 5-FU. In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject an effective amount of talazoparib, an effective amount of Compound A or Compound B, and an effective amount of 5-FU. In some embodiments, the cancer is colorectal cancer, lung cancer, or breast cancer. In some embodiments, each of the effective amounts is a therapeutically effective amount.

[0170] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to394927-6853-2615.1Atty. Dkt. No. 109290-0190the subject olaparib; Compound A or Compound B; and 5-FU. In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject an effective amount of olaparib, an effective amount of Compound A or Compound B, and an effective amount of 5-FU. In some embodiments, the cancer is colorectal cancer, lung cancer, or breast cancer. In some embodiments, each of the effective amounts is a therapeutically effective amount.

[0171] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject niraparib; Compound A or Compound B; and 5-FU. In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject an effective amount of niraparib, an effective amount of Compound A or Compound B, and an effective amount of 5-FU. In some embodiments, the cancer is colorectal cancer, lung cancer, or breast cancer. In some embodiments, each of the effective amounts is a therapeutically effective amount.

[0172] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject rucaparib; Compound A or Compound B; and 5-FU. In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject an effective amount of rucaparib, an effective amount of Compound A or Compound B, and an effective amount of 5-FU. In some embodiments, the cancer is colorectal cancer, lung cancer, or breast cancer. In some embodiments, each of the effective amounts is a therapeutically effective amount.

[0173] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject talazoparib, olaparib, niraparib, or rucaparib; Compound A or Compound B; and capecitabine. In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject an effective amount of talazoparib, olaparib, niraparib, or rucaparib; an effective amount of Compound A or Compound B; and an effective amount of capecitabine. In some embodiments, the cancer is colorectal cancer, lung cancer, or breast cancer. In some embodiments, each of the effective amounts is a therapeutically effective amount.404927-6853-2615.1Atty. Dkt. No. 109290-0190

[0174] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject talazoparib; Compound A or Compound B; and capecitabine. In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject an effective amount of talazoparib, an effective amount of Compound A or Compound B, and an effective amount of capecitabine. In some embodiments, the cancer is colorectal cancer, lung cancer, or breast cancer. In some embodiments, each of the effective amounts is a therapeutically effective amount.

[0175] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject olaparib; Compound A or Compound B; and capecitabine. In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject an effective amount of olaparib, an effective amount of Compound A or Compound B, and an effective amount of capecitabine. In some embodiments, the cancer is colorectal cancer, lung cancer, or breast cancer. In some embodiments, each of the effective amounts is a therapeutically effective amount.

[0176] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject niraparib; Compound A or Compound B; and capecitabine. In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject an effective amount of niraparib, an effective amount of Compound A or Compound B, and an effective amount of capecitabine. In some embodiments, the cancer is colorectal cancer, lung cancer, or breast cancer. In some embodiments, each of the effective amounts is a therapeutically effective amount.

[0177] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject rucaparib; Compound A or Compound B; and capecitabine. In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject an effective amount of rucaparib, an effective amount of Compound A or Compound B, and an effective 414927-6853-2615.1Atty. Dkt. No. 109290-0190amount of capecitabine. In some embodiments, the cancer is colorectal cancer, lung cancer, or breast cancer. In some embodiments, each of the effective amounts is a therapeutically effective amount.

[0178] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject talazoparib, olaparib, niraparib, or rucaparib; Compound A or Compound B; and pemetrexed. In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject an effective amount of talazoparib, olaparib, niraparib, or rucaparib; an effective amount of Compound A or Compound B; and an effective amount of pemetrexed. In some embodiments, the cancer is colorectal cancer, lung cancer, or breast cancer. In some embodiments, each of the effective amounts is a therapeutically effective amount.

[0179] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject talazoparib; Compound A or Compound B; and pemetrexed. In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject an effective amount of talazoparib, an effective amount of Compound A or Compound B, and an effective amount of pemetrexed. In some embodiments, the cancer is colorectal cancer, lung cancer, or breast cancer. In some embodiments, each of the effective amounts is a therapeutically effective amount.

[0180] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject olaparib; Compound A or Compound B; and pemetrexed. In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject an effective amount of olaparib, an effective amount of Compound A or Compound B, and an effective amount of pemetrexed. In some embodiments, the cancer is colorectal cancer, lung cancer, or breast cancer. In some embodiments, each of the effective amounts is a therapeutically effective amount.

[0181] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to424927-6853-2615.1Atty. Dkt. No. 109290-0190the subject niraparib; Compound A or Compound B; and pemetrexed. In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject an effective amount of niraparib, an effective amount of Compound A or Compound B, and an effective amount of pemetrexed. In some embodiments, the cancer is colorectal cancer, lung cancer, or breast cancer. In some embodiments, each of the effective amounts is a therapeutically effective amount.

[0182] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject rucaparib; Compound A or Compound B; and pemetrexed. In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject an effective amount of rucaparib, an effective amount of Compound A or Compound B, and an effective amount of pemetrexed. In some embodiments, the cancer is colorectal cancer, lung cancer, or breast cancer. In some embodiments, each of the effective amounts is a therapeutically effective amount.

[0183] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject talazoparib, olaparib, niraparib, or rucaparib; Compound A or Compound B; and methotrexate. In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject an effective amount of talazoparib, olaparib, niraparib, or rucaparib; an effective amount of Compound A or Compound B; and an effective amount of methotrexate. In some embodiments, the cancer is colorectal cancer, lung cancer, or breast cancer. In some embodiments, each of the effective amounts is a therapeutically effective amount.

[0184] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject talazoparib; Compound A or Compound B; and methotrexate. In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject an effective amount of talazoparib, an effective amount of Compound A or Compound B, and an effective amount of methotrexate. In some embodiments, the cancer is colorectal cancer, lung cancer,434927-6853-2615.1Atty. Dkt. No. 109290-0190or breast cancer. In some embodiments, each of the effective amounts is a therapeutically effective amount.

[0185] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject olaparib; Compound A or Compound B; and methotrexate. In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject an effective amount of olaparib, an effective amount of Compound A or Compound B, and an effective amount of methotrexate. In some embodiments, the cancer is colorectal cancer, lung cancer, or breast cancer. In some embodiments, each of the effective amounts is a therapeutically effective amount.

[0186] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject niraparib; Compound A or Compound B; and methotrexate. In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject an effective amount of niraparib, an effective amount of Compound A or Compound B, and an effective amount of methotrexate. In some embodiments, the cancer is colorectal cancer, lung cancer, or breast cancer. In some embodiments, each of the effective amounts is a therapeutically effective amount.

[0187] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject rucaparib; Compound A or Compound B; and methotrexate. In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject an effective amount of rucaparib, an effective amount of Compound A or Compound B, and an effective amount of methotrexate. In some embodiments, the cancer is colorectal cancer, lung cancer, or breast cancer. In some embodiments, each of the effective amounts is a therapeutically effective amount.

[0188] In another aspect, provided herein is a method of inhibiting growth of a cancer cell, the method comprising, consisting essentially of, or consisting of contacting the cell with a PARP inhibitor, a dUTPase inhibitor, and an inhibitor of thymidylate biosynthesis. In another444927-6853-2615.1Atty. Dkt. No. 109290-0190aspect, provided herein is a method of inhibiting growth of a cancer cell, the method comprising, consisting essentially of, or consisting of contacting the cell with an effective amount of a PARP inhibitor, an effective amount of a dUTPase inhibitor, and an effective amount of an inhibitor of thymidylate biosynthesis. In some embodiments, the contacting occurs in vitro. In some embodiments, the contacting occurs in vivo.

[0189] In another aspect, provided herein is a method of inhibiting growth of a cancer cell, the method comprising, consisting essentially of, or consisting of contacting the cell with talazoparib, olaparib, niraparib, or rucaparib; Compound A or Compound B; and FUdR. In another aspect, provided herein is a method of inhibiting growth of a cancer cell, the method comprising, consisting essentially of, or consisting of contacting the cell with an effective amount of talazoparib, olaparib, niraparib, or rucaparib; an effective amount of Compound A or Compound B; and an effective amount of FUdR.

[0190] In another aspect, provided herein is a method of inhibiting growth of a cancer cell, the method comprising, consisting essentially of, or consisting of contacting the cell with talazoparib, olaparib, niraparib, or rucaparib; Compound A or Compound B; and 5-FU. In another aspect, provided herein is a method of inhibiting growth of a cancer cell, the method comprising, consisting essentially of, or consisting of contacting the cell with an effective amount of talazoparib, olaparib, niraparib, or rucaparib; an effective amount of Compound A or Compound B; and an effective amount of 5-FU.

[0191] In another aspect, provided herein is a method of inhibiting growth of a cancer cell, the method comprising, consisting essentially of, or consisting of contacting the cell with talazoparib, olaparib, niraparib, or rucaparib; Compound A or Compound B; and capecitabine. In another aspect, provided herein is a method of inhibiting growth of a cancer cell, the method comprising, consisting essentially of, or consisting of contacting the cell with an effective amount of talazoparib, olaparib, niraparib, or rucaparib; an effective amount of Compound A or Compound B; and an effective amount of capecitabine.

[0192] In another aspect, provided herein is a method of inhibiting growth of a cancer cell, the method comprising, consisting essentially of, or consisting of contacting the cell with talazoparib, olaparib, niraparib, or rucaparib; Compound A or Compound B; and pemetrexed. In another aspect, provided herein is a method of inhibiting growth of a cancer cell, the method comprising, consisting essentially of, or consisting of contacting the cell with an454927-6853-2615.1Atty. Dkt. No. 109290-0190effective amount of talazoparib, olaparib, niraparib, or rucaparib; an effective amount of Compound A or Compound B; and an effective amount of pemetrexed.

[0193] In another aspect, provided herein is a method of inhibiting growth of a cancer cell, the method comprising, consisting essentially of, or consisting of contacting the cell with talazoparib, olaparib, niraparib, or rucaparib; Compound A or Compound B; and methotrexate. In another aspect, provided herein is a method of inhibiting growth of a cancer cell, the method comprising, consisting essentially of, or consisting of contacting the cell with an effective amount of talazoparib, olaparib, niraparib, or rucaparib; an effective amount of Compound A or Compound B; and an effective amount of methotrexate.

[0194] In some embodiments, the cancer cell is a primary cell isolated from a biopsy or cultured cancer cell that is cultured in the lab or obtained from a commercial vendor such as the American Type Culture Collection (ATCC), or a cancer cell in an animal model for evaluating therapeutic efficacy of potential therapies.

[0195] In some embodiments, inhibition of growth of the cancer cell is measured by comparing growth of a cancer cell after contacting the cell with the PARP inhibitor, the dUTPase inhibitor, and the inhibitor of thymidylate biosynthesis with growth of a cancer cell without any such contact (i.e., growth of a control sample). Methods and assays for detecting and / or quantifying the growth are known to one skilled in the art.

[0196] In some embodiments, the cancer cell is a cell of a cancer selected from cancers of the: circulatory system, for example, heart (sarcoma [angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma], myxoma, rhabdomyoma, fibroma, lipoma and teratoma), mediastinum and pleura, and other intrathoracic organs, vascular tumors and tumor-associated vascular tissue; respiratory tract, for example, nasal cavity and middle ear, accessory sinuses, larynx, trachea, bronchus and lung such as small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal system, for example, esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), gastric, pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large464927-6853-2615.1Atty. Dkt. No. 109290-0190bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); gastrointestinal stromal tumors and neuroendocrine tumors arising at any site; genitourinary tract, for example, kidney (adenocarcinoma, Wilm's tumor [nephroblastoma], lymphoma, leukemia), bladder and / or urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); liver, for example, hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, pancreatic endocrine tumors (such as pheochromocytoma, insulinoma, vasoactive intestinal peptide tumor, islet cell tumor and glucagonoma); bone, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; nervous system, for example, neoplasms of the central nervous system (CNS), primary CNS lymphoma, skull cancer (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); reproductive system, for example, gynecological, uterus (endometrial carcinoma), cervix (cervical carcinoma, pre- tumor cervical dysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma) and other sites associated with female genital organs; placenta, penis, prostate, testis, and other sites associated with male genital organs; hematologic system, for example, blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; oral cavity, for example, lip, tongue, gum, floor of mouth, palate, and other parts of mouth, parotid gland, and other parts of the salivary glands, tonsil, oropharynx, nasopharynx, pyriform sinus,474927-6853-2615.1Atty. Dkt. No. 109290-0190hypopharynx, and other sites in the lip, oral cavity and pharynx; skin, for example, malignant melanoma, cutaneous melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, and keloids; and other tissues comprising connective and soft tissue, retroperitoneum and peritoneum, eye, intraocular melanoma, and adnexa, breast, head or / and neck, anal region, thyroid, parathyroid, adrenal gland and other endocrine glands and related structures, secondary and unspecified malignant neoplasm of lymph nodes, secondary malignant neoplasm of respiratory and digestive systems and secondary malignant neoplasm of other sites. In some embodiments, the cancer cell is from a cancer selected from the group of cancers: a cancer of the circulatory system; a cancer of the respiratory system; a cancer of the gastrointestinal system; a cancer of the genitourinary system; a liver cancer; a cancer of the bone; a cancer of the nervous system; a cancer of the hematologic system; a cancer of skin or tissues comprising connective or soft tissue; a cancer of the retroperitoneum or peritoneum; an eye cancer; a breast cancer; a cancer of the head or / and neck; a thyroid cancer; a parathyroid cancer; a cancer of the adrenal gland; a cancer of the endocrine glands; and lymph nodes. Additionally or alternatively, the cancer is a solid tumor or a liquid cancer. In some embodiments, the cancer is a primary cancer. In another embodiment, the cancer is a metastasis.

[0197] In some embodiments, the cancer cell is from a carcinoma, a sarcoma, a myeloma, a leukemia, or a lymphoma. In some embodiments, the cancer cell is from a carcinoma. In some embodiments, the cancer cell is from a sarcoma. In some embodiments, the cancer cell is from a myeloma. In some embodiments, the cancer cell is from a leukemia. In some embodiments, the cancer cell is from a lymphoma.

[0198] In some embodiments, any method or steps / embodiments of a method as disclosed herein may be further combined with another anti-cancer therapy, such as chemotherapy other than those specified herein, radiation therapy, surgery and others. Other combined therapy may include but not limited to: oncolytic virus infecting and killing a cancer cell (such as an oncolytic HSV), an antisense oligonucleotide (ASO) killing or damaging a cancer cell, a RNA interference (RNAi) killing or damaging a cancer cell, a Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) system killing or damaging a cancer cell, an exosome killing or damaging a cancer cell, and a vector delivering each thereof.

[0199] In another aspect, provided herein is a method of enhancing a therapeutic efficacy of a PARP inhibitor in a subject in need thereof, the method comprising, consisting essentially 484927-6853-2615.1Atty. Dkt. No. 109290-0190of, or consisting of administering to the subject an effective amount of the PARP inhibitor with an effective amount of a dUTPase inhibitor and an effective amount of an inhibitor of thymidylate biosynthesis.

[0200] In another aspect, provided herein is a method of enhancing a therapeutic efficacy of a PARP inhibitor in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject an effective amount of the PARP inhibitor with an effective amount of Compound A or Compound B; and an effective amount of FUdR; wherein the PARP inhibitor is selected from the group consisting of talazoparib, olaparib, niraparib, rucaparib, and a combination of two or more thereof.

[0201] In another aspect, provided herein is a method of enhancing a therapeutic efficacy of a PARP inhibitor in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject an effective amount of the PARP inhibitor with an effective amount of Compound A or Compound B; and an effective amount of 5-FU; wherein the PARP inhibitor is selected from the group consisting of talazoparib, olaparib, niraparib, rucaparib, and a combination of two or more thereof.

[0202] In another aspect, provided herein is a method of enhancing a therapeutic efficacy of a PARP inhibitor in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject an effective amount of the PARP inhibitor with an effective amount of Compound A or Compound B; and an effective amount of capecitabine; wherein the PARP inhibitor is selected from the group consisting of talazoparib, olaparib, niraparib, rucaparib, and a combination of two or more thereof.

[0203] In another aspect, provided herein is a method of enhancing a therapeutic efficacy of a PARP inhibitor in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject an effective amount of the PARP inhibitor with an effective amount of Compound A or Compound B; and an effective amount of pemetrexed; wherein the PARP inhibitor is selected from the group consisting of talazoparib, olaparib, niraparib, rucaparib, and a combination of two or more thereof.

[0204] In another aspect, provided herein is a method of enhancing a therapeutic efficacy of a PARP inhibitor in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject an effective amount of the PARP inhibitor with an effective amount of Compound A or Compound B; and an effective amount of494927-6853-2615.1Atty. Dkt. No. 109290-0190methotrexate; wherein the PARP inhibitor is selected from the group consisting of talazoparib, olaparib, niraparib, rucaparib, and a combination of two or more thereof.

[0205] In another aspect, provided herein is a method of enhancing a therapeutic efficacy of a combination of a dUTPase inhibitor and an inhibitor of thymidylate biosynthesis in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject an effective amount of the combination with an effective amount of a PARP inhibitor.

[0206] In another aspect, provided herein is a method of enhancing a therapeutic efficacy of a combination of a dUTPase inhibitor and an inhibitor of thymidylate biosynthesis in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject an effective amount of the combination with an effective amount of a PARP inhibitor selected from the group consisting of talazoparib, olaparib, niraparib, rucaparib, and a combination of two or more thereof; wherein the dUTPase inhibitor is Compound A or Compound B, and the inhibitor of thymidylate biosynthesis is FUdR.

[0207] In another aspect, provided herein is a method of enhancing a therapeutic efficacy of a combination of a dUTPase inhibitor and an inhibitor of thymidylate biosynthesis in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject an effective amount of the combination with an effective amount of a PARP inhibitor selected from the group consisting of talazoparib, olaparib, niraparib, rucaparib, and a combination of two or more thereof; wherein the dUTPase inhibitor is Compound A or Compound B, and the inhibitor of thymidylate biosynthesis is 5-FU.

[0208] In another aspect, provided herein is a method of enhancing a therapeutic efficacy of a combination of a dUTPase inhibitor and an inhibitor of thymidylate biosynthesis in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject an effective amount of the combination with an effective amount of a PARP inhibitor selected from the group consisting of talazoparib, olaparib, niraparib, rucaparib, and a combination of two or more thereof; wherein the dUTPase inhibitor is Compound A or Compound B, and the inhibitor of thymidylate biosynthesis is capecitabine.

[0209] In another aspect, provided herein is a method of enhancing a therapeutic efficacy of a combination of a dUTPase inhibitor and an inhibitor of thymidylate biosynthesis in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject an effective amount of the combination with an effective amount504927-6853-2615.1Atty. Dkt. No. 109290-0190of a PARP inhibitor selected from the group consisting of talazoparib, olaparib, niraparib, rucaparib, and a combination of two or more thereof; wherein the dUTPase inhibitor is Compound A or Compound B, and the inhibitor of thymidylate biosynthesis is pemetrexed.

[0210] In another aspect, provided herein is a method of enhancing a therapeutic efficacy of a combination of a dUTPase inhibitor and an inhibitor of thymidylate biosynthesis in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject an effective amount of the combination with an effective amount of a PARP inhibitor selected from the group consisting of talazoparib, olaparib, niraparib, rucaparib, and a combination of two or more thereof; wherein the dUTPase inhibitor is Compound A or Compound B, and the inhibitor of thymidylate biosynthesis is methotrexate.

[0211] In another aspect, provided herein is a method of enhancing a therapeutic efficacy of a dUTPase inhibitor in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject an effective amount of the dUTPase inhibitor with an effective amount of a PARP inhibitor and an effective amount of an inhibitor of thymidylate biosynthesis.

[0212] In another aspect, provided herein is a method of enhancing a therapeutic efficacy of an inhibitor of thymidylate biosynthesis in a subject in need thereof, the method comprising, consisting essentially of, or consisting of administering to the subject an effective amount of the inhibitor of thymidylate biosynthesis with an effective amount of a dUTPase inhibitor and an effective amount of an inhibitor of a PARP inhibitor.

[0213] In some embodiments, the therapeutic efficacy of the PARP inhibitor, the dUTPase inhibitor, the inhibitor of thymidylate biosynthesis, or the combination of the dUTPase inhibitor and the inhibitor of thymidylate biosynthesis is enhanced by at least about 10%, or alternatively at least about 20%, or alternatively at least about 30%, or alternatively at least about 40%, or alternatively at least about 50%, or alternatively at least about 60%, or alternatively at least about 70%, or alternatively at least about 80%, or alternatively at least about 90%, or alternatively at least about 1-fold, or alternatively at least about 1.1 -fold, or alternatively at least about 1.2-fold, or alternatively at least about 1.3-fold, or alternatively at least about 1.4-fold, or alternatively at least about 1.5-fold, or alternatively at least about 1.6-fold, or alternatively at least about 1.7-fold, or alternatively at least about 1.8-fold, or alternatively at least about 1.9-fold, or alternatively at least about 2-fold versus administration of the PARP inhibitor, the dUTPase inhibitor, the inhibitor of thymidylate biosynthesis, or the514927-6853-2615.1Atty. Dkt. No. 109290-0190combination of the dUTPase inhibitor and the inhibitor of thymidylate biosynthesis without the enhancement. This also includes 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-, 18-, 19-, 20-, 25-, 30-, 35-, 40-, 45-, 50-, 55-, 60-, 65-, 70-, 75-, 80-, 85-, 90-, 95-, or 100-fold or more, including increments therein, of enhancement of therapeutic efficacy of the PARP inhibitor versus administration of the PARP inhibitor as monotherapy. This also includes 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-, 18-, 19-, 20-, 25-, 30-, 35-, 40-, 45-, 50-, 55-, 60-, 65-, 70-, 75-, 80-, 85-, 90-, 95-, or 100-fold or more, including increments therein, of enhancement of therapeutic efficacy of the combination of the dUTPase inhibitor and the inhibitor of thymidylate biosynthesis versus administration of the combination in the absence of a PARP inhibitor.

[0214] In certain embodiments, a therapeutic efficacy of a treatment refers to achieving one or more of clinical endpoints, optionally selected from the following:(1) elimination of a cancer in a subject or in a tissue / organ of the subject or in a cancer loci;(2) reduction in tumor burden (such as number of cancer cells, number of cancer foci, number of cancer cells in a foci, size of a solid cancer, concentrate of a liquid cancer in the body fluid, and / or amount of cancer in the body);(3) stabilizing or delay or slowing or inhibition of cancer growth and / or development, including but not limited to, cancer cell growth and / or division, size growth of a solid tumor or a cancer loci, cancer progression, and / or metastasis (such as time to form a new metastasis, number of total metastases, size of a metastasis, as well as variety of the tissues / organs to house metastatic cells);(4) less risk of having a cancer growth and / or development;(5) inducing an immune response of the patient to the cancer, such as higher number of tumor-infiltrating immune cell or higher number of activated immune cells; and(6) higher probability of survival and / or increased duration of survival, such as increased overall survival (OS, which may be shown as 1-year, 2-year, 5-year, 10-year, or 20-year survival rate), increased progression free survival (PFS), increased disease free survival (DFS), increased time to tumor recurrence (TTR) and increased time to tumor progression (TTP).524927-6853-2615.1Atty. Dkt. No. 109290-0190

[0215] In certain embodiments, enhancing a therapeutic efficacy refers to achieving one or more of clinical endpoints of treatment to a greater extend and / or in a faster speed and / or using less time, optionally compared to the treatment without the enhancement method / step. Additionally or alternatively, enhancing a therapeutic efficacy also refers to achieving more clinical endpoints, optionally compared to the treatment without the enhancement method / step.

[0216] Methods and tools for measuring such therapeutic efficacy is known to one of skill in the art, including measuring a clinical endpoint in a human patient and / or in an animal / tissue / cell model mimicking a patient having a cancer. For example, therapeutic efficacy may be monitored by CT scan or blood work analysis. In addition, tumor markers may be assessed. Non-limiting experimental settings can be found in the Examples.Inhibitors of poly (ADP-ribose) polymerase (PARP)

[0217] Non-limiting examples of PARP inhibitors include talazoparib, olaparib, niraparib, rucaparib, saruparib, pamiparib, and veliparib. Accordingly, in some embodiments, the PARP inhibitor comprises, consists essentially of, or consists of talazoparib, olaparib, niraparib, rucaparib, saruparib, pamiparib, or veliparib, or a combination of two or more thereof. In some embodiments, the PARP inhibitor comprises, consists essentially of, or consists of talazoparib, olaparib, niraparib, or rucaparib, or a combination of two or more thereof. In some embodiments, the PARP inhibitor comprises, consists essentially of, or consists of talazoparib. In some embodiments, the PARP inhibitor comprises, consists essentially of, or consists of olaparib. In some embodiments, the PARP inhibitor comprises, consists essentially of, or consists of niraparib. In some embodiments, the PARP inhibitor comprises, consists essentially of, or consists of rucaparib. In some embodiments, the PARP inhibitor comprises, consists essentially of, or consists of saruparib. In some embodiments, the PARP inhibitor comprises, consists essentially of, or consists of pamiparib. In some embodiments, the PARP inhibitor comprises, consists essentially of, or consists of veliparib.Inhibitors of thymidylate biosynthesis

[0218] In some embodiments, the inhibitor of thymidylate biosynthesis comprises, consists essentially of, or consists of a thymidylate synthase inhibitor. In some embodiments, the inhibitor of thymidylate biosynthesis comprises, consists essentially of, or consists of an inhibitor of folate-mediated one-carbon metabolism.534927-6853-2615.1Atty. Dkt. No. 109290-0190

[0219] In some embodiments, the inhibitor of thymidylate biosynthesis comprises, consists essentially of, or consists of 5 -fluorouracil (5-FU), floxuridine (FUdR), pemetrexed, raltitrexed, nolatrexed, plevitrexed, GS7904L, capecitabine, methotrexate, pralatrexate, CT-900, NUC-3373, or a combination of two or more thereof. In some embodiments, the inhibitor of thymidylate biosynthesis comprises, consists essentially of, or consists of 5-FU. In some embodiments, the inhibitor of thymidylate biosynthesis comprises, consists essentially of, or consists of FUdR. In some embodiments, the inhibitor of thymidylate biosynthesis comprises, consists essentially of, or consists of pemetrexed. In some embodiments, the inhibitor of thymidylate biosynthesis comprises, consists essentially of, or consists of raltitrexed. In some embodiments, the inhibitor of thymidylate biosynthesis comprises, consists essentially of, or consists of nolatrexed. In some embodiments, the inhibitor of thymidylate biosynthesis comprises, consists essentially of, or consists of plevitrexed. In some embodiments, the inhibitor of thymidylate biosynthesis comprises, consists essentially of, or consists of GS7904L. In some embodiments, the inhibitor of thymidylate biosynthesis comprises, consists essentially of, or consists of capecitabine. In some embodiments, the inhibitor of thymidylate biosynthesis comprises, consists essentially of, or consists of methotrexate. In some embodiments, the inhibitor of thymidylate biosynthesis comprises, consists essentially of, or consists of pralatrexate. In some embodiments, the inhibitor of thymidylate biosynthesis comprises, consists essentially of, or consists of CT-900. In some embodiments, the inhibitor of thymidylate biosynthesis comprises, consists essentially of, or consists of NUC-3373.

[0220] In some embodiments, the inhibitor of thymidylate biosynthesis comprises, consists essentially of, or consists of 5-FU based adjuvant therapy. In some embodiments, the 5-FU based adjuvant therapy comprises, consists essentially of, or consists of S-l, a combination of S-l and folinic acid, FOLFOX, FOLFOX-4, FOLFIRI, FOLFIRINOX, MOF, deflexifol, or a combination of 5-FU with one or more selected from radiation, methyl-CCNU, leucovorin, arfolitixorin, a platinum agent (such as oxaliplatin, cisplatin, or carboplatin), irinotecan, mitomycin, cytarabine, and levamisole. In some embodiments, the 5-FU based adjuvant therapy comprises, consists essentially of, or consists of FOLFOX, FOLFOX-4, FOLFIRI, FOLFIRINOX, MOF, deflexifol, or a combination of 5-FU with one or more selected from radiation, methyl-CCNU, leucovorin, a platinum agent (such as oxaliplatin, cisplatin, or carboplatin), irinotecan, mitomycin, cytarabine, and levamisole. In some embodiments, the inhibitor of thymidylate biosynthesis comprises, consists essentially of, or consists of S-l. In544927-6853-2615.1Atty. Dkt. No. 109290-0190some embodiments, the inhibitor of thymidylate biosynthesis comprises, consists essentially of, or consists of a combination of S-l and folinic acid. In some embodiments, the inhibitor of thymidylate biosynthesis comprises, consists essentially of, or consists of FOLFOX. In some embodiments, the inhibitor of thymidylate biosynthesis comprises, consists essentially of, or consists of FOLFOX-4. In some embodiments, the inhibitor of thymidylate biosynthesis comprises, consists essentially of, or consists of FOLFIRI. In some embodiments, the inhibitor of thymidylate biosynthesis comprises, consists essentially of, or consists of FOLFIRINOX. In some embodiments, the inhibitor of thymidylate biosynthesis comprises, consists essentially of, or consists of MOF. In some embodiments, the inhibitor of thymidylate biosynthesis comprises, consists essentially of, or consists of deflexifol. In some embodiments, the inhibitor of thymidylate biosynthesis comprises, consists essentially of, or consists of a combination of 5-FU with one or more selected from radiation, methyl-CCNU, leucovorin, arfolitixorin, a platinum agent (such as oxaliplatin, cisplatin, or carboplatin), irinotecan, mitomycin, cytarabine, and levamisole. In some embodiments, the inhibitor of thymidylate biosynthesis comprises, consists essentially of, or consists of a combination of 5-FU with one or more selected from radiation, methyl-CCNU, leucovorin, a platinum agent (such as oxaliplatin, cisplatin, or carboplatin), irinotecan, mitomycin, cytarabine, and levamisole.

[0221] In some embodiments, the inhibitor of thymidylate biosynthesis is formulated for nanoparticle-based delivery.

[0222] In some embodiments, the inhibitor of thymidylate biosynthesis is a 5-FU. Various regimens may be utilized by one of skill in the art (e.g., an oncologist), such as those listed below:(1) Colorectal cancer: 500 mg / m2, i.v. bolus on day 1; 1 hour prior to administering 5-FU bolus, give leucovorin 500 mg / m2, i.v. over 2 hours. Repeat weekly on days 1, 8, 15, 22, 29, and 36 every 8 weeks for 4 to 6 cycles.(2) Adjuvant treatment of high-risk stage II or stage III rectal cancer in combination with radiation therapy: 500 mg / m2, i.v. bolus daily for 5 days on days 1 and 36 beginning 22 to 70 days after surgery; radiation therapy for 6 weeks is begun on day 64 after initiation of 5-FU therapy. 5-FU 225 mg / m2 / day, i.v. continuous infusion is given throughout radiation therapy. Then, 5-FU 450 mg / m2, i.v. bolus daily for 5 days beginning 1 month after radiation (i.e., days 134 to 138) and repeated in 4 weeks.554927-6853-2615.1Atty. Dkt. No. 109290-0190(3) For the treatment of metastatic colorectal cancer in combination with irinotecan and leucovorin, with or without bevacizumab (FOLFIRI with or without bevacizumab): 400 mg / m2, i.v. bolus on day 1, followed by 5-FU 1,200 mg / m2 / day on days 1 and 2 by continuous i.v. infusion (CIV) (total infusional dose, 2,400 mg / m2over 46 hours) for cycles 1 and 2. If there is no toxicity greater than grade 1, the 5-FU infusion dose may be increased to 3,000 mg / m2for all subsequent cycles.(4) For the treatment of advanced colorectal cancer in combination with leucovorin (LV) and oxaliplatin with or without bevacizumab (FOLFOX4 with or without bevacizumab): 400 mg / m2, i.v. bolus over 2 to 4 minutes, followed by 5-FU 600 mg / m2continuous i.v. infusion (CIV) over 22 hours on day 1. Prior to 5-FU bolus on day 1, administer oxaliplatin 85 mg / m2, i.v. and leucovorin 200 mg / m2, i.v. (both over 120 minutes via Y-site). If giving FOLFOX4 plus bevacizumab, administer bevacizumab 10 mg / kg i.v. over 30 to 90 minutes prior to chemotherapy on day 1. On day 2, repeat leucovorin 200 mg / m2, i.v. over 2 hours followed by 5-FU 400 mg / m2, i.v. bolus, then 5-FU 600 mg / m2CIV over 22 hours. The order of administration is (bevacizumab) followed by oxaliplatin and leucovorin, followed by 5-FU. This 2-day regimen is repeated every 2 weeks until disease progression or unacceptable toxicity.

[0223] In some embodiments, the inhibitor of thymidylate biosynthesis is floxuridine (FUdR). Various regimens may be utilized by one of skill in the art (e.g., an oncologist), such as those listed below:(1) Stage IV colon cancer with lever metastases, intra-hepatic arterial infusion at 100-150 mg / m2 / day)as a continuous infusion over 14 days; subsequent courses repeated every 4-6 week interval, recommended duration of treatment is 6 months, adjust dose according to tolerability.(2) Metastatic pancreatic cancer with lever metastases, intra-hepatic arterial infusion at 100-150 mg / m2 / day)as a continuous infusion over 14 days; subsequent courses repeated every 4-6 week interval, recommended duration of treatment is 6 months, adjust dose according to tolerability.(3) Metastatic gastric cancer with lever metastases, intra-hepatic arterial infusion at 100-150 mg / m2 / day)as a continuous infusion over 14 days; subsequent courses repeated every 4-6 week interval, recommended duration of treatment is 6 months, adjust dose according to tolerability.564927-6853-2615.1Atty. Dkt. No. 109290-0190(4) Metastatic peritoneal cancer with lever metastases, intra-hepatic arterial infusion at 100-150 mg / m2 / day)as a continuous infusion over 14 days; subsequent courses repeated every 4-6 week interval, recommended duration of treatment is 6 months, adjust dose according to tolerability.

[0224] In some embodiments, the inhibitor of thymidylate biosynthesis is capecitabine. Various regimens may be utilized by one of skill in the art (e.g., an oncologist), such as those listed below:(1) Stage III colon cancer, adjuvant following surgery (monotherapy): 1.25 g / m2twice daily for 14 days, subsequent courses repeated after a 7-day interval, recommended duration of treatment is 6 months, adjust dose according to tolerability.(2) Stage III colon cancer, adjuvant following surgery (combination therapy): 0.8-1 g / m2twice daily for 14 days, subsequent courses repeated after a 7-day interval, recommended duration of treatment is 6 months, adjust dose according to tolerability.(3) Metastatic colorectal cancer (monotherapy): 1.25 g / m2twice daily for 14 days, subsequent courses repeated after a 7-day interval, adjust dose according to tolerability.(4) Metastatic colorectal cancer (combination therapy): 0.8-1 g / m2twice daily for 14 days, subsequent courses repeated after a 7-day interval, adjust dose according to tolerability.(5) Advanced gastric cancer (first-line treatment in combination with a platinumbased regimen): 0.8-1 g / m2twice daily for 14 days, subsequent courses repeated after a 7-day interval, alternatively 625 mg / m2twice daily given continuously, adjust dose according to tolerability.

[0225] In some embodiments, the inhibitor of thymidylate biosynthesis is methotrexate. Various regimens may be utilized by one of skill in the art (e.g., an oncologist), such as those listed below:(1) Choriocarcinoma and similar trophoblastic diseases: Methotrexate is administered orally or intramuscularly in doses of 15 to 30 mg daily for a five-day course. Such courses are usually repeated for 3 to 5 times as required.(2) Lymphomas: In Burkitt’s tumor, Stages I-II, Recommended dosage is 10 to 25 mg / day orally for 4 to 8 days.574927-6853-2615.1Atty. Dkt. No. 109290-0190(3) Mycosis fungoides (cutaneous T cell lymphoma): Dosage in early stages is usually 5 to 50 mg once weekly. Dose reduction or cessation is guided by patient response and hematologic monitoring.(4) Osteosarcoma: Methotrexate is used in combination with other agents. In addition to high-dose methotrexate with leucovorin rescue, these agents may include doxorubicin, cisplatin, and the combination of bleomycin, cyclophosphamide and dactinomycin (BCD). The starting dose for high-dose methotrexate treatment is 12 grams / m2. dUTPase inhibitors

[0226] In some embodiments, the dUTPase inhibitor is a compound of Formula (I):or a tautomer thereof, or a prodrug of each thereof; or a deuterium isotope of each of the above wherein up to 10, preferably up to 6, more preferably up to 3 hydrogen atoms that are attached to one or more carbon atoms are replaced with deuterium(s); or a pharmaceutically acceptable salt of each of the foregoing; or a pharmaceutically acceptable solvate of each of the above mentioned,whereinA is an optionally substituted 5-membered heterocyclyl containing a -C(O)NZC(O)-moiety, a -C(O)OC(O) moiety, a -C(O)CR10C(O) moiety, or a -C(O)NR10C(O) moiety; or A is a 5-membered heteroaryl or a 5-membered substantially planar heterocyclyl (i.e., a heterocyclyl wherein at least 3 or at least 4 atoms can stably be in a same plane) substituted at 1,3 positions with substituents selected from halo, optionally substituted hydroxy, and optionally substituted -SH groups, preferably two fluoros, wherein the 5-membered heteroaryl or substantially planar heterocyclyl is further optionally substituted; orA is584927-6853-2615.1Atty. Dkt. No. 109290-0190each R10independently is hydrogen, an optionally substituted C1-C10 alkoxy, or an optionally substituted C1-C10 alkyl, preferably R10is hydrogen;each R30independently is hydrogen; an optionally substituted C1-C10 alkoxy; optionally substituted amino, such as -NH2 or a mono or di-substituted form thereof; an optionally substituted C1-C10 alkyl; optionally substituted hydroxy; or Z; or A and L1, preferably, R30, wherein R30is attached to an atom that is adjacent to the atom attached to L1, and L1together with the atoms they are attached to form a 5-7 membered ring;L1is a linker having 2-13 chain atoms selected from C, N, O, S, and / or P, wherein the linker is optionally substituted; orL1is -Ln-L12-L13-, wherein L11is attached to A and L11is O, S, NR, C1-C2 alkylene, C2 alkenylene, C2 heteroalkylene, C3 heteroalkenylene, L12is arylene or heteroarylene, L13is a bond or an optionally substituted C1-C5 alkylene, and R is H or C1-C3 alkyl;L2is -SO2NR50-, wherein the sulfur is attached to L1; -NR50SO2-, wherein the nitrogen is attached to L1; -C(O)NR50-, wherein the carbon is attached to L1;-NR50C(O)-, wherein the nitrogen is attached to L1; -NR50SO2NR50-; or -NR50CONR50-;each R50independently is hydrogen, an optionally substituted Ci-Ce alkyl, an optionally substituted C2-C6 heteroalkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C3-C6 heteroalkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C6 heteroalkynyl, or Z;Z iseach R51and R52independently is hydrogen or an optionally substituted C1-C10 alkyl; X is an optionally substituted hydroxy group, an optionally substituted NH2 group, or an optionally substituted SH group;594927-6853-2615.1Atty. Dkt. No. 109290-0190L3is a bond, an optionally substituted Ci-Ce alkylene, an optionally substituted C2-C6 heteroalkylene, an optionally substituted C2-C6 alkenylene, an optionally substituted C3-C6 heteroalkenylene, an optionally substituted C2-C6 alkynylene, or an optionally substituted C3-Ce heteroalkynylene; andB is an optionally substituted 6-10 membered aryl; an optionally substituted 5-15 membered heteroaryl; an optionally substituted 4-15 membered heterocyclyl; or an optionally substituted 3-15 membered cycloalkyl, if cycloalkyl, then preferably at least a 4 membered, or more preferably a 5-10 membered cycloalkyl.

[0227] In some embodiments, A is

[0228] In some embodiments, the compound provided herein is a prodrug. As used herein, “prodrug” refers to a compound that, after administration, is metabolized or otherwise converted to a biologically active or more active compound (or drug) with respect to at least one property. A prodrug, relative to the drug, is modified chemically in a manner that renders it, relative to the drug, less active or inactive, but the chemical modification is such that the corresponding drug is generated by metabolic or other biological processes after the prodrug is administered. A prodrug may have, relative to the active drug, altered metabolic stability or transport characteristics, fewer side effects or lower toxicity, or improved flavor (for example, see the reference Nogrady, 1985, Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392, incorporated herein by reference). A prodrug may be synthesized using reactants other than the corresponding drug. Examples of604927-6853-2615.1Atty. Dkt. No. 109290-0190prodrugs and methods of making them are also provided in US Patent Application Publication No. 20160024127, which is incorporated herein in its entirety by reference.

[0229] In some embodiments, the compound provided herein contains one or more deuterium. Examples of a deuterium containing compound provided herein, wherein up to 10, preferably up to 6, more preferably up to 3 hydrogen atoms that are attached to carbon atoms are replaced with a deuterium, include, without limitation: a compound where a methyl group is converted to -CH2D, -CHD2, or -CD3; a compound where a methylene group is converted to a -CHD- or -CD2-, a phenyl ring where one or more hydrogen atoms are replaced with deuterium atoms, etc.

[0230] In some embodiments, A is an optionally substituted 5-membered heterocyclyl containing a -C(O)NZC(O)- moiety. In some embodiments, A is an optionally substituted 5-membered heterocyclyl containing a -C(O)OC(O) moiety. In some embodiments, A is an optionally substituted 5-membered heterocyclyl containing a -C(O)CR10C(O) moiety. In some embodiments, A is an optionally substituted 5-membered heterocyclyl containing a -C(O)NR10C(O) moiety.

[0231] In some embodiments, R10is hydrogen. In some embodiments, R10is an optionally substituted C1-C10 alkoxy. In some embodiments, R10is an optionally substituted C1-C10 alkyl.

[0232] In some embodiments, A is a 5-membered heteroaryl substituted at 1,3 positions with substituents selected from halo, optionally substituted hydroxy, and optionally substituted -SH groups, preferably two fluoros, wherein the 5-membered heteroaryl is further optionally substituted. In some embodiments, A is a 5-membered heteroaryl substituted at 1,3 positions with halo, wherein the 5-membered heteroaryl is further optionally substituted. In some embodiments, the 5-membered heteroaryl is substituted at 1,3 positions with two fluoros, wherein the 5-membered heteroaryl is further optionally substituted. In some embodiments, A is a 5-membered heteroaryl substituted at 1,3 positions with optionally substituted hydroxy, wherein the 5-membered heteroaryl is further optionally substituted. In some embodiments, A is a 5-membered heteroaryl substituted at 1,3 positions with optionally substituted -SH groups, wherein the 5-membered heteroaryl is further optionally substituted.

[0233] Non-limiting and illustrative examples of a 5-membered heteroaryl substituted at 1,3 positions with substituents selected from halo, optionally substituted hydroxy, optionally substituted -SH groups include, without limitation:614927-6853-2615.1Atty. Dkt. No. 109290-0190such aswhere Y10and Y11independently are selected from a halo, preferably chloro or fluoro, hydroxy, -SH, substituted hydroxy, and substituted -SH; Z20-Z22are independently selected from optionally substituted CH, optionally substituted NH, N, S, SO2, SO, and O, provided that the combination of Z20-Z22provides a planar valence matched heteroaryl or a tautomer thereof; and each Z23independently is CH or N.

[0234] In some embodiments, Y10is a halo. In some embodiments, Y10is a chloro. In some embodiments, Y10is a fluoro. In some embodiments, Y10is hydroxy. In some embodiments, Y10is -SH. In some embodiments, Y10is a substituted hydroxy. In some embodiments, Y10is a substituted -SH.

[0235] In some embodiments, Y11is a halo. In some embodiments, Y11is a chloro. In some embodiments, Y11is a fluoro. In some embodiments, Y11is hydroxy. In some embodiments, Y11is -SH. In some embodiments, Y11is a substituted hydroxy. In some embodiments, Y11is a substituted -SH.

[0236] In some embodiments, Z20is an optionally substituted CH. In some embodiments, Z20is an optionally substituted NH. In some embodiments, Z20is N. In some embodiments, Z20is S. In some embodiments, Z20is SO2. In some embodiments, Z20is SO. In some embodiments, Z20is O.

[0237] In some embodiments, Z21is an optionally substituted CH. In some embodiments, Z21is an optionally substituted NH. In some embodiments, Z21is N. In some embodiments,624927-6853-2615.1Atty. Dkt. No. 109290-0190Z21is S. In some embodiments, Z21is SO2. In some embodiments, Z21is SO. In some embodiments, Z21is O.

[0238] In some embodiments, Z22is an optionally substituted CH. In some embodiments, Z22is an optionally substituted NH. In some embodiments, Z22is N. In some embodiments, Z22is S. In some embodiments, Z22is SO2. In some embodiments, Z22is SO. In some embodiments, Z22is O.

[0239] In some embodiments, Z23is an optionally substituted CH. In some embodiments, Z23is N.

[0240] In some embodiments, A is a 5-membered substantially planar heterocyclyl (i.e., a heterocyclyl wherein at least 3 or at least 4 atoms can stably be in a same plane) substituted at 1,3 positions with substituents selected from halo, optionally substituted hydroxy, and optionally substituted -SH groups, preferably two fluoros, wherein the 5-membered substantially planar heterocyclyl is further optionally substituted. In some embodiments, A is a 5-membered substantially planar heterocyclyl substituted at 1,3 positions with halo, wherein the 5-membered substantially planar heterocyclyl is further optionally substituted. In some embodiments, the 5-membered substantially planar heterocyclyl is substituted at 1,3 positions with two fluoros, wherein the 5-membered substantially planar heterocyclyl is further optionally substituted. In some embodiments, A is a 5-membered substantially planar heterocyclyl substituted at 1,3 positions with optionally substituted hydroxy, wherein the 5-membered substantially planar heterocyclyl is further optionally substituted. In some embodiments, A is a 5-membered substantially planar heterocyclyl substituted at 1,3 positions with optionally substituted -SH groups, wherein the 5-membered substantially planar heterocyclyl is further optionally substituted.

[0241] Examples of a 5-membered substantially planar heterocyclyl substituted at 1,3 positions with halo, optionally substituted hydroxy, and optionally substituted -SH groups, have similar structures as the corresponding 5-membered heteroaryl except that the 5-membered ring is not an aromatic ring.

[0242] In some embodiments, A is:634927-6853-2615.1Atty. Dkt. No. 109290-0190

[0243] In some embodiments, A is:

[0244] In some embodiments, A is:

[0245] In some embodiments, A is:

[0246] In some embodiments, A is:644927-6853-2615.1Atty. Dkt. No. 109290-0190

[0247] In some embodiments, A is:

[0248] In some embodiments, A is:

[0249] In some embodiments, A is:

[0250] In some embodiments, A is:

[0251] In some embodiments, A is:654927-6853-2615.1Atty. Dkt. No. 109290-0190

[0252] In some embodiments, A is:

[0253] In some embodiments, A is:

[0254] In some embodiments, A is:

[0255] In some embodiments, A is:664927-6853-2615.1Atty. Dkt. No. 109290-0190

[0256] In some embodiments, R30is hydrogen. In some embodiments, R30is an optionally substituted Ci-Cio alkoxy. In some embodiments, R30is optionally substituted amino, such as -NH2 or a mono or di -substituted form thereof. In some embodiments, R30is an optionally substituted C1-C10 alkyl. In some embodiments, R30is an optionally substituted hydroxy. In some embodiments, R30is a prodrug moiety. Non-limiting and illustrative prodrug moieties include formyl ethers, and formyl esters as disclosed herein. In some embodiments, R30is Z.

[0257] Illustrative and non-limiting examples of R30include a substituted hydroxy or -CH2OC(O)R80, wherein R80is H or an optionally substituted C1-C10 alkyl. In some embodiments, R80is hydrogen. In some embodiments, R80is an optionally substituted C1-C10 alkyl.

[0258] In some embodiments, A and L1, preferably, R30and L1together with the atoms they are attached to form a 5-7 membered ring.

[0259] In some embodiments, A is selected from the group consisting of:674927-6853-2615.1Atty. Dkt. No. 109290-0190

[0261] In some embodiments, A is

[0262] In some embodiments, A is

[0263] The A moieties disclosed herein including herein above, can, in some embodiments, be further substituted with 1-3, preferably 1-2, more preferably, 1 R30substituent as provided herein. In some embodiments, where R30and L1are joined to adjacent atoms (i.e., atoms having a 1,2 positional relation), R30and a portion of L1, together with the intervening atoms can form a 5-6 membered, optionally substituted cycloalkyl or heterocyclyl ring.

[0264] In some embodiments, A is not:

[0265] In some embodiments, A is not:684927-6853-2615.1Atty. Dkt. No. 109290-0190

[0266] In some embodiments, L1is a linker having 2-13 chain atoms selected from C, N, O, S, and / or P, wherein the linker is optionally substituted. In various embodiments, L1having 2-13 chain atoms selected from C, N, O, S, and / or P can be: alkylene, alkenylene, alkynylene, wherein one or more carbon atoms are replaced with O, S, SO, SO2, optionally substituted NH,moieties where RQis H or Ci-Ce alkyl optionally substituted -CO-NH-, optionally substituted -SO2-NH-, optionally substituted -P(O)(OH)-, optionally substituted phosphoramide and optionally substituted phosporamidate, (such as -P(O)NH2-, -P(O)(OH)NH-, etc.), optionally substituted oligoethylene glycol, optionally substituted oligo ethanolamine, and the likes, as will be apparent to the skilled artisan based on the disclosure provided herein.

[0267] In some embodiments, L1is -(CH2)q-. In some embodiments, one or more hydrogens are optionally substituted with C1-C3 alkyl. In some embodiments, at least two or more geminal hydrogens together with the carbon(s) to which they are attached are optionally replaced with an optionally substituted 3-5 membered heterocyclyl. In some embodiments, at least two or more geminal hydrogens together with the carbon(s) to which they are attached are optionally replaced with an optionally substituted 3-5 membered cycloalkyl. In some embodiments, the optionally substituted 3-5 membered cycloalkyl is an optionally substituted cyclopropano. In some embodiments, the optionally substituted 3-5 membered cycloalkyl is an optionally substituted cyclobutano. In some embodiments, the optionally substituted 3-5 membered cycloalkyl is an optionally substituted cyclopentano. In some embodiments, the optionally substituted 3-5 membered heterocyclyl is an optionally substituted tetrahydrofurano.

[0268] In some embodiments, q is 3. In some embodiments, q is 4. In some embodiments, q is 5. In some embodiments, q is 6. In some embodiments, q is 7. In some embodiments, q is 8.

[0269] In some embodiments, L1is:694927-6853-2615.1Atty. Dkt. No. 109290-0190In some related embodiments, one or more hydrogens are optionally substituted with C1-C3 alkyl. In some embodiments, at least two or more geminal hydrogens together with the carbon(s) to which they are attached are optionally replaced with an optionally substituted 3-5 membered heterocyclyl. In some embodiments, at least two or more geminal hydrogens together with the carbon(s) to which they are attached are optionally replaced with an optionally substituted 3-5 membered cycloalkyl. In some embodiments, the optionally substituted 3-5 membered cycloalkyl is an optionally substituted cyclopropano. In some embodiments, the optionally substituted 3-5 membered cycloalkyl is an optionally substituted cyclobutano. In some embodiments, the optionally substituted 3-5 membered cycloalkyl is an optionally substituted cyclopentano. In some embodiments, the optionally substituted 3-5 membered cycloalkyl is an optionally substituted tetrahydrofurano.

[0270] In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5.

[0271] In some embodiments, z is 0. In some embodiments, z is 1. In some embodiments, z is 2. In some embodiments, z is 3. In some embodiments, z is 4. In some embodiments, z is 5.

[0272] In some embodiments, L1is -(CH2)m-X15-(CH2)n-. In some embodiments, one or more hydrogens are optionally substituted with C1-C3 alkyl. In some embodiments, at least two or more geminal hydrogens together with the carbon(s) to which they are attached are optionally replaced with an optionally substituted 3-5 membered heterocyclyl. In some embodiments, at least two or more geminal hydrogens together with the carbon(s) to which they are attached are optionally replaced with an optionally substituted 3-5 membered cycloalkyl. In some embodiments, the optionally substituted 3-5 membered cycloalkyl is an optionally substituted cyclopropano. In some embodiments, the optionally substituted 3-5 membered cycloalkyl is an optionally substituted cyclobutano. In some embodiments, the optionally substituted 3-5 membered cycloalkyl is an optionally substituted cyclopentano. In some embodiments, the optionally substituted 3-5 membered heterocyclyl is an optionally substituted tetrahydrofurano.

[0273] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.704927-6853-2615.1Atty. Dkt. No. 109290-0190

[0274] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7.

[0275] In some embodiments, X15is NR40. In some embodiments, X15is NR40(+)-O(-). In some embodiments, R40is H. In some embodiments, R40is Ci-Cio alkyl. In some embodiments, R40is C1-C3 alkyl. In some embodiments, X15is O. In some embodiments, X15is S. In some embodiments, X15is SO. In some embodiments, X15is SO2.

[0276] In some embodiments, L1is:defined as above.In some related embodiments, one or more hydrogens are optionally substituted with C1-C3 alkyl. In some embodiments, at least two or more geminal hydrogens together with the carbon(s) to which they are attached are optionally replaced with an optionally substituted 3-5 membered heterocyclyl. In some embodiments, at least two or more geminal hydrogens together with the carbon(s) to which they are attached are optionally replaced with an optionally substituted 3-5 membered cycloalkyl. In some embodiments, the optionally substituted 3-5 membered cycloalkyl is an optionally substituted cyclopropano. In some embodiments, the optionally substituted 3-5 membered cycloalkyl is an optionally substituted cyclobutano. In some embodiments, the optionally substituted 3-5 membered cycloalkyl is an optionally substituted cyclopentano. In some embodiments, the optionally substituted 3-5 membered heterocyclyl is an optionally substituted tetrahydrofurano.

[0277] In some embodiments, o is 0. In some embodiments, o is 1. In some embodiments, o is 2. In some embodiments, o is 3.

[0278] In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3.

[0279] In some embodiments, s is 0. In some embodiments, s is 1. In some embodiments, s is 2. In some embodiments, s is 3. In some embodiments, s is 4.

[0280] In some embodiments, L1is selected from the group consisting of4927-6853-2615.1Atty. Dkt. No. 109290-0190wherein the left side of the moi eties are attached to A. In some related embodiments, 1-5, preferably, 1-3 hydrogen atoms of the L1are optionally substituted, preferred substituents including without limitation, Ci-Ce alkyl optionally substituted with 1-3 halo, such as fluoro, and / or Ci-Ce alkoxy; optionally substituted Ci-Ce alkoxy; and halo, preferably fluoro, wherein the left side of the moieties are attached to A and wherein R70is an optionally substituted Ci-Cio alkyl. In some embodiments, L1is optionally substituted wherein 1-5 hydrogen atoms are optionally substituted. In some embodiments, L1is optionally substituted wherein 1-3 hydrogen atoms are optionally substituted. In some embodiments, substituents724927-6853-2615.1Atty. Dkt. No. 109290-0190include without limitation Ci-Ce alkyl optionally substituted with 1-3 halo, such as fluoro. In some embodiments, substituents include without limitation Ci-Ce alkyl optionally substituted with Ci-Ce alkoxy. In some embodiments, substituents include without limitation an optionally substituted Ci-Ce alkoxy. In some embodiments, substituents include without limitation a halo. In some embodiments, substituents include a fluoro.

[0281] In some embodiments, L1is:or an optionally substituted version of each thereof wherein 1-5, preferably, 1-3 hydrogen atoms are optionally substituted, preferred substituents including without limitation, Ci-Ce alkyl optionally substituted with 1-3 halo, such as fluoro, and / or Ci-Ce alkoxy; optionally substituted Ci-Ce alkoxy; and halo, preferably fluoro, wherein the left side of the moieties are attached to A.

[0282] In some embodiments, L1is:

[0283] In some embodiments, L1is:

[0284] In some embodiments, L1is optionally substituted wherein 1-5 hydrogen atoms are optionally substituted. In some embodiments, L1is optionally substituted wherein 1-3 hydrogen atoms are optionally substituted. In some embodiments, substituents include without limitation Ci-Ce alkyl optionally substituted with 1-3 halo, such as fluoro. In some embodiments, substituents include without limitation Ci-Ce alkyl optionally substituted with Ci-Ce alkoxy. In some embodiments, substituents include without limitation an optionally4927-6853-2615.1Atty. Dkt. No. 109290-0190substituted Ci-Ce alkoxy. In some embodiments, substituents include without limitation a halo. In some embodiments, substituents include a fluoro.

[0285] In some embodiments, L2is -SO2NR50-, wherein the sulfur is attached to L1. In some embodiments, L2is -NR50SO2-, wherein the nitrogen is attached to L1. In some embodiments, L2is -C(O)NR50-, wherein the carbon is attached to L1. In some embodiments, L2is -NR50C(O)-, wherein the nitrogen is attached to L1. In some embodiments, L2is -NR50SO2NR.50-. In some embodiments, L2is -NR50CONR50-.

[0286] In some embodiments, R50is hydrogen. In some embodiments, R50is an optionally substituted Ci-Ce alkyl. In some embodiments, R50is an optionally substituted C2-C6 heteroalkyl. In some embodiments, R50is an optionally substituted C2-C6 alkenyl. In some embodiments, R50is an optionally substituted C3-C6 heteroalkenyl. In some embodiments, R50is an optionally substituted C2-C6 alkynyl. In some embodiments, R50is an optionally substituted C3-C6 heteroalkynyl. In some embodiments, R50is Z.

[0287] In some embodiments, Z iswherein each R51and R52independently is hydrogen or an optionally substituted C1-C10 alkyl and X is an optionally substituted hydroxy group, an optionally substituted NH2 group, or an optionally substituted SH group.

[0288] In some embodiments, R51is hydrogen. In some embodiments, R51is an optionally substituted C1-C10 alkyl. In some embodiments, R52is hydrogen. In some embodiments, R52is an optionally substituted C1-C10 alkyl.

[0289] In some embodiments, X is an optionally substituted hydroxy group. In some embodiments, X is an optionally substituted NH2 group. In some embodiments, X is an optionally substituted SH group.

[0290] As used herein, an optionally substituted hydroxy group refers to without limitation alkylated, arylated, cycloalkylated, heterocyclylated, acylated, carboxylated (i.e., generating a carbonate, carbamate, a thiocarbonate, a thiacarbamate containing alkyl, aryl, heteroaryl, and / or heterocyclyl, and such other moieties), phosphorylated, phosphonylated, sulfonylated,744927-6853-2615.1Atty. Dkt. No. 109290-0190forms of a hydroxy group, as would be apparent to the skilled artisan in view of this disclosure.

[0291] As used herein, an optionally substituted NH2 group refers to without limitation alkylated, arylated, cycloalkylated, heterocyclylated, acylated, carboxylated (i.e., generating a carbonate, carbamate, a thiocarbonate, a thiacarbamate containing alkyl, aryl, heteroaryl, and / or heterocyclyl, and such other moieties), phosphorylated, phosphonylated, sulfonylated, forms of a NH2 group, as would be apparent to the skilled artisan in view of this disclosure.

[0292] As used herein, an optionally substituted SH group refers to without limitation alkylated, arylated, cycloalkylated, heterocyclylated, acylated, carboxylated (i.e., generating a carbonate, carbamate, a thiocarbonate, a thiacarbamate containing alkyl, aryl, heteroaryl, and / or heterocyclyl, and such other moieties), phosphorylated, phosphonylated, sulfonylated, forms of a -SH group, as would be apparent to the skilled artisan in view of this disclosure.

[0293] In some embodiments, L3is a bond. In some embodiments, L3is an optionally substituted Ci-Ce alkylene. In some embodiments, L3is -CH2-. In some embodiments, L3is an optionally substituted C2-C6 heteroalkylene. In some embodiments, L3is an optionally substituted C2-C6 alkenylene. In some embodiments, L3is an optionally substituted C3-C6 heteroalkenylene. In some embodiments, L3is an optionally substituted C2-C6 alkynylene. In some embodiments, L3is an optionally substituted C3-C6 heteroalkynylene. In some embodiments, L1is a linker optionally substituted with a C3-C6 cycloalkyl, preferably a cyclopropyl or a cyclobutyl. In some embodiments, the Ci-Ce alkylene is optionally substituted with a C3-C6 cycloalkyl.

[0294] In some embodiments, L3is selected from the group consisting of:and optionally substituted versions thereof wherein 1-5, preferably, 1-3 hydrogen atoms are optionally substituted, preferred substituents including without limitation, Ci-Ce alkyl optionally substituted with 1-3 halo, such as fluoro, and / or Ci-Ce alkoxy; optionally754927-6853-2615.1Atty. Dkt. No. 109290-0190substituted Ci-Ce alkoxy; and halo, preferably fluoro, wherein the left side of the moieties are attached to L2.

[0295] In some embodiments, L3is:

[0296] In some embodiments, L3is:

[0297] In some embodiments, L3is:

[0298] In some embodiments, L3is:

[0299] In some embodiments, L3is:

[0300] In some embodiments, L3is:4927-6853-2615.1Atty. Dkt. No. 109290-0190

[0301] In some embodiments, L3is:

[0302] In some embodiments, L3is:

[0303] In some embodiments, the L3is optionally substituted wherein 1-5 hydrogen atoms are optionally substituted. In some embodiments, L3is an optionally substituted version thereof wherein 1-3 hydrogen atoms are optionally substituted. In some embodiments, substituents include without limitation Ci-Ce alkyl optionally substituted with 1-3 halo, such as fluoro. In some embodiments, substituents include without limitation Ci-Ce alkyl optionally substituted with Ci-Ce alkoxy. In some embodiments, substituents include without limitation an optionally substituted Ci-Ce alkoxy. In some embodiments, substituents include without limitation a halo. In some embodiments, substituents include a fluoro.

[0304] In some embodiments, when L3isthen A is a hydantoin moiety as disclosed herein.

[0305] In some embodiments, when L3is a bond, then A is a hydantoin moiety as disclosed herein.

[0306] As used herein, a hydantoin moiety refers to:4927-6853-2615.1Atty. Dkt. No. 109290-0190wherein R30is as defined above.

[0307] In some embodiments, a hydantoin moiety is:

[0308] In some embodiments, L3is not:

[0309] In some embodiments, L3is selected from the group consisting of:and optionally substituted versions thereof wherein 1-5, preferably, 1-3 hydrogen atoms are optionally substituted, preferred substituents including without limitation, Ci-Ce alkyl optionally substituted with 1-3 halo, such as fluoro, and / or Ci-Ce alkoxy; optionally substituted Ci-Ce alkoxy; and halo, preferably fluoro, wherein the left side of the moieties are attached to L2.

[0310] In some embodiments, L3is:wherein the left side is attached to A.784927-6853-2615.1Atty. Dkt. No. 109290-0190

[0311] In some less preferred embodiments, L3is:wherein the left side is attached to A.

[0312] In some embodiments, L3is:wherein the left side is attached to A.

[0313] In some embodiments, L3is:wherein the left side is attached to A.

[0314] In some embodiments, L3is:wherein the left side is attached to A.

[0315] In some embodiments, L3is:wherein the left side is attached to A.

[0316] In some embodiments, the L3is optionally substituted, wherein 1-5 hydrogen atoms are optionally substituted. In some embodiments, L1is an optionally substituted version 794927-6853-2615.1Atty. Dkt. No. 109290-0190thereof wherein 1-3 hydrogen atoms are optionally substituted. In some embodiments, substituents include without limitation Ci-Ce alkyl optionally substituted with 1-3 halo, such as fluoro. In some embodiments, substituents include without limitation Ci-Ce alkyl optionally substituted with Ci-Ce alkoxy. In some embodiments, substituents include without limitation an optionally substituted Ci-Ce alkoxy. In some embodiments, substituents include without limitation a halo. In some embodiments, substituents include a fluoro.

[0317] In some embodiments, B is an optionally substituted 6-10 membered aryl. In some embodiments, B is an optionally substituted 5-15 membered heteroaryl. In some embodiments, B is an optionally substituted 4-15 membered heterocyclyl. In some embodiments, B is an optionally substituted 3-15 membered cycloalkyl. In some embodiments, if B is a 3-15 membered cycloalkyl, then B is at least a 4 membered cycloalkyl. In some embodiments, if B is a 3-15 membered cycloalkyl, then B is a 5-10 membered cycloalkyl.

[0318] In some embodiments, B is selected from the group consisting of:whereineach R6independently is hydrogen, an optionally substituted Ci-Ce alkoxy, or halo; each R7independently is an optionally substituted Ci-Ce alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C8 cycloalkyl, an optionally substituted C3-C10 heteroaryl, an optionally substituted C3-C10 heterocyclyl, or an optionally substituted Ce-Cio aryl such as optionally substituted phenyl; or 804927-6853-2615.1Atty. Dkt. No. 109290-0190R6and R7together with the atoms they are attached to form an optionally substituted 5-7 membered ring; or 2 R6groups together with the atoms they are attached to form an optionally substituted 5-7 membered ring;each R61and R62is independently N or CH, provided that at least one of R61and R62is N,each R63is independently NR90, S, or O;each R64is independently N or CH; andeach R90is independently hydrogen or R7,and wherein one or more hydrogen atoms on the 5 and 6 membered aryl or heteroaryl rings shown above can be further optionally substituted.

[0319] In some embodiments, B is:

[0320] In some embodiments, B is:

[0321] In some embodiments, B is:

[0322] In some embodiments, B is:814927-6853-2615.1Atty. Dkt. No. 109290-0190

[0323] In some embodiments, B is:

[0324] In some embodiments, B is:

[0325] In some embodiments, B is:

[0326] In some embodiments, B is:

[0327] In some embodiments, B is:

[0328] In some embodiments, B is:824927-6853-2615.1Atty. Dkt. No. 109290-0190

[0329] In some embodiments, B is:

[0330] In some embodiments, B is:

[0331] In some embodiments, R6is hydrogen. In some embodiments, R6is an optionally substituted Ci-Ce alkoxy. In some embodiments, R6is halo.

[0332] In some embodiments, R7is an optionally substituted Ci-Ce alkyl. In some embodiments, R7is an optionally substituted C2-C6 alkenyl. In some embodiments, R7is an optionally substituted C2-C6 alkynyl. In some embodiments, R7is an optionally substituted C3-C8 cycloalkyl. In some embodiments, R7is an optionally substituted C3-C10 heteroaryl. In some embodiments, R7is an optionally substituted C3-C10 heterocyclyl. In some embodiments, R7is an optionally substituted Ce-Cio aryl. In some embodiments, the optionally substituted Ce-Cio aryl is an optionally substituted phenyl.

[0333] In some embodiments, R6and R7together with the atoms they are attached to form an optionally substituted 5-7 membered ring. In some embodiments, 2 R6groups together with the atoms they are attached to form an optionally substituted 5-7 membered ring.

[0334] In some embodiments, one of R61and R62is N. In some embodiments, both the R61and R62are N.834927-6853-2615.1Atty. Dkt. No. 109290-0190

[0335] In some embodiments, R63is NR90. In some embodiments, R63is S. In some embodiments, R63is O.

[0336] In some embodiments, R64is N. In some embodiments, R64is CH.

[0337] In some embodiments, R90is hydrogen. In some embodiments, R90is R7.

[0338] In some embodiments, B iswhereineach RCR3independently is H, halo, an optionally substituted Ci-Ce alkyl, an optionally substituted 4-15 membered heterocyclyl, or -OR20or, if two of R1-R3are on adjacent carbon atoms, then two such substituents together with the atoms they are attached to form an optionally substituted 5-7 membered ring;R20is (CH2)W-R21, an optionally substituted C3-C6 cycloalkyl, or an optionally substituted Ci-Ce alkyl;R21is an optionally substituted C1-C10 alkyl, an optionally substituted C2-C10 alkenyl, an optionally substituted C2-C10 alkynyl, an optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 5-15 membered heteroaryl, an optionally substituted 4-15 membered heterocyclyl, orwherein each R22-R24independently is an optionally substituted C1-C3 alkyl or hydroxy or two of R22-R24together with the carbon atoms they are attached to form a 3-7 membered, preferably a 3-5 membered, or a 5-7 membered ring; andw is 1, 2, 3, 4, or 5.

[0339] In some embodiments, R1is H. In some embodiments, R1is halo. In some embodiments, R1is an optionally substituted Ci-Ce alkyl. In some embodiments, R1is H. In4927-6853-2615.1Atty. Dkt. No. 109290-0190some embodiments, R1is an optionally substituted 4-15 membered heterocyclyl. In some embodiments, R1is -OR20.

[0340] In some embodiments, R2is H. In some embodiments, R2is halo. In some embodiments, R2is an optionally substituted Ci-Ce alkyl. In some embodiments, R2is H. In some embodiments, R2is an optionally substituted 4-15 membered heterocyclyl. In some embodiments, R2is -OR20.

[0341] In some embodiments, R3is H. In some embodiments, R3is halo. In some embodiments, R3is an optionally substituted Ci-Ce alkyl. In some embodiments, R3is H. In some embodiments, R3is an optionally substituted 4-15 membered heterocyclyl. In some embodiments, R3is -OR20.

[0342] In some embodiments, if two of R1-R3are on adjacent carbon atoms, then two such substituents together with the atoms they are attached to form an optionally substituted 5-7 membered ring.

[0343] In some embodiments, each RAR3independently is H. In some embodiments, each R'-R3independently is F. In some embodiments, each R'-R3independently is Cl. In some embodiments, each R'-R3independently is C1-C3 alkyl. In some embodiments, each R'-R3independently is OR20.

[0344] In some embodiments, R20is (CFbjw-R21. In some embodiments, R20is an optionally substituted C3-C6 cycloalkyl. In some embodiments, R20is an optionally substituted Ci-Ce alkyl. In some embodiments, R20is a Ci-Ce alkyl. In some embodiments, R20is a Ci-Ce alkyl substituted with 1-3 fluoro. In some embodiments, R20is a Ci-Ce alkyl substituted with 1-2, preferably, a single hydroxy.

[0345] In some embodiments, R20is CH2-R21. In some embodiments, R20is methyl optionally substituted with 2 or 3 fluorine atoms. In some embodiments, R20is C3-C6 cycloalkyl.

[0346] In some embodiments, w is 1. In some embodiments, w is 2. In some embodiments, w is 3. In some embodiments, w is 4. In some embodiments, w is 5.

[0347] In some embodiments, R21is C1-C10 alkyl. In some embodiments, R21is a branched C3-C10 alkyl optionally substituted with one or more hydroxy or fluoro. In some embodiments, R21is isopropyl or t-butyl optionally substituted with one or more hydroxy or fluoro.854927-6853-2615.1Atty. Dkt. No. 109290-0190

[0348] In some embodiments, R21is

[0349] In some embodiments, R21is

[0350] In some embodiments, R21is

[0351] In some embodiments, R21is

[0352] In some embodiments, R21is

[0353] In some embodiments, R21is

[0354] In some embodiments, R21is864927-6853-2615.1Atty. Dkt. No. 109290-0190

[0355] In some embodiments, R21is

[0356] In some embodiments, R21is a C3-C6 cycloalkyl. In some embodiments, R21is a C3-Ce cycloalkyl substituted with 1-3, preferably 1-2 substituents. In some embodiments, R21is a cyclopropyl. In some embodiments, R21is a cyclopropyl substituted with 1-3, preferably 1-2 substituents. In some embodiments, R21is a cyclobutyl. In some embodiments, R21is a cyclobutyl substituted with 1-3, preferably 1-2 substituents. In some embodiments, R21is a cyclopentyl. In some embodiments, R21is a cyclopentyl substituted with 1-3, preferably 1-2 substituents. In some embodiments, R21is an optionally substituted C1-C10 alkyl. In some embodiments, R21is an optionally substituted C2-C10 alkenyl. In some embodiments, R21is an optionally substituted C2-C10 alkynyl. In some embodiments, R21is an optionally substituted 4-15 membered heterocyclyl.

[0357] In some embodiments, R21is

[0358] In some embodiments, R22is an optionally substituted C1-C3 alkyl. In some embodiments, R22is hydroxy. In some embodiments, R22is H.

[0359] In some embodiments, R23is an optionally substituted C1-C3 alkyl. In some embodiments, R23is hydroxy.

[0360] In some embodiments, R24is an optionally substituted C1-C3 alkyl. In some embodiments, R24is hydroxy.

[0361] In some embodiments, each R22-R24independently is an optionally substituted C1-C3 alkyl. In some embodiments, each R22-R24independently is a hydroxy.

[0362] In some embodiments, two of R22-R24together with the carbon atoms they are attached to form a 3-7 membered ring. In some embodiments, two of R22-R24together with the carbon atoms they are attached to form a 5-7 membered ring. In some embodiments, the4927-6853-2615.1Atty. Dkt. No. 109290-0190ring is optionally substituted cycloalkyl. In some embodiments, the ring is optionally substituted heterocyclyl.

[0363] In some embodiments, B iswhereinR1, R2, and R3are as defined above; orR1and R2together with the atoms they are attached to form an optionally substituted 5-7 membered ring; orR2and R3together with the atoms they are attached to form an optionally substituted 5-7 membered ring.

[0364] In some embodiments, R1and R2together with the atoms they are attached to form an optionally substituted 5-7 membered ring. In some embodiments, R2and R3together with the atoms they are attached to form an optionally substituted 5-7 membered ring.

[0365] In some embodiments, wherein R1is H.

[0366] In some embodiments, R2is F. In some embodiments, R2is H.

[0367] In some embodiments, R2is H or -OR20.

[0368] In some embodiments, R3is F or H.

[0369] In some embodiments, R3is H. In some embodiments, R3is -OR20, wherein R20is as defined above.

[0370] In some embodiments, B is:884927-6853-2615.1Atty. Dkt. No. 109290-0190and wherein R20is as defined above.

[0371] In some embodiments, provided herein is a compound wherein A is:Y1is H or C1-C3 alkyl;L1is an optionally substituted C3-C10 alkylene, further wherein at least two geminal hydrogens together with the carbon(s) to which they are attached are optionally replaced with cyclopropano or cyclobutano; optionally substituted C3-C10 alkenylene, optionally substituted C3-C10 heteroalkylene, optionally substituted C3-C10 heteroalkenylene, or -Ln-L12-L13-; wherein L11is attached to A and L11is O, S, NR, C1-C2 alkylene, C2 alkenylene, C2 heteroalkylene, C3 heteroalkenylene; L12is arylene or heteroarylene; L13is a bond or an optionally substituted C1-C5 alkylene; and R is H or C1-C3 alkyl;L2is -S(0)2NH-, wherein the sulfur is attached to L1or -NHS(0)2-, wherein the nitrogen is attached to L1;L3is a bond or an optionally substituted Ci-Ce alkylene, preferablymore preferably:B is:4927-6853-2615.1Atty. Dkt. No. 109290-0190each RkR3independently is H, F, Cl, C1-C3 alkyl, or OR20;R20is CH2-R21; methyl optionally substituted with 2 or 3 fluorine atoms; C3-C6 cycloalkyl; or Ci-Ce alkyl;R21is an optionally substituted C3-C6 cycloalkyl; an optionally substituted Ce-Cio aryl; an optionally substituted 5-15 membered heteroaryl; an optionally substituted 4-15 membered heterocyclyl; C1-C10 alkyl, preferably branched C3-C10 alkyl, more preferably isopropyl or t-butyl, optionally substituted with one or more hydroxy or fluoro; C3-C6 cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl; orwherein each R22-R24independently is an optionally substituted C1-C3 alkyl or hydroxyl, or two of R22-R24together with the atoms they are attached to form an optionally substituted 3-7 membered ring.

[0372] In some embodiments, provided herein is a compound wherein A isY1is H or C1-C3 alkyl;L1is an optionally substituted C3-C10 alkylene, further wherein at least two geminal hydrogens together with the carbon(s) to which they are attached are optionally replaced with cyclopropano or cyclobutano; optionally substituted C3-C10 alkenylene, optionally substituted 904927-6853-2615.1Atty. Dkt. No. 109290-0190C3-C10 heteroalkylene, optionally substituted C3-C10 heteroalkenylene, or -Ln-L12-L13-, wherein L11is attached to A and L11is O, S, NR, C1-C2 alkylene, C2 alkenylene, C2 heteroalkylene, C3 heteroalkenylene, L12is arylene or heteroarylene, L13is a bond or an optionally substituted C1-C5 alkylene, and R is H or C1-C3 alkyl;L2is -S(0)2NH-, wherein the sulfur is attached to L1or -NHS(0)2-, wherein the nitrogen is attached to L1;L3is a bond or an optionally substituted Ci-Ce alkylene;B iseach RkR3independently is H, F, Cl, C1-C3 alkyl, or -OR20; orR1and R2together with the atoms they are attached to form an optionally substituted 5-7 membered ring; orR2and R3together with the atoms they are attached to form an optionally substituted 5-7 membered ring;R20is CH2-R21; methyl optionally substituted with 2 or 3 fluorine atoms; C3-C6 cycloalkyl; or Ci-Ce alkyl;R21is an optionally substituted C3-C6 cycloalkyl; an optionally substituted Ce-Cio aryl; an optionally substituted 5-15 membered heteroaryl; an optionally substituted 4-15 membered heterocyclyl; C1-C10 alkyl, preferably branched C3-C10 alkyl optionally substituted with one or more hydroxy or fluoro; C3-C6 cycloalkyl; orwherein each R22-R24independently is an optionally substituted C1-C3 alkyl or hydroxy; or two of R22-R24together with the atoms they are attached to form an optionally substituted 3-7 membered ring.914927-6853-2615.1Atty. Dkt. No. 109290-0190

[0373] In some embodiments, Y1is H. In some embodiments, Y1is C1-C3 alkyl.

[0374] In some embodiments, L1is an optionally substituted C3-C10 alkylene, further wherein at least two geminal hydrogens together with the carbon(s) to which they are attached are optionally replaced with cyclopropano or cyclobutano. In some embodiments, L1is an optionally substituted C3-C10 alkenylene. In some embodiments, L1is optionally substituted C3-C10 heteroalkylene. In some embodiments, L1is optionally substituted C3-C10 heteroalkenyl ene .

[0375] In some embodiments, L1is -Ln-L12-L13-, wherein L11is attached to A. In some embodiments, L11is O. In some embodiments, L11is S. In some embodiments, L11is C1-C2 alkylene. In some embodiments, L11is C2 alkenylene. In some embodiments, L11is C2 heteroalkylene. In some embodiments, L11is C3 heteroalkenylene.

[0376] In some embodiments, L11is NR. In some embodiments, R is H. In some embodiments, Ris C1-C3 alkyl.

[0377] In some embodiments, L12is arylene. In some embodiments, L12is heteroarylene.

[0378] In some embodiments, L13is a bond. In some embodiments, L13is an optionally substituted C1-C5 alkylene.

[0379] In some embodiments, L2is -S(O)2NH-, wherein the sulfur is attached to L1or -NHS(O)2-, wherein the nitrogen is attached to L1.

[0380] In some embodiments, L3is a bond. In some embodiments, L3is an optionally substituted Ci-Ce alkylene.

[0381] In some embodiments, R1is H. In some embodiments, R1is F. In some embodiments, R1is Cl. In some embodiments, R1is C1-C3 alkyl. In some embodiments, R1is -OR20.

[0382] In some embodiments, R2is H. In some embodiments, R2is F. In some embodiments, R2is Cl. In some embodiments, R2is C1-C3 alkyl. In some embodiments, R2is -OR20.

[0383] In some embodiments, R3is H. In some embodiments, R3is F. In some embodiments, R3is Cl. In some embodiments, R3is C1-C3 alkyl. In some embodiments, R3is -OR20.924927-6853-2615.1Atty. Dkt. No. 109290-0190

[0384] In some embodiments, R1and R2together with the atoms they are attached to form an optionally substituted 5-7 membered ring. In some embodiments, R2and R3together with the atoms they are attached to form an optionally substituted 5-7 membered ring.

[0385] In some embodiments, R20is CH2-R21. In some embodiments, R20is a methyl optionally substituted with 2 or 3 fluorine atoms. In some embodiments, R20is C3-C6 cycloalkyl. In some embodiments, R20is Ci-Ce alkyl.

[0386] In some embodiments, R21is C1-C10 alkyl. In some embodiments, R21is a branched C3-C10 alkyl optionally substituted with one or more hydroxy or fluoro. In some embodiments, R21is C3-C6 cycloalkyl.

[0387] In some embodiments, R21is

[0388] In some embodiments, R22is an optionally substituted C1-C3 alkyl. In some embodiments, R22is hydroxy.

[0389] In some embodiments, R23is an optionally substituted C1-C3 alkyl. In some embodiments, R23is hydroxy.

[0390] In some embodiments, R24is an optionally substituted C1-C3 alkyl. In some embodiments, R24is hydroxy.

[0391] In some embodiments, two of R22-R24together with the atoms they are attached to form an optionally substituted 5-7 membered ring.

[0392] In some embodiments, B is selected from the group consisting of:934927-6853-2615.1Atty. Dkt. No. 109290-01904927-6853-2615.1Atty. Dkt. No. 109290-0190954927-6853-2615.1Atty. Dkt. No. 109290-0190In some embodiments, the alkoxy group is further substituted wherein 1-5, preferably, 1-3 hydrogen atoms are substituted, preferred substituents including without limitation, Ci-Ce alkyl optionally substituted with 1-3 halo, such as fluoro, and / or Ci-Ce alkoxy; optionally substituted Ci-Ce alkoxy; and halo, preferably fluoro. In some embodiments, substituents include without limitation Ci-Ce alkyl substituted with 1-3 halo, such as fluoro. In some embodiments, substituents include without limitation Ci-Ce alkyl optionally substituted with Ci-Ce alkoxy. In some embodiments, substituents include without limitation a substituted Ci-Ce alkoxy. In some embodiments, substituents include without limitation one or more halo. In some embodiments, substituents include one or more fluoro. In some embodiments, the ring moiety such as the cyclopropyl group is further substituted with 1-3 halo, preferably 1-2 halo. In some embodiments, the ring moiety, such as the cyclopropyl group, is further substituted with 1-2 halo. In some embodiments, the methylene group between the oxygen atom and the ring moiety, such as the cyclopropyl group, is substituted with 1-2 Ci-Ce alkyl, preferably methyl, ethyl, or propyl groups. In some embodiments, the methylene group is substituted with methyl groups. In some embodiments, the methylene group is substituted with ethyl groups. In some embodiments, the methylene group is substituted with propyl groups. In some embodiments, R70is an optionally substituted Ci-Cio alkyl.

[0393] In some embodiments, the alkoxy group is further optionally substituted wherein 1-5 hydrogen atoms are optionally substituted. In some embodiments, substituents include without limitation Ci-Ce alkyl optionally substituted with 1-3 halo, such as fluoro. In some embodiments, substituents include without limitation Ci-Ce alkyl optionally substituted with Ci-Ce alkoxy. In some embodiments, substituents include without limitation an optionally substituted Ci-Ce alkoxy. In some embodiments, substituents include without limitation a halo. In some embodiments, substituents include a fluoro.

[0394] In some embodiments, the ring moiety such as the cyclopropyl group is further optionally substituted with 1-3 halo. In some embodiments, the ring moiety, such as the cyclopropyl group, is further optionally substituted with 1-2 halo.

[0395] In some embodiments, the methylene group between the oxygen atom and the ring moiety, such as the cyclopropyl group, is optionally substituted with 1-2 Ci-Ce alkyl. In some embodiments, the methylene group is optionally substituted with methyl groups. In some embodiments, the methylene group is optionally substituted with ethyl groups. In some embodiments, the methylene group is optionally substituted with propyl groups.964927-6853-2615.1Atty. Dkt. No. 109290-0190

[0396] In some embodiments, B is:

[0397] In some embodiments, the compound of Formula (I) is not

[0398] This disclosure also provides a stereochemically pure enantiomer of a compound as described herein, its tautomer, diastereoisomer or its pharmaceutically acceptable salt.Methods to purify and identify the pure enantiomer are known in the art and described herein.

[0399] In some embodiments, the dUTPase inhibitor is a compound selected from Table 1 below.Table 1.974927-6853-2615.1Atty. Dkt. No. 109290-0190984927-6853-2615.1Atty. Dkt. No. 109290-0190994927-6853-2615.1Atty. Dkt. No. 109290-01901004927-6853-2615.1Atty. Dkt. No. 109290-01901014927-6853-2615.1Atty. Dkt. No. 109290-01901024927-6853-2615.1Atty. Dkt. No. 109290-01901034927-6853-2615.1Atty. Dkt. No. 109290-01901044927-6853-2615.1Atty. Dkt. No. 109290-01901054927-6853-2615.1Atty. Dkt. No. 109290-0190" "

[0400] In some embodiments, the dUTPase inhibitor is a compound selected from Table 2 below.1064927-6853-2615.1Atty. Dkt. No. 109290-0190wherein R70is as defined above and R30is as defined above.

[0401] In some embodiments, the dUTPase inhibitor is a compound selected from Table 3 below.Table 3.1074927-6853-2615.1Atty. Dkt. No. 109290-0190> > >"""1084927-6853-2615.1Atty. Dkt. No. 109290-0190">""1094927-6853-2615.1Atty. Dkt. No. 109290-0190><1104927-6853-2615.1Atty. Dkt. No. 109290-01901114927-6853-2615.1Atty. Dkt. No. 109290-01901124927-6853-2615.1Atty. Dkt. No. 109290-01901134927-6853-2615.1Atty. Dkt. No. 109290-01901144927-6853-2615.1Atty. Dkt. No. 109290-0190Table 5.>"><""1154927-6853-2615.1Atty. Dkt. No. 109290-0190>>< < <" "" < "1164927-6853-2615.1Atty. Dkt. No. 109290-0190<">"<"1174927-6853-2615.1Atty. Dkt. No. 109290-0190Table 6.1184927-6853-2615.1Atty. Dkt. No. 109290-01901194927-6853-2615.1Atty. Dkt. No. 109290-01901204927-6853-2615.1Atty. Dkt. No. 109290-01901214927-6853-2615.1Atty. Dkt. No. 109290-01901224927-6853-2615.1Atty. Dkt. No. 109290-01901234927-6853-2615.1Atty. Dkt. No. 109290-01901244927-6853-2615.1Atty. Dkt. No. 109290-01901254927-6853-2615.1Atty. Dkt. No. 109290-01901264927-6853-2615.1Atty. Dkt. No. 109290-01901274927-6853-2615.1Atty. Dkt. No. 109290-01901284927-6853-2615.1Atty. Dkt. No. 109290-01901294927-6853-2615.1Atty. Dkt. No. 109290-01901304927-6853-2615.1Atty. Dkt. No. 109290-01901314927-6853-2615.1Atty. Dkt. No. 109290-01901324927-6853-2615.1Atty. Dkt. No. 109290-01901334927-6853-2615.1Atty. Dkt. No. 109290-0190<">"<1344927-6853-2615.1Atty. Dkt. No. 109290-0190& &"1354927-6853-2615.1Atty. Dkt. No. 109290-01901364927-6853-2615.1Atty. Dkt. No. 109290-01901374927-6853-2615.1Atty. Dkt. No. 109290-01901384927-6853-2615.1Atty. Dkt. No. 109290-01901394927-6853-2615.1Atty. Dkt. No. 109290-01901404927-6853-2615.1Atty. Dkt. No. 109290-01901414927-6853-2615.1Atty. Dkt. No. 109290-01901424927-6853-2615.1Atty. Dkt. No. 109290-01901434927-6853-2615.1Atty. Dkt. No. 109290-0190Table 7.>" "" "1444927-6853-2615.1Atty. Dkt. No. 109290-0190Table 8.1454927-6853-2615.1Atty. Dkt. No. 109290-0190Table 9.1464927-6853-2615.1Atty. Dkt. No. 109290-01901474927-6853-2615.1Atty. Dkt. No. 109290-01901484927-6853-2615.1Atty. Dkt. No. 109290-01901494927-6853-2615.1Atty. Dkt. No. 109290-0190Table 11.1504927-6853-2615.1Atty. Dkt. No. 109290-0190<>"<<1514927-6853-2615.1Atty. Dkt. No. 109290-0190Table 12.1524927-6853-2615.1Atty. Dkt. No. 109290-01901534927-6853-2615.1Atty. Dkt. No. 109290-0190Table 13.>><>>1544927-6853-2615.1Atty. Dkt. No. 109290-01901554927-6853-2615.1Atty. Dkt. No. 109290-01901564927-6853-2615.1Atty. Dkt. No. 109290-0190Table 14.Table 15.1574927-6853-2615.1Atty. Dkt. No. 109290-01901584927-6853-2615.1Atty. Dkt. No. 109290-01901594927-6853-2615.1Atty. Dkt. No. 109290-01901604927-6853-2615.1Atty. Dkt. No. 109290-01901614927-6853-2615.1Atty. Dkt. No. 109290-01901624927-6853-2615.1Atty. Dkt. No. 109290-01901634927-6853-2615.1Atty. Dkt. No. 109290-01901644927-6853-2615.1Atty. Dkt. No. 109290-01901654927-6853-2615.1Atty. Dkt. No. 109290-01901664927-6853-2615.1Atty. Dkt. No. 109290-01901674927-6853-2615.1Atty. Dkt. No. 109290-01901684927-6853-2615.1Atty. Dkt. No. 109290-01901694927-6853-2615.1Atty. Dkt. No. 109290-01901704927-6853-2615.1Atty. Dkt. No. 109290-01901714927-6853-2615.1Atty. Dkt. No. 109290-01901724927-6853-2615.1Atty. Dkt. No. 109290-01901734927-6853-2615.1Atty. Dkt. No. 109290-01901744927-6853-2615.1Atty. Dkt. No. 109290-01901754927-6853-2615.1Atty. Dkt. No. 109290-01901764927-6853-2615.1Atty. Dkt. No. 109290-01901774927-6853-2615.1Atty. Dkt. No. 109290-01901784927-6853-2615.1Atty. Dkt. No. 109290-01901794927-6853-2615.1Atty. Dkt. No. 109290-01901804927-6853-2615.1Atty. Dkt. No. 109290-01901814927-6853-2615.1Atty. Dkt. No. 109290-01901824927-6853-2615.1Atty. Dkt. No. 109290-01901834927-6853-2615.1Atty. Dkt. No. 109290-01904927-6853-2615.1Atty. Dkt. No. 109290-01901854927-6853-2615.1Atty. Dkt. No. 109290-01901864927-6853-2615.1Atty. Dkt. No. 109290-01901874927-6853-2615.1Atty. Dkt. No. 109290-01901884927-6853-2615.1Atty. Dkt. No. 109290-01901894927-6853-2615.1Atty. Dkt. No. 109290-01901904927-6853-2615.1Atty. Dkt. No. 109290-01901914927-6853-2615.1Atty. Dkt. No. 109290-01901924927-6853-2615.1Atty. Dkt. No. 109290-0190

[0402] In some embodiments, the dUTPase inhibitor is a compound selected from Tables 1-15. In some embodiments, the dUTPase inhibitor is a compound selected from Tables 1-9. In some embodiments, the dUTPase inhibitor is a compound selected from Tables 1 and 2. In some embodiments, the dUTPase inhibitor is Compound A or Compound B.

[0403] These dUTPase inhibitors provided herein and others are synthesized following art recognized methods with the appropriate substitution of commercially available reagents as needed. For example, and without limitation, methods for synthesizing the dUTPase inhibitor disclosed herein are described in WO 2017 / 006282, WO 2017 / 006271, WO 2018 / 098206, WO 2018 / 098207, WO 2018 / 098208, and WO 2018 / 098209, each of which is hereby incorporated by reference herein. Non-limiting examples of other dUTPase inhibitors and methods for their synthesis are also described in US 2011 / 0082163; US 2012 / 0225838; WO 2014 / 107622; PCT / US2015 / 010059; Miyahara et al., J. Med. Chem. (2012) 55, 2970-2980; Miyakoshi et al., J. Med. Chem. (2012) 55, 2960-2969; Miyahara et al., J. Med. Chem. (2012) 55 (11), pp 5483-5496; and Miyakoshi et al., J. Med. Chem. (2012) 55 (14), pp 6427-1934927-6853-2615.1Atty. Dkt. No. 109290-01906437 (each supra), each of which is hereby incorporated by reference herein. Protection deprotection methods and protecting groups useful for such purposes are well known in the art, for example in Greene’s Protective Groups in Organic Synthesis, 4thEdition, Wiley, 2006, or a later edition of the book.

[0404] In some embodiments, the dUTPase inhibitor is not a uracil-containing compound. In some embodiments, the dUTPase inhibitor is not a fluorouracil-containing compound. In some embodiments, the dUTPase inhibitor is not (R)-N-(l-(3-(cyclopentyloxy) phenyl)ethyl)-3-((2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)methoxy)propane-l-sulfonamide.

[0405] In some embodiments, the dUTPase inhibitor is (R)-N-(l -(3 -(cyclopentyloxy) phenyl)ethyl)-3-((2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)methoxy)propane-l-sulfonamide.

[0406] In some embodiments, the dUTPase inhibitor is a compound of Formula (II):wherein:n represents an integer of 1 to 3;X represents a bond, an oxygen atom, a sulfur atom, an alkenylene group having 2 to 6 carbon atoms, a divalent aromatic hydrocarbon group which is optionally substituted, or a divalent saturated or unsaturated heterocyclic group which is optionally substituted; Y represents a bond or a linear or branched alkylene group having 1 to 8 carbon atoms which optionally have a cycloalkylidene structure on one carbon atom; andZ represents -SO2NRJR.2or -NR3SC>2R4, wherein:R1and R2are the same or different and each represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an aralkyl group which is optionally substituted, wherein when an aromatic hydrocarbon group constituting the aralkyl group is a phenyl group, the1944927-6853-2615.1Atty. Dkt. No. 109290-0190phenyl group may form a condensed bicyclic hydrocarbon group, together with the substituent, or R1and R2are taken together with the adjacent nitrogen atom to form a saturated heterocyclic group which is optionally substituted;R3represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; andR4represents an aromatic hydrocarbon group which is optionally substituted or an unsaturated heterocyclic group which is optionally substituted.Pharmaceutical Compositions

[0407] In another aspect, provided herein is a composition comprising, consisting essentially of, or consisting of the combination of compounds provided herein, and at least one pharmaceutically acceptable excipient.

[0408] Compositions, including pharmaceutical compositions comprising, consisting essentially of, or consisting of the combination of compounds described herein, can be manufactured by means of conventional mixing, dissolving, granulating, dragee-making levigating, emulsifying, encapsulating, entrapping, or lyophilization processes. The compositions can be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients, or auxiliaries which facilitate processing of the combinations of compounds provided herein into preparations which can be used pharmaceutically.

[0409] The combination of compounds of the present disclosure can be administered by parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intraci sternal injection or infusion, subcutaneous injection, or implant), oral, by inhalation spray nasal, vaginal, rectal, sublingual, urethral (e.g, urethral suppository) or topical routes of administration (e.g, gel, ointment, cream, aerosol, etc.) and can be formulated in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, excipients, and vehicles appropriate for each route of administration.

[0410] In one embodiment, this technology relates to a composition comprising a combination of compounds as described herein and a carrier.

[0411] In another embodiment, this technology relates to a pharmaceutical composition comprising a combination of compounds as described herein and a pharmaceutically acceptable carrier.1954927-6853-2615.1Atty. Dkt. No. 109290-0190

[0412] In another embodiment, this technology relates to a pharmaceutical composition comprising an effective amount or a therapeutically effective amount of a combination of compounds as described herein and a pharmaceutically acceptable carrier.

[0413] The pharmaceutical compositions for the administration of the combinations of compounds can be conveniently presented in dosage unit form and can be prepared by any of the methods well known in the art of pharmacy. The pharmaceutical compositions can be, for example, prepared by uniformly and intimately bringing the compounds provided herein into association with a liquid carrier, a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition, each compound of the combination provided herein is included in an amount sufficient to produce the desired therapeutic effect. For example, pharmaceutical compositions of the present technology may take a form suitable for virtually any mode of administration, including, for example, topical, ocular, oral, buccal, systemic, nasal, injection, infusion, transdermal, rectal, and vaginal, or a form suitable for administration by inhalation or insufflation.

[0414] For topical administration, the combination of compounds can be formulated as solutions, gels, ointments, creams, suspensions, etc., as is well-known in the art.

[0415] Systemic formulations include those designed for administration by injection (e.g., subcutaneous, intravenous, infusion, intramuscular, intrathecal, or intraperitoneal injection) as well as those designed for transdermal, transmucosal, oral, or pulmonary administration.

[0416] Useful injectable preparations include sterile suspensions, solutions, or emulsions of the compounds provided herein in aqueous or oily vehicles. The compositions may also contain formulating agents, such as suspending, stabilizing, and / or dispersing agents. The formulations for injection can be presented in unit dosage form, e.g., in ampules or in multidose containers, and may contain added preservatives.

[0417] Alternatively, the injectable formulation can be provided in powder form for reconstitution with a suitable vehicle, including but not limited to sterile pyrogen free water, buffer, and dextrose solution, before use. To this end, the combination of compounds provided herein can be dried by any art-known technique, such as lyophilization, and reconstituted prior to use.

[0418] For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are known in the art.1964927-6853-2615.1Atty. Dkt. No. 109290-0190

[0419] For oral administration, the pharmaceutical compositions may take the form of, for example, lozenges, tablets, or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). The tablets can be coated by methods well known in the art with, for example, sugars, films, or enteric coatings.

[0420] Compositions intended for oral use can be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the combination of compounds provided herein in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients can be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents (e.g., com starch or alginic acid); binding agents (e.g. starch, gelatin, or acacia); and lubricating agents (e.g., magnesium stearate, stearic acid, or talc). The tablets can be left uncoated or they can be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. They may also be coated by the techniques well known to the skilled artisan. The pharmaceutical compositions of the present technology may also be in the form of oil-in-water emulsions.

[0421] Liquid preparations for oral administration may take the form of, for example, elixirs, solutions, syrups, or suspensions, or they can be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats); emulsifying agents (e.g., lecithin, or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, cremophore™, or fractionated vegetable oils); and preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts, preservatives, flavoring, coloring, and sweetening agents as appropriate.1974927-6853-2615.1Atty. Dkt. No. 109290-0190

[0422] In some embodiments, one or more compositions disclosed herein are contained in a kit. Accordingly, in some embodiments, provided herein is a kit comprising, consisting essentially of, or consisting of one or more compositions disclosed herein and instructions for their use.Dosages and Dosing Regimens

[0423] The appropriate amount and dosing regimen of the PARP inhibitor, the inhibitor of thymidylate biosynthesis, or the dUTPase inhibitor, according to any of the methods disclosed herein, may be determined by one of ordinary skill in the art. In some embodiments, all three of the PARP inhibitor, the inhibitor of thymidylate biosynthesis, and the dUTPase inhibitor are administered concurrently. In some embodiments, all three of the PARP inhibitor, the inhibitor of thymidylate biosynthesis, and the dUTPase inhibitor are administered sequentially. In some embodiments, two of the PARP inhibitor, the inhibitor of thymidylate biosynthesis, and the dUTPase inhibitor are administered concurrently, with the remaining active agent administered before or after.

[0424] In some embodiments, the active compounds from a combination disclosed herein, or salts or solvates thereof, may be administered to a subject suffering from abnormal cell growth, such as a human, either alone or as part of a pharmaceutically acceptable formulation, once a week, once a day, twice a day, three times a day, or four times a day, or even more frequently.

[0425] Administration of the compounds within the combinations disclosed herein may be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical, and rectal administration. Bolus doses can be used, or infusions over a period of 1, 2, 3, 4, 5, 10, 15, 20, 30, 60, 90, 120 or more minutes, or any intermediate time period can also be used, as can infusions lasting 3, 4, 5, 6, 7, 8, 9, 10. 12, 14 16, 20, 24 or more hours or lasting for 1-7 days or more. Infusions can be administered by drip, continuous infusion, infusion pump, metering pump, depot formulation, or any other suitable means.

[0426] Dosage regimens may be adjusted to provide the optimum desired response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral 1984927-6853-2615.1Atty. Dkt. No. 109290-0190compositions 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 subjects 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 (a) the unique characteristics of the chemotherapeutic agent and the particular therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals.

[0427] Thus, the skilled artisan would appreciate, based upon the disclosure provided herein, that the dose and dosing regimen is adjusted in accordance with methods well-known in the therapeutic arts. That is, the maximum tolerable dose can be readily established, and the effective amount providing a detectable therapeutic benefit to a patient may also be determined, as can the temporal requirements for administering each agent to provide a detectable therapeutic benefit to the patient. Accordingly, while certain dose and administration regimens are exemplified herein, these examples in no way limit the dose and administration regimen that may be provided to a patient in practicing the present disclosure.

[0428] It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and / or laboratory values. Thus, the present disclosure encompasses intra-patient dose-escalation as determined by the skilled artisan. Determining appropriate dosages and regimens for administration of the chemotherapeutic agent are well-known in the relevant art and would be understood to be encompassed by the skilled artisan once provided the teachings disclosed herein.

[0429] In some embodiments, talazoparib is administered as a dose of 1 mg taken orally once daily for a 28 day cycle. Dosing is continuous until disease progression or unacceptable toxicity. Dosing may be adjusted in patients with hepatic or renal impairment.1994927-6853-2615.1Atty. Dkt. No. 109290-0190

[0430] In some embodiments, talazoparib is administered in combination with enzalutamide. Accordingly, in some embodiments, talazoparib is administered as a dose of 0.5 mg taken orally once daily for a 28 day cycle in combination with enzalutamide at a dose of 160 mg orally once daily. Dosing is continuous until disease progression or unacceptable toxicity.

[0431] In some embodiments, olaparib is administered as a dose of 300 mg taken orally twice daily for a 28 day cycle. Dosing is continuous until disease progression or unacceptable toxicity.

[0432] In some embodiments, olaparib is administered in combination with abiraterone acetate. Accordingly, in some embodiments, olaparib is administered as a dose of 300 mg taken orally twice daily for a 28 day cycle in combination with abiraterone at a dose of 1000 mg orally once daily alongside prednisone or prednisolone at 5 mg orally twice daily. Dosing is continuous until disease progression or unacceptable toxicity.

[0433] In some embodiments, niraparib is administered as a dose of 200 or 300 mg orally once daily for a 28 day cycle. Dosing is continuous until disease progression or unacceptable toxicity.

[0434] In some embodiments, niraparibis administered in combination with abiraterone acetate. Accordingly, in some embodiments, niraparib is administered as a dose of 200 or 300 mg taken orally once daily for a 28 day cycle in combination with abiraterone at a dose of 1000 mg orally once daily alongside prednisone or prednisolone at 5 mg orally twice daily. Dosing is continuous until disease progression or unacceptable toxicity

[0435] In some embodiments, rucaparib is administered as a dose of 600 mg orally twice daily (12 hours apart) for a 28 day cycle. Dosing is continuous until disease progression or unacceptable toxicity.

[0436] In some embodiments, 5-FU is administered as a dose of 500 mg / m2, i.v. bolus on day 1; and 1 hour prior to administering the 5-FU bolus, the patient is also administered leucovorin (500 mg / m2, i.v.) over 2 hours. This regimen is repeated weekly on days 1, 8, 15, 22, 29, and 36 every 8 weeks for 4 to 6 cycles.

[0437] In some embodiments, 5-FU is administered in combination with radiation therapy. In further embodiments, 5-FU is administered as a dose of 500 mg / m2, i.v. bolus for 5 days on days 1 and 36 beginning 22 to 70 days after surgery; and radiation therapy is administered for 6 weeks beginning on day 64 after initiation of 5-FU therapy, while 5-FU is administered 2004927-6853-2615.1Atty. Dkt. No. 109290-0190at a dose of 225 mg / m2 / day, i.v. continuous infusion throughout administration of radiation therapy. Then, 5-FU is administered at a dose of 450 mg / m2, i.v. bolus daily for 5 days beginning 1 month after radiation (i.e., days 134 to 138) and repeated for 4 weeks.

[0438] In some embodiments, 5-FU is administered in combination with irinotecan and leucovorin, with or without bevacizumab (FOLFIRI with or without bevacizumab), wherein 5-FU is administered as a dose of 400 mg / m2, i.v. bolus on day 1, followed by 5-FU 1,200 mg / m2 / day on days 1 and 2 by continuous i.v. infusion (CIV) (total infusional dose, 2,400 mg / m2over 46 hours) for cycles 1 and 2. If there is no toxicity greater than grade 1, the 5-FU infusion dose may be increased to 3,000 mg / m2for all subsequent cycles.

[0439] In some embodiments, 5-FU is administered in combination with leucovorin and oxaliplatin with or without bevacizumab (FOLFOX4 with or without bevacizumab), wherein 5-FU is administered as a dose of 400 mg / m2, i.v. bolus over 2 to 4 minutes, followed by 5-FU 600 mg / m2continuous i.v. infusion (CIV) over 22 hours on day 1. Prior to 5-FU bolus on day 1, oxaliplatin 85 mg / m2, i.v. and leucovorin 200 mg / m2, i.v. (both over 120 minutes via Y-site) are administered. If giving FOLFOX4 plus bevacizumab, bevacizumab 10 mg / kg, i.v. is administered over 30 to 90 minutes prior to chemotherapy on day 1. On day 2, a regimen of leucovorin 200 mg / m2, i.v. over 2 hours followed by 5-FU 400 mg / m2, i.v. bolus, followed by 5-FU 600 mg / m2CIV over 22 hours is repeated. The order of administration is bevacizumab followed by oxaliplatin and leucovorin, followed by 5-FU. This 2-day regimen is repeated every 2 weeks until disease progression or unacceptable toxicity is observed.

[0440] In some embodiments, capecitabine is administered as adjuvant following surgery (monotherapy) as a dose of 1.25 g / m2twice daily for 14 days, and subsequent courses are repeated after a 7-day interval, with recommended duration of treatment as 6 months, adjusted dose according to tolerability.

[0441] In some embodiments, capecitabine is administered as adjuvant following surgery (combination therapy) as a dose of 0.8-1 g / m2twice daily for 14 days, and subsequent courses are repeated after a 7-day interval, with recommended duration of treatment as 6 months, adjusted dose according to tolerability.

[0442] In some embodiments, capecitabine is administered as a dose of 1.25 g / m2twice daily for 14 days, and subsequent courses are repeated after a 7-day interval, adjusted dose according to tolerability.2014927-6853-2615.1Atty. Dkt. No. 109290-0190

[0443] In some embodiments, capecitabine is administered as a dose of 0.8-1 g / m2twice daily for 14 days, and subsequent courses are repeated after a 7-day interval, adjusted dose according to tolerability.

[0444] In some embodiments, capecitabine is administered in combination with a platinum based regimen, wherein capecitabine is administered as a dose of 0.8-1 g / m2twice daily for 14 days, and subsequent courses are repeated after a 7-day interval, or alternatively administered as a dose of 625 mg / m2twice daily given continuously, adjusted dose according to tolerability.

[0445] In some embodiments, capecitabine is administered in combination with irinotecan (CAPIRI), wherein capecitabine is administered as a dose of 0.8-1 g / m2twice daily for 14 days, and subsequent courses are repeated after a 7-day interval, or alternatively administered as a dose of 625 mg / m2twice daily given continuously for 14 days of a 3 week cycle, and irinotecan is administered at 250-350 mg / m2intravenously once on day 1 of a 3 week cycle.

[0446] In some embodiments, methotrexate is administered orally or intramuscularly in doses of 15 to 30 mg daily for a five-day course. Such courses are usually repeated for 3 to 5 times as necessary.

[0447] In some embodiments, methotrexate is administered as a dose of 10 to 25 mg / day orally for 4 to 8 days.

[0448] In some embodiments, methotrexate is administered as a dose of 5 to 50 mg once weekly. Dose reduction or cessation is guided by patient response and hematologic monitoring.

[0449] In some embodiments, methotrexate is used in combination with other agents. In further embodiments, in addition to high-dose methotrexate with leucovorin rescue, these agents may include doxorubicin, cisplatin, and the combination of bleomycin, cyclophosphamide and dactinomycin (BCD). The starting dose for high-dose methotrexate treatment is 12 grams / m2.

[0450] In some embodiments, floxuridine (FUdR) is administered at a dose of 100-150 mg / m2 / day) as a continuous infusion over 14 days, and subsequent courses are repeated every 4-6 week interval with a recommended duration of treatment of 6 months, with dose adjustment according to tolerability.2024927-6853-2615.1Atty. Dkt. No. 109290-0190

[0451] In some embodiments, floxuridine (FUdR) is administered at a dose of 100-150 mg / m2 / day) as a continuous infusion over 14 days in combination with other approved systemic therapies such as oxaliplatin or irinotecan-based regimens, depending on the patient's overall treatment plan.

[0452] The following examples are included to demonstrate some embodiments of the disclosure. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.EXAMPLES

[0453] Example 1. High-throughput Screening (HTS)

[0454] As part of a biomarker screen to identify compounds that directly impact the anticancer activity of the DNA uracilation pathway and the efficacy of dUTPase inhibitors, a compound library comprising 161 compounds, targeting 47 distinct cell cycle and DNA damage pathways, was screened across multiple cancer cell lines as single agents and in combination with the dUTPase inhibitor Compound A, with the fluoropyrimidine thymidylate synthase inhibitor FUdR, or with the dual combination of Compound A and FUdR. Cytotoxic effects were measured using the CELLTITER-GLO® 2.0 Viability Assay following 72 hour and 120 hour continuous exposures. Compounds that exhibited a marked increase in cytotoxicity when combined with Compound A, FUdR, or the combination of Compound A + FUdR when compared to monotherapy were identified as “hits.”

[0455] Talazoparib, a poly ADP-ribose polymerase (PARP) inhibitor approved for the treatment of HER2-negative, germline BRCA-mutated breast cancer, demonstrated a significant enhancement in cytotoxicity when used in conjunction with Compound A + FUdR across multiple cancer cell lines spanning three different cancer types. Talazoparib’ s mechanism of action is via the inhibition of PARP1 / 2 enzymes, crucial for the detection and repair of single-strand DNA breaks, and inducing PARP trapping, which blocks DNA repair, replication, and transcription, leading to cell death. PARP inhibitors are only clinically approved for treatment of distinct cancer types that harbor specific DNA repair defects including mutation in BRCA1 / 2 or homologous recombination (HR) deficiency. The synergistic anticancer activity of a PARP inhibitor in combination with a dUTPase and TS inhibitor has not been described previously.2034927-6853-2615.1Atty. Dkt. No. 109290-0190

[0456] Compound

[0457] Example 2: Combined effects of Compound A, FUdR and Talazoparib enhance cytotoxicity across multiple cancer cell lines.

[0458] Experimental overview: As noted in Example 1, HTS identified talazoparib as a potential compound to enhance the cytotoxicity of multiple cancer cell lines when combined with Compound A + FUdR. To validate this experimental result, a growth inhibition assay (GIA) was used to determine the cytotoxicity of multiple cancer cell lines when treated with a fixed dose of Compound A, a fixed dose of FUdR, or a fixed dose of the combination (Compound A + FUdR), in the presence or absence of increasing doses of the PARP inhibitor (talazoparib) following a continuous exposure period of 72 h or 120 h. Cytotoxicity was assessed using CELLTITER-GLO® 2.0 Cell Viability Assay. Cell lines assayed for cell survival included HCT116 (colorectal cancer), A549 (lung cancer), and MDA-MB-231 (breast cancer).

[0459] Cell line model selection: HCT116 (CCL-247™), A549 (CCL-185™) and MDA-MB-231 (HTB-26™) cell lines were acquired from American Type Culture Collection (ATCC). Cells were maintained in the appropriate culture media supplemented with 10% fetal bovine serum (FBS), 1% penicillin / streptomycin (P / S), 1% L-glutamine (L-Glut) and 1% sodium pyruvate (NaPyr). Cells were cultured and expanded in humidified incubators at 37°C and 5% CO2 until sufficient cells were available. All cell lines were routinely screened for mycoplasma infection using the MYCOALERT™ mycoplasma detection kit (Lonza) and have been authenticated using short tandem repeat (STR) profiling (Eurofins).

[0460] Cell preparation and drug treatments: 1000-2000 cells (HCT116, A549 and MDA-MB-231) suspended in 50 pL of complete media were added to the inner 60 wells of an opaque white 96-well plate. Sterile water (100 pL) was added to the outer wells of the 96-well plate to maintain adequate humidity, and the plates were placed in a humidified incubator at 5% CO2 to allow cells to adhere overnight. The following day, all compounds were prepared freshly in cell culture media from frozen stocks prior to treatment. Cells were treated with a fixed dose of Compound A, a fixed dose of FUdR, or a fixed dose of the combination (Compound A + FUdR), alone or in combination with increasing doses of talazoparib. Following treatment, the 96-well plates were gently shaken at 300 rpm for 22044927-6853-2615.1Atty. Dkt. No. 109290-0190minutes to ensure adequate mixing, and the plates were left in a humidified incubator at 5% CO2 for a continuous exposure period of 72 h and 120 h.

[0461] CELLTITER-GLO® 2.0 Viability Assay: Following 72 h and 120 h exposure period, cytotoxicity was assessed using CELLTITER-GLO® 2.0 Viability Assay. The CELLTITER-GLO® 2.0 Viability Assay provides a homogeneous method to determine the number of viable cells in culture by quantitating the amount of ATP present, which indicates the presence of metabolically active cells. Viable cells maintain ATP production, while non-viable cells rapidly lose this capability during cell death. Briefly, CELLTITER-GLO® 2.0 reagent was allowed to equilibrate to room temperature 30 minutes prior to use. An equal volume of CELLTITER-GLO® 2.0 reagent and culture media were mixed in a 50 mL tube (100 pL per well required). Media was removed from the cells on the 96-well plate and replaced with 100 pL of CELLTITER-GLO® 2.0 reagent / media mix. Wells containing 100 pL of CELLTITER-GLO® 2.0 reagent / media mix with no cells were used as a blank luminescence control. Plates were shaken on an orbital shaker for 2 minutes at 500 rpm to induce cell lysis and incubated at room temperature for 10 minutes covered in foil.Luminescence was measured on the CLARIOSTAR® (BMG Labtech) microplate reader. Cytotoxicity was expressed as a percentage of the untreated control.

[0462] Results: For each of cell lines, the concentrations of Compound A and FUdR used was consistent with the concentrations used in the original screening of these cell lines which identified talazoparib as a potential “hit.” At both the 72 h and 120 h timepoints, all cell lines demonstrated a dose-dependent increase in cytotoxicity with increasing doses of talazoparib. At the 72 h timepoint, the combination of Compound A + FUdR demonstrated a percentage control of -80% across all cell lines. Notably, none of the cell lines demonstrated a significant increase in cytotoxicity when Compound A + FUdR was combined with talazoparib, when compared to Compound A + Talazoparib, FUdR + talazoparib and talazoparib single agent (Figures 1A-1C). Contrary to this, at the 120 h timepoint, all cells lines demonstrated an enhanced cytotoxicity when Compound A + FUdR was combined with talazoparib (Figure 1A-1C). In the HCT116 cell line, the percentage control following 120 h continuous exposure to Compound A + FUdR in the absence of talazoparib is 73%. When treated with the lowest concentration of talazoparib assayed (0.005 pM), the percentage control was reduced to 48%, while Compound A + talazoparib (0.005 pM), FUdR + talazoparib (0.005 pM) and talazoparib single agent (0.005 pM) demonstrated no cytotoxicity (Figure 1A). Similarly, in the A549 cell line, at the lowest concentration of talazoparib 2054927-6853-2615.1Atty. Dkt. No. 109290-0190assayed (0.005 pM), Compound A + talazoparib (0.005 pM), FUdR + talazoparib (0.005 pM) and talazoparib single agent (0.005 pM) demonstrated minimal cytotoxicity. However, when Compound A + FUdR was combined with talazoparib (0.005 pM), cytotoxicity was reduced to 34% compared to 50% with Compound A + FUdR, alone (Figure IB). Finally, in the MDA-MB-231 cell line, the enhanced cytotoxicity when Compound A + FUdR was combined with talazoparib was not observed until concentrations of talazoparib greater than 0.025 pM (Figure 1C) were assessed.

[0463] This data validates the HTS identification of a PARP inhibitor as a hit, confirming the enhancement of cytotoxicity when a dUTPase inhibitor + a TS inhibitor is combined with a PARP inhibitor such as talazoparib. Inhibition of dUTPase in combination with an inhibitor of thymidylate biosynthesis induces DNA uracilation which causes highly specific DNA damage. Without being bound to any one particular theory, it is believed that PARP plays a key role in the repair of DNA damage caused by DNA uracilation, and the enhanced synergistic effect observed at 120 hours when compared to 72 hours is the result of DNA damage accumulation due to PARP inhibition.

[0464] Example 3: Combined effects of Compound A, FUdR, and PARP inhibition reduce long-term survival across multiple cancer cell lines using sub-lethal doses of PARP inhibitor.

[0465] Experimental overview: Cancer cells were treated with control, a fluoropyrimidine (FUdR) alone, Compound A alone, or the combination of Compound A and FUdR. Each of these treatment conditions was investigated in the presence or absence of increasing doses of the PARP inhibitors: olaparib, rucaparib, niraparib and talazoparib. Long-term cell survival was assessed using Colony Formation Assay (CFA). Cell lines assayed for cell survival included HCT116 (colorectal cancer), A549 (lung cancer); and MDA-MB-23 (breast cancer).

[0466] Cell line model selection: HCT116, A549 and MDA-MB-231 cells were maintained in the appropriate culture media supplemented with 10% fetal bovine serum (FBS), 1% penicillin / streptomycin (P / S), 1% L-glutamine (L-Glut) and 1% sodium pyruvate (NaPyr). Cells were cultured and expanded in humidified incubators at 37 °C and 5% CO2 until sufficient cells were available. All cell lines were routinely screened for mycoplasma infection using the MYCO ALERT™ mycoplasma detection kit (Lonza) and have been authenticated using short tandem repeat (STR) profiling (Eurofins).2064927-6853-2615.1Atty. Dkt. No. 109290-0190

[0467] Cell preparation and drug treatments: 200-250 cells (HCT116, A549 and MDA-MB-231) suspended in 500 pL of complete media were added to the inner 8 wells of a 24-well plate. Sterile water (1 mL) was added to the outer wells of the 24-well plate to maintain adequate humidity. The plates were placed in a humidified incubator at 5% CO2 to allow cells to adhere overnight. The following day, all compounds were prepared freshly in cell culture media from frozen stocks prior to treatment. Seeding media was removed and replaced with drug-containing media and incubated for 48 hours. Cells were treated with a fixed dose of Compound A, a fixed dose of FUdR, or a fixed dose of the combination of Compound A + FUdR, alone or in combination with increasing doses of PARP inhibitor. Following 48 h incubation, drug-containing media was removed and replaced with 1 mL of complete media, and cells were left in a humidified incubator at 5% CO2 to form colonies (>50 cells) for a period of 9-12 days.

[0468] Colony Formation Assay (CFA): Following sufficient colony formation (>50 cells), colonies were fixed and stained using the following protocol. Media was removed from each well and replaced with 500 pL of ice-cold 70% methanol, and plates were left to incubate for 15 minutes on an orbital rocker at room temperature (RT). Following fixation, methanol was removed from each well, and the plates were inverted and left to dry. Once dry, colonies were stained with 0.5% crystal violet solution by adding approximately 500 pL to each well and incubating on an orbital rocker at RT. Colonies were sufficiently stained after a 15-minute incubation. To remove excess stain, changes of IX PBS were added to each well. A final wash using distilled water was completed to prevent the formation of salt crystals. Colonies were counted by acquiring images and subsequent processing using the Oxford Optronix GELCOUNT™ Analyser. Cell survival was expressed as a percentage of the untreated control.

[0469] Results: For each of the cell lines assayed, a fixed dose of Compound A and FUdR was chosen based on previous optimization experiments. In the absence of a PARP inhibitor, all three cell lines demonstrated no significant decrease in cell survival when treated with Compound A and FUdR as single agents. When Compound A was combined with FUdR, all three cell lines demonstrated a statistically significant reduction in cell survival of approximately 20-30%. The synergistic increase in anticancer activity through use of a dUTPase inhibitor, such as Compound A, with fluoropyrimidines, such as FUdR, has been previously reported.2074927-6853-2615.1Atty. Dkt. No. 109290-0190

[0470] In both the HCT116 and A549 cell lines, single agent olaparib demonstrated no significant decrease in cell survival across all the investigated doses (0.05, 0.1, 1 pM).Marginally higher doses were assayed in the MDA-MB-231 cell line, where both the 0.1 and 1 pM doses demonstrated no single agent activity with olaparib; however, the 5 pM dose caused a reduction in cell survival of -30% (p=0.0102). When Compound A + FUdR was combined with olaparib, there was a dose dependent reduction in cell survival, an observation which was consistent across all three cell lines. In the HCT116 cell line, olaparib at all concentrations, in combination with Compound A + FUdR demonstrated a significant reduction in cell survival in comparison to Compound A + FUdR alone, causing a reduction in cell survival from 81% in the absence of olaparib to 49% (p=<0.0001), 46% (p=<0.0001) and 22%(p=<0.0001) when combined with 0.05, 0.1 and 1 pM of olaparib, respectively (Figure 2A). Similarly, in the A549 cell line, 0.1 and 1 pM of olaparib in combination with Compound A + FUdR demonstrated a significant reduction in cell survival from 70% in the absence of olaparib to 42% (p=0.0004) and 28% (p=<0.0001), respectively (Figure 2B). In the MDA-MB-231 cell line, treatment the combination of Compound A + FUdR in the absence of olaparib resulted in cell survival of -68%; however, when combined with 1 and 5 pM doses of olaparib, this cell survival was reduced to 37% (p=0.0001) and 18% (p=<0.0001), respectively (Figure 2C). Statistical analysis is shown in Figure 2D.

[0471] The same concentrations of rucaparib were assayed across each cell line as used with olaparib. The lower doses of rucaparib demonstrated no significant single agent activity across all three cell lines; however, at the highest concentration, all cell lines demonstrated a significant reduction in cell survival with single agent rucaparib in comparison to an untreated control. In both the HCT116 and A549 cell lines, 1 pM of rucaparib demonstrated a reduction in cell survival of -20%. In the MDA-MB-231, the 5 pM dose of rucaparib caused a reduction in cell survival of -50%. Despite some concentrations of rucaparib demonstrating single agent activity, there was still a significant reduction in cell survival when combined with Compound A + FUdR in comparison to rucaparib treatment alone. As with olaparib, the HCT116 cell line demonstrated a significant reduction in cell survival when Compound A + FUdR was combined with all three concentrations of rucaparib assayed, in comparison to Compound A + FUdR alone. Cell survival was reduced from 81% in the absence of rucaparib to 40% (p=<0.0001), 35% (p=<0.0001) and 15% (p=<0.0001) when combined with 0.05, 0.1 and 1 pM of rucaparib, respectively (Figure 3A). In the A549 cell line, two out of three doses of rucaparib assayed demonstrated a significant reduction in cell survival when2084927-6853-2615.1Atty. Dkt. No. 109290-0190combined with Compound A + FUdR in comparison to Compound A + FUdR alone. The combination of Compound A + FUdR demonstrated a cell survival of 70%, which was reduced to 42% (p=0.0003) and 24% (p=<0.0001) when combined with 0.1 and 1 pM of rucaparib, respectively (Figure 3B). Similarly, in the MDA-MB-231 cell line, two out of three doses of rucaparib demonstrated a significant reduction in cell survival when combined with Compound A + FUdR in comparison to Compound A + FUdR alone. In the absence of rucaparib treatment, the combination of Compound A + FUdR causes a cell survival of -68%, but this cell survival was reduced to 35% (p=<0.0001) and 24% (p=<0.0001), respectively when combined with 1 and 5 pM doses of rucaparib (Figure 3C). Statistical analysis shown in Figure 3D.

[0472] The same concentrations of niraparib were assayed across each cell line as used with rucaparib and olaparib. The single agent activity of niraparib demonstrated enhanced potency when compared to rucaparib and olaparib. The 0.05 pM dose of niraparib demonstrated no significant decrease in cell survival in the HCT116 and A549 cell lines. Similarly, the 0.1 pM dose of niraparib demonstrated no significant decrease in cell survival across all cell lines. At the 1 pM dose, the HCT116, A549 and MDA-MB-231 cell lines demonstrated a reduction in cell survival of 47% (p=<0.0001), 34% (p=<0.0001), and 34% (p=<0.0001) respectively, in comparison to the untreated control. The 5 pM dose was only assayed in the MDA-MB-231 cell line and demonstrated a significant reduction in cell survival of -88% (p=<0.0001). Given the significant single agent effects at this 5 pM dose, no additional effects on cell survival were observed when combined with Compound A + FUdR. However, when niraparib, at a dose of 0.05, 0.1, or 1 pM, was combined with Compound A + FUdR, there was a significant reduction in cell survival in comparison to niraparib treatment alone. As observed with both olaparib and rucaparib, all three doses of niraparib assayed in the HCT116 cell line demonstrated a significant reduction in cell survival (p=<0.0001) when combined with Compound A + FUdR in comparison to Compound A + FUdR alone (Figure 4A). In the A549 cell line, two out of three doses of niraparib assayed demonstrated a significant reduction in cell survival when combined with Compound A + FUdR in comparison to Compound A + FUdR alone. The combination of Compound A + FUdR in the absence of niraparib demonstrated a cell survival of 70%, this was reduced to 39% (p=0.0003) and 20% (p=<0.0001) when combined with 0.1 and IpM of niraparib, respectively (Figure 4B). Similarly, in the MDA-MB-231 cell line, two out of three doses of niraparib assayed demonstrated a significant reduction in cell survival when combined with2094927-6853-2615.1Atty. Dkt. No. 109290-0190Compound A + FUdR in comparison to Compound A + FUdR alone. The combination of Compound A + FUdR in the absence of niraparib demonstrated a cell survival of 68%, this was reduced to 49% (p=0.0324) and 35% (p=<0.0001) when combined with 0.1 and 1 pM of niraparib, respectively (Figure 4C). Statistical analysis shown in Figure 4D.

[0473] As reflected in the concentrations assayed across each cell line, talazoparib was the most potent of all the PARP inhibitors investigated. Each of the cell lines demonstrate some single agent activity with talazoparib resulting in a reduction in cell survival; however, when combined with Compound A + FUdR, significant reductions in cell survival in comparison to talazoparib treatment alone were still observed. Similarly to the other PARP inhibitors, talazoparib demonstrates a dose-dependent reduction in cell survival when combined with Compound A + FUdR. In the HCT116 cell line, all three doses of talazoparib assayed demonstrated a significant reduction in cell survival when combined with Compound A + FUdR in comparison to Compound A + FUdR alone. The combination of Compound A + FUdR in the absence of talazoparib demonstrated a cell survival of 81%, which was reduced to 20% (p=<0.0001), 11% (p=<0.0001) and 4% (p=<0.0001) when combined with 0.005, 0.01 and 0.1 pM of talazoparib, respectively (Figure 5A). Similarly, in the A549 cell line, Compound A + FUdR in the absence of talazoparib demonstrates a survival of -70%, which was reduced to 41% (p=<0.0001), 22% (p=<0.0001) and 14% (p=<0.0001) when combined with 0.001, 0.005 and 0.01 pM of talazoparib, respectively (Figure 5B). This effect is further illustrated in the MDA-MB-231 cell line, wherein, without talazoparib, Compound A + FUdR demonstrates a cell survival of 68%, which was reduced to 39% (p=<0.0001), 30% (p=<0.0001) and 11% (p=<0.0001) when combined with 0.005, 0.01 and 0.1 pM of talazoparib, respectively (Figure 5C). Statistical analysis is shown in Figure 5D.

[0474] This data demonstrates that the inhibition of PARP with any of the four abovedescribed clinically approved PARP inhibitors can significantly enhance the anticancer effect in models of three different cancer types when combined with a dUTPase inhibitor (e.g., Compound A) and a TS inhibitor. The improved anticancer effect is greater than that of any of the individual monotherapies or the combination of a dUTPase inhibitor with a TS inhibitor.

[0475] Example 4: Combined effects of Compound A, FUdR and PARP inhibition reduce long term cell survival of multiple cancer cell lines using sub-lethal doses of Compound A.2104927-6853-2615.1Atty. Dkt. No. 109290-0190

[0476] Experimental overview: Cancer cells were treated with control, a fluoropyrimidine (FUdR), Compound A (at concentrations ranging from 1.56 pM - 6.25 pM), or the combination of Compound A and FUdR using increasing doses of Compound A (1.56 pM -6.25 pM) and a fixed dose of FUdR. Each of these treatment conditions was investigated in the presence or absence of a fixed dose of the PARP inhibitors (olaparib, rucaparib, niraparib or talazoparib). Long-term cell survival was assessed using Colony Formation Assay (CFA). Cell lines assayed for cell survival included HCT116 (colorectal cancer), A549 (lung cancer), and MDA-MB-23 (breast cancer).

[0477] Cell line model selection: HCT116, A549 and MDA-MB-231 cells were maintained in the appropriate culture media supplemented with 10% fetal bovine serum (FBS), 1% penicillin / streptomycin (P / S), 1% L-glutamine (L-Glut) and 1% sodium pyruvate (NaPyr). Cells were cultured and expanded in humidified incubators at 37 °C and 5% CO2 until sufficient cells were available. All cell lines were routinely screened for mycoplasma infection using the MYCO ALERT™ mycoplasma detection kit (Lonza) and have been authenticated using short tandem repeat (STR) profiling (Eurofins).

[0478] Cell preparation and drug treatments: 200-250 cells (HCT116, A549 and MDA-MB-231) suspended in 500 pL of complete media were added to the inner 8 wells of a 24-well plate. Sterile water (1 mL) was added to the outer wells of the 24-well plate to maintain adequate humidity, and the plates were placed in a humidified incubator at 5% CO2 to allow cells to adhere overnight. The following day, all compounds were prepared freshly in cell culture media from frozen stocks prior to treatment. Seeding media was removed and replaced with drug-containing media and incubated for 48 h. Cells were treated with Compound A (1.56 pM - 6.25 pM), FUdR, or Compound A (1.56 pM - 6.25 pM) + FUdR, alone or in combination with a fixed dose of PARP inhibitor. Following 48 h incubation drug-containing media was removed and replaced with 1 mL of complete media, and cells were left in a humidified incubator at 5% CO2 to form colonies (>50 cells) for a period of 9-12 days.

[0479] Colony Formation Assay (CFA): Following sufficient colony formation (>50 cells), colonies were fixed and stained using the following protocol. Media was removed from each well and replaced with 500 pL of ice-cold 70% methanol, and plates were left to incubate for 15 minutes on an orbital rocker at room temperature (RT). Following fixation, methanol was removed from each well, and the plates were inverted and left to dry. Once dry, colonies were stained with 0.5% crystal violet solution by adding approximately 500 pL to 2114927-6853-2615.1Atty. Dkt. No. 109290-0190each well and incubating on an orbital rocker at RT. Colonies were sufficiently stained after a 15-minute incubation. To remove excess stain, changes of IX PBS were added to each well. A final wash using distilled water was completed to prevent the formation of salt crystals. Colonies were counted by acquiring images and subsequent processing using the Oxford Optronix GELCOUNT™ Analyser. Cell survival was expressed as a percentage of the untreated control.

[0480] Results: For each of the assayed cell lines, fixed doses of FUdR and PARP inhibitor were chosen based on the previous experiments. In the absence of a PARP inhibitor, all three cell lines demonstrated no significant decrease in cell survival when treated with Compound A at concentrations of 1.56 pM - 6.25 pM or FUdR as single agents, in comparison to control. When Compound A (1.56 pM - 6.25 pM) was combined with FUdR, there was a dose-dependent reduction in cell survival across all cell lines.

[0481] As a single agent, olaparib demonstrated a reduction in cell survival of 5% (p=0.2665), 10% (p=0.1102) and 13% (p=0.0097) in the HCT116, A549 and MDA-MB-231 cell lines, respectively, when compared to the control. In the HCT116 cell line, the combination of Compound A (1.56 pM - 6.25 pM) + FUdR in the absence of olaparib demonstrated a cell survival of 99%, 88% and 67%, but when each of these combinations was combined with olaparib (1 pM), cell survival was significantly reduced to 45% (p=<0.0001), 27% (p=<0.0001) and 13% (p=<0.0001), respectively (Figure 6A). Similarly, the A549 cell line demonstrated a significant reduction in cell survival when Compound A (1.56 pM - 6.25 pM) + FUdR was combined with olaparib (1 pM), in comparison to Compound A (1.56 pM - 6.25 pM) + FUdR without olaparib. In particular, cell survival was significantly reduced from 95%, 89% and 67% in the absence of olaparib to 52% (p=<0.0001), 41% (p=<0.0001) and 30% (p=<0.0001) when olaparib (1 pM) was combined with Compound A (1.56 pM) + FUdR, Compound A (3.13 pM) + FUdR, and Compound A (6.25 pM) + FUdR, respectively (Figure 6B). This effect was further illustrated in the MDA-MB-231 cell line: the combination of Compound A (1.56 pM - 6.25 pM) + FUdR demonstrated a cell survival of 77%, 74% and 61% in the absence of olaparib, but when each of these combinations was combined with olaparib (1 pM), cell survival was reduced to 49% (p=<0.0001), 41% (p=<0.0001) and 28% (p=<0.0001), respectively (Figure 6C). Statistical analysis is shown in Figure 6D.

[0482] As was observed with olaparib, rucaparib in combination with Compound A (1.56 pM - 6.25 pM) + FUdR demonstrated a dose-dependent reduction in cell survival when 2124927-6853-2615.1Atty. Dkt. No. 109290-0190compared to either treatment alone, a finding that was consistent across each of the assayed cell lines. Single agent rucaparib (1 pM) demonstrated an average reduction in cell survival of -14% in comparison to the control across all cell lines. In the HCT116 cell line, Compound A (1.56 pM) + FUdR, Compound A (3.13pM) + FUdR, and Compound A (6.25 pM) + FUdR demonstrated an overall reduction in cell survival of 63% (p=<0.0001), 67% (p=<0.0001) and 56% (p=<0.0001), respectively, when combined with rucaparib (0.5 pM), in comparison to Compound A (1.56 pM - 6.25 pM) + FUdR without rucaparib (Figure 7A). In the A549 cell line, cell survival was significantly decreased when increasing doses of Compound A (1.56 pM - 6.25 pM) + FUdR were combined with rucaparib (1 pM). More specifically, cell survival was reduced from 95%, 89% and 67% to 52% (p=<0.0001), 41% (p=<0.0001) and 30% (p=<0.0001), respectively (Figure 7B). Finally, the MDA-MB-231 cell line exhibited a similar effect to that observed in the HCT116 and A549 cell lines. Cell survival following treatment with increasing doses of Compound A (1.56 pM - 6.25 pM) + FUdR was 77%, 74% and 61%, which was significantly reduced to 58% (p=0.0093), 43% (p=<0.0001) and 28% (p=<0.0001) when combined with rucaparib (1 pM) (Figure 7C). Statistical analysis is shown in Figure 7D.

[0483] Niraparib demonstrates an enhanced potency in comparison to olaparib and rucaparib, as reflected in the assayed concentrations. Single agent niraparib (0.5 pM) demonstrated a reduction in cell survival of 20-23% across all cell lines. As observed with olaparib and rucaparib, niraparib in combination with increasing doses of Compound A (1.56 pM - 6.25 pM) + FUdR demonstrated a dose-dependent reduction in cell survival when compared to either treatment alone, a finding which was consistent across each of the assayed cell lines. In the HCT116 cell line, there was an overall reduction in cell survival of 70% (p=<0.0001), 71% (p=<0.0001) and 60% (p=<0.0001) when Compound A (1.56 pM - 6.25 pM) + FUdR was combined with niraparib (0.5 pM) in comparison to Compound A (1.56 pM - 6.25 pM) + FUdR in the absence of niraparib (Figure 8A). This effect was further illustrated in the A549 cell line, wherein Compound A (1.56 pM - 6.25 pM) + FUdR combined with niraparib (0.5 pM) demonstrated an overall reduction in cell survival of 45% (p=<0.0001), 45% (p=<0.0001) and 41% (p=<0.0001) when compared to Compound A (1.56 pM - 6.25 pM) + FUdR without niraparib (Figure 8B). Similarly, in the MDA-MB-231 cell line, there was an overall reduction in cell survival of 30% (p=0.0002), 41% (p=<0.0001) and 33% (p=<0.0001) when increasing doses of Compound A (1.56 pM - 6.25 pM) + FUdR were2134927-6853-2615.1Atty. Dkt. No. 109290-0190combined with niraparib (0.5 pM) in comparison to Compound A (1.56 pM - 6.25 pM) + FUdR without niraparib (Figure 8C). Statistical analysis is shown in Figure 8D.

[0484] As talazoparib was the most potent of the four clinically approved PARP inhibitors in these experiments, a lower dose was assayed across all cell lines. Single agent talazoparib (0.005 pM) exhibited a reduction in cell survival of 11% (p=0.0492), 25% (p=0.0001) and 23% (p=0.004) in the HCT116, A549 and MDA-MB-231 cell lines, respectively. Talazoparib in combination with increasing doses of Compound A (1.56 pM - 6.25 pM) + FUdR demonstrated a dose-dependent reduction in cell survival when compared to either treatment alone, which was consistent across each of the cell lines assayed. In the HCT116 cell line, there was an overall reduction in cell survival of 61% (p=<0.0001), 64% (p=<0.0001) and 54% (p=<0.0001) when Compound A (1.56 pM - 6.25 pM) + FUdR was combined with talazoparib (0.005pM) in comparison to Compound A (1.56 pM - 6.25 pM) + FUdR without talazoparib (Figure 9A). This effect was further illustrated in the A549 cell line, wherein Compound A (1.56 pM - 6.25 pM) + FUdR combined with talazoparib (0.005 pM) demonstrated an overall reduction in cell survival of 58% (p=<0.0001), 55% (p=<0.0001) and 42% (p=<0.0001) when compared to Compound A (1.56 pM - 6.25 pM) + FUdR, without talazoparib (Figure 9B). Similarly in the MDA-MB-231 cell line, there was an overall reduction in cell survival of 31% (p=0.0002), 38% (p=<0.0001) and 38% (p=<0.0001) when increasing doses of Compound A (1.56 pM - 6.25 pM) + FUdR was combined with talazoparib (0.005 pM) in comparison to Compound A (1.56 pM - 6.25 pM) + FUdR in the absence of talazoparib (Figure 9C). Statistical analysis is shown in Figure 9D.

[0485] Overall, this data presented demonstrated a clear dose-dependent increase in cancer cell lethality when increasing concentrations of the dUTPase inhibitor Compound A were combined with a TS inhibitor and a PARP inhibitor. This demonstrated that Compound A was critically important in driving this synergistic mechanism.

[0486] Example 5: Combined effects of Compound B (dUTPase inhibitor), FUdR and PARP inhibition reduce long term cell survival of colorectal cancer cells using sub-lethal doses of Compound B.

[0487] Experimental overview: Cancer cells were treated with control, the fluoropyrimidine, FUdR, Compound B (1.56-6.25pM) and the combination of Compound B and FUdR using escalating doses of Compound B (1.56-6.25pM) and a fixed dose of FUdR. Each of these treatment conditions was investigated in the presence and absence of a fixed2144927-6853-2615.1Atty. Dkt. No. 109290-0190dose of the PARP inhibitors: olaparib, rucaparib, niraparib and talazoparib. Long-term cell survival was assessed using Colony Formation Assay (CFA). Cell lines assayed for cell survival included HCT116 (colorectal cancer).

[0488] Compound

[0489] Cell line model selection: HCT116 cells were maintained in the appropriate culture media supplemented with 10% fetal bovine serum (FBS), 1% penicillin / streptomycin (P / S), 1% L-glutamine (L-Glut) and 1% sodium pyruvate (NaPyr). Cells were cultured and expanded in humidified incubators at 37 °C and 5% CO2 until sufficient cells were available. All cell lines were routinely screened for mycoplasma infection using the MYCO ALERT™ mycoplasma detection kit (Lonza) and have been authenticated using short tandem repeat (STR) profiling (Eurofins).

[0490] Cell preparation and drug treatments: 200-250 cells (HCT116) suspended in 500 pL of complete media was added to the inner 8 wells of a 24-well plate. Sterile water (1 mL) was added to the outer wells of the 24-well plate to maintain adequate humidity. The plates were placed in a humidified incubator at 5% CO2 to allow cells to adhere overnight. The following day, all compounds were prepared freshly in cell culture media from frozen stocks prior to treatment. Seeding media was removed and replaced with drug-containing media and incubated for 48 hours. Cells were treated with Compound B (1.56-6.25 pM), FUdR and Compound B (1.56-6.25 pM) + FUdR, alone and in combination with a fixed dose of PARP inhibitor. Following 48 h incubation drug-containing media was removed and replaced with 1 mL of complete media, cells were left in a humidified incubator at 5% CO2 to form colonies (>50 cells) for a period of 9-12 days.

[0491] Colony Formation Assay (CFA): Following sufficient colony formation (>50 cells), colonies were fixed and stained using the following protocol. Media was removed from each well and replaced with 500 pL of ice-cold 70% methanol, plates were left to incubate for 15 minutes on an orbital rocker at room temperature (RT). Following fixation, methanol was removed from each well and the plates were inverted and left to dry. Once dry, colonies were stained with 0.5% crystal violet solution by adding approximately 500 pL to each well and incubating on an orbital rocker at RT. Colonies are sufficiently stained after a 15-minute incubation. To remove excess stain, changes of IX PBS were added to each well. A final wash using distilled water was completed to prevent the formation of salt crystals.2154927-6853-2615.1Atty. Dkt. No. 109290-0190Colonies were counted by acquiring images and subsequent processing using the Oxford Optronix GELCOUNT™ Analyser. Cell survival was expressed as a percentage of the untreated control.

[0492] Results: For these experiments, a fixed dose of FUdR, and PARP inhibitor were chosen based on previous optimization experiments, and these concentrations mirrored those used in Example 3. In the absence of a PARP inhibitor, the HCT116 cell line demonstrated no significant decrease in cell survival when treated with Compound A (1.56-6.25 pM) or FUdR as single agents in comparison to control. When Compound A (1.56-6.25 pM) was combined with FUdR there was a dose dependent reduction in cell survival.

[0493] Single agent olaparib demonstrated a reduction in cell survival of 12% (p=0.0127) in the HCT116 cell line when compared to the control. In the HCT116 cell line, the combination of Compound A (1.56-6.25 pM) + FUdR demonstrated a cell survival of 86%, 81% and 59% in the absence of olaparib. When each of these combinations was combined with olaparib (1 pM), cell survival was reduced to 24% (p=<0.0001), 16% (p=<0.0001) and 10% (p=<0.0001), respectively (Figure 10A). Statistical analysis shown in Figure 10B.

[0494] As observed with olaparib, rucaparib in combination with Compound B (1.56-6.25 pM) + FUdR demonstrated a dose dependent reduction in cell survival, when compared to either treatment alone. Single agent rucaparib (1 pM) demonstrated an average reduction in cell survival of -23% in comparison to the control. In the HCT116 cell line, Compound B (1.56 pM) + FUdR, Compound B (3.13 pM) + FUdR and Compound B (6.25 pM) + FUdR demonstrated an overall reduction in cell survival of 65% (p=<0.0001), 69% (p=<0.0001) and 51% (p=<0.0001), respectively, when combined with rucaparib (1 pM), in comparison to Compound B (1.56-6.25 pM) + FUdR in the absence of rucaparib (Figure 11A). Statistical analysis shown in Figure 11B.

[0495] Niraparib demonstrated an enhanced potency in comparison to olaparib and rucaparib, as reflected in the concentration used in this experiment. Single agent niraparib (0.5 pM) demonstrated a reduction in cell survival of -23% in the HCT116 cell line. As observed with olaparib and rucaparib, niraparib in combination with escalating doses of Compound B (1.56-6.25 pM) + FUdR demonstrated a dose dependent reduction in cell survival, when compared to either treatment alone. In the HCT116 cell line, there was an overall reduction in cell survival of 65% (p=<0.0001), 68% (p=<0.0001) and 50% (p=<0.0001) when Compound B (1.56-6.25pM) + FUdR was combined with niraparib (0.52164927-6853-2615.1Atty. Dkt. No. 109290-0190pM) in comparison to Compound B (1.56-6.25 pM) + FUdR, without niraparib (Figure 12A). Statistical analysis shown in Figure 12B.

[0496] Talazoparib, the most potent of all the PARP inhibitors, was assayed using a much lower dose compared to the other PARP inhibitors investigated in this example. Single agent talazoparib (0.005 pM) exhibited a reduction in cell survival of less than 10% (p=0.1536), in the HCT116 cell line. Talazoparib in combination with escalating doses of Compound B (1.56-6.25 pM) + FUdR demonstrated a dose dependent reduction in cell survival when compared to either treatment alone. In the HCT116 cell line, there was an overall reduction in cell survival of 60% (p=<0.0001), 63% (p=<0.0001) and 48% (p=<0.0001) when Compound B (1.56-6.25 pM) + FUdR was combined with talazoparib (0.005 pM) in comparison to Compound B (1.56-6.25 pM) + FUdR without talazoparib (Figure 13A). Statistical analysis shown in Figure 13B.

[0497] Overall, the data presented underscores the profound effect of the triple combination therapy involving Compound B (a dUTPase inhibitor with a chemical structure distinct from Compound A), FUdR, and PARP inhibition on cell survival. Notably, the significant reduction in cell survival is exclusively observed with this triple combination. In contrast, dual combinations of PARP inhibition with either Compound B or FUdR exhibit only minimal impact on cell survival. Furthermore, the findings demonstrate the therapeutic efficacy of this approach when employing an alternative dUTPase inhibitor, reinforcing the robustness and versatility of the triple combination strategy.

[0498] Example 6. Additional assessments using cell lines for gastric, esophageal, head and neck, or hematological malignancies

[0499] The procedures of Examples 3 and 4 are repeated using cell lines for gastric (AGS -CRL-1739™), esophageal (OE33 - ECACC 96070808), head and neck (FaDu -HTB-43™) and hematological malignancies (RS4;11 -CRL-1873™). It is expected that the triple combination of Compound A + FUdR + PARP inhibitor will demonstrate synergistically effective results.

[0500] Example 7. Xenograft mouse study

[0501] Utilizing an athymic nude mouse model, human HCT116 colorectal cancer xenografts will be established via subcutaneous injection. Mice will be randomized into eight treatment groups: Vehicle, Compound A, 5-FU, PARP inhibitor, Compound A + 5-FU, Compound A + PARP inhibitor, 5-FU + PARP inhibitor, and the triple combination of 2174927-6853-2615.1Atty. Dkt. No. 109290-0190Compound A + 5-FU + PARP inhibitor. Group sizes will be statistically optimized to minimize animal use while maintaining the robustness of the data. Data collection will include biweekly tumour volume measurements, calculated using standard volumetric formulas, to evaluate treatment efficacy. Body weight and general health will be monitored continuously to identify any signs of toxicity, ensuring comprehensive safety assessments. Upon study completion, tumor samples will be collected for biomarker analysis to provide mechanistic insights, focusing on indicators of DNA damage (e.g., y-H2AX) and apoptosis (e.g., cleaved caspase-3). It is expected that the triple combination of Compound A + 5-FU + PARP inhibitor will demonstrate synergistically effective results.

[0502] Example 8. Xenograft mouse study

[0503] Utilizing an athymic nude mouse model, human HCT116 colorectal cancer xenografts will be established via subcutaneous injection. Mice will be randomized into eight treatment groups: Vehicle, Compound A, FUdR, PARP inhibitor, Compound A + FUdR, Compound A + PARP inhibitor, FUdR + PARP inhibitor, and the triple combination of Compound A + FUdR + PARP inhibitor. Group sizes will be statistically optimized to minimize animal use while maintaining the robustness of the data. Data collection will include biweekly tumour volume measurements, calculated using standard volumetric formulas, to evaluate treatment efficacy. Body weight and general health will be monitored continuously to identify any signs of toxicity, ensuring comprehensive safety assessments. Upon study completion, tumor samples will be collected for biomarker analysis to provide mechanistic insights, focusing on indicators of DNA damage (e.g., y-H2AX) and apoptosis (e.g., cleaved caspase-3). It is expected that the triple combination of Compound A + FUdR + PARP inhibitor will demonstrate synergistically effective results.

[0504] Example 9. Clinical trial in human subjects: cancer

[0505] A compound of the present disclosure is administered to human subjects suffering from cancer (e.g., solid tumor, or a cancer selected from a cancer of the circulatory system; a cancer of the respiratory system; a cancer of the gastrointestinal system; a cancer of the genitourinary system; a liver cancer; a cancer of the bone; a cancer of the nervous system; a cancer of the hematologic system; a cancer of skin or tissues comprising connective or soft tissue; a cancer of the retroperitoneum or peritoneum; an eye cancer; a breast cancer; a cancer of the head or / and neck; a thyroid cancer; a parathyroid cancer; a cancer of the adrenal gland; a cancer of the endocrine glands; and a cancer of the lymph nodes). Subject response to the2184927-6853-2615.1Atty. Dkt. No. 109290-0190compound administration is evaluated by monitoring for complete response (disappearance of all tumor(s) / lesion(s)); partial response (at least 30% decrease in the sum of diameters of tumor(s) / lesion(s)); progressive disease (at least 20% increase in the sum of diameters of tumor(s) / lesion(s)); stable disease (neither sufficient shrinkage to qualify for partial response nor sufficient to qualify for progressive disease); or deeming the response as not evaluable. Subjects show a positive clinical response to treatment (e.g., complete response, partial response, or stable disease). Disease control rate is determined.Certain Embodiments

[0506] Embodiment 1. A method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a poly (ADP-ribose) polymerase (PARP) inhibitor, a deoxyuridine triphosphatase (dUTPase) inhibitor, and an inhibitor of thymidylate biosynthesis.

[0507] Embodiment 2. The method of Embodiment 1, wherein the cancer is selected from a solid tumor cancer, a blood cancer, or a cancer of the lymphatic system.

[0508] Embodiment 3. The method of Embodiment 1, wherein the cancer is selected from the group of cancers: a cancer of the circulatory system; a cancer of the respiratory system; a cancer of the gastrointestinal system; a cancer of the genitourinary system; a liver cancer; a cancer of the bone; a cancer of the nervous system; a cancer of the hematologic system; a cancer of skin or tissues comprising connective or soft tissue; a cancer of the retroperitoneum or peritoneum; an eye cancer; a breast cancer; a cancer of the head or / and neck; a thyroid cancer; a parathyroid cancer; a cancer of the adrenal gland; a cancer of the endocrine glands; and lymph nodes.

[0509] Embodiment 4. The method of Embodiment 1, wherein the cancer is colon cancer, gastric cancer, breast cancer, lung cancer, pancreatic cancer, head and / or neck cancer, or esophageal cancer.

[0510] Embodiment 5. The method of any one of Embodiments 1-4, wherein the cancer is a primary cancer.

[0511] Embodiment 6. The method of any one of Embodiments 1-4, wherein the cancer is a metastasis.2194927-6853-2615.1Atty. Dkt. No. 109290-0190

[0512] Embodiment 7. The method of Embodiment 1, wherein the cancer is selected from a carcinoma, a sarcoma, a myeloma, a leukemia, or a lymphoma.

[0513] Embodiment 8. The method of any one of Embodiments 1-7, wherein the treatment comprises one or more endpoints selected from tumor response, reduction in tumor size, reduction in tumor burden, increase in overall survival, increase in progression free survival, inhibiting metastasis, improvement of quality of life, minimization of toxicity, or reduction of side-effects.

[0514] Embodiment 9. A method of inhibiting growth of a cancer cell comprising contacting the cell with an effective amount of a poly (ADP-ribose) polymerase (PARP) inhibitor, a deoxyuridine triphosphatase (dUTPase) inhibitor, and an inhibitor of thymidylate biosynthesis.

[0515] Embodiment 10. The method of Embodiment 9, wherein the contacting occurs in vitro.

[0516] Embodiment 11. The method of Embodiment 9, wherein the contacting occurs in vivo.

[0517] Embodiment 12. The method of any one of Embodiments 9-11, wherein the cancer cell is from a cancer selected from the group of cancers: a cancer of the circulatory system; a cancer of the respiratory system; a cancer of the gastrointestinal system; a cancer of the genitourinary system; a liver cancer; a cancer of the bone; a cancer of the nervous system; a cancer of the hematologic system; a cancer of skin or tissues comprising connective or soft tissue; a cancer of the retroperitoneum or peritoneum; an eye cancer; a breast cancer; a cancer of the head or / and neck; a thyroid cancer; a parathyroid cancer; a cancer of the adrenal gland; a cancer of the endocrine glands; and lymph nodes.

[0518] Embodiment 13. The method of any one of Embodiments 1-12, wherein the inhibitor of thymidylate biosynthesis comprises 5 -fluorouracil (5-FU), floxuridine (FUdR), pemetrexed, raltitrexed, nolatrexed, plevitrexed, GS7904L, capecitabine, methotrexate, pralatrexate, CT-900, NUC-3373, or a combination of two or more thereof.

[0519] Embodiment 14. The method of any one of Embodiments 1-12, wherein the inhibitor of thymidylate biosynthesis comprises S-l, a combination of S-l and folinic acid,2204927-6853-2615.1Atty. Dkt. No. 109290-0190FOLFOX, FOLFOX4, FOLFIRI, FOLFIRINOX, MOF, deflexifol, arfolitixorin, or a combination of 5-FU with one or more selected from radiation, methyl-CCNU, leucovorin, a platinum agent (such as oxaliplatin, cisplatin, or carboplatin), irinotecan, mitomycin, cytarabine, or levamisole.

[0520] Embodiment 15. The method of any one of Embodiments 1-12, wherein the inhibitor of thymidylate biosynthesis is an inhibitor of folate-mediated one-carbon metabolism.

[0521] Embodiment 16. The method of any one of Embodiments 1-15, wherein the PARP inhibitor comprises talazoparib, olaparib, niraparib, rucaparib, saruparib, pamiparib, and veliparib.

[0522] Embodiment 17. The method of any of Embodiments 1-16, wherein the dUTPase inhibitor is a compound of Formula (I):2214927-6853-2615.1Atty. Dkt. No. 109290-0190each R30independently is hydrogen; an optionally substituted C1-C10 alkoxy; optionally substituted amino, such as -NH2 or a mono or di-substituted form thereof; an optionally substituted C1-C10 alkyl; optionally substituted hydroxy; or Z;L1is:-(CH2)q-, wherein one or more hydrogens are optionally substituted with C1-C3 alkyl and / or at least two or more geminal hydrogens together with the carbon(s) to which they are attached are optionally replaced with an optionally substituted 3-5 membered heterocyclyl or an optionally substituted 3-5 membered cycloalkyl, preferably the optionally substituted 3-5 membered cycloalkyl is an optionally substituted cyclopropano, an optionally substituted cyclobutano, an optionally substituted cyclopentano, or an optionally substituted tetrahydrofurano; and wherein q is 3, 4, 5, 6, 7, or 8;< , wherein one or more hydrogens are optionally substituted with C1-C3 alkyl and / or at least two or more geminal hydrogens together with the carbon(s) to which they are attached are optionally replaced with an optionally substituted 3-5 membered heterocyclyl or an optionally substituted 3-5 membered cycloalkyl, preferably the optionally substituted 3-5 membered cycloalkyl is an optionally substituted cyclopropano, an optionally substituted cyclobutano, an optionally substituted cyclopentano, or an optionally substituted tetrahydrofurano; and wherein p is 0, 1, 2, 3, 4, or 5 and z is 0, 1, 2, 3, 4, or 5;-(CH2)m-X15-(CH2)n-, wherein one or more hydrogens are optionally substituted with C1-C3 alkyl and / or at least two or more geminal hydrogens together with the carbon(s) to which they are attached are optionally replaced with an optionally substituted 3-5 membered heterocyclyl or an optionally substituted 3-5 membered cycloalkyl, preferably the optionally substituted 3-5 membered cycloalkyl is an optionally substituted cyclopropano, an optionally substituted cyclobutano, an optionally substituted cyclopentano, or an optionally substituted tetrahydrofurano; and wherein m is 0, 1, 2, or 3 and n is 0, 1, 2, 3, 4, 5, 6, or 7; or2224927-6853-2615.1Atty. Dkt. No. 109290-0190, wherein one or more hydrogens are optionally substituted with C1-C3 alkyl and / or at least two or more geminal hydrogens together with the carbon(s) to which they are attached are optionally replaced with an optionally substituted 3-5 membered heterocyclyl or an optionally substituted 3-5 membered cycloalkyl, preferably the optionally substituted 3-5 membered cycloalkyl is an optionally substituted cyclopropano, an optionally substituted cyclobutano, an optionally substituted cyclopentano, or an optionally substituted tetrahydrofurano; and wherein o is 0, 1, 2, or 3; r is 1, 2 or 3; and s is 0, 1, 2, 3, or 4; andwherein X15is NR40, O, or S, wherein R40is H or C1-C10 alkyl; orL1is -Ln-L12-L13-, wherein L11is attached to A and L11is O, S, NR, C1-C2 alkylene, C2 alkenylene, C2 heteroalkylene, C3 heteroalkenylene, L12is arylene or heteroarylene, L13is a bond or an optionally substituted C1-C5 alkylene, and R is H or C1-C3 alkyl;L2is -SO2NR50-, wherein the sulfur is attached to L1; -NR50SO2-, wherein the nitrogen is attached to L1; -C(O)NR50-, wherein the carbon is attached to L1;-NR50C(O)-, wherein the nitrogen is attached to L1; -NR50SO2NR50-; or -NR50CONR50-;each R50independently is hydrogen, an optionally substituted Ci-Ce alkyl, an optionally substituted C2-C6 heteroalkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C3-C6 heteroalkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C6 heteroalkynyl, or Z;Z iseach R51and R52independently is hydrogen or an optionally substituted C1-C10 alkyl; X is an optionally substituted hydroxy group, an optionally substituted NH2 group, or an optionally substituted SH group;L3is a bond, an optionally substituted Ci-Ce alkylene, an optionally substituted C2-C6 heteroalkylene, an optionally substituted C2-C6 alkenylene, an optionally substituted C3-C6 heteroalkenylene, an optionally substituted C2-C6 alkynylene, or an optionally substituted C3-Ce heteroalkynyl ene; andB is an optionally substituted 6-10 membered aryl; an optionally substituted 5-15 membered heteroaryl; an optionally substituted 4-15 membered heterocyclyl; or an optionally 2234927-6853-2615.1Atty. Dkt. No. 109290-0190substituted 3-15 membered cycloalkyl, if cycloalkyl, then preferably at least a 4 membered, or more preferably a 5-10 membered cycloalkyl.

[0523] Embodiment 18. The method of Embodiment 17, wherein A is:

[0524] Embodiment 19. The method of Embodiment 17 or Embodiment 18, wherein A is:

[0525] Embodiment 20. The method of any one of Embodiments 17-19, wherein L1is selected from the group consisting of:2244927-6853-2615.1Atty. Dkt. No. 109290-0190and optionally substituted versions thereof wherein 1-5, preferably, 1-3 hydrogen atoms are optionally substituted, preferred substituents including without limitation, Ci-Ce alkyl optionally substituted with 1-3 halo, such as fluoro, and / or Ci-Ce alkoxy; optionally substituted Ci-Ce alkoxy; and halo, preferably fluoro, wherein the left side of the moieties are attached to A and wherein R70is an optionally substituted Ci-Cio alkyl.

[0526] Embodiment 21. The method any one of Embodiments 17-19, wherein L1is:2254927-6853-2615.1Atty. Dkt. No. 109290-0190or an optionally substituted version of each thereof wherein 1-5, preferably, 1-3 hydrogen atoms are optionally substituted, preferred substituents including without limitation, Ci-Ce alkyl optionally substituted with 1-3 halo, such as fluoro, and / or Ci-Ce alkoxy; optionally substituted Ci-Ce alkoxy; and halo, preferably fluoro, wherein the left side of the moieties are attached to A.

[0527] Embodiment 22. The method of any one of Embodiments 17-21, wherein L2is -S(O)2NR50- wherein the sulfur is attached to L1.

[0528] Embodiment 23. The method of any one of Embodiments 17-22, wherein L3is selected from the group consisting of:and optionally substituted versions thereof wherein 1-5, preferably, 1-3 hydrogen atoms are optionally substituted, preferred substituents including without limitation, Ci-Ce alkyl optionally substituted with 1-3 halo, such as fluoro, and / or Ci-Ce alkoxy; optionally substituted Ci-Ce alkoxy; and halo, preferably fluoro, wherein the left side of the moieties are attached to L2.

[0529] Embodiment 24. The method any one of Embodiments 17-23, wherein L3is selected from the group consisting of:2264927-6853-2615.1Atty. Dkt. No. 109290-0190and optionally substituted versions thereof wherein 1-5, preferably, 1-3 hydrogen atoms are optionally substituted, preferred substituents including without limitation, Ci-Ce alkyl optionally substituted with 1-3 halo, such as fluoro, and / or Ci-Ce alkoxy; optionally substituted Ci-Ce alkoxy; and halo, preferably fluoro, wherein the left side of the moieties are attached to L2.

[0530] Embodiment 25. The method of any one of Embodiments 17-24, wherein B is:2274927-6853-2615.1Atty. Dkt. No. 109290-0190whereineach R6independently is hydrogen, an optionally substituted Ci-Ce alkoxy, or halo; each R7independently is an optionally substituted Ci-Ce alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C8 cycloalkyl, an optionally substituted C3-C10 heteroaryl, an optionally substituted C3-C10 heterocyclyl, or an optionally substituted Ce-Cio aryl such as optionally substituted phenyl; or R6and R7together with the atoms they are attached to form an optionally substituted 5-7 membered ring; or 2 R6groups together with the atoms they are attached to form an optionally substituted 5-7 membered ring;each R61and R62is independently N or CH, provided that at least one of R61and R62is N,each R63is independently NR90, S, or O;each R64is independently N or CH; andeach R90is independently hydrogen or R7.

[0531] Embodiment 26. The method of any one of Embodiments 17-24, wherein B is:whereineach RkR3independently is H, halo, an optionally substituted Ci-Ce alkyl, an optionally substituted 4-15 membered heterocyclyl, or -OR20or, if two of R1-R3are on adjacent carbon atoms, then two such substituents together with the atoms they are attached to form an optionally substituted 5-7 membered ring;R20is (CH2)W-R21, an optionally substituted C3-C6 cycloalkyl, or an optionally substituted Ci-Ce alkyl;R21is an optionally substituted C3-C6 cycloalkyl, an optionally substituted Ce-Cio aryl, an optionally substituted 5-15 membered heteroaryl, an optionally substituted 4-15 membered heterocyclyl, an optionally substituted C1-C10 alkyl, an optionally substituted C2-C10 alkenyl, an optionally substituted C2-C10 alkynyl, an optionally substituted 4-15 membered heterocyclyl, or2284927-6853-2615.1Atty. Dkt. No. 109290-0190wherein each R22-R24independently is an optionally substituted C1-C3 alkyl or hydroxy or two of R22-R24together with the carbon atoms they are attached to form a 3-7 membered ring; andw is 1, 2, 3, 4, or 5.

[0532] Embodiment 27. The method of Embodiment 26, wherein B is:

[0533] Embodiment 28. The method of Embodiment 27, wherein R1is H.

[0534] Embodiment 29. The method of Embodiment 27, wherein R3is H or -OR20.

[0535] Embodiment 30. The method of Embodiment 27, wherein R2is F or H.

[0536] Embodiment 31. The method of Embodiment 27, wherein B is

[0537] Embodiment 32. The method of any one of Embodiments 17-24, wherein B is selected from the group consisting of:2294927-6853-2615.1Atty. Dkt. No. 109290-01902304927-6853-2615.1Atty. Dkt. No. 109290-0190wherein2314927-6853-2615.1Atty. Dkt. No. 109290-0190the alkoxy group is further optionally substituted wherein 1-5, preferably, 1-3 hydrogen atoms are optionally substituted, preferred substituents including without limitation, Ci-Ce alkyl optionally substituted with 1-3 halo, such as fluoro, and / or Ci-Ce alkoxy; optionally substituted Ci-Ce alkoxy; and halo, preferably fluoro;the ring moiety such as the cyclopropyl group is further optionally substituted with 1-3 halo, preferably 1-2 halo;the methylene group between the oxygen atom and the ring moiety, such as the cyclopropyl group, is optionally substituted with 1-2 Ci-Ce alkyl, preferably methyl, ethyl, or propyl groups; andR70is an optionally substituted Ci-Cio alkyl.

[0538] Embodiment 33. The method of Embodiment 32, wherein B is

[0539] Embodiment 34. The method of any one of Embodiments 1-16, wherein the dUTPase inhibitor is a compound selected from Tables 1-15.

[0540] Embodiment 35. A composition or system comprising a poly (ADP -ribose) polymerase (PARP) inhibitor, a deoxyuridine triphosphatase (dUTPase) inhibitor, and an inhibitor of thymidylate biosynthesis.

[0541] Embodiment 36. A composition for use in treating cancer in a subject in need thereof comprising a poly (ADP-ribose) polymerase (PARP) inhibitor, a deoxyuridine triphosphatase (dUTPase) inhibitor, and an inhibitor of thymidylate biosynthesis.

[0542] Embodiment 37. A composition for use in the preparation of a medicament for the treatment of cancer in a subject in need thereof, the composition comprising a poly (ADP-ribose) polymerase (PARP) inhibitor, a deoxyuridine triphosphatase (dUTPase) inhibitor, and an inhibitor of thymidylate biosynthesis.

[0543] It should be understood that although the present invention has been specifically disclosed by certain aspects, embodiments, and optional features, modification, improvement and variation of such aspects, embodiments, and optional features can be resorted to by those 2324927-6853-2615.1Atty. Dkt. No. 109290-0190skilled in the art, and that such modifications, improvements and variations are considered to be within the scope of this disclosure.

[0544] The invention has been described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the invention. In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group.2334927-6853-2615.1

Claims

Atty. Dkt. No. 109290-0190WHAT IS CLAIMED IS:

1. A method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a poly (ADP-ribose) polymerase (PARP) inhibitor, a deoxyuridine triphosphatase (dUTPase) inhibitor, and an inhibitor of thymidylate biosynthesis.

2. The method of claim 1, wherein the cancer is selected from a solid tumor cancer, a blood cancer, or a cancer of the lymphatic system.

3. The method of claim 1, wherein the cancer is selected from the group of cancers: a cancer of the circulatory system; a cancer of the respiratory system; a cancer of the gastrointestinal system; a cancer of the genitourinary system; a liver cancer; a cancer of the bone; a cancer of the nervous system; a cancer of the hematologic system; a cancer of skin or tissues comprising connective or soft tissue; a cancer of the retroperitoneum or peritoneum; an eye cancer; a breast cancer; a cancer of the head or / and neck; a thyroid cancer; a parathyroid cancer; a cancer of the adrenal gland; a cancer of the endocrine glands; and lymph nodes.

4. The method of claim 1, wherein the cancer is colon cancer, gastric cancer, breast cancer, lung cancer, pancreatic cancer, head and / or neck cancer, or esophageal cancer.

5. The method of any one of claims 1-4, wherein the cancer is a primary cancer.

6. The method of any one of claims 1-4, wherein the cancer is a metastasis.

7. The method of claim 1, wherein the cancer is selected from a carcinoma, a sarcoma, a myeloma, a leukemia, or a lymphoma.

8. The method of any one of claims 1-7, wherein the treatment comprises one or more endpoints selected from tumor response, reduction in tumor size, reduction in tumor burden, increase in overall survival, increase in progression free survival, inhibiting metastasis, improvement of quality of life, minimization of toxicity, or reduction of side-effects.

9. A method of inhibiting growth of a cancer cell comprising contacting the cell with an effective amount of a poly (ADP-ribose) polymerase (PARP) inhibitor, a deoxyuridine triphosphatase (dUTPase) inhibitor, and an inhibitor of thymidylate biosynthesis.2344927-6853-2615.1Atty. Dkt. No. 109290-019010. The method of claim 9, wherein the contacting occurs in vitro.

11. The method of claim 9, wherein the contacting occurs in vivo.

12. The method of any one of claims 9-11, wherein the cancer cell is from a cancer selected from the group of cancers: a cancer of the circulatory system; a cancer of the respiratory system; a cancer of the gastrointestinal system; a cancer of the genitourinary system; a liver cancer; a cancer of the bone; a cancer of the nervous system; a cancer of the hematologic system; a cancer of skin or tissues comprising connective or soft tissue; a cancer of the retroperitoneum or peritoneum; an eye cancer; a breast cancer; a cancer of the head or / and neck; a thyroid cancer; a parathyroid cancer; a cancer of the adrenal gland; a cancer of the endocrine glands; and lymph nodes.

13. The method of any one of claims 1-12, wherein the inhibitor of thymidylate biosynthesis comprises 5 -fluorouracil (5-FU), floxuridine (FUdR), pemetrexed, raltitrexed, nolatrexed, plevitrexed, GS7904L, capecitabine, methotrexate, pralatrexate, CT-900, NUC-3373, or a combination of two or more thereof.

14. The method of any one of claims 1-12, wherein the inhibitor of thymidylate biosynthesis comprises S-l, a combination of S-l and folinic acid, FOLFOX, FOLFOX4, FOLFIRI, FOLFIRINOX, MOF, deflexifol, arfolitixorin, or a combination of 5-FU with one or more selected from radiation, methyl-CCNU, leucovorin, a platinum agent (such as oxaliplatin, cisplatin, or carboplatin), irinotecan, mitomycin, cytarabine, or levamisole.

15. The method of any one of claims 1-12, wherein the inhibitor of thymidylate biosynthesis is an inhibitor of folate-mediated one-carbon metabolism.

16. The method of any one of claims 1-15, wherein the PARP inhibitor comprises talazoparib, olaparib, niraparib, rucaparib, saruparib, pamiparib, and veliparib.

17. The method of any of claims 1-16, wherein the dUTPase inhibitor is a compound of Formula (I):2354927-6853-2615.1Atty. Dkt. No. 109290-0190each R30independently is hydrogen; an optionally substituted C1-C10 alkoxy; optionally substituted amino, such as -NH2 or a mono or di-substituted form thereof; an optionally substituted C1-C10 alkyl; optionally substituted hydroxy; or Z;L1is:-(CH2)q-, wherein one or more hydrogens are optionally substituted with C1-C3 alkyl and / or at least two or more geminal hydrogens together with the carbon(s) to which they are attached are optionally replaced with an optionally substituted 3-5 membered heterocyclyl or an optionally substituted 3-5 membered cycloalkyl, preferably the optionally substituted 3-5 membered cycloalkyl is an optionally substituted cyclopropano, an optionally substituted cyclobutano, an optionally substituted cyclopentano, or an optionally substituted tetrahydrofurano; and wherein q is 3, 4, 5, 6, 7, or 8;, wherein one or more hydrogens are optionally substituted with C1-C3 alkyl and / or at least two or more geminal hydrogens together with the carbon(s) to which they are attached are optionally replaced with an optionally substituted 3-5 membered heterocyclyl or an optionally substituted 3-5 membered cycloalkyl, preferably2364927-6853-2615.1Atty. Dkt. No. 109290-0190the optionally substituted 3-5 membered cycloalkyl is an optionally substituted cyclopropano, an optionally substituted cyclobutano, an optionally substituted cyclopentano, or an optionally substituted tetrahydrofurano; and wherein p is 0, 1, 2, 3, 4, or 5 and z is 0, 1, 2, 3, 4, or 5;-(CH2)m-X15-(CH2)n-, wherein one or more hydrogens are optionally substituted with C1-C3 alkyl and / or at least two or more geminal hydrogens together with the carbon(s) to which they are attached are optionally replaced with an optionally substituted 3-5 membered heterocyclyl or an optionally substituted 3-5 membered cycloalkyl, preferably the optionally substituted 3-5 membered cycloalkyl is an optionally substituted cyclopropano, an optionally substituted cyclobutano, an optionally substituted cyclopentano, or an optionally substituted tetrahydrofurano; and wherein m is 0, 1, 2, or 3 and n is 0, 1, 2, 3, 4, 5, 6, or 7; or, wherein one or more hydrogens are optionally substituted with C1-C3 alkyl and / or at least two or more geminal hydrogens together with the carbon(s) to which they are attached are optionally replaced with an optionally substituted 3-5 membered heterocyclyl or an optionally substituted 3-5 membered cycloalkyl, preferably the optionally substituted 3-5 membered cycloalkyl is an optionally substituted cyclopropano, an optionally substituted cyclobutano, an optionally substituted cyclopentano, or an optionally substituted tetrahydrofurano; and wherein o is 0, 1, 2, or 3; r is 1, 2 or 3; and s is 0, 1, 2, 3, or 4; andwherein X15is NR40, O, or S, wherein R40is H or C1-C10 alkyl; orL1is -Ln-L12-L13-, wherein L11is attached to A and L11is O, S, NR, C1-C2 alkylene, C2 alkenylene, C2 heteroalkylene, C3 heteroalkenylene, L12is arylene or heteroarylene, L13is a bond or an optionally substituted C1-C5 alkylene, and R is H or C1-C3 alkyl;L2is -SO2NR50-, wherein the sulfur is attached to L1; -NR50SO2-, wherein the nitrogen is attached to L1; -C(O)NR50-, wherein the carbon is attached to L1;-NR50C(O)-, wherein the nitrogen is attached to L1; -NR50SO2NR50-; or -NR50CONR50-;each R50independently is hydrogen, an optionally substituted Ci-Ce alkyl, an optionally substituted C2-C6 heteroalkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C3-C6 heteroalkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C6 heteroalkynyl, or Z;Z is2374927-6853-2615.1Atty. Dkt. No. 109290-0190each R51and R52independently is hydrogen or an optionally substituted C1-C10 alkyl; X is an optionally substituted hydroxy group, an optionally substituted NH2 group, or an optionally substituted SH group;L3is a bond, an optionally substituted Ci-Ce alkylene, an optionally substituted C2-C6 heteroalkylene, an optionally substituted C2-C6 alkenylene, an optionally substituted C3-C6 heteroalkenylene, an optionally substituted C2-C6 alkynylene, or an optionally substituted C3-Ce heteroalkynylene; andB is an optionally substituted 6-10 membered aryl; an optionally substituted 5-15 membered heteroaryl; an optionally substituted 4-15 membered heterocyclyl; or an optionally substituted 3-15 membered cycloalkyl, if cycloalkyl, then preferably at least a 4 membered, or more preferably a 5-10 membered cycloalkyl.

18. The method of claim 17, wherein A is:2384927-6853-2615.1Atty. Dkt. No. 109290-019019. The method of claim 17 or claim 18, wherein A is:

20. The method of any one of claims 17-19, wherein L1is selected from the group consisting of:2394927-6853-2615.1Atty. Dkt. No. 109290-0190and optionally substituted versions thereof wherein 1-5, preferably, 1-3 hydrogen atoms are optionally substituted, preferred substituents including without limitation, Ci-Ce alkyl optionally substituted with 1-3 halo, such as fluoro, and / or Ci-Ce alkoxy; optionally substituted Ci-Ce alkoxy; and halo, preferably fluoro, wherein the left side of the moieties are attached to A and wherein R70is an optionally substituted Ci-Cio alkyl.

21. The method any one of claims 17-19, wherein L1is:or an optionally substituted version of each thereof wherein 1-5, preferably, 1-3 hydrogen atoms are optionally substituted, preferred substituents including without limitation, Ci-Ce alkyl optionally substituted with 1-3 halo, such as fluoro, and / or Ci-Ce alkoxy; optionally substituted Ci-Ce alkoxy; and halo, preferably fluoro, wherein the left side of the moieties are attached to A.

22. The method of any one of claims 17-21, wherein L2is -S(O)2NR50- wherein the sulfur is attached to L1.

23. The method of any one of claims 17-22, wherein L3is selected from the group consisting of:2404927-6853-2615.1Atty. Dkt. No. 109290-0190and optionally substituted versions thereof wherein 1-5, preferably, 1-3 hydrogen atoms are optionally substituted, preferred substituents including without limitation, Ci-Ce alkyl optionally substituted with 1-3 halo, such as fluoro, and / or Ci-Ce alkoxy; optionally substituted Ci-Ce alkoxy; and halo, preferably fluoro, wherein the left side of the moieties are attached to L2.

24. The method any one of claims 17-23, wherein L3is selected from the group consisting of:and optionally substituted versions thereof wherein 1-5, preferably, 1-3 hydrogen atoms are optionally substituted, preferred substituents including without limitation, Ci-Ce alkyl optionally substituted with 1-3 halo, such as fluoro, and / or Ci-Ce alkoxy; optionally substituted Ci-Ce alkoxy; and halo, preferably fluoro, wherein the left side of the moieties are attached to L2.

25. The method of any one of claims 17-24, wherein B is:2414927-6853-2615.1Atty. Dkt. No. 109290-0190whereineach R6independently is hydrogen, an optionally substituted Ci-Ce alkoxy, or halo; each R7independently is an optionally substituted Ci-Ce alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C8 cycloalkyl, an optionally substituted C3-C10 heteroaryl, an optionally substituted C3-C10 heterocyclyl, or an optionally substituted Ce-Cio aryl such as optionally substituted phenyl; or R6and R7together with the atoms they are attached to form an optionally substituted 5-7 membered ring; or 2 R6groups together with the atoms they are attached to form an optionally substituted 5-7 membered ring;each R61and R62is independently N or CH, provided that at least one of R61and R62is N,each R63is independently NR90, S, or O;each R64is independently N or CH; andeach R90is independently hydrogen or R7.2424927-6853-2615.1Atty. Dkt. No. 109290-019026. The method of any one of claims 17-24, wherein B is:whereineach RJ-R3independently is H, halo, an optionally substituted Ci-Ce alkyl, an optionally substituted 4-15 membered heterocyclyl, or -OR20or, if two of R1-R3are on adjacent carbon atoms, then two such substituents together with the atoms they are attached to form an optionally substituted 5-7 membered ring;R20is (CH2)W-R21, an optionally substituted C3-C6 cycloalkyl, or an optionally substituted Ci-Ce alkyl;R21is an optionally substituted C3-C6 cycloalkyl, an optionally substituted Ce-Cio aryl, an optionally substituted 5-15 membered heteroaryl, an optionally substituted 4-15 membered heterocyclyl, an optionally substituted C1-C10 alkyl, an optionally substituted C2-C10 alkenyl, an optionally substituted C2-C10 alkynyl, an optionally substituted 4-15 membered heterocyclyl, orwherein each R22-R24independently is an optionally substituted C1-C3 alkyl or hydroxy or two of R22-R24together with the carbon atoms they are attached to form a 3-7 membered ring; andw is 1, 2, 3, 4, or 5.

27. The method of claim 26, wherein B is:2434927-6853-2615.1Atty. Dkt. No. 109290-019028. The method of claim 27, wherein R1is H.

29. The method of claim 27, wherein R3is H or -OR20.

30. The method of claim 27, wherein R2is F or H.

31. The method of claim 27, wherein B is32. The method of any one of claims 17-24, wherein B is selected from the group consisting of:2444927-6853-2615.1Atty. Dkt. No. 109290-01902454927-6853-2615.1Atty. Dkt. No. 109290-0190whereinthe alkoxy group is further optionally substituted wherein 1-5, preferably, 1-3 hydrogen atoms are optionally substituted, preferred substituents including without limitation, Ci-Ce alkyl optionally substituted with 1-3 halo, such as fluoro, and / or Ci-Ce alkoxy; optionally substituted Ci-Ce alkoxy; and halo, preferably fluoro;the ring moiety such as the cyclopropyl group is further optionally substituted with 1-3 halo, preferably 1-2 halo;the methylene group between the oxygen atom and the ring moiety, such as the cyclopropyl group, is optionally substituted with 1-2 Ci-Ce alkyl, preferably methyl, ethyl, or propyl groups; andR70is an optionally substituted Ci-Cio alkyl.

33. The method of claim 32, wherein B is2464927-6853-2615.1Atty. Dkt. No. 109290-019034. The method of any one of claims 1-16, wherein the dUTPase inhibitor is a compound selected from Tables 1-15.

35. A composition or system comprising a poly (ADP-ribose) polymerase (PARP) inhibitor, a deoxyuridine triphosphatase (dUTPase) inhibitor, and an inhibitor of thymidylate biosynthesis.

36. A composition for use in treating cancer in a subject in need thereof comprising a poly (ADP-ribose) polymerase (PARP) inhibitor, a deoxyuridine triphosphatase (dUTPase) inhibitor, and an inhibitor of thymidylate biosynthesis.

37. A composition for use in the preparation of a medicament for the treatment of cancer in a subject in need thereof, the composition comprising a poly (ADP-ribose) polymerase (PARP) inhibitor, a deoxyuridine triphosphatase (dUTPase) inhibitor, and an inhibitor of thymidylate biosynthesis.2474927-6853-2615.1

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