Combination therapy including a WEE1 inhibitor and a DNA damage response (DDR) inhibitor

Abstract

Disclosed herein is a combination of compounds for treating a disease or condition, such as cancer. The combination includes a WEE1 inhibitor and a DDR inhibitor, such as an ATR, ATM, or CHK1 inhibitor.

Description

[Technical field]

[0001] (Incorporation by reference of any priority application) For example, any and all applications in which a claim of foreign or domestic priority is identified in an Application Data Sheet or claim filed with this application are incorporated by reference herein under 37 CFR 1.57 and Rules 4.18 and 20.6, and U.S. Provisional Application No. 63 / 263,224, filed October 28, 2021, is incorporated by reference in its entirety herein.

[0002] FIELD OF THEINVENTION This application relates to the fields of chemistry, biochemistry, and medicine. More specifically, disclosed herein are combination therapies and methods of treating diseases and / or conditions using the combination therapies described herein. [Background technology]

[0003] Cancer is a group of diseases involving abnormal cell growth that can invade or spread to other parts of the body. Today's cancer treatments include surgery, hormone therapy, radiation, chemotherapy, immunotherapy, targeted therapy, and combinations thereof. Survival rates vary by type of cancer and by the stage at which the cancer is diagnosed. In 2021, approximately 1.9 million people will be diagnosed with cancer in the United States, and an estimated 600,000 people will die from cancer. Thus, there remains a need for effective cancer treatments. Summary of the Invention

[0004] Some embodiments described herein relate to a combination of compounds that may include an effective amount of Compound (A) or a pharma- ceutically acceptable salt thereof, and an effective amount of Compound (B) or a pharma- ceutically acceptable salt of any of the foregoing. Other embodiments described herein relate to a combination of compounds that may include an effective amount of Compound (A) or a pharma- ceutically acceptable salt thereof, an effective amount of Compound (B) or a pharma- ceutically acceptable salt thereof, and an effective amount of Compound (C) or a pharma- ceutically acceptable salt thereof.

[0005] Some embodiments described herein relate to the use of a combination of compounds for treating a disease or condition, the combination comprising an effective amount of compound (A) or a pharma- ceutically acceptable salt thereof and an effective amount of compound (B) or a pharma- ceutically acceptable salt thereof. Other embodiments described herein relate to the use of a combination of compounds in the manufacture of a medicament for treating a disease or condition, the combination comprising an effective amount of compound (A) or a pharma- ceutically acceptable salt thereof and an effective amount of compound (B) or a pharma- ceutically acceptable salt thereof. Still other embodiments described herein relate to the use of a combination of compounds in a method for treating a disease or condition, the combination comprising an effective amount of compound (A) or a pharma- ceutically acceptable salt thereof and an effective amount of compound (B) or a pharma- ceutically acceptable salt thereof.

[0006] Some embodiments described herein relate to the use of a combination of compounds for treating a disease or condition, the combination comprising an effective amount of compound (A) or a pharma- ceutically acceptable salt thereof, an effective amount of compound (B) or a pharma- ceutically acceptable salt thereof, and an effective amount of compound (C) or a pharma- ceutically acceptable salt thereof. Other embodiments described herein relate to the use of a combination of compounds in the manufacture of a medicament for treating a disease or condition, the combination comprising an effective amount of compound (A) or a pharma- ceutically acceptable salt thereof, an effective amount of compound (B) or a pharma- ceutically acceptable salt thereof, and an effective amount of compound (C) or a pharma- ceutically acceptable salt thereof. Still other embodiments described herein relate to the use of a combination of compounds in a method for treating a disease or condition, the combination comprising an effective amount of compound (A) or a pharma- ceutically acceptable salt thereof, an effective amount of compound (B) or a pharma- ceutically acceptable salt thereof, and an effective amount of compound (C) or a pharma- ceutically acceptable salt thereof.

[0007] In some embodiments, the disease or condition may be a cancer as described herein. [Brief description of the drawings]

[0008] [Figure 1]Representative assay data obtained for a WEE1 inhibitor (ZN-c3) and a CHK1 inhibitor (Prexasertib) in MDA-MB-231 (TNBC) cell line are shown. The results show that single agent activity was observed for both ZN-c3 and Prexasertib, and surprisingly, the combination resulted in synergistic activity. [Diagram 2] Representative assay data obtained for a WEE1 inhibitor (ZN-c3) and an ATR inhibitor (Berzosertib) in MDA-MB-231 (TNBC) cell line are shown. The results show that single agent activity was observed with both ZN-c3 and Berzosertib, and surprisingly, the combination resulted in synergistic activity. [Diagram 3] Representative assay data obtained for a WEE1 inhibitor (ZN-c3) and a CHK1 inhibitor (prexasertib) in H23 (NSCLC) cell line are shown. The results show that single agent activity was observed with ZN-c3, virtually no activity with prexasertib, and surprisingly, the combination resulted in synergistic activity. [Figure 4] Representative assay data obtained for a WEE1 inhibitor (ZN-c3) and an ATR inhibitor (berzosertib) in H23 (NSCLC) cell line are shown. The results show that single agent activity was observed for both ZN-c3 and beruzosertib, and surprisingly, the combination resulted in synergistic activity. [Diagram 5] Representative assay data obtained for a WEE1 inhibitor (ZN-c3) and a CHK1 inhibitor (prexasertib) in MV4-11 (AML) cell line are shown. The results show that single agent activity was observed with ZN-c3, no activity with prexasertib, and surprisingly, the combination resulted in synergistic activity. [Figure 6]Representative assay data obtained for a WEE1 inhibitor (ZN-c3) and an ATM inhibitor (AZD0156) in the MV4-11 (AML) cell line are shown. The results show that single agent activity was observed for both ZN-c3 and AZD0156, and surprisingly, the combination resulted in synergistic activity. [Figure 7] Representative assay data obtained for a WEE1 inhibitor (ZN-c3) and a CHK1 inhibitor (prexasertib) in a THP-1 (AML) cell line are shown. The results show that single agent activity was observed for both ZN-c3 and AZD0156, and surprisingly, the combination resulted in synergistic activity. [Figure 8] Representative assay data obtained for a WEE1 inhibitor (ZN-c3) and an ATR inhibitor (berzosertib) in a THP-1 (AML) cell line are shown. The results show that single agent activity was observed with both ZN-c3 and AZD0156, and surprisingly, the combination resulted in synergistic activity. [Figure 9] Representative assay data obtained for a WEE1 inhibitor (ZN-c3) and a CHK1 inhibitor (prexasertib) in HL-60 (AML) cell lines are shown. The results show that single agent activity was observed with ZN-c3, no activity with prexasertib, and surprisingly, the combination resulted in synergistic activity. [Figure 10] Representative assay data obtained for a WEE1 inhibitor (ZN-c3) and an ATM inhibitor (AZD0156) in HL-60 (AML) cell lines are shown. The results show that single agent activity was observed with ZN-c3, virtually no activity with AZD0156, and surprisingly, the combination resulted in synergistic activity. [Figure 11] Representative assay data obtained for a WEE1 inhibitor (ZN-c3) and an ATR inhibitor (berzosertib) in HL-60 (AML) cell line are shown. The results show that single agent activity was observed for both ZN-c3 and beruzosertib, and surprisingly, the combination resulted in synergistic activity. [Figure 12]Representative assay data obtained for a WEE1 inhibitor (ZN-c3) and a CHK1 inhibitor (prexasertib) in LNCaP (prostate) cell line are shown. The results show that single agent activity was observed for both ZN-c3 and prexasertib, and surprisingly, the combination resulted in synergistic activity. [Figure 13] Representative assay data obtained for a WEE1 inhibitor (ZN-c3) and an ATM inhibitor (AZD0156) in LNCaP (prostate) cell line are shown. The results show that single agent activity was observed for both ZN-c3 and AZD0156, and surprisingly, the combination resulted in synergistic activity. [Figure 14] Representative assay data obtained for a WEE1 inhibitor (ZN-c3), a Bcl-2 inhibitor (Zn-d5) and a CHK1 inhibitor (prexasertib) in the MV4-11 (AML) cell line are shown. [Figure 15] Representative assay data obtained for a WEE1 inhibitor (ZN-c3), a Bcl-2 inhibitor (Zn-d5) and an ATM inhibitor (AZD0156) in the MV4-11 (AML) cell line are shown. [Figure 16] Representative assay data obtained for a WEE1 inhibitor (ZN-c3), a Bcl-2 inhibitor (Zn-d5) and an ATR inhibitor (berzosertib) in the MV4-11 (AML) cell line are shown. [Figure 17] Representative assay data obtained for a WEE1 inhibitor (ZN-c3), a Bcl-2 inhibitor (Zn-d5) and a CHK1 inhibitor (prexasertib) in a THP-1 (AML) cell line are shown. [Figure 18] Representative assay data obtained for a WEE1 inhibitor (ZN-c3), a Bcl-2 inhibitor (Zn-d5) and an ATM inhibitor (AZD0156) in a THP-1 (AML) cell line are shown. [Figure 19] Representative assay data obtained for a WEE1 inhibitor (ZN-c3), a Bcl-2 inhibitor (Zn-d5) and an ATR inhibitor (berzosertib) in a THP-1 (AML) cell line are shown. [Figure 20] Representative assay data obtained for a WEE1 inhibitor (ZN-c3), a Bcl-2 inhibitor (Zn-d5) and a CHK1 inhibitor (prexasertib) in the HL-60 (AML) cell line are shown. [Figure 21] Representative assay data obtained for a WEE1 inhibitor (ZN-c3), a Bcl-2 inhibitor (Zn-d5) and an ATM inhibitor (AZD0156) in the HL-60 (AML) cell line are shown. [Figure 22] Representative assay data obtained for a WEE1 inhibitor (ZN-c3), a Bcl-2 inhibitor (Zn-d5) and an ATR inhibitor (berzosertib) in the HL-60 (AML) cell line are shown. [Diagram 23] 1 shows chemical structures of example WEE1 inhibitors. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] definition Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety unless otherwise specified. In the event that there are a plurality of definitions for a term herein, the definition in this section prevails unless otherwise specified.

[0010] The term "pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abolish the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts are salts of a compound that is prepared by the addition of an inorganic acid, e.g., a halogenated acid. Pharmaceutical salts can also be obtained by reacting the compound with an organic acid, such as an aliphatic or aromatic carboxylic or sulfonic acid, for example, formic acid, acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, benzoic acid, salicylic acid, 2-oxopentanedioic acid, or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt, for example, an ammonium salt, an alkali metal salt, for example, sodium, potassium, or lithium salt, an alkaline earth metal salt, for example, calcium or magnesium salt, a salt of carbonate, a salt of bicarbonate, a salt of an organic base, for example, dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamines, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine and lysine. Those skilled in the art will appreciate that when a salt is formed by protonation of a nitrogen-based group (e.g., NH2), the nitrogen-based group may be associated with a positive charge (e.g., NH2 becomes NH3). + ), and the positive charge can be a negatively charged counterion (Cl - Understand that balance can be achieved by

[0011] In any compound described herein having one or more chiral centers, unless the absolute stereochemistry is explicitly indicated, it is understood that each center may be independently in the R or S configuration, or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure compounds, enantiomerically enriched compounds, racemic mixtures, diastereomerically pure compounds, diastereomerically enriched compounds, or stereoisomeric mixtures. In addition, in any compound described herein having one or more double bonds that generate geometric isomers that can be defined as E or Z, it is understood that each double bond may be independently E or Z, or a mixture thereof. Similarly, it is understood that in any compound described, all tautomeric forms are also intended to be included.

[0012] Where the compounds disclosed herein have unfilled valences, it is understood that the valences are filled with hydrogen or an isotope thereof, such as hydrogen-1 (protium) and hydrogen-2 (deuterium).

[0013] It is understood that the compounds described herein can be isotopically labeled. Substitution with an isotope such as deuterium can provide certain therapeutic advantages due to greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. Each chemical element represented in a compound structure can include any isotope of that element. For example, in a compound structure, a hydrogen atom can be expressly disclosed or understood as being present in the compound. In any position of a compound where a hydrogen atom can be present, the hydrogen atom can be any isotope of hydrogen, including, but not limited to, hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, reference to a compound herein encompasses all possible isotopic forms, unless the context clearly indicates otherwise.

[0014] It is understood that the methods and combinations described herein include crystalline forms (also known as polymorphs, which include different crystal packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates, and hydrates. In some embodiments, the compounds described herein exist in solvated forms with pharma- ceutically acceptable solvents such as water, ethanol, etc. In other embodiments, the compounds described herein exist in nonsolvated forms. Solvates contain either stoichiometric or nonstoichiometric amounts of solvent, and may be formed during the crystallization process with pharma-ceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In addition, the compounds provided herein can exist in nonsolvated as well as solvated forms. In general, solvated forms are considered equivalent to nonsolvated forms for the purposes of the compounds and methods provided herein.

[0015] When a range of values ​​is provided, it is understood that the upper and lower limits, as well as every intervening value between the upper and lower limits of that range, are encompassed within an embodiment.

[0016] Terms and phrases used in this application, and variations thereof, particularly in the appended claims, should be construed as open-ended rather than limiting, unless expressly stated otherwise. As an example above, the term "including" should be construed to mean "including without limitation," "including but not limited to," and the like. As used herein, the term "comprising" is synonymous with "including," "containing," or "featuring," and is inclusive or open-ended, and does not exclude additional unrecited elements or method steps. The term "having" should be construed as "having at least." The term "including" should be construed as "including but not limited to." The term "example" is used to provide illustrative examples rather than an exhaustive or exclusive list of the items under discussion. The use of terms such as "preferably," "preferred," "desired," or "desirable," and words of similar import, should not be understood as implying that a particular feature is critical, essential, or even important to the structure or function, but rather is intended merely to highlight alternative or additional features that may or may not be utilized in a particular embodiment. Additionally, the term "comprising" is intended to be construed as synonymous with the phrases "having at least" or "including at least." When used in the context of a compound, composition, or device, the term "comprising" means that the compound, composition, or device includes at least the recited features or components, but may also include additional features or components.

[0017] With respect to the use of substantially any plural and / or singular term herein, those skilled in the art can convert from plural to singular and / or from singular to plural as appropriate depending on the context and / or application. Various singular / plural permutations may be expressly stated herein for clarity. The indefinite article "a" or "an" does not exclude a plurality. The mere fact that certain means are recited in mutually different dependent claims does not indicate that a combination of these means cannot be used to advantage. Any reference signs in the claims should not be interpreted as limiting the scope thereof.

[0018] compound Some embodiments disclosed herein relate to the use of a combination of compounds for treating a disease or condition, the combination may include an effective amount of compound (A), or a pharma- ceutically acceptable salt thereof, and an effective amount of compound (B), or a pharma- ceutically acceptable salt of any of the foregoing, where compound (A) is a WEE1 inhibitor and compound (B) is a DNA damage response (DDR) inhibitor selected from inhibitors of ataxia telangiectasia and Rad3-related protein kinase ("ATR inhibitors" or "ATRi"), inhibitors of ataxia telangiectasia mutated kinase ("ATM inhibitors" or "ATMi"), and inhibitors of checkpoint kinase 1 ("CHK1 inhibitors" or "CHKi").

[0019] Examples of suitable WEE1 inhibitors of compound (A) include those described in the following publications: WO 2019 / 074979, WO 2020 / 210383, WO 2020 / 210375, WO 2020 / 210377, WO 2020 / 210380, WO 2020 / 210381, WO 2022 / 082174, U.S. Patent Application Publication No. No. 2022 / 0162229, U.S. Patent Application Publication No. 2022 / 0168313, U.S. Patent Application Publication No. 2022 / 0169646, U.S. Patent Application Publication No. 2022 / 0220115, U.S. Patent No. 11,332,473, WO 2019 / 173082, WO 2019 / 011228, WO 2019 / 138227, WO 2018 / 162 932, WO 2018 / 011570, WO 2018 / 011569, U.S. Patent Application Publication No. 2022 / 0194947, WO 2018 / 090939, WO 2015 / 092431, WO 2015 / 019037, WO 2014 / 167347, WO 2007 / 126122, WO 2011 / 03 4743, U.S. Patent Application Publication No. 2007 / 0254892, International Publication No. 2008 / 133866, U.S. Patent Application Publication No. 2016 / 0060258, U.S. Patent Application Publication No. 2019 / 0308984, U.S. Patent Application Publication No. 2020 / 0131192, International Publication No. 2021 / 073491, U.S. Patent No. 11,345,710, U.S. Patent No. 11,345,711 WO 2019 / 085933, WO 2020 / 221358, EP 3712150, WO 2018 / 133829, WO 2021 / 047627, U.S. Patent Application Publication No. 2021 / 0403451, WO 2020 / 083404, WO 2019 / 037678, WO 2018 / 17 1633, Chinese Patent Application Publication No. 113387962, International Publication No. WO 2019 / 165204, International Publication No. WO 2012 / 161812, International Publication No. WO 2013 / 012681, International Publication No. WO 2013 / 013031, International Publication No. WO 2013 / 059485, International Publication No. WO 2013 / 126656, US Patent Application Publication No. 2012 / 0220572,U.S. Patent Application Publication No. 2013 / 0018045, Korean Patent No. 2016035878, Korean Patent No. 2020016567, International Publication No. 2018 / 056621, International Publication No. 2017 / 075629, International Publication No. 2019 / 169065, International Publication No. 2019 / 134539, International Publication No. 2020 / 028814, U.S. Patent Application Publication No. 2021 / 0309630, International Publication No. 2020 / 069105, International Publication No. 2020 / 192581, U.S. Patent Application Publication No. 2022 / 0194960, Chinese Patent Application Publication No. 114831993, Chinese Patent Application Publication No. 111718348, International Publication No. 2022 / 188802, International Publication No. 96 / 34867, International Publication No. 2008 / 153207, International Publication No. 2010 / 067888, International Publication No. 2009 / 054332, International Publication No. 2021 / 073491, International Publication No. 2021 / 074251, Chinese Patent Application Publication No. 112142763, WO 2020 / 259724, U.S. Patent Application Publication No. 2022 / 0259210, WO 2019 / 096322, Chinese Patent Application Publication No. 112142747, Chinese Patent Application Publication No. 112142747, WO 2021 / 043152, WO 2021 / 254389, WO 2022 / 171088, WO 2022 / 171126, WO 2022 / 171128, WO 2022 / 174765 , International Publication No. 2022 / 174796, Chinese Patent Application Publication No. 112442049, Chinese Patent Application Publication No. 114072411, Chinese Patent Application Publication No. 113402520, Chinese Patent Application Publication No. 113387962, Korean Patent No. 2022081171, International Publication No. 2022 / 124748, International Publication No. 2022 / 155202, Chinese Patent Application Publication No. 114591334 and International Publication No. 2021 / 074251.

[0020] In some embodiments, the WEE1 inhibitor may be selected from AZD1775, SC0191, PD0166285, NUV-569, SDR-7995, SDR-7778, IMP7068, Debio 0123, SY-4835, SPH-6162, and ATRN-W1051, or any combination thereof. Further details regarding WEE1 inhibitors are provided in FIG. 23. In other embodiments, the WEE1 inhibitor is:

[0021] [ka] (ZN-c3), or a pharma- ceutically acceptable salt thereof. In yet another embodiment, the WEE1 inhibitor may be:

[0022] [ka] or a pharma- ceutically acceptable salt or N-oxide thereof. In still yet other embodiments, the WEE1 inhibitor is

[0023] [ka] or a pharma- ceutically acceptable salt thereof of any of the foregoing. In some embodiments, the WEE1 inhibitor is

[0024] [ka] or a pharma- ceutically acceptable salt thereof of any of the foregoing. In other embodiments, the WEE1 inhibitor is

[0025] [ka] or a pharma- ceutically acceptable salt thereof. In yet another embodiment, the WEE1 inhibitor is

[0026] [ka] or a pharma- ceutically acceptable salt thereof of any of the foregoing.

[0027] Examples of ATR inhibitors include gartisertib, beruzosertib, and sera. These include Ceralasertib, Schisandrin B, Elimsertib, NU6027, Dactolisib, ETP-46464, Torin2, VE-821, AZ20, Camonsertib, CGK733, ART-0380, ATRN-119 and ATRN-212.

[0028] Examples of ATM inhibitors include AZD7648, AZD0156, AZ31, AZ32, AZD1390, KU55933, KU59403, KU60019, CP-466722, CGK733, NVP-BEZ235, SJ573017, AZ31, AZ32, AZD1390, SKLB-197, CGK733, M4076, M3541, and M4076.

[0029] Examples of CHK1 inhibitors include prexasertib, AZD7762, ravusertib, MK-8776, CCT245737, CCT244747, CHIR-124, PD 407824, PD-321852, PF-00477736, GDC-0425, GDC-0575, SB-218078, V158411, SAR-020106, XL-844, UCN-01, SOL-578, IMP 10, and CBP501.

[0030] The combinations described herein may further include a compound (C), including pharma- ceutically acceptable salts thereof, which may be a Bcl-2 inhibitor such as 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide. 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide, or a pharma- ceutically acceptable salt thereof, can be prepared as provided in WO 2019 / 139899 and has the structure

[0031] [ka] has.

[0032] The order of administration of the compounds in the combinations described herein may vary. In some embodiments, compound (A), including a pharma- ceutically acceptable salt thereof, may be administered before compound (B) or a pharma- ceutically acceptable salt thereof. In other embodiments, compound (A), including a pharma- ceutically acceptable salt thereof, may be administered simultaneously with compound (B) or a pharma- ceutically acceptable salt thereof. In yet other embodiments, compound (A), including a pharma- ceutically acceptable salt thereof, may be administered subsequent to the administration of compound (B) or a pharma- ceutically acceptable salt thereof. In some embodiments, compound (C), including a pharma- ceutically acceptable salt thereof, may be administered prior to both compound (A) and compound (B) (including their pharma- ceutically acceptable salts). In other embodiments, compound (C), including its pharma- ceutically acceptable salt, may be administered after both compound (A) and compound (B), including their pharma- ceutically acceptable salts. In yet other embodiments, compound (C), including its pharma- ceutically acceptable salt, may be administered before one of compounds (A), including its pharma- ceutically acceptable salt, and after compound (B), including its pharma- ceutically acceptable salt. In yet still other embodiments, compound (C), including its pharma- ceutically acceptable salt, may be administered before one of compounds (B), including its pharma- ceutically acceptable salt, and after compound (A), including its pharma- ceutically acceptable salt.

[0033] There may be some advantages to using the combination of compounds described herein.For example, combining compounds that attack multiple pathways simultaneously may be more effective in treating cancers such as those described herein compared to when the combination compounds are used as monotherapy.

[0034] In some embodiments, the combinations described herein (e.g., Compound (A) and Compound (B) or a pharma- ceutically acceptable salt thereof, including pharma- ceutically acceptable salts thereof, and Compound (A), Compound (B) or a pharma- ceutically acceptable salt thereof, and Compound (C) or a pharma- ceutically acceptable salt thereof) may reduce the number and / or severity of side effects that may be attributable to a compound described herein, such as Compound (B), or a pharma- ceutically acceptable salt thereof.

[0035] The use of the combinations of compounds described herein can result in additive, synergistic, or strongly synergistic effects. The combinations of compounds described herein can result in effects that are not antagonistic.

[0036] In some embodiments, the combinations described herein (e.g., Compound (A) and Compound (B) or a pharma- ceutically acceptable salt thereof, including pharma- ceutically acceptable salts thereof, and Compound (A), Compound (B) or a pharma- ceutically acceptable salt thereof, and Compound (C) or a pharma- ceutically acceptable salt thereof) may provide an additive effect. In some embodiments, the combinations described herein (e.g., Compound (A) and Compound (B) or a pharma- ceutically acceptable salt thereof, including pharma- ceutically acceptable salts thereof, and Compound (A), Compound (B) or a pharma- ceutically acceptable salt thereof, and Compound (C) or a pharma- ceutically acceptable salt thereof) may provide a synergistic effect. In some embodiments, the combinations described herein (e.g., Compound (A) and Compound (B) or a pharma- ceutically acceptable salt thereof, and Compound (A) or a pharma- ceutically acceptable salt thereof, Compound (B) or a pharma- ceutically acceptable salt thereof, and Compound (C) or a pharma- ceutically acceptable salt thereof) may produce strong synergistic effects. In some embodiments, the combinations described herein (e.g., Compound (A) and Compound (B) or a pharma- ceutically acceptable salt thereof, and Compound (A) or a pharma- ceutically acceptable salt thereof, Compound (B) or a pharma- ceutically acceptable salt thereof, and Compound (C) or a pharma- ceutically acceptable salt thereof) are not antagonistic.

[0037] As used herein, the term "antagonistic" means that the activity of the combination of compounds is lower than the sum of the activities of each compound in the combination when the activity of each compound is measured individually (i.e., as a single compound). As used herein, the term "synergistic" means that the activity of the combination of compounds is higher than the sum of the individual activities of each compound in the combination when the activity of each compound is measured individually. As used herein, the term "additive" means that the activity of the combination of compounds is approximately equal to the sum of the individual activities of each compound in the combination when the activity of each compound is measured individually.

[0038] A potential advantage of utilizing the combinations described herein may be that a reduced amount of the compounds is required to be effective in treating a disease condition disclosed herein, compared to when each compound is administered as a monotherapy. For example, the amount of compound (B), or a pharma- ceutically acceptable salt thereof, used in the combinations described herein may be less than the amount of compound (B), or a pharma- ceutically acceptable salt thereof, required to achieve the same reduction in a disease marker (e.g., tumor size) when administered as a monotherapy. Another potential advantage of utilizing the combinations described herein is that the use of two or more compounds with different mechanisms of action may be a higher barrier to the development of resistance, compared to when the compounds are administered as a monotherapy. Further advantages of utilizing the combinations described herein may include little or no cross-resistance between each compound of the combinations described herein, different routes of elimination for each compound of the combinations described herein, and / or little overlapping toxicity between each compound of the combinations described herein.

[0039] Pharmaceutical Compositions Compound (A), including its pharma- ceutically acceptable salts, may be provided in a pharmaceutical composition.Similarly, Compound (B) and Compound (C), including their pharma- ceutically acceptable salts, may be provided in a pharmaceutical composition.

[0040] The term "pharmaceutical composition" refers to a mixture of one or more compounds and / or salts disclosed herein with other chemical components, such as diluents, carriers, and / or excipients. Pharmaceutical compositions facilitate administration of a compound to an organism. Pharmaceutical compositions can also be obtained by reacting a compound with an inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutical compositions will generally be tailored to the specific intended route of administration.

[0041] As used herein, "carrier" refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, and without limitation, dimethyl sulfoxide (DMSO) is a commonly used carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.

[0042] As used herein, "diluent" refers to an ingredient in a pharmaceutical composition that has no apparent pharmacological activity, but may be pharma- ceutically necessary or desirable. For example, a diluent may be used to bulk a potent drug whose mass is too small for manufacture and / or administration. It may also be a liquid for dissolving a drug to be administered by injection, ingestion, or inhalation. A common form of diluent in the art is a buffered aqueous solution, such as, without limitation, phosphate buffered saline, which mimics the pH and isotonicity of human blood.

[0043] As used herein, "excipient" refers to an essentially inert substance added to a pharmaceutical composition to provide the composition with, but not limited to, bulk, consistency, stability, binding ability, lubrication, disintegration ability, etc. For example, stabilizers such as antioxidants and metal chelators are excipients. In one embodiment, the pharmaceutical composition includes an antioxidant and / or a metal chelator. A "diluent" is a type of excipient.

[0044] In some embodiments, compound (B) may be provided in a pharmaceutical composition that includes compound (A) with its pharma- ceutically acceptable salt, together with a pharma- ceutically acceptable salt thereof. In other embodiments, compound (B) may be administered in a pharmaceutical composition that includes compound (A) with its pharma- ceutically acceptable salt, together with a pharma- ceutically acceptable salt thereof, in a separate pharmaceutical composition. When compound (C) with its pharma- ceutically acceptable salt is included, the pharma- ceutically acceptable salt may be included in the pharmaceutical composition. Compound (C), including its pharma- ceutically acceptable salt, may be provided in a pharmaceutical composition that includes compound (A) together with its pharma- ceutically acceptable salt and / or compound (B) together with its pharma- ceutically acceptable salt. In another example, compound (C), including its pharma- ceutically acceptable salt, may be provided in a pharmaceutical composition that is separate from compound (A) (together with its pharma- ceutically acceptable salt) and compound (B) (together with its pharma- ceutically acceptable salt).

[0045] The pharmaceutical compositions described herein can be administered to human patients by themselves or in pharmaceutical compositions in which they are mixed with other active ingredients, such as in combination therapy, or with carriers, diluents, excipients, or combinations thereof.The appropriate formulation depends on the route of administration selected.Techniques for formulation and administration of the compounds described herein are known to those skilled in the art.

[0046] The pharmaceutical compositions disclosed herein can be prepared in a manner known per se, for example, by conventional mixing, dissolving, granulating, dragee-making, elutriating, emulsifying, encapsulating, entrapping, or tabletting processes. Additionally, the active ingredient is contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharma-ceutically compatible counterions.

[0047] There are multiple techniques in the art for administering compounds, salts, and / or compositions, including, but not limited to, oral, rectal, pulmonary, topical, aerosol, injection, infusion, and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injection, intrathecal, direct intraventricular, intraperitoneal, intranasal, and intraocular injection. In some embodiments, compound (A), including its pharmaceutically acceptable salt, can be administered orally. In some embodiments, compound (A), including its pharmaceutically acceptable salt, can be provided to a subject by the same route of administration as compound (B) (with its pharmaceutically acceptable salt) and / or compound (C) (with its pharmaceutically acceptable salt). In other embodiments, compound (A), including its pharmaceutically acceptable salt, can be provided to a subject by a different route of administration than compound (B) (with its pharmaceutically acceptable salt) and / or compound (C) (with its pharmaceutically acceptable salt).

[0048] The compounds, salts, and / or compositions may also be administered in a local rather than systemic manner, for example, by injecting or implanting the compounds directly into the affected area, often as a depot or sustained release formulation. Additionally, the compounds can be administered in targeted drug delivery systems, for example, in liposomes coated with tissue-specific antibodies. The liposomes will be targeted to and taken up selectively by the organ. For example, intranasal or intrapulmonary delivery may be desired to target respiratory diseases or conditions.

[0049] The composition may be provided in a pack or dispenser device, which may contain one or more unit dosage forms containing the active ingredient, if desired. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied by a notice associated with the container, in a format prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects the approval by the agency of the form of the drug for human or animal administration. Such notice may, for example, be a label approved by the U.S. Food and Drug Administration for prescription drugs, or an approved product insert. The composition may comprise the compound and / or salt described herein, formulated in a compatible pharmaceutical carrier, and may also be prepared for the treatment of an indicated condition, placed in an appropriate container, and labeled.

[0050] Methods of Use and Treatment As provided herein, in some embodiments, an effective amount of a pharma- ceutically acceptable A combination of compounds comprising compound (A), including a pharma- ceutically acceptable salt thereof, and an effective amount of compound (B), or a pharma- ceutically acceptable salt of any of the foregoing, can be used to treat a disease or condition. In some embodiments, a combination of compounds comprising an effective amount of compound (A), including a pharma- ceutically acceptable salt thereof, an effective amount of compound (B), including a pharma- ceutically acceptable salt thereof, and an effective amount of compound (C), including a pharma- ceutically acceptable salt thereof, can be used to treat a disease or condition.

[0051] In some embodiments, the disease or condition is selected from the group consisting of glioblastoma, astrocytoma, meningioma, craniopharyngioma, medulloblastoma, other brain cancers, head and neck cancer, leukemia, acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), myelodysplastic syndrome (MDS), skin cancer, adrenal gland cancer, anal cancer, bile duct cancer, bladder cancer, bone cancer, breast cancer (e.g., triple negative breast cancer), cervical cancer, colorectal cancer (e.g., colon adenocarcinoma), prostate cancer, endometrial cancer, esophageal cancer, eye cancer, gallbladder cancer, gastric cancer, and the like. cancer), gastrointestinal cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hematological malignancies, Kaposi's sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, liver cancer, lung cancer, non-small cell lung cancer, small cell, lymphoma, mesothelioma, melanoma, multiple myeloma, neuroblastoma, nasopharyngeal cancer, ovarian cancer, osteosarcoma, sarcoma, gastrointestinal stromal tumor (GIST), pancreatic cancer, pituitary cancer, retinoblastoma, salivary gland cancer, stomach cancer, small intestine cancer, testicular cancer, thymic cancer, thyroid cancer, uterine cancer, uterine sarcoma, uterine serous carcinoma, vaginal cancer, vulvar cancer, Waldenstrom's macroglobulinemia, Wilms' tumor, solid tumors, and liquid tumors. In some embodiments, the disease or condition may be leukemia, AML (acute myeloid leukemia), CLL (chronic lymphocytic leukemia) and / or ALL (acute lymphocytic leukemia). In some embodiments, the disease or condition may be breast cancer, such as triple negative breast cancer. In some embodiments, the disease or condition may be prostate cancer. In some embodiments, the disease or condition may be non-small cell lung cancer.

[0052] In some cases, following cancer treatment, a subject may experience a relapse or recurrence of cancer. As used herein, the terms "relapse" and "recurrence" are used in their ordinary sense as understood by those of skill in the art. Thus, the cancer may be a recurrent cancer.

[0053] As used herein, "subject" refers to an animal that is the object of treatment, observation, or experiment. "Animals" include cold-blooded and warm-blooded vertebrates and invertebrates, such as fish, crustaceans, reptiles, and especially mammals. "Mammals" include, but are not limited to, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes, and especially humans. In some embodiments, the subject may be a human. In some embodiments, the subject may be a child and / or infant. In other embodiments, the subject may be an adult.

[0054] As used herein, the terms "treat," "treating," "treatment," "therapeutic," and "therapy" do not necessarily mean a complete cure or elimination of a disease or condition. Any alleviation of any undesirable signs or symptoms of a disease or condition, to any degree, may be considered treatment and / or therapy. Additionally, treatment may include actions that may worsen a subject's overall feeling of health or appearance.

[0055] The term "effective amount" is used to indicate an amount of an active compound or agent that elicits a indicated biological or pharmaceutical response. For example, an effective amount of a compound, salt or composition will prevent, alleviate, or ameliorate symptoms of a disease or condition, or prolong the survival of the subject being treated. The amount of the compound disclosed herein may be the amount required to achieve the desired effect. This response may occur in a tissue, system, animal, or human and includes alleviation of signs or symptoms of the disease or condition being treated. Determination of an effective amount is well within the capabilities of one of ordinary skill in the art in light of the disclosure provided herein. The effective amount of the compound disclosed herein required as a dose will depend on the route of administration, the type of animal, including humans, being treated, and the physical characteristics of the particular animal under consideration. Dosages can be adjusted to achieve the desired effect, but will depend on factors such as body weight, diet, concurrent medications, and other factors that one of ordinary skill in the medical arts would recognize.

[0056] For example, an effective amount of a compound or radiation is an amount that results in: (a) a reduction, alleviation, or elimination of one or more symptoms caused by cancer; (b) a reduction in tumor size; (c) elimination of the tumor; and / or (d) long-term disease stabilization (growth cessation) of the tumor.

[0057] The amount of compound, salt, and / or composition required for use in treatment will vary depending on the specific compound or salt selected, the route of administration, the nature and / or symptoms of the disease or condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the attending physician or clinician.In the case of administration of a pharmaceutically acceptable salt, the dosage amount can be calculated as a free base.As will be understood by those skilled in the art, in certain circumstances, it may be necessary to administer the compounds disclosed herein in amounts that exceed or even far exceed the dosage ranges described herein in order to effectively and aggressively treat, particularly progressive, diseases or conditions.

[0058] As will be readily apparent to those skilled in the art, the useful in vivo dosages and the specific administration methods administered will vary depending on the age, weight, severity of the affliction, the mammalian species being treated, the specific compounds used, and the specific applications for which these compounds are used. The determination of effective dosage levels, i.e., the dosage levels required to achieve the desired results, can be accomplished by those skilled in the art using routine methods, such as human clinical trials, in vivo studies, and in vitro studies. For example, the useful dosages of compounds (A) and / or (B), or the pharma-ceutically acceptable salts described above, can be determined by comparing their in vitro activity and in vivo activity in animal models. Such comparisons can be made by comparison with established drugs such as cisplatin and / or gemcitabine.

[0059] Dosage amount and interval may be adjusted individually to provide a plasma concentration sufficient for the active moiety to maintain a modulatory effect or minimal effective concentration (MEC). The MEC varies from compound to compound but can be estimated from in vivo and / or in vitro data. The dosage required to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using the MEC value. Compositions should be administered using a regimen that maintains plasma levels above the MEC for 10-90% of the time, preferably 30-90% and most preferably 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to the plasma concentration.

[0060] It should be noted that the attending physician would know how and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunction. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response is not adequate (precluding toxicity). The magnitude of the dose administered in the management of the disease of interest will vary with the severity of the disease or condition to be treated and with the route of administration. The severity of the disease or condition can, for example, be assessed, in part, by standard prognostic evaluation methods. Furthermore, the dose and perhaps dose frequency will also vary with the age, weight, and response of the individual patient. Programs comparable to those discussed above can be used in veterinary medicine.

[0061] The compounds, salts, and compositions disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of a particular compound or a subset of compounds sharing a certain chemical moiety can be established by evaluating in vitro toxicity on cell lines, such as mammalian cell lines, preferably human cell lines. The results of such studies often predict toxicity in animals, such as mammals, or especially humans. Alternatively, the toxicity of a particular compound in an animal model, such as mice, rats, rabbits, dogs, or monkeys, can be determined using known methods. The efficacy of a particular compound can be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model to determine efficacy, a person skilled in the art can be guided by the state of the art in selecting the appropriate model, dose, route of administration, and / or regimen. EXAMPLES

[0062] Further embodiments, which are not intended to limit the scope of the claims in any way, are disclosed in more detail in the following examples.

[0063] 20,000 MDA-MB-231 cells were incubated in triplicate with 500 nM ZN-c3 and 10 nM CHK inhibitor or 700 nM ATR inhibitor (as single agents or in combination of both) in 96-well plates for 72 hours. 20,000 H23 cells were incubated in triplicate with 150 nM ZN-c3 and 5 nM CHK inhibitor or 500 nM ATR inhibitor (as single agents or in combination of both) in 96-well plates for 72 hours. 10,000 MV4-11 cells were incubated in triplicate with 400 nM ZN-c3 and 2 nM CHK inhibitor or 2000 nM ATM inhibitor (as single agents or in combination of both) in 96-well plates for 72 hours. 20,000 THP-1 cells were incubated in triplicate with 600 nM ZN-c3 and 4 nM CHK inhibitor or 1000 nM ATR inhibitor (as single agents or in combination of both) in 96-well plates for 72 hours. 10,000 HL-60 cells were incubated in triplicate with 750 nM ZN-c3 and 15 nM CHK inhibitor or 2000 nM ATM inhibitor (as single agents or in combination of both) in 96-well plates for 72 hours. 10,000 LNCaP cells were incubated in triplicate with 500 nM ZN-c3 and 10 nM CHK inhibitor or 1000 nM ATM inhibitor (as single agents or in combination of both) in 96-well plates for 72 hours. Cell viability was assessed for each cell line using the CellTiter-Glo® (CTG) assay.

[0064] Tables 1, 2 and 3 provide representative data and show that the tested combinations of ZN-c3 (WEE1 inhibitor) and DNA damage response (DDR) inhibitors demonstrated synergistic effects in all cell lines tested. The data are also summarized in Figures 1-13.

[0065] [Table 1]

[0066] [Table 2]

[0067] [Table 3]

[0068] 10,000 MV4-11 cells were incubated in 96-well plates with 2 nM ZN-d5, 400 nM ZN-c3 and 2 nM CHK inhibitor or 2000 nM ATM inhibitor or 150 nM ATR inhibitor in single, double or triple combinations in triplicate for 72 h. 20,000 THP-1 cells were incubated in 96-well plates with 100 nM ZN-d5, 600 nM ZN-c3 and 4 nM CHK inhibitor or 1000 nM ATM inhibitor or 1000 nM ATR inhibitor in single, double or triple combinations in triplicate for 72 h. 10,000 HL-60 cells were incubated in 96-well plates with 75 nM ZN-d5, 750 nM ZN-c3, and 15 nM CHK inhibitor, 2000 nM ATM inhibitor, or 1000 nM ATR inhibitor in single, double, or triple combinations in triplicate for 72 hours. For each cell line, cell viability was assessed using the CellTiter-Glo® (CTG) assay.

[0069] Table 4 provides representative data and shows that the tested combination of ZN-c3 (WEE1 inhibitor), ZN-d5 (Bcl-2 inhibitor) and DNA damage response (DDR) inhibitors was effective in all cell lines tested. The data are also summarized in Figures 14-22.

[0070] [Table 4]

[0071] In the Examples and Tables 1 to 4: CHK (Checkpoint kinase): Checkpoint kinase ATM (Ataxia-telangiectasia mutated): Ataxia-telangiectasia mutated ATR (Ataxia telangiectasia and Rad3-related protein) ZN-c3 (WEE1 inhibitor) Prexasertib (CHKi inhibitor) AZD0156 (ATMi inhibitor) Berzosertib (ATRi inhibitor)

[0072] Moreover, although the above has been described in some detail with reference to the figures and examples for clarity and understanding, it will be understood by those skilled in the art that numerous and various modifications may be made without departing from the spirit of the present disclosure. It should therefore be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure, but rather encompass all modifications and alternative forms consistent with the true scope and spirit of the present invention.

Claims

1. A pharmaceutical composition of a compound combination for treating a disease or condition, wherein the disease or condition is cancer, the combination comprising an effective amount of compound (A) or a pharmaceutically acceptable salt thereof and an effective amount of compound (B) or a pharmaceutically acceptable salt thereof, wherein compound (A) is 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, wherein compound (B) is a DNA damage response (DDR) inhibitor selected from an ATR inhibitor, an ATM inhibitor, a CHK1 inhibitor, or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition of claim 1, wherein compound (A) or a pharmaceutically acceptable salt thereof is provided before compound (B) or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition of claim 1, wherein compound (A) or a pharmaceutically acceptable salt thereof is provided simultaneously with compound (B) or a pharmaceutically acceptable salt thereof.

4. The pharmaceutical composition of claim 1, wherein compound (A) or a pharmaceutically acceptable salt thereof is provided after compound (B) or a pharmaceutically acceptable salt thereof.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the disease or condition is selected from the group consisting of leukemia, breast cancer, non-small cell lung cancer, and prostate cancer.

6. The pharmaceutical composition according to claim 5, wherein the leukemia is selected from the group consisting of AML (acute myeloid leukemia), CLL (chronic lymphocytic leukemia), and ALL (acute lymphocytic leukemia).

7. The pharmaceutical composition of claim 5 , wherein the disease or condition is breast cancer.

8. The pharmaceutical composition of claim 7, wherein the breast cancer is triple-negative breast cancer.

9. The pharmaceutical composition of claim 5, wherein the disease or condition is prostate cancer.

10. The pharmaceutical composition according to claim 5, wherein the disease or condition is non-small cell lung cancer.

11. The pharmaceutical composition of claim 5, wherein the ATR inhibitor is selected from the group consisting of galtisertib, berzosertib, selalasertib, schisandrin B, elimsertib, NU6027, dactolisib, ETP-46464, Torin2, VE-821, AZ20, camonsertib, CGK733, ART-0380, ATRN-119, and ATRN-212.

12. The pharmaceutical described in claim 11, wherein the ATR inhibitor is berzosertib.

13. The pharmaceutical composition of claim 11, wherein the combination further comprises 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide.

14. The pharmaceutical composition of claim 5, wherein the ATM inhibitor is selected from the group consisting of AZD7648, AZD0156, AZ31, AZ32, AZD1390, KU55933, KU59403, KU60019, CP-466722, CGK733, NVP-BEZ235, SJ573017, SKLB-197, M4076 and M3541.

15. The pharmaceutical described in claim 14, wherein the ATM inhibitor is AZD0156.

16. The pharmaceutical composition of claim 14, wherein the combination further comprises 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide.

17. The pharmaceutical composition of claim 5, wherein the CHK1 inhibitor is selected from the group consisting of prexasertib, AZD7762, ravusertib, MK-8776, CCT245737, CCT244747, CHIR-124, PD 407824, PD-321852, PF-00477736, GDC-0425, GDC-0575, SB-218078, V158411, SAR-020106, XL-844, UCN-01, SOL-578, IMP 10, and CBP501.

18. The pharmaceutical described in claim 17, wherein the CHK1 inhibitor is prexasertib.

19. The combination of claim 19, wherein the combination is 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(3-(difluoromethyl)bicyclo[1.1.1]pentane- 18. The pharmaceutical composition of claim 17, further comprising ((1-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide.

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