WO2024118596A1 - Checkpoint kinase 1 (chk1) inhibitors combinations and uses thereof - Google Patents

Checkpoint kinase 1 (chk1) inhibitors combinations and uses thereof Download PDF

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Publication number
WO2024118596A1
WO2024118596A1 PCT/US2023/081334 US2023081334W WO2024118596A1 WO 2024118596 A1 WO2024118596 A1 WO 2024118596A1 US 2023081334 W US2023081334 W US 2023081334W WO 2024118596 A1 WO2024118596 A1 WO 2024118596A1
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compound
formula
cancer
therapeutic agent
heterocycloalkyl
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PCT/US2023/081334
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French (fr)
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Christian Hassig
Anthony B. Pinkerton
Zachary D. HORNBY
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Boundless Bio, Inc.
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Publication of WO2024118596A1 publication Critical patent/WO2024118596A1/en

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    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • C12Q2600/00—Oligonucleotides characterized by their use
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    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/112—Disease subtyping, staging or classification
    • C—CHEMISTRY; METALLURGY
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    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers

Definitions

  • a method of treating a tumor or tumor cells comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a selected cancer-targeted therapeutic agent to a subject identified as having the tumor or tumor cells, wherein the tumor or tumor cells comprise a gene amplification, whereby growth or size of the tumor or growth or number of tumor cells is reduced.
  • Also disclosed herein is a method of delaying resistance to a selected cancer-targeted therapeutic agent, the method comprising: administering a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, to a subject in an amount sufficient to induce replication stress in tumor or tumor cells and administering the selected cancer-targeted therapeutic agent concurrently or subsequent to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.
  • Also disclosed herein is a method of treating a subject having a tumor or tumor cells that are non- responsive to a prior cancer-targeted therapeutic agent comprising administering a compound of Formula (I), Attorney Docket No.57547-724.601 or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a selected cancer- targeted therapeutic agent to the subject.
  • a compound of Formula (I) Attorney Docket No.57547-724.601 or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a selected cancer- targeted therapeutic agent to the subject.
  • the subject received one or more administrations of the prior cancer-targeted therapeutic agent prior to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and wherein the tumor or tumor cells developed decreased responsiveness or resistance to the prior cancer-targeted therapeutic agent.
  • Also disclosed herein is a method of provoking a response in a subject having a tumor or tumor cells that are non-responsive or have decreased responsiveness to a prior cancer-targeted therapeutic agent comprising administering a Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a selected cancer-targeted therapeutic agent to the subject; wherein the prior cancer-targeted therapeutic agent is the same as the selected cancer-targeted therapeutic agent.
  • a Formula (I) or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof
  • the tumor or tumor cells prior to treatment with the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, comprise a gene amplification and wherein the prior cancer-targeted therapeutic agent has an activity directed against a protein encoded by a gene contained within the gene amplification.
  • the selected cancer-targeted therapeutic agent is administered concurrent or subsequent to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.
  • the selected cancer-targeted therapeutic agent is administered prior to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.
  • the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof is administered in an amount sufficient to induce replication stress in the tumor or tumor cells.
  • the subject is identified as having the tumor or tumor cells comprising a gene amplification.
  • the gene amplification is a focal gene amplification.
  • the gene amplification is an ecDNA-derived amplification.
  • the gene amplification is comprised on ecDNA or an HSR (homogeneously staining region).
  • the tumor or tumor cells comprise an ecDNA signature.
  • the selected cancer-targeted therapeutic agent is directed against a protein encoded by a gene contained within the gene amplification.
  • cells comprised within the tumor or the tumor cells are ecDNA competent.
  • treatment with both the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the selected cancer-targeted therapeutic agent has a greater effect or a longer duration of effect on reduction of one or more of tumor growth, tumor size, number of tumor cells or tumor metastasis as compared to the treatment with either the compound of Formula (I) or the selected cancer-targeted therapeutic agent when administered alone.
  • the greater effect is a synergistic effect.
  • the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and/or the selected cancer- targeted therapeutic agent is administered orally.
  • treatment comprises administering multiple doses of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and/or the selected cancer-targeted therapeutic agent over a treatment period.
  • the gene amplification comprises an amplification of a gene selected from the group consisting of ABCB1, AKT, ALK, AR, BCL-2, BCR-ABL, BRAF, CDK4, CDK6, c-MET, EGFR, ER, ERBB3, ERRB2, AK, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, GR, HRAS, IGF1R, KIT, KRAS, MCL-1, MDM2, MDM4, MTOR, MYC, MYCL, MYCN, NRAS, NRG1, NTRK1, NTRK2, NTRK3, PDGFR, PIK3C ⁇ , PIK3CA/B, RET, and ROS1.
  • a gene selected from the group consisting of ABCB1, AKT, ALK, AR, BCL-2, BCR-ABL, BRAF, CDK4, CDK6, c-MET, EGFR, ER, ERBB3, ERRB2, AK, FGFR1, FGFR2,
  • the gene amplification comprises an amplification of a gene selected from the group consisting of CDK4, CDK6, c-MET, EGFR, FGFR1, FGFR2, FGFR3, and FGFR4.
  • the selected cancer therapeutic agent is an FGFR inhibitor.
  • the FGFR inhibitor is infigratinib, futibatinib, or pemigatinib.
  • the selected cancer therapeutic agent is a CDK4/6 inhibitor.
  • the CDK4/6 inhibitor is palbociclib or abemaciclib.
  • the selected cancer therapeutic agent is an EGFR inhibitor. In some embodiments of a method disclosed herein, the EGFR inhibitor is erlotinib.
  • the selected cancer therapeutic agent is a c- MET inhibitor. In some embodiments of a method disclosed herein, the c-MET inhibitor is tepotinib.
  • the tumor or tumor cells prior to treatment the tumor or tumor cells comprise ecDNA and wherein the treatment results in a reduction in the amount of ecDNA in the tumor or tumor cells.
  • Attorney Docket No.57547-724.601 [0033]
  • prior to treatment the tumor or tumor cells comprise ecDNA and wherein level or amount of ecDNA subsequent to the treatment is not increased as compared to prior to treatment.
  • the method further comprises assessing a sample from a subject for the presence or level of one or more of a gene amplification, a focal gene amplification, ecDNA, HSR or an ecDNA signature.
  • the method further comprises obtaining information of the presence or level of one or more of a gene amplification, a focal gene amplification, ecDNA, HSR or an ecDNA signature in the tumor or tumor cells from the subject prior to, during or subsequent to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.
  • the information is obtained from blood, tissue or one or more cells.
  • the information is obtained by liquid biopsy or tissue biopsy.
  • the prior cancer-targeted therapeutic agent is targeted to the protein encoded by a gene selected from the group consisting of ABCB1, AKT, ALK, AR, BCL-2, BCR-ABL, BRAF, CDK4, CDK6, c-MET, EGFR, ER, ERBB3, ERRB2, AK, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, GR, HRAS, IGF1R, KIT, KRAS, MCL-1, MDM2, MDM4, MTOR, MYC, MYCL, MYCN, NRAS, NRG1, NTRK1, NTRK2, NTRK3, PDGFR, PIK3C ⁇ , PIK3CA/B, RET, and ROS1.
  • a gene selected from the group consisting of ABCB1, AKT, ALK, AR, BCL-2, BCR-ABL, BRAF, CDK4, CDK6, c-MET, EGFR, ER, ERBB3, ERRB2, AK, FG
  • the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof is Formula (I) as disclosed herein.
  • the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof is a compound of Formula (Ib): Attorney Docket No.57547-724.601 Formula (Ib).
  • FIG.1A shows the tumor volume following treatment with the combination of Compound 31 (50 mg/kg PO dosed Q2D) and the pan-FGFR inhibitor infigratinib (15 mg/kg PO dosed QD) in the ecDNA+ FGFR2 amplified gastric cancer SNU-16 CDX model.
  • FIG.1B shows the tumor volume following treatment with the combination of Compound 31 (50 mg/kg PO dosed Q2D) and the pan-FGFR inhibitor infigratinib (15 mg/kg PO dosed QD) in the ecDNA+ FGFR2 amplified gastric cancer CTG-0353 PDX model.
  • FIG.1C shows the survival curves following treatment with the combination of Compound 31 (50 mg/kg PO dosed Q2D) and the pan-FGFR inhibitor infigratinib (15 mg/kg PO dosed QD) in the ecDNA+ FGFR2 amplified gastric cancer CTG-0353 PDX model.
  • FIG.1D shows the tumor volume following treatment with the combination of Compound 31 (50 mg/kg PO dosed Q2D) and the pan-FGFR inhibitor futibatinib (12.5 mg/kg PO dosed QD) in the ecDNA+ FGFR2 amplified gastric cancer SNU-16 CDX model.
  • FIG.1E shows the tumor volume following treatment with the combination of Compound 31 (50 mg/kg PO dosed Q2D) and the pan-FGFR inhibitor pemigatinib (1 mg/kg PO dosed QD) in the ecDNA+ FGFR2 amplified gastric cancer SNU-16 CDX model.
  • FIG.2A shows the tumor volume following treatment with the combination of Compound 31 (50 mg/kg PO dosed Q2D) and the CDK4/6 inhibitors palbociclib (50 mg/kg PO dosed QD) in the ecDNA+ CDK4 amplified osteosarcoma SJSA-1 CDX tumor model.
  • FIG.2B shows the tumor volume following treatment with the combination of Compound 31 (50 mg/kg PO dosed Q2D) and the CDK4/6 inhibitors abemaciclib (10.5 mg/kg PO dosed QD) in the ecDNA+ CDK4 amplified osteosarcoma SJSA-1 CDX tumor model.
  • FIG.3 shows the tumor volume following treatment with the combination of Compound 31 (50 mg/kg PO dosed Q2D) and the EGFR inhibitor erlotinib (50 mg/kg PO dosed QD) in the ecDNA+ EGFR amplified NSCLC PDX tumor models LU1206.
  • FIG.4 shows the tumor volume following treatment with the combination of Compound 31 (50 mg/kg PO dosed Q2D) and the MET inhibitor tepotinib (25 mg/kg PO dosed Q2D) in the ecDNA+ MET amplified NSCLC PDX tumor models LU1902.
  • FIG.5 shows that combination treatment of infigratinib plus Compound 31 blocked the increase of FGFR2 copy number on ecDNA that otherwise was induced by single agent infigratinib.
  • Alkyl refers to a straight-chain or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3- methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1- pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1- butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-penty
  • a numerical range such as “C 1 -C 6 alkyl” or “C 1-6 alkyl”, means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
  • the alkyl is a C1-10alkyl.
  • the alkyl is a C1-6alkyl.
  • the alkyl is a C 1-5 alkyl.
  • the alkyl is a C 1-4 alkyl.
  • the alkyl is a C 1-3 alkyl.
  • an alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • alkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.
  • alkenyl refers to a straight-chain, or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers.
  • a numerical range such as “C 2 -C 6 alkenyl” or “C 2-6 alkenyl”, means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated.
  • an alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2.
  • the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.
  • Alkynyl refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3- butadiynyl and the like.
  • an alkynyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2.
  • the alkynyl is optionally substituted with halogen, -CN, - OH, or -OMe.
  • alkynyl is optionally substituted with halogen.
  • Alkylene refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen. [0055] “Alkoxy” refers to a radical of the formula -OR a where R a is an alkyl radical as defined.
  • an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe.
  • the alkoxy is optionally substituted with halogen.
  • Aryl refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring.
  • the aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems.
  • the aryl is a 6- to 10- membered aryl.
  • the aryl is a 6-membered aryl (phenyl).
  • Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
  • an aryl may be optionally substituted, for example, with halogen, Attorney Docket No.57547-724.601 amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.
  • Cycloalkyl refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated.
  • Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C3-C15 cycloalkyl or C3-C15 cycloalkenyl), from three to ten carbon atoms (C3-C10 cycloalkyl or C3- C10 cycloalkenyl), from three to eight carbon atoms (C3-C8 cycloalkyl or C3-C8 cycloalkenyl), from three to six carbon atoms (C3-C6 cycloalkyl or C3-C6 cycloalkenyl), from three to five carbon atoms (C3-C5 cycloalkyl or C3-C5 cycloalkenyl), or three to four carbon atoms (C3-C4 cycloalkyl or C3-C4 cycloalkenyl).
  • the cycloalkyl is a 3- to 10-membered cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl or a 5- to 6-membered cycloalkenyl.
  • Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7- dimethyl-bicyclo[2.2.1]heptanyl.
  • Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe.
  • the cycloalkyl is optionally substituted with halogen.
  • Halo or “halogen” refers to bromo, chloro, fluoro or iodo.
  • halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2- trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.
  • “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl include, for example, hydroxymethyl, Attorney Docket No.57547-724.601 hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl. [0061] “Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines.
  • the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines.
  • Aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.
  • “Deuteroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more deuteriums. In some embodiments, the alkyl is substituted with one deuterium. In some embodiments, the alkyl is substituted with one, two, or three deuteriums.
  • the alkyl is substituted with one, two, three, four, five, or six deuteriums.
  • Deuteroalkyl include, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2.
  • the deuteroalkyl is CD3.
  • “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a C1-C6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • heteroalkyl examples include, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or - CH2CH2N(CH3)2.
  • a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or - OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
  • Heterocycloalkyl refers to a 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens.
  • the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen.
  • the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems; and the nitrogen, Attorney Docket No.57547-724.601 carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (C 2 -C 15 heterocycloalkyl or C 2 -C 15 heterocycloalkenyl), from two to ten carbon atoms (C 2 -C 10 heterocycloalkyl or C 2 -C 10 heterocycloalkenyl), from two to eight carbon atoms (C 2 -C 8 heterocycloalkyl or C 2 -C 8 heterocycloalkenyl), from two to seven carbon atoms (C 2 -C 7 heterocycloalkyl or C 2 -C 7 heterocycloalkenyl), from two to six carbon atoms (C 2 -C 6 heterocycloalkyl or C 2 - C 6 heterocycloalkenyl), from two to five carbon atoms (C 2 -C 5 heterocycloalkyl or C 2 -C 5 heterocycloalkenyl), or two to four carbon atoms (C 2 -C
  • heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyr
  • heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl.
  • the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl.
  • the heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl.
  • a heterocycloalkyl may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.
  • the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.
  • “Heteroaryl” refers to a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and Attorney Docket No.57547-724.601 sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, the heteroaryl comprises one nitrogen.
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5- membered heteroaryl.
  • Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furany
  • a heteroaryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.
  • the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.
  • the term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
  • “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above.
  • an optionally substituted group may be un-substituted (e.g., - CH 2 CH 3 ), fully substituted (e.g., -CF 2 CF 3 ), mono-substituted (e.g., -CH 2 CH 2 F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CH 3 , - CFHCHF 2 , etc.).
  • any substituents described should generally be understood as having a maximum molecular weight of about 1,000 daltons, and more typically, up to about 500 daltons.
  • the term “one or more” when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, four, or more substituents. In some embodiments, the subject group is optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents.
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization (i.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total), whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease.
  • Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.
  • the terms “treat,” “treated,” “treatment,” or “treating” as well as words stemming therefrom, as used herein, do not necessarily imply 100% or complete treatment. Rather, there are varying degrees of treatment of which one of ordinary skill in the art recognizes as having a potential benefit or therapeutic effect.
  • the disclosed methods can provide any amount of any level of treatment of the disorder in a mammal. For example, a disorder, including symptoms or conditions thereof, may be reduced by, for example, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%.
  • an “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of a compound disclosed herein being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated, e.g., cancer or an inflammatory disease. In some embodiments, the result is a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of the composition comprising a compound disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • an appropriate “effective” amount in any individual case is determined using techniques, such as a dose escalation study.
  • biological sample generally refers to a sample derived from or obtained from a subject, such as a mammal (e.g., a human).
  • Biological samples are contemplated to include Attorney Docket No.57547-724.601 but are not limited to, hair, fingernails, skin, sweat, tears, ocular fluids, nasal swab or nasopharyngeal wash, sputum, throat swab, saliva, mucus, blood, serum, plasma, placental fluid, amniotic fluid, cord blood, emphatic fluids, cavity fluids, earwax, oil, glandular secretions, bile, lymph, pus, microbiota, meconium, breast milk, bone marrow, bone, CNS tissue, cerebrospinal fluid, adipose tissue, synovial fluid, stool, gastric fluid, urine, semen, vaginal secretions, stomach, small intestine, large intestine
  • tumor or tumor cells
  • tumor cells generally refers to cells that grow and divide more than they should or do not die when they should.
  • tumor cells are present in a solid mass, such as a solid tumor, or in some cases, tumor cells are found in a non-solid form, such as in blood cancers.
  • Tumor or tumor cells also can include metastasis or metastasizing cells, where cancer cells break away from the original (primary) tumor and may form a new tumor in other organs or tissues of the body.
  • ecDNA signature as used herein, generally refers to one or more characteristics common to tumors or tumor cells that are ecDNA+.
  • the ecDNA signature is selected from the group consisting of a gene amplification; a p53 loss of function mutation; absence of microsatellite instability (MSI-H); a low level of PD-L1 expression; a low level of tumor inflammation signature (TIS); a low level of tumor mutational burden (TMB); an increased frequency of allele substitutions, insertions, or deletions (indels); and any combination thereof.
  • the ecDNA signature can include an increase in copy number (gene amplification) in conjunction with particular structural variations.
  • the ecDNA signature can include a focal amplification.
  • ecDNA signature includes a detection or identification of ecDNA using an imaging technology.
  • ecDNA signature does not include any imaging or direct detection of ecDNA.
  • W is N. In some embodiments of a compound of Formula (I), W is CR W .
  • X is N. In some embodiments of a compound of Formula (I), X is CR X .
  • Y is N. In some embodiments of a compound of Formula (I), Y is CR Y .
  • Z is N. In some embodiments of a compound of Formula (I), Z is CR Z .
  • the compound is a compound of Formula (Ia): [0080] In some embodiments of a compound of Formula (I), the compound is a compound of Formula (Ib): Attorney Docket No.57547-724.601 [0081] In some embodiments of a compound of Formula (I), the compound is a compound of Formula (Ic): Formula (Ic). [0082] In some embodiments of a compound of Formula (I), the compound is a compound of Formula (Id): [0083] In some embodiments of a compound of Formula (I) or (Ia)-(Id), Ring A is aryl or heteroaryl.
  • Ring A is heteroaryl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), Ring A is 6-membered heteroaryl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), Ring A is pyrazinyl. [0084] In some embodiments of a compound of Formula (I) or (Ia)-(Id), each R 1 is independently deuterium, halogen, -CN, -OH, -OR a , C1-C6alkyl, or C1-C6haloalkyl.
  • each R 1 is independently -CN.
  • n is 0-2. In some embodiments of a compound of Formula (I) or (Ia)-(Id), n is 1 or 2. In some embodiments of a compound of Formula (I) or (Ia)-(Id), n is 0 or 1. In some embodiments of a compound of Formula (I) or (Ia)-(Id), n is 0. In some embodiments of a compound of Formula (I) or (Ia)-(Id), n is 1.
  • n is 2. In some embodiments of a compound of Formula (I) or (Ia)-(Id), n is 3. [0086] In some embodiments of a compound of Formula (I) or (Ia)-(Id), R 2 is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), R 2 is hydrogen. [0087] In some embodiments of a compound of Formula (I) or (Ia)-(Id), R 3 is hydrogen, deuterium, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 3 is hydrogen.
  • R 4 is hydrogen or C 1 -C 6 alkyl.
  • R 4 is hydrogen.
  • L is -O-.
  • L is -NR 5 -.
  • R 5 is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), R 5 is hydrogen.
  • R W is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl and heterocycloalkyl is optionally substituted with one or more R.
  • R W is hydrogen, deuterium, halogen, -OH, -OR a , -NR c R d , C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl.
  • R W is hydrogen, halogen, -OH, -OR a , C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl.
  • R W is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), R W is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), R W is hydrogen, halogen, or C 1 -C 6 alkyl.
  • R W is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), R W is hydrogen or halogen. In some embodiments of a compound of Formula (I) or (Ia)-(Id), R W is hydrogen. [0092] In some embodiments of a compound of Formula (I) or (Ia)-(Id), R W is hydrogen, halogen, -OH, - OR a , or -NR c R d .
  • R W is hydrogen, -OH, or - OR a . In some embodiments of a compound of Formula (I) or (Ia)-(Id), R W is -OH or -OR a . In some embodiments of a compound of Formula (I) or (Ia)-(Id), R W is halogen or -OR a .
  • R X is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R.
  • R X is hydrogen, deuterium, halogen, -OH, -OR a , -NR c R d , C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl.
  • R X is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl.
  • R X is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), R X is hydrogen, halogen, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), R X is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), R X is hydrogen or halogen.
  • R X is hydrogen.
  • R Y is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R.
  • R Y is hydrogen, deuterium, halogen, -OH, -OR a , C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R.
  • R Y is hydrogen, halogen, -OH, - OR a , C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, or cycloalkyl; wherein the alkyl and cycloalkyl is optionally substituted with one or more R.
  • R Y is hydrogen, deuterium, halogen, -OH, -OR a , -NR c R d , C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl.
  • R Y is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), R Y is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), R Y is hydrogen, halogen, or C1-C6alkyl.
  • R Y is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), R Y is hydrogen or halogen. In some embodiments of a compound of Formula (I) or (Ia)-(Id), R Y is hydrogen. In some embodiments of a compound of Formula (I) or (Ia)-(Id), R Y is C1-C6alkyl.
  • R Z is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R.
  • R Z is hydrogen, deuterium, halogen, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl.
  • R Z is hydrogen, deuterium, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R Z is hydrogen, halogen, C 1 -C 6 alkyl, or Attorney Docket No.57547-724.601 C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), R Z is hydrogen, halogen, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), R Z is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), R Z is hydrogen or halogen.
  • R Z is hydrogen. In some embodiments of a compound of Formula (I) or (Ia)-(Id), R Z is C 1 -C 6 alkyl. [0096] In some embodiments of a compound of Formula (I) or (Ia)-(Id), Ring B is cycloalkyl or heterocycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), Ring B is cycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), Ring B is monocyclic cycloalkyl.
  • Ring B is bicyclic cycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), Ring B is monocyclic 4- to 6-membered cycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), Ring B is monocyclic 4- to 5-membered cycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), Ring B is monocyclic 4- membered cycloalkyl.
  • Ring B is monocyclic 5-membered cycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), Ring B is monocyclic 6-membered cycloalkyl. [0097] In some embodiments of a compound of Formula (I) or (Ia)-(Id), each R 6 is independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6alkyl, or C1-C6haloalkyl.
  • each R 6 is independently -OH, -OR a , or -NR c R d . In some embodiments of a compound of Formula (I) or (Ia)-(Id), each R 6 is independently -NR c R d . [0098] In some embodiments of a compound of Formula (I) or (Ia)-(Id), m is 0. In some embodiments of a compound of Formula (I) or (Ia)-(Id), m is 1. In some embodiments of a compound of Formula (I) or (Ia)- (Id), m is 2.
  • m is 3. In some embodiments of a compound of Formula (I) or (Ia)-(Id), m is 0 or 1. In some embodiments of a compound of Formula (I) or (Ia)-(Id), m is 0-2. In some embodiments of a compound of Formula (I) or (Ia)-(Id), m is 1 or 2.
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 alkylene(cycloalkyl), or C 1 -C 6 alkylene(heterocycloalkyl); wherein each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 alkylene(cycloalkyl), or C 1 -C 6 alkylene(heterocycloalkyl); wherein each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently Attorney Docket No.57547-724.601 optionally substituted with one or more R.
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl.
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl. In some embodiments of a compound disclosed herein, each R a is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound disclosed herein, each R a is independently C 1 -C 6 alkyl.
  • each R b is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, C1-C6alkylene(cycloalkyl), or C1-C6alkylene(heterocycloalkyl); wherein each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R b is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, heterocycloalkyl, C1-C6alkylene(cycloalkyl), or C1-C6alkylene(heterocycloalkyl); wherein each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R b is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R b is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R b is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl.
  • each R b is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, or C1-C6aminoalkyl. In some embodiments of a compound disclosed herein, each R b is independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each R b is independently hydrogen or C1-C6alkyl. In some embodiments of a compound disclosed herein, each R b is hydrogen. In some embodiments of a compound disclosed herein, each R b is independently C1-C6alkyl.
  • each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 alkylene(cycloalkyl), or C 1 -C 6 alkylene(heterocycloalkyl); wherein each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 alkylene(cycloalkyl), or C 1 -C 6 alkylene(heterocycloalkyl); wherein each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and Attorney Docket No.57547-724.601 heterocycloalkyl is independently optionally substituted with one or more R.
  • each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl.
  • each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl. In some embodiments of a compound disclosed herein, each R c and R d are independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound disclosed herein, each R c and R d are independently hydrogen or C1-C6alkyl. In some embodiments of a compound disclosed herein, each R c and R d are hydrogen.
  • each R c and R d are independently C1-C6alkyl. In some embodiments of a compound disclosed herein, R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R.
  • each R is independently halogen, -CN, -OH, -OC1-C3alkyl, -OC1-C3haloalkyl, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, C1-C3alkyl, C1-C3haloalkyl, C1-C3deuteroalkyl, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl; or two R on the same atom form an oxo.
  • each R is independently halogen, -CN, -OH, -OC1-C3alkyl, -OC1-C3haloalkyl, -NH2, C1-C3alkyl, C1- C3haloalkyl, C1-C3deuteroalkyl, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl; or two R on the same atom form an oxo.
  • each R is independently halogen, -CN, -OH, -OC1-C3alkyl, -OC1-C3haloalkyl, -NH2, C1-C3alkyl, or C1-C3haloalkyl; or two R on the same atom form an oxo.
  • each R is independently halogen, C1-C3alkyl, C1-C3haloalkyl, C1-C3deuteroalkyl, C1-C3hydroxyalkyl, C1- C3aminoalkyl, or C1-C3heteroalkyl; or two R on the same atom form an oxo.
  • each R is independently halogen, -CN, -OH, -NH2, C1-C3alkyl, or C1- C 3 haloalkyl; or two R on the same atom form an oxo.
  • each R is independently halogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl; or two R on the same atom form an oxo.
  • the compound is selected from a compound of Table 1 or table 2: Attorney Docket No.57547-724.601 TABLE 1 Attorney Docket No.57547-724.601 Attorney Docket No.57547-724.601 Attorney Docket No.57547-724.601 Attorney Docket No.57547-724.601 Attorney Docket No.57547-724.601 Attorney Docket No.57547-724.601 Attorney Docket No.57547-724.601 Attorney Docket No.57547-724.601 Attorney Docket No.57547-724.601 Attorney Docket No.57547-724.601 Attorney Docket No.57547-724.601 Attorney Docket No.57547-724.601 Attorney Docket No.57547-724.601 Attorney Docket No
  • the CHK1 inhibitor is compound pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.
  • the CHK1 inhibitor is compound Further Forms of Compounds Disclosed Herein Isomers/Stereoisomers
  • the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds.
  • the compounds presented herein include all cis, trans, syn, anti,
  • E
  • Z Greek
  • the compounds described herein possess one or more chiral centers and each center exists in the R configuration or S configuration.
  • the compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
  • mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
  • the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers.
  • dissociable complexes are preferred.
  • the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities.
  • the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent.
  • Labeled compounds [00106]
  • the compounds described herein exist in their isotopically-labeled forms.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions.
  • the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds described herein, or a solvate, tautomer, or stereoisomer thereof, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as 2 H, 3 H, 13 C, 14 C, l5 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • the isotopically labeled compound or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof is prepared by any suitable method.
  • the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • the compounds described herein exist as their pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
  • the compounds described herein possess acidic or basic groups and therefor react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
  • suitable acid or base examples include those salts prepared by reaction of the compounds described herein with a mineral, organic acid, or inorganic base, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate
  • the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-
  • those compounds described herein that comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • a suitable base such as the hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like.
  • bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C1-4 alkyl)4, and the like.
  • Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like of the tetrazole.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen- containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.
  • Solvates [00114] In some embodiments, the compounds described herein exist as solvates. The disclosure provides for methods of treating diseases by administering such solvates.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein.
  • the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • Tautomers [00116] In some situations, compounds exist as tautomers.
  • the compounds described herein include all possible tautomers within the formulas described herein.
  • Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.
  • Preparation of the Compounds [00117] The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature.
  • Suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation include for example, Attorney Docket No.57547-724.601 “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House, “Modern Synthetic Reactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif.1972; T. L. Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J.
  • compounds of Formula I may be prepared via metal-catalyzed carbon- carbon bond forming cross-coupling reactions.
  • appropriate cross-coupling reactions include the Suzuki, Negishi, Stille, Kumada or Heck reactions.
  • the cross- coupling reaction is a Suzuki reaction between an appropriately substituted aryl bromide and an appropriately substituted arylboronic acid or arylboronic ester.
  • Scheme I [00122] The synthesis of appropriately substituted intermediate building blocks for Suzuki reactions is described in Scheme I.
  • An aryl bromide of formula I-3 may be synthesized by a reaction between an appropriately substituted compound of formula I-1, where L represents a nucleophilic atom, and a compound of formula I-2, where LG represents a suitable leaving group.
  • L is oxygen or an optionally substituted nitrogen atom.
  • L is oxygen.
  • LG is an alkyl halide such as bromine or iodine; in other embodiments, LG may be oxygen.
  • I-2 where LG is oxygen it may be activated to increase its reactivity as a leaving group.
  • Such activation may occur via synthesis of an alkylsulfonate, such as a mesylate, tosylate, nosylate, brosylate, or other sulfonate known to one having ordinary skill in the art.
  • alkylsulfonates may be synthesized from the corresponding alkyl alcohol by reaction with an appropriate sulfonyl chloride or sulfonic anhydride, such as methanesulfonyl chloride or methanesulfonic anhydride.
  • Such sulfonylation reactions typically occur in a solvent such as dichloromethane, tetrahydrofuran, or toluene, in the presence of a base such as sodium hydride, triethylamine, diisopropylethylamine, pyridine, potassium carbonate or another base known to one having ordinary skill in the art.
  • Reactions typically proceed at sub-ambient or ambient temperature, for example between 0-25 °C. Reactions are typically complete within 1-18 hours and the product may be purified or used directly without purification, if it is unstable to purification.
  • an aryl bromide of formula I-3 may be synthesized by a reaction with a compound of formula I-2 where LG represents an alcohol that has been activated in situ without isolation, as in a Mitsunobu reaction.
  • activation of the alcohol occurs in the presence of an appropriate azodicarboxylate, such as diethyl azodicarboxylate or diisopropyl azodicarboxylate, and an appropriate phosphine, such as triphenylphosphine.
  • the activation may be achieved using an appropriate phosphorane, such as (tributylphosphoranylidene)acetonitrile (CMBP) or (trimethylphosphoranylidene)acetonitrile (CMMP).
  • CMBP tributylphosphoranylidene
  • CMMP trimethylphosphoranylideneacetonitrile
  • Mitsunobu reactions are typically carried out in a Attorney Docket No.57547-724.601 solvent such as dichloromethane, tetrahydrofuran, or toluene, and typically occur at ambient temperature or at elevated temperature from 25 to 110 °C. Reactions are typically complete within 1-18 hours.
  • a compound of formula I-3 may be synthesized by a reaction between a compound of formula I-4 and a compound of formula I-5.
  • LG is a halide such as fluorine, chlorine, bromine, or iodine.
  • L is nitrogen or oxygen.
  • L is oxygen.
  • the reaction between I-4 and I-5 may proceed under cross-coupling conditions, catalyzed by an appropriate transition metal, or by nucleophilic aromatic substitution.
  • the nucleophilic aromatic substitution reaction occurs when LG of I-4 is fluorine or chlorine and L of I-5 is oxygen.
  • LG of I-4 is fluorine.
  • nucleophilic aromatic substitution reactions typically occur in the presence of a strong base such as sodium hydride, lithium diisopropylamine, lithium bis(trimethylsilyl)amide, or an appropriate base known to one having ordinary skill in the art.
  • a strong base such as sodium hydride, lithium diisopropylamine, lithium bis(trimethylsilyl)amide, or an appropriate base known to one having ordinary skill in the art.
  • nucleophilic aromatic substitution reactions typically occur in a solvent such as tetrahydrofuran, dimethyl sulfoxide, 1,4-dioxane, N,N-dimethylformamide or N,N-dimethylacetamide.
  • Such nucleophilic aromatic substitution reactions typically occur at reduced temperature, such as -78 °C or 0 °C; in some embodiments, the reaction may occur at ambient temperature or elevated temperature, from 25 to 110 °C.
  • a compound of formula I-8 may be synthesized from an appropriately substituted aminopyrazole of formula I-6 via reaction with an appropriately substituted compound of formula I-7, where ring A contains a suitable leaving group LG.
  • a leaving group may be a chloride, bromide, iodide or activated alcohol such as a mesylate or tosylate.
  • ring A may be aromatic and the leaving group may be an aryl chloride.
  • the reaction may occur in the presence of a suitable base such as sodium hydride, triethylamine, diisopropylethylamine, pyridine, potassium carbonate or another base known to one having ordinary skill in the art.
  • a suitable base such as sodium hydride, triethylamine, diisopropylethylamine, pyridine, potassium carbonate or another base known to one having ordinary skill in the art.
  • Such reactions typically occur in a solvent such as tetrahydrofuran, dimethyl sulfoxide, 1,4-dioxane, N,N-dimethylformamide or N,N-dimethylacetamide.
  • Reactions may occur at ambient temperature or at elevated temperatures from 60- 110 °C. Reactions are typically complete within 1-18 hours.
  • a pyrazoleboronic ester compound of formula I-9 may be synthesized from a compound of formula I-8 by reaction with an appropriate borylating agent.
  • the compound of formula I-9 may contain a mixture of pyrazoleboronic ester and pyrazoleboronic acid. In some embodiments, the compound of formula I-9 may contain mostly pyrazoleboronic acid. In some embodiments, the compound of formula I-9 is synthesized by a Miyaura borylation reaction and the appropriate borylating agent is bis(pinacolato)diboron.
  • the Miyaura borylation reaction is carried out in the presence of a palladium catalyst in complex with a phosphine ligand, such as tetrakis(triphenylphosphine)palladium, bis(diphenylphosphino)ferrocene]dichloropalladium(II), or another catalyst system known to one having ordinary skill in the art.
  • a palladium catalyst in complex with a phosphine ligand, such as tetrakis(triphenylphosphine)palladium, bis(diphenylphosphino)ferrocene]dichloropalladium(II), or another catalyst system known to one having ordinary skill in the art.
  • a suitable base such as sodium carbonate, potassium carbonate, potassium tert-butoxide, sodium acetate, potassium acetate, or another base known to one having ordinary skill in the art.
  • the Miyaura Attorney Docket No.57547-724.601 reaction is typically carried out in a solvent such as 1,4-dioxane, ethyl acetate, or toluene at elevated temperature, typically between 60-110 °C. Reactions are typically complete within 6-24 hours.
  • Scheme II [00127] As shown in Scheme II, a compound of Formula I may be synthesized by a Suzuki reaction between a compound of formula I-3 and a compound of formula I-9.
  • Such a reaction will typically occur in the presence of a palladium catalyst in complex with a phosphine ligand, such as tetrakis(triphenylphosphine)palladium, bis(diphenylphosphino)ferrocene]dichloropalladium(II), RuPhos palladacycle G3, or another catalyst system known to one having ordinary skill in the art.
  • a palladium catalyst in complex with a phosphine ligand, such as tetrakis(triphenylphosphine)palladium, bis(diphenylphosphino)ferrocene]dichloropalladium(II), RuPhos palladacycle G3, or another catalyst system known to one having ordinary skill in the art.
  • a suitable base such as sodium carbonate, potassium carbonate, potassium tert-butoxide, sodium acetate, potassium acetate, or another base known to one having ordinary skill in the art.
  • a cyanoketone intermediate of formula III- 5 may be synthesized from a compound of formula I-3.
  • a compound of formula I-3 may be converted to a vinyl enol ether of formula III-1.
  • Such a reaction may occur between a compound of formula I-3 and an appropriately substituted vinyl building block under palladium-catalyzed cross-coupling conditions.
  • the cross-coupling reaction may be a Suzuki or a Stille reaction.
  • the vinyl building block will be substituted as a boronic ester, a boronic acid, a trifluoroborate or an alkylstannane.
  • Such cross-coupling reactions will typically occur in the presence of a palladium catalyst in complex with a phosphine ligand, such as tetrakis(triphenylphosphine)palladium, bis(diphenylphosphino)ferrocene]dichloropalladium(II), RuPhos palladacycle G3, or another catalyst system known to one having ordinary skill in the art.
  • a palladium catalyst in complex with a phosphine ligand, such as tetrakis(triphenylphosphine)palladium, bis(diphenylphosphino)ferrocene]dichloropalladium(II), RuPhos palladacycle G3, or another catalyst system known to one having ordinary skill in the art.
  • a suitable base such as sodium carbonate, potassium carbonate, potassium tert-butoxide, sodium acetate, potassium acetate, or another base known to one having ordinary skill in the art.
  • the cross-coupling reaction is typically carried out in a solvent such as 1,4-dioxane, ethyl acetate, or toluene.
  • the reaction will occur at elevated temperature, typically between 60-110 °C. Reactions are typically complete within 6-24 hours.
  • a compound of formula III-1 may be purified or used directly in the next step without purification, as it may be unstable to standard purification conditions.
  • a compound of formula III-1 may be converted to a ketone of formula III-2 via acidic hydrolysis.
  • Such a reaction is typically carried out using a strong Br ⁇ nsted acid, such as hydrochloric acid, in aqueous media. The reaction may take place at sub-ambient, ambient, or elevated temperature, typically between 0- 80 °C.
  • a ketone of formula III-2 may be converted to an enamine compound of formula III- 3 by reaction with N,N-dimethylformamide dimethyl acetal. In some embodiments, this reaction occurs in N,N-dimethylformamide as the solvent at elevated temperature, typically between 60-110 °C. Reactions are typically complete in 2-24 hours.
  • a compound of formula III-3 may be purified, or in some embodiments it may be used directly in the next step without purification, as it may be unstable to standard purification conditions.
  • a compound of formula III-3 may be converted to an isoxazole of formula III-4 by reaction with hydroxylamine. In some embodiments this reaction may employ hydroxylamine as free base or as a salt.
  • the reaction is carried out using hydroxylamine hydrochloride.
  • the reaction typically proceeds at ambient or elevated temperature between 25-110 °C in an appropriate solvent such as methanol, ethanol, isopropanol, n-butanol, tert-butanol, or toluene.
  • the reaction is typically complete within 2-24 hours.
  • An isoxazole of formula III-4 may be converted to a cyanoketone of formula III-5 by treatment with an appropriate base, such as lithium hydroxide, sodium hydroxide or potassium hydroxide.
  • the base is potassium hydroxide.
  • a cyanoketone of formula III-5 may be synthesized from an ester as shown in Scheme IV.
  • An ester of formula IV-5 may be synthesized from appropriate building blocks of formula IV-1, where L represents a nucleophilic atom, and a compound of formula IV-2, where LG represents a suitable leaving group.
  • L is oxygen or an optionally substituted nitrogen atom.
  • L is oxygen.
  • LG is an alkyl halide such as bromine or iodine; in other embodiments, it may be oxygen.
  • it may be activated to increase its reactivity as a leaving group. Such activation may occur via synthesis of an alkylsulfonate, such as a mesylate, tosylate, nosylate, brosylate, or other sulfonate known to one having ordinary skill in the art.
  • alkylsulfonates may be synthesized from the corresponding alkyl alcohol by reaction with an appropriate sulfonyl chloride or sulfonic anhydride, such as methanesulfonyl chloride or methanesulfonic anhydride.
  • sulfonylation reactions typically occur in a solvent such as dichloromethane, tetrahydrofuran, or toluene, in the presence of a base such as sodium hydride, triethylamine, diisopropylethylamine, pyridine, potassium carbonate or another base known to one having ordinary skill in the art. Reactions typically proceed at low temperature or at ambient temperature, for example at 0 °C.
  • an ester of formula IV-5 may be synthesized by a reaction with a compound of formula IV-2, where LG represents an alcohol that has been activated in situ without isolation, as in a Mistunobu reaction. Activation of the alcohol occurs in the presence of an appropriate azodicarboxylate, such as diethyl azodicarboxylate or diisopropyl azodicarboxylate, and an appropriate phosphine, such as triphenylphosphine.
  • an appropriate azodicarboxylate such as diethyl azodicarboxylate or diisopropyl azodicarboxylate
  • an appropriate phosphine such as triphenylphosphine.
  • the activation may be achieved using an appropriate phosphorane, such as (tributylphosphoranylidene)acetonitrile (CMBP) or (trimethylphosphoranylidene)acetonitrile (CMMP).
  • CMBP tributylphosphoranylidene
  • CMMP trimethylphosphoranylideneacetonitrile
  • Mitsunobu reactions are typically carried out in a solvent such as dichloromethane, tetrahydrofuran, or toluene, and typically occur at ambient temperature or at elevated temperature, from 25 to 110 °C. Reactions are typically complete within 1-18 hours.
  • a compound of formula IV-5 may be synthesized from a compound of formula IV-3 and a compound of formula IV-4.
  • LG is a halide such as fluorine, chlorine, bromine, or iodine.
  • L is nitrogen or oxygen.
  • L is oxygen.
  • the reaction between IV-3 and IV-4 may proceed under cross-coupling conditions, catalyzed by an appropriate transition metal, or by nucleophilic aromatic substitution.
  • the nucleophilic aromatic substitution reaction occurs when LG of IV-3 is fluorine or chlorine and L is oxygen.
  • LG of IV-3 is fluorine.
  • nucleophilic aromatic substitution reactions typically occur in the presence of a strong base such as sodium hydride, lithium diisopropylamine, lithium bis(trimethylsilyl)amide, or an appropriate base known to one having ordinary skill in the art.
  • a strong base such as sodium hydride, lithium diisopropylamine, lithium bis(trimethylsilyl)amide, or an appropriate base known to one having ordinary skill in the art.
  • nucleophilic aromatic substitution reactions typically occur in a solvent such as tetrahydrofuran, dimethyl sulfoxide, 1,4-dioxane, N,N-dimethylformamide or N,N-dimethylacetamide.
  • Such nucleophilic aromatic substitution reactions typically occur at reduced temperature, such as -78 °C or 0 °C; in some embodiments, the reaction may occur at ambient temperature or elevated temperature such as 100 °C. Reactions are typically complete within 1-18 hours.
  • An ester of formula IV-5 may be converted to a cyanoketone of formula III-5 in a reaction with the carbanion of an optionally substituted nitrile.
  • the nitrile is acetonitrile.
  • acetonitrile is deprotonated with a suitable strong base, such as sodium hydride, potassium tert- butoxide, n-butyllithium, sec-butyllithium, lithium diisopropylamine, lithium bis(trimethylsilyl)amide, or an appropriate base known to one having ordinary skill in the art.
  • the reaction may be carried out using acetonitrile as the solvent, or in another appropriate solvent such as tetrahydrofuran or diethyl ether. In some embodiments, the solvent is tetrahydrofuran.
  • the reaction typically occurs at reduced temperature, such as - 78 °C or 0 °C; in some embodiments, the reaction may occur at ambient temperature. The reaction is typically complete within 1-18 hours.
  • Scheme V [00136]
  • a cyanoketone of formula III-5 may be converted to an aminopyrazole of formula V-I as shown in Scheme V. Such a reaction may be performed using an optionally substituted hydrazine to form the aminopyrazole.
  • the optionally substituted hydrazine is hydrazine or hydrazine monohydrate.
  • the reaction is typically carried out in the presence of a Br ⁇ nsted acid, such as acetic acid or hydrochloric acid.
  • the reaction is carried out in an appropriate solvent such as methanol, ethanol, isopropanol, n-butanol, tert-butanol, or toluene.
  • the reaction may be carried out at ambient or elevated temperature between 25-110 °C.
  • the reaction is typically complete within 2-18 hours.
  • a compound of formula V-I may react with an appropriately substituted compound of formula I- 7, where ring A contains a suitable leaving group LG, to give a compound of Formula I.
  • a leaving group LG may be a chloride, bromide, iodide or activated alcohol such as a mesylate or tosylate.
  • ring A may be aromatic and the leaving group may be an aryl chloride.
  • the reaction may occur in the presence of a suitable base such as sodium hydride, triethylamine, diisopropylethylamine, pyridine, potassium carbonate or another base known to one having ordinary skill in the art.
  • reaction between a compound of formula V-I and a compound of formula I-7 may be carried out in the presence of an appropriate transition metal catalyst.
  • the transition metal is a copper catalyst as in an Ullmann reaction.
  • the catalyst is a palladium complex as in a Buchwald reaction.
  • Such cross-coupling reactions will typically occur in the presence of a palladium catalyst in complex with a phosphine ligand, such as tetrakis(triphenylphosphine)palladium, bis(diphenylphosphino)ferrocene]dichloropalladium(II), BrettPhos palladacycle G3, or another catalyst system known to one having ordinary skill in the art.
  • a palladium catalyst in complex with a phosphine ligand, such as tetrakis(triphenylphosphine)palladium, bis(diphenylphosphino)ferrocene]dichloropalladium(II), BrettPhos palladacycle G3, or another catalyst system known to one having ordinary skill in the art.
  • a suitable base such as sodium carbonate, potassium carbonate, potassium tert-butoxide, sodium acetate, potassium acetate, triethylamine or another base known to one having ordinary skill in the art
  • reaction is typically carried out in a solvent such as 1,4-dioxane or toluene.
  • the reaction will occur at elevated temperature, typically between 60-110 °C. Reactions are typically complete within 6-24 hours.
  • Scheme VI One having ordinary skill in the art will recognize that at times, it may be necessary to mask a reactive functional group or groups on a molecule with an appropriate protecting group.
  • the protecting group or groups may be carried through several synthetic steps.
  • the protecting group or groups may all be removed in a single global deprotection step.
  • the protecting group or groups will mask amine functional groups.
  • the protecting group or groups will be tert-butylcarbamate groups.
  • the tert-butylcarbamate protected amine will be on ring B.
  • a tert-butylcarbamate protecting group is typically removed via treatment with a Br ⁇ nsted acid, such as trifluoroacetic acid, hydrogen chloride or hydrochloric acid. Typical cleavage reactions occur in an appropriate solvent such as ethyl acetate, 1,4-dioxane, diethyl ether or dichloromethane. Reactions typically proceed at sub-ambient or ambient temperature but may proceed at elevated temperature, typically between 0-60 °C.
  • a compound of Formula I prepared under such conditions may be purified by standard methods including chromatography or recrystallization. In some embodiments the compound of Formula I is isolated directly from the deprotection reaction as a salt. In some embodiments the compound of Formula I is purified by preparative HPLC using an appropriate column and eluent conditions.
  • Pharmaceutical Compositions [00140] In certain embodiments, the compound described herein is administered as a pure chemical.
  • the compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005)).
  • a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable excipient.
  • the compound provided herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1% of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.
  • Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient’s disease, the particular form of the active ingredient, and the method of administration.
  • an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as increased overall response rate, increased duration of response, more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity.
  • therapeutic and/or prophylactic benefit e.g., an improved clinical outcome, such as increased overall response rate, increased duration of response, more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity.
  • Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.
  • the pharmaceutical composition is formulated for oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, intrapulmonary, intradermal, intrathecal, epidural, or intranasal administration.
  • Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
  • the pharmaceutical composition is formulated for intravenous injection, oral administration, inhalation, nasal administration, topical administration, or ophthalmic administration.
  • the pharmaceutical composition is formulated for oral administration.
  • the pharmaceutical composition is formulated for intravenous injection.
  • the pharmaceutical composition is formulated as a tablet, a pill, a capsule, a liquid, an inhalant, a nasal spray solution, a suppository, a suspension, a gel, a colloid, a dispersion, a suspension, a solution, an emulsion, an ointment, a lotion, an eye drop, or an ear drop.
  • the pharmaceutical composition is formulated as a tablet.
  • Suitable doses and dosage regimens are determined by conventional range-finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of the compound disclosed herein.
  • Methods [00146] Disclosed herein is a method of treating a tumor or tumor cells, comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a cancer-targeted therapeutic agent to a subject identified as having the tumor or tumor cells, wherein the tumor or tumor cells comprise a gene amplification, whereby growth or size of the tumor or growth or number of tumor cells is reduced.
  • Also disclosed herein is a method of delaying resistance to a cancer-targeted therapeutic agent, the method comprising: administering a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, to a subject in an amount sufficient to induce replication stress in tumor or tumor cells and administering a cancer-targeted therapeutic agent concurrently or subsequent to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.
  • a tumor or tumor cells in a subject comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.
  • the subject has had one or more prior treatments with a first cancer- targeted therapeutic agent (also referred to herein as a “prior cancer-targeted therapeutic agent”) prior to treatment with a compound of Formula (I).
  • a first cancer- targeted therapeutic agent also referred to herein as a “prior cancer-targeted therapeutic agent”
  • the compound of Formula (I) is administered in conjunction with the administration of a second cancer-targeted therapeutic agent (also referred to herein as a “selected cancer-targeted therapeutic agent”).
  • Also disclosed herein is a method of treating a subject having a tumor or tumor cells that are non- responsive to a first (prior) cancer-targeted therapeutic agent comprising administering a compound of Attorney Docket No.57547-724.601 Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a second (selected) cancer-targeted therapeutic agent to the subject.
  • a compound of Attorney Docket No.57547-724.601 Formula (I) or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof
  • Also disclosed herein is a method of provoking a response in a subject having a tumor or tumor cells that are non-responsive or have decreased responsiveness to a first (prior) cancer-targeted therapeutic agent comprising administering a Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the first (prior) cancer-targeted therapeutic agent to the subject.
  • the cancer-targeted therapeutic agent is administered concurrent or subsequent to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.
  • the first (prior) cancer-targeted therapeutic agent is administered concurrent or subsequent to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.
  • the second (selected) cancer-targeted therapeutic agent is administered concurrent or subsequent to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.
  • the cancer-targeted therapeutic agent is administered prior to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.
  • the first (prior) cancer-targeted therapeutic agent is administered prior to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.
  • the second (selected) cancer-targeted therapeutic agent is administered prior to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.
  • the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof is administered in an amount sufficient to induce replication stress in the tumor or tumor cells.
  • the subject is identified as having the tumor or tumor cells comprising a gene amplification.
  • the gene amplification is a focal gene amplification.
  • the gene amplification is an ecDNA-derived amplification.
  • the gene amplification is comprised on ecDNA or an HSR (homogeneously staining region).
  • the cancer-targeted therapeutic agent is directed against a protein encoded by a gene contained within the gene amplification.
  • the first (prior) cancer-targeted therapeutic agent is directed against a protein encoded by a gene contained within the gene amplification.
  • the second (selected) cancer-targeted therapeutic agent is directed against a protein encoded by a gene contained within the gene amplification.
  • the tumor or tumor cells comprise an ecDNA signature.
  • cells comprised within the tumor or the tumor cells are ecDNA competent.
  • an ecDNA competent tumor cell may have detectable levels of ecDNA amplification or an ecDNA competent tumor cell has the capacity to generate ecDNA amplification in response to selective pressure such as targeted therapy (e.g., a cancer-targeted therapeutic agent described herein).
  • targeted therapy e.g., a cancer-targeted therapeutic agent described herein.
  • treatment with both the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the cancer-targeted therapeutic agent has a greater effect or a longer duration of effect on reduction of one or more of tumor growth, tumor size, number of tumor cells or tumor metastasis as compared to the treatment with either the compound of Formula (I) or the cancer-targeted therapeutic agent when administered alone.
  • treatment with both the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the first (prior) cancer-targeted therapeutic agent has a greater effect or a longer duration of effect on reduction of one or more of tumor growth, tumor size, number of tumor cells or tumor metastasis as compared to the treatment with either the compound of Formula (I) or the first (prior) cancer-targeted therapeutic agent when administered alone.
  • treatment with both the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the second (selected) cancer-targeted therapeutic agent has a greater effect or a longer duration of effect on reduction of one or more of tumor growth, tumor size, number of tumor cells or tumor metastasis as compared to the treatment with either the compound of Formula (I) or the second (selected) cancer-targeted therapeutic agent when administered alone.
  • the greater effect is a synergistic effect.
  • the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and/or the cancer-targeted therapeutic agent is administered orally.
  • the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and/or the first (prior) cancer- targeted therapeutic agent is administered orally.
  • the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and/or the second (selected) cancer-targeted therapeutic agent is administered orally.
  • the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and/or the cancer-targeted therapeutic agent is administered parentally.
  • the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and/or the first (prior) cancer- targeted therapeutic agent is administered parentally.
  • the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and/or the second (selected) cancer-targeted therapeutic agent is administered parentally.
  • treatment comprises administering multiple doses of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and/or the cancer-targeted therapeutic agent over a treatment period.
  • treatment comprises administering multiple doses of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and/or the first (prior) cancer-targeted therapeutic agent over a treatment period.
  • treatment comprises administering multiple doses of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and/or the second (selected) cancer-targeted therapeutic agent over a treatment period.
  • the gene amplification comprises an amplification of a gene selected from the group consisting of ABCB1, AKT, ALK, AR, BCL-2, BCR-ABL, BRAF, CDK4, CDK6, c-MET, EGFR, ER, ERBB3, ERRB2, AK, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, GR, HER2, HRAS, IGF1R, KIT, KRAS, MCL-1, MDM2, MDM4, MTOR, MYC, MYCL, MYCN, NRAS, NRG1, NTRK1, NTRK2, NTRK3, PDGFR, PIK3C ⁇ , PIK3CA/B, RET, and ROS1.
  • a gene selected from the group consisting of ABCB1, AKT, ALK, AR, BCL-2, BCR-ABL, BRAF, CDK4, CDK6, c-MET, EGFR, ER, ERBB3, ERRB2, AK, FGFR1,
  • the gene amplification comprises an amplification of a gene selected from the group consisting of CDK4, CDK6, c-MET, EGFR, FGFR1, FGFR2, FGFR3, and FGFR4.
  • the first (prior) cancer-targeted therapeutic agent is different than the second (selected) cancer-targeted therapeutic agent.
  • the first (prior) cancer-targeted therapeutic agent is the same as the second (selected) cancer-targeted therapeutic agent.
  • the cancer-targeted therapeutic agent, the first (prior) cancer-targeted therapeutic agent, the second cancer-targeted therapeutic agent, or the selected cancer-targeted therapeutic agent is selected from the group consisting of abemaciclib, ado-trastuzumab emtansine, afatinib, alectinib, ALRN-6924, AMG232, AMG-510, apatinib, ARS-3248, AXL1717, AZD- Attorney Docket No.57547-724.601 3759, bevacizumab, BI 1701963, bortezomib, brigatinib, cabozantinib, capmatinib, ceritinib, cetuximab, CGM097, crizotinib, dabrafenib, dacomitinib, dasatinib, DS-3032b, encor
  • the cancer-targeted therapeutic agent, the first (prior) cancer-targeted therapeutic agent, the second cancer-targeted therapeutic agent, or the selected cancer-targeted therapeutic agent is an inhibitor of EFGR, FGFR, CDK4/CDK6 or KRAS.
  • the EGFR inhibitor is erlotinib, gefitinib, or an analog thereof, or an antibody such as cetuximab, necitumumab, nimotuzumab, and panitumumab.
  • the FGFR inhibitor is erdafitinib, futibatinib, infigratinib, pemigatinib, RLY-4008, or an analog thereof.
  • the KRAS inhibitor is adagrasib, BI 1701963, sotorasib, or an analog thereof.
  • the CDK4/CDK6 inhibitor is abemaciclib, palbociclib, ribociclib, PF-06873600, PF-07220060, or an analog thereof.
  • the cancer-targeted therapeutic agent, the first (prior) cancer-targeted therapeutic agent, the second cancer-targeted therapeutic agent, or the selected cancer-targeted therapeutic agent is an inhibitor of BRAF.
  • the BRAF inhibitors include ASN-003, AZ-304, AZ-628, DP-2874, EBI-907, EBI-945, GDC-0879, LYN 204, NMS-P285, NMS-P730, PF-04880594, TL-241, UAI-201,and UB-941.
  • the BRAF inhibitors include ABM-1310, agerafenib (RXDX-105), ARQ-736, BAL-3833, belvarafenib, BGB-3245, BI-882370, DAY101, lifirafenib, LUT-014, PF-07284890, PLX-8394, RX-208, VS-6766, and XL-281.
  • the BRAF inhibitors include dabrafenib, encorafenib, and vemurafenib.
  • the cancer-targeted therapeutic agent, the first (prior) cancer-targeted therapeutic agent, the second cancer-targeted therapeutic agent, or the selected cancer-targeted therapeutic agent is an inhibitor of MDM2 or MDM4.
  • MDM2 inhibitors include AD-021.32, CYC700, DS-5272, MI-1061, MI-219, MI-43, MD-224, MK-8242, NU-8231, OM-301, PXN-527, Rigel-3, RO-2468, RO-5353, RO-5963, and SIL-43.
  • MDM2 inhibitors include ALRN-6924, APG-115, ASTX-295, ATSP-7041, BI-907828, CGM-097, idasanutlin, KRT-232 (AMG-232), MI-77301 (SAR405838, SAR299155), NVP-CGM097, RAIN-32 (milademetan), RG7112 (RO5045337), RG7388 (RG7775), serdemetan (JNJ-26854165), siremadlin, and UBX-0101.
  • the MDM4 inhibitors include 17AAG, 489-PXN, CTX1, FL-118, Inulanolide A, K-178, and SAH-p53-8.
  • the MDM4 inhibitors include APG-115, ALRN-6924, ATSP-7041, and BI-907828. Attorney Docket No.57547-724.601 [00187]
  • the cancer-targeted therapeutic agent, the first (prior) cancer-targeted therapeutic agent, the second cancer-targeted therapeutic agent, or the selected cancer-targeted therapeutic agent is an inhibitor of MET.
  • the MET small molecule inhibitors such as ABP-1130, BPI-1831, BPI-2021, BYON-3521, CG-203306, CX-1003, Debio-1144, EMD-94283, EMT-100, EMT-101, HE-003, LMV-12, LS-177, NX-125, OMO-2, PF-4254644, PRX-MET, PTX-2173, QBH-196, RP-1400, SAB-Y14, SAR-125844, SGX-126, SYD-3521, WXSH-0011, X-379, and XL-265, and anti-MET antibodies such as ABX-900, GB-263, FS-101, LY-3164530, LY-3343544, PMC- 002, and SAIT-301.
  • the MET small molecule inhibitors such as ABN-401, ABT-700, AMG-208, AMG-337, ARGX-111, BAY-85-3474, BMS-817378, bozitinib, BPI-9016M, glumetinib, golvatinib tartrate, GST-HG161, HQP-8361, I-020, JNJ-38877605, kanitinib, merestinib, MK-2461, MK- 8033, OMO-1, pamufetinib, S-49076, savolitinib, SPH-3348, tivantinib, SAR-125844, SCR-1515, and TPX- 0022, and anti-MET antibodies such as APL-101, CKD-702, EMB-01, EMI-137, ficlatuzumab, HLX-55, HS-10241, MCLA-129, MT-8633, NOV-11
  • the MET small molecule inhibitors such as amivantamab, capmatinib, crizotinib, and tepotinib.
  • the cancer-targeted therapeutic agent, the first (prior) cancer-targeted therapeutic agent, the second cancer-targeted therapeutic agent, or the selected cancer-targeted therapeutic agent is an inhibitor of CDK4/6.
  • the CDK4/6 inhibitors include AG-122275, AM-5992, AU2-94, IIIM-985, IIIM-290, GW-491619, HEC-80797, MM-D37K, MS- 140, NP-102, QHRD-110, R-547, RGB-286199, RGT-419B, riviciclib, RO-0505124, THR-53, THR-79, TQB-3303, TY-302, VS2-370, XH-30002, and WXWH-0240.
  • the CDK4/6 inhibitors include auceliciclib, AT-7519, BEBT-209, BPI-1178, BPI-16350, CS-3002, fascaplysin, FCN-437, FN- 1501, GLR-2007, HS-10342, lerociclib, milciclib maleate, NUV-422, ON-123300, PF-06842874, PF- 06873600, PF-07220060, SHR-6390, TQB-3616, TY-302, voruciclib, and XZP-3287.
  • the CDK4/6 inhibitors include abemaciclib, palbociclib, ribociclib, and trilaciclib.
  • the cancer-targeted therapeutic agent, the first (prior) cancer-targeted therapeutic agent, the second cancer-targeted therapeutic agent, or the selected cancer-targeted therapeutic agent is palbociclib or abemaciclib.
  • the cancer-targeted therapeutic agent, the first (prior) cancer-targeted therapeutic agent, the second cancer-targeted therapeutic agent, or the selected cancer-targeted therapeutic agent is an inhibitor of EGFR.
  • the EGFR inhibitors include small molecule inhibitors such as APL-1898, BDTX-1535, BLU-701, BPI-361175, CH-7233163, DS-2087, E-10C, FWD-1509, IN-A008, JS-111, JS-113, LL-191, LYN 205, neptinib, NT-004, ORIC-114, PRB-001, SIM-200, TGRX-360, WJ-13404, yinlitinib maleate, and ZSP-0391, and anti-EGFR antibodies such as 705, 707, ABX-900, CMAB-017, GB-263, KN-023, SSGJ-612, and SHR-A1307.
  • small molecule inhibitors such as APL-1898, BDTX-1535, BLU-701, BPI-361175, CH-7233163, DS-2087, E-10C, FWD-1509, IN-A008, JS-111, JS-113, LL-191, LYN
  • the EGFR inhibitors include small molecule inhibitors such as abivertinib, alflutinib mesylate, agerafenib (RXDX-105), ASK-120067, BBT-176, BDTX-189, BEBT-109, befortinib mesylate, beitatini, Attorney Docket No.57547-724.601 BPI-7711, BPI-D0316, BLU-945, CK-101, dositinib, DFP-17729, DZD-9008, epertinib, epitinib (HMPL- 813), ES-072, FCN-411, FHND-9041, furmonertinib, GMA-204, Hemay-022, JRF-103, KP-673, larotinib, lazertinib, maihuatinib, marizomib, mobocertinib, naputinib tosil
  • the EGFR inhibitors include small molecule inhibitors such as afatinib, amivantamab, aumolertinib (almonertinib), dacomitinib, erlotinib, gefitinib, icotinib, lapatinib, osimertinib, and pyrotinib, and anti-EGFR antibodies such as cetuximab, necitumumab, nimotuzumab, and panitumumab.
  • the cancer-targeted therapeutic agent, the first (prior) cancer-targeted therapeutic agent, the second cancer-targeted therapeutic agent, or the selected cancer-targeted therapeutic agent is erlotinib.
  • the cancer-targeted therapeutic agent, the first (prior) cancer-targeted therapeutic agent, the second cancer-targeted therapeutic agent, or the selected cancer-targeted therapeutic agent is an inhibitor of FGFR.
  • FGFR inhibitors include small molecule inhibitors such as ABSK-012, ABSK-061, AST-56100, BIO-1262, BGS-2219, EVT-601, FPI-1966, JAB-6000, KIN-3248, SAR-439115, SC-0011, and WXSH-0011, and anti- FGFR antibodies such as M-6123, OM-RCA-001.
  • FGFR inhibitors include small molecule inhibitors such as 3D-185, ABSK-011, ABSK-091, aldafermin, alofanib, AZD-4547, BFKB-8488A, BPI-17509, BPI-43487, CPL-304-110, derazantinib, E- 7090, EVER-4010001, FGF-401, fisogatinib, futibatinib, gunagratinib, H3B-6527, HH-185, HMPL-453, HS-236, ICP-105, ICP-192, infigratinib, MAX-40279, RLY-4008, rogaratinib, SAR-442501, SY-4798, TT- 00434, and zoligratinib (FF-284), and anti- FGFR antibodies such as bemarituzumab.
  • small molecule inhibitors such as 3D-185, ABSK-011, ABSK-091, aldafermin, al
  • FGFR inhibitors include small molecule inhibitors such as erdafitinib and pemigatinib.
  • the cancer-targeted therapeutic agent, the first (prior) cancer-targeted therapeutic agent, the second cancer-targeted therapeutic agent, or the selected cancer-targeted therapeutic agent is infigratinib, futibatinib, or pemigatinib.
  • the cancer-targeted therapeutic agent, the first (prior) cancer-targeted therapeutic agent, the second cancer-targeted therapeutic agent, or the selected cancer-targeted therapeutic agent is an inhibitor of KRAS.
  • the KRAS inhibitor include small molecule inhibitors such as ABREV01, ARS-1620, APG-1842, ATG-012, BBP-454, BEPT- 607, BI-2852, BI-1823911, BPI-421286, BTX-2541, COTI-219, IMM-1811900, JAB-21000, JAB-22000, JAB-23000, JAB-BX300, JP-002, KR-12, LYN 202, MRTX-1133, RAS-F, RMC-6236, RMC-6291, SDGR 5, STX-301, and YL-15293, and anti-KRAS antibodies such as SBT-100, SBT-102, and SBT-300.
  • small molecule inhibitors such as ABREV01, ARS-1620, APG-1842, ATG-012, BBP-454, BEPT- 607, BI-2852, BI-1823911, BPI-421286, BTX-2541, COTI-219, IMM-1811900,
  • the KRAS include small molecule inhibitors such as adagrasib, ARS-3248, D-1553, GDC- 6036, JDQ-443, LY3537982, sotorasib (AMG 510), and BI 1701963.
  • the cancer-targeted therapeutic agent, the first (prior) cancer-targeted therapeutic agent, the second cancer-targeted therapeutic agent, or the selected cancer-targeted therapeutic agent is an inhibitor of c-MET, HER2, androgen receptor (AR), KIT, PDGFRA PI3K, AKT, BCL2, or MCL1.
  • the c-MET inhibitor includes crizotinib, tivantinib, cabozantinib, foretinib), or a monoclonal antibody against c-MET such as onartuzumab.
  • the cancer-targeted therapeutic agent, the first (prior) cancer-targeted therapeutic agent, the second cancer-targeted therapeutic agent, or the selected cancer-targeted therapeutic agent is a c-MET inhibitor.
  • the cancer-targeted therapeutic agent, the first (prior) cancer-targeted therapeutic agent, the second cancer-targeted therapeutic agent, or the selected cancer-targeted therapeutic agent is tepotinib.
  • the cancer-targeted therapeutic agent, the first (prior) cancer-targeted therapeutic agent, the second cancer-targeted therapeutic agent, or the selected cancer-targeted therapeutic agent targets a protein encoded by one or more genes provided in Table 3.
  • the tumor or tumor cells prior to treatment with the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, comprise a gene amplification and wherein the cancer-targeted therapeutic agent has an activity directed against a protein encoded by a gene contained within the gene amplification.
  • the tumor or tumor cells prior to treatment with the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, comprise a gene amplification and wherein the first (prior) cancer-targeted therapeutic agent has an activity directed against a protein encoded by a gene contained within the gene amplification.
  • the tumor or tumor cells prior to treatment with the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, comprise a gene amplification and wherein the second cancer-targeted therapeutic agent has an activity directed against a protein encoded by a gene contained within the gene amplification.
  • the tumor or tumor cells prior to treatment with the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, comprise a gene amplification and wherein the selected cancer-targeted therapeutic agent has an activity directed against a protein encoded by a gene contained within the gene amplification.
  • the subject received one or more administrations of the first (prior) cancer-targeted therapeutic agent prior to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and wherein the tumor or tumor cells developed resistance to the first (prior) cancer-targeted therapeutic agent.
  • Attorney Docket No.57547-724.601 [00205]
  • the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof is administered concurrently or prior to the administration of the cancer-targeted therapeutic agent.
  • the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof is administered concurrently or prior to the administration of the selected cancer-targeted therapeutic agent.
  • the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof is administered concurrently or prior to the administration of the first (prior) cancer-targeted therapeutic agent.
  • the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof is administered concurrently or prior to the administration of the second (selected) cancer-targeted therapeutic agent.
  • the subject received one or more administrations of the first (prior) cancer-targeted therapeutic agent prior to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and wherein the tumor or tumor cells developed decreased responsiveness or resistance to the first (prior) cancer-targeted therapeutic agent.
  • treatment with both the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the cancer-targeted therapeutic agent has a greater effect or a longer duration of effect on reduction of one or more of tumor growth, tumor size, number of tumor cells or tumor metastasis as compared to the treatment with either the compound of Formula (I) or the cancer-targeted therapeutic agent when administered alone.
  • treatment with both the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the first (prior) cancer- targeted therapeutic agent has a greater effect or a longer duration of effect on reduction of one or more of tumor growth, tumor size, number of tumor cells or tumor metastasis as compared to the treatment with either the compound of Formula (I) or the first (prior) cancer-targeted therapeutic agent when administered alone.
  • treatment with both the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the second (selected) cancer-targeted therapeutic agent has a greater effect or a longer duration of effect on reduction of one or more of tumor growth, tumor size, number of tumor cells or tumor metastasis as compared to the treatment with either the compound of Formula (I) or the second (selected) cancer-targeted therapeutic agent when administered alone.
  • different therapeutically effective dosages of the compounds disclosed herein will be utilized in formulating a pharmaceutical composition and/or in treatment regimens when the compounds disclosed herein are administered in combination with a second (selected) therapeutic agent.
  • Therapeutically effective dosages of drugs and other agents for use in combination treatment regimens are optionally determined by means similar to those set forth hereinabove for the actives themselves. Furthermore, the methods of prevention/treatment described herein encompasses the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side effects.
  • a combination treatment regimen encompasses treatment regimens in which administration of a compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is initiated prior to, during, or after treatment with a second (selected) agent described herein, and continues until any time during treatment with the second (selected) agent or after termination of treatment with the second (selected) agent. It also includes treatments in which a compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the second (selected) agent being used in combination are administered simultaneously or at different times and/or at decreasing or increasing intervals during the treatment period.
  • Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient.
  • the dosage regimen to treat, prevent, or ameliorate the condition(s) for which relief is sought is modified in accordance with a variety of factors (e.g., the disease, disorder, or condition from which the subject suffers; the age, weight, sex, diet, and medical condition of the subject).
  • the dosage regimen employed varies and, in some embodiments, deviates from the dosage regimens set forth herein.
  • dosages of the co-administered compounds vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated, and so forth.
  • the compounds described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, as well as combination therapies, are administered before, during, or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies.
  • the compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof is administered in combination with an adjuvant.
  • the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).
  • the subject identified as having the tumor or tumor cells has cancer.
  • the cancer includes malignant tumors whose size can be decreased, whose growth or spread can be slowed or halted, or whose symptom is in remission or alleviated, reduced, and/or completely cured by deleting or suppressing and/or inhibiting functions of Chk1.
  • Malignant tumors of interest are, but not limited to, head and neck cancer, gastrointestinal cancer (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancer (gallbladder, bile duct cancer, etc.), pancreatic cancer, colorectal cancer (colon cancer, rectal cancer, etc.), etc.), lung cancer (non-small cell lung cancer, small cell lung cancer, squamous cell lung carcinoma, mesothelioma, etc.), breast cancer, genital cancer (ovarian cancer, Attorney Docket No.57547-724.601 uterine cancer, cervical cancer, endometrial cancer, etc.), urinary cancer (kidney cancer, bladder cancer, prostate cancer, testicular tumor, etc.), hematopoietic tumors (leukemia, malignant lymphoma, multiple myeloma, etc.), bone and soft tissue tumors (e.g., soft tissue sarcomas and osteosarcomas), skin cancer
  • cancer is used in accordance with its plain ordinary meaning in light of the present disclosure and refers to all types of cancer, neoplasm or malignant tumors found in mammals, including leukemias, lymphomas, melanomas, neuroendocrine tumors, carcinomas, and sarcomas.
  • Exemplary cancers that may be treated with a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, pharmaceutical compositions include acute myeloid leukemia, adrenal cortical cancer, adrenal gland cancer, bladder cancer, bone cancer, brain cancer, breast cancer (e.g., ductal carcinoma, lobular carcinoma, primary, metastatic), breast cancer, cancer of the endocrine system, cancer of the hepatic stellate cells, cancer of the pancreatic stellate cells, cervical cancer, colon cancer, colorectal cancer, ductal carcinoma, endometrial cancer, esophageal cancer, gastric cancer, genitourinary tract cancer, glioblastoma, glioma, head and neck cancer, hepatocellular carcinoma, Hodgkin’s Disease, kidney cancer, leukemia (e.g., lymphoblastic leukemia, chronic lymphocytic leukemia, hairy cell leukemia), liver cancer (e.g.,
  • the cancer is selected from bladder cancer, breast cancer, colon cancer, esophageal cancer, esophageal cancer, glioblastoma, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, salivary gland cancer, soft tissue sarcoma, squamous cell lung carcinoma, stomach cancer, and uterine cancer.
  • Gene amplification plays a role in the response of a tumor or tumor cells to cancer-directed therapies and in the development of resistance to targeted therapies.
  • gene amplification includes amplification of one or more genes, such as oncogenes, in a focal amplification, where the one or more oncogenes are in higher copy number, whereas surrounding genetic material (e.g., from the chromosomal location of such amplified gene) is not amplified or not at the same level of amplification.
  • Focal amplifications may be located on ecDNA or ecDNA-derived, (i.e., derived from ecDNA, such as ecDNA that has reintegrated into a chromosomal location).
  • ecDNA mediates an important and clinically Attorney Docket No.57547-724.601 distinct mechanism of resistance to targeted therapies.
  • Tumor cells with ecDNA and/or ecDNA-derived amplifications may become non-responsive, less responsive, or resistant to a targeted therapy.
  • the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof may be used in combination with a therapeutic agent to treat an ecDNA+ cancer, ecDNA+ tumor or ecDNA+ tumor cells (i.e., tumor cells containing gene amplifications on ecDNA or derived from ecDNA).
  • a therapeutic agent to treat an ecDNA+ cancer, ecDNA+ tumor or ecDNA+ tumor cells (i.e., tumor cells containing gene amplifications on ecDNA or derived from ecDNA).
  • the combination of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof and a therapeutic agent may be used to treat tumors, such as with one or more amplified oncogenes (e.g., BRAF, CDK4, CDK6, EGFR, FGFR, HER2, KRAS, MET, MDM2 amplifications); in some cases, the one or more amplified oncogenes comprise non-mutant forms of the oncogene and in some cases, the amplified oncogenes comprises mutant forms of the oncogenes.
  • one or more amplified oncogenes e.g., BRAF, CDK4, CDK6, EGFR, FGFR, HER2, KRAS, MET, MDM2 amplifications
  • the one or more amplified oncogenes comprise non-mutant forms of the oncogene and in some cases, the amplified oncogenes comprises mutant forms of the onc
  • the one or more amplified oncogenes are extrachromosomal (i.e., on ecDNA) and/or are ecDNA-derived and located on a chromosome.
  • the therapeutic agent used in combination with the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof is an inhibitor of a protein encoded by a gene that is amplified on ecDNA or the ecDNA-derived amplification.
  • the combinations described herein may be used to treat tumors that have developed resistance to another therapy such as a resistance to a targeted agent.
  • a tumor (or tumor cells) treated with a first (prior) targeted agent develops resistance to the first (prior) targeted agent or becomes less responsive or non-responsive to the first (prior) targeted agent.
  • the first (prior) therapeutic agent is an inhibitor of a protein encoded by a gene that is amplified on ecDNA or the ecDNA-derived amplification and the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof and the first (prior) targeted agent may be used to treat such tumors or tumor cells.
  • the first (prior) therapeutic agent is an inhibitor of a protein encoded by a gene that is amplified on ecDNA or the ecDNA-derived amplification and the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof and a second (selected) targeted agent may be used to treat such tumors or tumor cells, where the second (selected) targeted agent is an inhibitor of a different protein from the protein target of the first (prior) targeted agent.
  • a tumor background is identified as hyper-sensitive to a Chk1 inhibitor and allows a sufficient therapeutic index to enable tolerated doses that are efficacious.
  • synthetic lethality arises with the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof in combination with a cancer-targeted agent where the tumor Attorney Docket No.57547-724.601 or tumor cells are ecDNA+ (i.e., contain ecDNA or ecDNA-derived gene amplification) .
  • a cancer-targeted agent where the tumor Attorney Docket No.57547-724.601 or tumor cells are ecDNA+ (i.e., contain ecDNA or ecDNA-derived gene amplification) .
  • Chk1 inhibition results in reduced ecDNA copy number.
  • Chk1 inhibition results in enhanced cytotoxicity in ecDNA+ cells.
  • enhanced cytotoxicity results from the combination of Chk1 inhibition and inhibition of a cancer-target, such as an oncogene.
  • the tumor or tumor cells prior to treatment the tumor or tumor cells comprise ecDNA and wherein the treatment results in a reduction in the amount of ecDNA in the tumor or tumor cells.
  • prior to treatment the tumor or tumor cells comprise ecDNA and wherein level or amount of ecDNA subsequent to the treatment is not increased as compared to prior to treatment.
  • the method further comprises assessing a sample from a subject for the presence or level of one or more of a gene amplification, a focal gene amplification, ecDNA, HSR or an ecDNA signature.
  • the method further comprises obtaining information of the presence or level of one or more of a gene amplification, a focal gene amplification, ecDNA, HSR or an ecDNA signature in the tumor or tumor cells from the subject prior to, during or subsequent to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.
  • information is obtained prior to treatment with the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof and a targeted cancer therapeutic agent.
  • such information is obtained during the course of treatment with the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof inhibitor and a targeted cancer therapeutic agent.
  • such information is obtained after treatment with a first (prior) targeted cancer therapeutic agent but prior to treatment with the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and if the information indicates the presence of ecDNA, or an ecDNA-derived gene amplification, the subject is treated with a combination of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof and the first (prior) targeted cancer therapeutic agent or with a combination of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof and a second (selected) targeted cancer therapeutic agent.
  • a tumor or tumor cells are determined to have an ecDNA signature. In some cases, a tumor or tumor cells are determined to have an ecDNA signature when the tumor or tumor cells have one or more characteristics associated with ecDNA+ tumors or tumor cells.
  • the ecDNA signature is selected from the group consisting of a gene amplification; a focal gene amplification; characterization of a structural variation; a p53 loss of function mutation; absence of microsatellite instability (MSI-H); a low level of PD-L1 expression; a low level of tumor inflammation Attorney Docket No.57547-724.601 signature (TIS); a low level of tumor mutational burden (TMB); an increased frequency of allele substitutions, insertions, or deletions (indels); and any combination thereof.
  • the tumor or tumor cells have an ecDNA signature.
  • the tumor or tumor cells develop the ecDNA signature after administration of a first (prior) cancer-targeted therapeutic agent. In some cases, the tumor or tumor cells develop the ecDNA signature prior to treatment. [00227] In some embodiments of a method disclosed herein, the information of the presence or level of one or more of a gene amplification, a focal gene amplification, ecDNA, HSR or an ecDNA signature in the tumor or tumor cells is obtained from blood, tissue or one or more cells.
  • the information of the presence or level of one or more of a gene amplification, a focal gene amplification, ecDNA, HSR or an ecDNA signature in the tumor or tumor cells is obtained by liquid biopsy or tissue biopsy.
  • Embodiment 1 A method of treating a tumor or tumor cells, comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a cancer-targeted therapeutic agent to a subject identified as having the tumor or tumor cells, wherein the tumor or tumor cells comprise a gene amplification, whereby growth or size of the tumor or growth or number of tumor cells is reduced.
  • Embodiment 2 The method of embodiment 1, wherein the cancer-targeted therapeutic agent is administered concurrent or subsequent to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.
  • Embodiment 3 The method of embodiment 1 or embodiment 2, wherein the cancer-targeted therapeutic agent is administered prior to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.
  • Embodiment 4 The method of any one of embodiments 1-3, wherein the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is administered in an amount sufficient to induce replication stress in the tumor or tumor cells.
  • Embodiment 5 A method of delaying resistance to a cancer-targeted therapeutic agent, the method comprising: administering a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, to a subject in an amount sufficient to induce replication stress in tumor or tumor cells and administering a cancer-targeted therapeutic agent concurrently or subsequent to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.
  • Embodiment 6 The method of embodiment 5, wherein the subject is identified as having the tumor or tumor cells comprising a gene amplification.
  • Embodiment 7 The method of any one of embodiments 1-4 or 6, wherein the gene amplification is a focal gene amplification. Attorney Docket No.57547-724.601 [00236] Embodiment 8: The method of any one of embodiments 1-4, 6, or 7, wherein the gene amplification is an ecDNA-derived amplification. [00237] Embodiment 9: The method of any one of embodiments 1-4 or 6-8, wherein the gene amplification is comprised on ecDNA or an HSR (homogeneously staining region).
  • HSR homogeneously staining region
  • Embodiment 10 The method of any one of embodiments 1-4 or 6-9, wherein the cancer-targeted therapeutic agent is directed against a protein encoded by a gene contained within the gene amplification.
  • Embodiment 11 The method of any one of embodiments 1-10, wherein the tumor or tumor cells comprise an ecDNA signature.
  • Embodiment 12 The method of any one of embodiments 1-11, wherein cells comprised within the tumor or the tumor cells are ecDNA competent.
  • Embodiment 13 The method of any one of embodiments 1-12, wherein treatment with both the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the cancer therapeutic agent has a greater effect or a longer duration of effect on reduction of one or more of tumor growth, tumor size, number of tumor cells or tumor metastasis as compared to the treatment with either the compound of Formula (I) or the cancer therapeutic agent when administered alone.
  • Embodiment 14 The method of embodiment 13, wherein the greater effect is a synergistic effect.
  • Embodiment 15 The method of any one of embodiments 1-14, wherein the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and/or the cancer- targeted therapeutic agent is administered orally.
  • Embodiment 16 The method of any one of embodiments 1-14, wherein the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and/or the cancer- targeted therapeutic agent is administered parentally.
  • Embodiment 17 The method of any one of embodiments 1-16, wherein treatment comprises administering multiple doses of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and/or the cancer-targeted therapeutic agent over a treatment period.
  • Embodiment 18 The method of any one of embodiments 1-4 or 6-17, wherein the gene amplification comprises an amplification of a gene selected from the group consisting of ABCB1, AKT, ALK, AR, BCL-2, BCR-ABL, BRAF, CDK4, CDK6, c-MET, EGFR, ER, ERBB3, ERRB2, AK, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, GR, HER2, HRAS, IGF1R, KIT, KRAS, MCL-1, MDM2, MDM4, MTOR, MYC, MYCL, MYCN, NRAS, NRG1, NTRK1, NTRK2, NTRK3, PDGFR, PIK3C ⁇ , PIK3CA/B, RET, and ROS1.
  • a gene selected from the group consisting of ABCB1, AKT, ALK, AR, BCL-2, BCR-ABL, BRAF, CDK4, CDK6, c-MET, EG
  • Embodiment 19 The method of any one of embodiments 1-18, wherein the cancer therapeutic agent is selected from the group consisting of abemaciclib, ado-trastuzumab emtansine, afatinib, alectinib, ALRN-6924, AMG232, AMG-510, apatinib, ARS-3248, AXL1717, AZD-3759, bevacizumab, BI 1701963, bortezomib, brigatinib, cabozantinib, capmatinib, ceritinib, cetuximab, CGM097, crizotinib, dabrafenib, dacomitinib, dasatinib, DS-3032b, encorafenib, entrectinib, ERAS-801, erdafitinib, erlotinib, everolimus, fam-t
  • Embodiment 20 A method of treating a subject having a tumor or tumor cells that are non- responsive to a first cancer-targeted therapeutic agent comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a second cancer- targeted therapeutic agent to the subject.
  • Embodiment 21 The method of the embodiment 20, wherein prior to treatment with the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, the tumor or tumor cells comprise a gene amplification and wherein the first cancer-targeted therapeutic agent has an activity directed against a protein encoded by a gene contained within the gene amplification.
  • Embodiment 22 The method of embodiment 21, wherein the subject received one or more administrations of the first cancer-targeted therapeutic agent prior to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and wherein the tumor or tumor cells developed resistance to the first cancer-targeted therapeutic agent.
  • Embodiment 23 The method of any one of embodiments 20-22, wherein the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is administered concurrently or prior to the administration of the second cancer-targeted therapeutic agent.
  • Embodiment 24 The method of any one of embodiments 21-23, wherein the gene amplification is a focal gene amplification.
  • Embodiment 25 The method of any one of embodiments 21-24, wherein the gene amplification is an ecDNA-derived amplification.
  • Embodiment 26 The method of any one of embodiments 21-25, wherein the gene amplification is comprised on ecDNA or an HSR (homogeneously staining region).
  • Embodiment 27 The method of any one of embodiments 21-26, wherein the second cancer- targeted therapeutic agent is directed against a protein encoded by a gene contained within the gene amplification.
  • Embodiment 28 The method of any one of embodiments 20-27, wherein the tumor or tumor cells comprise an ecDNA signature.
  • Embodiment 29 The method of any one of embodiments 20-28, wherein cells comprised within the tumor or the tumor cells are ecDNA competent.
  • Embodiment 30 The method of any one of embodiments 20-29, wherein treatment with both the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the cancer therapeutic agent has a greater effect or a longer duration of effect on reduction of one or Attorney Docket No.57547-724.601 more of tumor growth, tumor size, number of tumor cells or tumor metastasis as compared to the treatment with either the compound of Formula (I) or the cancer therapeutic agent when administered alone.
  • Embodiment 31 The method of embodiment 30, wherein the greater effect is a synergistic effect.
  • Embodiment 32 The method of any one of embodiments 20-31, wherein the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and/or the second cancer-targeted therapeutic agent is administered orally.
  • Embodiment 33 The method of any one of embodiments 20-31, wherein the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and/or the second cancer-targeted therapeutic agent is administered parentally.
  • Embodiment 34 The method of any one of embodiments 20-33, wherein treatment comprises administering multiple doses of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and/or the second cancer-targeted therapeutic agent over a treatment period.
  • Embodiment 35 The method of any one of embodiments 21-34, wherein the gene amplification comprises an amplification of a gene selected from the group consisting of ABCB1, AKT, ALK, AR, BCL- 2, BCR-ABL, BRAF, CDK4, CDK6, c-MET, EGFR, ER, ERBB3, ERRB2, AK, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, GR, HRAS, IGF1R, KIT, KRAS, MCL-1, MDM2, MDM4, MTOR, MYC, MYCL, MYCN, NRAS, NRG1, NTRK1, NTRK2, NTRK3, PDGFR, PIK3C ⁇ , PIK3CA/B, RET, and ROS1.
  • a gene selected from the group consisting of ABCB1, AKT, ALK, AR, BCL- 2, BCR-ABL, BRAF, CDK4, CDK6, c-MET, EGFR, ER,
  • Embodiment 36 The method of any one of embodiments 20-35, wherein the first cancer-targeted therapeutic agent is selected from the group consisting of abemaciclib, ado-trastuzumab emtansine, afatinib, alectinib, ALRN-6924, AMG232, AMG-510, apatinib, ARS-3248, AXL1717, AZD-3759, bevacizumab, BI 1701963, bortezomib, brigatinib, cabozantinib, capmatinib, ceritinib, cetuximab, CGM097, crizotinib, dabrafenib, dacomitinib, dasatinib, DS-3032b, encorafenib, entrectinib, ERAS-801, erdafitinib, erlotinib, everolimus,
  • Embodiment 37 The method of any one of embodiments 20-35, wherein the second cancer- targeted therapeutic agent is selected from the group consisting of abemaciclib, ado-trastuzumab emtansine, afatinib, alectinib, ALRN-6924, AMG232, AMG-510, apatinib, ARS-3248, AXL1717, AZD-3759, bevacizumab, BI 1701963, bortezomib, brigatinib, cabozantinib, capmatinib, ceritinib, cetuximab, CGM097, crizotinib, dabrafenib, dacomitinib, dasatinib, DS-3032b, encorafenib, entrectinib, ERAS-801, erdafitinib, erlotinib, everolimus,
  • Embodiment 38 A method of provoking a response in a subject having a tumor or tumor cells that are non-responsive or have decreased responsiveness to a first cancer-targeted therapeutic agent comprising administering a Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the first cancer-targeted therapeutic agent to the subject.
  • a Formula (I) or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof
  • Embodiment 39 The method of the embodiment 38, wherein prior to treatment with the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, the tumor or tumor cells comprise a gene amplification and wherein the first cancer-targeted therapeutic agent has an activity directed against a protein encoded by a gene contained within the gene amplification.
  • Embodiment 40 The method of embodiment 38 or embodiment 39, wherein the subject received one or more administrations of the first cancer-targeted therapeutic agent prior to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and wherein the tumor or tumor cells developed decreased responsiveness or resistance to the first cancer- targeted therapeutic agent.
  • Embodiment 41 The method of embodiment 39 or embodiment 40, wherein the gene amplification is a focal gene amplification.
  • Embodiment 42 The method of any one of embodiments 39-41, wherein the gene amplification is an ecDNA-derived amplification.
  • Embodiment 43 The method of any one of embodiments 39-42, wherein the gene amplification is comprised on ecDNA or an HSR (homogeneously staining region).
  • Embodiment 44 The method of any one of embodiments 38-43, wherein the tumor or tumor cells comprise an ecDNA signature.
  • Embodiment 45 The method of any one of embodiments 38-44, wherein cells comprised within the tumor or the tumor cells are ecDNA competent.
  • Embodiment 46 The method of any one of embodiments 38-45, wherein treatment with both the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the first cancer-targeted therapeutic agent has a greater effect or a longer duration of effect on reduction of one or more of tumor growth, tumor size, number of tumor cells or tumor metastasis as compared to the treatment with either the compound of Formula (I) or the first cancer-targeted therapeutic agent when administered alone.
  • Embodiment 47 The method of embodiment 46, wherein the greater effect is a synergistic effect.
  • Embodiment 48 The method of any one of embodiments 38-47, wherein the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and/or the first cancer-targeted therapeutic agent is administered orally.
  • Embodiment 49 The method of any one of embodiments 38-47, wherein the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and/or the second cancer-targeted therapeutic agent is administered parentally.
  • Embodiment 50 The method of any one of embodiments 38-49, wherein treatment comprises administering multiple doses of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and/or the first cancer-targeted therapeutic agent over a treatment period.
  • Embodiment 51 The method of any one of embodiments 39-50, wherein the gene amplification comprises an amplification of a gene selected from the group consisting of ABCB1, AKT, ALK, AR, BCL- 2, BCR-ABL, BRAF, CDK4, CDK6, c-MET, EGFR, ER, ERBB3, ERRB2, AK, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, GR, HRAS, IGF1R, KIT, KRAS, MCL-1, MDM2, MDM4, MTOR, MYC, MYCL, MYCN, NRAS, NRG1, NTRK1, NTRK2, NTRK3, PDGFR, PIK3C ⁇ , PIK3CA/B, RET, and ROS1.
  • a gene selected from the group consisting of ABCB1, AKT, ALK, AR, BCL- 2, BCR-ABL, BRAF, CDK4, CDK6, c-MET, EGFR, ER,
  • Embodiment 52 The method of any one of embodiments 20-51, wherein the first cancer-targeted therapeutic agent is selected from the group consisting of abemaciclib, ado-trastuzumab emtansine, afatinib, alectinib, ALRN-6924, AMG232, AMG-510, apatinib, ARS-3248, AXL1717, AZD-3759, bevacizumab, BI 1701963, bortezomib, brigatinib, cabozantinib, capmatinib, ceritinib, cetuximab, CGM097, crizotinib, dabrafenib, dacomitinib, dasatinib, DS-3032b, encorafenib, entrectinib, ERAS-801, erdafitinib, erlotinib, everolimus,
  • Embodiment 53 The method of any one of embodiments 1-52, wherein prior to treatment the tumor or tumor cells comprise ecDNA and wherein the treatment results in a reduction in the amount of ecDNA in the tumor or tumor cells.
  • Embodiment 54 The method of any one of embodiments 1-52, wherein prior to treatment the tumor or tumor cells comprise ecDNA and wherein level or amount of ecDNA subsequent to the treatment is not increased as compared to prior to treatment.
  • Embodiment 55 The method of any one of embodiments 1-54, wherein the method further comprises assessing a sample from a subject for the presence or level of one or more of a gene amplification, a focal gene amplification, ecDNA, HSR or an ecDNA signature.
  • Embodiment 56 The method of any one of embodiments 1-55, wherein the method further comprises obtaining information of the presence or level of one or more of a gene amplification, a focal gene amplification, ecDNA, HSR or an ecDNA signature in the tumor or tumor cells from the subject prior to, during or subsequent to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.
  • Embodiment 57 The method of embodiment 55, wherein the information is obtained from blood, tissue or one or more cells.
  • Embodiment 58 The method of embodiment 55, wherein the information is obtained by liquid biopsy or tissue biopsy.
  • Example 1 Kinase HTRF biochemical assay
  • Chk1 enzyme activity was measured using an HTRF KinEASE assay (Cisbio, catalog no. 62ST1PEC).
  • Full-length human CHK1 protein (GenBank accession number NP_001265.1) was obtained from Carna Biosciences, Inc. (Kobe, Japan, catalog no.02-117). The enzyme reaction was carried out in assay buffer containing (final concentrations): CHK1 enzyme (0.012 ng/ ⁇ L), MgCl2 (5 mM) and DTT (1 mM).
  • DMSO stock solutions were serially diluted in a 10-point concentration series in duplicate.
  • Compound solution 50 nL was added to 384-well assay plates (Greiner, catalog no.784075). To each well containing compound solution was added assay buffer solution (5 ⁇ L). Plates were centrifuged at 1000 rpm for 1 minute, then incubated at room temperature for 10 minutes. The reaction was started by addition of substrate buffer (5 ⁇ L/well) containing (final concentrations): STK substrate 1-biotin (120 nM) and ATP (1 mM). Assay plates were centrifuged at 1000 rpm for 1 minute, then incubated at room temperature for 60 minutes.
  • the reaction was stopped by addition of detection buffer (Cisbio, 10 ⁇ L) containing (final concentrations): STK antibody-cryptate (0.25 nM) and streptavidin-XL665 (7.5 nM). Plates were centrifuged at 1000 rpm for 1 minute, then incubated at 25 °C for 2 hours.
  • HTRF signal was read on an EnVision multimode plate reader (CisBio) in HTRF mode. Data were fit to dose- response curves using XLfit (IDBS, Surrey, UK) or Prism (GraphPad Software, La Jolla, CA, US) to calculate IC50 values for each compound tested.
  • Example 2 AlphaLisa cellular assay
  • Compound activity in cells was measured using an AlphaLISA® SureFire® UltraTM p-CHK1 (Ser345) assay (Perkin Elmer, catalog no. ALSU-PCHK1-A10K).
  • HT29 cells were cultured in McCoy 5A medium with 10% FBS and 1% penicillin-streptomycin and seeded to 96-well plates (Corning, catalog no. 3599).
  • Compounds were serially diluted in DMSO over a 10-point dose range with 3-fold dilution and to each well containing cells was added compound solution. Plates were centrifuged at 1000 rpm for 30 seconds. Plates were incubated at 37 °C for 16 h.
  • mice were implanted with the tumor cells and once the tumors were established (e.g., reached a volume of about 100-350 mm 3 ), the mice were started on the therapeutic regimens as further described below.
  • synergy of the combination therapy compared to corresponding single agent arms was determined using the Fractional Product Method (Webb et al., 1963). A summary of the results is shown in Table 5. Fraction unaffected (fu) is the % where tumor growth inhibition was not observed.
  • the fu observed with the combination treatment (fu)A+B (“observed fu”) was compared to the predicted fu calculated as the product of the observed fu for the single treatments (fu)A x (fu)B.
  • CDK4/6 [00295] The combination of Compound 31 (50 mg/kg PO dosed Q2D) plus the CDK4/6 inhibitors palbociclib (50 mg/kg PO dosed QD) or abemaciclib (10.5 mg/kg PO dosed QD) was evaluated in the ecDNA+ CDK4 amplified osteosarcoma SJSA-1 CDX tumor model. Results are shown in FIG.2A (Palbociclib) and FIG.2B (abemaciclib).
  • the combination of Compound 31 plus palbociclib or abemaciclib Attorney Docket No.57547-724.601 resulted in significant anti-tumor activity, including tumor regressions, when compared to vehicle.
  • the combination of Compound 31 plus abemaciclib was determined to be synergistic.
  • EGFR [00296] The combination of Compound 31 (50 mg/kg PO dosed Q2D) plus the EGFR inhibitor erlotinib (50 mg/kg PO dosed QD) was evaluated in the ecDNA+ EGFR amplified NSCLC PDX tumor models LU1206. Results are shown in FIG.3.
  • the combination therapy resulted in significant tumor growth inhibition when compared to vehicle, and the therapy was determined to be synergistic.
  • Example 4 Suppression of ecDNA amplification
  • Prolonged treatment of SNU-16 tumor cells in vitro and SNU-16 CDX tumors in vivo with the pan-FGFR tyrosine kinase inhibitor infigratinib resulted in tumor cell stasis for a period of 1-2 weeks but acquired resistance to infigratinib treatment occurred resulting in re-initiation of tumor growth.
  • Infigratinib resistance was directly correlated with increased amplification of FGFR2 (copy number) on ecDNA.
  • Combination treatment of infigratinib plus Compound 31 blocked the increase of FGFR2 copy number on ecDNA that otherwise was induced by single agent infigratinib.

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Abstract

Provided herein are methods for the treatment of cancer. The methods include administering to a subject in need a therapeutically effective amount of a Chkl inhibitor disclosed herein in combination with an additional therapeutic agent.

Description

Attorney Docket No.57547-724.601 CHECKPOINT KINASE 1 (CHK1) INHIBITORS COMBINATIONS AND USES THEREOF CROSS-REFERENCE [0001] This application claims the benefit of U. S. Provisional Application Serial No.63/385,347 filed November 29, 2022 which is hereby incorporated by reference in its entirety. FIELD OF THE INVENTION [0002] Described herein are combinations, comprising compounds for inhibiting checkpoint kinase 1 (Chk1). BACKGROUND OF THE INVENTION [0003] Some cancers prove resistant to the therapeutics that are used to treat them, frustrating efforts to maintain a durable and progression free survival in cancer patients. Patients whose tumors harbor oncogene amplification can prove particularly difficult to treat. For example, patients whose tumors harbor oncogene amplification on or derived from extrachromosomal DNA (ecDNA) may fail to respond to targeted or immune therapy and have poor prognosis. [0004] Single agent therapies may be less effective in some patient populations or have shorter durability before the tumor or tumor cells develop resistance. There is a need to develop multiple points of attack on such cancers. However, combinations of therapeutic agents have also proven susceptible to similar development of resistance or reduced responsiveness. [0005] There is a need for combinations are potent therapeutic treatments with increased durability and longevity of effect to address the need for safe and effective treatments of cancer. BRIEF SUMMARY OF THE INVENTION [0006] Disclosed herein is a method of treating a tumor or tumor cells, comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a selected cancer-targeted therapeutic agent to a subject identified as having the tumor or tumor cells, wherein the tumor or tumor cells comprise a gene amplification, whereby growth or size of the tumor or growth or number of tumor cells is reduced. [0007] Also disclosed herein is a method of delaying resistance to a selected cancer-targeted therapeutic agent, the method comprising: administering a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, to a subject in an amount sufficient to induce replication stress in tumor or tumor cells and administering the selected cancer-targeted therapeutic agent concurrently or subsequent to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. [0008] Also disclosed herein is a method of treating a subject having a tumor or tumor cells that are non- responsive to a prior cancer-targeted therapeutic agent comprising administering a compound of Formula (I), Attorney Docket No.57547-724.601 or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a selected cancer- targeted therapeutic agent to the subject. [0009] In some embodiments of a method disclosed herein, the subject received one or more administrations of the prior cancer-targeted therapeutic agent prior to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and wherein the tumor or tumor cells developed decreased responsiveness or resistance to the prior cancer-targeted therapeutic agent. [0010] Also disclosed herein is a method of provoking a response in a subject having a tumor or tumor cells that are non-responsive or have decreased responsiveness to a prior cancer-targeted therapeutic agent comprising administering a Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a selected cancer-targeted therapeutic agent to the subject; wherein the prior cancer-targeted therapeutic agent is the same as the selected cancer-targeted therapeutic agent. [0011] In some embodiments of a method disclosed herein, prior to treatment with the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, the tumor or tumor cells comprise a gene amplification and wherein the prior cancer-targeted therapeutic agent has an activity directed against a protein encoded by a gene contained within the gene amplification. [0012] In some embodiments of a method disclosed herein, the selected cancer-targeted therapeutic agent is administered concurrent or subsequent to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. [0013] In some embodiments of a method disclosed herein, the selected cancer-targeted therapeutic agent is administered prior to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. [0014] In some embodiments of a method disclosed herein, the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is administered in an amount sufficient to induce replication stress in the tumor or tumor cells. [0015] In some embodiments of a method disclosed herein, the subject is identified as having the tumor or tumor cells comprising a gene amplification. [0016] In some embodiments of a method disclosed herein, the gene amplification is a focal gene amplification. [0017] In some embodiments of a method disclosed herein, the gene amplification is an ecDNA-derived amplification. [0018] In some embodiments of a method disclosed herein, the gene amplification is comprised on ecDNA or an HSR (homogeneously staining region). [0019] In some embodiments of a method disclosed herein, the tumor or tumor cells comprise an ecDNA signature. [0020] In some embodiments of a method disclosed herein, the selected cancer-targeted therapeutic agent is directed against a protein encoded by a gene contained within the gene amplification. Attorney Docket No.57547-724.601 [0021] In some embodiments of a method disclosed herein, cells comprised within the tumor or the tumor cells are ecDNA competent. [0022] In some embodiments of a method disclosed herein, treatment with both the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the selected cancer-targeted therapeutic agent has a greater effect or a longer duration of effect on reduction of one or more of tumor growth, tumor size, number of tumor cells or tumor metastasis as compared to the treatment with either the compound of Formula (I) or the selected cancer-targeted therapeutic agent when administered alone. [0023] In some embodiments of a method disclosed herein, the greater effect is a synergistic effect. [0024] In some embodiments of a method disclosed herein, the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and/or the selected cancer- targeted therapeutic agent is administered orally. [0025] In some embodiments of a method disclosed herein, treatment comprises administering multiple doses of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and/or the selected cancer-targeted therapeutic agent over a treatment period. [0026] In some embodiments of a method disclosed herein, the gene amplification comprises an amplification of a gene selected from the group consisting of ABCB1, AKT, ALK, AR, BCL-2, BCR-ABL, BRAF, CDK4, CDK6, c-MET, EGFR, ER, ERBB3, ERRB2, AK, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, GR, HRAS, IGF1R, KIT, KRAS, MCL-1, MDM2, MDM4, MTOR, MYC, MYCL, MYCN, NRAS, NRG1, NTRK1, NTRK2, NTRK3, PDGFR, PIK3Cδ, PIK3CA/B, RET, and ROS1. [0027] In some embodiments of a method disclosed herein, the gene amplification comprises an amplification of a gene selected from the group consisting of CDK4, CDK6, c-MET, EGFR, FGFR1, FGFR2, FGFR3, and FGFR4. [0028] In some embodiments of a method disclosed herein, the selected cancer therapeutic agent is an FGFR inhibitor. In some embodiments of a method disclosed herein, the FGFR inhibitor is infigratinib, futibatinib, or pemigatinib. [0029] In some embodiments of a method disclosed herein, the selected cancer therapeutic agent is a CDK4/6 inhibitor. In some embodiments of a method disclosed herein, the CDK4/6 inhibitor is palbociclib or abemaciclib. [0030] In some embodiments of a method disclosed herein, the selected cancer therapeutic agent is an EGFR inhibitor. In some embodiments of a method disclosed herein, the EGFR inhibitor is erlotinib. [0031] In some embodiments of a method disclosed herein, the selected cancer therapeutic agent is a c- MET inhibitor. In some embodiments of a method disclosed herein, the c-MET inhibitor is tepotinib. [0032] In some embodiments of a method disclosed herein, prior to treatment the tumor or tumor cells comprise ecDNA and wherein the treatment results in a reduction in the amount of ecDNA in the tumor or tumor cells. Attorney Docket No.57547-724.601 [0033] In some embodiments of a method disclosed herein, prior to treatment the tumor or tumor cells comprise ecDNA and wherein level or amount of ecDNA subsequent to the treatment is not increased as compared to prior to treatment. [0034] In some embodiments of a method disclosed herein, the method further comprises assessing a sample from a subject for the presence or level of one or more of a gene amplification, a focal gene amplification, ecDNA, HSR or an ecDNA signature. [0035] In some embodiments of a method disclosed herein, the method further comprises obtaining information of the presence or level of one or more of a gene amplification, a focal gene amplification, ecDNA, HSR or an ecDNA signature in the tumor or tumor cells from the subject prior to, during or subsequent to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. [0036] In some embodiments of a method disclosed herein, the information is obtained from blood, tissue or one or more cells. [0037] In some embodiments of a method disclosed herein, the information is obtained by liquid biopsy or tissue biopsy. [0038] In some embodiments of a method disclosed herein, the prior cancer-targeted therapeutic agent is targeted to the protein encoded by a gene selected from the group consisting of ABCB1, AKT, ALK, AR, BCL-2, BCR-ABL, BRAF, CDK4, CDK6, c-MET, EGFR, ER, ERBB3, ERRB2, AK, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, GR, HRAS, IGF1R, KIT, KRAS, MCL-1, MDM2, MDM4, MTOR, MYC, MYCL, MYCN, NRAS, NRG1, NTRK1, NTRK2, NTRK3, PDGFR, PIK3Cδ, PIK3CA/B, RET, and ROS1. [0039] In some embodiments of a method disclosed herein, the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is
Figure imgf000006_0001
Formula (I) as disclosed herein. [0040] In some embodiments of a method disclosed herein, the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is a compound of Formula (Ib): Attorney Docket No.57547-724.601
Figure imgf000007_0001
Formula (Ib). [0041] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof,
Figure imgf000007_0002
pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. INCORPORATION BY REFERENCE [0042] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purposes identified herein. BRIEF DESCRIPTION OF THE DRAWINGS [0043] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which: [0044] FIG.1A shows the tumor volume following treatment with the combination of Compound 31 (50 mg/kg PO dosed Q2D) and the pan-FGFR inhibitor infigratinib (15 mg/kg PO dosed QD) in the ecDNA+ FGFR2 amplified gastric cancer SNU-16 CDX model. FIG.1B shows the tumor volume following treatment with the combination of Compound 31 (50 mg/kg PO dosed Q2D) and the pan-FGFR inhibitor infigratinib (15 mg/kg PO dosed QD) in the ecDNA+ FGFR2 amplified gastric cancer CTG-0353 PDX model. FIG.1C shows the survival curves following treatment with the combination of Compound 31 (50 mg/kg PO dosed Q2D) and the pan-FGFR inhibitor infigratinib (15 mg/kg PO dosed QD) in the ecDNA+ FGFR2 amplified gastric cancer CTG-0353 PDX model. Attorney Docket No.57547-724.601 FIG.1D shows the tumor volume following treatment with the combination of Compound 31 (50 mg/kg PO dosed Q2D) and the pan-FGFR inhibitor futibatinib (12.5 mg/kg PO dosed QD) in the ecDNA+ FGFR2 amplified gastric cancer SNU-16 CDX model. FIG.1E shows the tumor volume following treatment with the combination of Compound 31 (50 mg/kg PO dosed Q2D) and the pan-FGFR inhibitor pemigatinib (1 mg/kg PO dosed QD) in the ecDNA+ FGFR2 amplified gastric cancer SNU-16 CDX model. FIG.2A shows the tumor volume following treatment with the combination of Compound 31 (50 mg/kg PO dosed Q2D) and the CDK4/6 inhibitors palbociclib (50 mg/kg PO dosed QD) in the ecDNA+ CDK4 amplified osteosarcoma SJSA-1 CDX tumor model. FIG.2B shows the tumor volume following treatment with the combination of Compound 31 (50 mg/kg PO dosed Q2D) and the CDK4/6 inhibitors abemaciclib (10.5 mg/kg PO dosed QD) in the ecDNA+ CDK4 amplified osteosarcoma SJSA-1 CDX tumor model. FIG.3 shows the tumor volume following treatment with the combination of Compound 31 (50 mg/kg PO dosed Q2D) and the EGFR inhibitor erlotinib (50 mg/kg PO dosed QD) in the ecDNA+ EGFR amplified NSCLC PDX tumor models LU1206. FIG.4 shows the tumor volume following treatment with the combination of Compound 31 (50 mg/kg PO dosed Q2D) and the MET inhibitor tepotinib (25 mg/kg PO dosed Q2D) in the ecDNA+ MET amplified NSCLC PDX tumor models LU1902. FIG.5 shows that combination treatment of infigratinib plus Compound 31 blocked the increase of FGFR2 copy number on ecDNA that otherwise was induced by single agent infigratinib. DETAILED DESCRIPTION OF THE INVENTION Definitions [0045] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention. [0046] Reference throughout this specification to “some embodiments” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms Attorney Docket No.57547-724.601 “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise. [0047] The terms below, as used herein, have the following meanings, unless indicated otherwise: [0048] “oxo” refers to =O. [0049] “Carboxyl” refers to -COOH. [0050] “Cyano” refers to -CN. [0051] “Alkyl” refers to a straight-chain or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3- methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1- pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1- butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, a numerical range such as “C1-C6 alkyl” or “C1-6alkyl”, means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a C1-10alkyl. In some embodiments, the alkyl is a C1-6alkyl. In some embodiments, the alkyl is a C1-5alkyl. In some embodiments, the alkyl is a C1-4alkyl. In some embodiments, the alkyl is a C1-3alkyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen. [0052] “Alkenyl” refers to a straight-chain, or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to ethenyl (- CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkenyl” or “C2-6alkenyl”, means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In Attorney Docket No.57547-724.601 some embodiments, the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen. [0053] “Alkynyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3- butadiynyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkynyl” or “C2- 6alkynyl”, means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkynyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is optionally substituted with halogen, -CN, - OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen. [0054] “Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen. [0055] “Alkoxy” refers to a radical of the formula -ORa where Ra is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen. [0056] “Aryl” refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10- membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with halogen, Attorney Docket No.57547-724.601 amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen. [0057] “Cycloalkyl” refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C3-C15 cycloalkyl or C3-C15 cycloalkenyl), from three to ten carbon atoms (C3-C10 cycloalkyl or C3- C10 cycloalkenyl), from three to eight carbon atoms (C3-C8 cycloalkyl or C3-C8 cycloalkenyl), from three to six carbon atoms (C3-C6 cycloalkyl or C3-C6 cycloalkenyl), from three to five carbon atoms (C3-C5 cycloalkyl or C3-C5 cycloalkenyl), or three to four carbon atoms (C3-C4 cycloalkyl or C3-C4 cycloalkenyl). In some embodiments, the cycloalkyl is a 3- to 10-membered cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl or a 5- to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7- dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen. [0058] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro. [0059] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2- trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. [0060] “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl include, for example, hydroxymethyl, Attorney Docket No.57547-724.601 hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl. [0061] “Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl. [0062] “Deuteroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more deuteriums. In some embodiments, the alkyl is substituted with one deuterium. In some embodiments, the alkyl is substituted with one, two, or three deuteriums. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuteriums. Deuteroalkyl include, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuteroalkyl is CD3. [0063] “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or - CH2CH2N(CH3)2. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or - OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen. [0064] “Heterocycloalkyl” refers to a 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens. In some embodiments, the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems; and the nitrogen, Attorney Docket No.57547-724.601 carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (C2-C15 heterocycloalkyl or C2-C15 heterocycloalkenyl), from two to ten carbon atoms (C2-C10 heterocycloalkyl or C2-C10 heterocycloalkenyl), from two to eight carbon atoms (C2-C8 heterocycloalkyl or C2-C8 heterocycloalkenyl), from two to seven carbon atoms (C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to six carbon atoms (C2-C6 heterocycloalkyl or C2- C6 heterocycloalkenyl), from two to five carbon atoms (C2-C5 heterocycloalkyl or C2-C5 heterocycloalkenyl), or two to four carbon atoms (C2-C4 heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3- dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen. [0065] “Heteroaryl” refers to a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and Attorney Docket No.57547-724.601 sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, the heteroaryl comprises one nitrogen. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5- membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2- oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1- oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen. [0066] The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group may be un-substituted (e.g., - CH2CH3), fully substituted (e.g., -CF2CF3), mono-substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, - CFHCHF2, etc.). It will be understood by those skilled in the art with respect to any group containing one or more substituents that such groups are not intended to introduce any substitution or substitution patterns Attorney Docket No.57547-724.601 (e.g., substituted alkyl includes optionally substituted cycloalkyl groups, which in turn are defined as including optionally substituted alkyl groups, potentially ad infinitum) that are sterically impractical and/or synthetically non-feasible. Thus, any substituents described should generally be understood as having a maximum molecular weight of about 1,000 daltons, and more typically, up to about 500 daltons. [0067] The term “one or more” when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, four, or more substituents. In some embodiments, the subject group is optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents. [0068] The terms “treat,” “treated,” “treatment,” or “treating” as used herein refers to therapeutic treatment, wherein the object is to prevent or slow (lessen) an undesired physiological condition, disorder, or disease, or to obtain beneficial or desired clinical results. For the purposes described herein, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization (i.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total), whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. The terms “treat,” “treated,” “treatment,” or “treating” as well as words stemming therefrom, as used herein, do not necessarily imply 100% or complete treatment. Rather, there are varying degrees of treatment of which one of ordinary skill in the art recognizes as having a potential benefit or therapeutic effect. In this respect, the disclosed methods can provide any amount of any level of treatment of the disorder in a mammal. For example, a disorder, including symptoms or conditions thereof, may be reduced by, for example, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%. [0069] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of a compound disclosed herein being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated, e.g., cancer or an inflammatory disease. In some embodiments, the result is a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound disclosed herein required to provide a clinically significant decrease in disease symptoms. In some embodiments, an appropriate “effective” amount in any individual case is determined using techniques, such as a dose escalation study. [0070] The term “biological sample,” as used herein, generally refers to a sample derived from or obtained from a subject, such as a mammal (e.g., a human). Biological samples are contemplated to include Attorney Docket No.57547-724.601 but are not limited to, hair, fingernails, skin, sweat, tears, ocular fluids, nasal swab or nasopharyngeal wash, sputum, throat swab, saliva, mucus, blood, serum, plasma, placental fluid, amniotic fluid, cord blood, emphatic fluids, cavity fluids, earwax, oil, glandular secretions, bile, lymph, pus, microbiota, meconium, breast milk, bone marrow, bone, CNS tissue, cerebrospinal fluid, adipose tissue, synovial fluid, stool, gastric fluid, urine, semen, vaginal secretions, stomach, small intestine, large intestine, rectum, pancreas, liver, kidney, bladder, lung, and other tissues and fluids derived from or obtained from a subject. [0071] The term “tumor” or “tumor cells” as used herein, generally refers to cells that grow and divide more than they should or do not die when they should. In some cases, tumor cells are present in a solid mass, such as a solid tumor, or in some cases, tumor cells are found in a non-solid form, such as in blood cancers. Tumor or tumor cells also can include metastasis or metastasizing cells, where cancer cells break away from the original (primary) tumor and may form a new tumor in other organs or tissues of the body. [0072] The term “ecDNA signature” as used herein, generally refers to one or more characteristics common to tumors or tumor cells that are ecDNA+. In some cases, the ecDNA signature is selected from the group consisting of a gene amplification; a p53 loss of function mutation; absence of microsatellite instability (MSI-H); a low level of PD-L1 expression; a low level of tumor inflammation signature (TIS); a low level of tumor mutational burden (TMB); an increased frequency of allele substitutions, insertions, or deletions (indels); and any combination thereof. In some cases, the ecDNA signature can include an increase in copy number (gene amplification) in conjunction with particular structural variations. In some cases, the ecDNA signature can include a focal amplification. In some cases, ecDNA signature includes a detection or identification of ecDNA using an imaging technology. In some cases, ecDNA signature does not include any imaging or direct detection of ecDNA. Compounds [0073] Described herein are Chk1 inhibitor that are useful for the treatment of cancer. [0074] Disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof:
Figure imgf000016_0001
wherein: Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Attorney Docket No.57547-724.601 each R1 is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R1 on the same atom are taken together to form an oxo; n is 0-4; R2 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; R3 is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; R4 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; W is N or CRW; RW is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R; X is N or CRX; RX is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R; Y is N or CRY; RY is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R; Z is N or CRZ; Attorney Docket No.57547-724.601 RZ is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R; provided that at least one of W, X, Y, or Z is N; L is -O- or -NR5-; R5 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R6 is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R6 on the same atom are taken together to form an oxo; or two R6 on the same carbon are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with one or more R; or two R6 on different atoms are taken together to form a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl; each optionally substituted with one or more R; m is 0-8; each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; and each Rc and Rd are independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Attorney Docket No.57547-724.601 or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; each R is independently halogen, -CN, -OH, -OC1-C3alkyl, -OC1-C3haloalkyl, -SC1-C3alkyl, -S(=O)C1- C3alkyl, -S(=O)2C1-C3alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -NH2, -NHC1- C3alkyl, -N(C1-C3alkyl)2, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, - C(=O)NHC1-C3alkyl, -C(=O)N(C1-C3alkyl)2, C1-C3alkyl, C1-C3haloalkyl, C1-C3deuteroalkyl, C1- C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl; or two R on the same atom form an oxo. [0075] In some embodiments of a compound of Formula (I), W is N. In some embodiments of a compound of Formula (I), W is CRW. [0076] In some embodiments of a compound of Formula (I), X is N. In some embodiments of a compound of Formula (I), X is CRX. [0077] In some embodiments of a compound of Formula (I), Y is N. In some embodiments of a compound of Formula (I), Y is CRY. [0078] In some embodiments of a compound of Formula (I), Z is N. In some embodiments of a compound of Formula (I), Z is CRZ. [0079] In some embodiments of a compound of Formula (I), the compound is a compound of Formula (Ia):
Figure imgf000019_0001
[0080] In some embodiments of a compound of Formula (I), the compound is a compound of Formula (Ib):
Figure imgf000019_0002
Attorney Docket No.57547-724.601 [0081] In some embodiments of a compound of Formula (I), the compound is a compound of Formula (Ic):
Figure imgf000020_0001
Formula (Ic). [0082] In some embodiments of a compound of Formula (I), the compound is a compound of Formula (Id):
Figure imgf000020_0002
[0083] In some embodiments of a compound of Formula (I) or (Ia)-(Id), Ring A is aryl or heteroaryl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), Ring A is heteroaryl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), Ring A is 6-membered heteroaryl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), Ring A is pyrazinyl. [0084] In some embodiments of a compound of Formula (I) or (Ia)-(Id), each R1 is independently deuterium, halogen, -CN, -OH, -ORa, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), each R1 is independently -CN. [0085] In some embodiments of a compound of Formula (I) or (Ia)-(Id), n is 0-2. In some embodiments of a compound of Formula (I) or (Ia)-(Id), n is 1 or 2. In some embodiments of a compound of Formula (I) or (Ia)-(Id), n is 0 or 1. In some embodiments of a compound of Formula (I) or (Ia)-(Id), n is 0. In some embodiments of a compound of Formula (I) or (Ia)-(Id), n is 1. In some embodiments of a compound of Formula (I) or (Ia)-(Id), n is 2. In some embodiments of a compound of Formula (I) or (Ia)-(Id), n is 3. [0086] In some embodiments of a compound of Formula (I) or (Ia)-(Id), R2 is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), R2 is hydrogen. [0087] In some embodiments of a compound of Formula (I) or (Ia)-(Id), R3 is hydrogen, deuterium, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), R3 is hydrogen. Attorney Docket No.57547-724.601 [0088] In some embodiments of a compound of Formula (I) or (Ia)-(Id), R4 is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), R4 is hydrogen. [0089] In some embodiments of a compound of Formula (I) or (Ia)-(Id), L is -O-. In some embodiments of a compound of Formula (I) or (Ia)-(Id), L is -NR5-. [0090] In some embodiments of a compound of Formula (I) or (Ia)-(Id), R5 is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), R5 is hydrogen. [0091] In some embodiments of a compound of Formula (I) or (Ia)-(Id), RW is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R. In some embodiments of a compound of Formula (I) or (Ia)-(Id), RW is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl and heterocycloalkyl is optionally substituted with one or more R. In some embodiments of a compound of Formula (I) or (Ia)-(Id), RW is hydrogen, deuterium, halogen, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), RW is hydrogen, halogen, -OH, -ORa, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), RW is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), RW is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), RW is hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), RW is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), RW is hydrogen or halogen. In some embodiments of a compound of Formula (I) or (Ia)-(Id), RW is hydrogen. [0092] In some embodiments of a compound of Formula (I) or (Ia)-(Id), RW is hydrogen, halogen, -OH, - ORa, or -NRcRd. In some embodiments of a compound of Formula (I) or (Ia)-(Id), RW is hydrogen, -OH, or - ORa. In some embodiments of a compound of Formula (I) or (Ia)-(Id), RW is -OH or -ORa. In some embodiments of a compound of Formula (I) or (Ia)-(Id), RW is halogen or -ORa. [0093] In some embodiments of a compound of Formula (I) or (Ia)-(Id), RX is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R. In some embodiments of a compound of Formula (I) or (Ia)-(Id), RX is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R. In some embodiments of a compound of Formula (I) or (Ia)-(Id), RX is hydrogen, deuterium, halogen, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), RX is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl. Attorney Docket No.57547-724.601 In some embodiments of a compound of Formula (I) or (Ia)-(Id), RX is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), RX is hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), RX is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), RX is hydrogen or halogen. In some embodiments of a compound of Formula (I) or (Ia)-(Id), RX is hydrogen. [0094] In some embodiments of a compound of Formula (I) or (Ia)-(Id), RY is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R. In some embodiments of a compound of Formula (I) or (Ia)-(Id), RY is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R. In some embodiments of a compound of Formula (I) or (Ia)-(Id), RY is hydrogen, deuterium, halogen, -OH, -ORa, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R. In some embodiments of a compound of Formula (I) or (Ia)-(Id), RY is hydrogen, halogen, -OH, - ORa, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, or cycloalkyl; wherein the alkyl and cycloalkyl is optionally substituted with one or more R. In some embodiments of a compound of Formula (I) or (Ia)-(Id), RY is hydrogen, deuterium, halogen, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), RY is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), RY is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), RY is hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), RY is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), RY is hydrogen or halogen. In some embodiments of a compound of Formula (I) or (Ia)-(Id), RY is hydrogen. In some embodiments of a compound of Formula (I) or (Ia)-(Id), RY is C1-C6alkyl. [0095] In some embodiments of a compound of Formula (I) or (Ia)-(Id), RZ is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R. In some embodiments of a compound of Formula (I) or (Ia)-(Id), RZ is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R. In some embodiments of a compound of Formula (I) or (Ia)-(Id), RZ is hydrogen, deuterium, halogen, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), RZ is hydrogen, deuterium, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), RZ is hydrogen, halogen, C1-C6alkyl, or Attorney Docket No.57547-724.601 C1-C6haloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), RZ is hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), RZ is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), RZ is hydrogen or halogen. In some embodiments of a compound of Formula (I) or (Ia)-(Id), RZ is hydrogen. In some embodiments of a compound of Formula (I) or (Ia)-(Id), RZ is C1-C6alkyl. [0096] In some embodiments of a compound of Formula (I) or (Ia)-(Id), Ring B is cycloalkyl or heterocycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), Ring B is cycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), Ring B is monocyclic cycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), Ring B is bicyclic cycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), Ring B is monocyclic 4- to 6-membered cycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), Ring B is monocyclic 4- to 5-membered cycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), Ring B is monocyclic 4- membered cycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), Ring B is monocyclic 5-membered cycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), Ring B is monocyclic 6-membered cycloalkyl. [0097] In some embodiments of a compound of Formula (I) or (Ia)-(Id), each R6 is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), each R6 is independently -OH, -ORa, or -NRcRd. In some embodiments of a compound of Formula (I) or (Ia)-(Id), each R6 is independently -NRcRd. [0098] In some embodiments of a compound of Formula (I) or (Ia)-(Id), m is 0. In some embodiments of a compound of Formula (I) or (Ia)-(Id), m is 1. In some embodiments of a compound of Formula (I) or (Ia)- (Id), m is 2. In some embodiments of a compound of Formula (I) or (Ia)-(Id), m is 3. In some embodiments of a compound of Formula (I) or (Ia)-(Id), m is 0 or 1. In some embodiments of a compound of Formula (I) or (Ia)-(Id), m is 0-2. In some embodiments of a compound of Formula (I) or (Ia)-(Id), m is 1 or 2. [0099] In some embodiments of a compound disclosed herein, each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, C1-C6alkylene(cycloalkyl), or C1-C6alkylene(heterocycloalkyl); wherein each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Ra is independently C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, heterocycloalkyl, C1-C6alkylene(cycloalkyl), or C1-C6alkylene(heterocycloalkyl); wherein each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Ra is independently C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently Attorney Docket No.57547-724.601 optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Ra is independently C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound disclosed herein, each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, or C1-C6aminoalkyl. In some embodiments of a compound disclosed herein, each Ra is independently C1-C6alkyl or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each Ra is independently C1-C6alkyl. [00100] In some embodiments of a compound disclosed herein, each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, C1-C6alkylene(cycloalkyl), or C1-C6alkylene(heterocycloalkyl); wherein each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, heterocycloalkyl, C1-C6alkylene(cycloalkyl), or C1-C6alkylene(heterocycloalkyl); wherein each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound disclosed herein, each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, or C1-C6aminoalkyl. In some embodiments of a compound disclosed herein, each Rb is independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each Rb is independently hydrogen or C1-C6alkyl. In some embodiments of a compound disclosed herein, each Rb is hydrogen. In some embodiments of a compound disclosed herein, each Rb is independently C1-C6alkyl. [00101] In some embodiments of a compound disclosed herein, each Rc and Rd are independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, C1-C6alkylene(cycloalkyl), or C1-C6alkylene(heterocycloalkyl); wherein each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rc and Rd are independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, heterocycloalkyl, C1-C6alkylene(cycloalkyl), or C1-C6alkylene(heterocycloalkyl); wherein each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rc and Rd are independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and Attorney Docket No.57547-724.601 heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rc and Rd are independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rc and Rd are independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound disclosed herein, each Rc and Rd are independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, or C1-C6aminoalkyl. In some embodiments of a compound disclosed herein, each Rc and Rd are independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each Rc and Rd are independently hydrogen or C1-C6alkyl. In some embodiments of a compound disclosed herein, each Rc and Rd are hydrogen. In some embodiments of a compound disclosed herein, each Rc and Rd are independently C1-C6alkyl. In some embodiments of a compound disclosed herein, Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R. [00102] In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, - OH, -OC1-C3alkyl, -OC1-C3haloalkyl, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, -C(=O)C1-C3alkyl, - C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1-C3alkyl)2, C1-C3alkyl, C1- C3haloalkyl, C1-C3deuteroalkyl, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -OC1-C3alkyl, -OC1-C3haloalkyl, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, C1-C3alkyl, C1-C3haloalkyl, C1-C3deuteroalkyl, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -OC1-C3alkyl, -OC1-C3haloalkyl, -NH2, C1-C3alkyl, C1- C3haloalkyl, C1-C3deuteroalkyl, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -OC1-C3alkyl, -OC1-C3haloalkyl, -NH2, C1-C3alkyl, or C1-C3haloalkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, C1-C3alkyl, C1-C3haloalkyl, C1-C3deuteroalkyl, C1-C3hydroxyalkyl, C1- C3aminoalkyl, or C1-C3heteroalkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -NH2, C1-C3alkyl, or C1- C3haloalkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, C1-C3alkyl, or C1-C3haloalkyl; or two R on the same atom form an oxo. [00103] In some embodiments of a compound disclosed herein, the compound is selected from a compound of Table 1 or table 2: Attorney Docket No.57547-724.601 TABLE 1
Figure imgf000026_0001
Attorney Docket No.57547-724.601
Figure imgf000027_0001
Attorney Docket No.57547-724.601
Figure imgf000028_0001
Attorney Docket No.57547-724.601
Figure imgf000029_0001
Attorney Docket No.57547-724.601
Figure imgf000030_0001
Attorney Docket No.57547-724.601
Figure imgf000031_0001
Attorney Docket No.57547-724.601
Figure imgf000032_0001
Attorney Docket No.57547-724.601
Figure imgf000033_0001
Attorney Docket No.57547-724.601
Figure imgf000034_0001
Attorney Docket No.57547-724.601
Figure imgf000035_0001
Attorney Docket No.57547-724.601
Figure imgf000036_0001
Attorney Docket No.57547-724.601
Figure imgf000037_0001
Attorney Docket No.57547-724.601
Figure imgf000038_0001
Attorney Docket No.57547-724.601
Figure imgf000039_0001
Attorney Docket No.57547-724.601
Figure imgf000040_0001
Attorney Docket No.57547-724.601
Figure imgf000041_0001
Attorney Docket No.57547-724.601
Figure imgf000042_0001
or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. Attorney Docket No.57547-724.601 Table 2
Figure imgf000043_0001
Attorney Docket No.57547-724.601
Figure imgf000044_0001
Attorney Docket No.57547-724.601
Figure imgf000045_0003
or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. [00104] In some embodiments, the CHK1 inhibitor is compound
Figure imgf000045_0001
pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. In some embodiments, the CHK1 inhibitor is compound
Figure imgf000045_0002
Further Forms of Compounds Disclosed Herein Isomers/Stereoisomers [00105] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the Attorney Docket No.57547-724.601 corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent. Labeled compounds [00106] In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds described herein, or a solvate, tautomer, or stereoisomer thereof, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as 2H, 3H, 13C, 14C, l5N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. Compounds described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this disclosure. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e., 2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically labeled compound or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof is prepared by any suitable method. [00107] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. Attorney Docket No.57547-724.601 Pharmaceutically acceptable salts [00108] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions. [00109] In some embodiments, the compounds described herein possess acidic or basic groups and therefor react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed. [00110] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid, or inorganic base, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3- phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylenesulfonate. [00111] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct- 2-ene-1-carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3- phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. Attorney Docket No.57547-724.601 [00112] In some embodiments, those compounds described herein that comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(C1-4 alkyl)4, and the like. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like of the tetrazole. [00113] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen- containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization. Solvates [00114] In some embodiments, the compounds described herein exist as solvates. The disclosure provides for methods of treating diseases by administering such solvates. The disclosure further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions. [00115] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. Tautomers [00116] In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Preparation of the Compounds [00117] The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature. [00118] Suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Attorney Docket No.57547-724.601 “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House, “Modern Synthetic Reactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif.1972; T. L. Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts, Methods, Starting Materials”, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3- 527-29871-1; Patai, S. “Patai’s 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., “Intermediate Organic Chemistry” 2nd Edition (1993) Wiley- Interscience, ISBN: 0-471-57456-2; “Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann’s Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over 55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes. [00119] Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line. Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth “Handbook of Pharmaceutical Salts,” Verlag Helvetica Chimica Acta, Zurich, 2002. [00120] Compounds of Formula I may be synthesized as described in the general Schemes I-VI below. [00121] In some embodiments, compounds of Formula I may be prepared via metal-catalyzed carbon- carbon bond forming cross-coupling reactions. In some embodiments, appropriate cross-coupling reactions include the Suzuki, Negishi, Stille, Kumada or Heck reactions. In a particular embodiment, the cross- coupling reaction is a Suzuki reaction between an appropriately substituted aryl bromide and an appropriately substituted arylboronic acid or arylboronic ester. Attorney Docket No.57547-724.601 Scheme I
Figure imgf000050_0001
[00122] The synthesis of appropriately substituted intermediate building blocks for Suzuki reactions is described in Scheme I. An aryl bromide of formula I-3 may be synthesized by a reaction between an appropriately substituted compound of formula I-1, where L represents a nucleophilic atom, and a compound of formula I-2, where LG represents a suitable leaving group. In some embodiments of I-1, L is oxygen or an optionally substituted nitrogen atom. In some embodiments, L is oxygen. In some embodiments of I-2, LG is an alkyl halide such as bromine or iodine; in other embodiments, LG may be oxygen. In some embodiments of I-2 where LG is oxygen, it may be activated to increase its reactivity as a leaving group. Such activation may occur via synthesis of an alkylsulfonate, such as a mesylate, tosylate, nosylate, brosylate, or other sulfonate known to one having ordinary skill in the art. Such alkylsulfonates may be synthesized from the corresponding alkyl alcohol by reaction with an appropriate sulfonyl chloride or sulfonic anhydride, such as methanesulfonyl chloride or methanesulfonic anhydride. Such sulfonylation reactions typically occur in a solvent such as dichloromethane, tetrahydrofuran, or toluene, in the presence of a base such as sodium hydride, triethylamine, diisopropylethylamine, pyridine, potassium carbonate or another base known to one having ordinary skill in the art. Reactions typically proceed at sub-ambient or ambient temperature, for example between 0-25 °C. Reactions are typically complete within 1-18 hours and the product may be purified or used directly without purification, if it is unstable to purification. [00123] In other embodiments, an aryl bromide of formula I-3 may be synthesized by a reaction with a compound of formula I-2 where LG represents an alcohol that has been activated in situ without isolation, as in a Mitsunobu reaction. In a Mitsunobu reaction, activation of the alcohol occurs in the presence of an appropriate azodicarboxylate, such as diethyl azodicarboxylate or diisopropyl azodicarboxylate, and an appropriate phosphine, such as triphenylphosphine. In some embodiments the activation may be achieved using an appropriate phosphorane, such as (tributylphosphoranylidene)acetonitrile (CMBP) or (trimethylphosphoranylidene)acetonitrile (CMMP). Mitsunobu reactions are typically carried out in a Attorney Docket No.57547-724.601 solvent such as dichloromethane, tetrahydrofuran, or toluene, and typically occur at ambient temperature or at elevated temperature from 25 to 110 °C. Reactions are typically complete within 1-18 hours. [00124] In some embodiments, a compound of formula I-3 may be synthesized by a reaction between a compound of formula I-4 and a compound of formula I-5. In some embodiments of I-4, LG is a halide such as fluorine, chlorine, bromine, or iodine. In some embodiments of I-5, L is nitrogen or oxygen. In some embodiments of I-5, L is oxygen. The reaction between I-4 and I-5 may proceed under cross-coupling conditions, catalyzed by an appropriate transition metal, or by nucleophilic aromatic substitution. In some embodiments, the nucleophilic aromatic substitution reaction occurs when LG of I-4 is fluorine or chlorine and L of I-5 is oxygen. In some embodiments, LG of I-4 is fluorine. When L of I-5 is oxygen, nucleophilic aromatic substitution reactions typically occur in the presence of a strong base such as sodium hydride, lithium diisopropylamine, lithium bis(trimethylsilyl)amide, or an appropriate base known to one having ordinary skill in the art. Such nucleophilic aromatic substitution reactions typically occur in a solvent such as tetrahydrofuran, dimethyl sulfoxide, 1,4-dioxane, N,N-dimethylformamide or N,N-dimethylacetamide. Such nucleophilic aromatic substitution reactions typically occur at reduced temperature, such as -78 °C or 0 °C; in some embodiments, the reaction may occur at ambient temperature or elevated temperature, from 25 to 110 °C. Reactions are typically complete within 1-18 hours. [00125] A compound of formula I-8 may be synthesized from an appropriately substituted aminopyrazole of formula I-6 via reaction with an appropriately substituted compound of formula I-7, where ring A contains a suitable leaving group LG. In some embodiments, such a leaving group may be a chloride, bromide, iodide or activated alcohol such as a mesylate or tosylate. In some embodiments, ring A may be aromatic and the leaving group may be an aryl chloride. In some embodiments, the reaction may occur in the presence of a suitable base such as sodium hydride, triethylamine, diisopropylethylamine, pyridine, potassium carbonate or another base known to one having ordinary skill in the art. Such reactions typically occur in a solvent such as tetrahydrofuran, dimethyl sulfoxide, 1,4-dioxane, N,N-dimethylformamide or N,N-dimethylacetamide. Reactions may occur at ambient temperature or at elevated temperatures from 60- 110 °C. Reactions are typically complete within 1-18 hours. [00126] A pyrazoleboronic ester compound of formula I-9 may be synthesized from a compound of formula I-8 by reaction with an appropriate borylating agent. In some embodiments, the compound of formula I-9 may contain a mixture of pyrazoleboronic ester and pyrazoleboronic acid. In some embodiments, the compound of formula I-9 may contain mostly pyrazoleboronic acid. In some embodiments, the compound of formula I-9 is synthesized by a Miyaura borylation reaction and the appropriate borylating agent is bis(pinacolato)diboron. The Miyaura borylation reaction is carried out in the presence of a palladium catalyst in complex with a phosphine ligand, such as tetrakis(triphenylphosphine)palladium, bis(diphenylphosphino)ferrocene]dichloropalladium(II), or another catalyst system known to one having ordinary skill in the art. Such reactions typically proceed in the presence of a suitable base, such as sodium carbonate, potassium carbonate, potassium tert-butoxide, sodium acetate, potassium acetate, or another base known to one having ordinary skill in the art. The Miyaura Attorney Docket No.57547-724.601 reaction is typically carried out in a solvent such as 1,4-dioxane, ethyl acetate, or toluene at elevated temperature, typically between 60-110 °C. Reactions are typically complete within 6-24 hours. Scheme II
Figure imgf000052_0001
[00127] As shown in Scheme II, a compound of Formula I may be synthesized by a Suzuki reaction between a compound of formula I-3 and a compound of formula I-9. Such a reaction will typically occur in the presence of a palladium catalyst in complex with a phosphine ligand, such as tetrakis(triphenylphosphine)palladium, bis(diphenylphosphino)ferrocene]dichloropalladium(II), RuPhos palladacycle G3, or another catalyst system known to one having ordinary skill in the art. Such reactions typically proceed in the presence of a suitable base, such as sodium carbonate, potassium carbonate, potassium tert-butoxide, sodium acetate, potassium acetate, or another base known to one having ordinary skill in the art. The Suzuki reaction is typically carried out in a solvent such as 1,4-dioxane, ethyl acetate, or toluene. Water is used as an additive in all cases, independent of solvent choice. The reaction will occur at elevated temperature, typically between 60-110 °C. Reactions are typically complete within 6-24 hours. Scheme III
Figure imgf000052_0002
Attorney Docket No.57547-724.601 [00128] In an alternative embodiment, as shown in Scheme III, a cyanoketone intermediate of formula III- 5 may be synthesized from a compound of formula I-3. In some embodiments, a compound of formula I-3 may be converted to a vinyl enol ether of formula III-1. Such a reaction may occur between a compound of formula I-3 and an appropriately substituted vinyl building block under palladium-catalyzed cross-coupling conditions. In some embodiments, the cross-coupling reaction may be a Suzuki or a Stille reaction. In some embodiments, the vinyl building block will be substituted as a boronic ester, a boronic acid, a trifluoroborate or an alkylstannane. Such cross-coupling reactions will typically occur in the presence of a palladium catalyst in complex with a phosphine ligand, such as tetrakis(triphenylphosphine)palladium, bis(diphenylphosphino)ferrocene]dichloropalladium(II), RuPhos palladacycle G3, or another catalyst system known to one having ordinary skill in the art. Such reactions typically proceed in the presence of a suitable base, such as sodium carbonate, potassium carbonate, potassium tert-butoxide, sodium acetate, potassium acetate, or another base known to one having ordinary skill in the art. The cross-coupling reaction is typically carried out in a solvent such as 1,4-dioxane, ethyl acetate, or toluene. The reaction will occur at elevated temperature, typically between 60-110 °C. Reactions are typically complete within 6-24 hours. A compound of formula III-1 may be purified or used directly in the next step without purification, as it may be unstable to standard purification conditions. [00129] A compound of formula III-1 may be converted to a ketone of formula III-2 via acidic hydrolysis. Such a reaction is typically carried out using a strong Brønsted acid, such as hydrochloric acid, in aqueous media. The reaction may take place at sub-ambient, ambient, or elevated temperature, typically between 0- 80 °C. In some embodiments, a ketone of formula III-2 may be converted to an enamine compound of formula III- 3 by reaction with N,N-dimethylformamide dimethyl acetal. In some embodiments, this reaction occurs in N,N-dimethylformamide as the solvent at elevated temperature, typically between 60-110 °C. Reactions are typically complete in 2-24 hours. In some embodiments a compound of formula III-3 may be purified, or in some embodiments it may be used directly in the next step without purification, as it may be unstable to standard purification conditions. [00130] A compound of formula III-3 may be converted to an isoxazole of formula III-4 by reaction with hydroxylamine. In some embodiments this reaction may employ hydroxylamine as free base or as a salt. In some embodiments the reaction is carried out using hydroxylamine hydrochloride. The reaction typically proceeds at ambient or elevated temperature between 25-110 °C in an appropriate solvent such as methanol, ethanol, isopropanol, n-butanol, tert-butanol, or toluene. The reaction is typically complete within 2-24 hours. [00131] An isoxazole of formula III-4 may be converted to a cyanoketone of formula III-5 by treatment with an appropriate base, such as lithium hydroxide, sodium hydroxide or potassium hydroxide. In some embodiments, the base is potassium hydroxide. The reaction will typically proceed in an appropriate solvent such as methanol, ethanol, isopropanol, n-butanol, tert-butanol, or toluene. The reaction may be carried out at ambient or elevated temperature between 25-110 °C, over a reaction time of 1-8 hours. Attorney Docket No.57547-724.601 Scheme IV
Figure imgf000054_0001
[00132] In an alternative embodiment, a cyanoketone of formula III-5 may be synthesized from an ester as shown in Scheme IV. An ester of formula IV-5 may be synthesized from appropriate building blocks of formula IV-1, where L represents a nucleophilic atom, and a compound of formula IV-2, where LG represents a suitable leaving group. In some embodiments of IV-1, L is oxygen or an optionally substituted nitrogen atom. In some embodiments, L is oxygen. In some embodiments of IV-2, LG is an alkyl halide such as bromine or iodine; in other embodiments, it may be oxygen. In some embodiments of IV-2 where LG is oxygen, it may be activated to increase its reactivity as a leaving group. Such activation may occur via synthesis of an alkylsulfonate, such as a mesylate, tosylate, nosylate, brosylate, or other sulfonate known to one having ordinary skill in the art. Such alkylsulfonates may be synthesized from the corresponding alkyl alcohol by reaction with an appropriate sulfonyl chloride or sulfonic anhydride, such as methanesulfonyl chloride or methanesulfonic anhydride. Such sulfonylation reactions typically occur in a solvent such as dichloromethane, tetrahydrofuran, or toluene, in the presence of a base such as sodium hydride, triethylamine, diisopropylethylamine, pyridine, potassium carbonate or another base known to one having ordinary skill in the art. Reactions typically proceed at low temperature or at ambient temperature, for example at 0 °C. Reactions are typically complete within 1-18 hours and the product may be purified or used directly without purification. [00133] In other embodiments an ester of formula IV-5 may be synthesized by a reaction with a compound of formula IV-2, where LG represents an alcohol that has been activated in situ without isolation, as in a Mistunobu reaction. Activation of the alcohol occurs in the presence of an appropriate azodicarboxylate, such as diethyl azodicarboxylate or diisopropyl azodicarboxylate, and an appropriate phosphine, such as triphenylphosphine. In some embodiments the activation may be achieved using an appropriate phosphorane, such as (tributylphosphoranylidene)acetonitrile (CMBP) or (trimethylphosphoranylidene)acetonitrile (CMMP). Mitsunobu reactions are typically carried out in a solvent such as dichloromethane, tetrahydrofuran, or toluene, and typically occur at ambient temperature or at elevated temperature, from 25 to 110 °C. Reactions are typically complete within 1-18 hours. Attorney Docket No.57547-724.601 [00134] In some embodiments, a compound of formula IV-5 may be synthesized from a compound of formula IV-3 and a compound of formula IV-4. In some embodiments of IV-3, LG is a halide such as fluorine, chlorine, bromine, or iodine. In some embodiments of IV-4, L is nitrogen or oxygen. In some embodiments of I-5, L is oxygen. The reaction between IV-3 and IV-4 may proceed under cross-coupling conditions, catalyzed by an appropriate transition metal, or by nucleophilic aromatic substitution. In some embodiments, the nucleophilic aromatic substitution reaction occurs when LG of IV-3 is fluorine or chlorine and L is oxygen. In some embodiments, LG of IV-3 is fluorine. When L is oxygen, nucleophilic aromatic substitution reactions typically occur in the presence of a strong base such as sodium hydride, lithium diisopropylamine, lithium bis(trimethylsilyl)amide, or an appropriate base known to one having ordinary skill in the art. Such nucleophilic aromatic substitution reactions typically occur in a solvent such as tetrahydrofuran, dimethyl sulfoxide, 1,4-dioxane, N,N-dimethylformamide or N,N-dimethylacetamide. Such nucleophilic aromatic substitution reactions typically occur at reduced temperature, such as -78 °C or 0 °C; in some embodiments, the reaction may occur at ambient temperature or elevated temperature such as 100 °C. Reactions are typically complete within 1-18 hours. [00135] An ester of formula IV-5 may be converted to a cyanoketone of formula III-5 in a reaction with the carbanion of an optionally substituted nitrile. In some embodiments, the nitrile is acetonitrile. In such a reaction, acetonitrile is deprotonated with a suitable strong base, such as sodium hydride, potassium tert- butoxide, n-butyllithium, sec-butyllithium, lithium diisopropylamine, lithium bis(trimethylsilyl)amide, or an appropriate base known to one having ordinary skill in the art. The reaction may be carried out using acetonitrile as the solvent, or in another appropriate solvent such as tetrahydrofuran or diethyl ether. In some embodiments, the solvent is tetrahydrofuran. The reaction typically occurs at reduced temperature, such as - 78 °C or 0 °C; in some embodiments, the reaction may occur at ambient temperature. The reaction is typically complete within 1-18 hours. Scheme V
Figure imgf000055_0001
[00136] In some embodiments, a cyanoketone of formula III-5 may be converted to an aminopyrazole of formula V-I as shown in Scheme V. Such a reaction may be performed using an optionally substituted hydrazine to form the aminopyrazole. In some embodiments, the optionally substituted hydrazine is hydrazine or hydrazine monohydrate. The reaction is typically carried out in the presence of a Brønsted acid, such as acetic acid or hydrochloric acid. The reaction is carried out in an appropriate solvent such as methanol, ethanol, isopropanol, n-butanol, tert-butanol, or toluene. The reaction may be carried out at ambient or elevated temperature between 25-110 °C. The reaction is typically complete within 2-18 hours. Attorney Docket No.57547-724.601 [00137] A compound of formula V-I may react with an appropriately substituted compound of formula I- 7, where ring A contains a suitable leaving group LG, to give a compound of Formula I. In some embodiments, such a leaving group LG may be a chloride, bromide, iodide or activated alcohol such as a mesylate or tosylate. In some embodiments, ring A may be aromatic and the leaving group may be an aryl chloride. In some embodiments, the reaction may occur in the presence of a suitable base such as sodium hydride, triethylamine, diisopropylethylamine, pyridine, potassium carbonate or another base known to one having ordinary skill in the art. Such reactions typically occur in a solvent such as tetrahydrofuran, dimethyl sulfoxide, 1,4-dioxane, N,N-dimethylformamide or N,N-dimethylacetamide. Reactions may occur at ambient temperature or at elevated temperatures from 60-110 °C. Reactions are typically complete within 1- 18 hours. [00138] In some embodiments, the reaction between a compound of formula V-I and a compound of formula I-7 may be carried out in the presence of an appropriate transition metal catalyst. In some embodiments the transition metal is a copper catalyst as in an Ullmann reaction. In some embodiments the catalyst is a palladium complex as in a Buchwald reaction. Such cross-coupling reactions will typically occur in the presence of a palladium catalyst in complex with a phosphine ligand, such as tetrakis(triphenylphosphine)palladium, bis(diphenylphosphino)ferrocene]dichloropalladium(II), BrettPhos palladacycle G3, or another catalyst system known to one having ordinary skill in the art. Such reactions typically proceed in the presence of a suitable base, such as sodium carbonate, potassium carbonate, potassium tert-butoxide, sodium acetate, potassium acetate, triethylamine or another base known to one having ordinary skill in the art. The reaction is typically carried out in a solvent such as 1,4-dioxane or toluene. The reaction will occur at elevated temperature, typically between 60-110 °C. Reactions are typically complete within 6-24 hours. Scheme VI
Figure imgf000056_0001
[00139] One having ordinary skill in the art will recognize that at times, it may be necessary to mask a reactive functional group or groups on a molecule with an appropriate protecting group. In some embodiments, the protecting group or groups may be carried through several synthetic steps. In some embodiments, the protecting group or groups may all be removed in a single global deprotection step. In some embodiments, the protecting group or groups will mask amine functional groups. In some Attorney Docket No.57547-724.601 embodiments, the protecting group or groups will be tert-butylcarbamate groups. In some embodiments, the tert-butylcarbamate protected amine will be on ring B. A tert-butylcarbamate protecting group is typically removed via treatment with a Brønsted acid, such as trifluoroacetic acid, hydrogen chloride or hydrochloric acid. Typical cleavage reactions occur in an appropriate solvent such as ethyl acetate, 1,4-dioxane, diethyl ether or dichloromethane. Reactions typically proceed at sub-ambient or ambient temperature but may proceed at elevated temperature, typically between 0-60 °C. A compound of Formula I prepared under such conditions may be purified by standard methods including chromatography or recrystallization. In some embodiments the compound of Formula I is isolated directly from the deprotection reaction as a salt. In some embodiments the compound of Formula I is purified by preparative HPLC using an appropriate column and eluent conditions. Pharmaceutical Compositions [00140] In certain embodiments, the compound described herein is administered as a pure chemical. In some embodiments, the compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)). [00141] Accordingly, provided herein is a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable excipient. [00142] In certain embodiments, the compound provided herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1% of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method. [00143] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient’s disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as increased overall response rate, increased duration of response, more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient. Attorney Docket No.57547-724.601 [00144] In some embodiments, the pharmaceutical composition is formulated for oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, intrapulmonary, intradermal, intrathecal, epidural, or intranasal administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In some embodiments, the pharmaceutical composition is formulated for intravenous injection, oral administration, inhalation, nasal administration, topical administration, or ophthalmic administration. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated for intravenous injection. In some embodiments, the pharmaceutical composition is formulated as a tablet, a pill, a capsule, a liquid, an inhalant, a nasal spray solution, a suppository, a suspension, a gel, a colloid, a dispersion, a suspension, a solution, an emulsion, an ointment, a lotion, an eye drop, or an ear drop. In some embodiments, the pharmaceutical composition is formulated as a tablet. [00145] Suitable doses and dosage regimens are determined by conventional range-finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of the compound disclosed herein. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. Methods [00146] Disclosed herein is a method of treating a tumor or tumor cells, comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a cancer-targeted therapeutic agent to a subject identified as having the tumor or tumor cells, wherein the tumor or tumor cells comprise a gene amplification, whereby growth or size of the tumor or growth or number of tumor cells is reduced. [00147] Also disclosed herein is a method of delaying resistance to a cancer-targeted therapeutic agent, the method comprising: administering a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, to a subject in an amount sufficient to induce replication stress in tumor or tumor cells and administering a cancer-targeted therapeutic agent concurrently or subsequent to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. [00148] Disclosed herein are methods of treating a tumor or tumor cells in a subject, comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. In some cases, the subject has had one or more prior treatments with a first cancer- targeted therapeutic agent (also referred to herein as a “prior cancer-targeted therapeutic agent”) prior to treatment with a compound of Formula (I). In some cases, the compound of Formula (I) is administered in conjunction with the administration of a second cancer-targeted therapeutic agent (also referred to herein as a “selected cancer-targeted therapeutic agent”). [00149] Also disclosed herein is a method of treating a subject having a tumor or tumor cells that are non- responsive to a first (prior) cancer-targeted therapeutic agent comprising administering a compound of Attorney Docket No.57547-724.601 Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a second (selected) cancer-targeted therapeutic agent to the subject. [00150] Also disclosed herein is a method of provoking a response in a subject having a tumor or tumor cells that are non-responsive or have decreased responsiveness to a first (prior) cancer-targeted therapeutic agent comprising administering a Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the first (prior) cancer-targeted therapeutic agent to the subject. [00151] In some embodiments of a method disclosed herein, the cancer-targeted therapeutic agent is administered concurrent or subsequent to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. [00152] In some embodiments of a method disclosed herein, the first (prior) cancer-targeted therapeutic agent is administered concurrent or subsequent to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. [00153] In some embodiments of a method disclosed herein, the second (selected) cancer-targeted therapeutic agent is administered concurrent or subsequent to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. [00154] In some embodiments of a method disclosed herein, the cancer-targeted therapeutic agent is administered prior to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. [00155] In some embodiments of a method disclosed herein, the first (prior) cancer-targeted therapeutic agent is administered prior to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. [00156] In some embodiments of a method disclosed herein, the second (selected) cancer-targeted therapeutic agent is administered prior to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. [00157] In some embodiments of a method disclosed herein, the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is administered in an amount sufficient to induce replication stress in the tumor or tumor cells. [00158] In some embodiments of a method disclosed herein, the subject is identified as having the tumor or tumor cells comprising a gene amplification. [00159] In some embodiments of a method disclosed herein, the gene amplification is a focal gene amplification. [00160] In some embodiments of a method disclosed herein, the gene amplification is an ecDNA-derived amplification. [00161] In some embodiments of a method disclosed herein, the gene amplification is comprised on ecDNA or an HSR (homogeneously staining region). [00162] In some embodiments of a method disclosed herein, the cancer-targeted therapeutic agent is directed against a protein encoded by a gene contained within the gene amplification. Attorney Docket No.57547-724.601 [00163] In some embodiments of a method disclosed herein, the first (prior) cancer-targeted therapeutic agent is directed against a protein encoded by a gene contained within the gene amplification. [00164] In some embodiments of a method disclosed herein, the second (selected) cancer-targeted therapeutic agent is directed against a protein encoded by a gene contained within the gene amplification. [00165] In some embodiments of a method disclosed herein, the tumor or tumor cells comprise an ecDNA signature. [00166] In some embodiments of a method disclosed herein, cells comprised within the tumor or the tumor cells are ecDNA competent. For example, an ecDNA competent tumor cell may have detectable levels of ecDNA amplification or an ecDNA competent tumor cell has the capacity to generate ecDNA amplification in response to selective pressure such as targeted therapy (e.g., a cancer-targeted therapeutic agent described herein). [00167] In some embodiments of a method disclosed herein, treatment with both the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the cancer-targeted therapeutic agent has a greater effect or a longer duration of effect on reduction of one or more of tumor growth, tumor size, number of tumor cells or tumor metastasis as compared to the treatment with either the compound of Formula (I) or the cancer-targeted therapeutic agent when administered alone. [00168] In some embodiments of a method disclosed herein, treatment with both the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the first (prior) cancer-targeted therapeutic agent has a greater effect or a longer duration of effect on reduction of one or more of tumor growth, tumor size, number of tumor cells or tumor metastasis as compared to the treatment with either the compound of Formula (I) or the first (prior) cancer-targeted therapeutic agent when administered alone. [00169] In some embodiments of a method disclosed herein, treatment with both the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the second (selected) cancer-targeted therapeutic agent has a greater effect or a longer duration of effect on reduction of one or more of tumor growth, tumor size, number of tumor cells or tumor metastasis as compared to the treatment with either the compound of Formula (I) or the second (selected) cancer-targeted therapeutic agent when administered alone. [00170] In some embodiments of a method disclosed herein, the greater effect is a synergistic effect. [00171] In some embodiments of a method disclosed herein, the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and/or the cancer-targeted therapeutic agent is administered orally. [00172] In some embodiments of a method disclosed herein, the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and/or the first (prior) cancer- targeted therapeutic agent is administered orally. Attorney Docket No.57547-724.601 [00173] In some embodiments of a method disclosed herein, the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and/or the second (selected) cancer-targeted therapeutic agent is administered orally. [00174] In some embodiments of a method disclosed herein, the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and/or the cancer-targeted therapeutic agent is administered parentally. [00175] In some embodiments of a method disclosed herein, the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and/or the first (prior) cancer- targeted therapeutic agent is administered parentally. [00176] In some embodiments of a method disclosed herein, the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and/or the second (selected) cancer-targeted therapeutic agent is administered parentally. [00177] In some embodiments of a method disclosed herein, treatment comprises administering multiple doses of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and/or the cancer-targeted therapeutic agent over a treatment period.In some embodiments of a method disclosed herein, treatment comprises administering multiple doses of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and/or the first (prior) cancer-targeted therapeutic agent over a treatment period. [00178] In some embodiments of a method disclosed herein, treatment comprises administering multiple doses of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and/or the second (selected) cancer-targeted therapeutic agent over a treatment period. [00179] In some embodiments of a method disclosed herein, the gene amplification comprises an amplification of a gene selected from the group consisting of ABCB1, AKT, ALK, AR, BCL-2, BCR-ABL, BRAF, CDK4, CDK6, c-MET, EGFR, ER, ERBB3, ERRB2, AK, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, GR, HER2, HRAS, IGF1R, KIT, KRAS, MCL-1, MDM2, MDM4, MTOR, MYC, MYCL, MYCN, NRAS, NRG1, NTRK1, NTRK2, NTRK3, PDGFR, PIK3Cδ, PIK3CA/B, RET, and ROS1. [00180] In some embodiments of a method disclosed herein, the gene amplification comprises an amplification of a gene selected from the group consisting of CDK4, CDK6, c-MET, EGFR, FGFR1, FGFR2, FGFR3, and FGFR4. [00181] In some embodiments of a method disclosed herein, the first (prior) cancer-targeted therapeutic agent is different than the second (selected) cancer-targeted therapeutic agent. [00182] In some embodiments of a method disclosed herein, the first (prior) cancer-targeted therapeutic agent is the same as the second (selected) cancer-targeted therapeutic agent. [00183] In some embodiments of a method disclosed herein, the cancer-targeted therapeutic agent, the first (prior) cancer-targeted therapeutic agent, the second cancer-targeted therapeutic agent, or the selected cancer-targeted therapeutic agent is selected from the group consisting of abemaciclib, ado-trastuzumab emtansine, afatinib, alectinib, ALRN-6924, AMG232, AMG-510, apatinib, ARS-3248, AXL1717, AZD- Attorney Docket No.57547-724.601 3759, bevacizumab, BI 1701963, bortezomib, brigatinib, cabozantinib, capmatinib, ceritinib, cetuximab, CGM097, crizotinib, dabrafenib, dacomitinib, dasatinib, DS-3032b, encorafenib, entrectinib, ERAS-801, erdafitinib, erlotinib, everolimus, fam-trastuzumab deruxtecan, figitumumab, futibatinib, gefitinib, gossypol, HDM201, idasanutlin, imatinib, infigratinib, iniparib, lapatinib, larotrectinib, LEE011, lenvatinib, LGX818, lorlatinib, MEK162, MK-8242 SCH 900242, MRTX849, navitoclax, necitumumab, nilotinib, obatoclax, olaparib, OSI-906, osimertinib, palbociclib, panitumumab, PD-0332991, perisofine, pertuzumab, PF- 06873600, PF-07220060, PL225B, repotrectinib, ribociclib, RLY-4008, RO5045337, salinomycin, salirasib, SAR405838 MI-77301, sorafenib, sotorasib, sunitinib, tamoxifen, temsirolimus, tipifarnib, tivanitab, tofacitinib, trametinib, trastuzumab, tucatinib, UPR1376, VAL-083, vemurafenib, vemurafenib, vintafolide, and zoptarelin doxorubicin. [00184] In some embodiments of a method disclosed herein, the cancer-targeted therapeutic agent, the first (prior) cancer-targeted therapeutic agent, the second cancer-targeted therapeutic agent, or the selected cancer-targeted therapeutic agent is an inhibitor of EFGR, FGFR, CDK4/CDK6 or KRAS. In some cases, the EGFR inhibitor is erlotinib, gefitinib, or an analog thereof, or an antibody such as cetuximab, necitumumab, nimotuzumab, and panitumumab. In some cases, the FGFR inhibitor is erdafitinib, futibatinib, infigratinib, pemigatinib, RLY-4008, or an analog thereof. In some cases, the KRAS inhibitor is adagrasib, BI 1701963, sotorasib, or an analog thereof. In some cases, the CDK4/CDK6 inhibitor is abemaciclib, palbociclib, ribociclib, PF-06873600, PF-07220060, or an analog thereof. [00185] In some embodiments of a method disclosed herein, the cancer-targeted therapeutic agent, the first (prior) cancer-targeted therapeutic agent, the second cancer-targeted therapeutic agent, or the selected cancer-targeted therapeutic agent is an inhibitor of BRAF. In some embodiments, the BRAF inhibitors include ASN-003, AZ-304, AZ-628, DP-2874, EBI-907, EBI-945, GDC-0879, LYN 204, NMS-P285, NMS-P730, PF-04880594, TL-241, UAI-201,and UB-941. In some embodiments, the BRAF inhibitors include ABM-1310, agerafenib (RXDX-105), ARQ-736, BAL-3833, belvarafenib, BGB-3245, BI-882370, DAY101, lifirafenib, LUT-014, PF-07284890, PLX-8394, RX-208, VS-6766, and XL-281. In some embodiments, the BRAF inhibitors include dabrafenib, encorafenib, and vemurafenib. [00186] In some embodiments of a method disclosed herein, the cancer-targeted therapeutic agent, the first (prior) cancer-targeted therapeutic agent, the second cancer-targeted therapeutic agent, or the selected cancer-targeted therapeutic agent is an inhibitor of MDM2 or MDM4. In some embodiments, MDM2 inhibitors include AD-021.32, CYC700, DS-5272, MI-1061, MI-219, MI-43, MD-224, MK-8242, NU-8231, OM-301, PXN-527, Rigel-3, RO-2468, RO-5353, RO-5963, and SIL-43. In some embodiments, MDM2 inhibitors include ALRN-6924, APG-115, ASTX-295, ATSP-7041, BI-907828, CGM-097, idasanutlin, KRT-232 (AMG-232), MI-77301 (SAR405838, SAR299155), NVP-CGM097, RAIN-32 (milademetan), RG7112 (RO5045337), RG7388 (RG7775), serdemetan (JNJ-26854165), siremadlin, and UBX-0101. In some embodiments, the MDM4 inhibitors include 17AAG, 489-PXN, CTX1, FL-118, Inulanolide A, K-178, and SAH-p53-8. In some embodiments, the MDM4 inhibitors include APG-115, ALRN-6924, ATSP-7041, and BI-907828. Attorney Docket No.57547-724.601 [00187] In some embodiments of a method disclosed herein, the cancer-targeted therapeutic agent, the first (prior) cancer-targeted therapeutic agent, the second cancer-targeted therapeutic agent, or the selected cancer-targeted therapeutic agent is an inhibitor of MET. In some embodiments, the MET small molecule inhibitors such as ABP-1130, BPI-1831, BPI-2021, BYON-3521, CG-203306, CX-1003, Debio-1144, EMD-94283, EMT-100, EMT-101, HE-003, LMV-12, LS-177, NX-125, OMO-2, PF-4254644, PRX-MET, PTX-2173, QBH-196, RP-1400, SAB-Y14, SAR-125844, SGX-126, SYD-3521, WXSH-0011, X-379, and XL-265, and anti-MET antibodies such as ABX-900, GB-263, FS-101, LY-3164530, LY-3343544, PMC- 002, and SAIT-301. In some embodiments, the MET small molecule inhibitors such as ABN-401, ABT-700, AMG-208, AMG-337, ARGX-111, BAY-85-3474, BMS-817378, bozitinib, BPI-9016M, glumetinib, golvatinib tartrate, GST-HG161, HQP-8361, I-020, JNJ-38877605, kanitinib, merestinib, MK-2461, MK- 8033, OMO-1, pamufetinib, S-49076, savolitinib, SPH-3348, tivantinib, SAR-125844, SCR-1515, and TPX- 0022, and anti-MET antibodies such as APL-101, CKD-702, EMB-01, EMI-137, ficlatuzumab, HLX-55, HS-10241, MCLA-129, MT-8633, NOV-1105, RC-108, REGN-5093, SHR-A1403, Sym-015, telisotuzumab vedotin. In some embodiments, the MET small molecule inhibitors such as amivantamab, capmatinib, crizotinib, and tepotinib. [00188] In some embodiments of a method disclosed herein, the cancer-targeted therapeutic agent, the first (prior) cancer-targeted therapeutic agent, the second cancer-targeted therapeutic agent, or the selected cancer-targeted therapeutic agent is an inhibitor of CDK4/6. In some embodiments, the CDK4/6 inhibitors include AG-122275, AM-5992, AU2-94, IIIM-985, IIIM-290, GW-491619, HEC-80797, MM-D37K, MS- 140, NP-102, QHRD-110, R-547, RGB-286199, RGT-419B, riviciclib, RO-0505124, THR-53, THR-79, TQB-3303, TY-302, VS2-370, XH-30002, and WXWH-0240. In some embodiments, the CDK4/6 inhibitors include auceliciclib, AT-7519, BEBT-209, BPI-1178, BPI-16350, CS-3002, fascaplysin, FCN-437, FN- 1501, GLR-2007, HS-10342, lerociclib, milciclib maleate, NUV-422, ON-123300, PF-06842874, PF- 06873600, PF-07220060, SHR-6390, TQB-3616, TY-302, voruciclib, and XZP-3287. In some embodiments, the CDK4/6 inhibitors include abemaciclib, palbociclib, ribociclib, and trilaciclib. [00189] In some embodiments of a method disclosed herein, the cancer-targeted therapeutic agent, the first (prior) cancer-targeted therapeutic agent, the second cancer-targeted therapeutic agent, or the selected cancer-targeted therapeutic agent is palbociclib or abemaciclib. [00190] In some embodiments of a method disclosed herein, the cancer-targeted therapeutic agent, the first (prior) cancer-targeted therapeutic agent, the second cancer-targeted therapeutic agent, or the selected cancer-targeted therapeutic agent is an inhibitor of EGFR. In some embodiments, the EGFR inhibitors include small molecule inhibitors such as APL-1898, BDTX-1535, BLU-701, BPI-361175, CH-7233163, DS-2087, E-10C, FWD-1509, IN-A008, JS-111, JS-113, LL-191, LYN 205, neptinib, NT-004, ORIC-114, PRB-001, SIM-200, TGRX-360, WJ-13404, yinlitinib maleate, and ZSP-0391, and anti-EGFR antibodies such as 705, 707, ABX-900, CMAB-017, GB-263, KN-023, SSGJ-612, and SHR-A1307. In some embodiments, the EGFR inhibitors include small molecule inhibitors such as abivertinib, alflutinib mesylate, agerafenib (RXDX-105), ASK-120067, BBT-176, BDTX-189, BEBT-109, befortinib mesylate, beitatini, Attorney Docket No.57547-724.601 BPI-7711, BPI-D0316, BLU-945, CK-101, dositinib, DFP-17729, DZD-9008, epertinib, epitinib (HMPL- 813), ES-072, FCN-411, FHND-9041, furmonertinib, GMA-204, Hemay-022, JRF-103, KP-673, larotinib, lazertinib, maihuatinib, marizomib, mobocertinib, naputinib tosilate, nazartinib, NRC-2694-A, OBX1-012, olafertinib, olmutinib, oritinib, pirotinib, poziotinib, SPH-1188, tarloxotinib, theliatinib (HMPL-309), TAS- 6417, TPC-064, TQB-3804, TY-9591, WSD-0922, XZP-5809, YK-029A, YZJ-0318, and zorifertinib, and anti-EGFR antibodies such as 602, C-005, CDP1, depatuxizumab, E01001, GC-1118A, GR-1401, HLX-07, HS-627, I-010, imgatuzumab, JMT-101, JZB-28, KN-026, MP-0274, QL-1203, SCT-200, serclutamab, SYN-004, and TAD-011. In some embodiments, the EGFR inhibitors include small molecule inhibitors such as afatinib, amivantamab, aumolertinib (almonertinib), dacomitinib, erlotinib, gefitinib, icotinib, lapatinib, osimertinib, and pyrotinib, and anti-EGFR antibodies such as cetuximab, necitumumab, nimotuzumab, and panitumumab. [00191] In some embodiments of a method disclosed herein, the cancer-targeted therapeutic agent, the first (prior) cancer-targeted therapeutic agent, the second cancer-targeted therapeutic agent, or the selected cancer-targeted therapeutic agent is erlotinib. [00192] In some embodiments of a method disclosed herein, the cancer-targeted therapeutic agent, the first (prior) cancer-targeted therapeutic agent, the second cancer-targeted therapeutic agent, or the selected cancer-targeted therapeutic agent is an inhibitor of FGFR. [00193] In some embodiments, FGFR inhibitors include small molecule inhibitors such as ABSK-012, ABSK-061, AST-56100, BIO-1262, BGS-2219, EVT-601, FPI-1966, JAB-6000, KIN-3248, SAR-439115, SC-0011, and WXSH-0011, and anti- FGFR antibodies such as M-6123, OM-RCA-001. In some embodiments, FGFR inhibitors include small molecule inhibitors such as 3D-185, ABSK-011, ABSK-091, aldafermin, alofanib, AZD-4547, BFKB-8488A, BPI-17509, BPI-43487, CPL-304-110, derazantinib, E- 7090, EVER-4010001, FGF-401, fisogatinib, futibatinib, gunagratinib, H3B-6527, HH-185, HMPL-453, HS-236, ICP-105, ICP-192, infigratinib, MAX-40279, RLY-4008, rogaratinib, SAR-442501, SY-4798, TT- 00434, and zoligratinib (FF-284), and anti- FGFR antibodies such as bemarituzumab. In some embodiments, FGFR inhibitors include small molecule inhibitors such as erdafitinib and pemigatinib. [00194] In some embodiments of a method disclosed herein, the cancer-targeted therapeutic agent, the first (prior) cancer-targeted therapeutic agent, the second cancer-targeted therapeutic agent, or the selected cancer-targeted therapeutic agent is infigratinib, futibatinib, or pemigatinib. [00195] In some embodiments of a method disclosed herein, the cancer-targeted therapeutic agent, the first (prior) cancer-targeted therapeutic agent, the second cancer-targeted therapeutic agent, or the selected cancer-targeted therapeutic agent is an inhibitor of KRAS. In some embodiments, the KRAS inhibitor include small molecule inhibitors such as ABREV01, ARS-1620, APG-1842, ATG-012, BBP-454, BEPT- 607, BI-2852, BI-1823911, BPI-421286, BTX-2541, COTI-219, IMM-1811900, JAB-21000, JAB-22000, JAB-23000, JAB-BX300, JP-002, KR-12, LYN 202, MRTX-1133, RAS-F, RMC-6236, RMC-6291, SDGR 5, STX-301, and YL-15293, and anti-KRAS antibodies such as SBT-100, SBT-102, and SBT-300. In some Attorney Docket No.57547-724.601 embodiments, the KRAS include small molecule inhibitors such as adagrasib, ARS-3248, D-1553, GDC- 6036, JDQ-443, LY3537982, sotorasib (AMG 510), and BI 1701963. [00196] In some embodiments of a method disclosed herein, the cancer-targeted therapeutic agent, the first (prior) cancer-targeted therapeutic agent, the second cancer-targeted therapeutic agent, or the selected cancer-targeted therapeutic agent is an inhibitor of c-MET, HER2, androgen receptor (AR), KIT, PDGFRA PI3K, AKT, BCL2, or MCL1. In some embodiments, the c-MET inhibitor includes crizotinib, tivantinib, cabozantinib, foretinib), or a monoclonal antibody against c-MET such as onartuzumab. [00197] In some embodiments of a method disclosed herein, the cancer-targeted therapeutic agent, the first (prior) cancer-targeted therapeutic agent, the second cancer-targeted therapeutic agent, or the selected cancer-targeted therapeutic agent is a c-MET inhibitor. [00198] In some embodiments of a method disclosed herein, the cancer-targeted therapeutic agent, the first (prior) cancer-targeted therapeutic agent, the second cancer-targeted therapeutic agent, or the selected cancer-targeted therapeutic agent is tepotinib. [00199] In some embodiments of a method disclosed herein, the cancer-targeted therapeutic agent, the first (prior) cancer-targeted therapeutic agent, the second cancer-targeted therapeutic agent, or the selected cancer-targeted therapeutic agent targets a protein encoded by one or more genes provided in Table 3. TABLE 3: Example Genes
Figure imgf000065_0001
Attorney Docket No.57547-724.601
Figure imgf000066_0001
[00200] In some embodiments of a method disclosed herein, prior to treatment with the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, the tumor or tumor cells comprise a gene amplification and wherein the cancer-targeted therapeutic agent has an activity directed against a protein encoded by a gene contained within the gene amplification. [00201] In some embodiments of a method disclosed herein, prior to treatment with the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, the tumor or tumor cells comprise a gene amplification and wherein the first (prior) cancer-targeted therapeutic agent has an activity directed against a protein encoded by a gene contained within the gene amplification. [00202] In some embodiments of a method disclosed herein, prior to treatment with the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, the tumor or tumor cells comprise a gene amplification and wherein the second cancer-targeted therapeutic agent has an activity directed against a protein encoded by a gene contained within the gene amplification. [00203] In some embodiments of a method disclosed herein, prior to treatment with the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, the tumor or tumor cells comprise a gene amplification and wherein the selected cancer-targeted therapeutic agent has an activity directed against a protein encoded by a gene contained within the gene amplification. [00204] In some embodiments of a method disclosed herein, the subject received one or more administrations of the first (prior) cancer-targeted therapeutic agent prior to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and wherein the tumor or tumor cells developed resistance to the first (prior) cancer-targeted therapeutic agent. Attorney Docket No.57547-724.601 [00205] In some embodiments of a method disclosed herein, the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is administered concurrently or prior to the administration of the cancer-targeted therapeutic agent. [00206] In some embodiments of a method disclosed herein, the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is administered concurrently or prior to the administration of the selected cancer-targeted therapeutic agent. [00207] In some embodiments of a method disclosed herein, the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is administered concurrently or prior to the administration of the first (prior) cancer-targeted therapeutic agent. [00208] In some embodiments of a method disclosed herein, the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is administered concurrently or prior to the administration of the second (selected) cancer-targeted therapeutic agent. [00209] In some embodiments of a method disclosed herein, the subject received one or more administrations of the first (prior) cancer-targeted therapeutic agent prior to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and wherein the tumor or tumor cells developed decreased responsiveness or resistance to the first (prior) cancer-targeted therapeutic agent. [00210] In some embodiments of a method disclosed herein, treatment with both the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the cancer-targeted therapeutic agent has a greater effect or a longer duration of effect on reduction of one or more of tumor growth, tumor size, number of tumor cells or tumor metastasis as compared to the treatment with either the compound of Formula (I) or the cancer-targeted therapeutic agent when administered alone. In some embodiments of a method disclosed herein, treatment with both the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the first (prior) cancer- targeted therapeutic agent has a greater effect or a longer duration of effect on reduction of one or more of tumor growth, tumor size, number of tumor cells or tumor metastasis as compared to the treatment with either the compound of Formula (I) or the first (prior) cancer-targeted therapeutic agent when administered alone. [00211] In some embodiments of a method disclosed herein, treatment with both the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the second (selected) cancer-targeted therapeutic agent has a greater effect or a longer duration of effect on reduction of one or more of tumor growth, tumor size, number of tumor cells or tumor metastasis as compared to the treatment with either the compound of Formula (I) or the second (selected) cancer-targeted therapeutic agent when administered alone. [00212] In certain embodiments, different therapeutically effective dosages of the compounds disclosed herein will be utilized in formulating a pharmaceutical composition and/or in treatment regimens when the compounds disclosed herein are administered in combination with a second (selected) therapeutic agent. Attorney Docket No.57547-724.601 Therapeutically effective dosages of drugs and other agents for use in combination treatment regimens are optionally determined by means similar to those set forth hereinabove for the actives themselves. Furthermore, the methods of prevention/treatment described herein encompasses the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side effects. In some embodiments, a combination treatment regimen encompasses treatment regimens in which administration of a compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is initiated prior to, during, or after treatment with a second (selected) agent described herein, and continues until any time during treatment with the second (selected) agent or after termination of treatment with the second (selected) agent. It also includes treatments in which a compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the second (selected) agent being used in combination are administered simultaneously or at different times and/or at decreasing or increasing intervals during the treatment period. Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient. [00213] It is understood that the dosage regimen to treat, prevent, or ameliorate the condition(s) for which relief is sought, is modified in accordance with a variety of factors (e.g., the disease, disorder, or condition from which the subject suffers; the age, weight, sex, diet, and medical condition of the subject). Thus, in some instances, the dosage regimen employed varies and, in some embodiments, deviates from the dosage regimens set forth herein. For combination therapies described herein, dosages of the co-administered compounds vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated, and so forth. [00214] The compounds described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, as well as combination therapies, are administered before, during, or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies. [00215] In some embodiments, the compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is administered in combination with an adjuvant. In one embodiment, the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). [00216] In some embodiments, the subject identified as having the tumor or tumor cells has cancer. In some embodiments, the cancer includes malignant tumors whose size can be decreased, whose growth or spread can be slowed or halted, or whose symptom is in remission or alleviated, reduced, and/or completely cured by deleting or suppressing and/or inhibiting functions of Chk1. Malignant tumors of interest are, but not limited to, head and neck cancer, gastrointestinal cancer (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancer (gallbladder, bile duct cancer, etc.), pancreatic cancer, colorectal cancer (colon cancer, rectal cancer, etc.), etc.), lung cancer (non-small cell lung cancer, small cell lung cancer, squamous cell lung carcinoma, mesothelioma, etc.), breast cancer, genital cancer (ovarian cancer, Attorney Docket No.57547-724.601 uterine cancer, cervical cancer, endometrial cancer, etc.), urinary cancer (kidney cancer, bladder cancer, prostate cancer, testicular tumor, etc.), hematopoietic tumors (leukemia, malignant lymphoma, multiple myeloma, etc.), bone and soft tissue tumors (e.g., soft tissue sarcomas and osteosarcomas), skin cancer, brain tumor (e.g., glioblastoma) and the like. [00217] In some embodiments, the term cancer is used in accordance with its plain ordinary meaning in light of the present disclosure and refers to all types of cancer, neoplasm or malignant tumors found in mammals, including leukemias, lymphomas, melanomas, neuroendocrine tumors, carcinomas, and sarcomas. Exemplary cancers that may be treated with a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, pharmaceutical compositions include acute myeloid leukemia, adrenal cortical cancer, adrenal gland cancer, bladder cancer, bone cancer, brain cancer, breast cancer (e.g., ductal carcinoma, lobular carcinoma, primary, metastatic), breast cancer, cancer of the endocrine system, cancer of the hepatic stellate cells, cancer of the pancreatic stellate cells, cervical cancer, colon cancer, colorectal cancer, ductal carcinoma, endometrial cancer, esophageal cancer, gastric cancer, genitourinary tract cancer, glioblastoma, glioma, head and neck cancer, hepatocellular carcinoma, Hodgkin’s Disease, kidney cancer, leukemia (e.g., lymphoblastic leukemia, chronic lymphocytic leukemia, hairy cell leukemia), liver cancer (e.g., hepatocellular carcinoma), lobular carcinoma, lung cancer (e.g., non-small cell lung carcinoma, squamous cell lung carcinoma, adenocarcinoma, large cell lung carcinoma, small cell lung carcinoma, carcinoid, sarcoma), lymph node cancer, lymphoma (e.g., Mantel cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, marginal zona lymphoma, Burkitt’s lymphoma, Non-Hodgkin’s Lymphoma) malignant carcinoid, malignant hypercalcemia, malignant pancreatic insulinoma, medullary thyroid cancer, Medulloblastoma, melanoma, mesothelioma, multiple myeloma muscle cancer, neoplasms of the endocrine or exocrine pancreas, neuroblastoma, ovarian cancer, Paget’s Disease of the Nipple, pancreatic cancer, papillary thyroid cancer, Phyllodes Tumors, premalignant skin lesions, primary thrombocytosis, prostate cancer (e.g. castration-resistant prostate cancer) rhabdomyosarcoma, salivary gland cancer, sarcoma, soft tissue sarcoma, squamous cell carcinoma (e.g., head, neck, or esophagus), stomach cancer, testicular cancer, thyroid cancer, urinary bladder cancer, or uterine cancer. In embodiments, the cancer is selected from bladder cancer, breast cancer, colon cancer, esophageal cancer, esophageal cancer, glioblastoma, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, salivary gland cancer, soft tissue sarcoma, squamous cell lung carcinoma, stomach cancer, and uterine cancer. [00218] Gene amplification plays a role in the response of a tumor or tumor cells to cancer-directed therapies and in the development of resistance to targeted therapies. In some instances, gene amplification includes amplification of one or more genes, such as oncogenes, in a focal amplification, where the one or more oncogenes are in higher copy number, whereas surrounding genetic material (e.g., from the chromosomal location of such amplified gene) is not amplified or not at the same level of amplification. Focal amplifications may be located on ecDNA or ecDNA-derived, (i.e., derived from ecDNA, such as ecDNA that has reintegrated into a chromosomal location). ecDNA mediates an important and clinically Attorney Docket No.57547-724.601 distinct mechanism of resistance to targeted therapies. Tumor cells with ecDNA and/or ecDNA-derived amplifications may become non-responsive, less responsive, or resistant to a targeted therapy. There are immediate therapeutic opportunities for utility of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof in combination with other therapies. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof may be used in combination with a therapeutic agent to treat an ecDNA+ cancer, ecDNA+ tumor or ecDNA+ tumor cells (i.e., tumor cells containing gene amplifications on ecDNA or derived from ecDNA). The combination of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof and a therapeutic agent may be used to treat tumors, such as with one or more amplified oncogenes (e.g., BRAF, CDK4, CDK6, EGFR, FGFR, HER2, KRAS, MET, MDM2 amplifications); in some cases, the one or more amplified oncogenes comprise non-mutant forms of the oncogene and in some cases, the amplified oncogenes comprises mutant forms of the oncogenes. In some cases, the one or more amplified oncogenes are extrachromosomal (i.e., on ecDNA) and/or are ecDNA-derived and located on a chromosome. In some embodiments herein, the therapeutic agent used in combination with the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof is an inhibitor of a protein encoded by a gene that is amplified on ecDNA or the ecDNA-derived amplification. [00219] The combinations described herein may be used to treat tumors that have developed resistance to another therapy such as a resistance to a targeted agent. In some cases, a tumor (or tumor cells) treated with a first (prior) targeted agent develops resistance to the first (prior) targeted agent or becomes less responsive or non-responsive to the first (prior) targeted agent. In some cases, the first (prior) therapeutic agent is an inhibitor of a protein encoded by a gene that is amplified on ecDNA or the ecDNA-derived amplification and the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof and the first (prior) targeted agent may be used to treat such tumors or tumor cells. In some cases, the first (prior) therapeutic agent is an inhibitor of a protein encoded by a gene that is amplified on ecDNA or the ecDNA-derived amplification and the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof and a second (selected) targeted agent may be used to treat such tumors or tumor cells, where the second (selected) targeted agent is an inhibitor of a different protein from the protein target of the first (prior) targeted agent. [00220] Provided herein are methods wherein inhibition of Chk1 by the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof exhibits synthetic lethality with a cancer-targeted agent. In some embodiments, synthetic lethality arises with the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof in combination with a cancer targeted agent. In some cases, a tumor background is identified as hyper-sensitive to a Chk1 inhibitor and allows a sufficient therapeutic index to enable tolerated doses that are efficacious. In some embodiments, synthetic lethality arises with the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof in combination with a cancer-targeted agent where the tumor Attorney Docket No.57547-724.601 or tumor cells are ecDNA+ (i.e., contain ecDNA or ecDNA-derived gene amplification) . In some cases, Chk1 inhibition results in reduced ecDNA copy number. In some cases, Chk1 inhibition results in enhanced cytotoxicity in ecDNA+ cells. In some cases, enhanced cytotoxicity results from the combination of Chk1 inhibition and inhibition of a cancer-target, such as an oncogene. [00221] In some embodiments of a method disclosed herein, prior to treatment the tumor or tumor cells comprise ecDNA and wherein the treatment results in a reduction in the amount of ecDNA in the tumor or tumor cells. [00222] In some embodiments of a method disclosed herein, prior to treatment the tumor or tumor cells comprise ecDNA and wherein level or amount of ecDNA subsequent to the treatment is not increased as compared to prior to treatment. [00223] In some embodiments of a method disclosed herein, the method further comprises assessing a sample from a subject for the presence or level of one or more of a gene amplification, a focal gene amplification, ecDNA, HSR or an ecDNA signature. In some cases, such assessment is performed prior to treatment, during a course of treatment or subsequent to treatment. [00224] In some embodiments of a method disclosed herein, the method further comprises obtaining information of the presence or level of one or more of a gene amplification, a focal gene amplification, ecDNA, HSR or an ecDNA signature in the tumor or tumor cells from the subject prior to, during or subsequent to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. In some cases, such information is obtained prior to treatment with the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof and a targeted cancer therapeutic agent. In some cases, such information is obtained during the course of treatment with the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof inhibitor and a targeted cancer therapeutic agent. In some cases, such information is obtained after treatment with a first (prior) targeted cancer therapeutic agent but prior to treatment with the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and if the information indicates the presence of ecDNA, or an ecDNA-derived gene amplification, the subject is treated with a combination of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof and the first (prior) targeted cancer therapeutic agent or with a combination of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof and a second (selected) targeted cancer therapeutic agent. [00225] In an aspect of methods herein, a tumor or tumor cells are determined to have an ecDNA signature. In some cases, a tumor or tumor cells are determined to have an ecDNA signature when the tumor or tumor cells have one or more characteristics associated with ecDNA+ tumors or tumor cells. For example, in some cases, the ecDNA signature is selected from the group consisting of a gene amplification; a focal gene amplification; characterization of a structural variation; a p53 loss of function mutation; absence of microsatellite instability (MSI-H); a low level of PD-L1 expression; a low level of tumor inflammation Attorney Docket No.57547-724.601 signature (TIS); a low level of tumor mutational burden (TMB); an increased frequency of allele substitutions, insertions, or deletions (indels); and any combination thereof. [00226] In an aspect of methods herein, the tumor or tumor cells have an ecDNA signature. In some cases, the tumor or tumor cells develop the ecDNA signature after administration of a first (prior) cancer-targeted therapeutic agent. In some cases, the tumor or tumor cells develop the ecDNA signature prior to treatment. [00227] In some embodiments of a method disclosed herein, the information of the presence or level of one or more of a gene amplification, a focal gene amplification, ecDNA, HSR or an ecDNA signature in the tumor or tumor cells is obtained from blood, tissue or one or more cells. [00228] In some embodiments of a method disclosed herein, the information of the presence or level of one or more of a gene amplification, a focal gene amplification, ecDNA, HSR or an ecDNA signature in the tumor or tumor cells is obtained by liquid biopsy or tissue biopsy. Numbered Embodiments [00229] Embodiment 1: A method of treating a tumor or tumor cells, comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a cancer-targeted therapeutic agent to a subject identified as having the tumor or tumor cells, wherein the tumor or tumor cells comprise a gene amplification, whereby growth or size of the tumor or growth or number of tumor cells is reduced. [00230] Embodiment 2: The method of embodiment 1, wherein the cancer-targeted therapeutic agent is administered concurrent or subsequent to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. [00231] Embodiment 3: The method of embodiment 1 or embodiment 2, wherein the cancer-targeted therapeutic agent is administered prior to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. [00232] Embodiment 4: The method of any one of embodiments 1-3, wherein the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is administered in an amount sufficient to induce replication stress in the tumor or tumor cells. [00233] Embodiment 5: A method of delaying resistance to a cancer-targeted therapeutic agent, the method comprising: administering a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, to a subject in an amount sufficient to induce replication stress in tumor or tumor cells and administering a cancer-targeted therapeutic agent concurrently or subsequent to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. [00234] Embodiment 6: The method of embodiment 5, wherein the subject is identified as having the tumor or tumor cells comprising a gene amplification. [00235] Embodiment 7: The method of any one of embodiments 1-4 or 6, wherein the gene amplification is a focal gene amplification. Attorney Docket No.57547-724.601 [00236] Embodiment 8: The method of any one of embodiments 1-4, 6, or 7, wherein the gene amplification is an ecDNA-derived amplification. [00237] Embodiment 9: The method of any one of embodiments 1-4 or 6-8, wherein the gene amplification is comprised on ecDNA or an HSR (homogeneously staining region). [00238] Embodiment 10: The method of any one of embodiments 1-4 or 6-9, wherein the cancer-targeted therapeutic agent is directed against a protein encoded by a gene contained within the gene amplification. [00239] Embodiment 11: The method of any one of embodiments 1-10, wherein the tumor or tumor cells comprise an ecDNA signature. [00240] Embodiment 12: The method of any one of embodiments 1-11, wherein cells comprised within the tumor or the tumor cells are ecDNA competent. [00241] Embodiment 13: The method of any one of embodiments 1-12, wherein treatment with both the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the cancer therapeutic agent has a greater effect or a longer duration of effect on reduction of one or more of tumor growth, tumor size, number of tumor cells or tumor metastasis as compared to the treatment with either the compound of Formula (I) or the cancer therapeutic agent when administered alone. [00242] Embodiment 14: The method of embodiment 13, wherein the greater effect is a synergistic effect. [00243] Embodiment 15: The method of any one of embodiments 1-14, wherein the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and/or the cancer- targeted therapeutic agent is administered orally. [00244] Embodiment 16: The method of any one of embodiments 1-14, wherein the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and/or the cancer- targeted therapeutic agent is administered parentally. [00245] Embodiment 17: The method of any one of embodiments 1-16, wherein treatment comprises administering multiple doses of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and/or the cancer-targeted therapeutic agent over a treatment period. [00246] Embodiment 18: The method of any one of embodiments 1-4 or 6-17, wherein the gene amplification comprises an amplification of a gene selected from the group consisting of ABCB1, AKT, ALK, AR, BCL-2, BCR-ABL, BRAF, CDK4, CDK6, c-MET, EGFR, ER, ERBB3, ERRB2, AK, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, GR, HER2, HRAS, IGF1R, KIT, KRAS, MCL-1, MDM2, MDM4, MTOR, MYC, MYCL, MYCN, NRAS, NRG1, NTRK1, NTRK2, NTRK3, PDGFR, PIK3Cδ, PIK3CA/B, RET, and ROS1. [00247] Embodiment 19: The method of any one of embodiments 1-18, wherein the cancer therapeutic agent is selected from the group consisting of abemaciclib, ado-trastuzumab emtansine, afatinib, alectinib, ALRN-6924, AMG232, AMG-510, apatinib, ARS-3248, AXL1717, AZD-3759, bevacizumab, BI 1701963, bortezomib, brigatinib, cabozantinib, capmatinib, ceritinib, cetuximab, CGM097, crizotinib, dabrafenib, dacomitinib, dasatinib, DS-3032b, encorafenib, entrectinib, ERAS-801, erdafitinib, erlotinib, everolimus, fam-trastuzumab deruxtecan, figitumumab, futibatinib, gefitinib, gossypol, HDM201, idasanutlin, imatinib, Attorney Docket No.57547-724.601 infigratinib, iniparib, lapatinib, larotrectinib, LEE011, lenvatinib, LGX818, lorlatinib, MEK162, MK-8242 SCH 900242, MRTX849, navitoclax, necitumumab, nilotinib, obatoclax, olaparib, OSI-906, osimertinib, palbociclib, panitumumab, PD-0332991, perisofine, pertuzumab, PF-06873600, PF-07220060, PL225B, repotrectinib, ribociclib, RLY-4008, RO5045337, salinomycin, salirasib, SAR405838 MI-77301, sorafenib, sotorasib, sunitinib, tamoxifen, temsirolimus, tipifarnib, tivanitab, tofacitinib, trametinib, trastuzumab, tucatinib, UPR1376, VAL-083, vemurafenib, vemurafenib, vintafolide, and zoptarelin doxorubicin. [00248] Embodiment 20: A method of treating a subject having a tumor or tumor cells that are non- responsive to a first cancer-targeted therapeutic agent comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a second cancer- targeted therapeutic agent to the subject. [00249] Embodiment 21: The method of the embodiment 20, wherein prior to treatment with the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, the tumor or tumor cells comprise a gene amplification and wherein the first cancer-targeted therapeutic agent has an activity directed against a protein encoded by a gene contained within the gene amplification. [00250] Embodiment 22: The method of embodiment 21, wherein the subject received one or more administrations of the first cancer-targeted therapeutic agent prior to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and wherein the tumor or tumor cells developed resistance to the first cancer-targeted therapeutic agent. [00251] Embodiment 23: The method of any one of embodiments 20-22, wherein the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is administered concurrently or prior to the administration of the second cancer-targeted therapeutic agent. [00252] Embodiment 24: The method of any one of embodiments 21-23, wherein the gene amplification is a focal gene amplification. [00253] Embodiment 25: The method of any one of embodiments 21-24, wherein the gene amplification is an ecDNA-derived amplification. [00254] Embodiment 26: The method of any one of embodiments 21-25, wherein the gene amplification is comprised on ecDNA or an HSR (homogeneously staining region). [00255] Embodiment 27: The method of any one of embodiments 21-26, wherein the second cancer- targeted therapeutic agent is directed against a protein encoded by a gene contained within the gene amplification. [00256] Embodiment 28: The method of any one of embodiments 20-27, wherein the tumor or tumor cells comprise an ecDNA signature. [00257] Embodiment 29: The method of any one of embodiments 20-28, wherein cells comprised within the tumor or the tumor cells are ecDNA competent. [00258] Embodiment 30: The method of any one of embodiments 20-29, wherein treatment with both the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the cancer therapeutic agent has a greater effect or a longer duration of effect on reduction of one or Attorney Docket No.57547-724.601 more of tumor growth, tumor size, number of tumor cells or tumor metastasis as compared to the treatment with either the compound of Formula (I) or the cancer therapeutic agent when administered alone. [00259] Embodiment 31: The method of embodiment 30, wherein the greater effect is a synergistic effect. [00260] Embodiment 32: The method of any one of embodiments 20-31, wherein the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and/or the second cancer-targeted therapeutic agent is administered orally. [00261] Embodiment 33: The method of any one of embodiments 20-31, wherein the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and/or the second cancer-targeted therapeutic agent is administered parentally. [00262] Embodiment 34: The method of any one of embodiments 20-33, wherein treatment comprises administering multiple doses of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and/or the second cancer-targeted therapeutic agent over a treatment period. [00263] Embodiment 35: The method of any one of embodiments 21-34, wherein the gene amplification comprises an amplification of a gene selected from the group consisting of ABCB1, AKT, ALK, AR, BCL- 2, BCR-ABL, BRAF, CDK4, CDK6, c-MET, EGFR, ER, ERBB3, ERRB2, AK, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, GR, HRAS, IGF1R, KIT, KRAS, MCL-1, MDM2, MDM4, MTOR, MYC, MYCL, MYCN, NRAS, NRG1, NTRK1, NTRK2, NTRK3, PDGFR, PIK3Cδ, PIK3CA/B, RET, and ROS1. [00264] Embodiment 36: The method of any one of embodiments 20-35, wherein the first cancer-targeted therapeutic agent is selected from the group consisting of abemaciclib, ado-trastuzumab emtansine, afatinib, alectinib, ALRN-6924, AMG232, AMG-510, apatinib, ARS-3248, AXL1717, AZD-3759, bevacizumab, BI 1701963, bortezomib, brigatinib, cabozantinib, capmatinib, ceritinib, cetuximab, CGM097, crizotinib, dabrafenib, dacomitinib, dasatinib, DS-3032b, encorafenib, entrectinib, ERAS-801, erdafitinib, erlotinib, everolimus, fam-trastuzumab deruxtecan, figitumumab, futibatinib, gefitinib, gossypol, HDM201, idasanutlin, imatinib, infigratinib, iniparib, lapatinib, larotrectinib, LEE011, lenvatinib, LGX818, lorlatinib, MEK162, MK-8242 SCH 900242, MRTX849, navitoclax, necitumumab, nilotinib, obatoclax, olaparib, OSI- 906, osimertinib, palbociclib, panitumumab, PD-0332991, perisofine, pertuzumab, PF-06873600, PF- 07220060, PL225B, repotrectinib, ribociclib, RLY-4008, RO5045337, salinomycin, salirasib, SAR405838 MI-77301, sorafenib, sotorasib, sunitinib, tamoxifen, temsirolimus, tipifarnib, tivanitab, tofacitinib, trametinib, trastuzumab, tucatinib, UPR1376, VAL-083, vemurafenib, vemurafenib, vintafolide, and zoptarelin doxorubicin. [00265] Embodiment 37: The method of any one of embodiments 20-35, wherein the second cancer- targeted therapeutic agent is selected from the group consisting of abemaciclib, ado-trastuzumab emtansine, afatinib, alectinib, ALRN-6924, AMG232, AMG-510, apatinib, ARS-3248, AXL1717, AZD-3759, bevacizumab, BI 1701963, bortezomib, brigatinib, cabozantinib, capmatinib, ceritinib, cetuximab, CGM097, crizotinib, dabrafenib, dacomitinib, dasatinib, DS-3032b, encorafenib, entrectinib, ERAS-801, erdafitinib, erlotinib, everolimus, fam-trastuzumab deruxtecan, figitumumab, futibatinib, gefitinib, gossypol, HDM201, Attorney Docket No.57547-724.601 idasanutlin, imatinib, infigratinib, iniparib, lapatinib, larotrectinib, LEE011, lenvatinib, LGX818, lorlatinib, MEK162, MK-8242 SCH 900242, MRTX849, navitoclax, necitumumab, nilotinib, obatoclax, olaparib, OSI- 906, osimertinib, palbociclib, panitumumab, PD-0332991, perisofine, pertuzumab, PF-06873600, PF- 07220060, PL225B, repotrectinib, ribociclib, RLY-4008, RO5045337, salinomycin, salirasib, SAR405838 MI-77301, sorafenib, sotorasib, sunitinib, tamoxifen, temsirolimus, tipifarnib, tivanitab, tofacitinib, trametinib, trastuzumab, tucatinib, UPR1376, VAL-083, vemurafenib, vemurafenib, vintafolide, and zoptarelin doxorubicin. [00266] Embodiment 38: A method of provoking a response in a subject having a tumor or tumor cells that are non-responsive or have decreased responsiveness to a first cancer-targeted therapeutic agent comprising administering a Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the first cancer-targeted therapeutic agent to the subject. [00267] Embodiment 39: The method of the embodiment 38, wherein prior to treatment with the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, the tumor or tumor cells comprise a gene amplification and wherein the first cancer-targeted therapeutic agent has an activity directed against a protein encoded by a gene contained within the gene amplification. [00268] Embodiment 40: The method of embodiment 38 or embodiment 39, wherein the subject received one or more administrations of the first cancer-targeted therapeutic agent prior to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and wherein the tumor or tumor cells developed decreased responsiveness or resistance to the first cancer- targeted therapeutic agent. [00269] Embodiment 41: The method of embodiment 39 or embodiment 40, wherein the gene amplification is a focal gene amplification. [00270] Embodiment 42: The method of any one of embodiments 39-41, wherein the gene amplification is an ecDNA-derived amplification. [00271] Embodiment 43: The method of any one of embodiments 39-42, wherein the gene amplification is comprised on ecDNA or an HSR (homogeneously staining region). [00272] Embodiment 44: The method of any one of embodiments 38-43, wherein the tumor or tumor cells comprise an ecDNA signature. [00273] Embodiment 45: The method of any one of embodiments 38-44, wherein cells comprised within the tumor or the tumor cells are ecDNA competent. [00274] Embodiment 46: The method of any one of embodiments 38-45, wherein treatment with both the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the first cancer-targeted therapeutic agent has a greater effect or a longer duration of effect on reduction of one or more of tumor growth, tumor size, number of tumor cells or tumor metastasis as compared to the treatment with either the compound of Formula (I) or the first cancer-targeted therapeutic agent when administered alone. [00275] Embodiment 47: The method of embodiment 46, wherein the greater effect is a synergistic effect. Attorney Docket No.57547-724.601 [00276] Embodiment 48: The method of any one of embodiments 38-47, wherein the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and/or the first cancer-targeted therapeutic agent is administered orally. [00277] Embodiment 49: The method of any one of embodiments 38-47, wherein the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and/or the second cancer-targeted therapeutic agent is administered parentally. [00278] Embodiment 50: The method of any one of embodiments 38-49, wherein treatment comprises administering multiple doses of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and/or the first cancer-targeted therapeutic agent over a treatment period. [00279] Embodiment 51: The method of any one of embodiments 39-50, wherein the gene amplification comprises an amplification of a gene selected from the group consisting of ABCB1, AKT, ALK, AR, BCL- 2, BCR-ABL, BRAF, CDK4, CDK6, c-MET, EGFR, ER, ERBB3, ERRB2, AK, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, GR, HRAS, IGF1R, KIT, KRAS, MCL-1, MDM2, MDM4, MTOR, MYC, MYCL, MYCN, NRAS, NRG1, NTRK1, NTRK2, NTRK3, PDGFR, PIK3Cδ, PIK3CA/B, RET, and ROS1. [00280] Embodiment 52: The method of any one of embodiments 20-51, wherein the first cancer-targeted therapeutic agent is selected from the group consisting of abemaciclib, ado-trastuzumab emtansine, afatinib, alectinib, ALRN-6924, AMG232, AMG-510, apatinib, ARS-3248, AXL1717, AZD-3759, bevacizumab, BI 1701963, bortezomib, brigatinib, cabozantinib, capmatinib, ceritinib, cetuximab, CGM097, crizotinib, dabrafenib, dacomitinib, dasatinib, DS-3032b, encorafenib, entrectinib, ERAS-801, erdafitinib, erlotinib, everolimus, fam-trastuzumab deruxtecan, figitumumab, futibatinib, gefitinib, gossypol, HDM201, idasanutlin, imatinib, infigratinib, iniparib, lapatinib, larotrectinib, LEE011, lenvatinib, LGX818, lorlatinib, MEK162, MK-8242 SCH 900242, MRTX849, navitoclax, necitumumab, nilotinib, obatoclax, olaparib, OSI- 906, osimertinib, palbociclib, panitumumab, PD-0332991, perisofine, pertuzumab, PF-06873600, PF- 07220060, PL225B, repotrectinib, ribociclib, RLY-4008, RO5045337, salinomycin, salirasib, SAR405838 MI-77301, sorafenib, sotorasib, sunitinib, tamoxifen, temsirolimus, tipifarnib, tivanitab, tofacitinib, trametinib, trastuzumab, tucatinib, UPR1376, VAL-083, vemurafenib, vemurafenib, vintafolide, and zoptarelin doxorubicin. [00281] Embodiment 53: The method of any one of embodiments 1-52, wherein prior to treatment the tumor or tumor cells comprise ecDNA and wherein the treatment results in a reduction in the amount of ecDNA in the tumor or tumor cells. [00282] Embodiment 54: The method of any one of embodiments 1-52, wherein prior to treatment the tumor or tumor cells comprise ecDNA and wherein level or amount of ecDNA subsequent to the treatment is not increased as compared to prior to treatment. [00283] Embodiment 55: The method of any one of embodiments 1-54, wherein the method further comprises assessing a sample from a subject for the presence or level of one or more of a gene amplification, a focal gene amplification, ecDNA, HSR or an ecDNA signature. Attorney Docket No.57547-724.601 [00284] Embodiment 56: The method of any one of embodiments 1-55, wherein the method further comprises obtaining information of the presence or level of one or more of a gene amplification, a focal gene amplification, ecDNA, HSR or an ecDNA signature in the tumor or tumor cells from the subject prior to, during or subsequent to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. [00285] Embodiment 57: The method of embodiment 55, wherein the information is obtained from blood, tissue or one or more cells. [00286] Embodiment 58: The method of embodiment 55, wherein the information is obtained by liquid biopsy or tissue biopsy. EXAMPLES Example 1: Kinase HTRF biochemical assay [00287] Chk1 enzyme activity was measured using an HTRF KinEASE assay (Cisbio, catalog no. 62ST1PEC). Full-length human CHK1 protein (GenBank accession number NP_001265.1) was obtained from Carna Biosciences, Inc. (Kobe, Japan, catalog no.02-117). The enzyme reaction was carried out in assay buffer containing (final concentrations): CHK1 enzyme (0.012 ng/µL), MgCl2 (5 mM) and DTT (1 mM). To determine compound dose response, DMSO stock solutions were serially diluted in a 10-point concentration series in duplicate. Compound solution (50 nL) was added to 384-well assay plates (Greiner, catalog no.784075). To each well containing compound solution was added assay buffer solution (5 µL). Plates were centrifuged at 1000 rpm for 1 minute, then incubated at room temperature for 10 minutes. The reaction was started by addition of substrate buffer (5 µL/well) containing (final concentrations): STK substrate 1-biotin (120 nM) and ATP (1 mM). Assay plates were centrifuged at 1000 rpm for 1 minute, then incubated at room temperature for 60 minutes. The reaction was stopped by addition of detection buffer (Cisbio, 10 µL) containing (final concentrations): STK antibody-cryptate (0.25 nM) and streptavidin-XL665 (7.5 nM). Plates were centrifuged at 1000 rpm for 1 minute, then incubated at 25 °C for 2 hours. HTRF signal was read on an EnVision multimode plate reader (CisBio) in HTRF mode. Data were fit to dose- response curves using XLfit (IDBS, Surrey, UK) or Prism (GraphPad Software, La Jolla, CA, US) to calculate IC50 values for each compound tested. Example 2: AlphaLisa cellular assay [00288] Compound activity in cells was measured using an AlphaLISA® SureFire® Ultra™ p-CHK1 (Ser345) assay (Perkin Elmer, catalog no. ALSU-PCHK1-A10K). HT29 cells were cultured in McCoy 5A medium with 10% FBS and 1% penicillin-streptomycin and seeded to 96-well plates (Corning, catalog no. 3599). Compounds were serially diluted in DMSO over a 10-point dose range with 3-fold dilution and to each well containing cells was added compound solution. Plates were centrifuged at 1000 rpm for 30 seconds. Plates were incubated at 37 °C for 16 h. Supernatant was removed by flicking the plate against a paper towel. Wells were washed once with PBS solution. To each well was added freshly prepared lysis Attorney Docket No.57547-724.601 buffer and plates were agitated on a plate shaker at 400 rpm for 30 min. The 96-well cell plates were centrifuged at 1500 rpm for 1 minute. From each well was transferred 10 µL of the lysates to a 384-well Optiplate™ (Perkin Elmer, catalog no.6007290). To each well was added Acceptor Mix (5 µL) and the plates were sealed and wrapped in foil. Plates were agitated on a plate shaker for 2 minutes, then incubated at room temperature for 1 h. To each well was added Donor Mix (5 µL) and the plates were sealed and wrapped in foil. Plates were agitated on a plate shaker for 2 minutes, then incubated at room temperature for 1 h. AlphaLisa signal was read on an EnVision multimode plate reader (Perkin Elmer). Data were fit to dose-response curves using XLfit (IDBS, Surrey, UK) or Prism (GraphPad Software, La Jolla, CA, US) to calculate IC50 values for each compound tested. [00289] The data from example 1 and 2 is found in table 4. TABLE 4
Figure imgf000079_0001
Attorney Docket No.57547-724.601
Figure imgf000080_0001
Attorney Docket No.57547-724.601
Figure imgf000081_0001
Figure imgf000081_0002
Example 3: Synergistic activity of Compound 31 with additional therapeutic agents [00290] In vivo anti-tumor activity and tolerability of Compound 31 in combination with various targeted agents was evaluated in mice using a series of cell line derived xenograft (CDX) and patient derived xenograft (PDX) tumor models representing various solid tumors harboring focal amplifications on ecDNA (e.g., focal amplifications of one or more oncogenes). For each study, mice were implanted with the tumor cells and once the tumors were established (e.g., reached a volume of about 100-350 mm3), the mice were started on the therapeutic regimens as further described below. For each study, synergy of the combination therapy compared to corresponding single agent arms was determined using the Fractional Product Method (Webb et al., 1963). A summary of the results is shown in Table 5. Fraction unaffected (fu) is the % where tumor growth inhibition was not observed. The fu observed with the combination treatment (fu)A+B (“observed fu”) was compared to the predicted fu calculated as the product of the observed fu for the single treatments (fu)A x (fu)B. If (fu)A+B = (fu)A x (fu)B then the combination was determined to be additive; if (fu)A+B < (fu)A x (fu)B then the combination was determined to be synergistic. Table 5: Synergy of Compound 31 in combination with targeted therapeutic agents
Figure imgf000081_0003
Attorney Docket No.57547-724.601
Figure imgf000082_0001
PO = orally; QD = once daily; Q2D = once every other day [00291] Collectively, these findings demonstrate that combination of Compound 31 plus a targeted agent can result in significant and synergistic anti-tumor activity, including tumor regressions, in tumors bearing oncogene amplification on ecDNA. FGFR [00292] The combination of Compound 31 (50 mg/kg PO dosed Q2D) plus the pan-FGFR inhibitor infigratinib (15 mg/kg PO dosed QD) was evaluated in the ecDNA+ FGFR2 amplified gastric cancer SNU- 16 CDX and CTG-0353 PDX models. Results are shown in FIG.1A and FIG.1B, respectively. Survival curves for the therapies CTG-0353 PDX model are shown in FIG.1C. In both models, the combination therapy demonstrated durable and significant tumor growth inhibition, including tumor regressions, when compared to vehicle. The combination of Compound 31 plus infigratinib was determined to be synergistic. [00293] The combination of Compound 31 (50 mg/kg PO dosed Q2D) plus the pan-FGFR inhibitor futibatinib (12.5 mg/kg PO dosed QD) was evaluated in the ecDNA+ FGFR2 amplified gastric cancer SNU- 16 CDX model. Results are shown in FIG.1D. The combination therapy demonstrated durable and significant tumor growth inhibition, including tumor regressions, when compared to vehicle or either agent alone. [00294] The combination of Compound 31 (50 mg/kg PO dosed Q2D) plus the pan-FGFR inhibitor pemigatinib (1 mg/kg PO dosed QD) was evaluated in the ecDNA+ FGFR2 amplified gastric cancer SNU- 16 CDX model. Results are shown in FIG.1E. The combination therapy demonstrated durable and significant tumor growth inhibition, including tumor regressions, when compared to vehicle or either agent alone. CDK4/6 [00295] The combination of Compound 31 (50 mg/kg PO dosed Q2D) plus the CDK4/6 inhibitors palbociclib (50 mg/kg PO dosed QD) or abemaciclib (10.5 mg/kg PO dosed QD) was evaluated in the ecDNA+ CDK4 amplified osteosarcoma SJSA-1 CDX tumor model. Results are shown in FIG.2A (Palbociclib) and FIG.2B (abemaciclib). The combination of Compound 31 plus palbociclib or abemaciclib Attorney Docket No.57547-724.601 resulted in significant anti-tumor activity, including tumor regressions, when compared to vehicle. The combination of Compound 31 plus abemaciclib was determined to be synergistic. EGFR [00296] The combination of Compound 31 (50 mg/kg PO dosed Q2D) plus the EGFR inhibitor erlotinib (50 mg/kg PO dosed QD) was evaluated in the ecDNA+ EGFR amplified NSCLC PDX tumor models LU1206. Results are shown in FIG.3. The combination therapy resulted in significant tumor growth inhibition when compared to vehicle, and the therapy was determined to be synergistic. MET [00297] The combination of Compound 31 (50 mg/kg PO dosed Q2D) plus the MET inhibitor tepotinib (25 mg/kg PO dosed Q2D) was evaluated in the ecDNA+ MET amplified NSCLC PDX tumor models LU1902. T Results are shown in FIG.4. he combination therapy resulted in significant tumor growth inhibition when compared to vehicle; The combination therapy with tepotinib resulted in complete tumor regressions. The combination therapy was determined to be synergistic. Example 4 Suppression of ecDNA amplification [00298] Prolonged treatment of SNU-16 tumor cells in vitro and SNU-16 CDX tumors in vivo with the pan-FGFR tyrosine kinase inhibitor infigratinib resulted in tumor cell stasis for a period of 1-2 weeks but acquired resistance to infigratinib treatment occurred resulting in re-initiation of tumor growth. Infigratinib resistance was directly correlated with increased amplification of FGFR2 (copy number) on ecDNA. Combination treatment of infigratinib plus Compound 31 blocked the increase of FGFR2 copy number on ecDNA that otherwise was induced by single agent infigratinib. Results for the SNU-16 tumor cells in vitro are shown in FIG.5. [00299] The examples and embodiments described herein are for illustrative purposes only and in some embodiments, various modifications or changes are to be included within the purview of disclosure and scope of the appended claims.

Claims

Attorney Docket No.57547-724.601 CLAIMS WHAT IS CLAIMED IS: 1. A method of treating a tumor or tumor cells, comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a selected cancer-targeted therapeutic agent to a subject identified as having the tumor or tumor cells, wherein the tumor or tumor cells comprise a gene amplification, whereby growth or size of the tumor or growth or number of tumor cells is reduced. 2 A method of delaying resistance to a selected cancer-targeted therapeutic agent, the method comprising: administering a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, to a subject in an amount sufficient to induce replication stress in tumor or tumor cells and administering the selected cancer-targeted therapeutic agent concurrently or subsequent to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. 3 A method of treating a subject having a tumor or tumor cells that are non-responsive to a prior cancer-targeted therapeutic agent comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a selected cancer- targeted therapeutic agent to the subject. 4 The method of claim 3, wherein the subject received one or more administrations of the prior cancer-targeted therapeutic agent prior to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and wherein the tumor or tumor cells developed decreased responsiveness or resistance to the prior cancer-targeted therapeutic agent. 5 A method of provoking a response in a subject having a tumor or tumor cells that are non-responsive or have decreased responsiveness to a prior cancer-targeted therapeutic agent comprising administering a Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a selected cancer-targeted therapeutic agent to the subject; wherein the prior cancer-targeted therapeutic agent is the same as the selected cancer-targeted therapeutic agent. 6 The method of any one of claims 3-5, wherein prior to treatment with the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, the tumor or tumor cells comprise a gene amplification and wherein the prior cancer-targeted therapeutic agent has an activity directed against a protein encoded by a gene contained within the gene amplification. 7 The method of any one of claims 1-6, wherein the selected cancer-targeted therapeutic agent is administered concurrent or subsequent to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. 8 The method of any one of claims 1-6, wherein the selected cancer-targeted therapeutic agent is administered prior to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. Attorney Docket No.57547-724.601 9. The method of any one of claims 1-8, wherein the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is administered in an amount sufficient to induce replication stress in the tumor or tumor cells. 10. The method of any one of claims 1-9, wherein the subject is identified as having the tumor or tumor cells comprising a gene amplification. 11. The method of claim 10, wherein the gene amplification is a focal gene amplification. 12. The method of claim 10 or 11, wherein the gene amplification is an ecDNA-derived amplification. 13. The method of any one of claims 10-12, wherein the gene amplification is comprised on ecDNA or an HSR (homogeneously staining region). 14. The method of any one of claims 10-13, wherein the tumor or tumor cells comprise an ecDNA signature. 15. The method of any one of claims 10-14, wherein the selected cancer-targeted therapeutic agent is directed against a protein encoded by a gene contained within the gene amplification. 16. The method of any one of claims 10-15, wherein cells comprised within the tumor or the tumor cells are ecDNA competent. 17. The method of any one of claims 1-16, wherein treatment with both the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the selected cancer-targeted therapeutic agent has a greater effect or a longer duration of effect on reduction of one or more of tumor growth, tumor size, number of tumor cells or tumor metastasis as compared to the treatment with either the compound of Formula (I) or the selected cancer-targeted therapeutic agent when administered alone. 18. The method of claim 17, wherein the greater effect is a synergistic effect. 19. The method of any one of claims 1-18, wherein the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and/or the selected cancer-targeted therapeutic agent is administered orally. 20. The method of any one of claims 1-19, wherein treatment comprises administering multiple doses of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and/or the selected cancer-targeted therapeutic agent over a treatment period. 21. The method of any one of claims 1-20, wherein the gene amplification comprises an amplification of a gene selected from the group consisting of ABCB1, AKT, ALK, AR, BCL-2, BCR-ABL, BRAF, CDK4, CDK6, c-MET, EGFR, ER, ERBB3, ERRB2, AK, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, GR, HRAS, IGF1R, KIT, KRAS, MCL-1, MDM2, MDM4, MTOR, MYC, MYCL, MYCN, NRAS, NRG1, NTRK1, NTRK2, NTRK3, PDGFR, PIK3Cδ, PIK3CA/B, RET, and ROS1. 22. The method of any one of claims 1-21, wherein the gene amplification comprises an amplification of a gene selected from the group consisting of CDK4, CDK6, c-MET, EGFR, FGFR1, FGFR2, FGFR3, and FGFR4. Attorney Docket No.57547-724.601 23. The method of any one of claims 1-22, wherein the selected cancer therapeutic agent is an FGFR inhibitor. 24. The method of claim 23, wherein the FGFR inhibitor is infigratinib, futibatinib, or pemigatinib. 25. The method of any one of claims 1-22, wherein the selected cancer therapeutic agent is a CDK4/6 inhibitor. 26. The method of claim 25, wherein the CDK4/6 inhibitor is palbociclib or abemaciclib. 27. The method of any one of claims 1-22, wherein the selected cancer therapeutic agent is an EGFR inhibitor. 28. The method of claim 27, wherein the EGFR inhibitor is erlotinib. 29. The method of any one of claims 1-22, wherein the selected cancer therapeutic agent is a c-MET inhibitor. 30. The method of claim 29, wherein the c-MET inhibitor is tepotinib. 31. The method of any one of claims 1-30, wherein prior to treatment the tumor or tumor cells comprise ecDNA and wherein the treatment results in a reduction in the amount of ecDNA in the tumor or tumor cells. 32. The method of any one of claims 1-30, wherein prior to treatment the tumor or tumor cells comprise ecDNA and wherein level or amount of ecDNA subsequent to the treatment is not increased as compared to prior to treatment. 33. The method of any one of claims 1-32, wherein the method further comprises assessing a sample from a subject for the presence or level of one or more of a gene amplification, a focal gene amplification, ecDNA, HSR or an ecDNA signature. 34. The method of any one of claims 1-33, wherein the method further comprises obtaining information of the presence or level of one or more of a gene amplification, a focal gene amplification, ecDNA, HSR or an ecDNA signature in the tumor or tumor cells from the subject prior to, during or subsequent to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. 35. The method of claim 34, wherein the information is obtained from blood, tissue or one or more cells. 36. The method of claim 34, wherein the information is obtained by liquid biopsy or tissue biopsy. 37. The method of any one of claims 1-36, wherein the prior cancer-targeted therapeutic agent is targeted to the protein encoded by a gene selected from the group consisting of ABCB1, AKT, ALK, AR, BCL-2, BCR-ABL, BRAF, CDK4, CDK6, c-MET, EGFR, ER, ERBB3, ERRB2, AK, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, GR, HRAS, IGF1R, KIT, KRAS, MCL-1, MDM2, MDM4, MTOR, MYC, MYCL, MYCN, NRAS, NRG1, NTRK1, NTRK2, NTRK3, PDGFR, PIK3Cδ, PIK3CA/B, RET, and ROS1. 38. The method of any one of claims 1-37, wherein the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is Attorney Docket No.57547-724.601
Figure imgf000087_0001
wherein: Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R1 is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R1 on the same atom are taken together to form an oxo; n is 0-4; R is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; R is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; R is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; W is N or CRW; R is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R; X is N or CRX; R is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R; Attorney Docket No.57547-724.601 Y is N or CRY; RY is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R; Z is N or CRZ; R is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R; provided that at least one of W, X, Y, or Z is N; L is -O- or -NR5-; R is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R6 is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R6 on the same atom are taken together to form an oxo; or two R6 on the same carbon are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with one or more R; or two R6 on different atoms are taken together to form a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl; each optionally substituted with one or more R; m is 0-8; each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Attorney Docket No.57547-724.601 C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; and each Rc and Rd are independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; each R is independently halogen, -CN, -OH, -OC1-C3alkyl, -OC1-C3haloalkyl, -SC1-C3alkyl, -S(=O)C1- C3alkyl, -S(=O)2C1-C3alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -NH2, -NHC1- C3alkyl, -N(C1-C3alkyl)2, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, - C(=O)NHC1-C3alkyl, -C(=O)N(C1-C3alkyl)2, C1-C3alkyl, C1-C3haloalkyl, C1-C3deuteroalkyl, C1- C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl; or two R on the same atom form an oxo. 39. The method of any one of claims 1-37, wherein the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is a compound of Formula (Ib):
Figure imgf000089_0001
40. The method of any one of claims 1-39, wherein the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof,
Figure imgf000089_0002
pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.
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