EP4626433A1 - Combinaisons d'inhibiteurs de la checkpoint kinase 1 (chk1) et leurs utilisations - Google Patents

Combinaisons d'inhibiteurs de la checkpoint kinase 1 (chk1) et leurs utilisations

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Publication number
EP4626433A1
EP4626433A1 EP23898692.1A EP23898692A EP4626433A1 EP 4626433 A1 EP4626433 A1 EP 4626433A1 EP 23898692 A EP23898692 A EP 23898692A EP 4626433 A1 EP4626433 A1 EP 4626433A1
Authority
EP
European Patent Office
Prior art keywords
compound
formula
cancer
therapeutic agent
heterocycloalkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP23898692.1A
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German (de)
English (en)
Inventor
Christian Hassig
Anthony B. Pinkerton
Zachary D. HORNBY
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boundless Bio Inc
Original Assignee
Boundless Bio Inc
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Filing date
Publication date
Application filed by Boundless Bio Inc filed Critical Boundless Bio Inc
Publication of EP4626433A1 publication Critical patent/EP4626433A1/fr
Pending legal-status Critical Current

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    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/112—Disease subtyping, staging or classification
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers

Definitions

  • 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 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.
  • 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 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
  • 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.
  • 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.
  • 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, 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 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 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.
  • 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%.
  • 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 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, -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, -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, 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 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.
  • 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 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 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 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, 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, 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.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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 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 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 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 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.
  • 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 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 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 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 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • 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 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 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 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 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 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 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.
  • 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.
  • 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).

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Abstract

L'invention concerne des méthodes de traitement du cancer. Les méthodes comprennent l'administration à un sujet en ayant besoin d'une dose thérapeutiquement efficace d'un inhibiteur de Chk1 présentement décrit en combinaison avec un agent thérapeutique supplémentaire.
EP23898692.1A 2022-11-29 2023-11-28 Combinaisons d'inhibiteurs de la checkpoint kinase 1 (chk1) et leurs utilisations Pending EP4626433A1 (fr)

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