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WO2022155202A1 - Fused heterocycles and uses of same - Google Patents

Fused heterocycles and uses of same Download PDF

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Publication number
WO2022155202A1
WO2022155202A1 PCT/US2022/012121 US2022012121W WO2022155202A1 WO 2022155202 A1 WO2022155202 A1 WO 2022155202A1 US 2022012121 W US2022012121 W US 2022012121W WO 2022155202 A1 WO2022155202 A1 WO 2022155202A1
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Prior art keywords
compound
independently selected
optionally substituted
gene
alkyl
Prior art date
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PCT/US2022/012121
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French (fr)
Inventor
Aleksey Igorevich Gerasyuto
Jennifer Lynn KNIGHT
Anthony John Clark
Jiashi WANG
Andrew PLACZEK
Pieter Harm BOS
Zhe Nie
Nicholas Adam BOYLES
Alexandre Cote
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Schrödinger, Inc.
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Publication of WO2022155202A1 publication Critical patent/WO2022155202A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/16—Peri-condensed systems

Definitions

  • This present application relates to fused heterocyclic compounds that are useful for treating proliferative disorders such as cancer.
  • Weel is a highly conserved serine/threonine kinase that inhibits cell cycle progress and cell entry into mitosis through inhibitory phosphorylation of cyclin-dependent kinase 1 and 2 (CDK1 and 2). It is a key regulator of cell cycle progression through S-phase and at the G2-M checkpoint. See, e.g., Hamer, et al., Clin. Cancer Res., Vol. 17, No. 13, pp. 4200-4207 (2011) and McGowan and Russell, EMBO J., Vol. 14, No. 10, pp. 2166-2175 (1995).
  • DNA damage response In normal cells, DNA damage response (DDR) is mediated by various checkpoints which either activate the DNA repair system or induce cellular apoptosis/senescence, therefore maintaining overall genomic integrity.
  • DDR DNA damage response
  • cancer cells with a loss of or defect in DDR due to oncogenic activation or tumor suppressor inactivation, DNA replication may persist to meet the demands of unrestrained proliferation despite the presence of unrepaired DNA lesions, which then leads to replication stress — a hallmark of cancer cells that typically includes the perturbation of error-free DNA replication and/or slow-down of DNA synthesis. See, e.g., Zhang et al, Genes, 2016, 7, 51; 1-16.
  • oncogenes KRAS, MYC, and CCNE1, and CDC25A result in replication stress, for example, through the creation of conflicts between replication and transcription, increasing topological stress, and/or producing a nucleotide shortage.
  • Replication stress can cause cells to slow down replication cycles; therefore, in order to maintain its proliferative program, a cancer cell typically has ways of dealing with and resolving replication stress in order to continue growing.
  • One example is by bypassing mechanisms of DNA damage repair, for example the loss of p53, the mutation of ATM, and defects in the homologous recombination repair pathway (such as via mutation to BRCA1, BRCA2, and PALB2).
  • Weel kinase activity enhances CDK activity, and cells in S phase can be induced to enter mitosis prematurely even if DNA replication is defective or incomplete.
  • the increased CDK activity driven by Weel inhibition can also rapidly increase replication initiation, leading to a shortage of nucleotides that are required for DNA replication.
  • Weel inhibitors can thus be effective to enhance replicative stress and drive cancer cells undergoing a high level of this stress into premature mitosis and subsequent death from mitotic catastrophe.
  • Weel inhibitors currently there are no marketed therapeutic Weel inhibitors.
  • Ring A, X, and m are as defined herein.
  • compounds of Formula (I), or pharmaceutically acceptable salts thereof are selected from compounds of Formula (II), Formula (III), Formula (IV), and pharmaceutically acceptable salts of any of the foregoing.
  • X, and m are as defined herein.
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • Also provided herein is a method of inhibiting mammalian cell proliferation, in vitro or in vivo, comprising contacting the mammalian cell with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.
  • Also provided herein is a method of inhibiting Weel kinase activity in a mammalian cell, in vitro or in vivo, comprising contacting the mammalian cell with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.
  • Also provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.
  • Also provided herein is a method of a cancer in a subject in need thereof, the method comprising:
  • Also provided herein is a method of treating a cancer in a subject in need thereof, the method comprising: administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein, to a subject identified as having a cancer having replication stress.
  • Also provided herein is a method of treating a cancer in a subject in need thereof, the method comprising:
  • Also provided herein is a method of treating a cancer in a subject in need thereof, the method comprising: administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein, to a subject identified as having a cancer having an inactivated tumor suppressor gene.
  • Also provided herein is a method of treating a cancer in a subject in need thereof, the method comprising:
  • Also provided herein is a method of treating a cancer in a subject in need thereof, the method comprising: administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein, to a subject identified as having a cancer having an activated oncogene.
  • Also provided herein is a method of treating a cancer in a subject in need thereof, the method comprising:
  • a method of treating a cancer in a subject in need thereof comprising: administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein, to a subject previously administered one or more doses of a therapy comprising:
  • Also provided herein is a method of treating a cancer in a subject in need thereof, the method comprising: administering to the subject:
  • Also provided herein is a method for inducing mitotic collapse in a mammalian cell, comprising contacting the mammalian cell with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as defined herein, for use in the treatment of cancer (e.g., a cancer with replication stress).
  • cancer e.g., a cancer with replication stress
  • Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein for use in the treatment of cancer.
  • Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the inhibition of Weel kinase activity.
  • Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, in the manufacture of a medicament for the treatment of cancer (e.g., a cancer with replication stress).
  • cancer e.g., a cancer with replication stress
  • Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, defined herein in the manufacture of a medicament for the inhibition of Weel kinase activity.
  • Also provided herein is a process for preparing a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof obtained by a process of preparing the compound as defined herein.
  • tautomer refers to compounds whose structures differ markedly in arrangement of atoms, but which exist in easy and rapid equilibrium, and it is to be understood that compounds provided herein may be depicted as different tautomers, and when compounds have tautomeric forms, all tautomeric forms are intended to be within the scope of the disclosure, and the naming of the compounds does not exclude any tautomer.
  • An example of a tautomeric forms includes the following example:
  • certain compounds provided herein may contain one or more centers of asymmetry and may therefore be prepared and isolated in a mixture of isomers such as a racemic mixture, or in an enantiomerically pure form.
  • halo refers to one of the halogens, group 17 of the periodic table.
  • the term refers to fluorine, chlorine, bromine and iodine.
  • the term refers to fluorine or chlorine.
  • Cl -C6 alkyl refers to a linear or branched hydrocarbon chain containing 1, 2, 3, 4, 5 or 6 carbon atoms, for example methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl.
  • a C1-C3 alkyl group is a linear or branched hydrocarbon chain containing 1, 2, or 3 carbon atoms.
  • C1-C6 alkoxy refers to a C1-C6 alkyl group which is attached to a molecule via oxygen. This includes moieties where the alkyl part may be linear or branched, such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, tertbutoxy, n-pentoxy and n-hexoxy.
  • cyano refers to a -CN radical
  • hydroxyl refers to an -OH radical
  • amino refers to a -NH2 radical.
  • C6-C10 aryl refers to a 6 to 10 carbon mono- or bicyclic ring system wherein at least one ring in the system is aromatic.
  • aryl groups include phenyl, naphthyl, tetrahydronaphthyl.
  • the non-aromatic ring can be a cycloalkyl group, as defined herein.
  • heteroaryl refers to a mono- or bicyclic ring system with, for example, 5 to 10 ring atoms, wherein the ring system is aromatic; wherein one or more carbon atoms in at least one ring in the system is/are replaced with an heteroatom independently selected from N, O, and S.
  • heteroaryl groups include pyridine, pyrimidine, pyrrole, pyrazole, imidazole, and indole.
  • cycloalkyl refers to a saturated or partially unsaturated 3-10 mono- or bicyclic hydrocarbon group; wherein bicyclic systems include fused, spiro (optionally referred to as “spirocycloalkyl” groups), and bridged ring systems.
  • spirocycloalkyl groups include cyclopropyl, cyclohexyl, spiro[2.3]hexyl, and bicyclo[l.l. l]pentyl.
  • heterocyclyl refers to a saturated or partially unsaturated 3-12 membered hydrocarbon monocyclic or bicyclic ring system, having at least one heteroatom within the ring selected from N, O and S.
  • Bicyclic heterocyclyl groups include fused, spiro, and bridged ring systems.
  • the heterocyclyl ring system may include oxo substitution at one or more C, N, or S ring members.
  • one ring can be aromatic, if the other ring is not aromatic.
  • one ring could be phenyl and the other ring could be pyrrolidine, or, one ring could be pyridine and the other ring could be cyclohexane.
  • the heterocyclyl group may be denoted as, for example, a “5-10 membered heterocyclyl group,” which is a ring system containing 5, 6, 7, 8, 9 or 10 atoms at least one being a heteroatom. For example, there may be 1, 2 or 3 heteroatoms, optionally 1 or 2.
  • the heterocyclyl group may be bonded to the rest of the molecule through any carbon atom or through a heteroatom such as nitrogen.
  • heterocyclyl groups include, but are not limited to, piperidinyl, piperazinyl, morpholino, tetrahydropyranyl, azetidinyl, oxetanyl, 2-azaspiro[3.3]heptanyl, pyrrolidin-2-one, sulfolane, isothiazoline S,S-dioxide, and decahydronaphthalenyl.
  • the symbol depicts the point of attachment of an atom or moiety to the indicated atom or group in the remainder of the molecule.
  • the compounds of Formula (I) include pharmaceutically acceptable salts thereof.
  • the compounds of Formula (I) also include other salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and/or purifying compounds of Formula (I) and/or for separating enantiomers of compounds of Formula (I).
  • Non-limiting examples of pharmaceutically acceptable salts of compounds of Formula (I) include trifluoroacetic acid and hydrochloride salts.
  • the compounds of Formula (I) or their salts may be isolated in the form of solvates, and accordingly that any such solvate is included within the scope of the present disclosure.
  • compounds of Formula (I) and salts thereof can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the compounds of Formula (I) include the compounds of Examples 1-47 and stereoisomers and pharmaceutically acceptable salts thereof.
  • the compounds of Examples 1-47 are present in the form of a free base.
  • the compounds of Examples 1-47 are present in the form of a pharmaceutically acceptable salt.
  • pharmaceutically acceptable indicates that the compound, or salt or composition thereof is compatible chemically and/or toxicologically with the other ingredients comprising a formulation and/or the subject being treated therewith.
  • Compounds provided herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. That is, an atom, in particular when mentioned in relation to a compound according to Formula (I), comprises all isotopes and isotopic mixtures of that atom, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form.
  • the compounds provided herein therefore also comprise compounds with one or more isotopes of one or more atoms, and mixtures thereof, including radioactive compounds, wherein one or more non-radioactive atoms has been replaced by one of its radioactive enriched isotopes.
  • Radiolabeled compounds are useful as therapeutic agents, e.g., cancer therapeutic agents, research reagents, e.g., assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds provided herein, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure.
  • Protecting groups can be a temporary substituent which protects a potentially reactive functional group from undesired chemical transformations.
  • the choice of the particular protecting group employed is well within the skill of one of ordinary skill in the art. A number of considerations can determine the choice of protecting group including, but not limited to, the functional group being protected, other functionality present in the molecule, reaction conditions at each step of the synthetic sequence, other protecting groups present in the molecule, functional group tolerance to conditions required to remove the protecting group, and reaction conditions for the thermal decomposition of the compounds provided herein.
  • the field of protecting group chemistry has been reviewed in Greene, T. W .; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2 nd ed.; Wiley: New York, 1991, which is incorporated by reference herein in its entirety.
  • IC50 values are shown in Table A.
  • treat or “treatment” refer to therapeutic or palliative measures.
  • Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease or disorder or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • the term “subject” refers to any animal, including mammals such as humans. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented.
  • Persistent replication stress (sometimes also called replicative stress) is a phenomenon that is observed in cancer cells and is rarely observed in non-cancerous cells.
  • replication stress is fork stalling.
  • a tumor that has “replication stress” is one that has stalled replication forks.
  • ssDNA single-stranded DNA
  • RPA Replication protein A
  • replication stress is exacerbated, for example, by inactivation of one or more tumor suppressor genes (e.g., p53, RBI, CDKN2A, BRCA1, BRCA2, FBXW7, SETD2, NOTCH1 or a combination thereof) (for instance, resulting in the premature onset of S phase), activation of one or more oncogenes (e.g., Cyclin E, CDC25A, Myc, a RAS gene (e.g., KRAS, NRAS, HRAS, or a combination thereof), or a combination thereof), increased DNA damage (e.g., through reactive oxygen species (ROS), chemotherapy (e.g., platinum-based chemotherapy, alkylating agents, nucleobase/nucleoside/nucleotide analogs, topoisomerase I and/or II inhibitors, PARP1 and/or PARP2 inhibitors, ATR inhibitors, Chkl inhibitors), and/or radiation therapy), premature entry into M phase (e.g., via inhibition of We
  • the subject has been identified or diagnosed as having a cancer with replication stress.
  • the subj ect has a tumor that is positive for replication stress.
  • the subject can be a subject with a tumor(s) that tests positive for replication stress.
  • the subject can be a subject whose tumors have replication stress.
  • the subject is suspected of having a tumor with replication stress.
  • the subject has a clinical record indicating that the subject has a tumor that has replication stress.
  • the subject is a pediatric subject.
  • the subject has been identified or diagnosed as having a cancer that, based on histological examination, is determined to be associated with replication stress.
  • replication stress in any appropriate way.
  • detection of replication stress can be detected directly.
  • replication stress can be detected indirectly.
  • replication stress can be detected using H2AX immunohistological staining to measure, for example, ⁇ H2AX .
  • replication stress can be detected by measuring cleaved caspase.
  • replication stress can be detected using a terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay.
  • TUNEL terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling
  • replication stress can be detected by measuring the immune response to cytosolic DNA. See, e.g., Ubhi and Brown. Cancer Research 79.8 (2019): 1730-1739.
  • replication stress can be detected via DNA fiber analyses, for example, by measuring DNA synthesis rates of individual DNA replication forks.
  • replication stress can be detected via DNA pull-downs to identify proteins bound directly at replication forks in vivo. See, e.g., Ubhi and Brown. Cancer Research 79.8 (2019): 1730-1739.
  • replication stress can be detected using a biomarker of replication stress.
  • a biomarker of replication stress can include Ki- 67, Cyclin E, POLD3, ⁇ H2AX, FANCD2, or a combination thereof.
  • a biomarker of replication stress can include pH2AX Serl39 ( ⁇ H2AX), pATR Thrl989, pCHKl Ser345, pRPA32 Ser33, or a combination thereof. See, e.g., Forment and O’Connor, Pharmacology & Therapeutics, 188 (2016) 155-16.
  • a biomarker of replication stress can be an activated oncogene.
  • a biomarker of replication stress can be an inactivated tumor suppressor gene.
  • a biomarker of replication stress can be one or more genes listed in Tables 1A or IB in WO2019173456(Al). In some embodiments, two or more of these methods can be combined.
  • replication stress can be detected using the p53 status of the tumor(s) of the subject, optionally combined with the proliferation index of the tumor(s) (e.g., as measured by Ki67). See, e.g., Reaper et al. Nature Chemical Biology 7.7 (2011): 428-430.
  • replication stress can be detected using chromosomal instability (e.g., by karyotype or by measuring chromosomal instability genes). See, e.g., Burrell et al. Nature 494.7438 (2013): 492-496.
  • the subject has been identified or diagnosed as having a cancer with an inactivation of one or more tumor suppressor genes (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit).
  • the subject has a tumor that is positive for inactivation of one or more tumor suppressor genes (e.g., as determined using a regulatory agency-approved, e.g., FDA- approved, assay or kit).
  • the subject can be a subject with a tumor(s) that is positive for inactivation of one or more tumor suppressor genes (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit).
  • the subject can be a subject whose tumors have inactivation of one or more tumor suppressor genes (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay).
  • the subject is suspected of having a cancer with inactivation of one or more tumor suppressor genes.
  • the subject has a clinical record indicating that the subject has a tumor that has inactivation of one or more tumor suppressor genes (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein).
  • the subject is a pediatric subject.
  • the subject has been identified or diagnosed as having a cancer that, based on histological examination, is determined to inactivation of one or more tumor suppressor genes.
  • Inactivation of a tumor suppressor gene can be through any appropriate mechanism, including, but not limited to, gene deletion, inactivating mutation, inactivating translocation, transcriptional silencing, epigenetic alteration, and degradation of mRNA and/or protein products of the gene.
  • a tumor suppressor gene can be any appropriate tumor suppressor gene.
  • a tumor suppressor gene can be p53, RBI, CDKN2A, BRCA1, BRCA2, FBXW7, SETD2, NOTCH1, or a combination thereof. See, e.g., Forment and O’Connor, Pharmacology & Therapeutics, 188 (2016) 155-167, Reaper et al. Nature Chemical Biology 7.7 (2011): 428-430, and Mendez et al. Clinical Cancer Research 24.12 (2018): 2740-2748.
  • an inactivated tumor suppressor gene is a mutated p53 gene.
  • an inactivated tumor suppressor gene is a deleted p53 gene.
  • an inactivated tumor suppressor gene is a mutated CDKN2A gene. In some embodiments, an inactivated tumor suppressor gene is a mutated NOTCH1 gene. In some embodiments, an inactivated tumor suppressor gene is a deleted FBXW7 gene. A non-limiting example of a cancer that can have a deleted FBXW7 gene is uterine serous carcinoma. In some embodiments, an inactivated tumor suppressor gene is a mutated FBXW7 gene. In some embodiments, an inactivated tumor suppressor gene is a mutated RBI gene. In some embodiments, an inactivated tumor suppressor gene is a deleted BRCA1 gene.
  • an inactivated tumor suppressor gene is a mutated BRCA1 gene. In some embodiments, an inactivated tumor suppressor gene is a BRCA1 gene with a hypermethylated promoter region. In some embodiments, an inactivated tumor suppressor gene is a deleted BRCA2 gene. In some embodiments, an inactivated tumor suppressor gene is a mutated BRCA2 gene. In some embodiments, an inactivated tumor suppressor gene is a BRCA2 gene with a hypermethylated promoter region. In some embodiments, an inactivated tumor suppressor gene is a mutated NOTCH1 gene. In some embodiments, an inactivated tumor suppressor gene is a mutated SETD2 gene.
  • the subject has been identified or diagnosed as having a cancer with an activation of one or more oncogenes (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit).
  • the subject has a tumor that is positive for activation of one or more oncogenes (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit).
  • the subject can be a subject with a tumor(s) that is positive for activation of one or more oncogenes (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit).
  • the subject can be a subject whose tumors have activation of one or more oncogenes (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA- approved, kit or assay).
  • the subject is suspected of having a cancer with activation of one or more oncogenes.
  • the subject has a clinical record indicating that the subject has a tumor that has activation of one or more oncogenes (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein).
  • the subject is a pediatric subject.
  • the subject has been identified or diagnosed as having a cancer that, based on histological examination, is determined to activation of one or more oncogenes.
  • Activation of an oncogene can be through any appropriate mechanism, including, but not limited to, gene amplification, activating mutation, activating translocation, transcriptional activation, epigenetic alteration, and/or overexpression of the protein product of the oncogene.
  • an oncogene can be any appropriate oncogene.
  • an oncogene can be cyclin E (sometimes also called cyclin El or CCNE1), CDC25A, Myc, a RAS gene (e.g., KRAS, NRAS, HRAS, or a combination thereof), or a combination thereof.
  • cyclin E sometimes also called cyclin El or CCNE1
  • CDC25A Myc
  • RAS gene e.g., KRAS, NRAS, HRAS, or a combination thereof
  • an activated oncogene is an amplified cyclin E gene.
  • cancers that can have amplified cyclin E (e.g., cyclin El) include rhabdomyosarcoma, urinary bladder adenocarcinoma, malignant fibrous histiocytoma, small intestine adenocarcinoma, medullary breast cancer, gallbladder adenocarcinoma, stomach adenocarcinoma, urinary bladder transitional cell carcinoma, urinary bladder small cell carcinoma, non-serous ovarian carcinoma, uterine cervix squamous cell carcinoma, and ovarian endometrial (endometrioid) carcinoma.
  • an activated oncogene is an overexpressed CDC25A.
  • cancer that can have overexpressed CDC25 A include breast cancer, colorectal cancer, lung cancer, hepatocellular carcinoma, prostate cancer, esophageal cancer (e.g., esophageal squamous cell carcinoma), pancreatic ductal adenocarcinoma, thyroid neoplasms, non-Hodgkin's lymphoma, and neuroblastoma.
  • an activated oncogene is an amplified Myc gene.
  • Non-limiting examples of cancers that can have Myc amplification include breast invasive ductal carcinoma, lung adenocarcinoma, prostate adenocarcinoma, colon adenocarcinoma, and high grade ovarian serous adenocarcinoma.
  • an activated oncogene is a Myc gene with an activating translocation.
  • an activated oncogene is a transcriptionally activated Myc gene.
  • an activated oncogene is a mutated RAS gene (e.g., a KRAS gene, an NRAS gene, an HRAS gene, or a combination thereof).
  • a mutated RAS gene (e.g., a KRAS gene, an NRAS gene, an HRAS gene, or a combination thereof) includes a mutation at position G12 of the protein product of the gene.
  • a mutated RAS gene (e.g., a KRAS gene, an NRAS gene, an HRAS gene, or a combination thereof) includes a mutation at position G13 of the protein product of the gene.
  • a mutated RAS gene (e.g., a KRAS gene, an NRAS gene, an HRAS gene, or a combination thereof) includes a mutation at position Q61 of the protein product of the gene.
  • Non-limiting examples of cancers that can have KRAS mutations include pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and non-small cell lung cancer (NSCLC).
  • the subject has been identified or diagnosed as having a cancer with increased DNA damage.
  • the subject has a tumor that is positive for increased DNA damage.
  • the subject can be a subject with a tumor(s) that tests positive for increased DNA damage.
  • the subject can be a subject whose tumors have increased DNA damage.
  • the subject is suspected of having a tumor with increased DNA damage.
  • the subject has a clinical record indicating that the subject has a tumor that has increased DNA damage.
  • the subject is a pediatric subject.
  • the subject has been identified or diagnosed as having a cancer that, based on histological examination, is determined to be associated with increased DNA damage.
  • a DNA-damaging agent can include a platinum-based chemotherapy, an alkylating agent, a nucleobase, nucleoside, and/or nucleotide analog, or a combination thereof.
  • a DNA repair inhibiting agent can include a topoisomerase I inhibitor, a topoisomerase II inhibitor, a PARP inhibitor, an ATR inhibitor, a Chk inhibitor, or a combination thereof.
  • platinum-based chemotherapeutics include carboplatin, cisplatin, and oxaplatin.
  • Non-limiting examples of alkylating agents include cyclophosphamide, carmustine, busulfan, procarbazine, dacarbazine, temozoloamide, thiotepa, and mitomycin C.
  • Non-limiting examples of nucleobase, nucleoside, and/or nucleotide analogs include fluorouracil, cytarabine, gemcitabine, azacitidine, and decitabine.
  • Non-limiting examples of topoisomerase I inhibitors include topotecan, irinotecan, belotecan, and camptothecin.
  • Non-limiting examples of topoisomerase II inhibitors include etoposide, tenoposide, doxorubicin, daunorubicin, epirubicin, and idarubacin.
  • Non-limiting examples of PARP inhibitors include olaparib, niraparib, rucaparib, talazoparib, and veliparib.
  • Non-limiting examples of ATR inhibitors include AZD6738, BAY1895344, and M6620.
  • Non-limiting examples of Chkl inhibitors include prexasertib, GDC-0575, SCH 900776, and SRA737.
  • the term “pediatric subject” as used herein refers to a subject under the age of 21 years at the time of diagnosis or treatment.
  • the term “pediatric” can be further be divided into various subpopulations including: neonates (from birth through the first month of life); infants (1 month up to two years of age); children (two years of age up to 12 years of age); and adolescents (12 years of age through 21 years of age (up to, but not including, the twenty-second birthday)).
  • Berhman RE Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: W.B. Saunders Company, 1996; Rudolph AM, et al . Rudolph ’s Pediatrics, 21 st Ed.
  • a pediatric subject is from birth through the first 28 days of life, from 29 days of age to less than two years of age, from two years of age to less than 12 years of age, or 12 years of age through 21 years of age (up to, but not including, the twenty-second birthday).
  • a pediatric subject is from birth through the first 28 days of life, from 29 days of age to less than 1 year of age, from one month of age to less than four months of age, from three months of age to less than seven months of age, from six months of age to less than 1 year of age, from 1 year of age to less than 2 years of age, from 2 years of age to less than 3 years of age, from 2 years of age to less than seven years of age, from 3 years of age to less than 5 years of age, from 5 years of age to less than 10 years of age, from 6 years of age to less than 13 years of age, from 10 years of age to less than 15 years of age, or from 15 years of age to less than 22 years of age.
  • compounds of Formula (I), or a pharmaceutically acceptable salt thereof are useful for preventing diseases and disorders as defined herein (for example, cancer).
  • preventing means the prevention of the onset, recurrence or spread, in whole or in part, of the disease or condition as described herein, or a symptom thereof.
  • cancers that exhibit replication stress are more reliant on the cell cycle checkpoint regulators such as Weel.
  • cancers that exhibit replication stress overexpress Weel .
  • Non-limiting examples of cancers that can overexpress Weel include hepatocellular carcinoma, breast cancers, cervical cancers, lung cancers, squamous cell carcinoma, diffuse intrinsic pontine glioma, glioblastoma, medulloblastoma, leukemia, melanoma, ovarian cancers, pancreatic cancers, and colorectal cancers. See, e.g., P Reigan et al Trends in Pharmacol Sci 2016; Mir, et al., Cancer Cell, Vol. 18, No. 3, pp. 244-257 (2010)).
  • regulatory agency refers to a country's agency for the approval of the medical use of pharmaceutical agents with the country.
  • FDA U.S. Food and Drug Administration
  • R 1 is a C6-C10 aryl optionally substituted with 1-3 independently selected R A or a 5-10 membered heteroaryl optionally substituted with 1-3 independently selected R A ;
  • R 2 is a C1-C6 alkyl optionally substituted with 1-3 independently selected R B or a C3-C8 cycloalkyl optionally substituted with 1-3 independently selected R B ;
  • R 2A is hydrogen, a C1-C6 alkyl optionally substituted with 1-3 independently selected R B , or a C3-C8 cycloalkyl optionally substituted with 1-3 independently selected R B ;
  • R 2B is hydrogen, a C1-C6 alkyl optionally substituted with 1-3 independently selected R B , or a C3-C8 cycloalkyl optionally substituted with 1-3 independently selected R B ;
  • Ring A is a 4-10 membered heterocyclyl, 5-10 membered heteroaryl, or C6-C10 aryl; or wherein Ring A and R 5 are absent;
  • R 3 is hydrogen, halogen, or C1-C6 alkyl optionally substituted with 1-3 independently selected R c ;
  • R 4 is hydrogen or C1-C6 alkyl; each R 5 is independently halogen, C1-C6 alkyl, C3-C8 cycloalkyl, cyano, -(CH2)q- NR5AR5B, _(CH2)n-4-10 membered heterocyclyl optionally substituted with 1-3 independently selected R D , or -(CH2)p-5-10 membered heteroaryl optionally substituted with 1-3 independently selected R E ; m is 0, 1, 2, or 3; n is 0-6; p is 0-6; q is 0-6;
  • X is O, S, or NR 6 ;
  • R 6 is hydrogen or C1-C6 alkyl; each R A is independently selected from halogen, cyano, hydroxyl, -NR F R G , C1-C6 alkyl, C1-C6 alkoxy, and C3-C8 cycloalkyl; each R B , R C , R D , and R E are independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, and -NR F R G ; and each R 5A , R 5B , R F , and R G are independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl.
  • R 2A is hydrogen, a C1-C6 alkyl optionally substituted with 1-3 independently selected R B (as described herein), or a C3-C8 cycloalkyl optionally substituted with 1-3 independently selected R B (as described herein). In some embodiments, R 2A is hydrogen.
  • R 2A is C1-C6 alkyl optionally substituted with 1-3 independently selected R B . In some embodiments, R 2A is C3-C8 cycloalkyl optionally substituted with 1-3 independently selected R B . In some embodiments, R 2A is C1-C6 alkyl substituted with 1-3 independently selected R B . In some embodiments, R 2A is C3-C8 cycloalkyl substituted with 1-3 independently selected R B . In some embodiments, R 2A is C1-C6 alkyl. In some embodiments, R 2A is C3-C8 cycloalkyl.
  • R 2B is hydrogen, a C1-C6 alkyl optionally substituted with 1-3 independently selected R B (as described herein), or a C3-C8 cycloalkyl optionally substituted with 1-3 independently selected R B (as described herein). In some embodiments, R 2B is hydrogen. In some embodiments, R 2B is C1-C6 alkyl optionally substituted with 1-3 independently selected R B . In some embodiments, R 2B is C3-C8 cycloalkyl optionally substituted with 1-3 independently selected R B . In some embodiments, R 2B is C1-C6 alkyl substituted with 1-3 independently selected R B .
  • R 2B is C3-C8 cycloalkyl substituted with 1-3 independently selected R B . In some embodiments, R 2B is C1-C6 alkyl. In some embodiments, R 2B is C3-C8 cycloalkyl.
  • benzophenyl is a double bond
  • R 2 and R 2B are absent
  • R 2A is hydrogen, a C1-C6 alkyl optionally substituted with 1-3 independently selected R B (as described herein), or a C3-C8 cycloalkyl optionally substituted with 1-3 independently selected R B (as described herein), for example, in compounds of Formula (IV).
  • R 1 is a C6-C10 aryl optionally substituted with 1-3 independently selected R A or a 5-10 membered heteroaryl optionally substituted with 1-3 independently selected R A ;
  • R 2 is a C1-C6 alkyl optionally substituted with 1-3 independently selected R B or a C3-C8 cycloalkyl optionally substituted with 1-3 independently selected R B ;
  • Ring A is a 4-10 membered heterocyclyl, 5-10 membered heteroaryl, or C6-C10 aryl; or wherein Ring A and R 5 are absent;
  • R 3 is hydrogen, halogen, or C1-C6 alkyl optionally substituted with 1-3 independently selected R c ;
  • R 4 is hydrogen or C1-C6 alkyl; each R 5 is independently halogen, C1-C6 alkyl, C3-C8 cycloalkyl, cyano, -(CH2)q- NR5AR5B, _(CH2)n-4-10 membered heterocyclyl optionally substituted with 1-3 independently selected R D , or -(CH2)p-5-10 membered heteroaryl optionally substituted with 1-3 independently selected R E ; m is 0, 1, 2, or 3; n is 0-6; p is 0-6; q is 0-6;
  • X is O, S, or NR 6 ;
  • R 6 is hydrogen or C1-C6 alkyl; each R A is independently selected from halogen, cyano, hydroxyl, -NR F R G , C1-C6 alkyl, C1-C6 alkoxy, and C3-C8 cycloalkyl; each R B , R C , R D , and R E are independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, and -NR F R G ; and each R 5A , R 5B , R F , and R G are independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl.
  • R 1 is a C6-C10 aryl optionally substituted with 1-3 independently selected R A or a 5-10 membered heteroaryl optionally substituted with 1-3 independently selected R A ;
  • R 2 is a C1-C6 alkyl optionally substituted with 1-3 independently selected R B or a C3-C8 cycloalkyl optionally substituted with 1-3 independently selected R B ;
  • Ring A is a 4-10 membered heterocyclyl, 5-10 membered heteroaryl, or C6-C10 aryl; or wherein Ring A and R 5 are absent;
  • R 3 is hydrogen, halogen, or C1-C6 alkyl optionally substituted with 1-3 independently selected R c ;
  • R 4 is hydrogen or C1-C6 alkyl; each R 5 is independently halogen, C1-C6 alkyl, C3-C8 cycloalkyl, cyano, -(CH2)q- NRSARSB, _(CH2)n-4-10 membered heterocyclyl optionally substituted with 1-3 independently selected R D , or -(CH2)p-5-10 membered heteroaryl optionally substituted with 1-3 independently selected R E ; m is 0, 1, 2, or 3; n is 0-6; p is 0-6; q is 0-6;
  • X is O, S, or NR 6 ;
  • R 6 is hydrogen or C1-C6 alkyl;
  • each R A is independently selected from halogen, cyano, hydroxyl, -NR F R G , C1-C6 alkyl, C1-C6 alkoxy, and C3-C8 cycloalkyl;
  • each R B , R C , R D , and R E are independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, and -NR F R G ;
  • each R 5A , R 5B , R F , and R G are independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl.
  • R 1 is a C6-C10 aryl optionally substituted with 1-3 independently selected R A or a 5-10 membered heteroaryl optionally substituted with 1-3 independently selected R A ;
  • R 2A is hydrogen, a C1-C6 alkyl optionally substituted with 1-3 independently selected R B , or a C3-C8 cycloalkyl optionally substituted with 1-3 independently selected R B ;
  • Ring A is a 4-10 membered heterocyclyl, 5-10 membered heteroaryl, or C6-C10 aryl; or wherein Ring A and R 5 are absent;
  • R 3 is hydrogen, halogen, or C1-C6 alkyl optionally substituted with 1-3 independently selected R c ;
  • R 4 is hydrogen or C1-C6 alkyl; each R 5 is independently halogen, C1-C6 alkyl, C3-C8 cycloalkyl, cyano, -(CH2)q- NRSARSB, _(CH2)n-4-10 membered heterocyclyl optionally substituted with 1-3 independently selected R D , or -(CH2)p-5-10 membered heteroaryl optionally substituted with 1-3 independently selected R E ; m is 0, 1, 2, or 3; n is 0-6; p is 0-6; q is 0-6;
  • X is O, S, or NR 6 ;
  • R 6 is hydrogen or C1-C6 alkyl; each R A is independently selected from halogen, cyano, hydroxyl, -NR F R G , C1-C6 alkyl, C1-C6 alkoxy, and C3-C8 cycloalkyl; each R B , R C , R D , and R E are independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, and -NR F R G ; and each R 5A , R 5B , R F , and R G are independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl.
  • R 1 is a C6-C10 aryl substituted with 1-3 independently selected R A .
  • R 1 is phenyl substituted with 1-3 independently selected R A .
  • R 1 is phenyl substituted with 1 R A .
  • R 1 is phenyl substituted with 2 independently selected R A .
  • R 1 is phenyl substituted with 3 independently selected R A .
  • R 1 is a 5-10 membered heteroaryl optionally substituted with 1-3 independently selected R A . In some embodiments, R 1 is a 5-10 membered heteroaryl substituted with 1 R A . In some embodiments, R 1 is a 5-10 membered heteroaryl substituted with 2 independently selected R A . In some embodiments, R 1 is a 5-10 membered heteroaryl substituted with 3 independently selected R A . In some embodiments, R 1 is a 5-6 membered heteroaryl optionally substituted with 1 or 2 independently selected R A
  • R 1 is an unsubstituted C6-C10 aryl. In some embodiments, R 1 is an unsubstituted phenyl. In some embodiments, R 1 is an unsubstituted 5-10 membered heteroaryl. In some embodiments, R 1 is an unsubstituted 5-6 membered heteroaryl, such as pyridine, pyrimidine, pyrrole, imidazole, and pyrazole.
  • each R A is independently selected from halogen, cyano, hydroxyl, -NR F R G , C1-C6 alkyl, C1-C6 alkoxy, and C3-C8 cycloalkyl.
  • each R A is independently halogen. In some embodiments, each R A is cyano. In some embodiments, each R A is hydroxyl. In some embodiments, each R A is independently -NR F R G , In some embodiments, each R A is independently Cl- C6 alkyl. In some embodiments, each R A is independently C1-C6 alkoxy. In some embodiments, each R A is independently C3-C8 cycloalkyl.
  • one or two R A is independently halogen. In some embodiments, one R A is cyano. In some embodiments, one R A is hydroxyl. In some embodiments, one R A is -NR F R G , In some embodiments, one R A is C1-C6 alkyl. In some embodiments, one R A is C1-C6 alkoxy. In some embodiments, one R A is C3-C8 cycloalkyl.
  • each R A is independently selected from fluoro, chloro, bromo, cyano, hydroxyl, amino, C1-C3 alkyl, C1-C3 alkoxy, and C3-C6 cycloalkyl. In some embodiments, each R A is independently selected from chloro, bromo, cyano, and methoxy. In some embodiments, each R A is independently selected from chloro and bromo. In some embodiments, each R A is chloro. In some embodiments, each R A is independently selected from chloro and cyano. In some embodiments, each R A is cyano.
  • R 1 when R 1 is phenyl substituted with two R A groups, the R A groups can be ortho, meta, or para to each other. In some embodiments, when R 1 is 5-6 membered heteroaryl substituted with at least one R A group, the at least one R A group can be substituted on a carbon atom, or on a nitrogen atom, such as the nitrogen atom of a pyrazole.
  • R 1 is In some embodiments, R 1 is
  • R 2 is a C1-C6 alkyl optionally substituted with 1-3 independently selected R B or a C3-C8 cycloalkyl optionally substituted with 1-3 independently selected R B ;
  • R 2 is a C1-C6 alkyl optionally substituted with 1-3 independently selected R B . In some embodiments, R 2 is a C1-C6 alkyl substituted with 1- 3 independently selected R B . In some embodiments, R 2 is C1-C6 alkyl substituted with 1 R B . In some embodiments, R 2 is C1-C6 alkyl substituted with 2 independently selected R B . In some embodiments, R 2 is C1-C6 alkyl substituted with 3 independently selected R B .
  • R 2 is a C3-C8 cycloalkyl optionally substituted with 1-3 independently selected R B . In some embodiments, R 2 is a C3-C8 cycloalkyl substituted with 1-3 independently selected R B . In some embodiments, R 2 is C3-C8 cycloalkyl substituted with 1 R B . In some embodiments, R 2 is C3-C8 cycloalkyl substituted with 2 independently selected R B . In some embodiments, R 2 is C3-C8 cycloalkyl substituted with 3 independently selected R B .
  • R 2 is absent, for example, in compounds of Formula (IV).
  • each R B is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, and -NR F R G . In some embodiments, each R B is independently selected from fluoro, chloro, hydroxyl, cyano, C1-C3 alkyl, C1-C3 alkoxy, and -NR F R G . In some embodiments, each R B is independently selected from fluoro, hydroxyl, C1-C3 alkoxy, and -NR F R G . In some embodiments, each R B is independently selected from fluoro, hydroxyl, methoxy, and -NR F R G . In some embodiments, each R B is independently selected from fluoro, hydroxyl, and methoxy.
  • R 2 is an unsubstituted C1-C6 alkyl. In some embodiments, R 2 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 2 is methyl. In some embodiments, R 2 is an unsubstituted C3-C8 cycloalkyl. In some embodiments, R 2 is cyclopropyl or cyclobutyl.
  • R 3 is hydrogen, halogen, or C1-C6 alkyl optionally substituted with 1-3 independently selected R c .
  • R 3 is C1-C3 alkyl optionally substituted with 1-3 independently selected R c . In some embodiments, is C1-C3 alkyl substituted with 1-3 independently selected R c . In some embodiments, R 3 is C1-C3 alkyl substituted with 1 R c . In some embodiments, R 3 is C1-C3 alkyl substituted with 2 independently selected R c . In some embodiments, R 3 is C1-C3 alkyl substituted with 3 independently selected R c . In some embodiments, each R c is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, and -NR F R G .
  • each R c is independently selected from fluoro, chloro, hydroxyl, cyano, C1-C3 alkyl, C1-C3 alkoxy, and -NR F R G . In some embodiments, each R c is independently selected from fluoro, hydroxyl, C1-C3 alkoxy, and -NR F R G . In some embodiments, each R c is independently selected from fluoro, hydroxyl, methoxy, and -NR F R G . In some embodiments, each R c is independently selected from fluoro, hydroxyl, and methoxy.
  • one or two R c is independently halogen. In some embodiments, one R c is hydroxyl. In some embodiments, one R c is cyano. In some embodiments, one R c is C1-C6 alkyl. In some embodiments, one R c is C1-C6 alkoxy. In some embodiments, one R c is -NR F R G .
  • R 3 is hydrogen, halogen, or unsubstituted C1-C3 alkyl. In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is halogen. In some embodiments, R 3 is fluoro or chloro. In some embodiments, R 3 is an unsubstituted C1-C3 alkyl. In some embodiments, R 3 is methyl.
  • R 4 is hydrogen or C1-C6 alkyl. In some embodiments, R 4 is hydrogen or C1-C3 alkyl. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is C1-C3 alkyl. In some embodiments, R 4 is methyl.
  • X is NR 6 .
  • R 6 is hydrogen or C1-C6 alkyl. In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is C1-C6 alkyl. In some embodiments, R 6 is C1-C3 alkyl. In some embodiments, R 6 is methyl.
  • X is S. In some embodiments, X is O.
  • Ring A and R 5 are absent, and the bond from Ring A to Formula (I) (including compounds of Formulae (II), (III), and (IV)) is replaced with a hydrogen atom.
  • Ring A is a C6-C10 aryl. In some embodiments, Ring A is phenyl.
  • Ring A is a 5-10 membered heteroaryl. In some embodiments, Ring A is monocyclic. In some embodiments, Ring A is bicyclic. In some embodiments, Ring A is a 5, 6, or 10 membered heteroaryl. In some embodiments, Ring A is a 5 membered heteroaryl, such as pyrrole, pyrazole, or imidazole. In some embodiments, Ring A is a pyrazole. In some embodiments, Ring A is a 6 membered heteroaryl, such as pyridine, pyrimidine, or pyridazine. In some embodiments, Ring A is pyridine. In some embodiments, Ring A is a 10 membered fused bicyclic heteroaryl, such as quinoline.
  • Ring A is a 4-10 membered heterocyclyl. In some embodiments, Ring A is a 5-10 membered heterocyclyl containing 2-4 heteroatoms selected from O and N. In some embodiments, Ring A is a 5 or 6 membered monocyclic heterocyclyl containing one nitrogen atom and 1 or 2 additional heteroatoms selected from O and N. In some embodiments, Ring A is an 8-10 membered bicyclic heterocyclyl containing one nitrogen atom and 1 or 2 additional heteroatoms selected from O and N. In some embodiments, Ring A is 5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine.
  • Ring A is attached to the fused tricyclic moiety of Formula (I) (including compounds of Formulae (II), (III), and (IV)) by a carbon atom in Ring A. In some embodiments, Ring A is attached to the fused tricyclic moiety of Formula (I) (including compounds of Formulae (II), (III), and (IV)) by a nitrogen atom in Ring A.
  • Ring A is In some embodiments, Ring A is
  • Ring A is In some embodiments,
  • each R 5 is independently halogen, C1-C6 alkyl, C3-C8 cycloalkyl, cyano, -(CH2)q-NR 5A R 5B , -(CH2)n-4-10 membered heterocyclyl optionally substituted with 1-3 independently selected R D , or -(CH2)p-5-10 membered heteroaryl optionally substituted with 1-3 independently selected R E .
  • one R 5 is halogen, C1-C6 alkyl, C3-C8 cycloalkyl, cyano, -(CH2)q-NR 5A R 5B , -(CH2)n-4-10 membered heterocyclyl optionally substituted with 1-3 independently selected R D , or -(CH2)p-5-10 membered heteroaryl optionally substituted with 1-3 independently selected R E .
  • each R 5 is independently halogen, C1-C3 alkyl, C3-C6 cycloalkyl, cyano, -(CH2)q-NR 5A R 5B , -(CH2)n-4-6 membered heterocyclyl optionally substituted with R D , or -(CH2)p-5-6 membered heteroaryl optionally substituted with R E .
  • one R 5 is independently halogen, C1-C3 alkyl, C3-C6 cycloalkyl, cyano, -(CH2)q-NR 5A R 5B , -(CH2)n-4-6 membered heterocyclyl optionally substituted with R D , or -(CH2) P -5-6 membered heteroaryl optionally substituted with R E .
  • each R 5 is independently fluoro, chloro, methyl, cyclopropyl, cyclobutyl, cyano, or -(CH2)n-4-6 membered heterocyclyl optionally substituted with C1-C6 alkyl.
  • one R 5 is independently fluoro, chloro, methyl, cyclopropyl, cyclobutyl, cyano, or -(CH2)n-4-6 membered heterocyclyl optionally substituted with C1-C6 alkyl.
  • one R 5 is halogen, C1-C6 alkyl, C3-C8 cycloalkyl, or cyano; and the other R 5 group is -(CH2)n-4-10 membered heterocyclyl optionally substituted with 1-3 independently selected R D .
  • one R 5 is halogen or C1-C6 alkyl; and the other R 5 group is -(CH2)n-4-10 membered heterocyclyl optionally substituted with 1-3 independently selected R D .
  • one R 5 is halogen or C1-C6 alkyl; and the other R 5 group is -(CH2)n-4-10 membered heterocyclyl optionally substituted with R D .
  • one R 5 is halogen or C1-C6 alkyl; and the other R 5 group is -(CH2)n-4-10 membered heterocyclyl.
  • each R 5 is independently -(CH2)n-4-10 membered heterocyclyl optionally substituted with 1-3 independently selected R D . In some embodiments, each R 5 is independently -(CH2)n-4-10 membered heterocyclyl substituted with 1 R D . In some embodiments, each R 5 is independently -(CH2)n-4-10 membered heterocyclyl substituted with 2 independently selected R D . In some embodiments, each R 5 is independently -(CH2)n-4-10 membered heterocyclyl substituted with 3 independently selected R D . In some embodiments, one R 5 is independently -(CH2)n-4-10 membered heterocyclyl optionally substituted with 1-3 independently selected R D .
  • one R 5 is independently -(CH2)n-4-10 membered heterocyclyl substituted with 1 R D . In some embodiments, one R 5 is independently -(CH2)n-4-10 membered heterocyclyl substituted with 2 independently selected R D . In some embodiments, one R 5 is independently -(CH2)n-4-10 membered heterocyclyl substituted with 3 independently selected R D .
  • n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3, 4, 5, or 6.
  • each R D is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, and -NR F R G . In some embodiments, each R D is independently selected from fluoro, chloro, hydroxyl, cyano, C1-C3 alkyl, C1-C3 alkoxy, and -NR F R G . In some embodiments, each R D is independently selected from fluoro, hydroxyl, cyano, methoxy, and C1-C3 alkyl. In some embodiments, each R D is an independently selected C1-C3 alkyl. In some embodiments, each R D is methyl.
  • one R D is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, and -NR F R G . In some embodiments, one R D is independently selected from fluoro, chloro, hydroxyl, cyano, C1-C3 alkyl, C1-C3 alkoxy, and -NR F R G . In some embodiments, one R D is independently selected from fluoro, hydroxyl, cyano, methoxy, and C1-C3 alkyl. In some embodiments, one R D is an independently selected C1-C3 alkyl. In some embodiments, one R D is methyl.
  • each R 5 is independently -(CH2)n-4-6 membered heterocyclyl optionally substituted with C1-C6 alkyl. In some embodiments, R 5 is -(CH2)n-4-6 membered heterocyclyl optionally substituted with C1-C6 alkyl. In some embodiments, R 5 is -(CH2)n-4-6 membered heterocyclyl substituted with C1-C6 alkyl. In some embodiments, R 5 is -(CH2)n-4-6 membered heterocyclyl substituted with methyl. In some embodiments, R 5 is a 4-6 membered heterocyclyl. In some embodiments, R 5 is -(CH2)-4-6 membered heterocyclyl.
  • R 5 is -(CH2)2-4-6 membered heterocyclyl.
  • the heterocyclyl is connected to Formula (I) (including compounds of Formulae (II), (III), and (IV)) via a carbon atom.
  • the heterocyclyl is connected to Formula (I) (including compounds of Formulae (II), (III), and (IV)) via a nitrogen atom.
  • the heterocyclyl of R 5 is selected from azetidine, pyrrolidine, 2-pyrrolidinone, piperidine, and piperazine.
  • the heterocyclyl of R 5 is selected from azetidine, pyrrolidine, 2-pyrrolidinone, and piperidine.
  • heterocyclyl of R 5 is selected from
  • each R 5 is -(CH2)q-NR 5A R 5B .
  • q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3, 4, 5, or 6.
  • each R 5A and R 5B are independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl. In some embodiments, each R 5A and R 5B are independently selected from hydrogen and C1-C3 alkyl. In some embodiments, one of R 5A and R 5B is hydrogen and the other of R 5A and R 5B is C1-C3 alkyl. In some embodiments, R 5A and R 5B are the same. In some embodiments, R 5A and R 5B are different. In some embodiments, R 5A and R 5B are both hydrogen. In some embodiments, R 5A and R 5B are both methyl. In some embodiments, one of R 5A and R 5B is hydrogen, and the other of R 5A and R 5B is methyl.
  • each R 5 is independently -(CH2)p-5-10 membered heteroaryl optionally substituted with 1-3 independently selected R E . In some embodiments, each R 5 is independently -(CH2)p-5-6 membered heteroaryl optionally substituted with 1-3 independently selected R E . In some embodiments, each R 5 is independently -(CH2) P -5-6 membered heteroaryl optionally substituted with 1 R E . In some embodiments, each R 5 is independently -(CH2) P -5-6 membered heteroaryl optionally substituted with 2 independently selected R E . In some embodiments, each R 5 is independently -(CH2)p-5-6 membered heteroaryl optionally substituted with 3 independently selected R E .
  • each R 5 is independently -(CH2)p-5-6 membered heteroaryl. In some embodiments, one R 5 is independently -(CH2)p-5-10 membered heteroaryl optionally substituted with 1-3 independently selected R E . In some embodiments, one R 5 is independently -(CH2) P -5-6 membered heteroaryl optionally substituted with 1-3 independently selected R E . In some embodiments, one R 5 is independently -(CH2) P -5-6 membered heteroaryl optionally substituted with 1 R E . In some embodiments, one R 5 is independently -(CH2) P -5-6 membered heteroaryl optionally substituted with 2 independently selected R E . In some embodiments, one R 5 is independently -(CH2) P -5-6 membered heteroaryl optionally substituted with 3 independently selected R E . In some embodiments, one R 5 is independently -(CH2) P -5-6 membered heteroaryl.
  • p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3, 4, 5, or 6.
  • each R E is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, and -NR F R G . In some embodiments, each R E is independently selected from fluoro, chloro, hydroxyl, cyano, C1-C3 alkyl, C1-C3 alkoxy, and -NR F R G . In some embodiments, each R E is independently selected from fluoro, hydroxyl, cyano, methoxy, and C1-C3 alkyl. In some embodiments, each R E is an independently selected C1-C3 alkyl. In some embodiments, each R E is methyl.
  • each R F and R G are independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl. In some embodiments, each R F and R G are independently selected from hydrogen, C1-C3 alkyl, and C3-C6 cycloalkyl. In some embodiments, each R F and R G are independently selected from hydrogen and C1-C3 alkyl. In some embodiments, R F and R G are the same. In some embodiments, R F and R G are different. In some embodiments, R F and R G are both hydrogen. In some embodiments, R F and R G are both methyl. In some embodiments, one of R F and R G is hydrogen, and the other of R F and R G is methyl.
  • m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 0.
  • Ring A and R 5 are absent.
  • Ring A is a 5 membered heteroaryl; m is 1; and R 5 is -(CH2)n-4-6 membered heterocyclyl optionally substituted with C1-C6 alkyl.
  • Ring A is pyrazole; m is 1; and R 5 is -(CH2)n-4-6 membered heterocyclyl optionally substituted with C1-C6 alkyl.
  • Ring A is pyrazole; m is 1; R 5 is - (CH2)n-4-6 membered heterocyclyl optionally substituted with C1-C6 alkyl; and n is 0.
  • Ring A is pyrazole; m is 1; R 5 is -(CH2)n-4-6 membered heterocyclyl optionally substituted with C1-C6 alkyl; and n is 1. In some embodiments, Ring A is pyrazole; m is 1; and R 5 is -(CH2)n-4-6 membered heterocyclyl optionally substituted with C1-C6 alkyl; wherein R 5 is connected to the pyrazole via a nitrogen atom in the pyrazole ring.
  • Ring A is pyrazole; m is 1; R 5 is -(CH2)n-4-6 membered heterocyclyl optionally substituted with C1-C6 alkyl; and n is 0; wherein R 5 is connected to the pyrazole via a nitrogen atom in the pyrazole ring.
  • Ring A is pyrazole; m is 1; R 5 is -(CH2)n-4-6 membered heterocyclyl optionally substituted with Cl -C6 alkyl; and n is 1; wherein R 5 is connected to the pyrazole via a nitrogen atom in the pyrazole ring.
  • the compound of Formula (I) is selected from the compounds described in Table 1, or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) has the structure of Formula (II- A): wherein:
  • R A1 and R A2 are independently selected from halogen, cyano, and C1-C6 alkoxy;
  • R 2 is a C1-C6 alkyl optionally substituted with 1-3 independently selected R B or a C3-C8 cycloalkyl optionally substituted with 1-3 independently selected R B ;
  • R 5 is C1-C6 alkyl, C3-C8 cycloalkyl, -(CH2)n-4-10 membered heterocyclyl optionally substituted with 1-3 independently selected R D , or -(CH2)p-5-10 membered heteroaryl optionally substituted with 1-3 independently selected R E ; n is 0-6; p is 0-6; and each R B , R D , and R E are independently selected from halogen, hydroxyl, C1-C3 alkyl, and C1-C3 alkoxy.
  • the compound of Formula (I) has the structure of Formula (III- A):
  • R A1 and R A2 are independently selected from halogen, cyano, and C1-C6 alkoxy;
  • R 2 is a C1-C6 alkyl optionally substituted with 1-3 independently selected R B or a C3-C8 cycloalkyl optionally substituted with 1-3 independently selected R B ;
  • R 5 is C1-C6 alkyl, C3-C8 cycloalkyl, -(CH2)n-4-10 membered heterocyclyl optionally substituted with 1-3 independently selected R D , or -(CH2)p-5-10 membered heteroaryl optionally substituted with 1-3 independently selected R E ; n is 0-6; p is 0-6; and each R B , R D , and R E are independently selected from halogen, hydroxyl, C1-C3 alkyl, and C1-C3 alkoxy.
  • the compound of Formula (I) has the structure of Formula (IV- A): wherein:
  • R A1 and R A2 are independently selected from halogen, cyano, and C1-C6 alkoxy;
  • R 2A is hydrogen or C1-C6 alkyl
  • R 5 is C1-C6 alkyl, C3-C8 cycloalkyl, -(CH2)n-4-10 membered heterocyclyl optionally substituted with 1-3 independently selected R D , or -(CH2)p-5-10 membered heteroaryl optionally substituted with 1-3 independently selected R E ;
  • n is 0-6;
  • p is 0-6; and each R D and R E are independently selected from halogen, hydroxyl, C1-C3 alkyl, and C1-C3 alkoxy.
  • R 2A is hydrogen. In some embodiments, R 2A is C1-C6 alkyl. In some embodiments, R 2A is methyl.
  • R A1 and R A2 are independently selected from halogen and C1-C6 alkoxy. In some embodiments, R A1 and R A2 are independently selected from halogen and cyano. In some embodiments, R A1 and R A2 are independently selected halogen. In some embodiments, R A1 and R A2 are chloro.
  • R 2 is a C1-C6 alkyl optionally substituted with 1-3 independently selected R B or a C3-C8 cycloalkyl optionally substituted with 1-3 independently selected R B ;
  • R 2 is a C1-C6 alkyl optionally substituted with 1-3 independently selected R B . In some embodiments, R 2 is a C1-C6 alkyl substituted with 1- 3 independently selected R B . In some embodiments, R 2 is C1-C6 alkyl substituted with 1 R B . In some embodiments, R 2 is C1-C6 alkyl substituted with 2 independently selected R B . In some embodiments, R 2 is C1-C6 alkyl substituted with 3 independently selected R B .
  • R 2 is a C3-C8 cycloalkyl optionally substituted with 1-3 independently selected R B . In some embodiments, R 2 is a C3-C8 cycloalkyl substituted with 1-3 independently selected R B . In some embodiments, R 2 is C3-C8 cycloalkyl substituted with 1 R B . In some embodiments, R 2 is C3-C8 cycloalkyl substituted with 2 independently selected R B . In some embodiments, R 2 is C3-C8 cycloalkyl substituted with 3 independently selected R B .
  • each R B is independently selected from halogen, hydroxyl, C1-C3 alkyl, and C1-C3 alkoxy. In some embodiments, each R B is independently selected from fluoro, chloro, hydroxyl, and methoxy.
  • R 2 is an unsubstituted C1-C6 alkyl. In some embodiments, R 2 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 2 is methyl. In some embodiments, R 2 is an unsubstituted C3-C8 cycloalkyl. In some embodiments, R 2 is cyclopropyl or cyclobutyl.
  • R 5 is C1-C6 alkyl, C3-C8 cycloalkyl, -(CH2)n-4-10 membered heterocyclyl optionally substituted with 1-3 independently selected R D , or -(CH2)p-5-10 membered heteroaryl optionally substituted with 1-3 independently selected R E .
  • R 5 is -(CH2)n-4-10 membered heterocyclyl optionally substituted with 1-3 independently selected R D . In some embodiments, R 5 is -(CH2)n-4- 10 membered heterocyclyl substituted with 1 R D . In some embodiments, R 5 is -(CH2)n-4- 10 membered heterocyclyl substituted with 2 independently selected R D . In some embodiments, R 5 is -(CH2)n-4-10 membered heterocyclyl substituted with 3 independently selected R D .
  • n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3, 4, 5, or 6.
  • each R D is independently selected from halogen, hydroxyl, C1-C3 alkyl, and C1-C3 alkoxy. In some embodiments, each R D is independently selected from fluoro, chloro, hydroxyl, C1-C3 alkyl, and methoxy. In some embodiments, each R D is independently a C1-C3 alkyl. In some embodiments, each R D is methyl.
  • each R 5 is independently -(CH2)n-4-6 membered heterocyclyl optionally substituted with C1-C6 alkyl. In some embodiments, R 5 is -(CH2)n-4-6 membered heterocyclyl optionally substituted with C1-C6 alkyl. In some embodiments, R 5 is -(CH2)n-4-6 membered heterocyclyl substituted with C1-C6 alkyl. In some embodiments, R 5 is -(CH2)n-4-6 membered heterocyclyl substituted with methyl. In some embodiments, R 5 is a 4-6 membered heterocyclyl. In some embodiments, R 5 is -(CH2)-4-6 membered heterocyclyl.
  • R 5 is -(CH2)2-4-6 membered heterocyclyl.
  • the heterocyclyl is connected to the Formula (I) (including compounds of Formulae (II), (III), and (IV)) via a carbon atom.
  • the heterocyclyl is connected to Formula (I) (including compounds of Formulae (II), (III), and (IV)) via a nitrogen atom.
  • the heterocyclyl of R 5 is selected from azetidine, pyrrolidine, 2- pyrrolidinone, piperidine, and piperazine.
  • the heterocyclyl of R 5 is selected from azetidine, pyrrolidine, 2-pyrrolidinone, and piperidine.
  • heterocyclyl of R 5 is selected from embodiments, the heterocyclyl of R 5 is selected from
  • R 5 is -(CH2)p-5-10 membered heteroaryl optionally substituted with 1-3 independently selected R E . In some embodiments, R 5 is -(CH2)p-5-6 membered heteroaryl optionally substituted with 1-3 independently selected R E . In some embodiments, R 5 is -(CH2) P -5-6 membered heteroaryl optionally substituted with 1 R E . In some embodiments, R 5 is -(CH2) P -5-6 membered heteroaryl optionally substituted with 2 independently selected R E . In some embodiments, R 5 is -(CH2) P -5-6 membered heteroaryl optionally substituted with 3 independently selected R E .
  • p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3, 4, 5, or 6.
  • each R E is independently selected from halogen, hydroxyl, C1-C3 alkyl, and C1-C3 alkoxy. In some embodiments, each R E is independently selected from fluoro, chloro, hydroxyl, C1-C3 alkyl, and methoxy. In some embodiments, each R E is independently a C1-C3 alkyl. In some embodiments, each R E is methyl.
  • the compound of Formula (I) (e.g., compounds of Formulae (I), (II), (III), and (IV)) is present in the form of a pharmaceutically acceptable salt.
  • the compound of Formula (I) e.g., compounds of Formulae (I), (II), (III), and (IV)
  • the free base form is present in some embodiments, the compound is selected from the group consisting of the compounds in Table 1, or a pharmaceutically acceptable salt thereof.
  • a nitrogen protecting group can be any temporary substituent which protects an amine or an NH-containing heteroaryl moiety from undesired chemical transformations.
  • nitrogen protecting groups include allyl, benzyl (e.g., benzyl, p- methoxybenzyl, 2,4-dimethoxybenzyl, and trityl), acetyl, tri chloroacetyl, trifluoroacetyl, pent-4-enoyl, alkoxycarbonyls (e.g., methoxycarbonyl, /-butoxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, and 2,2,2-trichloroethoxycarbonyl), sulfonyls (e.g., benzenesulfonyl, /?-toluenesulfonyl, and -nitrobenzenesulfonyl), alkoxyalkyl groups, (e.g.,
  • An oxygen protecting group can be any temporary substituent which protects a hydroxyl moiety from undesired chemical transformations.
  • oxygen protecting groups include, but are not limited to alkanoyl (e.g., acetyl and /-butyl carbonyl), benzoyl, benzyl (e.g., benzyl, p-m ethoxybenzyl, and 2,4-dimethoxybenzyl, and trityl), alkoxycarbonyls (e.g., methyloxycarbonyl, t-butyl carbonyl, benzyloxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethylcarbonyl, and 9-fluorenylmethylcarbonyl), sulfonyls (e.g., benzene sulfonyl, p-toluenesulfyl, and p-nitrobenzenesulfonyl), alkoxyalky
  • R 1 , R 2 , R 2A , R 2B , R 3 , R 4 , and X are as defined herein;
  • Z is selected from halogen and trifluoromethanesulfonyl; with a compound of Formula (A) wherein:
  • Ring A, R 5 , and m are as defined herein;
  • M is selected from -B(OH)2, -Sn(R 7A )3, -Zn-R 7B , and -Mg-R 7C ; each occurrence of R 7A is an independently selected C1-C6 alkyl;
  • R 7B is chloro, bromo, or iodo
  • R 7C is chloro, bromo, or iodo; wherein when the compound of Formula (F-A) and/or Formula (A) collectively comprise one or more N-H and/or O-H moieties, at least one of the one or more N-H and/or O-H moieties is optionally protected with an independently selected nitrogen or oxygen protecting group; to form an optionally protected compound of Formula (I); and
  • R 1 , R 2 , R 2A , R 2B , R 3 , R 4 , and X are as defined herein.
  • Z is halogen.
  • Z is chloro.
  • Z is bromo.
  • Z is iodo.
  • Z is trifluoromethanesulfonyl.
  • Ring A, R 5 , and m are as defined herein.
  • M is selected from -B(OH)2, and -Sn(R 7A )3. In some embodiments, M is selected from and -B(OH)2. In some embodiments,
  • M is In some embodiments, M is -B(OH)2. In some embodiments, M is -
  • M is -Zn-R 7B . In some embodiments, M is -Mg-R 7C .
  • each occurrence of R 7A is an independently selected C1-C4 alkyl. In some embodiments, each occurrence of R 7A is an independently selected methyl or n-butyl. In some embodiments, each occurrence of R 7A is methyl. In some embodiments, each occurrence of R 7A is n-butyl.
  • R 7B is chloro. In some embodiments, R 7B is bromo. In some embodiments, R 7B is iodo.
  • R 7C is chloro. In some embodiments, R 7C is bromo. In some embodiments, R 7C is iodo.
  • reacting the compound of Formula (I’ -A) with the compound of Formula (A) is performed in the presence of a transition metal catalyst.
  • the transition metal catalyst is selected from a palladium catalyst and a nickel catalyst.
  • the transition metal catalyst is a palladium catalyst.
  • the palladium catalyst is selected from tetrakistriphenylphospine palladium(O), bis(triphenylphosphine)palladium(II) dichloride and [1,1’- bis(diphenylphosphino)ferrocene]dichloropalladium(II).
  • the palladium catalyst is [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II).
  • the transition metal catalyst is a nickel catalyst.
  • reacting the compound of Formula (F-A) with the compound of Formula (A) is performed in the presence of a ligand.
  • the ligand is a phosphine ligand.
  • the ligand is triphenylphosphine.
  • reacting the compound of Formula (F-A) with the compound of Formula (A) is performed in the presence of a base.
  • the base is selected from potassium carbonate, a potassium alkoxide (e.g., potassium tert- butoxide), sodium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, and a non-nucleophilic amine base (e.g., trimethylamine or diisopropylethylamine).
  • the base is sodium carbonate.
  • reacting the compound of Formula (I’ -A) with the compound of Formula (A) is performed in one or more solvents.
  • the one or more solvents are selected from 1,4-di oxane, water, acetonitrile, toluene, tetrahydrofuran, and N,N-dimethylformamide.
  • the one or more solvents are 1,4-di oxane and water.
  • reacting the compound of Formula (F-A) with the compound of Formula (A) is performed in the presence of [1,1’- bis(diphenylphosphino)ferrocene] dichloropalladium(II) and sodium carbonate in water and 1,4-di oxane.
  • reacting the compound of Formula (F-A) with the compound of Formula (A) is performed at from about 20 °C to about 150 °C, for example, from about 20 °C to about 100 °C, from about 40 °C to about 100 °C, from about 60 °C to about 100 °C, from about 80 °C to about 100 °C, from about 85 °C to about 95 °C, from about 70 °C to about 150 °C, from about 90 °C to about 150 °C, from about 110 °C to about 150 °C, from about 87 °C to about 93 °C, or about 90 °C. In some embodiments, reacting the compound of Formula (F-A) with the compound of Formula (A) is performed at about 90 °C.
  • the compound of Formula (F-A) and/or Formula (A) collectively comprise one or more (e.g., one or two) N-H and/or O-H moieties. In some embodiments, at least one of the one or more (e.g., one or two) N-H and/or O-H moieties is protected with a nitrogen or oxygen protecting group. In some embodiments, one N-H moiety (e.g., one N-H moiety in the compound of Formula (F-A) is protected with a nitrogen protecting group.
  • two N-H moieties e.g., one N-H moiety in the compound of Formula (F-A) and one N-H moiety on the compound of Formula (A) are each protected with an independently selected nitrogen protecting group.
  • one O-H moiety is protected with an oxygen protecting group.
  • two O-H moieties are each protected with an independently selected oxygen protecting group.
  • one N-H moiety is protected with a nitrogen protecting group and one O-H moiety is protected with an oxygen protecting group.
  • the nitrogen protecting group is selected from p- toluenesulfonyl, tert-butoxycarbonyl, and 2-(trimethylsilyl)ethoxymethyl.
  • the nitrogen protecting group is p-toluenesulfonyl. In some embodiments, the nitrogen protecting group is tert-butoxy carbonyl. In some embodiments, the nitrogen protecting group is 2-(trimethylsilyl)ethoxymethyl.
  • the compound of Formula (F-A) is a compound of Formula (I’-A-i): (F-A-i).
  • the compound of Formula (A) comprises an N-H moiety protected with a tert-butoxycarbonyl.
  • the protected compound of Formula (I) is a compound of Formula (I-i):
  • the moiety comprises an N-H moiety protected with a nitrogen protecting group.
  • the nitrogen protecting group is tert-butoxycarbonyl.
  • the protected compound of Formula (I) is a compound of Formula (I-i), and step (ii) comprises treating the compound of Formula (I-i) with acid.
  • the acid comprises hydrogen chloride.
  • the protected compound of Formula (I) is a compound of Formula (I-i), and step (ii) comprises treating the compound of Formula (I-i) with a fluoride source.
  • the fluoride source is tetrabutylammonium fluoride.
  • the compound of Formula (F-A) and/or Formula (A) comprises no N-H and/or O-H moieties and step (ii) is absent.
  • the compound of Formula (F-A) is prepared by reacting a compound of Formula (F-B) to form the compound of Formula (F-A).
  • reacting the compound of Formula (F-B) to form the compound of Formula (I’ -A) comprises reacting the compound of Formula (F-B) with a base, then an electrophilic halogenating reagent.
  • the base is a lithium base.
  • the lithium base is selected from methyllithium, n- butyllithium, phenyllithium, lithium tetramethylpiperidide, lithium bis(trimethylsilyl)amide, and lithium diisopropylamide.
  • the base is lithium diisopropylamide.
  • the electrophilic halogenating reagent is l,2-dibromo-l,l,2,2-tetrachloro-ethane. In some embodiments, the electrophilic halogenating reagent is N-bromosuccinimide.
  • the compound of Formula (I’-B) is a compound of Formula
  • the compound of Formula (F-B) is a compound of Formula
  • the compound of Formula (F-B) is a compound of Formula
  • the compound of Formula (F-B-i) is prepared by reacting a compound of Formula (F-C) to form the compound of Formula (F-B).
  • reacting the compound of Formula (F-C) to form the compound of Formula (F-B-i) comprises reacting the compound of Formula (F-C) with formaldehyde and acid to form the compound of Formula (I’-B-i).
  • the acid is p-toluenesulfonic acid.
  • the compound of Formula (I’-B-ii) is prepared by reacting the compound of Formula (F-C) to form the compound of Formula (I’-B-ii). In some embodiments, reacting the compound of Formula (F-C) to form the compound of Formula (I’-B-ii) comprises reacting the compound of Formula (I’-C) with a carbonyl equivalent.
  • the carbonyl equivalent is triphosgene or carbonyldiimidazole. In some embodiments, the carbonyl equivalent is triphosgene. In some embodiments, the carbonyl equivalent is carbonyldiimidazole.
  • the compound of Formula (I’-B-iii) is prepared by reacting a compound of Formula (I’-C-i): to form the compound of Formula (I’-B-iii).
  • reacting the compound of Formula (I’-C-i) to form the compound of Formula (I’-B-iii) comprises reacting the compound of Formula (I’-C-i) with CR 2A (OEt)3 or CR 2A (OMe)3.
  • the compound of Formula (I’-C) is prepared by reacting a compound of Formula (I’-D) wherein Z’ is a halogen; with R 2 -NH2 to form the compound of Formula (I’-C).
  • Z’ is selected from chloro, bromo, and iodo. In some embodiments, Z’ is chloro. In some embodiments, Z’ is bromo. In some embodiments, Z’ is iodo. In some embodiments, reacting the compound of Formula (I’-D) with R 2 -NH2 to form the compound of Formula (I’-C) is performed in the presence of a base.
  • the base is trimethylamine or N-ethyl-N-isopropyl-propan-2-amine. In some embodiments, the base is N-ethyl-N-isopropyl-propan-2-amine.
  • reacting the compound of Formula (F-D) with R 2 -NH2 to form the compound of Formula (I’-C) is performed under microwave irradiation. In some embodiments, reacting the compound of Formula (F-D) with R 2 -NH2 to form the compound of Formula (I’-C) is performed at from about 90 °C to about 200 °C, for example, from about 90 °C to about 180 °C, from about 90 °C to about 160 °C, from about 100 °C to about 200 °C, from about 120 °C to about 200 °C, from about 140 °C to about 200 °C, from about 120 °C to about 180 °C, from about 140 °C to about 160 °C, from about 145 °C to about 155 °C, from about 148 °C to about 152 °C, or about 150 °C.
  • the compound of Formula (I’-C-i) is prepared by reacting the compound of Formula (I’-D) with NH3 to form the compound of Formula (I’-C-i).
  • reacting the compound of Formula (I’-D) with NH3 to form the compound of Formula (I’-C-i) is performed in methanol, water, or 1,4-dioxane optionally in a sealed tube at a pressure greater than atmospheric pressure.
  • reacting the compound of Formula (I’-D) with NH3 to form the compound of Formula (I’-C-i) is performed at from about 90 °C to about 200 °C, for example, from about 90 °C to about 180 °C, from about 90 °C to about 160 °C, from about 100 °C to about 200 °C, from about 120 °C to about 200 °C, from about 140 °C to about 200 °C, from about 120 °C to about 180 °C, from about 140 °C to about 160 °C, from about 145 °C to about 155 °C, from about 148 °C to about 152 °C, or about 150 °C.
  • the compound of Formula (I’-D) is prepared by reacting a compound of Formula (I’-E) wherein Z’ is a halogen; with R 1 -NH2 to form the compound of Formula (I’-D).
  • reacting the compound of Formula (I’-E) to form the compound of Formula (I’-D) comprises reacting the compound of Formula (I’-E) to form a compound of Formula (I’-E-i) then reacting the compound of Formula (I’-E-i) with Rj-NEb to form the compound of Formula (I’-D).
  • reacting the compound of Formula (I’-E) to form a compound of Formula (I’-E-i) comprises reacting the compound of Formula (I’-E) with thionyl chloride or oxalyl chloride. In some embodiments, reacting the compound of Formula (I’-E) to form a compound of Formula (I’-E-i) comprises reacting the compound of Formula (I’-E) with thionyl chloride.
  • reacting the compound of Formula (I’-E-i) with Rj-NEb to form the compound of Formula (I’-D) further comprises reacting Rj-NEb with a base, then with the compound of Formula (I’-E-i) to form the compound of Formula (I’-D).
  • the base is a metal bis(trimethylsilyl)amide.
  • the metal bis(trimethylsilyl)amide is selected from lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, and potassium bis(trimethylsilyl)amide.
  • the metal bis(trimethylsilyl)amide is lithium bis(trimethylsilyl)amide.
  • the compound of Formula (F-A) is a compound of Formula (I’-A-ii) -ii).
  • the compound of Formula (I’-A-ii) is prepared by reacting a compound of Formula (I’-F) to form the compound of Formula (I’-A-ii).
  • the compound of Formula (F-A-ii) is prepared by reacting the compound of Formula (F-F) to form the compound of Formula (F-A-ii).
  • reacting the compound of Formula (I’-F) to form the compound of Formula (F-A-ii) comprises reacting the compound of Formula (F-F) with a carbonyl equivalent.
  • the carbonyl equivalent is triphosgene or carbonyldiimidazole.
  • the carbonyl equivalent is triphosgene.
  • the carbonyl equivalent is carbonyldiimidazole.
  • the compound of Formula (F-F) is prepared by reacting a compound of Formula (F-G) wherein Z’ is a halogen; with R 2 -NH2 to form the compound of Formula (F-F).
  • Z’ is selected from chloro, bromo, and iodo. In some embodiments, Z’ is chloro. In some embodiments, Z’ is bromo. In some embodiments, Z’ is iodo.
  • reacting the compound of Formula (F-G) with R 2 -NH2 to form the compound of Formula (I’-F) is performed in the presence of a base.
  • the base is trimethylamine or N-ethyl-N-isopropyl-propan-2-amine. In some embodiments, the base is N-ethyl-N-isopropyl-propan-2-amine.
  • reacting the compound of Formula (F-G) with R 2 -NH2 to form the compound of Formula (I’-F) is performed under microwave irradiation. In some embodiments, reacting the compound of Formula (F-G) with R 2 -NH2 to form the compound of Formula (I’-F) is performed at from about 90 °C to about 200 °C, for example, from about 90 °C to about 180 °C, from about 90 °C to about 160 °C, from about 100 °C to about 200 °C, from about 120 °C to about 200 °C, from about 140 °C to about 200 °C, from about 120 °C to about 180 °C, from about 140 °C to about 160 °C, from about 145 °C to about 155 °C, from about 148 °C to about 152 °C, or about 150 °C.
  • preparing the compound of Formula (F-G) comprises reacting a compound of Formula (F-H) wherein Z’ is a halogen; with Rj-NFb to form the compound of Formula (I’-H).
  • reacting the compound of Formula (F-H) to form the compound of Formula (I’-G) comprises reacting the compound of Formula (F-H) to form a compound of Formula (I’-H-i) then reacting the compound of Formula (F-H-i) with R 1 -NH2 to form the compound of Formula (F-G).
  • reacting the compound of Formula (F-H) to form the compound of Formula (F-H-i) comprises reacting the compound of Formula (I’-H) with thionyl chloride or oxalyl chloride. In some embodiments, reacting the compound of Formula (F-H) to form a compound of Formula (F-H-i) comprises reacting the compound of Formula (I’-H) with thionyl chloride.
  • reacting the compound of Formula (F-H-i) with R 1 -NH2 to form the compound of Formula (I’-G) further comprises reacting R 1 -NH2 with a base, then with the compound of Formula (F-H-i) to form the compound of Formula (I’-G).
  • the base is a metal bis(trimethylsilyl)amide.
  • the metal bis(trimethylsilyl)amide is selected from lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, and potassium bis(trimethylsilyl)amide.
  • the metal bis(trimethylsilyl)amide is lithium bis(trimethylsilyl)amide.
  • Replication stress is present in many cancers, and as noted herein, it can in some cases be exacerbated by one or more factors, such as genetic features of the cancer and/or administration of DNA-damaging agents, DNA repair inhibiting agents, and/or radiation.
  • a method of treating a cancer in a subject in need thereof including identifying the cancer as having replication stress; and administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof.
  • Identifying the cancer as having replication stress can include any appropriate method of identification, such as the methods described herein.
  • identifying the cancer as having replication stress includes staining for replication forks in a sample from the subject.
  • identifying the cancer as having replication stress includes detecting a biomarker of replication stress in a sample from the subject.
  • a biomarker of replication stress can include any appropriate biomarker or set of biomarkers.
  • a biomarker of replication stress includes Ki- 67, Cyclin E, POLD3, yH2AX, FANCD2, or a combination thereof.
  • a biomarker of replication stress includes pH2AX Serl39, pATR Thrl989, pCHKl Ser345, pRPA32 Ser33, or a combination thereof.
  • a biomarker of replication stress includes an activated oncogene.
  • a biomarker of replication stress includes an inactivated tumor suppressor gene.
  • Also provided herein is a method of treating a cancer in a subject in need thereof, the method comprising administering an effective amount of a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof to a subject identified as having a cancer having replication stress.
  • a genetic characteristic of a cancer can be indicative that the cancer can be treated effectively with a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof.
  • Some such genetic characteristics include one or more inactivated tumor suppressor genes and/or one or more activated oncogenes.
  • a method of treating a cancer in a subject in need thereof including: identifying the cancer as having an inactivated tumor suppressor gene; and administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof.
  • a method of treating a cancer in a subject in need thereof including administering an effective amount of a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof to a subject identified as having a cancer having an inactivated tumor suppressor gene.
  • an inactivated tumor suppressor gene can be achieved by any appropriate mechanism, such as those described herein.
  • an inactivated tumor suppressor gene includes an inactivation selected from the group consisting of a deletion of the gene, an inactivating mutation in the protein product of the gene, an inactivating translocation in the protein product of the gene, a transcriptional silencing of the gene, an epigenetic alteration of the gene, degradation of mRNA products of the gene, degradation of protein products of the gene, and combinations thereof.
  • An inactive tumor suppressor gene can be any appropriate inactivated tumor suppressor gene, such as any of those described herein.
  • the tumor suppressor gene is selected from the group consisting of p53, RBI, CDKN2A, BRCA1, BRCA2, FBXW7, SETD2, NOTCH 1, and a combination thereof.
  • the inactivated tumor suppressor gene includes a mutation in the protein product of a p53 gene. In some embodiments, the inactivated tumor suppressor gene includes a deleted p53 gene. In some embodiments, the inactivated tumor suppressor gene includes a mutation in the protein product of a CDKN2A gene. In some embodiments, the inactivated tumor suppressor gene includes a mutation in the protein product of a NOTCH1 gene. In some embodiments, the inactivated tumor suppressor gene includes a deleted FBXW7 gene. In some embodiments, the inactivated tumor suppressor gene includes a mutation in the protein product of a FBXW7 gene.
  • the inactivated tumor suppressor gene includes a mutation in the protein product of a RBI gene. In some embodiments, the inactivated tumor suppressor gene includes a deleted BRCA1 gene. In some embodiments, the inactivated tumor suppressor gene includes a mutation in the protein product of a BRCA1 gene. In some embodiments, the inactivated tumor suppressor gene includes a BRCA1 gene with a hypermethylated promoter region. In some embodiments, the inactivated tumor suppressor gene includes a deleted BRCA2 gene. In some embodiments, the inactivated tumor suppressor gene includes a mutation in the protein product of a BRCA2 gene. In some embodiments, the inactivated tumor suppressor gene includes a BRCA2 gene with a hypermethylated promoter region. In some embodiments, the inactivated tumor suppressor gene includes a mutation in the protein product of a NOTCH1 gene. In some embodiments, the inactivated tumor suppressor gene includes a mutation in the protein product of a SETD2 gene.
  • the inactivated tumor suppressor gene is selected from the group consisting of a mutation in the protein product of a p53 gene, a deleted p53 gene, a mutation in the protein product of a CDKN2A gene, a mutation in the protein product of a NOTCH1 gene, a deleted FBXW7 gene, a mutation in the protein product of a FBXW7 gene, a mutation in the protein product of a RBI gene, a deleted BRCA1 gene, a mutation in the protein product of a BRCA1 gene, a BRCA1 gene with a hypermethylated promoter region, a deleted BRCA2 gene, a mutation in the protein product of a BRCA2 gene, a BRCA2 gene with a hypermethylated promoter region, a mutation in the protein product of a NOTCH1 gene, a mutation in the protein product of a SETD2 gene, and a combination thereof.
  • Also provided herein is a method of treating a cancer in a subject in need thereof, the method including: identifying the cancer as having an activated oncogene; and administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof. Also provided herein is a method of treating a cancer in a subject in need thereof, the method including administering an effective amount of a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof to a subject identified as having a cancer having an activated oncogene.
  • an activation of an oncogene can be achieved by any appropriate mechanism, such as those described herein
  • the activated oncogene has an activation selected from the group consisting of an amplification of the oncogene, an activating mutation of the protein product of the oncogene, an activating translocation of the protein product of the oncogene, transcriptional activation of the oncogene, epigenetic alteration of the oncogene, overexpression of the protein product of the oncogene, and combinations thereof.
  • An activated oncogene can be any appropriate oncogene, such as those described herein.
  • the oncogene is selected from the group consisting of cyclin E, CDC25A, Myc, a RAS gene, and combinations thereof.
  • RAS gene includes a KRAS gene.
  • the RAS gene includes an NRAS gene.
  • the RAS gene includes an HRAS gene.
  • the activated oncogene includes an amplified cyclin E gene. In some embodiments, the activated oncogene includes an overexpression of the protein product of the CDC25A gene. In some embodiments, the activated oncogene includes an amplified Myc gene. In some embodiments, the activated oncogene includes an activating translocation in the protein product of a Myc gene. In some embodiments, the activated oncogene includes a transcriptionally activated Myc gene. In some embodiments, the activated oncogene includes a mutation in the protein product of a RAS gene. In some embodiments, the mutated RAS gene includes a mutation at position G12 of the protein product of the RAS gene.
  • the mutated RAS gene includes a mutation at position G13 of the protein product of the RAS gene. In some embodiments, wherein the mutated RAS gene includes a mutation at position Q61 of the protein product of the RAS gene. In some embodiments, the RAS gene includes a KRAS gene.
  • the activated oncogene is selected from the group consisting of an amplified cyclin E gene, an overexpression of the protein product of the CDC25A gene, an amplified Myc gene, an activating translocation in the protein product of a Myc gene, a transcriptionally activated Myc gene, a mutation in the protein product of a RAS gene, and a combination thereof.
  • the mutated RAS gene includes a mutation at position G12, G13, Q61, or a combination thereof, of the protein product of the RAS gene.
  • the RAS gene includes a KRAS gene. In the field of medical oncology, it is normal practice to use a combination of different forms of treatment to treat each subject with cancer.
  • compositions provided herein may be, for example, surgery, radiotherapy, and chemotherapeutic agents, such as other kinase inhibitors, kinase inhibitors, signal transduction inhibitors, and/or monoclonal antibodies.
  • chemotherapeutic agents such as other kinase inhibitors, kinase inhibitors, signal transduction inhibitors, and/or monoclonal antibodies.
  • a surgery may be open surgery or minimally invasive surgery.
  • Compounds of Formula (I), or a pharmaceutically acceptable salt thereof therefore may also be useful as adjuvants to cancer treatment, that is, they can be used in combination with one or more additional therapies or therapeutic agents, for example, a chemotherapeutic agent that works by the same or by a different mechanism of action.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be used prior to administration of an additional therapeutic agent or additional therapy.
  • a subject in need thereof can be administered one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof for a period of time and then undergo at least partial resection of the tumor.
  • the treatment with one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof reduces the size of the tumor (e.g., the tumor burden) prior to the at least partial resection of the tumor.
  • a subject in need thereof can be administered one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof for a period of time and under one or more rounds of radiation therapy.
  • the treatment with one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof reduces the size of the tumor (e.g., the tumor burden) prior to the one or more rounds of radiation therapy.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered in combination with an effective amount of at least one additional therapeutic agent selected from one or more additional therapies or therapeutic (e.g., chemotherapeutic or immunomodulatory) agents.
  • Non-limiting examples of additional therapeutic agents include: PARP inhibitors, other DNA repair inhibiting agents (e.g. topoisomerase inhibitors, DNA-dependent protein kinase (DNA-PK) inhibitors, ATM inhibitors, Aurora kinase inhibitors (such as Aurora A and/or Aurora B inhibitors), ATR inhibitors, and CHK1 inhibitors), signal transduction pathway inhibitors, Bcr-Abl inhibitors, histone deacetylase (HD AC) inhibitors, checkpoint inhibitors, modulators of the apoptosis pathway, cytotoxic chemotherapeutics, angiogenesis-targeted therapies, immune-targeted agents, including immunotherapy, and radiotherapy.
  • the additional therapeutic agent is an immunotherapy.
  • Non-limiting examples of checkpoint inhibitors include ipilimumab, tremelimumab, nivolumab, pidilizumab, MPDL3208A, MEDI4736, MSB0010718C, BMS-936559, BMS-956559, BMS-935559 (MDX-1105), AMP-224, and pembrolizumab.
  • cytotoxic chemotherapeutics are selected from bleomycin, cabazitaxel, capecitabine, carboplatin, cisplatin, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, docetaxel, paclitaxel, doxorubicin, etoposide, fluorouracil, gemcitabine, irinotecan, lomustine, methotrexate, mitomycin C, oxaliplatin, paclitaxel, pemetrexed, temozolomide, and vincristine.
  • Non-limiting examples of angiogenesis-targeted therapies include aflibercept and bevacizumab.
  • a DNA repair inhibiting agent can include a topoisomerase I inhibitor, a topoisomerase II inhibitor, a PARP inhibitor, an ATR inhibitor, a Chk inhibitor, a DNA-dependent protein kinase (DNA-PK) inhibitor, an ATM inhibitor, an Aurora kinase inhibitor (such as an Aurora A and/or B inhibitor), or a combination thereof.
  • Non-limiting examples of PARP inhibitors include olaparib, niraparib, rucaparib, talazoparib, and veliparib.
  • Non-limiting examples of ATR inhibitors include AZD6738, BAY1895344, and M6620.
  • Chkl inhibitors include prexasertib, GDC-0575, SCH 900776, and SRA737.
  • Non-limiting examples of DNA-PK inhibitors include AZD7648, M3814, LY294002, nedisertib, and samotolisib.
  • Non-limiting examples of ATM inhibitors include KU55933, AZD0156, AZD1390, dactosilib, and berzosertib.
  • Non-limiting examples of Aurora kinase inhibitors include LY3295668, ZM447439, tozasertib, hesparadin, alisertib, and MLN8054.
  • Non-limiting examples of modulators of the apoptosis pathway include Bcl-2 inhibitors such as obataclax, venetoclax, and navitoclax.
  • signal transduction pathway inhibitors include Ras-Raf- MEK-ERK pathway inhibitors (e.g., binimetinib, selumetinib, encorafenib, sorafenib, trametinib, and vemurafenib) or PI3K-Akt-mTOR-S6K pathway inhibitors (e.g., sirolimus, everolimus, rapamycin, perifosine, temsirolimus).
  • Ras-Raf- MEK-ERK pathway inhibitors e.g., binimetinib, selumetinib, encorafenib, sorafenib, trametinib, and vemurafenib
  • PI3K-Akt-mTOR-S6K pathway inhibitors e.g., sirolimus, everolimus, rapamycin, perifosine, temsirolimus.
  • Bcr-Abl inhibitors include imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib.
  • HDAC inhibitors include pabinostat, vorinostat, belinostat, panobinostat, entinostat, tacedinaline, and mocetinostat.
  • Non-limiting examples of platinum-based chemotherapeutics include carboplatin, cisplatin, and oxaplatin.
  • Non-limiting examples of alkylating agents include cyclophosphamide, carmustine, busulfan, procarbazine, dacarbazine, temozoloamide, thiotepa, and mitomycin C.
  • Non-limiting examples of nucleobase, nucleoside, and/or nucleotide analogs include fluorouracil, cytarabine, gemcitabine, azacitidine, and decitabine.
  • Non-limiting examples of topoisomerase I inhibitors include topotecan, irinotecan, belotecan, and camptothecin.
  • Non-limiting examples of topoisomerase II inhibitors include etoposide, tenoposide, doxorubicin, daunorubicin, epirubicin, and idarubacin.
  • an immunotherapy refers to an agent that modulates the immune system.
  • an immunotherapy can increase the expression and/or activity of a regulator of the immune system.
  • an immunotherapy can decrease the expression and/or activity of a regulator of the immune system.
  • an immunotherapy can recruit and/or enhance the activity of an immune cell.
  • the immunotherapy is a cellular immunotherapy (e.g., adoptive T-cell therapy, dendritic cell therapy, natural killer cell therapy).
  • the cellular immunotherapy is sipuleucel-T (APC8015; ProvengeTM; Plosker (2011) Drugs 71(1): 101-108).
  • the cellular immunotherapy includes cells that express a chimeric antigen receptor (CAR).
  • the cellular immunotherapy is a CAR-T cell therapy.
  • the CAR-T cell therapy is tisagenlecleucel (KymriahTM).
  • the immunotherapy is an antibody therapy (e.g., a monoclonal antibody, a conjugated antibody).
  • the antibody therapy is bevacizumab (MvastiTM, Avastin®), trastuzumab (Herceptin®), avelumab (Bavencio®), rituximab (Mab TheraTM, Rituxan®), edrecolomab (Panorex), daratumuab (Darzalex®), olaratumab (LartruvoTM), ofatumumab (Arzerra®), alemtuzumab (Campath®), cetuximab (Erbitux®), oregovomab, pembrolizumab (Keytruda®), dinutiximab (Unituxin®), obinutuzumab (Gazyva®), tremelimumab (CP-675,206), ramucirumab (Cyramza®), ublituximab (TG-1101), panitumumab (Vectibix®
  • the immunotherapy is an antibody-drug conjugate.
  • the antibody-drug conjugate is gemtuzumab ozogamicin (MylotargTM), inotuzumab ozogamicin (Besponsa®), brentuximab vedotin (Adcetris®), ado-trastuzumab emtansine (TDM-1; Kadcyla®), mirvetuximab soravtansine (IMGN853) or anetumab ravtansine
  • the immunotherapy includes blinatumomab (AMG103; Blincyto®) or midostaurin (Rydapt).
  • the immunotherapy includes a toxin. In some embodiments, the immunotherapy is denileukin diftitox (Ontak®).
  • the immunotherapy is a cytokine therapy.
  • the cytokine therapy is an interleukin 2 (IL-2) therapy, an interferon alpha (IFNa) therapy, a granulocyte colony stimulating factor (G-CSF) therapy, an interleukin 12 (IL- 12) therapy, an interleukin 15 (IL- 15) therapy, an interleukin 7 (IL-7) therapy or an erythropoietin-alpha (EPO) therapy.
  • the IL-2 therapy is aldesleukin (Proleukin®).
  • the IFNa therapy is IntronA® (Roferon-A®).
  • the G-CSF therapy is filgrastim (Neupogen®).
  • the immunotherapy is an immune checkpoint inhibitor. In some embodiments, the immunotherapy includes one or more immune checkpoint inhibitors. In some embodiments, the immune checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor or a PD-L1 inhibitor. In some embodiments, the CTLA-4 inhibitor is ipilimumab (Yervoy®) or tremelimumab (CP-675,206). In some embodiments, the PD-1 inhibitor is pembrolizumab (Keytruda®) or nivolumab (Opdivo®). In some embodiments, the PD-L1 inhibitor is atezolizumab (Tecentriq®), avelumab (Bavencio®) or durvalumab (ImfinziTM).
  • Non-limiting examples of radiotherapy include radioiodide therapy, external-beam radiation, and radium 223 therapy.
  • the one or more additional therapies or therapeutic agents are selected from cytarabine, fludarabine, cisplatin, carboplatin, docetaxel, gemcitabine, belinostat, radiotherapy, irinotecan, olaparib, pemetrexed, savolitinib, and temozolomide.
  • a cancer having replication stress and/or including a genetic characteristic indicative that the cancer can be treated effectively with a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof can be treated with a combination of a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof and another agent that promotes genomic instability, such as a DNA-damaging agent, a DNA repair inhibiting agent, radiation, or a combination thereof.
  • the methods described herein can further include administering to the subject a DNA-damaging agent, a DNA repair inhibiting agent, radiation, or a combination thereof.
  • identification of replication stress might not be carried out on the cancer or might not be able to be carried out on a cancer.
  • genetic analysis might not be carried out on the cancer or might not be able to be carried out on a cancer.
  • a cancer might be negative for a genetic characteristic of a cancer can be indicative that the cancer can be treated effectively with a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof.
  • many first- line treatment regimens for cancer include a DNA-damaging agent, a DNA repair inhibiting agent, or a combination thereof.
  • a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof can still be indicated for treatment with a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof, as the combination of factors can promote mitotic collapse, thereby treating the cancer.
  • a method of treating a cancer in a subject in need thereof comprising: (i) administering to the subject an effective amount of a therapy comprising: (a) a DNA-damaging agent; (b) a DNA repair inhibiting agent; (c) radiation; (d) a DNA-damaging agent and a DNA repair inhibiting agent; (e) a DNA- damaging agent and radiation; (f) a DNA repair inhibiting agent and radiation; or (g) a DNA-damaging agent, a DNA repair inhibiting agent, and radiation; and (ii) after (i), administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof.
  • a therapy comprising: (a) a DNA-damaging agent; (b) a DNA repair inhibiting agent; (c) radiation; (d) a DNA-damaging agent and a DNA repair inhibiting agent; (e) a DNA- damaging agent and radiation; (f) a DNA repair inhibiting agent and radiation; or (g)
  • Also provided herein is a method of treating a cancer in a subject in need thereof, the method comprising: administering an effective amount of a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof to a subject previously administered one or more doses of a therapy comprising: (a) a DNA-damaging agent; (b) a DNA repair inhibiting agent; (c) radiation; (d) a DNA-damaging agent and a DNA repair inhibiting agent; (e) a DNA-damaging agent and radiation; (f) a DNA repair inhibiting agent and radiation; or (g) a DNA-damaging agent, a DNA repair inhibiting agent, and radiation.
  • a therapy comprising: (a) a DNA-damaging agent; (b) a DNA repair inhibiting agent; (c) radiation; (d) a DNA-damaging agent and a DNA repair inhibiting agent; (e) a DNA-damaging agent and radiation; (f) a DNA repair inhibiting agent and radiation; or (g) a DNA-
  • the therapy (e.g., of (a) to (g)) is continued to be administered to the subject as combination therapy with the compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof.
  • a method of treating a cancer in a subject in need thereof comprising: administering to the subject: (i) an effective amount of a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof; and (ii) an effective amount of a therapy comprising: (a) a DNA-damaging agent; (b) a DNA repair inhibiting agent; (c) radiation; (d) a DNA-damaging agent and a DNA repair inhibiting agent; (e) a DNA-damaging agent and radiation; (f) a DNA repair inhibiting agent and radiation; or (g) a DNA-damaging agent, a DNA repair inhibiting agent, and radiation.
  • the compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof and the therapy are administered simultaneously as separate dosages.
  • the compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof and the therapy are administered separate dosages sequentially in any order.
  • a DNA-damaging agent can be any appropriate DNA-damaging agent, such as those described herein.
  • the DNA-damaging agent is selected from the group consisting of a platinum-based chemotherapy, an alkylating agent, a nucleobase, nucleoside, or nucleotide analog, and combinations thereof.
  • the platinum-based chemotherapy comprises carboplatin, cisplatin, oxaplatin, or a combination thereof.
  • the alkylating agent comprises cyclophosphamide, carmustine, busulfan, procarbazine, dacarbazine, temozoloamide, thiotepa, mitomycin C, or combinations thereof.
  • the nucleobase, nucleoside, or nucleotide analog comprises fluorouracil, cytarabine, gemcitabine, azacitidine, decitabine, or combinations thereof.
  • a DNA repair inhibiting agent can be any appropriate DNA repair inhibiting agent, such as those described herein.
  • the DNA repair inhibiting agent is selected from the group consisting of a topoisomerase I inhibitor, a topoisomerase II inhibitor, a PARP inhibitor, an ATR inhibitor, a Chk inhibitor, a DNA-dependent protein kinase (DNA-PK) inhibitor, an ATM inhibitors, an Aurora kinase inhibitor (such as Aurora A and/or Aurora B inhibitors), and a combination thereof.
  • the topoisomerase I inhibitor comprises topotecan, irinotecan, belotecan, camptothecin, or combinations thereof.
  • the topoisomerase II inhibitor comprises etoposide, tenoposide, doxorubicin, daunorubicin, epirubicin, idarubacin, or combinations thereof.
  • the PARP inhibitor comprises olaparib, niraparib, rucaparib, talazoparib, veliparib, or combinations thereof.
  • the ATR inhibitor comprises AZD6738, BAY1895344, M6620, or a combination thereof.
  • the Chkl inhibitor comprises prexasertib, GDC-0575, SCH 900776, SRA737, or a combination thereof.
  • the DNA-PK inhibitor comprises AZD7648, M3814, LY294002, nedisertib, samotolisib, or combinations thereof.
  • the ATM inhibitor comprises KU55933, AZD0156, AZD1390, dactosilib, berzosertib, or combinations thereof.
  • the Aurora kinase inhibitor comprises LY3295668, ZM447439, tozasertib, hesparadin, alisertib, MLN8054, or combinations thereof.
  • the topoisomerase I inhibitor is topotecan, irinotecan, belotecan, camptothecin, or a combination thereof.
  • the topoisomerase II inhibitor is etoposide, tenoposide, doxorubicin, daunorubicin, epirubicin, idarubacin, or a combination thereof.
  • the PARP inhibitor is olaparib, niraparib, rucaparib, talazoparib, veliparib, or a combination thereof.
  • the ATR inhibitor is AZD6738, BAY1895344, M6620, or a combination thereof.
  • the Chkl inhibitor is prexasertib, GDC-0575, SCH 900776, SRA737, or a combination thereof.
  • the DNA-PK inhibitor is AZD7648, M3814, LY294002, nedisertib, samotolisib, or a combination thereof.
  • the ATM inhibitor is KU55933, AZD0156, AZD1390, dactosilib, berzosertib, or a combination thereof.
  • the Aurora kinase inhibitor is LY3295668, ZM447439, tozasertib, hesparadin, alisertib, MLN8054, or a combination thereof.
  • Also provided herein is a method for treating a subject diagnosed with or identified as having a cancer associated with replication stress, e.g., any of the exemplary cancers disclosed herein, comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.
  • the method further includes administering an additional therapy or therapeutic agent to the subject.
  • An additional therapy or therapeutic agent can be any appropriate therapy or therapeutic agent.
  • the additional therapy or therapeutic agent is selected from radiotherapy, cytotoxic chemotherapeutics, kinase-targeted therapeutics, kinase-targeted therapeutics, apoptosis modulators, signal transduction inhibitors, immune-targeted therapies, angiogenesis-targeted therapies, and combinations thereof.
  • the additional therapy or therapeutic agent is selected from kinase-targeted therapeutics, kinase-targeted therapeutics, apoptosis modulators, signal transduction inhibitors, immune-targeted therapies, angiogenesis-targeted therapies, and combinations thereof.
  • the additional therapy or therapeutic agent is an immune- targeted therapy.
  • the immune-targeted therapy is an immunotherapy.
  • Also provided herein is a method for inhibiting mammalian cell proliferation comprising contacting the mammalian cell with a compound of Formula (I), or a pharmaceutical salt thereof.
  • a method for inducing mitotic collapse in a mammalian cell comprising contacting the mammalian cell with a compound of Formula (I), or a pharmaceutical salt thereof.
  • the contacting occurs in vivo.
  • the contacting occurs in vitro.
  • a mammalian cell can be any appropriate species or type of cell.
  • the mammalian cell is a mammalian immune cell.
  • the mammalian cell is a mammalian cancer cell.
  • the mammalian cancer cell is a mammalian cancer cell having replicative stress. In some embodiments, the mammalian cancer cell has an inactivated tumor suppressor gene. In some embodiments, the mammalian cancer cell has an activated oncogene. In some embodiments, the method further includes contacting the mammalian cell with a DNA-damaging agent, a DNA repair inhibitor, radiation, or a combination thereof.
  • the cancer is a cancer having replication stress.
  • the cancer is a cancer having an inactivated tumor suppressor gene.
  • the cancer is a cancer having an activated oncogene.
  • the medicament is labeled for concurrent use with a DNA-damaging agent, a DNA repair inhibitor, radiation therapy, or a combination thereof.
  • the medicament is labeled for use subsequent to a DNA-damaging agent, a DNA repair inhibitor, radiation therapy, or a combination thereof.
  • the cancer is a hematological cancer.
  • the cancer is a solid tumor.
  • the cancer is small cell lung cancer, ovarian cancer, solid tumors with BRCA mutations, head and neck cancer squamous cell carcinoma, adenocarcinoma of the pancreas, acute myeloid leukemia, osteosarcoma, multiple myeloma, epithelial ovarian cancers, triple negative breast cancer, cervical cancer, mantle cell lymphoma and diffuse large B-cell lymphoma, laryngeal squamous cell carcinoma, basal-like breast cancer, medulloblastoma, oropharyngeal cancers, sarcoma, kidney cancer, clear cell renal cell carcinoma, acute lymphoblastic leukemia, pediatric gliomas, head and neck precancer, Ewing sarcoma, gastrointestinal stromal tumors, giant cell tumor of bone, clear cell ovarian cancer, mucinous
  • the subject is a human.
  • a compound of Formula (I) is selected from Examples 1-47, or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is a compound of Formula (II), or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is a compound of Formula (III), or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is a compound of Formula (IV), or a pharmaceutically acceptable salt thereof.
  • a method for inhibiting Weel kinase activity in a mammalian cell comprising contacting the mammalian cell with a compound of Formula (I).
  • the contacting is in vitro.
  • the contacting is in vivo.
  • the contacting is in vivo, wherein the method comprises administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof to a subject having a mammalian cell having Weel kinase activity.
  • the mammalian cell is a mammalian immune cell.
  • the mammalian cell is a mammalian cancer cell.
  • the mammalian cancer cell is any cancer as described herein.
  • the mammalian cancer cell is a mammalian cancer cell having replication stress.
  • a method for inhibiting Weel kinase activity in a mammalian cell comprising contacting the mammalian cell with a compound of Formula (I).
  • the contacting is in vitro.
  • the contacting is in vivo.
  • the contacting is in vivo, wherein the method comprises administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof to a mammal having a mammalian cell having Weel kinase activity.
  • the mammalian cell is a mammalian immune cell.
  • the mammalian cell is a mammalian cancer cell.
  • the mammalian cancer cell is any cancer as described herein. In some embodiments, the mammalian cancer cell is a mammalian cancer cell with replication stress. In some embodiments, the mammalian cell is a gastrointestinal mammalian cell. In some embodiments, the mammalian cell is a hematological mammalian cell.
  • contacting refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • “contacting” a Weel kinase with a compound provided herein includes the administration of a compound provided herein to a subject, such as a human, having a Weel kinase, as well as, for example, introducing a compound provided herein into a sample containing a mammalian cellular or purified preparation containing the Weel kinase.
  • Also provided herein is a method of inhibiting mammalian cell proliferation, in vitro or in vivo, the method comprising contacting a mammalian cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.
  • a “Weel kinase inhibitor” as defined herein includes any compound exhibiting Weel inhibition activity.
  • a Weel kinase inhibitor is selective for a Weel kinase.
  • Exemplary Weel kinase inhibitors can exhibit inhibition activity (IC50) against a Weel kinase of less than about 1000 nM, less than about 500 nM, less than about 200 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, or less than about 1 nM as measured in an assay as described herein.
  • a Weel kinase inhibitor can exhibit inhibition activity (ICso) against a Weel kinase of less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM as measured in an assay as provided herein.
  • ICso inhibition activity against a Weel kinase of less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM as measured in an assay as provided herein.
  • the phrase “effective amount” means an amount of compound that, when administered to a subject in need thereof, is sufficient to (i) treat a cancer (such as cancer associated with replication stress as described herein), (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular cancer, or (iii) delay the onset of one or more symptoms of the particular cancer described herein.
  • a cancer such as cancer associated with replication stress as described herein
  • the amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the subject in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
  • compounds of Formula (I), including pharmaceutically acceptable salts thereof can be administered in the form of pharmaceutical compositions.
  • These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration can be topical (including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g. , by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral or parenteral.
  • topical including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery
  • pulmonary e.g. , by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal
  • Oral administration can include a dosage form formulated for once-daily or twice-daily (BID) administration.
  • Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration.
  • Parenteral administration can be in the form of a single bolus dose, or can be, for example, by a continuous perfusion pump.
  • Pharmaceutical compositions and formulations for topical administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
  • compositions which contain, as the active ingredient, a compound of Formula (I) or pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable excipients.
  • a pharmaceutical composition prepared using a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the composition is suitable for topical administration.
  • the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the composition is formulated for oral administration.
  • the composition is a solid oral formulation.
  • the composition is formulated as a tablet or capsule.
  • compositions containing a compound of Formula (I) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier can be prepared by intimately mixing the compound of Formula (I), or a pharmaceutically acceptable salt thereof with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier can take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral).
  • the composition is a solid oral composition.
  • Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers can be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.
  • any of the usual pharmaceutical media can be employed.
  • suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like;
  • suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like.
  • Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • Solid oral preparations can also be coated with substances such as sugars or be enteric-coated so as to modulate major site of absorption.
  • the carrier will usually consist of sterile water and other ingredients can be added to increase solubility or preservation.
  • Injectable suspensions or solutions can also be prepared utilizing aqueous carriers along with appropriate additives.
  • the pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described herein.
  • compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof can be formulated in a unit dosage form, each dosage containing from about 5 to about 1,000 mg (1 g), more usually about 100 mg to about 500 mg, of the active ingredient.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other subjects, each unit containing a predetermined quantity of active material (i.e., a compound of Formula (I) or a pharmaceutically acceptable salt thereof ) calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the compositions provided herein contain from about 5 mg to about 50 mg of the active ingredient.
  • the compositions provided herein contain from about 50 mg to about 500 mg of the active ingredient.
  • the compositions provided herein contain about 50 mg to about 100 mg, about 100 mg to about 150 mg, about 150 mg to about 200 mg, about 200 mg to about 250 mg, about 250 mg to about 300 mg, about 350 mg to about 400 mg, or about 450 mg to about 500 mg of the active ingredient.
  • the compositions provided herein contain about 10 mg, about 20 mg, about 80 mg, or about 160 mg of the active ingredient.
  • the compositions provided herein contain from about 500 mg to about 1,000 mg of the active ingredient.
  • the active ingredient contains from about 500 mg to about 1,000 mg of the active ingredient.
  • this embodies compounds or compositions containing about 500 mg to about 550 mg, about 550 mg to about 600 mg, about 600 mg to about 650 mg, about 650 mg to about 700 mg, about 700 mg to about 750 mg, about 750 mg to about 800 mg, about 800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg to about 950 mg, or about 950 mg to about 1,000 mg of the active ingredient.
  • the daily dosage of the compound of Formula (I) or a pharmaceutically acceptable salt thereof can be varied over a wide range from 1.0 to 10,000 mg per adult human per day, or higher, or any range therein.
  • the compositions are preferably provided in the form of tablets containing, 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 160, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated.
  • An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.1 mg/kg to about 1000 mg/kg of body weight per day, or any range therein.
  • the range is from about 0.5 to about 500 mg/kg of body weight per day, or any range therein. More preferably, from about 1.0 to about 250 mg/kg of body weight per day, or any range therein. More preferably, from about 0.1 to about 100 mg/kg of body weight per day, or any range therein. In an example, the range can be from about 0.1 to about 50.0 mg/kg of body weight per day, or any amount or range therein. In another example, the range can be from about 0.1 to about 15.0 mg/kg of body weight per day, or any range therein. In yet another example, the range can be from about 0.5 to about 7.5 mg/kg of body weight per day, or any amount to range therein. Pharmaceutical compositions containing a compound of Formula (I) or a pharmaceutically acceptable salt thereof can be administered on a regimen of 1 to 4 times per day or in a single daily dose.
  • the active compound may be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount.
  • Optimal dosages to be administered can be readily determined by those skilled in the art. It will be understood, therefore, that the amount of the compound actually administered will usually be determined by a physician, and will vary according to the relevant circumstances, including the mode of administration, the actual compound administered, the strength of the preparation, the condition to be treated, and the advancement of the disease condition.
  • factors associated with the particular subj ect being treated including subj ect response, age, weight, diet, time of administration and severity of the subject’s symptoms, will result in the need to adjust dosages.
  • the compounds provided herein can be administered in an amount ranging from about 1 mg/kg to about 100 mg/kg. In some embodiments, the compound provided herein can be administered in an amount of about 1 mg/kg to about 20 mg/kg, about 5 mg/kg to about 50 mg/kg, about 10 mg/kg to about 40 mg/kg, about 15 mg/kg to about 45 mg/kg, about 20 mg/kg to about 60 mg/kg, or about 40 mg/kg to about 70 mg/kg.
  • kits useful for example, in the treatment of cancer (such as replication sensitive cancers), which include one or more containers containing a pharmaceutical composition comprising an effective amount of a compound provided herein.
  • Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art.
  • Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.
  • the compounds provided herein, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes.
  • the reactions for preparing the compounds provided herein can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis.
  • suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected by the skilled artisan.
  • Preparation of the compounds provided herein can involve the protection and deprotection of various chemical groups.
  • the need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art.
  • the chemistry of protecting groups can be found, for example, in Protecting Group Chemistry, 1 st Ed., Oxford University Press, 2000; March ’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5 th Ed., Wiley -Interscience Publication, 2001; and Petursson, S. el al., “Protecting Groups in Carbohydrate Chemistry,” J. Chem. Educ., 74(11), 1297 (1997).
  • reactions sensitive to moisture or air were performed under nitrogen or argon using anhydrous solvents and reagents.
  • the progress of reactions was determined by either analytical thin layer chromatography (TLC) usually performed with Sanpont precoated TLC plates, silica gel GF-254, layer thickness 0.25 mm or liquid chromatography-mass spectrometry (LC-MS).
  • TLC analytical thin layer chromatography
  • LC-MS liquid chromatography-mass spectrometry
  • the analytical LC-MS system used consisted of a Shimadzu LCMS-2020 with electrospray ionization in positive ion detection mode with a 20ADXR pump, SIL- 20ACXR autosampler, CTO-20AC column oven, M20A PDA Detector, and a LCMS 2020 MS detector.
  • the column was usually a HALO Cl 8 30*5.0 mm, 2.7 pm.
  • the mobile phase A is water containing 0.05% TFA and mobile phase B is acetonitrile containing 0.05% TFA.
  • the gradient is from 5% mobile phase B to 95% in 2.0 min, hold 0.7 min, then reverting to 5% mobile phase B over 0.05 min and maintained for 0.25 min.
  • the Column Oven (CTO-20AC) was operated at a temperature of 40.0 °C.
  • the flow rate was 1.5 mL/min, and the injection volume was 1 pl.
  • PDA (SPD-M20A) detection was in the 190- 400 nm range.
  • the MS detector which was configured with electrospray ionization as ionizable source; Acquisition mode: Scan; Nebulizing Gas Flow: 1.5 L/min; Drying Gas Flow: 15 L/min; Detector Voltage: Tuning Voltage ⁇ 0.2 kV ; DL Temperature: 250 °C; Heat Block Temperature: 250 °C; Scan Range: 90.00 - 900.00 m/z.
  • the GC-MS system was usually performed with a Shimadzu GCMS-QP2010 Ultra with FID and MS Detector.
  • acquisition mode the MS detector was set to the following parameters: Start Time: 2.00 min; End Time: 9.00 min; ACQ Mode: Scan; Event Time: 0.30 sec; Scan Speed: 2000; Start m/z: 50.00; End m/z: 550.00; Ion Source temperature: 200.00 °C; Interface temperature: 250.00 °C; Solvent Cut Time: 2.00 min.
  • Preparative HPLC purifications were usually performed with a Waters Auto purification system (2545-2767) with a 2489 UV detector and a Waters Cl 8 column (19 xl50 mm, 5 pm; XBridge Prep OBD C18 Column, 30* 150mm, 5pm; XSelect CSH Prep C18 OBD Column, 19x 150mm, 5pm ; XBridge Shield RP18 OBD Column, 30x150mm, 5p m; Xselect CSH Fluoro Phenyl, 30 x 150 mm, 5 p m; YMC-Actus Triart C18, 30 x 150 mm, 5 p m.
  • the mobile phases consisted of mixtures of acetonitrile (5-95%) in water containing 0.1% FA or lOmmol/L NH4HCO3. Flow rates were maintained at 25 mL/min, the injection volume was 1200 pL, and the UV detector used two channels: 254 nm and 220 nm. Mobile phase gradients were optimized for the individual compounds.
  • Chiral analytical chromatography was performed on one of Chiralpak AS, AD, Chiralcel OD, OJ Chiralpak IA, IB, IC, ID, IE, IF, IG, IH columns (Daicel Chemical Industries, Ltd.); (A,A)-Whelk-Ol, (5,5)-Whelk-01 columns (Regis technologies, Inc.
  • CHIRAL Cellulose-SB, SC, SA columns (YMC Co., Ltd.) at different column sizes (50x4.6mm, 100x4.6mm, 150x4.6mm, 250x4.6mm, 50x3.0mm, 100x3.0mm) with noted percentage of either ethanol in hexane (%Et/Hex) or isopropanol in hexane (%IPA/Hex) as isocratic solvent systems or by supercritical fluid (SFC) conditions.
  • Chiral preparative chromatography was conducted on one of Chiralpak AS, AD, Chiralcel OD, OJ, Chiralpak IA, IB, IC, ID, IE, IF, IG, IH columns (Daicel Chemical Industries, Ltd.); ( ’.
  • Example 1 3-(2,6-dichlorophenyl)-l-methyl-8-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)- l,2,3,7-tetrahydro-4H-pyrrolo [3', 2' : 5,6] pyrido [4, 3-d] pyrimidin-4-one.
  • Step 8 8-bromo-3-(2,6-dichlorophenyl)-l-methyl-7-tosyl-l,2,3,7-tetrahydro-4H- pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-4-one (Intermediate J)
  • the mixture was allowed to cool down to room temperature. The reaction was monitored by LC-MS. The resulting mixture was diluted with EA (20 mL). The resulting mixture was washed with brine (3 *20 mL), then combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • Example 2 was prepared by a procedure analogous to steps 1-7 used to prepare intermediate I in Example 1, with an added step of removing the para-toluenesulfonyl group from the azaindole nitrogen of intermediate I to form Example 2.
  • LCMS (ES, m/z): 346.95 [M+H] + . Rt 0.78 min.
  • Examples 3-36 were prepared analogously to compound 1 in Example 1, with one or both of the following modifications: (1) amine D used in step 3 of Example 1 was interchanged with the appropriate amine shown in Table 3 below, and/or (2) boronate ester K used in step 9 of Example 1 was interchanged with the appropriate boronate ester shown in Table 3 below (the corresponding boronic acid may also be used depending, e.g., on the structure of the organometallic fragment and conditions used). For each example number shown in Table 3, an additional number of steps may be required to complete the indicated structure following the use of the appropriate boronate ester in Table 3. LC-MS characterization for each compound is also shown in Table 3.
  • Example 37 3-(2,6-dichlorophenyl)-8-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-3,7- dihydro-4H-pyrrolo [3 * ,2 5,6] pyrido [4, 3-d] pyrimidin-4-one Step 1. 4-amino-2-bromo-N-(2,6-dichlorophenyl)-l-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridine-5-carboxamide (A/2)
  • Step 2 8-bromo-3-(2,6-dichlorophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-3,7- dihydro-4H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-4-one (B/3)
  • Example 37 The title compound was prepared by a procedure analogous to prepare Example 41 except using 3-(2,6-dichlorophenyl)-8-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-3,7-dihydro-4H- pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-4-one (Example 37).
  • Example 40 3-(2,6-dichlorophenyl)-l-methyl-8-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)- l,7-dihydro-2H-pyrrolo [3', 2' : 5,6] pyrido [4, 3-d] pyrimidine-2,4(3H)-dione
  • Step 1 methyl 4-chloro-l-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridine-5- carboxylate (Intermediate A/4)
  • Step 6 8-bromo-3-(2,6-dichlorophenyl)-l-methyl-7-((2-(trimethylsilyl)ethoxy) methyl)-!, 7-dihydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2,4(3H)-dione (Intermediate F/10)
  • Step 7 tert-butyl 4-(4-(3-(2,6-dichlorophenyl)-l-methyl-2,4-dioxo-7-((2- (trimethylsilyl)ethoxy)methyl)-2,3,4,7-tetrahydro-lH-pyrrolo[3',2':5,6]pyrido[4,3- d]pyrimidin-8-yl)-lH-pyrazol-l-yl)piperidine-l-carboxylate (Intermediate G/ll)
  • Example 42 3-(2-chloro-6-fluorophenyl)-8-(l-(l-methylpiperidin-4-yl)-lH-pyrazol- 4-yl )-3.7-dihydro-4//-py r rolo [3 ’ ,2 ’ : 5,6] pyrido [4,3- d] pyrimidin-4-one Step . 4-chloro-/V-(2-chloro-6-fluorophenyl)-l-((2-(trimethylsilyl)ethoxy)methyl)- l//-pyrrolo
  • Step 2' 3-(2-chloro-6-fluorophenyl)-8-( l-(l-methylpiperidin-4-yl)-TH-pyrazol-4-yl)- 3.7-dihydro-4//-py rrolo [3', 2' : 5,6] pyrido [4,3- ⁇ /
  • the title compound was prepared starting with Intermediate E and procedures analogous to steps 1-4 used to prepare Example 37, followed by the methylation step in Example 41.
  • Example 44 (/?)-3-(2.6-dichlorophenyl)-l-methyl-8-(l-(pyrrolidin-2-ylmethyl)-l//- pyrazol-4-yl)- 1 ,7-d ihyd ro-2//-py rrolo [3' ,2' : 5,6] pyrido [4,3- d] pyrimidine-2,4(3H )- dione
  • Step 2 (S)-3-(2-chloro-6-fluorophenyl)-l-methyl-8-( l-(pyrrolidin-2-ylmethyl)-LH- pyrazol-4-yl)- 1 ,7-d ihyd ro-2//-py rrolo [3' ,2' : 5,6] pyrido [4,3- d] pyrimidine-2,4(3H )- dione (Example 45)
  • Example 46 (l?)-3-(2-chloro-6-fluorophenyl)-l-methyl-8-(l-(pyrrolidin-2-ylmethyl)- 1H-py razol-4-yl)- 1 ,7-d ihyd ro-2//-py rrolo [3' ,2' : 5,6] pyrido [4,3- d] pyrimidine-2,4(3H )- dione
  • a total of 40,000 A427 or OVCAR3 cells in 100 uL culture medium (1640 medium + 10% Fetal bovine serum + 1% Penicillin-Streptomycin) were plated in 96-well cell culture plates.
  • 3 -fold serial dilutions of test compounds were prepared in completed PBS at 25X final concentration and 4 pL of each were added to the cells and incubated with shaking for 4 hours at 37°C, 5% CO2. Each concentration was tested in duplicate. After a total 6 hours incubation, cells were washed with 200 pL PBS and lysed with 50 pL MSD lysis buffer (Meso Scale Diagnostics) supplied with IX complete ULTRA cocktail inhibitor (Roche).
  • Cdc2 Y15 To detect phosphorylation of Cdc2 Y15, 30 pL of capture antibody solution (CST catalog #9116S 1 :200) was added into each well of the MSD plate (MSD catalog # L15XB- 6), sealed and incubated at 4°C with shaking (450 rpm) overnight. The antibody solution was removed, wells blocked with BSA solution and plates washed, followed by addition of 30 pl of cell lysate per well. After 2 h incubation, plates were washed. 30 pL of IX detection antibody solution (CST catalog #4539S 1 :200) was then added to each well and incubated for 1 hour.
  • CST catalog #9116S 1 :200 was added into each well of the MSD plate (MSD catalog # L15XB- 6), sealed and incubated at 4°C with shaking (450 rpm) overnight. The antibody solution was removed, wells blocked with BSA solution and plates washed, followed by addition of 30 pl of cell lysate
  • Weel kinase domain was purchased from Carna (catalog #05-177). Weel kinase activity was determined with Poly(Lys,Tyr 4: 1) hydrobromide as a substrate (Sigma- Aldrich) and by measuring ADP production using the ADP-Glo Kinase Assay kit (Promega) following the manufacturer’s instructions. The kinase reaction was performed using the following conditions:
  • Buffer 40 mM Tris-HCl, 20 mM magnesium chloride, supplemented with 0.1 mg/mL bovine serum albumin and 2 mM DTT.
  • the final reaction mix contained 1 nM Weel enzyme, 15 uM ATP, and 2 ng/mL Poly(Lys,Tyr 4: 1) hydrobromide substrate.
  • the reaction time was 4 hours at 25 °C.
  • the ADP-Glo signal was measured using the Envision plate reader and the percentage inhibition of kinase activity calculated for each inhibitor tested. Percent inhibition of Weel kinase activity was calculated based on the following formula.
  • PLK1 kinase activity was determined with Native Cow Casein protein, dephosphorylated, as a substrate (abeam) and by measuring ADP production using the ADP-Glo Kinase Assay kit (Promega) following the manufacturer’s instructions. The kinase reaction was performed using the following conditions:
  • Buffer 40 mM Tris-HCl, 20 mM magnesium chloride, supplemented with 0.1 mg/mL bovine serum albumin and 2 mM DTT.
  • the final reaction mix contained 10 nM PLK1 enzyme, 3 uM ATP, and 5 uM Native Cow Casein protein substrate.
  • the reaction time was 2 hours at 25 degrees C.
  • the ADP-Glo signal was measured using the Envision plate reader and the percentage inhibition of kinase activity calculated for each inhibitor tested. Percent inhibition of PLK 1 kinase activity was calculated based on the following formula.
  • the WEE1 IC50 ranges are as follows:
  • the A427 pCDC2 and OVCAR3 pCDC2 IC50 ranges are as follows:
  • the PLK1 IC50 ranges are as follows:

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Abstract

The present application relates to compounds of Formula (I), as defined herein, and pharmaceutically acceptable salts thereof. The present application also describes pharmaceutical composition comprising a compound of Formula (I), and pharmaceutically acceptable salts thereof, and methods of using the compounds and compositions for treating diseases such as cancer.

Description

FUSED HETEROCYCLES AND USES OF SAME
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority to U.S. Provisional Patent Application Serial No. 63/136,941, filed on January 13, 2021 and U.S. Provisional Patent Application Serial No. 63/290,481, filed on December 16, 2021, which are incorporated herein by reference in their entireties.
TECHNICAL FIELD
This present application relates to fused heterocyclic compounds that are useful for treating proliferative disorders such as cancer.
BACKGROUND
Weel is a highly conserved serine/threonine kinase that inhibits cell cycle progress and cell entry into mitosis through inhibitory phosphorylation of cyclin-dependent kinase 1 and 2 (CDK1 and 2). It is a key regulator of cell cycle progression through S-phase and at the G2-M checkpoint. See, e.g., Hamer, et al., Clin. Cancer Res., Vol. 17, No. 13, pp. 4200-4207 (2011) and McGowan and Russell, EMBO J., Vol. 14, No. 10, pp. 2166-2175 (1995).
In normal cells, DNA damage response (DDR) is mediated by various checkpoints which either activate the DNA repair system or induce cellular apoptosis/senescence, therefore maintaining overall genomic integrity. In cancer cells, however, with a loss of or defect in DDR due to oncogenic activation or tumor suppressor inactivation, DNA replication may persist to meet the demands of unrestrained proliferation despite the presence of unrepaired DNA lesions, which then leads to replication stress — a hallmark of cancer cells that typically includes the perturbation of error-free DNA replication and/or slow-down of DNA synthesis. See, e.g., Zhang et al, Genes, 2016, 7, 51; 1-16.
Overexpression and activation of oncogenes are a major driver of replication stress. For example, oncogenes KRAS, MYC, and CCNE1, and CDC25A result in replication stress, for example, through the creation of conflicts between replication and transcription, increasing topological stress, and/or producing a nucleotide shortage. Replication stress can cause cells to slow down replication cycles; therefore, in order to maintain its proliferative program, a cancer cell typically has ways of dealing with and resolving replication stress in order to continue growing. One example is by bypassing mechanisms of DNA damage repair, for example the loss of p53, the mutation of ATM, and defects in the homologous recombination repair pathway (such as via mutation to BRCA1, BRCA2, and PALB2). See Forment and O’Connor, Pharmacology & Therapeutics, 188 (2018) 155— 167. Together, these compensatory mechanisms can result in increased genomic instability, which in turn lead to further replication stress. In general, in tumors where DNA damage response elements are bypassed or impaired, the cancer cells may become more dependent on the remaining active components of the DNA damage response and cell cycle checkpoints such as Weel.
Inhibition of Weel kinase activity enhances CDK activity, and cells in S phase can be induced to enter mitosis prematurely even if DNA replication is defective or incomplete. The increased CDK activity driven by Weel inhibition can also rapidly increase replication initiation, leading to a shortage of nucleotides that are required for DNA replication. Weel inhibitors can thus be effective to enhance replicative stress and drive cancer cells undergoing a high level of this stress into premature mitosis and subsequent death from mitotic catastrophe. However, currently there are no marketed therapeutic Weel inhibitors.
SUMMARY
Accordingly, provided herein is are compounds of Formula (I):
Figure imgf000003_0001
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R2A, R2B, R3, R4, R5,
Ring A, X, and m are as defined herein. In some embodiments, compounds of Formula (I), or pharmaceutically acceptable salts thereof, are selected from compounds of Formula (II), Formula (III), Formula (IV), and pharmaceutically acceptable salts of any of the foregoing.
Also provided herein are compounds of (Formula (II):
Figure imgf000004_0001
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, Ring A, X, and m are as defined herein.
Also provided herein are compounds of (Formula (III):
Figure imgf000004_0002
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, Ring A, X, and m are as defined herein.
Also provided herein are compounds of (Formula (IV):
Figure imgf000004_0003
or a pharmaceutically acceptable salt thereof, wherein R1, R2A, R3, R4, R5, Ring A,
X, and m are as defined herein. Also provided herein is a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
Also provided herein is a method of inhibiting mammalian cell proliferation, in vitro or in vivo, comprising contacting the mammalian cell with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.
Also provided herein is a method of inhibiting Weel kinase activity in a mammalian cell, in vitro or in vivo, comprising contacting the mammalian cell with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.
Also provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.
Also provided herein is a method of a cancer in a subject in need thereof, the method comprising:
(a) identifying the cancer as having replication stress; and
(b) administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.
Also provided herein is a method of treating a cancer in a subject in need thereof, the method comprising: administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein, to a subject identified as having a cancer having replication stress.
Also provided herein is a method of treating a cancer in a subject in need thereof, the method comprising:
(a) identifying the cancer as having an inactivated tumor suppressor gene; and
(b) administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.
Also provided herein is a method of treating a cancer in a subject in need thereof, the method comprising: administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein, to a subject identified as having a cancer having an inactivated tumor suppressor gene.
Also provided herein is a method of treating a cancer in a subject in need thereof, the method comprising:
(a) identifying the cancer as having an activated oncogene; and
(b) administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.
Also provided herein is a method of treating a cancer in a subject in need thereof, the method comprising: administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein, to a subject identified as having a cancer having an activated oncogene.
Also provided herein is a method of treating a cancer in a subject in need thereof, the method comprising:
(i) administering to the subject an effective amount of a therapy comprising:
(a) a DNA-damaging agent;
(b) a DNA repair inhibiting agent;
(c) radiation;
(d) (a) and (b);
(e) (a) and (c);
(f) (b) and (c);
(g) (a), (b), and (c); and
(ii) after (i), administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. Also provided herein is a method of treating a cancer in a subject in need thereof, the method comprising: administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein, to a subject previously administered one or more doses of a therapy comprising:
(a) a DNA-damaging agent;
(b) a DNA repair inhibiting agent;
(c) radiation;
(d) (a) and (b);
(e) (a) and (c);
(f) (b) and (c);
(g) (a), (b), and (c).
Also provided herein is a method of treating a cancer in a subject in need thereof, the method comprising: administering to the subject:
(i) an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein; and
(ii) an effective amount of a therapy comprising:
(a) a DNA-damaging agent;
(b) a DNA repair inhibiting agent;
(c) radiation;
(d) (a) and (b);
(e) (a) and (c);
(f) (b) and (c);
(g) (a), (b), and (c).
Also provided herein is a method for inducing mitotic collapse in a mammalian cell, comprising contacting the mammalian cell with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as defined herein, for use in the treatment of cancer (e.g., a cancer with replication stress).
Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein for use in the treatment of cancer.
Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the inhibition of Weel kinase activity.
Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, in the manufacture of a medicament for the treatment of cancer (e.g., a cancer with replication stress).
Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, defined herein in the manufacture of a medicament for the inhibition of Weel kinase activity.
Also provided herein is a process for preparing a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof obtained by a process of preparing the compound as defined herein.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Methods and materials are described herein for use in the present disclosure; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.
Other features and advantages of the disclosure will be apparent from the following detailed description and figures, and from the claims.
DETAILED DESCRIPTION
Definitions
The term “compound,” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopically enriched variants of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.
The term “tautomer,” as used herein refers to compounds whose structures differ markedly in arrangement of atoms, but which exist in easy and rapid equilibrium, and it is to be understood that compounds provided herein may be depicted as different tautomers, and when compounds have tautomeric forms, all tautomeric forms are intended to be within the scope of the disclosure, and the naming of the compounds does not exclude any tautomer. An example of a tautomeric forms includes the following example:
Figure imgf000009_0001
It will be appreciated that certain compounds provided herein may contain one or more centers of asymmetry and may therefore be prepared and isolated in a mixture of isomers such as a racemic mixture, or in an enantiomerically pure form.
The term “halo” refers to one of the halogens, group 17 of the periodic table. In particular the term refers to fluorine, chlorine, bromine and iodine. Preferably, the term refers to fluorine or chlorine.
The term “Cl -C6 alkyl” refers to a linear or branched hydrocarbon chain containing 1, 2, 3, 4, 5 or 6 carbon atoms, for example methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. Similarly, a C1-C3 alkyl group is a linear or branched hydrocarbon chain containing 1, 2, or 3 carbon atoms.
The term “C1-C6 alkoxy” refers to a C1-C6 alkyl group which is attached to a molecule via oxygen. This includes moieties where the alkyl part may be linear or branched, such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, tertbutoxy, n-pentoxy and n-hexoxy.
As used herein, the term “cyano” refers to a -CN radical.
As used herein, the term “hydroxyl” refers to an -OH radical.
As used herein, the term “amino” refers to a -NH2 radical.
As used herein, the term “C6-C10 aryl” refers to a 6 to 10 carbon mono- or bicyclic ring system wherein at least one ring in the system is aromatic. Non-limiting examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl. In bicyclic ring systems where only one ring is aromatic, the non-aromatic ring can be a cycloalkyl group, as defined herein.
As used herein, the term “heteroaryl” refers to a mono- or bicyclic ring system with, for example, 5 to 10 ring atoms, wherein the ring system is aromatic; wherein one or more carbon atoms in at least one ring in the system is/are replaced with an heteroatom independently selected from N, O, and S. Non-limiting examples of heteroaryl groups include pyridine, pyrimidine, pyrrole, pyrazole, imidazole, and indole.
As used herein, the term “cycloalkyl” refers to a saturated or partially unsaturated 3-10 mono- or bicyclic hydrocarbon group; wherein bicyclic systems include fused, spiro (optionally referred to as “spirocycloalkyl” groups), and bridged ring systems. Nonlimiting examples of cycloalkyl groups include cyclopropyl, cyclohexyl, spiro[2.3]hexyl, and bicyclo[l.l. l]pentyl.
The term “heterocyclyl” refers to a saturated or partially unsaturated 3-12 membered hydrocarbon monocyclic or bicyclic ring system, having at least one heteroatom within the ring selected from N, O and S. Bicyclic heterocyclyl groups include fused, spiro, and bridged ring systems. The heterocyclyl ring system may include oxo substitution at one or more C, N, or S ring members. In bicyclic ring systems, one ring can be aromatic, if the other ring is not aromatic. For example, one ring could be phenyl and the other ring could be pyrrolidine, or, one ring could be pyridine and the other ring could be cyclohexane. The heterocyclyl group may be denoted as, for example, a “5-10 membered heterocyclyl group,” which is a ring system containing 5, 6, 7, 8, 9 or 10 atoms at least one being a heteroatom. For example, there may be 1, 2 or 3 heteroatoms, optionally 1 or 2. The heterocyclyl group may be bonded to the rest of the molecule through any carbon atom or through a heteroatom such as nitrogen. Exemplary heterocyclyl groups include, but are not limited to, piperidinyl, piperazinyl, morpholino, tetrahydropyranyl, azetidinyl, oxetanyl, 2-azaspiro[3.3]heptanyl, pyrrolidin-2-one, sulfolane, isothiazoline S,S-dioxide, and decahydronaphthalenyl.
As used herein, the term “oxo” refers to an “=O” group attached to a carbon atom.
As used herein, the symbol
Figure imgf000010_0001
depicts the point of attachment of an atom or moiety to the indicated atom or group in the remainder of the molecule.
The compounds of Formula (I) (e.g., compounds of Formula (II), Formula (III), and Formula (IV)) include pharmaceutically acceptable salts thereof. In addition, the compounds of Formula (I) also include other salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and/or purifying compounds of Formula (I) and/or for separating enantiomers of compounds of Formula (I). Non-limiting examples of pharmaceutically acceptable salts of compounds of Formula (I) include trifluoroacetic acid and hydrochloride salts.
It will further be appreciated that the compounds of Formula (I) or their salts may be isolated in the form of solvates, and accordingly that any such solvate is included within the scope of the present disclosure. For example, compounds of Formula (I) and salts thereof can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
In one embodiment, the compounds of Formula (I) include the compounds of Examples 1-47 and stereoisomers and pharmaceutically acceptable salts thereof. In some embodiments, the compounds of Examples 1-47 are present in the form of a free base. In some embodiments, the compounds of Examples 1-47 are present in the form of a pharmaceutically acceptable salt.
The term “pharmaceutically acceptable” indicates that the compound, or salt or composition thereof is compatible chemically and/or toxicologically with the other ingredients comprising a formulation and/or the subject being treated therewith.
Compounds provided herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. That is, an atom, in particular when mentioned in relation to a compound according to Formula (I), comprises all isotopes and isotopic mixtures of that atom, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form. For example, when hydrogen is mentioned, it is understood to refer to 1H, 2H, 3H or mixtures thereof; when carbon is mentioned, it is understood to refer to nC, 12C, 13C, 14C or mixtures thereof; when nitrogen is mentioned, it is understood to refer to 13N, 14N, 15N or mixtures thereof; when oxygen is mentioned, it is understood to refer to 14O, 15O, 16O, 17O, 18O or mixtures thereof; and when fluoro is mentioned, it is understood to refer to 18F, 19F or mixtures thereof; unless expressly noted otherwise. For example, in deuteroalkyl and deuteroalkoxy groups, where one or more hydrogen atoms are specifically replaced with deuterium (2H). As some of the aforementioned isotopes are radioactive, the compounds provided herein therefore also comprise compounds with one or more isotopes of one or more atoms, and mixtures thereof, including radioactive compounds, wherein one or more non-radioactive atoms has been replaced by one of its radioactive enriched isotopes. Radiolabeled compounds are useful as therapeutic agents, e.g., cancer therapeutic agents, research reagents, e.g., assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds provided herein, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure.
Protecting groups can be a temporary substituent which protects a potentially reactive functional group from undesired chemical transformations. The choice of the particular protecting group employed is well within the skill of one of ordinary skill in the art. A number of considerations can determine the choice of protecting group including, but not limited to, the functional group being protected, other functionality present in the molecule, reaction conditions at each step of the synthetic sequence, other protecting groups present in the molecule, functional group tolerance to conditions required to remove the protecting group, and reaction conditions for the thermal decomposition of the compounds provided herein. The field of protecting group chemistry has been reviewed in Greene, T. W .; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991, which is incorporated by reference herein in its entirety.
The ability of selected compounds to act as Weel inhibitors may be demonstrated by the biological assays described herein. IC50 values are shown in Table A.
As used herein, terms “treat” or “treatment” refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease or disorder or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.
As used herein, the term “subject” refers to any animal, including mammals such as humans. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented.
Persistent replication stress (sometimes also called replicative stress) is a phenomenon that is observed in cancer cells and is rarely observed in non-cancerous cells. One hallmark of replication stress is fork stalling. In some embodiments, a tumor that has “replication stress” is one that has stalled replication forks. In many cases, when DNA damage occurs to a strand being replicated, the replication machinery cannot pass the lesion, resulting in fork stalling. To repair the stalled replication fork, single-stranded DNA (ssDNA) on the leading strand is typically exposed, initiating the Replication protein A (RPA) to bind to the ssDNA and activate the ATR/Chkl pathway. By activating this pathway, entry into M phase is limited. If replication stress is exacerbated, for example, by inactivation of one or more tumor suppressor genes (e.g., p53, RBI, CDKN2A, BRCA1, BRCA2, FBXW7, SETD2, NOTCH1 or a combination thereof) (for instance, resulting in the premature onset of S phase), activation of one or more oncogenes (e.g., Cyclin E, CDC25A, Myc, a RAS gene (e.g., KRAS, NRAS, HRAS, or a combination thereof), or a combination thereof), increased DNA damage (e.g., through reactive oxygen species (ROS), chemotherapy (e.g., platinum-based chemotherapy, alkylating agents, nucleobase/nucleoside/nucleotide analogs, topoisomerase I and/or II inhibitors, PARP1 and/or PARP2 inhibitors, ATR inhibitors, Chkl inhibitors), and/or radiation therapy), premature entry into M phase (e.g., via inhibition of Weel), or a combination thereof, mitotic catastrophe can occur, leading to cell death. See, e.g., U.S. Publication No. 2020/0157638, Zhang et al, Genes, 2016, 7, 51; 1-16, Berti and Vindigni Nature Structural & Molecular Biology, 2016, 23, 2: 103-109, and Ren et al. Oncotarget, 2017 8, 23: 36996. Without being bound by any particular theory, it is believed that cells that have replication stress are more dependent on the activity of Weel (e.g., to prevent aberrant entry into M phase) due to the dysregulation of one or more other mechanisms that typically regulate the cell cycle.
In some embodiments, the subject has been identified or diagnosed as having a cancer with replication stress. In some embodiments, the subj ect has a tumor that is positive for replication stress. The subject can be a subject with a tumor(s) that tests positive for replication stress. The subject can be a subject whose tumors have replication stress. In some embodiments, the subject is suspected of having a tumor with replication stress. In some embodiments, the subject has a clinical record indicating that the subject has a tumor that has replication stress. In some embodiments, the subject is a pediatric subject. In some embodiments, the subject has been identified or diagnosed as having a cancer that, based on histological examination, is determined to be associated with replication stress. The presence of replication stress in a subject (e.g., in a tumor of a subject (e.g., a sample of the tumor)) can be detected in any appropriate way. In some embodiments, detection of replication stress can be detected directly. In some embodiments, replication stress can be detected indirectly. In some embodiments, replication stress can be detected using H2AX immunohistological staining to measure, for example, γH2AX . In some embodiments, replication stress can be detected by measuring cleaved caspase. In some embodiments, replication stress can be detected using a terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay. In some embodiments, replication stress can be detected by measuring the immune response to cytosolic DNA. See, e.g., Ubhi and Brown. Cancer Research 79.8 (2019): 1730-1739.
In some embodiments, replication stress can be detected via DNA fiber analyses, for example, by measuring DNA synthesis rates of individual DNA replication forks. In some embodiments, replication stress can be detected via DNA pull-downs to identify proteins bound directly at replication forks in vivo. See, e.g., Ubhi and Brown. Cancer Research 79.8 (2019): 1730-1739.
In some embodiments, replication stress can be detected using a biomarker of replication stress. In some embodiments, a biomarker of replication stress can include Ki- 67, Cyclin E, POLD3, γH2AX, FANCD2, or a combination thereof. In some embodiments, a biomarker of replication stress can include pH2AX Serl39 (γH2AX), pATR Thrl989, pCHKl Ser345, pRPA32 Ser33, or a combination thereof. See, e.g., Forment and O’Connor, Pharmacology & Therapeutics, 188 (2018) 155-16. In some embodiments, a biomarker of replication stress can be an activated oncogene. In some embodiments, a biomarker of replication stress can be an inactivated tumor suppressor gene. In some embodiments, a biomarker of replication stress can be one or more genes listed in Tables 1A or IB in WO2019173456(Al). In some embodiments, two or more of these methods can be combined. For example, in some embodiments, replication stress can be detected using the p53 status of the tumor(s) of the subject, optionally combined with the proliferation index of the tumor(s) (e.g., as measured by Ki67). See, e.g., Reaper et al. Nature Chemical Biology 7.7 (2011): 428-430. In some embodiments, replication stress can be detected using chromosomal instability (e.g., by karyotype or by measuring chromosomal instability genes). See, e.g., Burrell et al. Nature 494.7438 (2013): 492-496.
In some embodiments, the subject has been identified or diagnosed as having a cancer with an inactivation of one or more tumor suppressor genes (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for inactivation of one or more tumor suppressor genes (e.g., as determined using a regulatory agency-approved, e.g., FDA- approved, assay or kit). The subject can be a subject with a tumor(s) that is positive for inactivation of one or more tumor suppressor genes (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject can be a subject whose tumors have inactivation of one or more tumor suppressor genes (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having a cancer with inactivation of one or more tumor suppressor genes. In some embodiments, the subject has a clinical record indicating that the subject has a tumor that has inactivation of one or more tumor suppressor genes (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein). In some embodiments, the subject is a pediatric subject. In some embodiments, the subject has been identified or diagnosed as having a cancer that, based on histological examination, is determined to inactivation of one or more tumor suppressor genes. Inactivation of a tumor suppressor gene can be through any appropriate mechanism, including, but not limited to, gene deletion, inactivating mutation, inactivating translocation, transcriptional silencing, epigenetic alteration, and degradation of mRNA and/or protein products of the gene.
A tumor suppressor gene can be any appropriate tumor suppressor gene. In some embodiments, a tumor suppressor gene can be p53, RBI, CDKN2A, BRCA1, BRCA2, FBXW7, SETD2, NOTCH1, or a combination thereof. See, e.g., Forment and O’Connor, Pharmacology & Therapeutics, 188 (2018) 155-167, Reaper et al. Nature Chemical Biology 7.7 (2011): 428-430, and Mendez et al. Clinical Cancer Research 24.12 (2018): 2740-2748. In some embodiments, an inactivated tumor suppressor gene is a mutated p53 gene. In some embodiments, an inactivated tumor suppressor gene is a deleted p53 gene. In some embodiments, an inactivated tumor suppressor gene is a mutated CDKN2A gene. In some embodiments, an inactivated tumor suppressor gene is a mutated NOTCH1 gene. In some embodiments, an inactivated tumor suppressor gene is a deleted FBXW7 gene. A non-limiting example of a cancer that can have a deleted FBXW7 gene is uterine serous carcinoma. In some embodiments, an inactivated tumor suppressor gene is a mutated FBXW7 gene. In some embodiments, an inactivated tumor suppressor gene is a mutated RBI gene. In some embodiments, an inactivated tumor suppressor gene is a deleted BRCA1 gene. In some embodiments, an inactivated tumor suppressor gene is a mutated BRCA1 gene. In some embodiments, an inactivated tumor suppressor gene is a BRCA1 gene with a hypermethylated promoter region. In some embodiments, an inactivated tumor suppressor gene is a deleted BRCA2 gene. In some embodiments, an inactivated tumor suppressor gene is a mutated BRCA2 gene. In some embodiments, an inactivated tumor suppressor gene is a BRCA2 gene with a hypermethylated promoter region. In some embodiments, an inactivated tumor suppressor gene is a mutated NOTCH1 gene. In some embodiments, an inactivated tumor suppressor gene is a mutated SETD2 gene.
In some embodiments, the subject has been identified or diagnosed as having a cancer with an activation of one or more oncogenes (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for activation of one or more oncogenes (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject can be a subject with a tumor(s) that is positive for activation of one or more oncogenes (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject can be a subject whose tumors have activation of one or more oncogenes (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA- approved, kit or assay). In some embodiments, the subject is suspected of having a cancer with activation of one or more oncogenes. In some embodiments, the subject has a clinical record indicating that the subject has a tumor that has activation of one or more oncogenes (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein). In some embodiments, the subject is a pediatric subject. In some embodiments, the subject has been identified or diagnosed as having a cancer that, based on histological examination, is determined to activation of one or more oncogenes. Activation of an oncogene can be through any appropriate mechanism, including, but not limited to, gene amplification, activating mutation, activating translocation, transcriptional activation, epigenetic alteration, and/or overexpression of the protein product of the oncogene.
An oncogene can be any appropriate oncogene. In some embodiments, an oncogene can be cyclin E (sometimes also called cyclin El or CCNE1), CDC25A, Myc, a RAS gene (e.g., KRAS, NRAS, HRAS, or a combination thereof), or a combination thereof. See, e.g., Haigis, Trends in Cancer 3.10 (2017): 686-697, Kalkat, et al. Genes (2017) 8, 151, Feng et al. Molecular and Cellular Biology 31.16 (2011): 3457-3471, Kok et al. Oncogenesis (2020) 9:88, Dang, Cell 149.1 (2012): 22-35. In some embodiments, an activated oncogene is an amplified cyclin E gene. Non-limiting examples of cancers that can have amplified cyclin E (e.g., cyclin El) include rhabdomyosarcoma, urinary bladder adenocarcinoma, malignant fibrous histiocytoma, small intestine adenocarcinoma, medullary breast cancer, gallbladder adenocarcinoma, stomach adenocarcinoma, urinary bladder transitional cell carcinoma, urinary bladder small cell carcinoma, non-serous ovarian carcinoma, uterine cervix squamous cell carcinoma, and ovarian endometrial (endometrioid) carcinoma. In some embodiments, an activated oncogene is an overexpressed CDC25A. Non-limiting examples of cancer that can have overexpressed CDC25 A include breast cancer, colorectal cancer, lung cancer, hepatocellular carcinoma, prostate cancer, esophageal cancer (e.g., esophageal squamous cell carcinoma), pancreatic ductal adenocarcinoma, thyroid neoplasms, non-Hodgkin's lymphoma, and neuroblastoma. In some embodiments, an activated oncogene is an amplified Myc gene. Non-limiting examples of cancers that can have Myc amplification include breast invasive ductal carcinoma, lung adenocarcinoma, prostate adenocarcinoma, colon adenocarcinoma, and high grade ovarian serous adenocarcinoma. In some embodiments, an activated oncogene is a Myc gene with an activating translocation. In some embodiments, an activated oncogene is a transcriptionally activated Myc gene. In some embodiments, an activated oncogene is a mutated RAS gene (e.g., a KRAS gene, an NRAS gene, an HRAS gene, or a combination thereof). In some embodiments, a mutated RAS gene (e.g., a KRAS gene, an NRAS gene, an HRAS gene, or a combination thereof) includes a mutation at position G12 of the protein product of the gene. In some embodiments, a mutated RAS gene (e.g., a KRAS gene, an NRAS gene, an HRAS gene, or a combination thereof) includes a mutation at position G13 of the protein product of the gene. In some embodiments, a mutated RAS gene (e.g., a KRAS gene, an NRAS gene, an HRAS gene, or a combination thereof) includes a mutation at position Q61 of the protein product of the gene. Non-limiting examples of cancers that can have KRAS mutations include pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and non-small cell lung cancer (NSCLC).
In some embodiments, the subject has been identified or diagnosed as having a cancer with increased DNA damage. In some embodiments, the subject has a tumor that is positive for increased DNA damage. The subject can be a subject with a tumor(s) that tests positive for increased DNA damage. The subject can be a subject whose tumors have increased DNA damage. In some embodiments, the subject is suspected of having a tumor with increased DNA damage. In some embodiments, the subject has a clinical record indicating that the subject has a tumor that has increased DNA damage. In some embodiments, the subject is a pediatric subject. In some embodiments, the subject has been identified or diagnosed as having a cancer that, based on histological examination, is determined to be associated with increased DNA damage.
Typically, “increased” DNA damage is achieved by administration of one or more DNA-damaging agents, one or more DNA repair inhibiting agents, and/or radiation to the subject. In some embodiments, a DNA-damaging agent can include a platinum-based chemotherapy, an alkylating agent, a nucleobase, nucleoside, and/or nucleotide analog, or a combination thereof. In some embodiments, a DNA repair inhibiting agent can include a topoisomerase I inhibitor, a topoisomerase II inhibitor, a PARP inhibitor, an ATR inhibitor, a Chk inhibitor, or a combination thereof. Non-limiting examples of platinum-based chemotherapeutics include carboplatin, cisplatin, and oxaplatin. Non-limiting examples of alkylating agents include cyclophosphamide, carmustine, busulfan, procarbazine, dacarbazine, temozoloamide, thiotepa, and mitomycin C. Non-limiting examples of nucleobase, nucleoside, and/or nucleotide analogs include fluorouracil, cytarabine, gemcitabine, azacitidine, and decitabine. Non-limiting examples of topoisomerase I inhibitors include topotecan, irinotecan, belotecan, and camptothecin. Non-limiting examples of topoisomerase II inhibitors include etoposide, tenoposide, doxorubicin, daunorubicin, epirubicin, and idarubacin. Non-limiting examples of PARP inhibitors include olaparib, niraparib, rucaparib, talazoparib, and veliparib. Non-limiting examples of ATR inhibitors include AZD6738, BAY1895344, and M6620. Non-limiting examples of Chkl inhibitors include prexasertib, GDC-0575, SCH 900776, and SRA737.
The term “pediatric subject” as used herein refers to a subject under the age of 21 years at the time of diagnosis or treatment. The term “pediatric” can be further be divided into various subpopulations including: neonates (from birth through the first month of life); infants (1 month up to two years of age); children (two years of age up to 12 years of age); and adolescents (12 years of age through 21 years of age (up to, but not including, the twenty-second birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: W.B. Saunders Company, 1996; Rudolph AM, et al . Rudolph ’s Pediatrics, 21 st Ed. New Y ork: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994. In some embodiments, a pediatric subject is from birth through the first 28 days of life, from 29 days of age to less than two years of age, from two years of age to less than 12 years of age, or 12 years of age through 21 years of age (up to, but not including, the twenty-second birthday). In some embodiments, a pediatric subject is from birth through the first 28 days of life, from 29 days of age to less than 1 year of age, from one month of age to less than four months of age, from three months of age to less than seven months of age, from six months of age to less than 1 year of age, from 1 year of age to less than 2 years of age, from 2 years of age to less than 3 years of age, from 2 years of age to less than seven years of age, from 3 years of age to less than 5 years of age, from 5 years of age to less than 10 years of age, from 6 years of age to less than 13 years of age, from 10 years of age to less than 15 years of age, or from 15 years of age to less than 22 years of age.
In certain embodiments, compounds of Formula (I), or a pharmaceutically acceptable salt thereof are useful for preventing diseases and disorders as defined herein (for example, cancer). The term "preventing” as used herein means the prevention of the onset, recurrence or spread, in whole or in part, of the disease or condition as described herein, or a symptom thereof. Without being bound by any particular theory, it is believed that cancers that exhibit replication stress are more reliant on the cell cycle checkpoint regulators such as Weel. In some embodiments, cancers that exhibit replication stress overexpress Weel . Non-limiting examples of cancers that can overexpress Weel include hepatocellular carcinoma, breast cancers, cervical cancers, lung cancers, squamous cell carcinoma, diffuse intrinsic pontine glioma, glioblastoma, medulloblastoma, leukemia, melanoma, ovarian cancers, pancreatic cancers, and colorectal cancers. See, e.g., P Reigan et al Trends in Pharmacol Sci 2016; Mir, et al., Cancer Cell, Vol. 18, No. 3, pp. 244-257 (2010)).
The term “regulatory agency” refers to a country's agency for the approval of the medical use of pharmaceutical agents with the country. For example, a non-limiting example of a regulatory agency is the U.S. Food and Drug Administration (FDA).
Compounds
Accordingly, provided herein is are compounds of Formula (I):
Figure imgf000020_0001
or a pharmaceutically acceptable salt thereof, wherein:
= is a single bond or a double bond; when = is a double bond, R2 and R2B are absent;
R1 is a C6-C10 aryl optionally substituted with 1-3 independently selected RA or a 5-10 membered heteroaryl optionally substituted with 1-3 independently selected RA;
R2 is a C1-C6 alkyl optionally substituted with 1-3 independently selected RB or a C3-C8 cycloalkyl optionally substituted with 1-3 independently selected RB;
R2A is hydrogen, a C1-C6 alkyl optionally substituted with 1-3 independently selected RB, or a C3-C8 cycloalkyl optionally substituted with 1-3 independently selected RB; R2B is hydrogen, a C1-C6 alkyl optionally substituted with 1-3 independently selected RB, or a C3-C8 cycloalkyl optionally substituted with 1-3 independently selected RB;
R2A and R2B, with the carbon atom to which they are attached, together form a C=O group;
Ring A is a 4-10 membered heterocyclyl, 5-10 membered heteroaryl, or C6-C10 aryl; or wherein Ring A and R5 are absent;
R3 is hydrogen, halogen, or C1-C6 alkyl optionally substituted with 1-3 independently selected Rc;
R4 is hydrogen or C1-C6 alkyl; each R5 is independently halogen, C1-C6 alkyl, C3-C8 cycloalkyl, cyano, -(CH2)q- NR5AR5B, _(CH2)n-4-10 membered heterocyclyl optionally substituted with 1-3 independently selected RD, or -(CH2)p-5-10 membered heteroaryl optionally substituted with 1-3 independently selected RE; m is 0, 1, 2, or 3; n is 0-6; p is 0-6; q is 0-6;
X is O, S, or NR6;
R6 is hydrogen or C1-C6 alkyl; each RA is independently selected from halogen, cyano, hydroxyl, -NRFRG, C1-C6 alkyl, C1-C6 alkoxy, and C3-C8 cycloalkyl; each RB, RC, RD, and RE are independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, and -NRFRG; and each R5A, R5B, RF, and RG are independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl.
In some embodiments, = is a single bond, for example, in compounds of Formula (II) and compounds of Formula (III). In some embodiments, = is a double bond, for example, in compounds of Formula (IV). In some embodiments, when = is a double bond (for example, in compounds of Formula IV), R2 and R2B are absent. In some embodiments, R2A is hydrogen, a C1-C6 alkyl optionally substituted with 1-3 independently selected RB (as described herein), or a C3-C8 cycloalkyl optionally substituted with 1-3 independently selected RB (as described herein). In some embodiments, R2A is hydrogen. In some embodiments, R2A is C1-C6 alkyl optionally substituted with 1-3 independently selected RB. In some embodiments, R2A is C3-C8 cycloalkyl optionally substituted with 1-3 independently selected RB. In some embodiments, R2A is C1-C6 alkyl substituted with 1-3 independently selected RB. In some embodiments, R2A is C3-C8 cycloalkyl substituted with 1-3 independently selected RB. In some embodiments, R2A is C1-C6 alkyl. In some embodiments, R2A is C3-C8 cycloalkyl.
In some embodiments, R2B is hydrogen, a C1-C6 alkyl optionally substituted with 1-3 independently selected RB (as described herein), or a C3-C8 cycloalkyl optionally substituted with 1-3 independently selected RB (as described herein). In some embodiments, R2B is hydrogen. In some embodiments, R2B is C1-C6 alkyl optionally substituted with 1-3 independently selected RB. In some embodiments, R2B is C3-C8 cycloalkyl optionally substituted with 1-3 independently selected RB. In some embodiments, R2B is C1-C6 alkyl substituted with 1-3 independently selected RB. In some embodiments, R2B is C3-C8 cycloalkyl substituted with 1-3 independently selected RB. In some embodiments, R2B is C1-C6 alkyl. In some embodiments, R2B is C3-C8 cycloalkyl.
In some embodiments, R2A and R2B, together with the carbon atom to which they are attached, together form a C=O group.
In some embodiments, = is a single bond and R2A and R2B are each hydrogen, for example, in compounds of Formula (II). In some embodiments, = is a single bond and R2A and R2B, together with the carbon atom to which they are attached, together form a C=O group, for example, in compounds of Formula (III).
In some embodiments, = is a double bond, R2 and R2B are absent, and R2A is hydrogen, a C1-C6 alkyl optionally substituted with 1-3 independently selected RB (as described herein), or a C3-C8 cycloalkyl optionally substituted with 1-3 independently selected RB (as described herein), for example, in compounds of Formula (IV).
Also provided herein are compounds of (Formula (II), or a pharmaceutically acceptable salt thereof:
Figure imgf000023_0001
or a pharmaceutically acceptable salt thereof, wherein:
R1 is a C6-C10 aryl optionally substituted with 1-3 independently selected RA or a 5-10 membered heteroaryl optionally substituted with 1-3 independently selected RA;
R2 is a C1-C6 alkyl optionally substituted with 1-3 independently selected RB or a C3-C8 cycloalkyl optionally substituted with 1-3 independently selected RB;
Ring A is a 4-10 membered heterocyclyl, 5-10 membered heteroaryl, or C6-C10 aryl; or wherein Ring A and R5 are absent;
R3 is hydrogen, halogen, or C1-C6 alkyl optionally substituted with 1-3 independently selected Rc;
R4 is hydrogen or C1-C6 alkyl; each R5 is independently halogen, C1-C6 alkyl, C3-C8 cycloalkyl, cyano, -(CH2)q- NR5AR5B, _(CH2)n-4-10 membered heterocyclyl optionally substituted with 1-3 independently selected RD, or -(CH2)p-5-10 membered heteroaryl optionally substituted with 1-3 independently selected RE; m is 0, 1, 2, or 3; n is 0-6; p is 0-6; q is 0-6;
X is O, S, or NR6;
R6 is hydrogen or C1-C6 alkyl; each RA is independently selected from halogen, cyano, hydroxyl, -NRFRG, C1-C6 alkyl, C1-C6 alkoxy, and C3-C8 cycloalkyl; each RB, RC, RD, and RE are independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, and -NRFRG; and each R5A, R5B, RF, and RG are independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl.
Also provided herein are compounds of Formula (III), or a pharmaceutically acceptable salt thereof:
Figure imgf000024_0001
or a pharmaceutically acceptable salt thereof, wherein:
R1 is a C6-C10 aryl optionally substituted with 1-3 independently selected RA or a 5-10 membered heteroaryl optionally substituted with 1-3 independently selected RA;
R2 is a C1-C6 alkyl optionally substituted with 1-3 independently selected RB or a C3-C8 cycloalkyl optionally substituted with 1-3 independently selected RB;
Ring A is a 4-10 membered heterocyclyl, 5-10 membered heteroaryl, or C6-C10 aryl; or wherein Ring A and R5 are absent;
R3 is hydrogen, halogen, or C1-C6 alkyl optionally substituted with 1-3 independently selected Rc;
R4 is hydrogen or C1-C6 alkyl; each R5 is independently halogen, C1-C6 alkyl, C3-C8 cycloalkyl, cyano, -(CH2)q- NRSARSB, _(CH2)n-4-10 membered heterocyclyl optionally substituted with 1-3 independently selected RD, or -(CH2)p-5-10 membered heteroaryl optionally substituted with 1-3 independently selected RE; m is 0, 1, 2, or 3; n is 0-6; p is 0-6; q is 0-6;
X is O, S, or NR6; R6 is hydrogen or C1-C6 alkyl; each RA is independently selected from halogen, cyano, hydroxyl, -NRFRG, C1-C6 alkyl, C1-C6 alkoxy, and C3-C8 cycloalkyl; each RB, RC, RD, and RE are independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, and -NRFRG; and each R5A, R5B, RF, and RG are independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl.
Also provided herein are compounds of Formula (IV), or a pharmaceutically acceptable salt thereof:
Figure imgf000025_0001
or a pharmaceutically acceptable salt thereof, wherein:
R1 is a C6-C10 aryl optionally substituted with 1-3 independently selected RA or a 5-10 membered heteroaryl optionally substituted with 1-3 independently selected RA;
R2A is hydrogen, a C1-C6 alkyl optionally substituted with 1-3 independently selected RB, or a C3-C8 cycloalkyl optionally substituted with 1-3 independently selected RB;
Ring A is a 4-10 membered heterocyclyl, 5-10 membered heteroaryl, or C6-C10 aryl; or wherein Ring A and R5 are absent;
R3 is hydrogen, halogen, or C1-C6 alkyl optionally substituted with 1-3 independently selected Rc;
R4 is hydrogen or C1-C6 alkyl; each R5 is independently halogen, C1-C6 alkyl, C3-C8 cycloalkyl, cyano, -(CH2)q- NRSARSB, _(CH2)n-4-10 membered heterocyclyl optionally substituted with 1-3 independently selected RD, or -(CH2)p-5-10 membered heteroaryl optionally substituted with 1-3 independently selected RE; m is 0, 1, 2, or 3; n is 0-6; p is 0-6; q is 0-6;
X is O, S, or NR6;
R6 is hydrogen or C1-C6 alkyl; each RA is independently selected from halogen, cyano, hydroxyl, -NRFRG, C1-C6 alkyl, C1-C6 alkoxy, and C3-C8 cycloalkyl; each RB, RC, RD, and RE are independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, and -NRFRG; and each R5A, R5B, RF, and RG are independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl.
In some embodiments of the compounds described herein (e.g., compounds of Formulae (I), (II), (III), and (IV)), R1 is a C6-C10 aryl substituted with 1-3 independently selected RA. In some embodiments, R1 is phenyl substituted with 1-3 independently selected RA. In some embodiments, R1 is phenyl substituted with 1 RA. In some embodiments, R1 is phenyl substituted with 2 independently selected RA. In some embodiments, R1 is phenyl substituted with 3 independently selected RA.
In some embodiments, R1 is a 5-10 membered heteroaryl optionally substituted with 1-3 independently selected RA. In some embodiments, R1 is a 5-10 membered heteroaryl substituted with 1 RA. In some embodiments, R1 is a 5-10 membered heteroaryl substituted with 2 independently selected RA. In some embodiments, R1 is a 5-10 membered heteroaryl substituted with 3 independently selected RA. In some embodiments, R1 is a 5-6 membered heteroaryl optionally substituted with 1 or 2 independently selected RA
In some embodiments, R1 is an unsubstituted C6-C10 aryl. In some embodiments, R1 is an unsubstituted phenyl. In some embodiments, R1 is an unsubstituted 5-10 membered heteroaryl. In some embodiments, R1 is an unsubstituted 5-6 membered heteroaryl, such as pyridine, pyrimidine, pyrrole, imidazole, and pyrazole.
In some embodiments, two RA are the same. In some embodiments, three RA are the same. In some embodiments, two RA are different. In some embodiments, three RA are different. In some embodiments, each RA is independently selected from halogen, cyano, hydroxyl, -NRFRG, C1-C6 alkyl, C1-C6 alkoxy, and C3-C8 cycloalkyl.
In some embodiments, each RA is independently halogen. In some embodiments, each RA is cyano. In some embodiments, each RA is hydroxyl. In some embodiments, each RA is independently -NRFRG, In some embodiments, each RA is independently Cl- C6 alkyl. In some embodiments, each RA is independently C1-C6 alkoxy. In some embodiments, each RA is independently C3-C8 cycloalkyl.
In some embodiments, one or two RA is independently halogen. In some embodiments, one RA is cyano. In some embodiments, one RA is hydroxyl. In some embodiments, one RA is -NRFRG, In some embodiments, one RA is C1-C6 alkyl. In some embodiments, one RA is C1-C6 alkoxy. In some embodiments, one RA is C3-C8 cycloalkyl.
In some embodiments, each RA is independently selected from fluoro, chloro, bromo, cyano, hydroxyl, amino, C1-C3 alkyl, C1-C3 alkoxy, and C3-C6 cycloalkyl. In some embodiments, each RA is independently selected from chloro, bromo, cyano, and methoxy. In some embodiments, each RA is independently selected from chloro and bromo. In some embodiments, each RA is chloro. In some embodiments, each RA is independently selected from chloro and cyano. In some embodiments, each RA is cyano.
In some embodiments, when R1 is phenyl substituted with two RA groups, the RA groups can be ortho, meta, or para to each other. In some embodiments, when R1 is 5-6 membered heteroaryl substituted with at least one RA group, the at least one RA group can be substituted on a carbon atom, or on a nitrogen atom, such as the nitrogen atom of a pyrazole.
In some embodiments, R1 is In some embodiments, R1 is
Figure imgf000027_0001
Figure imgf000027_0002
In some embodiments, R2 is a C1-C6 alkyl optionally substituted with 1-3 independently selected RB or a C3-C8 cycloalkyl optionally substituted with 1-3 independently selected RB;
In some embodiments, R2 is a C1-C6 alkyl optionally substituted with 1-3 independently selected RB. In some embodiments, R2 is a C1-C6 alkyl substituted with 1- 3 independently selected RB. In some embodiments, R2 is C1-C6 alkyl substituted with 1 RB. In some embodiments, R2 is C1-C6 alkyl substituted with 2 independently selected RB. In some embodiments, R2 is C1-C6 alkyl substituted with 3 independently selected RB.
In some embodiments, R2 is a C3-C8 cycloalkyl optionally substituted with 1-3 independently selected RB. In some embodiments, R2 is a C3-C8 cycloalkyl substituted with 1-3 independently selected RB. In some embodiments, R2 is C3-C8 cycloalkyl substituted with 1 RB. In some embodiments, R2 is C3-C8 cycloalkyl substituted with 2 independently selected RB. In some embodiments, R2 is C3-C8 cycloalkyl substituted with 3 independently selected RB.
In some embodiments of Formula (I), R2 is absent, for example, in compounds of Formula (IV).
In some embodiments, each RB is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, and -NRFRG. In some embodiments, each RB is independently selected from fluoro, chloro, hydroxyl, cyano, C1-C3 alkyl, C1-C3 alkoxy, and -NRFRG. In some embodiments, each RB is independently selected from fluoro, hydroxyl, C1-C3 alkoxy, and -NRFRG. In some embodiments, each RB is independently selected from fluoro, hydroxyl, methoxy, and -NRFRG. In some embodiments, each RB is independently selected from fluoro, hydroxyl, and methoxy.
In some embodiments, R2 is an unsubstituted C1-C6 alkyl. In some embodiments, R2 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R2 is methyl. In some embodiments, R2 is an unsubstituted C3-C8 cycloalkyl. In some embodiments, R2 is cyclopropyl or cyclobutyl.
In some embodiments, R3 is hydrogen, halogen, or C1-C6 alkyl optionally substituted with 1-3 independently selected Rc.
In some embodiments, R3 is C1-C3 alkyl optionally substituted with 1-3 independently selected Rc. In some embodiments, is C1-C3 alkyl substituted with 1-3 independently selected Rc. In some embodiments, R3 is C1-C3 alkyl substituted with 1 Rc. In some embodiments, R3 is C1-C3 alkyl substituted with 2 independently selected Rc. In some embodiments, R3 is C1-C3 alkyl substituted with 3 independently selected Rc. In some embodiments, each Rc is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, and -NRFRG. In some embodiments, each Rc is independently selected from fluoro, chloro, hydroxyl, cyano, C1-C3 alkyl, C1-C3 alkoxy, and -NRFRG. In some embodiments, each Rc is independently selected from fluoro, hydroxyl, C1-C3 alkoxy, and -NRFRG. In some embodiments, each Rc is independently selected from fluoro, hydroxyl, methoxy, and -NRFRG. In some embodiments, each Rc is independently selected from fluoro, hydroxyl, and methoxy.
In some embodiments, one or two Rc is independently halogen. In some embodiments, one Rc is hydroxyl. In some embodiments, one Rc is cyano. In some embodiments, one Rc is C1-C6 alkyl. In some embodiments, one Rc is C1-C6 alkoxy. In some embodiments, one Rc is -NRFRG.
In some embodiments, R3 is hydrogen, halogen, or unsubstituted C1-C3 alkyl. In some embodiments, R3 is hydrogen. In some embodiments, R3 is halogen. In some embodiments, R3 is fluoro or chloro. In some embodiments, R3 is an unsubstituted C1-C3 alkyl. In some embodiments, R3 is methyl.
In some embodiments, R4 is hydrogen or C1-C6 alkyl. In some embodiments, R4 is hydrogen or C1-C3 alkyl. In some embodiments, R4 is hydrogen. In some embodiments, R4 is C1-C3 alkyl. In some embodiments, R4 is methyl.
In some embodiments, X is NR6. In some embodiments, R6 is hydrogen or C1-C6 alkyl. In some embodiments, R6 is hydrogen. In some embodiments, R6 is C1-C6 alkyl. In some embodiments, R6 is C1-C3 alkyl. In some embodiments, R6 is methyl.
In some embodiments, X is S. In some embodiments, X is O.
In some embodiments, Ring A and R5 are absent, and the bond from Ring A to Formula (I) (including compounds of Formulae (II), (III), and (IV)) is replaced with a hydrogen atom.
In some embodiments, Ring A is a C6-C10 aryl. In some embodiments, Ring A is phenyl.
In some embodiments, Ring A is a 5-10 membered heteroaryl. In some embodiments, Ring A is monocyclic. In some embodiments, Ring A is bicyclic. In some embodiments, Ring A is a 5, 6, or 10 membered heteroaryl. In some embodiments, Ring A is a 5 membered heteroaryl, such as pyrrole, pyrazole, or imidazole. In some embodiments, Ring A is a pyrazole. In some embodiments, Ring A is a 6 membered heteroaryl, such as pyridine, pyrimidine, or pyridazine. In some embodiments, Ring A is pyridine. In some embodiments, Ring A is a 10 membered fused bicyclic heteroaryl, such as quinoline.
In some embodiments, Ring A is a 4-10 membered heterocyclyl. In some embodiments, Ring A is a 5-10 membered heterocyclyl containing 2-4 heteroatoms selected from O and N. In some embodiments, Ring A is a 5 or 6 membered monocyclic heterocyclyl containing one nitrogen atom and 1 or 2 additional heteroatoms selected from O and N. In some embodiments, Ring A is an 8-10 membered bicyclic heterocyclyl containing one nitrogen atom and 1 or 2 additional heteroatoms selected from O and N. In some embodiments, Ring A is 5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine. In some embodiments, Ring A is attached to the fused tricyclic moiety of Formula (I) (including compounds of Formulae (II), (III), and (IV)) by a carbon atom in Ring A. In some embodiments, Ring A is attached to the fused tricyclic moiety of Formula (I) (including compounds of Formulae (II), (III), and (IV)) by a nitrogen atom in Ring A.
In some embodiments, Ring A is In some embodiments, Ring A is
Figure imgf000030_0001
In some embodiments, Ring A is In some embodiments,
Figure imgf000030_0002
Figure imgf000030_0003
Ring A is
Figure imgf000030_0004
In some embodiments, each R5 is independently halogen, C1-C6 alkyl, C3-C8 cycloalkyl, cyano, -(CH2)q-NR5AR5B, -(CH2)n-4-10 membered heterocyclyl optionally substituted with 1-3 independently selected RD, or -(CH2)p-5-10 membered heteroaryl optionally substituted with 1-3 independently selected RE. In some embodiments, one R5 is halogen, C1-C6 alkyl, C3-C8 cycloalkyl, cyano, -(CH2)q-NR5AR5B, -(CH2)n-4-10 membered heterocyclyl optionally substituted with 1-3 independently selected RD, or -(CH2)p-5-10 membered heteroaryl optionally substituted with 1-3 independently selected RE.
In some embodiments, each R5 is independently halogen, C1-C3 alkyl, C3-C6 cycloalkyl, cyano, -(CH2)q-NR5AR5B, -(CH2)n-4-6 membered heterocyclyl optionally substituted with RD, or -(CH2)p-5-6 membered heteroaryl optionally substituted with RE. In some embodiments, one R5 is independently halogen, C1-C3 alkyl, C3-C6 cycloalkyl, cyano, -(CH2)q-NR5AR5B, -(CH2)n-4-6 membered heterocyclyl optionally substituted with RD, or -(CH2)P-5-6 membered heteroaryl optionally substituted with RE.
In some embodiments, each R5 is independently fluoro, chloro, methyl, cyclopropyl, cyclobutyl, cyano, or -(CH2)n-4-6 membered heterocyclyl optionally substituted with C1-C6 alkyl. In some embodiments, one R5 is independently fluoro, chloro, methyl, cyclopropyl, cyclobutyl, cyano, or -(CH2)n-4-6 membered heterocyclyl optionally substituted with C1-C6 alkyl.
In some embodiments, where there are two R5 groups, one R5 is halogen, C1-C6 alkyl, C3-C8 cycloalkyl, or cyano; and the other R5 group is -(CH2)n-4-10 membered heterocyclyl optionally substituted with 1-3 independently selected RD. In some embodiments, where there are two R5 groups, one R5 is halogen or C1-C6 alkyl; and the other R5 group is -(CH2)n-4-10 membered heterocyclyl optionally substituted with 1-3 independently selected RD. In some embodiments, where there are two R5 groups, one R5 is halogen or C1-C6 alkyl; and the other R5 group is -(CH2)n-4-10 membered heterocyclyl optionally substituted with RD. In some embodiments, where there are two R5 groups, one R5 is halogen or C1-C6 alkyl; and the other R5 group is -(CH2)n-4-10 membered heterocyclyl.
In some embodiments, each R5 is independently -(CH2)n-4-10 membered heterocyclyl optionally substituted with 1-3 independently selected RD. In some embodiments, each R5 is independently -(CH2)n-4-10 membered heterocyclyl substituted with 1 RD. In some embodiments, each R5 is independently -(CH2)n-4-10 membered heterocyclyl substituted with 2 independently selected RD. In some embodiments, each R5 is independently -(CH2)n-4-10 membered heterocyclyl substituted with 3 independently selected RD. In some embodiments, one R5 is independently -(CH2)n-4-10 membered heterocyclyl optionally substituted with 1-3 independently selected RD. In some embodiments, one R5 is independently -(CH2)n-4-10 membered heterocyclyl substituted with 1 RD. In some embodiments, one R5 is independently -(CH2)n-4-10 membered heterocyclyl substituted with 2 independently selected RD. In some embodiments, one R5 is independently -(CH2)n-4-10 membered heterocyclyl substituted with 3 independently selected RD.
In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3, 4, 5, or 6.
In some embodiments, each RD is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, and -NRFRG. In some embodiments, each RD is independently selected from fluoro, chloro, hydroxyl, cyano, C1-C3 alkyl, C1-C3 alkoxy, and -NRFRG. In some embodiments, each RD is independently selected from fluoro, hydroxyl, cyano, methoxy, and C1-C3 alkyl. In some embodiments, each RD is an independently selected C1-C3 alkyl. In some embodiments, each RD is methyl. In some embodiments, one RD is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, and -NRFRG. In some embodiments, one RD is independently selected from fluoro, chloro, hydroxyl, cyano, C1-C3 alkyl, C1-C3 alkoxy, and -NRFRG. In some embodiments, one RD is independently selected from fluoro, hydroxyl, cyano, methoxy, and C1-C3 alkyl. In some embodiments, one RD is an independently selected C1-C3 alkyl. In some embodiments, one RD is methyl.
In some embodiments, each R5 is independently -(CH2)n-4-6 membered heterocyclyl optionally substituted with C1-C6 alkyl. In some embodiments, R5 is -(CH2)n-4-6 membered heterocyclyl optionally substituted with C1-C6 alkyl. In some embodiments, R5 is -(CH2)n-4-6 membered heterocyclyl substituted with C1-C6 alkyl. In some embodiments, R5 is -(CH2)n-4-6 membered heterocyclyl substituted with methyl. In some embodiments, R5 is a 4-6 membered heterocyclyl. In some embodiments, R5 is -(CH2)-4-6 membered heterocyclyl. In some embodiments, R5 is -(CH2)2-4-6 membered heterocyclyl. In some embodiments, the heterocyclyl is connected to Formula (I) (including compounds of Formulae (II), (III), and (IV)) via a carbon atom. In some embodiments, the heterocyclyl is connected to Formula (I) (including compounds of Formulae (II), (III), and (IV)) via a nitrogen atom. In some embodiments, the heterocyclyl of R5 is selected from azetidine, pyrrolidine, 2-pyrrolidinone, piperidine, and piperazine. In some embodiments, the heterocyclyl of R5 is selected from azetidine, pyrrolidine, 2-pyrrolidinone, and piperidine.
In some embodiments, the heterocyclyl of R5 is selected from
Figure imgf000033_0001
Figure imgf000033_0002
Figure imgf000033_0003
In some embodiments, each R5 is -(CH2)q-NR5AR5B.
In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3, 4, 5, or 6.
In some embodiments, each R5A and R5B are independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl. In some embodiments, each R5A and R5B are independently selected from hydrogen and C1-C3 alkyl. In some embodiments, one of R5A and R5B is hydrogen and the other of R5A and R5B is C1-C3 alkyl. In some embodiments, R5A and R5B are the same. In some embodiments, R5A and R5B are different. In some embodiments, R5A and R5B are both hydrogen. In some embodiments, R5A and R5B are both methyl. In some embodiments, one of R5A and R5B is hydrogen, and the other of R5A and R5B is methyl.
In some embodiments, each R5 is independently -(CH2)p-5-10 membered heteroaryl optionally substituted with 1-3 independently selected RE. In some embodiments, each R5 is independently -(CH2)p-5-6 membered heteroaryl optionally substituted with 1-3 independently selected RE. In some embodiments, each R5 is independently -(CH2)P-5-6 membered heteroaryl optionally substituted with 1 RE. In some embodiments, each R5 is independently -(CH2)P-5-6 membered heteroaryl optionally substituted with 2 independently selected RE. In some embodiments, each R5 is independently -(CH2)p-5-6 membered heteroaryl optionally substituted with 3 independently selected RE. In some embodiments, each R5 is independently -(CH2)p-5-6 membered heteroaryl. In some embodiments, one R5 is independently -(CH2)p-5-10 membered heteroaryl optionally substituted with 1-3 independently selected RE. In some embodiments, one R5 is independently -(CH2)P-5-6 membered heteroaryl optionally substituted with 1-3 independently selected RE. In some embodiments, one R5 is independently -(CH2)P-5-6 membered heteroaryl optionally substituted with 1 RE. In some embodiments, one R5 is independently -(CH2)P-5-6 membered heteroaryl optionally substituted with 2 independently selected RE. In some embodiments, one R5 is independently -(CH2)P-5-6 membered heteroaryl optionally substituted with 3 independently selected RE. In some embodiments, one R5 is independently -(CH2)P-5-6 membered heteroaryl.
In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3, 4, 5, or 6.
In some embodiments, each RE is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, and -NRFRG. In some embodiments, each RE is independently selected from fluoro, chloro, hydroxyl, cyano, C1-C3 alkyl, C1-C3 alkoxy, and -NRFRG. In some embodiments, each RE is independently selected from fluoro, hydroxyl, cyano, methoxy, and C1-C3 alkyl. In some embodiments, each RE is an independently selected C1-C3 alkyl. In some embodiments, each RE is methyl.
In some embodiments, each RF and RG are independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl. In some embodiments, each RF and RG are independently selected from hydrogen, C1-C3 alkyl, and C3-C6 cycloalkyl. In some embodiments, each RF and RG are independently selected from hydrogen and C1-C3 alkyl. In some embodiments, RF and RG are the same. In some embodiments, RF and RG are different. In some embodiments, RF and RG are both hydrogen. In some embodiments, RF and RG are both methyl. In some embodiments, one of RF and RG is hydrogen, and the other of RF and RG is methyl.
In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 0.
In some embodiments, Ring A and R5 are absent. In some embodiments, Ring A is a 5 membered heteroaryl; m is 1; and R5 is -(CH2)n-4-6 membered heterocyclyl optionally substituted with C1-C6 alkyl. In some embodiments, Ring A is pyrazole; m is 1; and R5 is -(CH2)n-4-6 membered heterocyclyl optionally substituted with C1-C6 alkyl. In some embodiments, Ring A is pyrazole; m is 1; R5 is - (CH2)n-4-6 membered heterocyclyl optionally substituted with C1-C6 alkyl; and n is 0. In some embodiments, Ring A is pyrazole; m is 1; R5 is -(CH2)n-4-6 membered heterocyclyl optionally substituted with C1-C6 alkyl; and n is 1. In some embodiments, Ring A is pyrazole; m is 1; and R5 is -(CH2)n-4-6 membered heterocyclyl optionally substituted with C1-C6 alkyl; wherein R5 is connected to the pyrazole via a nitrogen atom in the pyrazole ring. In some embodiments, Ring A is pyrazole; m is 1; R5 is -(CH2)n-4-6 membered heterocyclyl optionally substituted with C1-C6 alkyl; and n is 0; wherein R5 is connected to the pyrazole via a nitrogen atom in the pyrazole ring. In some embodiments, Ring A is pyrazole; m is 1; R5 is -(CH2)n-4-6 membered heterocyclyl optionally substituted with Cl -C6 alkyl; and n is 1; wherein R5 is connected to the pyrazole via a nitrogen atom in the pyrazole ring.
In some embodiments, is selected from the group consisting of:
Figure imgf000035_0002
Figure imgf000035_0001
Figure imgf000036_0001
In some embodiments, the compound of Formula (I) is selected from the compounds described in Table 1, or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (I) has the structure of Formula (II- A):
Figure imgf000036_0002
wherein:
RA1 and RA2 are independently selected from halogen, cyano, and C1-C6 alkoxy;
R2 is a C1-C6 alkyl optionally substituted with 1-3 independently selected RB or a C3-C8 cycloalkyl optionally substituted with 1-3 independently selected RB;
R5 is C1-C6 alkyl, C3-C8 cycloalkyl, -(CH2)n-4-10 membered heterocyclyl optionally substituted with 1-3 independently selected RD, or -(CH2)p-5-10 membered heteroaryl optionally substituted with 1-3 independently selected RE; n is 0-6; p is 0-6; and each RB, RD, and RE are independently selected from halogen, hydroxyl, C1-C3 alkyl, and C1-C3 alkoxy.
In some embodiments, the compound of Formula (I) has the structure of Formula (III- A):
Figure imgf000037_0001
wherein:
RA1 and RA2 are independently selected from halogen, cyano, and C1-C6 alkoxy;
R2 is a C1-C6 alkyl optionally substituted with 1-3 independently selected RB or a C3-C8 cycloalkyl optionally substituted with 1-3 independently selected RB;
R5 is C1-C6 alkyl, C3-C8 cycloalkyl, -(CH2)n-4-10 membered heterocyclyl optionally substituted with 1-3 independently selected RD, or -(CH2)p-5-10 membered heteroaryl optionally substituted with 1-3 independently selected RE; n is 0-6; p is 0-6; and each RB, RD, and RE are independently selected from halogen, hydroxyl, C1-C3 alkyl, and C1-C3 alkoxy.
In some embodiments, the compound of Formula (I) has the structure of Formula (IV- A):
Figure imgf000037_0002
wherein:
RA1 and RA2 are independently selected from halogen, cyano, and C1-C6 alkoxy;
R2A is hydrogen or C1-C6 alkyl; R5 is C1-C6 alkyl, C3-C8 cycloalkyl, -(CH2)n-4-10 membered heterocyclyl optionally substituted with 1-3 independently selected RD, or -(CH2)p-5-10 membered heteroaryl optionally substituted with 1-3 independently selected RE; n is 0-6; p is 0-6; and each RD and RE are independently selected from halogen, hydroxyl, C1-C3 alkyl, and C1-C3 alkoxy.
In some embodiments, R2A is hydrogen. In some embodiments, R2A is C1-C6 alkyl. In some embodiments, R2A is methyl.
In some embodiments, RA1 and RA2 are independently selected from halogen and C1-C6 alkoxy. In some embodiments, RA1 and RA2 are independently selected from halogen and cyano. In some embodiments, RA1 and RA2 are independently selected halogen. In some embodiments, RA1 and RA2 are chloro.
In some embodiments, R2 is a C1-C6 alkyl optionally substituted with 1-3 independently selected RB or a C3-C8 cycloalkyl optionally substituted with 1-3 independently selected RB;
In some embodiments, R2 is a C1-C6 alkyl optionally substituted with 1-3 independently selected RB. In some embodiments, R2 is a C1-C6 alkyl substituted with 1- 3 independently selected RB. In some embodiments, R2 is C1-C6 alkyl substituted with 1 RB. In some embodiments, R2 is C1-C6 alkyl substituted with 2 independently selected RB. In some embodiments, R2 is C1-C6 alkyl substituted with 3 independently selected RB.
In some embodiments, R2 is a C3-C8 cycloalkyl optionally substituted with 1-3 independently selected RB. In some embodiments, R2 is a C3-C8 cycloalkyl substituted with 1-3 independently selected RB. In some embodiments, R2 is C3-C8 cycloalkyl substituted with 1 RB. In some embodiments, R2 is C3-C8 cycloalkyl substituted with 2 independently selected RB. In some embodiments, R2 is C3-C8 cycloalkyl substituted with 3 independently selected RB.
In some embodiments, each RB is independently selected from halogen, hydroxyl, C1-C3 alkyl, and C1-C3 alkoxy. In some embodiments, each RB is independently selected from fluoro, chloro, hydroxyl, and methoxy. In some embodiments, R2 is an unsubstituted C1-C6 alkyl. In some embodiments, R2 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R2 is methyl. In some embodiments, R2 is an unsubstituted C3-C8 cycloalkyl. In some embodiments, R2 is cyclopropyl or cyclobutyl.
In some embodiments, R5 is C1-C6 alkyl, C3-C8 cycloalkyl, -(CH2)n-4-10 membered heterocyclyl optionally substituted with 1-3 independently selected RD, or -(CH2)p-5-10 membered heteroaryl optionally substituted with 1-3 independently selected RE.
In some embodiments, R5 is -(CH2)n-4-10 membered heterocyclyl optionally substituted with 1-3 independently selected RD. In some embodiments, R5 is -(CH2)n-4- 10 membered heterocyclyl substituted with 1 RD. In some embodiments, R5 is -(CH2)n-4- 10 membered heterocyclyl substituted with 2 independently selected RD. In some embodiments, R5 is -(CH2)n-4-10 membered heterocyclyl substituted with 3 independently selected RD.
In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3, 4, 5, or 6.
In some embodiments, each RD is independently selected from halogen, hydroxyl, C1-C3 alkyl, and C1-C3 alkoxy. In some embodiments, each RD is independently selected from fluoro, chloro, hydroxyl, C1-C3 alkyl, and methoxy. In some embodiments, each RD is independently a C1-C3 alkyl. In some embodiments, each RD is methyl.
In some embodiments, each R5 is independently -(CH2)n-4-6 membered heterocyclyl optionally substituted with C1-C6 alkyl. In some embodiments, R5 is -(CH2)n-4-6 membered heterocyclyl optionally substituted with C1-C6 alkyl. In some embodiments, R5 is -(CH2)n-4-6 membered heterocyclyl substituted with C1-C6 alkyl. In some embodiments, R5 is -(CH2)n-4-6 membered heterocyclyl substituted with methyl. In some embodiments, R5 is a 4-6 membered heterocyclyl. In some embodiments, R5 is -(CH2)-4-6 membered heterocyclyl. In some embodiments, R5 is -(CH2)2-4-6 membered heterocyclyl. In some embodiments, the heterocyclyl is connected to the Formula (I) (including compounds of Formulae (II), (III), and (IV)) via a carbon atom. In some embodiments, the heterocyclyl is connected to Formula (I) (including compounds of Formulae (II), (III), and (IV)) via a nitrogen atom. In some embodiments, the heterocyclyl of R5 is selected from azetidine, pyrrolidine, 2- pyrrolidinone, piperidine, and piperazine. In some embodiments, the heterocyclyl of R5 is selected from azetidine, pyrrolidine, 2-pyrrolidinone, and piperidine.
In some embodiments, the heterocyclyl of R5 is selected from
Figure imgf000040_0001
embodiments, the heterocyclyl of R5 is selected from
Figure imgf000040_0002
Figure imgf000040_0003
In some embodiments, R5 is -(CH2)p-5-10 membered heteroaryl optionally substituted with 1-3 independently selected RE. In some embodiments, R5 is -(CH2)p-5-6 membered heteroaryl optionally substituted with 1-3 independently selected RE. In some embodiments, R5 is -(CH2)P-5-6 membered heteroaryl optionally substituted with 1 RE. In some embodiments, R5 is -(CH2)P-5-6 membered heteroaryl optionally substituted with 2 independently selected RE. In some embodiments, R5 is -(CH2)P-5-6 membered heteroaryl optionally substituted with 3 independently selected RE.
In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3, 4, 5, or 6.
In some embodiments, each RE is independently selected from halogen, hydroxyl, C1-C3 alkyl, and C1-C3 alkoxy. In some embodiments, each RE is independently selected from fluoro, chloro, hydroxyl, C1-C3 alkyl, and methoxy. In some embodiments, each RE is independently a C1-C3 alkyl. In some embodiments, each RE is methyl.
In some embodiments, the compound of Formula (I) (e.g., compounds of Formulae (I), (II), (III), and (IV)) is present in the form of a pharmaceutically acceptable salt. In some embodiments, the compound of Formula (I) (e.g., compounds of Formulae (I), (II), (III), and (IV)) is present in the free base form. In some embodiments, the compound is selected from the group consisting of the compounds in Table 1, or a pharmaceutically acceptable salt thereof.
Table 1
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Processes of Preparation
For illustrative purposes, general methods for preparing the compounds are provided herein as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the compounds disclosed herein. Although specific starting materials and reagents are discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.
A nitrogen protecting group can be any temporary substituent which protects an amine or an NH-containing heteroaryl moiety from undesired chemical transformations. Non-limiting examples of nitrogen protecting groups include allyl, benzyl (e.g., benzyl, p- methoxybenzyl, 2,4-dimethoxybenzyl, and trityl), acetyl, tri chloroacetyl, trifluoroacetyl, pent-4-enoyl, alkoxycarbonyls (e.g., methoxycarbonyl, /-butoxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, and 2,2,2-trichloroethoxycarbonyl), sulfonyls (e.g., benzenesulfonyl, /?-toluenesulfonyl, and -nitrobenzenesulfonyl), alkoxyalkyl groups, (e.g., benzyloxymethyl, 2, 2, 2-tri chloroethoxy methyl, p-methoxybenzyloxymethyl, and (2- methoxyethoxy)methyl), and silyl protecting groups (e.g., trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, diethylisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and 2-(trimethylsilyl)ethoxymethyl).
An oxygen protecting group can be any temporary substituent which protects a hydroxyl moiety from undesired chemical transformations. Examples of oxygen protecting groups include, but are not limited to alkanoyl (e.g., acetyl and /-butyl carbonyl), benzoyl, benzyl (e.g., benzyl, p-m ethoxybenzyl, and 2,4-dimethoxybenzyl, and trityl), alkoxycarbonyls (e.g., methyloxycarbonyl, t-butyl carbonyl, benzyloxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethylcarbonyl, and 9-fluorenylmethylcarbonyl), sulfonyls (e.g., benzene sulfonyl, p-toluenesulfyl, and p-nitrobenzenesulfonyl), alkoxyalkyl groups, (e.g., benzyloxymethyl, 2, 2, 2-tri chloroethoxymethyl, p-methoxybenzyloxymethyl, and (2- methoxyethoxy)methyl), alkyl (e.g., methyl and allyl), and silyl protecting groups (e.g., trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, diethylisopropylsilyl, t- butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and 2- (trimethylsilyl)ethoxymethyl).
Provided herein is a process of preparing a compound of Formula (I), or a pharmaceutically acceptable salt (as described herein), comprising:
(i) reacting a compound of Formula (F-A)
Figure imgf000052_0001
wherein:
R1, R2, R2A, R2B, R3, R4, and X are as defined herein;
Z is selected from halogen and trifluoromethanesulfonyl; with a compound of Formula (A)
Figure imgf000052_0002
wherein:
Ring A, R5, and m are as defined herein;
M is selected from -B(OH)2, -Sn(R7A)3, -Zn-R7B, and -Mg-R7C;
Figure imgf000052_0003
each occurrence of R7Ais an independently selected C1-C6 alkyl;
R7B is chloro, bromo, or iodo;
R7C is chloro, bromo, or iodo; wherein when the compound of Formula (F-A) and/or Formula (A) collectively comprise one or more N-H and/or O-H moieties, at least one of the one or more N-H and/or O-H moieties is optionally protected with an independently selected nitrogen or oxygen protecting group; to form an optionally protected compound of Formula (I); and
(ii) when the optionally protected compound of Formula (I) is protected, removing the protecting group(s) to form a compound of Formula (I).
In some embodiments, R1, R2, R2A, R2B, R3, R4, and X are as defined herein.
In some embodiments, Z is halogen. For example, Z is chloro. For example, Z is bromo. For example, Z is iodo. In some embodiments, Z is trifluoromethanesulfonyl.
In some embodiments, Ring A, R5, and m are as defined herein. In some embodiments, M is selected from -B(OH)2, and -Sn(R7A)3. In some embodiments, M is selected from and -B(OH)2. In some embodiments,
Figure imgf000053_0001
M is In some embodiments, M is -B(OH)2. In some embodiments, M is -
Figure imgf000053_0002
Sn(R7A)3. In some embodiments, M is -Zn-R7B. In some embodiments, M is -Mg-R7C.
In some embodiments, each occurrence of R7A is an independently selected C1-C4 alkyl. In some embodiments, each occurrence of R7A is an independently selected methyl or n-butyl. In some embodiments, each occurrence of R7A is methyl. In some embodiments, each occurrence of R7A is n-butyl.
In some embodiments, R7B is chloro. In some embodiments, R7B is bromo. In some embodiments, R7B is iodo.
In some embodiments, R7C is chloro. In some embodiments, R7C is bromo. In some embodiments, R7C is iodo.
In some embodiments, reacting the compound of Formula (I’ -A) with the compound of Formula (A) is performed in the presence of a transition metal catalyst. In some embodiments, the transition metal catalyst is selected from a palladium catalyst and a nickel catalyst. In some embodiments, the transition metal catalyst is a palladium catalyst. In some embodiments, the palladium catalyst is selected from tetrakistriphenylphospine palladium(O), bis(triphenylphosphine)palladium(II) dichloride and [1,1’- bis(diphenylphosphino)ferrocene]dichloropalladium(II). For example, the palladium catalyst is [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II). In some embodiments, the transition metal catalyst is a nickel catalyst.
In some embodiments, reacting the compound of Formula (F-A) with the compound of Formula (A) is performed in the presence of a ligand. In some embodiments, the ligand is a phosphine ligand. In some embodiments, the ligand is triphenylphosphine.
In some embodiments, reacting the compound of Formula (F-A) with the compound of Formula (A) is performed in the presence of a base. In some embodiments, the base is selected from potassium carbonate, a potassium alkoxide (e.g., potassium tert- butoxide), sodium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, and a non-nucleophilic amine base (e.g., trimethylamine or diisopropylethylamine). In some embodiments, the base is sodium carbonate.
In some embodiments, reacting the compound of Formula (I’ -A) with the compound of Formula (A) is performed in one or more solvents. In some embodiments, the one or more solvents are selected from 1,4-di oxane, water, acetonitrile, toluene, tetrahydrofuran, and N,N-dimethylformamide. In some embodiments, the one or more solvents are 1,4-di oxane and water.
In some embodiments, reacting the compound of Formula (F-A) with the compound of Formula (A) is performed in the presence of [1,1’- bis(diphenylphosphino)ferrocene] dichloropalladium(II) and sodium carbonate in water and 1,4-di oxane.
In some embodiments, reacting the compound of Formula (F-A) with the compound of Formula (A) is performed at from about 20 °C to about 150 °C, for example, from about 20 °C to about 100 °C, from about 40 °C to about 100 °C, from about 60 °C to about 100 °C, from about 80 °C to about 100 °C, from about 85 °C to about 95 °C, from about 70 °C to about 150 °C, from about 90 °C to about 150 °C, from about 110 °C to about 150 °C, from about 87 °C to about 93 °C, or about 90 °C. In some embodiments, reacting the compound of Formula (F-A) with the compound of Formula (A) is performed at about 90 °C.
In some embodiments, the compound of Formula (F-A) and/or Formula (A) collectively comprise one or more (e.g., one or two) N-H and/or O-H moieties. In some embodiments, at least one of the one or more (e.g., one or two) N-H and/or O-H moieties is protected with a nitrogen or oxygen protecting group. In some embodiments, one N-H moiety (e.g., one N-H moiety in the compound of Formula (F-A) is protected with a nitrogen protecting group. In some embodiments, two N-H moieties (e.g., one N-H moiety in the compound of Formula (F-A) and one N-H moiety on the compound of Formula (A) are each protected with an independently selected nitrogen protecting group. In some embodiments, one O-H moiety is protected with an oxygen protecting group. In some embodiments, two O-H moieties are each protected with an independently selected oxygen protecting group. In some embodiments, one N-H moiety is protected with a nitrogen protecting group and one O-H moiety is protected with an oxygen protecting group. In some embodiments, the nitrogen protecting group is selected from p- toluenesulfonyl, tert-butoxycarbonyl, and 2-(trimethylsilyl)ethoxymethyl. In some embodiments, the nitrogen protecting group is p-toluenesulfonyl. In some embodiments, the nitrogen protecting group is tert-butoxy carbonyl. In some embodiments, the nitrogen protecting group is 2-(trimethylsilyl)ethoxymethyl.
In some embodiments of the compound of Formula (I’-A) and any applicable intermediates used in the preparation of the compound of Formula (F-A), = is a single bond and R2A and R2B are each hydrogen.
In some embodiments of the compound of Formula (I’-A) and any applicable intermediates used in the preparation of the compound of Formula (F-A), = is a single bond and R2A and R2B, together with the carbon atom to which they are attached, together form a C=O group.
In some embodiments of the compound of Formula (I’-A) and any applicable intermediates used in the preparation of the compound of Formula (I’-A), = is a double bond and R2 and R2B are absent.
In some embodiments, the compound of Formula (F-A) is a compound of Formula (I’-A-i):
Figure imgf000055_0001
(F-A-i).
In some embodiments, the compound of Formula (A) comprises an N-H moiety protected with a tert-butoxycarbonyl. In some embodiments, the protected compound of Formula (I) is a compound of Formula (I-i):
Figure imgf000056_0001
In some embodiments of the compound of Formula (I-i), the
Figure imgf000056_0002
moiety comprises an N-H moiety protected with a nitrogen protecting group. In some embodiments, the nitrogen protecting group is tert-butoxycarbonyl.
In some embodiments, the protected compound of Formula (I) is a compound of Formula (I-i), and step (ii) comprises treating the compound of Formula (I-i) with acid. In some embodiments, the acid comprises hydrogen chloride.
In some embodiments, the protected compound of Formula (I) is a compound of Formula (I-i), and step (ii) comprises treating the compound of Formula (I-i) with a fluoride source. In some embodiments, the fluoride source is tetrabutylammonium fluoride.
In some embodiments, the compound of Formula (F-A) and/or Formula (A) comprises no N-H and/or O-H moieties and step (ii) is absent.
In some embodiments, the compound of Formula (F-A) is prepared by reacting a compound of Formula (F-B)
Figure imgf000056_0003
to form the compound of Formula (F-A).
In some embodiments, reacting the compound of Formula (F-B) to form the compound of Formula (I’ -A) comprises reacting the compound of Formula (F-B) with a base, then an electrophilic halogenating reagent. In some embodiments, the base is a lithium base. In some embodiments, the lithium base is selected from methyllithium, n- butyllithium, phenyllithium, lithium tetramethylpiperidide, lithium bis(trimethylsilyl)amide, and lithium diisopropylamide. In some embodiments, the base is lithium diisopropylamide. In some embodiments, the electrophilic halogenating reagent is l,2-dibromo-l,l,2,2-tetrachloro-ethane. In some embodiments, the electrophilic halogenating reagent is N-bromosuccinimide.
In some embodiments, the compound of Formula (I’-B) is a compound of Formula
Figure imgf000057_0001
In some embodiments, the compound of Formula (F-B) is a compound of Formula
Figure imgf000057_0002
In some embodiments, the compound of Formula (F-B) is a compound of Formula
Figure imgf000057_0003
In some embodiments, the compound of Formula (F-B-i) is prepared by reacting a compound of Formula (F-C)
Figure imgf000057_0004
to form the compound of Formula (F-B).
In some embodiments, reacting the compound of Formula (F-C) to form the compound of Formula (F-B-i) comprises reacting the compound of Formula (F-C) with formaldehyde and acid to form the compound of Formula (I’-B-i). In some embodiments, the acid is p-toluenesulfonic acid.
In some embodiments, the compound of Formula (I’-B-ii) is prepared by reacting the compound of Formula (F-C) to form the compound of Formula (I’-B-ii). In some embodiments, reacting the compound of Formula (F-C) to form the compound of Formula (I’-B-ii) comprises reacting the compound of Formula (I’-C) with a carbonyl equivalent. In some embodiments, the carbonyl equivalent is triphosgene or carbonyldiimidazole. In some embodiments, the carbonyl equivalent is triphosgene. In some embodiments, the carbonyl equivalent is carbonyldiimidazole.
In some embodiments, the compound of Formula (I’-B-iii) is prepared by reacting a compound of Formula (I’-C-i):
Figure imgf000058_0001
to form the compound of Formula (I’-B-iii). In some embodiments, reacting the compound of Formula (I’-C-i) to form the compound of Formula (I’-B-iii) comprises reacting the compound of Formula (I’-C-i) with CR2A(OEt)3 or CR2A(OMe)3.
In some embodiments, the compound of Formula (I’-C) is prepared by reacting a compound of Formula (I’-D)
Figure imgf000058_0002
wherein Z’ is a halogen; with R2-NH2 to form the compound of Formula (I’-C).
In some embodiments, Z’ is selected from chloro, bromo, and iodo. In some embodiments, Z’ is chloro. In some embodiments, Z’ is bromo. In some embodiments, Z’ is iodo. In some embodiments, reacting the compound of Formula (I’-D) with R2-NH2 to form the compound of Formula (I’-C) is performed in the presence of a base. In some embodiments, the base is trimethylamine or N-ethyl-N-isopropyl-propan-2-amine. In some embodiments, the base is N-ethyl-N-isopropyl-propan-2-amine.
In some embodiments, reacting the compound of Formula (F-D) with R2-NH2 to form the compound of Formula (I’-C) is performed under microwave irradiation. In some embodiments, reacting the compound of Formula (F-D) with R2-NH2 to form the compound of Formula (I’-C) is performed at from about 90 °C to about 200 °C, for example, from about 90 °C to about 180 °C, from about 90 °C to about 160 °C, from about 100 °C to about 200 °C, from about 120 °C to about 200 °C, from about 140 °C to about 200 °C, from about 120 °C to about 180 °C, from about 140 °C to about 160 °C, from about 145 °C to about 155 °C, from about 148 °C to about 152 °C, or about 150 °C.
In some embodiments, the compound of Formula (I’-C-i) is prepared by reacting the compound of Formula (I’-D) with NH3 to form the compound of Formula (I’-C-i).
In some embodiments, reacting the compound of Formula (I’-D) with NH3 to form the compound of Formula (I’-C-i) is performed in methanol, water, or 1,4-dioxane optionally in a sealed tube at a pressure greater than atmospheric pressure.
In some embodiments, reacting the compound of Formula (I’-D) with NH3 to form the compound of Formula (I’-C-i) is performed at from about 90 °C to about 200 °C, for example, from about 90 °C to about 180 °C, from about 90 °C to about 160 °C, from about 100 °C to about 200 °C, from about 120 °C to about 200 °C, from about 140 °C to about 200 °C, from about 120 °C to about 180 °C, from about 140 °C to about 160 °C, from about 145 °C to about 155 °C, from about 148 °C to about 152 °C, or about 150 °C.
In some embodiments, the compound of Formula (I’-D) is prepared by reacting a compound of Formula (I’-E)
Figure imgf000059_0001
wherein Z’ is a halogen; with R1-NH2 to form the compound of Formula (I’-D). In some embodiments, reacting the compound of Formula (I’-E) to form the compound of Formula (I’-D) comprises reacting the compound of Formula (I’-E) to form a compound of Formula (I’-E-i)
Figure imgf000060_0001
then reacting the compound of Formula (I’-E-i) with Rj-NEb to form the compound of Formula (I’-D).
In some embodiments, reacting the compound of Formula (I’-E) to form a compound of Formula (I’-E-i) comprises reacting the compound of Formula (I’-E) with thionyl chloride or oxalyl chloride. In some embodiments, reacting the compound of Formula (I’-E) to form a compound of Formula (I’-E-i) comprises reacting the compound of Formula (I’-E) with thionyl chloride.
In some embodiments, reacting the compound of Formula (I’-E-i) with Rj-NEb to form the compound of Formula (I’-D) further comprises reacting Rj-NEb with a base, then with the compound of Formula (I’-E-i) to form the compound of Formula (I’-D). In some embodiments, the base is a metal bis(trimethylsilyl)amide. In some embodiments, the metal bis(trimethylsilyl)amide is selected from lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, and potassium bis(trimethylsilyl)amide. In some embodiments, the metal bis(trimethylsilyl)amide is lithium bis(trimethylsilyl)amide.
In some embodiments, the compound of Formula (F-A) is a compound of Formula (I’-A-ii)
Figure imgf000060_0002
-ii).
In some embodiments, the compound of Formula (I’-A-ii) is prepared by reacting a compound of Formula (I’-F)
Figure imgf000061_0001
to form the compound of Formula (I’-A-ii).
In some embodiments, the compound of Formula (F-A-ii) is prepared by reacting the compound of Formula (F-F) to form the compound of Formula (F-A-ii). In some embodiments, reacting the compound of Formula (I’-F) to form the compound of Formula (F-A-ii) comprises reacting the compound of Formula (F-F) with a carbonyl equivalent. In some embodiments, the carbonyl equivalent is triphosgene or carbonyldiimidazole. In some embodiments, the carbonyl equivalent is triphosgene. In some embodiments, the carbonyl equivalent is carbonyldiimidazole.
In some embodiments, the compound of Formula (F-F) is prepared by reacting a compound of Formula (F-G)
Figure imgf000061_0002
wherein Z’ is a halogen; with R2-NH2 to form the compound of Formula (F-F).
In some embodiments, Z’ is selected from chloro, bromo, and iodo. In some embodiments, Z’ is chloro. In some embodiments, Z’ is bromo. In some embodiments, Z’ is iodo.
In some embodiments, reacting the compound of Formula (F-G) with R2-NH2 to form the compound of Formula (I’-F) is performed in the presence of a base. In some embodiments, the base is trimethylamine or N-ethyl-N-isopropyl-propan-2-amine. In some embodiments, the base is N-ethyl-N-isopropyl-propan-2-amine.
In some embodiments, reacting the compound of Formula (F-G) with R2-NH2 to form the compound of Formula (I’-F) is performed under microwave irradiation. In some embodiments, reacting the compound of Formula (F-G) with R2-NH2 to form the compound of Formula (I’-F) is performed at from about 90 °C to about 200 °C, for example, from about 90 °C to about 180 °C, from about 90 °C to about 160 °C, from about 100 °C to about 200 °C, from about 120 °C to about 200 °C, from about 140 °C to about 200 °C, from about 120 °C to about 180 °C, from about 140 °C to about 160 °C, from about 145 °C to about 155 °C, from about 148 °C to about 152 °C, or about 150 °C.
In some embodiments, preparing the compound of Formula (F-G) comprises reacting a compound of Formula (F-H)
Figure imgf000062_0001
wherein Z’ is a halogen; with Rj-NFb to form the compound of Formula (I’-H).
In some embodiments, reacting the compound of Formula (F-H) to form the compound of Formula (I’-G) comprises reacting the compound of Formula (F-H) to form a compound of Formula (I’-H-i)
Figure imgf000062_0002
then reacting the compound of Formula (F-H-i) with R1-NH2 to form the compound of Formula (F-G).
In some embodiments, reacting the compound of Formula (F-H) to form the compound of Formula (F-H-i) comprises reacting the compound of Formula (I’-H) with thionyl chloride or oxalyl chloride. In some embodiments, reacting the compound of Formula (F-H) to form a compound of Formula (F-H-i) comprises reacting the compound of Formula (I’-H) with thionyl chloride.
In some embodiments, reacting the compound of Formula (F-H-i) with R1-NH2 to form the compound of Formula (I’-G) further comprises reacting R1-NH2 with a base, then with the compound of Formula (F-H-i) to form the compound of Formula (I’-G). In some embodiments, the base is a metal bis(trimethylsilyl)amide. In some embodiments, the metal bis(trimethylsilyl)amide is selected from lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, and potassium bis(trimethylsilyl)amide. In some embodiments, the metal bis(trimethylsilyl)amide is lithium bis(trimethylsilyl)amide.
Methods of Treatment
Also provided herein are methods of treating cancer in a subject with a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof. Replication stress is present in many cancers, and as noted herein, it can in some cases be exacerbated by one or more factors, such as genetic features of the cancer and/or administration of DNA-damaging agents, DNA repair inhibiting agents, and/or radiation.
Accordingly, provided herein is a method of treating a cancer in a subject in need thereof, the method including identifying the cancer as having replication stress; and administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof.
Identifying the cancer as having replication stress can include any appropriate method of identification, such as the methods described herein. For example, in some embodiments, identifying the cancer as having replication stress includes staining for replication forks in a sample from the subject. In some embodiments, identifying the cancer as having replication stress includes detecting a biomarker of replication stress in a sample from the subject. A biomarker of replication stress can include any appropriate biomarker or set of biomarkers. In some embodiments, a biomarker of replication stress includes Ki- 67, Cyclin E, POLD3, yH2AX, FANCD2, or a combination thereof. In some embodiments, a biomarker of replication stress includes pH2AX Serl39, pATR Thrl989, pCHKl Ser345, pRPA32 Ser33, or a combination thereof. In some embodiments, a biomarker of replication stress includes an activated oncogene. In some embodiments, a biomarker of replication stress includes an inactivated tumor suppressor gene.
Also provided herein is a method of treating a cancer in a subject in need thereof, the method comprising administering an effective amount of a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof to a subject identified as having a cancer having replication stress. In some cases, a genetic characteristic of a cancer can be indicative that the cancer can be treated effectively with a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof. Some such genetic characteristics include one or more inactivated tumor suppressor genes and/or one or more activated oncogenes.
Accordingly, also provided herein is a method of treating a cancer in a subject in need thereof, the method including: identifying the cancer as having an inactivated tumor suppressor gene; and administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof. Also provided herein is a method of treating a cancer in a subject in need thereof, the method including administering an effective amount of a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof to a subject identified as having a cancer having an inactivated tumor suppressor gene.
An inactivation of a tumor suppressor gene can be achieved by any appropriate mechanism, such as those described herein. In some embodiments, an inactivated tumor suppressor gene includes an inactivation selected from the group consisting of a deletion of the gene, an inactivating mutation in the protein product of the gene, an inactivating translocation in the protein product of the gene, a transcriptional silencing of the gene, an epigenetic alteration of the gene, degradation of mRNA products of the gene, degradation of protein products of the gene, and combinations thereof.
An inactive tumor suppressor gene can be any appropriate inactivated tumor suppressor gene, such as any of those described herein. In some embodiments, the tumor suppressor gene is selected from the group consisting of p53, RBI, CDKN2A, BRCA1, BRCA2, FBXW7, SETD2, NOTCH 1, and a combination thereof.
In some embodiments, the inactivated tumor suppressor gene includes a mutation in the protein product of a p53 gene. In some embodiments, the inactivated tumor suppressor gene includes a deleted p53 gene. In some embodiments, the inactivated tumor suppressor gene includes a mutation in the protein product of a CDKN2A gene. In some embodiments, the inactivated tumor suppressor gene includes a mutation in the protein product of a NOTCH1 gene. In some embodiments, the inactivated tumor suppressor gene includes a deleted FBXW7 gene. In some embodiments, the inactivated tumor suppressor gene includes a mutation in the protein product of a FBXW7 gene. In some embodiments, the inactivated tumor suppressor gene includes a mutation in the protein product of a RBI gene. In some embodiments, the inactivated tumor suppressor gene includes a deleted BRCA1 gene. In some embodiments, the inactivated tumor suppressor gene includes a mutation in the protein product of a BRCA1 gene. In some embodiments, the inactivated tumor suppressor gene includes a BRCA1 gene with a hypermethylated promoter region. In some embodiments, the inactivated tumor suppressor gene includes a deleted BRCA2 gene. In some embodiments, the inactivated tumor suppressor gene includes a mutation in the protein product of a BRCA2 gene. In some embodiments, the inactivated tumor suppressor gene includes a BRCA2 gene with a hypermethylated promoter region. In some embodiments, the inactivated tumor suppressor gene includes a mutation in the protein product of a NOTCH1 gene. In some embodiments, the inactivated tumor suppressor gene includes a mutation in the protein product of a SETD2 gene.
In some embodiments, the inactivated tumor suppressor gene is selected from the group consisting of a mutation in the protein product of a p53 gene, a deleted p53 gene, a mutation in the protein product of a CDKN2A gene, a mutation in the protein product of a NOTCH1 gene, a deleted FBXW7 gene, a mutation in the protein product of a FBXW7 gene, a mutation in the protein product of a RBI gene, a deleted BRCA1 gene, a mutation in the protein product of a BRCA1 gene, a BRCA1 gene with a hypermethylated promoter region, a deleted BRCA2 gene, a mutation in the protein product of a BRCA2 gene, a BRCA2 gene with a hypermethylated promoter region, a mutation in the protein product of a NOTCH1 gene, a mutation in the protein product of a SETD2 gene, and a combination thereof.
Also provided herein is a method of treating a cancer in a subject in need thereof, the method including: identifying the cancer as having an activated oncogene; and administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof. Also provided herein is a method of treating a cancer in a subject in need thereof, the method including administering an effective amount of a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof to a subject identified as having a cancer having an activated oncogene. An activation of an oncogene can be achieved by any appropriate mechanism, such as those described herein For example, in some embodiments, the activated oncogene has an activation selected from the group consisting of an amplification of the oncogene, an activating mutation of the protein product of the oncogene, an activating translocation of the protein product of the oncogene, transcriptional activation of the oncogene, epigenetic alteration of the oncogene, overexpression of the protein product of the oncogene, and combinations thereof.
An activated oncogene can be any appropriate oncogene, such as those described herein. In some embodiments, the oncogene is selected from the group consisting of cyclin E, CDC25A, Myc, a RAS gene, and combinations thereof. In some embodiments, RAS gene includes a KRAS gene. In some embodiments, the RAS gene includes an NRAS gene. In some embodiments, the RAS gene includes an HRAS gene.
In some embodiments, the activated oncogene includes an amplified cyclin E gene. In some embodiments, the activated oncogene includes an overexpression of the protein product of the CDC25A gene. In some embodiments, the activated oncogene includes an amplified Myc gene. In some embodiments, the activated oncogene includes an activating translocation in the protein product of a Myc gene. In some embodiments, the activated oncogene includes a transcriptionally activated Myc gene. In some embodiments, the activated oncogene includes a mutation in the protein product of a RAS gene. In some embodiments, the mutated RAS gene includes a mutation at position G12 of the protein product of the RAS gene. In some embodiments, the mutated RAS gene includes a mutation at position G13 of the protein product of the RAS gene. In some embodiments, wherein the mutated RAS gene includes a mutation at position Q61 of the protein product of the RAS gene. In some embodiments, the RAS gene includes a KRAS gene.
In some embodiments, the activated oncogene is selected from the group consisting of an amplified cyclin E gene, an overexpression of the protein product of the CDC25A gene, an amplified Myc gene, an activating translocation in the protein product of a Myc gene, a transcriptionally activated Myc gene, a mutation in the protein product of a RAS gene, and a combination thereof. In some embodiments, the mutated RAS gene includes a mutation at position G12, G13, Q61, or a combination thereof, of the protein product of the RAS gene. In some embodiments, the RAS gene includes a KRAS gene. In the field of medical oncology, it is normal practice to use a combination of different forms of treatment to treat each subject with cancer. In medical oncology the other component(s) of such conjoint treatment or therapy in addition to compositions provided herein may be, for example, surgery, radiotherapy, and chemotherapeutic agents, such as other kinase inhibitors, kinase inhibitors, signal transduction inhibitors, and/or monoclonal antibodies. For example, a surgery may be open surgery or minimally invasive surgery. Compounds of Formula (I), or a pharmaceutically acceptable salt thereof therefore may also be useful as adjuvants to cancer treatment, that is, they can be used in combination with one or more additional therapies or therapeutic agents, for example, a chemotherapeutic agent that works by the same or by a different mechanism of action. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be used prior to administration of an additional therapeutic agent or additional therapy. For example, a subject in need thereof can be administered one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof for a period of time and then undergo at least partial resection of the tumor. In some embodiments, the treatment with one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof reduces the size of the tumor (e.g., the tumor burden) prior to the at least partial resection of the tumor. In some embodiments, a subject in need thereof can be administered one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof for a period of time and under one or more rounds of radiation therapy. In some embodiments, the treatment with one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof reduces the size of the tumor (e.g., the tumor burden) prior to the one or more rounds of radiation therapy.
In some embodiments of any of the methods described herein, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in combination with an effective amount of at least one additional therapeutic agent selected from one or more additional therapies or therapeutic (e.g., chemotherapeutic or immunomodulatory) agents.
Non-limiting examples of additional therapeutic agents include: PARP inhibitors, other DNA repair inhibiting agents (e.g. topoisomerase inhibitors, DNA-dependent protein kinase (DNA-PK) inhibitors, ATM inhibitors, Aurora kinase inhibitors (such as Aurora A and/or Aurora B inhibitors), ATR inhibitors, and CHK1 inhibitors), signal transduction pathway inhibitors, Bcr-Abl inhibitors, histone deacetylase (HD AC) inhibitors, checkpoint inhibitors, modulators of the apoptosis pathway, cytotoxic chemotherapeutics, angiogenesis-targeted therapies, immune-targeted agents, including immunotherapy, and radiotherapy. In some embodiments, the additional therapeutic agent is an immunotherapy.
Non-limiting examples of checkpoint inhibitors include ipilimumab, tremelimumab, nivolumab, pidilizumab, MPDL3208A, MEDI4736, MSB0010718C, BMS-936559, BMS-956559, BMS-935559 (MDX-1105), AMP-224, and pembrolizumab.
In some embodiments, cytotoxic chemotherapeutics are selected from bleomycin, cabazitaxel, capecitabine, carboplatin, cisplatin, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, docetaxel, paclitaxel, doxorubicin, etoposide, fluorouracil, gemcitabine, irinotecan, lomustine, methotrexate, mitomycin C, oxaliplatin, paclitaxel, pemetrexed, temozolomide, and vincristine.
Non-limiting examples of angiogenesis-targeted therapies include aflibercept and bevacizumab.
In some embodiments, a DNA repair inhibiting agent can include a topoisomerase I inhibitor, a topoisomerase II inhibitor, a PARP inhibitor, an ATR inhibitor, a Chk inhibitor, a DNA-dependent protein kinase (DNA-PK) inhibitor, an ATM inhibitor, an Aurora kinase inhibitor (such as an Aurora A and/or B inhibitor), or a combination thereof.
Non-limiting examples of PARP inhibitors include olaparib, niraparib, rucaparib, talazoparib, and veliparib.
Non-limiting examples of ATR inhibitors include AZD6738, BAY1895344, and M6620.
Non-limiting examples of Chkl inhibitors include prexasertib, GDC-0575, SCH 900776, and SRA737.
Non-limiting examples of DNA-PK inhibitors include AZD7648, M3814, LY294002, nedisertib, and samotolisib.
Non-limiting examples of ATM inhibitors include KU55933, AZD0156, AZD1390, dactosilib, and berzosertib.
Non-limiting examples of Aurora kinase inhibitors include LY3295668, ZM447439, tozasertib, hesparadin, alisertib, and MLN8054. Non-limiting examples of modulators of the apoptosis pathway include Bcl-2 inhibitors such as obataclax, venetoclax, and navitoclax.
In some embodiments, signal transduction pathway inhibitors include Ras-Raf- MEK-ERK pathway inhibitors (e.g., binimetinib, selumetinib, encorafenib, sorafenib, trametinib, and vemurafenib) or PI3K-Akt-mTOR-S6K pathway inhibitors (e.g., sirolimus, everolimus, rapamycin, perifosine, temsirolimus).
Non-limiting examples of Bcr-Abl inhibitors include imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib.
Non-limiting examples of HDAC inhibitors include pabinostat, vorinostat, belinostat, panobinostat, entinostat, tacedinaline, and mocetinostat.
Non-limiting examples of platinum-based chemotherapeutics include carboplatin, cisplatin, and oxaplatin. Non-limiting examples of alkylating agents include cyclophosphamide, carmustine, busulfan, procarbazine, dacarbazine, temozoloamide, thiotepa, and mitomycin C. Non-limiting examples of nucleobase, nucleoside, and/or nucleotide analogs include fluorouracil, cytarabine, gemcitabine, azacitidine, and decitabine. Non-limiting examples of topoisomerase I inhibitors include topotecan, irinotecan, belotecan, and camptothecin. Non-limiting examples of topoisomerase II inhibitors include etoposide, tenoposide, doxorubicin, daunorubicin, epirubicin, and idarubacin.
The term “immunotherapy” refers to an agent that modulates the immune system. In some embodiments, an immunotherapy can increase the expression and/or activity of a regulator of the immune system. In some embodiments, an immunotherapy can decrease the expression and/or activity of a regulator of the immune system. In some embodiments, an immunotherapy can recruit and/or enhance the activity of an immune cell.
In some embodiments, the immunotherapy is a cellular immunotherapy (e.g., adoptive T-cell therapy, dendritic cell therapy, natural killer cell therapy). In some embodiments, the cellular immunotherapy is sipuleucel-T (APC8015; Provenge™; Plosker (2011) Drugs 71(1): 101-108). In some embodiments, the cellular immunotherapy includes cells that express a chimeric antigen receptor (CAR). In some embodiments, the cellular immunotherapy is a CAR-T cell therapy. In some embodiments, the CAR-T cell therapy is tisagenlecleucel (Kymriah™). In some embodiments, the immunotherapy is an antibody therapy (e.g., a monoclonal antibody, a conjugated antibody). In some embodiments, the antibody therapy is bevacizumab (Mvasti™, Avastin®), trastuzumab (Herceptin®), avelumab (Bavencio®), rituximab (Mab Thera™, Rituxan®), edrecolomab (Panorex), daratumuab (Darzalex®), olaratumab (Lartruvo™), ofatumumab (Arzerra®), alemtuzumab (Campath®), cetuximab (Erbitux®), oregovomab, pembrolizumab (Keytruda®), dinutiximab (Unituxin®), obinutuzumab (Gazyva®), tremelimumab (CP-675,206), ramucirumab (Cyramza®), ublituximab (TG-1101), panitumumab (Vectibix®), elotuzumab (Empliciti™), avelumab (Bavencio®), necitumumab (Portrazza™), cirmtuzumab (UC-961), ibritumomab (Zevalin®), isatuximab (SAR650984), nimotuzumab, fresolimumab (GC1008), lirilumab (INN), mogamulizumab (Poteligeo®), ficlatuzumab (AV-299), denosumab (Xgeva®), ganitumab, urelumab, pidilizumab or amatuximab.
In some embodiments, the immunotherapy is an antibody-drug conjugate. In some embodiments, the antibody-drug conjugate is gemtuzumab ozogamicin (Mylotarg™), inotuzumab ozogamicin (Besponsa®), brentuximab vedotin (Adcetris®), ado-trastuzumab emtansine (TDM-1; Kadcyla®), mirvetuximab soravtansine (IMGN853) or anetumab ravtansine
In some embodiments, the immunotherapy includes blinatumomab (AMG103; Blincyto®) or midostaurin (Rydapt).
In some embodiments, the immunotherapy includes a toxin. In some embodiments, the immunotherapy is denileukin diftitox (Ontak®).
In some embodiments, the immunotherapy is a cytokine therapy. In some embodiments, the cytokine therapy is an interleukin 2 (IL-2) therapy, an interferon alpha (IFNa) therapy, a granulocyte colony stimulating factor (G-CSF) therapy, an interleukin 12 (IL- 12) therapy, an interleukin 15 (IL- 15) therapy, an interleukin 7 (IL-7) therapy or an erythropoietin-alpha (EPO) therapy. In some embodiments, the IL-2 therapy is aldesleukin (Proleukin®). In some embodiments, the IFNa therapy is IntronA® (Roferon-A®). In some embodiments, the G-CSF therapy is filgrastim (Neupogen®).
In some embodiments, the immunotherapy is an immune checkpoint inhibitor. In some embodiments, the immunotherapy includes one or more immune checkpoint inhibitors. In some embodiments, the immune checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor or a PD-L1 inhibitor. In some embodiments, the CTLA-4 inhibitor is ipilimumab (Yervoy®) or tremelimumab (CP-675,206). In some embodiments, the PD-1 inhibitor is pembrolizumab (Keytruda®) or nivolumab (Opdivo®). In some embodiments, the PD-L1 inhibitor is atezolizumab (Tecentriq®), avelumab (Bavencio®) or durvalumab (Imfinzi™).
Non-limiting examples of radiotherapy include radioiodide therapy, external-beam radiation, and radium 223 therapy.
In some embodiments, the one or more additional therapies or therapeutic agents are selected from cytarabine, fludarabine, cisplatin, carboplatin, docetaxel, gemcitabine, belinostat, radiotherapy, irinotecan, olaparib, pemetrexed, savolitinib, and temozolomide.
In some cases, a cancer having replication stress and/or including a genetic characteristic indicative that the cancer can be treated effectively with a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof can be treated with a combination of a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof and another agent that promotes genomic instability, such as a DNA-damaging agent, a DNA repair inhibiting agent, radiation, or a combination thereof.
Accordingly, in some embodiments, the methods described herein can further include administering to the subject a DNA-damaging agent, a DNA repair inhibiting agent, radiation, or a combination thereof.
In some cases, identification of replication stress might not be carried out on the cancer or might not be able to be carried out on a cancer. In some cases, genetic analysis might not be carried out on the cancer or might not be able to be carried out on a cancer. In some cases, a cancer might be negative for a genetic characteristic of a cancer can be indicative that the cancer can be treated effectively with a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof. However, many first- line treatment regimens for cancer include a DNA-damaging agent, a DNA repair inhibiting agent, or a combination thereof. In some such cases, a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof can still be indicated for treatment with a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof, as the combination of factors can promote mitotic collapse, thereby treating the cancer.
Accordingly, provided herein is a method of treating a cancer in a subject in need thereof, the method comprising: (i) administering to the subject an effective amount of a therapy comprising: (a) a DNA-damaging agent; (b) a DNA repair inhibiting agent; (c) radiation; (d) a DNA-damaging agent and a DNA repair inhibiting agent; (e) a DNA- damaging agent and radiation; (f) a DNA repair inhibiting agent and radiation; or (g) a DNA-damaging agent, a DNA repair inhibiting agent, and radiation; and (ii) after (i), administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof. Also provided herein is a method of treating a cancer in a subject in need thereof, the method comprising: administering an effective amount of a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof to a subject previously administered one or more doses of a therapy comprising: (a) a DNA-damaging agent; (b) a DNA repair inhibiting agent; (c) radiation; (d) a DNA-damaging agent and a DNA repair inhibiting agent; (e) a DNA-damaging agent and radiation; (f) a DNA repair inhibiting agent and radiation; or (g) a DNA-damaging agent, a DNA repair inhibiting agent, and radiation. In some embodiments, the therapy (e.g., of (a) to (g)) is continued to be administered to the subject as combination therapy with the compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof. Also provided herein is a method of treating a cancer in a subject in need thereof, the method comprising: administering to the subject: (i) an effective amount of a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof; and (ii) an effective amount of a therapy comprising: (a) a DNA-damaging agent; (b) a DNA repair inhibiting agent; (c) radiation; (d) a DNA-damaging agent and a DNA repair inhibiting agent; (e) a DNA-damaging agent and radiation; (f) a DNA repair inhibiting agent and radiation; or (g) a DNA-damaging agent, a DNA repair inhibiting agent, and radiation.
In some embodiments, the compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof and the therapy (e.g., of (a) to (g)) are administered simultaneously as separate dosages. In some embodiments, the compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof and the therapy (e.g., of (a) to (g)) are administered separate dosages sequentially in any order.
A DNA-damaging agent can be any appropriate DNA-damaging agent, such as those described herein. In some embodiments, the DNA-damaging agent is selected from the group consisting of a platinum-based chemotherapy, an alkylating agent, a nucleobase, nucleoside, or nucleotide analog, and combinations thereof. In some embodiments, the platinum-based chemotherapy comprises carboplatin, cisplatin, oxaplatin, or a combination thereof. In some embodiments, the alkylating agent comprises cyclophosphamide, carmustine, busulfan, procarbazine, dacarbazine, temozoloamide, thiotepa, mitomycin C, or combinations thereof. In some embodiments, the nucleobase, nucleoside, or nucleotide analog comprises fluorouracil, cytarabine, gemcitabine, azacitidine, decitabine, or combinations thereof.
A DNA repair inhibiting agent can be any appropriate DNA repair inhibiting agent, such as those described herein. In some embodiments, the DNA repair inhibiting agent is selected from the group consisting of a topoisomerase I inhibitor, a topoisomerase II inhibitor, a PARP inhibitor, an ATR inhibitor, a Chk inhibitor, a DNA-dependent protein kinase (DNA-PK) inhibitor, an ATM inhibitors, an Aurora kinase inhibitor (such as Aurora A and/or Aurora B inhibitors), and a combination thereof.
In some embodiments, the topoisomerase I inhibitor comprises topotecan, irinotecan, belotecan, camptothecin, or combinations thereof. In some embodiments, the topoisomerase II inhibitor comprises etoposide, tenoposide, doxorubicin, daunorubicin, epirubicin, idarubacin, or combinations thereof. In some embodiments, the PARP inhibitor comprises olaparib, niraparib, rucaparib, talazoparib, veliparib, or combinations thereof. In some embodiments, the ATR inhibitor comprises AZD6738, BAY1895344, M6620, or a combination thereof. In some embodiments, the Chkl inhibitor comprises prexasertib, GDC-0575, SCH 900776, SRA737, or a combination thereof. In some embodiments, the DNA-PK inhibitor comprises AZD7648, M3814, LY294002, nedisertib, samotolisib, or combinations thereof. In some embodiments, the ATM inhibitor comprises KU55933, AZD0156, AZD1390, dactosilib, berzosertib, or combinations thereof. In some embodiments, the Aurora kinase inhibitor comprises LY3295668, ZM447439, tozasertib, hesparadin, alisertib, MLN8054, or combinations thereof. In some embodiments, the topoisomerase I inhibitor is topotecan, irinotecan, belotecan, camptothecin, or a combination thereof. In some embodiments, the topoisomerase II inhibitor is etoposide, tenoposide, doxorubicin, daunorubicin, epirubicin, idarubacin, or a combination thereof. In some embodiments, the PARP inhibitor is olaparib, niraparib, rucaparib, talazoparib, veliparib, or a combination thereof. In some embodiments, the ATR inhibitor is AZD6738, BAY1895344, M6620, or a combination thereof. In some embodiments, the Chkl inhibitor is prexasertib, GDC-0575, SCH 900776, SRA737, or a combination thereof. In some embodiments, the DNA-PK inhibitor is AZD7648, M3814, LY294002, nedisertib, samotolisib, or a combination thereof. In some embodiments, the ATM inhibitor is KU55933, AZD0156, AZD1390, dactosilib, berzosertib, or a combination thereof. In some embodiments, the Aurora kinase inhibitor is LY3295668, ZM447439, tozasertib, hesparadin, alisertib, MLN8054, or a combination thereof.
Also provided herein is a method for treating a subject diagnosed with or identified as having a cancer associated with replication stress, e.g., any of the exemplary cancers disclosed herein, comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.
Also provided herein is a method for treating cancer in a subject in need thereof, the method comprising: determining that the cancer is associated with replication stress; and administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof. Also provided herein is a method for treating cancer in a subject in need thereof, the method comprising: administering an effective amount of a compound of Formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition thereof to a subject identified as having a cancer associated with replication stress.
In some embodiments of any of the methods described herein, the method further includes administering an additional therapy or therapeutic agent to the subject. An additional therapy or therapeutic agent can be any appropriate therapy or therapeutic agent. In some embodiments, the additional therapy or therapeutic agent is selected from radiotherapy, cytotoxic chemotherapeutics, kinase-targeted therapeutics, kinase-targeted therapeutics, apoptosis modulators, signal transduction inhibitors, immune-targeted therapies, angiogenesis-targeted therapies, and combinations thereof. In some embodiments, the additional therapy or therapeutic agent is selected from kinase-targeted therapeutics, kinase-targeted therapeutics, apoptosis modulators, signal transduction inhibitors, immune-targeted therapies, angiogenesis-targeted therapies, and combinations thereof. In some embodiments, the additional therapy or therapeutic agent is an immune- targeted therapy. In some embodiments, the immune-targeted therapy is an immunotherapy.
Also provided herein is a method for inhibiting mammalian cell proliferation, comprising contacting the mammalian cell with a compound of Formula (I), or a pharmaceutical salt thereof. Also provided herein is a method for inducing mitotic collapse in a mammalian cell, comprising contacting the mammalian cell with a compound of Formula (I), or a pharmaceutical salt thereof. In some embodiments, the contacting occurs in vivo. In some embodiments, the contacting occurs in vitro. A mammalian cell can be any appropriate species or type of cell. In some embodiments, the mammalian cell is a mammalian immune cell. In some embodiments, the mammalian cell is a mammalian cancer cell. In some embodiments, the mammalian cancer cell is a mammalian cancer cell having replicative stress. In some embodiments, the mammalian cancer cell has an inactivated tumor suppressor gene. In some embodiments, the mammalian cancer cell has an activated oncogene. In some embodiments, the method further includes contacting the mammalian cell with a DNA-damaging agent, a DNA repair inhibitor, radiation, or a combination thereof.
Also provided herein is use of a compound of Formula (I), or a pharmaceutical salt thereof in the manufacture of a medicament for the treatment of cancer. In some embodiments, the cancer is a cancer having replication stress. In some embodiments, the cancer is a cancer having an inactivated tumor suppressor gene. In some embodiments, the cancer is a cancer having an activated oncogene. In some embodiments, the medicament is labeled for concurrent use with a DNA-damaging agent, a DNA repair inhibitor, radiation therapy, or a combination thereof. In some embodiments, the medicament is labeled for use subsequent to a DNA-damaging agent, a DNA repair inhibitor, radiation therapy, or a combination thereof. In some embodiments of any of the methods or uses described herein, the cancer is a hematological cancer. In some embodiments of any of the methods or uses described herein, the cancer is a solid tumor. In some embodiments of any of the methods or uses described herein, the cancer is small cell lung cancer, ovarian cancer, solid tumors with BRCA mutations, head and neck cancer squamous cell carcinoma, adenocarcinoma of the pancreas, acute myeloid leukemia, osteosarcoma, multiple myeloma, epithelial ovarian cancers, triple negative breast cancer, cervical cancer, mantle cell lymphoma and diffuse large B-cell lymphoma, laryngeal squamous cell carcinoma, basal-like breast cancer, medulloblastoma, oropharyngeal cancers, sarcoma, kidney cancer, clear cell renal cell carcinoma, acute lymphoblastic leukemia, pediatric gliomas, head and neck precancer, Ewing sarcoma, gastrointestinal stromal tumors, giant cell tumor of bone, clear cell ovarian cancer, mucinous ovarian cancer, primary peritoneal carcinoma, serous surface papillary carcinoma, teratoma, dysgerminoma, endodermal sinus tumors, choriocarcinomas, granulosa cell tumors, granulosa-theca tumors, sertoli-leydig cell tumors, endometrial adenocarcinoma, adenosquamous carcinoma, papillary serous carcinoma, and uterine sarcoma.
In some embodiments, the subject is a human.
In some embodiments of any of the methods described herein, a compound of Formula (I) is selected from Examples 1-47, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (II), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (III), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (IV), or a pharmaceutically acceptable salt thereof.
Also provided is a method for inhibiting Weel kinase activity in a mammalian cell, comprising contacting the mammalian cell with a compound of Formula (I). In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof to a subject having a mammalian cell having Weel kinase activity. In some embodiments, the mammalian cell is a mammalian immune cell. In some embodiments, the mammalian cell is a mammalian cancer cell. In some embodiments, the mammalian cancer cell is any cancer as described herein. In some embodiments, the mammalian cancer cell is a mammalian cancer cell having replication stress.
Also provided is a method for inhibiting Weel kinase activity in a mammalian cell, comprising contacting the mammalian cell with a compound of Formula (I). In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof to a mammal having a mammalian cell having Weel kinase activity. In some embodiments, the mammalian cell is a mammalian immune cell. In some embodiments, the mammalian cell is a mammalian cancer cell. In some embodiments, the mammalian cancer cell is any cancer as described herein. In some embodiments, the mammalian cancer cell is a mammalian cancer cell with replication stress. In some embodiments, the mammalian cell is a gastrointestinal mammalian cell. In some embodiments, the mammalian cell is a hematological mammalian cell.
As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, “contacting” a Weel kinase with a compound provided herein includes the administration of a compound provided herein to a subject, such as a human, having a Weel kinase, as well as, for example, introducing a compound provided herein into a sample containing a mammalian cellular or purified preparation containing the Weel kinase.
Also provided herein is a method of inhibiting mammalian cell proliferation, in vitro or in vivo, the method comprising contacting a mammalian cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.
A “Weel kinase inhibitor” as defined herein includes any compound exhibiting Weel inhibition activity. In some embodiments, a Weel kinase inhibitor is selective for a Weel kinase. Exemplary Weel kinase inhibitors can exhibit inhibition activity (IC50) against a Weel kinase of less than about 1000 nM, less than about 500 nM, less than about 200 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, or less than about 1 nM as measured in an assay as described herein. In some embodiments, a Weel kinase inhibitor can exhibit inhibition activity (ICso) against a Weel kinase of less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM as measured in an assay as provided herein.
The phrase “effective amount” means an amount of compound that, when administered to a subject in need thereof, is sufficient to (i) treat a cancer (such as cancer associated with replication stress as described herein), (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular cancer, or (iii) delay the onset of one or more symptoms of the particular cancer described herein. The amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the subject in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
When employed as pharmaceuticals, compounds of Formula (I), including pharmaceutically acceptable salts thereof, can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration can be topical (including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g. , by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral or parenteral. Oral administration can include a dosage form formulated for once-daily or twice-daily (BID) administration. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose, or can be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
Also provided herein are pharmaceutical compositions which contain, as the active ingredient, a compound of Formula (I) or pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable excipients. For example, a pharmaceutical composition prepared using a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition is suitable for topical administration. In making the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. In some embodiments, the composition is formulated for oral administration. In some embodiments, the composition is a solid oral formulation. In some embodiments, the composition is formulated as a tablet or capsule.
Further provided herein are pharmaceutical compositions containing a compound of Formula (I) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier. Pharmaceutical compositions containing a compound of Formula (I) or a pharmaceutically acceptable salt thereof as the active ingredient can be prepared by intimately mixing the compound of Formula (I), or a pharmaceutically acceptable salt thereof with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral). In some embodiments, the composition is a solid oral composition.
Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers can be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.
Methods of formulating pharmaceutical compositions have been described in numerous publications such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3, edited by Lieberman et al; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al; published by Marcel Dekker, Inc.
In preparing the compositions in oral dosage form, any of the usual pharmaceutical media can be employed. Thus for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like; for solid oral preparations, such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. Solid oral preparations can also be coated with substances such as sugars or be enteric-coated so as to modulate major site of absorption. For parenteral administration, the carrier will usually consist of sterile water and other ingredients can be added to increase solubility or preservation. Injectable suspensions or solutions can also be prepared utilizing aqueous carriers along with appropriate additives. The pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described herein.
The compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof can be formulated in a unit dosage form, each dosage containing from about 5 to about 1,000 mg (1 g), more usually about 100 mg to about 500 mg, of the active ingredient. The term “unit dosage form” refers to physically discrete units suitable as unitary dosages for human subjects and other subjects, each unit containing a predetermined quantity of active material (i.e., a compound of Formula (I) or a pharmaceutically acceptable salt thereof ) calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. In some embodiments, the compositions provided herein contain from about 5 mg to about 50 mg of the active ingredient. One having ordinary skill in the art will appreciate that this embodies compounds or compositions containing about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, or about 45 mg to about 50 mg of the active ingredient.
In some embodiments, the compositions provided herein contain from about 50 mg to about 500 mg of the active ingredient. One having ordinary skill in the art will appreciate that this embodies compounds or compositions containing about 50 mg to about 100 mg, about 100 mg to about 150 mg, about 150 mg to about 200 mg, about 200 mg to about 250 mg, about 250 mg to about 300 mg, about 350 mg to about 400 mg, or about 450 mg to about 500 mg of the active ingredient. In some embodiments, the compositions provided herein contain about 10 mg, about 20 mg, about 80 mg, or about 160 mg of the active ingredient.
In some embodiments, the compositions provided herein contain from about 500 mg to about 1,000 mg of the active ingredient. One having ordinary skill in the art will appreciate that this embodies compounds or compositions containing about 500 mg to about 550 mg, about 550 mg to about 600 mg, about 600 mg to about 650 mg, about 650 mg to about 700 mg, about 700 mg to about 750 mg, about 750 mg to about 800 mg, about 800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg to about 950 mg, or about 950 mg to about 1,000 mg of the active ingredient.
The daily dosage of the compound of Formula (I) or a pharmaceutically acceptable salt thereof can be varied over a wide range from 1.0 to 10,000 mg per adult human per day, or higher, or any range therein. For oral administration, the compositions are preferably provided in the form of tablets containing, 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 160, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.1 mg/kg to about 1000 mg/kg of body weight per day, or any range therein. Preferably, the range is from about 0.5 to about 500 mg/kg of body weight per day, or any range therein. More preferably, from about 1.0 to about 250 mg/kg of body weight per day, or any range therein. More preferably, from about 0.1 to about 100 mg/kg of body weight per day, or any range therein. In an example, the range can be from about 0.1 to about 50.0 mg/kg of body weight per day, or any amount or range therein. In another example, the range can be from about 0.1 to about 15.0 mg/kg of body weight per day, or any range therein. In yet another example, the range can be from about 0.5 to about 7.5 mg/kg of body weight per day, or any amount to range therein. Pharmaceutical compositions containing a compound of Formula (I) or a pharmaceutically acceptable salt thereof can be administered on a regimen of 1 to 4 times per day or in a single daily dose.
The active compound may be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. Optimal dosages to be administered can be readily determined by those skilled in the art. It will be understood, therefore, that the amount of the compound actually administered will usually be determined by a physician, and will vary according to the relevant circumstances, including the mode of administration, the actual compound administered, the strength of the preparation, the condition to be treated, and the advancement of the disease condition. In addition, factors associated with the particular subj ect being treated, including subj ect response, age, weight, diet, time of administration and severity of the subject’s symptoms, will result in the need to adjust dosages.
In some embodiments, the compounds provided herein can be administered in an amount ranging from about 1 mg/kg to about 100 mg/kg. In some embodiments, the compound provided herein can be administered in an amount of about 1 mg/kg to about 20 mg/kg, about 5 mg/kg to about 50 mg/kg, about 10 mg/kg to about 40 mg/kg, about 15 mg/kg to about 45 mg/kg, about 20 mg/kg to about 60 mg/kg, or about 40 mg/kg to about 70 mg/kg. For example, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, about 90 mg/kg, about 95 mg/kg, or about 100 mg/kg.
One skilled in the art will recognize that both in vivo and in vitro trials using suitable, known and generally accepted cell and/or animal models are predictive of the ability of a test compound to treat or prevent a given disorder. One skilled in the art will further recognize that human clinical trials including first- in-human, dose ranging and efficacy trials, in healthy subjects and/or those suffering from a given disorder, can be completed according to methods well known in the clinical and medical arts.
Provided herein are pharmaceutical kits useful, for example, in the treatment of cancer (such as replication sensitive cancers), which include one or more containers containing a pharmaceutical composition comprising an effective amount of a compound provided herein. Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.
EXAMPLES
Materials and Methods
The compounds provided herein, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes.
The reactions for preparing the compounds provided herein can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan.
Preparation of the compounds provided herein can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Protecting Group Chemistry, 1st Ed., Oxford University Press, 2000; March ’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th Ed., Wiley -Interscience Publication, 2001; and Petursson, S. el al., “Protecting Groups in Carbohydrate Chemistry,” J. Chem. Educ., 74(11), 1297 (1997).
Reactions sensitive to moisture or air were performed under nitrogen or argon using anhydrous solvents and reagents. The progress of reactions was determined by either analytical thin layer chromatography (TLC) usually performed with Sanpont precoated TLC plates, silica gel GF-254, layer thickness 0.25 mm or liquid chromatography-mass spectrometry (LC-MS).
Typically, the analytical LC-MS system used consisted of a Shimadzu LCMS-2020 with electrospray ionization in positive ion detection mode with a 20ADXR pump, SIL- 20ACXR autosampler, CTO-20AC column oven, M20A PDA Detector, and a LCMS 2020 MS detector. The column was usually a HALO Cl 8 30*5.0 mm, 2.7 pm. The mobile phase A is water containing 0.05% TFA and mobile phase B is acetonitrile containing 0.05% TFA. The gradient is from 5% mobile phase B to 95% in 2.0 min, hold 0.7 min, then reverting to 5% mobile phase B over 0.05 min and maintained for 0.25 min. The Column Oven (CTO-20AC) was operated at a temperature of 40.0 °C. The flow rate was 1.5 mL/min, and the injection volume was 1 pl. PDA (SPD-M20A) detection was in the 190- 400 nm range. The MS detector, which was configured with electrospray ionization as ionizable source; Acquisition mode: Scan; Nebulizing Gas Flow: 1.5 L/min; Drying Gas Flow: 15 L/min; Detector Voltage: Tuning Voltage ± 0.2 kV ; DL Temperature: 250 °C; Heat Block Temperature: 250 °C; Scan Range: 90.00 - 900.00 m/z. ELSD (Alltech 3300) detector Parameters: Drift Tube Temperature: 60 ± 5 °C; N2 Flow-Rate: 1.8 ± 0.2 L/min. Mobile phase gradients were optimized for the individual compounds.
The GC-MS system was usually performed with a Shimadzu GCMS-QP2010 Ultra with FID and MS Detector. In acquisition mode the MS detector was set to the following parameters: Start Time: 2.00 min; End Time: 9.00 min; ACQ Mode: Scan; Event Time: 0.30 sec; Scan Speed: 2000; Start m/z: 50.00; End m/z: 550.00; Ion Source temperature: 200.00 °C; Interface temperature: 250.00 °C; Solvent Cut Time: 2.00 min.
Preparative HPLC purifications were usually performed with a Waters Auto purification system (2545-2767) with a 2489 UV detector and a Waters Cl 8 column (19 xl50 mm, 5 pm; XBridge Prep OBD C18 Column, 30* 150mm, 5pm; XSelect CSH Prep C18 OBD Column, 19x 150mm, 5pm ; XBridge Shield RP18 OBD Column, 30x150mm, 5p m; Xselect CSH Fluoro Phenyl, 30 x 150 mm, 5 p m; YMC-Actus Triart C18, 30 x 150 mm, 5 p m. The mobile phases consisted of mixtures of acetonitrile (5-95%) in water containing 0.1% FA or lOmmol/L NH4HCO3. Flow rates were maintained at 25 mL/min, the injection volume was 1200 pL, and the UV detector used two channels: 254 nm and 220 nm. Mobile phase gradients were optimized for the individual compounds.
Chiral analytical chromatography was performed on one of Chiralpak AS, AD, Chiralcel OD, OJ Chiralpak IA, IB, IC, ID, IE, IF, IG, IH columns (Daicel Chemical Industries, Ltd.); (A,A)-Whelk-Ol, (5,5)-Whelk-01 columns (Regis technologies, Inc. ); CHIRAL Cellulose-SB, SC, SA columns (YMC Co., Ltd.) at different column sizes (50x4.6mm, 100x4.6mm, 150x4.6mm, 250x4.6mm, 50x3.0mm, 100x3.0mm) with noted percentage of either ethanol in hexane (%Et/Hex) or isopropanol in hexane (%IPA/Hex) as isocratic solvent systems or by supercritical fluid (SFC) conditions. Chiral preparative chromatography was conducted on one of Chiralpak AS, AD, Chiralcel OD, OJ, Chiralpak IA, IB, IC, ID, IE, IF, IG, IH columns (Daicel Chemical Industries, Ltd.); ( ’. ’j-Whelk- 01, (5,5)-Whelk-01 columns (Regis technologies, Inc.); CHIRAL Cellulose-SB, SC, SA columns (YMC Co., Ltd.) at different column sizes (250x20mm, 250x30mm, 250x50mm) with desired isocratic solvent systems or supercritical fluid (SFC) conditions identified on chiral analytical chromatography.
Concentration of solutions was carried out on a rotary evaporator under reduced pressure. Flash column chromatography was usually performed using a Biotage Flash Chromatography apparatus (Dyax Corp.) on silica gel (40-60 pM, 60 A pore size) in prepacked cartridges of the size noted. ’H NMR spectra were acquired at 400 MHz or 300 MHz spectrometers in DMSO-de solutions unless otherwise noted. Chemical shifts were reported in parts per million (ppm). Tetramethylsilane (TMS) was used as internal reference in DMSO-de solutions, and residual CH3OH peak or TMS was used as internal reference in CD3OD solutions. Coupling constants (J) were reported in hertz (Hz). Table 2. Abbreviations.
Figure imgf000086_0001
Figure imgf000087_0001
Example 1: 3-(2,6-dichlorophenyl)-l-methyl-8-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)- l,2,3,7-tetrahydro-4H-pyrrolo [3', 2' : 5,6] pyrido [4, 3-d] pyrimidin-4-one.
Step 1. 4-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine-5- carbaldehyde (Intermediate B)
To a solution of 4-chloro-lH-pyrrolo[2,3-b]pyridine-5-carbaldehyde (2.0 g, 11.07 mmol, 1 eq.) in DMF (10 mL) was added NaH (1.33 g, 33.22 mmol, 60% purity, 3 eq.) in portions. The mixture was stirred for 0.5 h at 0 °C. To the above solution was added SEMC1 (2.22 g, 13.29 mmol, 1.2 eq.) dropwise. The mixture was stirred for an additional 1.5 h at 0 °C. The reaction was monitored by TLC. The resulting mixture was diluted with EA (100 mL) and quenched with ice/water. The resulting mixture was extracted with EA (3x50 mL). The combined organic phase was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 1 :9 EA/PE) to afford 4-chloro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine-5-carbaldehyde (1.8 g, 5.79 mmol, 52% yield) as a white solid. LCMS (ES, m/z): 311, 313 [M+H]+, Rt 1.465 min.
Step 2. 4-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine-5- carboxylic acid (Intermediate C)
To a stirred solution of 4-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3- b]pyridine-5-carbaldehyde (1.8 g, 5.79 mmol, 1 eq.), NH2SO3H (398.0 pL, 8.69 mmol, 1.5 eq.) and 2-methylbut-2-ene (1.22 g, 17.37 mmol, 3 eq.) in AcOH (40 mL) was added NaCICh (943.0 mg, 10.42 mmol, 1.8 eq.) in H2O (2 mL) dropwise at 0 °C. The resulting mixture was stirred for 2 h at 25 °C. The reaction was monitored by LC-MS. The mixture was diluted with water (20 mL), and neutralized with NaOH (6 M in H2O) to pH 7 and extracted with chloroform (3 ^50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 3 : 1 EA/PE) to afford 4-chl oro-1 -((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2, 3-b]pyridine-5- carboxylic acid (1.6 g, 4.91 mmol, 85% yield) as a white solid. LCMS (ES, m/z): 327, 329 [M+H]+, Rt 1.389 min.
Step 3. 4-chloro-N-(2,6-dichlorophenyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- pyrrolo[2,3-b]pyridine-5-carboxamide (Intermediate E)
To a stirred solution of 2,6-dichloroaniline (115.66 mg, 0.71 mmol, 90.36 pL, 1 eq.) in THF (10 mL) was added LiHMDS (2.0 M in THF, 428.33 pL, 1.2 eq.) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred for 2 h at 0 °C. To a stirred solution of 4-chl oro-1 -((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine-5-carboxylic acid (350 mg, 1.07 mmol, 1.5 eq.) in DCM (10 mL) was added SOCI2 (127.40 mg, 1.07 mmol, 1.5 eq.) dropwise at 0 °C. The resulting mixture was stirred for 2 h at 0 °C before it was concentrated under reduced pressure. The residue was dissolved in DCM (2 mL), and added into the first reaction flask dropwise at 0 °C. The resulting mixture was stirred for an additional 2 h at 25 °C. The reaction was monitored by TLC. The mixture was diluted with brine (30 mL), and extracted with EA (3x20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 1 : 1 EA/PE) to afford 4-chloro-N-(2,6-dichlorophenyl)-l-((2-(trimethylsilyl)ethoxy)methyl)- lH-pyrrolo[2,3-b]pyridine-5-carboxamide (200 mg, 0.43 mmol, 61% yield) as a white solid. LCMS (ES, m/z): 470, 472 [M+H]+, Rt 1.458 min.
Step 4. N-(2,6-dichlorophenyl)-4-(methylamino)-l-((2-
(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine-5-carboxamide (Intermediate F)
A solution of 4-chloro-N-(2,6-dichlorophenyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- pyrrolo[2,3-b]pyridine-5-carboxamide (1 g, 2.12 mmol, 1 eq.), methanamine (2 M in THF, 3.19 mL, 3 eq.) and N-ethyl-N-isopropyl-propan-2-amine (548.0 mg, 4.25 mmol, 2 eq.) in DMSO (10 mL) was irradiated for 3 h at 150 °C under the microwave condition. The reaction was monitored by LC-MS. The mixture was allowed to cool to room temperature, diluted with brine (60 mL), and extracted with EA (3x50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 1 : 1 EA/PE) to afford N-(2,6-di chi orophenyl)-4-(m ethylamino)- 1 -((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine-5-carboxamide (600 mg, 1.29 mmol, 61% yield) as a white solid. LCMS (ES, m/z): 465, 467 [M+H]+, Rt 0.827 min.
Step 5. 3-(2,6-dichlorophenyl)-l-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-l,2,3,7- tetrahydro-4H-pyrrolo [3 * ,2 5,6] pyrido [4, 3-d] pyrimidin-4-one (Intermediate G) A solution of N-(2,6-dichlorophenyl)-4-(methylamino)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine-5-carboxamide (550 mg, 1.18 mmol, 1 eq.) and PTSA (2 mg, 11.82 umol, 0.01 eq.) in HCHO (37% in water, 6 mL) and toluene (3 mL) was stirred at 100 °C for 16 h. The reaction was monitored by TLC. The mixture was allowed to cool to room temperature, diluted with brine (20 mL), and extracted with EA (3x20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 1 : 1 EA/PE) to afford 3- (2,6-dichlorophenyl)-l-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-l,2,3,7-tetrahydro- 4H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-4-one (400 mg, 0.84 mmol, 71% yield) as a white solid. ’H NMR (400 MHz, DMSO-d 6) 5 5 8.51 (s, 1H), 7.64-7.61, (m, 2H), 7.50- 7.43 (m, 2H), 6.87 (d, J= 4.0 Hz, 1H), 5.58 (s, 2H), 4.97 (s, 2H), 3.50 (t, J= 8.0 Hz, 2H), 3.42 (s, 3H), 0.85-0.78 (m, 2H), 0.08 (s, 9H). LCMS (ES, m/z): 477, 479 [M+H]+, Rt 1.407 min.
Step 6. 3-(2,6-dichlorophenyl)-l-methyl-l,2,3,7-tetrahydro-4H- pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-4-one (Intermediate H)
To a stirred solution of 3-(2,6-dichlorophenyl)-l-methyl-7-((2- (trimethylsilyl)ethoxy)methyl)-l,2,3,7-tetrahydro-4H-pyrrolo[3',2':5,6]pyrido[4,3- d]pyrimidin-4-one (400 mg, 0.84 mmol, 1 eq.) in DCM (5 mL) was added TFA (5 mL) dropwise at 0 °C and the resulting mixture was stirred for 2 h at 25 °C. The resulting mixture was concentrated under reduced pressure and NH3 (7 M in MeOH, 10.00 mL) was added dropwise at 0 °C and the resulting mixture was stirred for an additional 2 h at 25 °C. The reaction was monitored by LC-MS. The resulting mixture was concentrated under vacuum and the residue purified by silica gel column chromatography (eluting with 1 : 1 EA/PE) to afford 3-(2,6-dichlorophenyl)-l-methyl-l,2,3,7-tetrahydro-4H- pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-4-one (250 mg, 0.72 mmol, 86% yield) as a white solid. LCMS (ES, m/z): 347, 349 [M+H]+, Rt 1.036 min.
Step 7. 3-(2,6-dichlorophenyl)-l-methyl-7-tosyl-l,2,3,7-tetrahydro-4H- pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-4-one (Intermediate I)
To a stirred mixture of 3-(2,6-dichlorophenyl)-l-methyl-l,2,3,7-tetrahydro-4H- pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-4-one (200 mg, 0.58 mmol, 1 eq.) in DMF (5 mL) was added NaH (35 mg, 0.87 mmol, 60% purity, 1.5 eq.). The resulting mixture was stirred for 30 min at 0 °C. To above solution was added 4-methylbenzenesulfonyl chloride (132 mg, 0.69 mmol, 1.2 eq.) in portions at 0 °C. The resulting mixture was stirred for 2 h at 25 °C. The reaction was monitored by TLC. The mixture was quenched with water/ice (2 OmL), extracted with EA (3x 10 mL) and the combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 1 :2 EA/PE) to afford 3-(2,6-dichlorophenyl)-l-methyl-7-tosyl-l,2,3,7-tetrahydro-4H- pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-4-one (260 mg, 0.52 mmol, 90% yield) as a white solid. LCMS (ES, m/z): 501, 503 [M+H]+, Rt 1.308 min.
Step 8. 8-bromo-3-(2,6-dichlorophenyl)-l-methyl-7-tosyl-l,2,3,7-tetrahydro-4H- pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-4-one (Intermediate J)
To a stirred solution of 3-(2,6-dichlorophenyl)-l-methyl-7-tosyl-l,2,3,7-tetrahydro-4H- pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-4-one (650 mg, 1.30 mmol, 1 eq.) in THF (10 mL) was added LDA (1.3 M in THF, 1.20 mL, 1.2 eq.) dropwise. The resulting mixture was stirred for 1 h at -78 °C under a nitrogen atmosphere. To the above solution was added 1,2- dibromo-l,l,2,2-tetrachloro-ethane (464 mg, 1.43 mmol, 1.1 eq.) in THF (1 mL) dropwise. The resulting mixture was stirred for an additional 2 h at -78 °C. The reaction was monitored by LC-MS. The mixture was allowed to warm to room temperature, quenched with water/ice (30 mL), and extracted with EA (3x30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 1:2 EA/PE) to afford 8-bromo-3-(2,6-dichlorophenyl)-l-methyl-7-tosyl-l, 2,3,7- tetrahydro-4H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-4-one (500 mg, 0.86 mmol, 66% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d 6) 8 8.49 (s, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 7.49-7.41 (m, 3H), 7.35 (s, 1H), 4.97 (s, 2H), 3.32 (s, 3H), 2.34 (s, 3H). LCMS (ES, m/z): 579, 581, 583 [M+H]+, Rt 1.371 min.
Step 9. tert-butyl 4-(4-(3-(2,6-dichlorophenyl)-l-methyl-4-oxo-7-tosyl-2, 3,4,7- tetrahydro-lH-pyrrolo [3 * ,2 5,6] pyrido [4, 3-d] pyrimidin-8-yl)-lH-pyrazol-l- yl)piperidine-l-carboxylate (Intermediate L)
To a solution of 8-bromo-3-(2,6-dichlorophenyl)-l-methyl-7-tosyl-l,2,3,7-tetrahydro-4H- pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-4-one (80 mg, 0.14 mmol, 1 eq.), tert-butyl 4-[4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazol-l-yl]piperidine-l-carboxylate (62.42 mg, 0.17 mmol, 1.2 eq.), Pd(dppf)C12 -DCM (11.25 mg, 13.79 pmol, 0.1 eq.) and Na2CCh (29.23 mg, 275.73 pmol, 2 eq.) in dioxane (1.6 mL) and H2O (0.4 mL) was stirred for 1 h at 90°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was monitored by LC-MS. The resulting mixture was diluted with EA (20 mL). The resulting mixture was washed with brine (3 *20 mL), then combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 2: 1 EA/PE) to afford tert-butyl 4-(4-(3-(2,6- dichlorophenyl)-l-methyl-4-oxo-7-tosyl-2,3,4,7-tetrahydro-lH- pyrrolo[3 ',2' : 5,6]pyrido[4,3 -d]pyrimidin-8-yl)- IH-pyrazol- 1 -yl)piperidine- 1 -carboxylate (100 mg, 0.13 mmol, 93% yield) as a light-yellow solid. LCMS (ES, m/z): 750, 752 [M+H]+. Rt 1.380 min.
Step 10. 3-(2,6-dichlorophenyl)-l-methyl-8-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)- l,2,3,7-tetrahydro-4H-pyrrolo [3', 2' : 5,6] pyrido [4, 3-d] pyrimidin-4-one (Example 1)
To a solution of tert-butyl 4-(4-(3-(2,6-dichlorophenyl)-l-methyl-4-oxo-7-tosyl-2,3,4,7- tetrahydro-lH-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-8-yl)-lH-pyrazol-l-yl)piperidine- 1-carboxylate (50 mg, 66.6 pmol, 1 eq.) and TBAF (1 M in THF, 2 mL, 30 eq.) in THF (3 mL) was stirred for 2 h at 25 °C. The reaction was monitored by TLC. The resulting mixture was diluted with EA (100 mL). The resulting mixture was washed with brine (3 *20 mL), then combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 1 :2 EA/PE) to afford tert-butyl 4-(4-(3-(2,6- dichlorophenyl)-l-methyl-4-oxo-2,3,4,7-tetrahydro-lH-pyrrolo[3',2':5,6]pyrido[4,3- d]pyrimidin-8-yl)-lH-pyrazol-l-yl)piperidine-l-carboxylate. The crude product was dissolved in DCM (3 mL). Then TFA (0.5 mL) was added dropwise at 0°C. The mixture was stirred for 2 h at 25 °C. The reaction was monitored by LC-MS. The crude product was purified by (Column: XBridge Prep Phenyl OBD Column, 19x 150 mm, 5 pm, 13 nm; Mobile Phase A: water (10 mmol/L NH4HCO3 + 0.1% NH3.H2O), Mobile Phase B : CH3CN (25% to 45% in 8 min); Flow rate:25 mL/min; 254 nm; Rt: 6.42) to afford 3-(2,6- di chi orophenyl)-l-methyl-8-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)- 1,2,3, 7-tetrahydro-4H- pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-4-one (13.3 mg, 26.81 pmol, 40% yield) as a white solid. ’H NMR (400 MHz, DMSO-d 6) 8 12.11 (s, 1H), 8.43 (s, 1H), 8.26 (s, 1H), 7.98 (s, 1H), 7.65 (d, J= 8.0 Hz, 2H), 7.47 (dd, J= 8.8, 7.6 Hz, 1H), 6.97 (s, 1H), 4.95 (s, 2H), 4.29-4.17 (m, 1H), 3.46 (s, 3H), 3.30-3.33 (m, 1H), 3.05-3.08 (m, 2H), 2.50-2.62 (m, 2H), 2.01-1.98 (m, 2H), 1.75-1.80 (m, 2H). LCMS (ES, m/z): 496, 498 [M+H]+. Rt 0.821 min.
Example 2: 3-(2,6-dichlorophenyl)-l-methyl-l,2,3,7-tetrahydro-4H- pyrrolo [3', 2' : 5,6] pyrido [4, 3-d] pyrimidin-4-one
Example 2 was prepared by a procedure analogous to steps 1-7 used to prepare intermediate I in Example 1, with an added step of removing the para-toluenesulfonyl group from the azaindole nitrogen of intermediate I to form Example 2. 1H NMR (400 MHz, DMSO-d 6) 8 11.85 (s, 1H), 8.47 (s, 1H), 7.64 (d, J = 8.4 Hz. 2H), 7.47 (dd, 8.8 Hz, 7.6 Hz, 1H), 7.32 (m, 1H), 6.79 (d, J = 3.2 Hz, 1H), 4.96 (s, 2H), 3.43 (s, 3H). LCMS (ES, m/z): 346.95 [M+H]+. Rt 0.78 min.
Examples 3-36: Preparation of Examples 3-36
Examples 3-36 were prepared analogously to compound 1 in Example 1, with one or both of the following modifications: (1) amine D used in step 3 of Example 1 was interchanged with the appropriate amine shown in Table 3 below, and/or (2) boronate ester K used in step 9 of Example 1 was interchanged with the appropriate boronate ester shown in Table 3 below (the corresponding boronic acid may also be used depending, e.g., on the structure of the organometallic fragment and conditions used). For each example number shown in Table 3, an additional number of steps may be required to complete the indicated structure following the use of the appropriate boronate ester in Table 3. LC-MS characterization for each compound is also shown in Table 3.
Table 3. Intermediates used in the synthesis of compounds 3-36.
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
* denotes the first eluting compound; ** denotes the second eluting compound
Example 37 : 3-(2,6-dichlorophenyl)-8-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-3,7- dihydro-4H-pyrrolo [3 * ,2 5,6] pyrido [4, 3-d] pyrimidin-4-one Step 1. 4-amino-2-bromo-N-(2,6-dichlorophenyl)-l-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridine-5-carboxamide (A/2)
A solution of 2-bromo-4-chloro-N-(2,6-dichlorophenyl)-l-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridine-5-carboxamide (1 g, 1.82 mmol), N- ethyl-N-isopropyl-propan-2-amine (470.19 mg, 3.64 mmol, 633.68 uL) and ammonia solution (14 M, 1.30 mL) in DMSO (10 mL) was stirred for 24 h at 100 °C. The reaction was monitored by TLC. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with brine (50 mL). The resulting mixture was extracted with ethyl acetate (3 x 10 mL), and the combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 1 :3 ethyl acetate/petroleum ether) to afford 4-amino-2-bromo-N-(2,6-dichlorophenyl)-l-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridine-5-carboxamide (800 mg, 1.43 mmol, 79% yield, 95% purity) as a white solid. LCMS m/z 531.0 [M+H]+
Step 2. 8-bromo-3-(2,6-dichlorophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-3,7- dihydro-4H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-4-one (B/3)
A solution of 4-amino-2-bromo-N-(2,6-dichlorophenyl)-l-(2-trimethylsilylethoxymethyl) pyrrolo[2,3-b]pyridine-5-carboxamide (200 mg, 377.1 pmol, 1 equiv) in acetic acid (4 mL) was added triethyl orthoformate (167.7 mg, 1.1 mmol, 188.2 pL, 3 equiv). The mixture was stirred at 50 °C for 12 h. LCMS showed complete consumption of starting material and mass of the desired compound. The mixture was concentrated to give a residue, which was added to cold sat. sodium bicarbonate (5 mL), extracted twice with 8 mL of ethyl acetate. The combined organic layers were washed with brine (5 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was triturated in methanol (3 mL) at 20 °C for 5 min, filtered and the filter cake was dried to give 8-bromo-3-(2,6-dichlorophenyl)-7-((2- (trimethylsilyl)ethoxy)methyl)-3,7-dihydro-4H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin- 4-one (99 mg, crude) as a white solid. LCMS m/z 541.0 [M+H]+
Step 3. tert-butyl 4-(4-(3-(2,6-dichlorophenyl)-4-oxo-7-((2-
(trimethylsilyl)ethoxy)methyl)-4,7-dihydro-3H-pyrrolo [3', 2' : 5,6] pyrido [4,3- d]pyrimidin-8-yl)-lH-pyrazol-l-yl)piperidine-l-carboxylate (C/4)
The title compound was prepared by a procedure analogous to steps 9 used to prepare intermediate L in Example 1. LCMS m/z 710.2 [M+H]+
Step 4. 3-(2,6-dichlorophenyl)-8-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-3,7-dihydro- 4H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-4-one (Example 37)
The title compound was prepared by a procedure analogous to step 6 used to prepare Intermediate H in Example 1 except with tert-butyl 4-(4-(3-(2,6-dichlorophenyl)-4-oxo- 7-((2-(trimethylsilyl)ethoxy)methyl)-4,7-dihydro-3H-pyrrolo [3', 2' : 5,6] pyrido [4,3- d]pyrimidin-8-yl)-lH-pyrazol-l-yl)piperidine-l-carboxylate as the starting material. LCMS m/z 480.1 [M+H]+
Example 38: 3-(2,6-dichlorophenyl)-8-(l-(l-methylpiperidin-4-yl)-lH-pyrazol-4-yl)- 3,7-dihydro-4H-pyrrolo [3', 2' : 5,6] pyrido [4, 3-d] pyrimidin-4-one
The title compound was prepared by a procedure analogous to prepare Example 41 except using 3-(2,6-dichlorophenyl)-8-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-3,7-dihydro-4H- pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-4-one (Example 37).
'H-NMR (DMSO-d6, 400 MHz) 8 (ppm): 12.68 (s, 1H), 8.97 (s, 1H), 8.63 (s, 1H), 8.43 (s, 1H), 8.13 (s, 1H), 7.83-7.81 (m, 2H), 7.71-7.65 (m, 1H), 7.12 (d, J = 1.6 Hz, 1H), 4.23- 4.16 (m, 1H), 2.91-2.88 (m, 2H), 2.24 (s, 3H), 2.10-1.96 (m, 6H). LCMS (ES, m/z): 494.05 [M+H]+, Rt 1.350 min.
Example 39: 3-(2,6-dichlorophenyl)-2-methyl-8-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)- 3,7-dihydro-4H-pyrrolo [3', 2' : 5,6] pyrido [4, 3-d] pyrimidin-4-one
The title compound was prepared by a procedure analogous to steps 2-4 used to prepare Example 37 except tri ethyl orthoacetate was used in step 2 in place of triethyl orthoformate. 'H-NMR (DMSO-d6, 400 MHz) 8 (ppm): 12.66 (s, 1H), 8.88 (s, 1H), 8.41 (s, 1H), 8.38- 8.32 (m, 1H), 8.14 (s, 1H), 7.90-7.81 (m, 1H), 7.70-7.65 (m, 1H), 7.14 (s, 1H), 4.42-4.25 (m, 1H), 3.26-3.18 (m, 2H), 2.84-2.73 (m, 2H), 2.25 (s, 3H), 2.12-1.91 (m, 4H). LCMS (ES, m/z): 494.10 [M+H]+, Rt 0.759 min.
Example 40: 3-(2,6-dichlorophenyl)-l-methyl-8-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)- l,7-dihydro-2H-pyrrolo [3', 2' : 5,6] pyrido [4, 3-d] pyrimidine-2,4(3H)-dione
Step 1. methyl 4-chloro-l-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridine-5- carboxylate (Intermediate A/4)
To a mixture of Example 1/Intermediate C (15 g, 45.9 mmol, 1 equiv) in di chloromethane (150 mL) was added sulfonyl chloride (10.9 g, 91.8 mmol, 6.7 mL, 2 equiv) at 0 °C under nitrogen. The mixture was stirred at 20 °C for 1 h. Then the reaction was quenched with methanol (50 mL) and the mixture was stirred at 20 °C for 0.5 h. TLC (SiO2, eluting with petroleum ether : ethyl acetate=5: l) showed the starting material was consumed. The mixture was concentrated. The residue was diluted with water (200 mL) and adjusted pH to 8-9 with saturated sodium bicarbonate solution and extracted four times with 100 mL of ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel; eluting with a gradient of petroleum ether/ethyl acetate, 1/0 to 1/1) to give methyl 4-chloro-l-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridine-5-carboxylate (11.0 g, 32.3 mmol, 70% yield) as a white solid.
Step 2. methyl 2-bromo-4-chloro-l-(2-trimethylsilylethoxymethyl)pyrrolo[2,3- b]pyridine-5- carboxylate (Intermediate B/5)
To a solution of 2,2,6,6-tetramethylpiperidine (15 g, 106.2 mmol, 18.0 mL, 1 equiv) in tetrahydrofuran (50 mL) was added n-butyllithium (2.5 M, 38.2 mL, 0.9 equiv) at -78°C under nitrogen. The mixture was stirred at 0 °C for 10 min. Then it can be used directly into next step.
To a mixture of methyl 4-chloro-l-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridine- 5- carboxylate (5.5 g, 16.1 mmol, 1 equiv) in tetrahydrofuran (50 mL) was added (2, 2,6,6- tetramethyl -4,5-dihydro-3H-pyridin-l-yl)lithium (1 M, 32.27 mL, 2 eq) at -78 °C under nitrogen. l,2-dibromo-l,l,2,2-tetrachloro-ethane (5.8 g, 17.8 mmol, 2.1 mL, 1.1 equiv) in tetrahydrofuran (20 mL) was added at -78 °C and stirred for 1 h under nitrogen. (SiO2, eluting with petroleum ether : ethyl acetate=5: l) showed the starting material was consumed and a new spot with less polar was observed. The reaction was quenched with saturated ammonium chloride solution (100 mL), extracted four times with 200 mL of ethyl acetate. The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluting with a gradient of petroleum ether/ethyl acetate, 1/0 to 10/1) to give 4 g of crude methyl 2-bromo-4-chloro-l-(2-trimethylsilylethoxymethyl)pyrrolo[2,3- b]pyridine-5-carboxylate as a white solid. LCMS m/z 421.0 [M+H]+
Step 3. 2-bromo-4-chloro-l-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridine-5- carboxylic acid (Intermediate C/6)
A mixture of methyl 2-bromo-4-chloro-l-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b] pyridine-5-carboxylate (5.4 g, 12.9 mmol, 1 equiv) and lithium;hydroxide; hydrate (1.1 g, 25.7 mmol, 2 equiv) in tetrahydrofuran (30 mL) and water (15 mL) was stirred at 50 °C for 1 h. LCMS showed the starting material was consumed and the desired mass was observed. The mixture was diluted with ice water (50 mL), and adjusted pH to 4 - 5 with 5N hydrochloric acid solution, filtered, filter cake was concentrated to give 4.2 g of crude 2- bromo-4-chloro-l-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridine-5-carboxylic acid as a white solid. LCMS m/z 407.0 [M+H]+
Step 4. 2-bromo-4-chloro-N-(2,6-dichlorophenyl)-l-(2-trimethylsilylethoxymethyl) pyrrolo[2,3-b] pyridine-5-carboxamide (Intermediate D/8)
The title compound was prepared by a procedure analogous to step 3 used to prepare intermediate E in Example 1. LCMS m/z 549.9 [M+H]+
Step 5.2-bromo-N-(2,6-dichlorophenyl)-4-(methylamino)-l-(2-trimethylsilyl ethoxymethyl)pyrrolo [2,3-b] pyridine-5-carboxamide (Intermediate E/9)
The title compound was prepared by a procedure analogous to step 4 used to prepare intermediate F in Example 1. LCMS m/z 545.0 [M+H]+
Step 6. 8-bromo-3-(2,6-dichlorophenyl)-l-methyl-7-((2-(trimethylsilyl)ethoxy) methyl)-!, 7-dihydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2,4(3H)-dione (Intermediate F/10)
Into a microwave tube was added 2-bromo-N-(2,6-dichlorophenyl)-4-(methylamino)-l-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridine-5-carboxamide (200 mg, 367.42 umol), DIPEA (1 mL) and DMAc (1 mL). Then di(imidazol-l-yl)methanone (297.88 mg, 1.84 mmol) was added. The mixture was stirred at 150°C for 2 h under microwave condition. The reaction was cooled to room temperature. Then water (20 mL) was added. The mixture was extracted with EA (3X20 mL). The combined organic layer was washed with brine (2X30 mL), dried with sodium sulfate, filtered and concentrated. The residue was purified by silica gel column with PE:EA (1 : 1) to afford 8-bromo-3-(2,6- dichlorophenyl)-l-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-l,7-dihydro-2H- pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2,4(3H)-dione (140 mg, 220.92 umol, 60% yield, 90% purity) as a white solid.
Step 7. tert-butyl 4-(4-(3-(2,6-dichlorophenyl)-l-methyl-2,4-dioxo-7-((2- (trimethylsilyl)ethoxy)methyl)-2,3,4,7-tetrahydro-lH-pyrrolo[3',2':5,6]pyrido[4,3- d]pyrimidin-8-yl)-lH-pyrazol-l-yl)piperidine-l-carboxylate (Intermediate G/ll)
The title compound was prepared by a procedure analogous to step 9 used to prepare intermediate L in Example 1 except with 8-bromo-3-(2,6-dichlorophenyl)-l-methyl-7-((2- (trimethylsilyl)ethoxy)methyl)-l,7-dihydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine- 2,4(3H)-dione (Example 40 Intermediate F/10). The residue was purified by preparative HPLC (neutral condition; column: Waters Xbridge BEH Cl 8 100 * 25 mm * 5 um; mobile phase: [water (10 mM ammonium hydrogen carbonate) - acetonitrile]; B%: 75% - 98%, 10 min) to give tert-butyl 4-[4-[l l-(2,6-dichlorophenyl)-13-methyl-10,12-dioxo-5-(2- trimethylsilylethoxymethyl)-5,7,l l,13-tetrazatricyclo[7.4.0.02,6]trideca-l(9),2(6),3,7- tetraen-4-yl]pyrazol-l-yl]piperidine-l -carboxylate (20 mg, crude) as a white solid.
XH NMR (400 MHz, CHLOROFORM-d) 8 = 9.08 (d, J = 1.1 Hz, 1H), 8.05 (s, 1H), 7.96 (s, 1H), 7.54 - 7.46 (m, 2H), 7.42 - 7.35 (m, 1H), 7.01 (s, 1H), 5.80 (s, 2H), 4.46 - 4.22 (m, 3H), 4.10 (s, 3H), 3.74 (br t, J= 8.2 Hz, 2H), 2.94 (br s, 2H), 2.21 (br d, J= 11.4 Hz, 2H), 2.11 - 1.93 (m, 2H), 1.65 (br s, 2H), 1.54 - 1.47 (m, 9H), 1.04 - 0.95 (m, 2H), -0.01 (d, J= 1.1 Hz, 9H); LCMS m/z 740.2 [M+H]+
Step 8. 3-(2,6-dichlorophenyl)-l-methyl-8-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-lH- pyrrolo [3', 2' : 5,6] pyrido [4, 3-d] pyrimidine-2,4(3H,7H)-dione (Example 40)
A mixture of tert-butyl 4-(4-(3-(2,6-dichlorophenyl)-l-methyl-2,4-dioxo-7-((2- (trimethylsilyl)ethoxy)methyl)-2,3,4,7-tetrahydro-lH-pyrrolo[3',2':5,6]pyrido[4,3- d]pyrimidin-8-yl)-lH-pyrazol-l-yl)piperidine-l-carboxylate(20 mg, 27.0 pmol, 1 equiv) in trifluoroacetic acid (0.5 mL) and dichloromethane (0.5 mL) was stirred at 20 °C for 1 h. LCMS showed complete consumption of starting material and mass of the desired compound. The mixture was concentrated. The residue was diluted with 7N ammonia; methyl alcohol solution (2 mL). The mixture was purified by preparative HPLC (neutral condition; column: Waters Xbridge BEH C18 100 * 30 mm * 10 um; mobile phase: [water (10 mM ammonium hydrogen carbonate) - acetonitrile]; B%: 20% - 50%, 10 min) to give 3-(2,6-dichlorophenyl)-l-methyl-8-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-lH- pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-dione (11 mg, 75% yield) as a white solid.
'H-NMR (DMSO-d6, 400 MHz) 8 (ppm): 12.77 (s, 1H), 8.79 (s, 1H), 8.41 (s, 1H), 8.11 (s, 1H), 7.76-7.73 (m, 2H), 7.62-7.56 (m, 1H), 7.32 (s, 1H), 4.22-4.13(m, 1H), 4.02 (s, 3H), 2.90-2.86 (m, 2H), 2.23 (s, 3H), 2.13-1.90 (m, 6H). LCMS (ES, m/z . 524.10 [M+H]+, Rt 0.724 min.
Example 41: 3-(2,6-dichlorophenyl)-l-methyl-8-(l-(l-methylpiperidin-4-yl)-lH- pyrazol-4-yl)-lH-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-dione
To a mixture of 3-(2,6-dichlorophenyl)-l-methyl-8-(l-(piperidin-4-yl)-lH-pyrazol-4-yl) - lH-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-dione (Example 40) (18 mg, 35.3 pmol, 1 equiv) and paraformaldehyde (21.2 mg, 705.4 pmol, 20 equiv) in methanol (1 mL) was added acetic acid (4.2 mg, 70.5 pmol, 2 equiv) at 20 °C and the mixture was stirred for 0.5 h. Sodium cyanoborohydride (4.4 mg, 70.5 pmol, 2 equiv) was added and stirred at 20 °C for 2 h. LCMS showed the starting material was consumed and the desired mass was observed. The mixture was concentrated. The residue was diluted with N,N- dimethylformamide (1 mL) and methanol (1 mL). The mixture was filtered and the filtrate was purified by preparative HPLC (neutral condition; column: Waters Xbridge BEH Cl 8 100 * 25 mm * 5 um; mobile phase: [water (10 mM ammonium hydrogen carbonate) - acetonitrile]; B%: 30% - 60%, 10 min) to give 3-(2,6-dichlorophenyl)-l-methyl-8-(l-(l- methylpiperidin-4-yl)-lH-pyrazol-4-yl)-lH-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine- 2,4(3H,7H)-dione (8.5 mg, 45% yield) as a white solid.
'H-NMR (DMSO-d6, 400 MHz) 8 (ppm): 12.78 (br, 1H), 8.76 (s, 1H), 8.38 (s, 1H), 8.11 (s, 1H), 7-79-7.71 (m, 2H), 7.59-7. 54 (m, 1H), 7.32 (s, 1H), 4.45-4.31 (m, 1H), 3.98 (s, 3H), 3.11-3.08 (m, 2H), 2.93-2.86 (m, 2H), 2.26-2.25 (m, 2H), 1.98-1.94 (m, 2H). LCMS (ES, m/z . 510.10 [M+H]+, Rt 0.764 min.
Example 42: 3-(2-chloro-6-fluorophenyl)-8-(l-(l-methylpiperidin-4-yl)-lH-pyrazol- 4-yl )-3.7-dihydro-4//-py r rolo [3 ’ ,2 ’ : 5,6] pyrido [4,3- d] pyrimidin-4-one Step . 4-chloro-/V-(2-chloro-6-fluorophenyl)-l-((2-(trimethylsilyl)ethoxy)methyl)- l//-pyrrolo|2.3-/j|pyridine-5-carboxainide (Intermediate E)
The title compound was prepared by a procedure analogous to step 3 used to prepare Intermediate E in Example 1 except 2-chloro-6-fluoroaniline was used in place of 2,6- dichloroaniline.
Step 2'. 3-(2-chloro-6-fluorophenyl)-8-( l-(l-methylpiperidin-4-yl)-TH-pyrazol-4-yl)- 3.7-dihydro-4//-py rrolo [3', 2' : 5,6] pyrido [4,3-</| pyrimidin-4-one (Example 42) The title compound was prepared starting with Intermediate E and procedures analogous to steps 1-4 used to prepare Example 37, followed by the methylation step in Example 41. LCMS (ES, m/z): 478.10 [M+H]+, Rt 0.69 min.
Example 43: (S)-3-(2.6-dichlorophenyl)-l-methyl-8-(l-(pyrrolidin-2-ylmethyl)-l//- pyrazol-4-yl)- 1 ,7-d ihyd ro-2//-py rrolo [3' ,2' : 5,6] pyrido [4, 3-d] pyrimidine-2,4(3H )- dione
The title compound was prepared in an analogous manner as Example 40 except with tert-butyl (5)-2-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-17/-pyrazol-l- yl)methyl)pyrrolidine-l -carboxylate substituted for tert-butyl 4-[4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyrazol-l-yl]piperidine-l-carboxylate in step 7, followed by Boc deprotection procedure analogous to Example 40 step 8. LCMS (ES, m/z): 510.10 [M+H]+, Rt 0.72 min.
Example 44: (/?)-3-(2.6-dichlorophenyl)-l-methyl-8-(l-(pyrrolidin-2-ylmethyl)-l//- pyrazol-4-yl)- 1 ,7-d ihyd ro-2//-py rrolo [3' ,2' : 5,6] pyrido [4,3- d] pyrimidine-2,4(3H )- dione
The title compound was prepared in an analogous manner as Example 40 except with tert-butyl (R)-2-((4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)- 1 Tt-pyrazol- 1 - yl)methyl)pyrrolidine-l -carboxylate substituted for tert-butyl 4-[4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyrazol-l-yl]piperidine-l-carboxylate in step 7, followed by Boc deprotection procedure analogous to Example 40 step 8. LCMS (ES, m/z): 510.10 [M+H]+, Rt 0.72 min. Example 45: (3)-3-(2-chloro-6-fluorophenyl)-l-methyl-8-(l-(pyrrolidin-2-ylmethyl)- 1H-py razol-4-yl)- 1 ,7-dihydro-2H-pyr rolo [3' ,2' : 5,6] pyr ido [4,3- d] pyrimidine-2,4(3H )- dione
Step 1: 8-bromo-3-(2-chloro-6-fluorophenyl)-l-methyl-7-((2-
( trimet hylsilyl )ethoxy)methyl )- 1.7-dihydro-2//-py rrolo [3', 2' : 5,6] pyrido [4,3- d] pyrimidine-2,4(3H )-dione
The title compound was prepared in an analogous manner as steps 1-6 in Example 40 except 2-chloro-6-fluoroaniline was used in place of 2,6-dichloroaniline in Step 4.
Step 2: (S)-3-(2-chloro-6-fluorophenyl)-l-methyl-8-( l-(pyrrolidin-2-ylmethyl)-LH- pyrazol-4-yl)- 1 ,7-d ihyd ro-2//-py rrolo [3' ,2' : 5,6] pyrido [4,3- d] pyrimidine-2,4(3H )- dione (Example 45)
The title compound was prepared in an analogous manner as Example 43 except with 8- bromo-3-(2-chloro-6-fluorophenyl)-l-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-l,7- dihydro-2H -pyrrolo[3',2':5,6]pyrido[4,3-J]pyrimidine-2,4(3J7)-dione in place of 8-bromo- 3-(2,6-dichlorophenyl)-l-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-l,7-dihydro-2H- pyrrolo[3',2':5,6]pyrido[4,3-J]pyrimidine-2,4(3H )-dione. LCMS (ES, m/z) 494.2 [M+H]+, Rt 0.71 min.
Example 46 : (l?)-3-(2-chloro-6-fluorophenyl)-l-methyl-8-(l-(pyrrolidin-2-ylmethyl)- 1H-py razol-4-yl)- 1 ,7-d ihyd ro-2//-py rrolo [3' ,2' : 5,6] pyrido [4,3- d] pyrimidine-2,4(3H )- dione
The title compound was prepared in an analogous manner as Example 45 except with tert-butyl (R)-2-((4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)- 1 H -pyrazol- 1 - yl)methyl)pyrrolidine-l -carboxylate in place of tert-butyl (5)-2-((4-(4,4,5,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1 JT-pyrazol- 1 -yl)methyl)pyrrolidine- 1 -carboxylate. LCMS (ES, m/z) 494.2 [M+H]+, Rt 1.3 min.
Example 47 : 3-(2-chloro-6-fluorophenyl)-l-methyl-8-(l-(l-methylpiperidin-4-yl)-
1H-py razol-4-yl)- 1 ,7-d ihyd ro-2//-py rrolo [3' ,2' : 5,6] pyrido [4,3- d] pyrimidine-2,4(3H )- dione
The title compound was prepared in an analogous manner as Example 41 except 2- chloro-6-fluoroaniline was used in place of 2,6-dichloroaniline in Example 40/Step 4. LCMS (ES, m/z . 508.15 [M+H]+, Rt 0.72 min.
Phosphorylated Cdc2 MSP Electrochemiluminescence Assay
The effect of Weel inhibitors on cellular phosphorylation of the Weel substrate Cdc2 was determined using the following protocol:
A total of 40,000 A427 or OVCAR3 cells in 100 uL culture medium (1640 medium + 10% Fetal bovine serum + 1% Penicillin-Streptomycin) were plated in 96-well cell culture plates. 3 -fold serial dilutions of test compounds were prepared in completed PBS at 25X final concentration and 4 pL of each were added to the cells and incubated with shaking for 4 hours at 37°C, 5% CO2. Each concentration was tested in duplicate. After a total 6 hours incubation, cells were washed with 200 pL PBS and lysed with 50 pL MSD lysis buffer (Meso Scale Diagnostics) supplied with IX complete ULTRA cocktail inhibitor (Roche).
To detect phosphorylation of Cdc2 Y15, 30 pL of capture antibody solution (CST catalog #9116S 1 :200) was added into each well of the MSD plate (MSD catalog # L15XB- 6), sealed and incubated at 4°C with shaking (450 rpm) overnight. The antibody solution was removed, wells blocked with BSA solution and plates washed, followed by addition of 30 pl of cell lysate per well. After 2 h incubation, plates were washed. 30 pL of IX detection antibody solution (CST catalog #4539S 1 :200) was then added to each well and incubated for 1 hour. Plates were washed and 30 pL of IX secondary antibody solution (MSD, catalog #:R32AB-1, 1 :5000) was added to each well and incubated for 1 hour. Plates were washed and 150 pL of IX Read Buffer T (MSD, catalog #R92TC-1) was added to each well of the MSD plate. The electrochemiluminescence signal was measured on a MESO SECTOR S600 plate reader. The percentage of remaining phosphorylated Cdc2 signal was calculated following the equation below.
Figure imgf000108_0001
HC (high control): Cells treated with DMSO
Cpds: Cells treated with test compounds
LC (low control): Cells treated with positive control Weel inhibitor
Weel Kinase Biochemical Assay Protocol
Weel kinase domain was purchased from Carna (catalog #05-177). Weel kinase activity was determined with Poly(Lys,Tyr 4: 1) hydrobromide as a substrate (Sigma- Aldrich) and by measuring ADP production using the ADP-Glo Kinase Assay kit (Promega) following the manufacturer’s instructions. The kinase reaction was performed using the following conditions:
Buffer: 40 mM Tris-HCl, 20 mM magnesium chloride, supplemented with 0.1 mg/mL bovine serum albumin and 2 mM DTT. The final reaction mix contained 1 nM Weel enzyme, 15 uM ATP, and 2 ng/mL Poly(Lys,Tyr 4: 1) hydrobromide substrate. The reaction time was 4 hours at 25 °C.
The ADP-Glo signal was measured using the Envision plate reader and the percentage inhibition of kinase activity calculated for each inhibitor tested. Percent inhibition of Weel kinase activity was calculated based on the following formula.
Figure imgf000109_0001
Ssampie : the signal of compounds
Singh Ctrl : the signal of high control (DMSO)
SLOW Ctrl : the signal of low control (positive control Weel inhibitor at saturating concentration)
PLK1 Kinase Biochemical Assay Protocol
Full-length PLK1 kinase was purchased from Carna (catalog #05-157). PLK1 kinase activity was determined with Native Cow Casein protein, dephosphorylated, as a substrate (abeam) and by measuring ADP production using the ADP-Glo Kinase Assay kit (Promega) following the manufacturer’s instructions. The kinase reaction was performed using the following conditions:
Buffer: 40 mM Tris-HCl, 20 mM magnesium chloride, supplemented with 0.1 mg/mL bovine serum albumin and 2 mM DTT. The final reaction mix contained 10 nM PLK1 enzyme, 3 uM ATP, and 5 uM Native Cow Casein protein substrate. The reaction time was 2 hours at 25 degrees C. The ADP-Glo signal was measured using the Envision plate reader and the percentage inhibition of kinase activity calculated for each inhibitor tested. Percent inhibition of PLK 1 kinase activity was calculated based on the following formula.
Figure imgf000110_0001
Ssampie : the signal of compounds
Singh Ctrl : the signal of high control (DMSO)
SLOW Ctrl : the signal of low control (positive control PLK inhibitor at saturating concentration)
The WEE1 IC50 ranges are as follows:
ND = “not determined”
A: IC50 < 10 nM; B: 10 nM < IC50 < 100 nM; C: 100 nM < IC50 < 1000 nM; D: IC50 > 1000 nM.
The A427 pCDC2 and OVCAR3 pCDC2 IC50 ranges are as follows:
A: IC50 < 100 nM; B: 100 nM < IC50 < 1000 nM; C: 1000 nM < IC50 < 10000 nM;
D: IC50 > 10000 nM.
The PLK1 IC50 ranges are as follows:
A: IC50 > 10000 nM; B: 1000 nM < IC50 < 100000 nM; C: 100 nM < IC50 < 1000 nM; D: IC50 < 100 nM.
Table A, Biological Data Obtained in the above assays.
Figure imgf000110_0002
Figure imgf000111_0001
Figure imgf000112_0001
A number of embodiments of the present disclosure have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the disclosure. Accordingly, other embodiments are within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:
1. A compound of F ormul a (I) :
Figure imgf000113_0001
or a pharmaceutically acceptable salt thereof, wherein:
= is a single bond or a double bond; when = is a double bond, R2 and R2B are absent;
R1 is a C6-C10 aryl optionally substituted with 1-3 independently selected RA or a 5-10 membered heteroaryl optionally substituted with 1-3 independently selected RA;
R2 is a C1-C6 alkyl optionally substituted with 1-3 independently selected RB or a C3-C8 cycloalkyl optionally substituted with 1-3 independently selected RB;
R2A is hydrogen, a C1-C6 alkyl optionally substituted with 1-3 independently selected RB, or a C3-C8 cycloalkyl optionally substituted with 1-3 independently selected RB;
R2B is hydrogen, a C1-C6 alkyl optionally substituted with 1-3 independently selected RB, or a C3-C8 cycloalkyl optionally substituted with 1-3 independently selected RB; or
R2A and R2B, with the carbon atom to which they are attached, together form a C=O group;
Ring A is a 4-10 membered heterocyclyl, 5-10 membered heteroaryl, or C6-C10 aryl; or wherein Ring A and R5 are absent;
R3 is hydrogen, halogen, or C1-C6 alkyl optionally substituted with 1-3 independently selected Rc;
R4 is hydrogen or C1-C6 alkyl; each R5 is independently halogen, C1-C6 alkyl, C3-C8 cycloalkyl, cyano, -(CH2)q- NR5AR5B, _(CH2)n-4-10 membered heterocyclyl optionally substituted with 1-3 independently selected RD, or -(CH2)p-5-10 membered heteroaryl optionally substituted with 1-3 independently selected RE; m is 0, 1, 2, or 3; n is 0-6; p is 0-6; q is 0-6;
X is O, S, or NR6;
R6 is hydrogen or C1-C6 alkyl; each RA is independently selected from halogen, cyano, hydroxyl, -NRFRG, C1-C6 alkyl, C1-C6 alkoxy, and C3-C8 cycloalkyl; each RB, RC, RD, and RE are independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, and -NRFRG; and each R5A, R5B, RF, and RG are independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl.
2. The compound of Claim 1, wherein = is a single bond.
3. The compound of Claim 1, wherein = is a double bond, and R2 and R2B are absent.
4. The compound of any one of Claims 1-3, wherein R2A is hydrogen.
5. The compound of any one of Claims 1-3, wherein R2A is C1-C6 alkyl optionally substituted with 1-3 independently selected RB.
6. The compound of any one of Claims 1-3 or 5, wherein R2A is C1-C6 alkyl substituted with 1-3 independently selected RB.
7. The compound of any one of Claims 1-3, wherein R2A is C3-C8 cycloalkyl optionally substituted with 1-3 independently selected RB.
8. The compound of any one of Claims 1-3 or 7, wherein R2A is C3-C8 cycloalkyl substituted with 1-3 independently selected RB.
9. The compound of any one of Claims 1-8, wherein R2B is hydrogen
10. The compound of any one of Claims 1-8, wherein R2B is C1-C6 alkyl optionally substituted with 1-3 independently selected RB.
11. The compound of any one of Claims 1-8 or 10, wherein R2B is C1-C6 alkyl substituted with 1-3 independently selected RB.
12. The compound of any one of Claims 1-8, wherein R2B is C3-C8 cycloalkyl optionally substituted with 1-3 independently selected RB.
13. The compound of any one of Claims 1-8 or 12, wherein R2B is C3-C8 cycloalkyl substituted with 1-3 independently selected RB.
14. The compound of any one of Claims 1-2, wherein R2A and R2B, together with the carbon atom to which they are attached, together form a C=O group.
15. The compound of Claim 1, wherein is a single bond and R2A and R
Figure imgf000115_0002
2B are each hydrogen.
16. The compound of Claim 1, wherein
Figure imgf000115_0003
is a single bond and R2A and R2B, together with the carbon atom to which they are attached, together form a C=O group.
17. The compound of Claim 1, wherein
Figure imgf000115_0004
is a double bond, R2 and R2B are absent, and R2A is hydrogen, a C1-C6 alkyl optionally substituted with 1-3 independently selected RB, or a C3-C8 cycloalkyl optionally substituted with 1-3 independently selected RB.
18. The compound of Claim 1, wherein the compound is a compound of Formula (II):
Figure imgf000115_0001
or a pharmaceutically acceptable salt thereof, wherein R1, R2, Ring A, R3, R4, R5, m, n, p, q, X, R6, RA, RB, Rc, RD, RE, R5A, R5B, RF, and RG.
19. The compound of Claim 1, wherein the compound is a compound of Formula (III):
114
Figure imgf000116_0001
or a pharmaceutically acceptable salt thereof, wherein R1, R2, Ring A, R3, R4, R5, m, n, p, q, X, R6, RA, RB, Rc, RD, RE, R5A, R5B, RF, and RG
20. The compound of Claim 1, wherein the compound is a compound of
Formula (IV)
Figure imgf000116_0002
or a pharmaceutically acceptable salt thereof, wherein R1, R2A, Ring A, R3, R4, R5, m, n, p, q, X, R6, RA, RB, Rc, RD, RE, R5A, R5B, RF, and RG
21. The compound of Claim 20, wherein R2A is hydrogen.
22. The compound of Claim 20, wherein R2A is C1-C6 alkyl optionally substituted with 1-3 independently selected RB.
23. The compound of Claim 20 or 22, wherein R2A is C1-C6 alkyl substituted with 1-3 independently selected RB.
24. The compound of Claim 20, wherein R2A is C3-C8 cycloalkyl optionally substituted with 1-3 independently selected RB.
25. The compound of Claim 20 or 24, wherein R2A is C3-C8 cycloalkyl substituted with 1-3 independently selected RB.
26. The compound of any one of Claims 1-25, wherein R1 is a C6-C10 aryl substituted with 1-3 independently selected RA.
115
27. The compound of any one of Claims 1-26, wherein R1 is phenyl substituted with 1-3 independently selected RA.
28. The compound of any one of Claims 1-27, wherein R1 is phenyl substituted with 1 RA.
29. The compound of any one of Claims 1-27, wherein R1 is phenyl substituted with 2 independently selected RA.
30. The compound of any one of Claims 1-25, wherein R1 is a 5-10 membered heteroaryl optionally substituted with 1-3 independently selected RA.
31. The compound of any one of Claims 1-25 or 30, wherein R1 is a 5-10 membered heteroaryl optionally substituted with 1 RA.
32. The compound of any one of Claims 1-25 or 30, wherein R1 is a 5-10 membered heteroaryl optionally substituted with 2 independently selected RA.
33. The compound of any one of Claims 1-25 or 30, wherein R1 is a 5-10 membered heteroaryl optionally substituted with 3 independently selected RA.
34. The compound of any one of Claims 1-25 or 30, wherein R1 is a 5-6 membered heteroaryl optionally substituted with 1-2 independently selected RA.
35. The compound of any one of Claims 1-34, wherein each RA is independently selected from fluoro, chloro, bromo, cyano, hydroxyl, amino, C1-C3 alkyl, C1-C3 alkoxy, and C3-C6 cycloalkyl.
36. The compound of any one of Claims 1-35, wherein each RA is independently selected from chloro, bromo, cyano, and methoxy.
37. The compound of any one of Claims 1-36, wherein each RA is independently selected from chloro and bromo.
38. The compound of any one of Claims 1-37, wherein each RA is chloro.
39. The compound of any one of Claims 1-27 or 35-38, wherein R1 is
Figure imgf000117_0001
40. The compound of any one of Claims 1-35, wherein each RA is independently selected from chloro and cyano.
41. The compound of any one of Claims 1-35 and 40, wherein each RA is cyano.
116
42. The compound of any one of Claims 1-35 and 40-41, wherein R1 is
Figure imgf000118_0001
43. The compound of any one of Claims 1-25, wherein R1 is an unsubstituted C6-C10 aryl.
44. The compound of any one of Claims 1-25 or 43, wherein R1 is an unsubstituted phenyl.
45. The compound of any one of Claims 1-25, wherein R1 is an unsubstituted 5-10 membered heteroaryl.
46. The compound of any one of Claims 1-25 or 45, wherein R1 is an unsubstituted 5-6 membered heteroaryl.
47. The compound of any one of Claims 1-16, 18-19, or 21-46, wherein R2 is a C1-C6 alkyl optionally substituted with 1-3 independently selected RB.
48. The compound of any one of Claims 1-16, 18-19, or 21-46, wherein R2 is a C1-C6 alkyl substituted with 1-3 independently selected RB.
49. The compound of any one of Claims 1-16, 18-19, or 21-46, wherein R2 is a C3-C8 cycloalkyl optionally substituted with 1-3 independently selected RB.
50. The compound of any one of Claims 1-16, 18-19, or 21-46, wherein R2 is a C3-C8 cycloalkyl substituted with 1-3 independently selected RB.
51. The compound of any one of Claims 1-16, 18-19, or 21-50, wherein each RB is independently selected from fluoro, chloro, hydroxyl, cyano, C1-C3 alkyl, C1-C3 alkoxy, and -NRFRG.
52. The compound of any one of Claims 1-16, 18-19, or 21-51, wherein each RB is independently selected from fluoro, hydroxyl, C1-C3 alkoxy, and -NRFRG.
53. The compound of any one of Claims 1-16, 18-19, or 21-52, wherein each RB is independently selected from fluoro, hydroxyl, methoxy, and -NRFRG.
54. The compound of any one of Claims 1-16, 18-19, or 21-53, wherein each RF and RG are independently selected from hydrogen, C1-C3 alkyl, and C3-C6 cycloalkyl.
55. The compound of any one of Claims 1-16, 18-19, or 21-54, wherein each RF and RG are independently selected from hydrogen and C1-C3 alkyl.
56. The compound of any one of Claims 1-53, wherein each RB is independently selected from fluoro, hydroxyl, and methoxy.
57. The compound of any one of Claims 1-16, 18-19, or 21-46, wherein R2 is an unsubstituted C1-C6 alkyl.
58. The compound of any one of Claims 1-16, 18-19, 21-46, or 57, wherein R2 is methyl, ethyl, n-propyl, or isopropyl.
59. The compound of any one of Claims 1-16, 18-19, 21-46, or 57-58, wherein R2 is methyl.
60. The compound of any one of Claims 1-16, 18-19, or 21-46, wherein R2 is an unsubstituted C3-C8 cycloalkyl.
61. The compound of any one of Claims 1-16, 18-19, 21-46, or 60, wherein R2 is cyclopropyl or cyclobutyl.
62. The compound of any one of Claims 1-61, wherein R3 is hydrogen, halogen, or C1-C3 alkyl optionally substituted with 1-3 independently selected Rc.
63. The compound of any one of Claims 1-62, wherein R3 is hydrogen, halogen, or unsubstituted C1-C3 alkyl.
64. The compound of any one of Claims 1-63, wherein R3 is hydrogen.
65. The compound of any one of Claims 1-64, wherein R4 is hydrogen or Cl- C3 alkyl.
66. The compound of any one of Claims 1-65, wherein R4 is hydrogen.
67. The compound of any one of Claims 1-66, wherein X is NR6.
68. The compound of any one of Claims 1-67, wherein R6 is hydrogen or Cl- C3 alkyl.
69. The compound of any one of Claims 1-68, wherein R6 is hydrogen.
70. The compound of any one of Claims 1-66, wherein X is S.
71. The compound of any one of Claims 1-66, wherein X is O.
72. The compound of any one of Claims 1-71, wherein Ring A is a 5-10 membered heteroaryl.
73. The compound of any one of Claims 1-72, wherein Ring A is a 5, 6, or 10 membered heteroaryl.
118
74. The compound of any one of Claims 1-73, wherein Ring A is a 5 membered heteroaryl.
75. The compound of any one of Claims 1-74, wherein Ring A is a pyrazole.
76. The compound of any one of Claims 1-75, wherein Ring A is
Figure imgf000120_0003
77. The compound of any one of Claims 1-73, wherein Ring A is a 6 membered heteroaryl.
78. The compound of any one of Claims 1-73 and 77, wherein Ring A is a pyridine.
79. The compound of any one of Claims 1-73 and 77-78, wherein Ring A is
Figure imgf000120_0001
80. The compound of any one of Claims 1-71, wherein Ring A is a 4-10 membered heterocyclyl.
81. The compound of any one of Claims 1-71 and 80, wherein Ring A is a 5-10 membered heterocyclyl containing 2-4 heteroatoms selected from O and N.
82. The compound of any one of Claims 1-71 and 80-81, wherein Ring A is 5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine.
83. The compound of any one of Claims 1-82, wherein Ring A is attached to the fused tricyclic moiety of Formula (I) by a carbon atom in Ring A.
84. The compound of any one of Claims 1-71 or 80-83, wherein Ring A is
Figure imgf000120_0002
85. The compound of any one of Claims 1-75 or 80-82, wherein Ring A is attached to the fused tricyclic moiety of Formula (I) by a nitrogen atom in Ring A.
86. The compound of any one of Claims 1-71, wherein Ring A is a C6-C10 aryl.
87. The compound of any one of Claims 1-71 or 86, wherein Ring A is phenyl.
119
88. The compound of any one of Claims 1-87, wherein each R5 is independently halogen, C1-C6 alkyl, C3-C8 cycloalkyl, cyano, -(CH2)q-NR5AR5B, -(CH2)n-4-10 membered heterocyclyl optionally substituted with 1-3 independently selected RD, or - (CH2)p-5-10 membered heteroaryl optionally substituted with 1-3 independently selected RE.
89. The compound of any one of Claims 1-88, wherein each R5 is an independently selected -(CH2)q-NR5AR5B.
90. The compound of any one of Claims 1-89, wherein each R5A and R5B are independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl.
91. The compound of any one of Claims 1-90, wherein each R5A and R5B are independently selected from hydrogen and C1-C3 alkyl.
92. The compound of any one of Claims 1-91, wherein each R5A and R5B are independently selected from hydrogen and methyl.
93. The compound of any one of Claims 1-92, wherein R5A is hydrogen and R5B is methyl.
94. The compound of any one of claims 1-93, wherein q is 0.
95. The compound of any one of claims 1-93, wherein q is 1.
96. The compound of any one of claims 1-93, wherein q is 2, 3, 4, 5, or 6.
97. The compound of any one of Claims 1-88, wherein each R5 is independently
C1-C6 alkyl, -(CH2)n-4-10 membered heterocyclyl optionally substituted with 1-3 independently selected RD, or -(CH2)p-5-10 membered heteroaryl optionally substituted with 1-3 independently selected RE.
98. The compound of any one of Claims 1-88 and 97, wherein each R5 is independently -(CH2)n-4-10 membered heterocyclyl optionally substituted with 1-3 independently selected RD or -(CH2)p-5-10 membered heteroaryl optionally substituted with 1-3 independently selected RE.
99. The compound of any one of Claims 1-88 and 97-98, wherein each R5 is independently -(CH2)n-4-10 membered heterocyclyl optionally substituted with 1-3 independently selected RD.
120
100. The compound of any one of Claims 1-88 and 97-99, wherein each R5 is independently -(CH2)n-4-6 membered heterocyclyl optionally substituted with 1-3 independently selected RD.
101. The compound of any one of Claims 1-88 and 97-100, wherein each R5 is independently -(CH2)n-4-6 membered heterocyclyl optionally substituted with 1 RD.
102. The compound of any one of Claims 1-88 and 97-101, wherein each R5 is independently -(CH2)n-4-6 membered heterocyclyl substituted with 1 RD.
103. The compound of any one of Claims 1-102, wherein each RD is independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, and -NRFRG.
104. The compound of any one of Claims 1-103, wherein each RD is an independently selected C1-C6 alkyl.
105. The compound of any one of Claims 1-104, wherein each RD is methyl.
106. The compound of any one of Claims 1-88 or 97-101, wherein each R5 is independently a -(CH2)n-4-6 membered unsubstituted heterocyclyl.
107. The compound of any one of claims 97-106, wherein the heterocyclyl of R5 is selected from azetidine, pyrrolidine, 2-pyrrolidinone, piperidine, and piperazine.
108. The compound of claim 107, wherein the heterocyclyl of R5 is selected from
Figure imgf000122_0001
109. The compound of any one of Claims 1-108, wherein n is 0.
110. The compound of any one of Claims 1-108, wherein n is 1.
111. The compound of any one of Claims 1-108, wherein n is 2.
112. The compound of any one of Claims 1-108, wherein n is 3, 4, 5, or 6.
113. The compound of any one of Claims 1-88 or 97-98, wherein each R5 is independently
-(CH2)p-5-10 membered heteroaryl optionally substituted with 1-3 independently selected RE.
114. The compound of any one of Claims 1-88, 97-98, or 113, wherein each R5 is independently -(CH2)p-5-6 membered heteroaryl optionally substituted with 1-3 independently selected RE.
115. The compound of any one of Claims 1-88 or 97-98, or 113-114, wherein each R5 is independently -(CH2)P-5-6 membered heteroaryl optionally substituted with 1 RE.
116. The compound of any one of Claims 1-88 or 97-98, or 113-115, wherein each R5 is independently -(CH2)p-5-6 membered unsubstituted heteroaryl.
117. The compound of any one of Claims 1-88, 97-98, or 113-116, wherein p is 0.
118. The compound of any one of Claims 1-88, 97-98, or 113-116, wherein p is 1.
119. The compound of any one of Claims 1-88, 97-98, or 113-116, wherein p is
2.
120. The compound of any one of Claims 1-88, 97-98, or 113-116, wherein p is
3, 4, 5, or 6.
121. The compound of any one of Claims 1-120, wherein m is 1.
122. The compound of any one of Claims 1-120, wherein m is 2.
123. The compound of any one of Claims 1-120, wherein m is 3.
124. The compound of any one of Claims 1-87, wherein m is 0.
125. The compound of any one of Claims 1-71, wherein Ring A and R5 are absent.
126. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (II-A):
Figure imgf000123_0001
wherein:
RA1 and RA2 are independently selected from halogen, cyano, and C1-C6 alkoxy;
R2 is a C1-C6 alkyl optionally substituted with 1-3 independently selected RB or a C3-C8 cycloalkyl optionally substituted with 1-3 independently selected RB;
R5 is C1-C6 alkyl, C3-C8 cycloalkyl, -(CH2)n-4-10 membered heterocyclyl optionally substituted with 1-3 independently selected RD, or -(CH2)p-5-10 membered heteroaryl optionally substituted with 1-3 independently selected RE; n is 0-6; p is 0-6; and each RB, RD, and RE are independently selected from halogen, hydroxyl, C1-C3 alkyl, and C1-C3 alkoxy.
127. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (III- A):
Figure imgf000124_0001
wherein:
RA1 and RA2 are independently selected from halogen, cyano, and C1-C6 alkoxy;
R2 is a C1-C6 alkyl optionally substituted with 1-3 independently selected RB or a C3-C8 cycloalkyl optionally substituted with 1-3 independently selected RB;
R5 is C1-C6 alkyl, C3-C8 cycloalkyl, -(CH2)n-4-10 membered heterocyclyl optionally substituted with 1-3 independently selected RD, or -(CH2)p-5-10 membered heteroaryl optionally substituted with 1-3 independently selected RE; n is 0-6; p is 0-6; and each RB, RD, and RE are independently selected from halogen, hydroxyl, C1-C3 alkyl, and C1-C3 alkoxy.
128. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (IV-A):
Figure imgf000125_0001
wherein:
RA1 and RA2 are independently selected from halogen, cyano, and C1-C6 alkoxy;
R2A is hydrogen or C1-C6 alkyl;
R5 is C1-C6 alkyl, C3-C8 cycloalkyl, -(CH2)n-4-10 membered heterocyclyl optionally substituted with 1-3 independently selected RD, or -(CH2)p-5-10 membered heteroaryl optionally substituted with 1-3 independently selected RE; n is 0-6; p is 0-6; and each RD and RE are independently selected from halogen, hydroxyl, C1-C3 alkyl, and C1-C3 alkoxy.
129. The compound of claim 128, wherein R2A is hydrogen.
130. The compound of claim 128, wherein R2A is C1-C6 alkyl.
131. The compound of claim 128, wherein R2A is methyl.
132. The compound of any one of Claims 1-131, wherein the compound of
Formula (I) is present in the form of a pharmaceutically acceptable salt.
133. The compound of any one of Claims 1-131, wherein the compound of Formula (I) is present in the free base form.
134. The compound of Claim 1, wherein the compound is selected from the group consisting of the compounds in Table 1, or a pharmaceutically acceptable salt thereof.
135. A pharmaceutical composition comprising a compound of any one of Claims 1-134, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
136. A method for treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of Claims 1- 134 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Claim 135.
137. A method of treating a cancer in a subject in need thereof, the method comprising:
(a) identifying the cancer as having replication stress; and
(b) administering to the subject an effective amount of a compound of any one of Claims 1-134 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Claim 135.
138. The method of Claim 137, wherein identifying the cancer as having replication stress comprises staining for replication forks in a sample from the subject.
139. The method of Claim 137 or Claim 138, wherein identifying the cancer as having replication stress comprises detecting a biomarker of replication stress in a sample from the subject.
140. The method of Claim 139, wherein the biomarker of replication stress comprises Ki-67, Cyclin E, POLD3, yH2AX, FANCD2, or a combination thereof.
141. The method of Claim 139 or Claim 140, wherein the biomarker of replication stress comprises pH2AX Serl39, pATR Thrl989, pCHKl Ser345, pRPA32 Ser33, or a combination thereof.
142. The method of any one of Claims 139-141, wherein the biomarker of replication stress comprises an activated oncogene.
143. The method of any one of Claims 139-142, wherein the biomarker of replication stress comprises an inactivated tumor suppressor gene.
144. A method of treating a cancer in a subject in need thereof, the method comprising: administering an effective amount of a compound of any one of Claims 1-134 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Claim 135 to a subject identified as having a cancer having replication stress.
125
145. A method of treating a cancer in a subject in need thereof, the method comprising:
(a) identifying the cancer as having an inactivated tumor suppressor gene; and
(b) administering to the subject an effective amount of a compound of any one of Claims 1-134 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Claim 135.
146. A method of treating a cancer in a subject in need thereof, the method comprising: administering an effective amount of a compound of any one of Claims 1-134 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Claim 135 to a subject identified as having a cancer having an inactivated tumor suppressor gene.
147. The method of Claim 145 or Claim 146, wherein inactivated tumor suppressor gene comprises an inactivation selected from the group consisting of a deletion of the gene, an inactivating mutation in the protein product of the gene, an inactivating translocation in the protein product of the gene, a transcriptional silencing of the gene, an epigenetic alteration of the gene, degradation of mRNA products of the gene, degradation of protein products of the gene, and combinations thereof.
148. The method of any one of Claims 145-147, wherein the tumor suppressor gene is selected from the group consisting of p53, RBI, CDKN2A, BRCA1, BRCA2, FBXW7, SETD2, NOTCH 1, and a combination thereof.
149. The method of any one of Claims 145-148, wherein the inactivated tumor suppressor gene comprises a mutation in the protein product of a p53 gene.
150. The method of any one of Claims 145-149, wherein the the inactivated tumor suppressor gene comprises a deleted p53 gene.
151. The method of any one of Claims 145-150, wherein the inactivated tumor suppressor gene comprises a mutation in the protein product of a CDKN2A gene.
152. The method of any one of Claims 145-151, wherein the inactivated tumor suppressor gene comprises a mutation in the protein product of a NOTCH1 gene.
153. The method of any one of Claims 145-152, wherein the inactivated tumor suppressor gene comprises a deleted FBXW7 gene.
126
154. The method of any one of Claims 145-153, wherein the inactivated tumor suppressor gene comprises a mutation in the protein product of a FBXW7 gene.
155. The method of any one of Claims 145-154, wherein the inactivated tumor suppressor gene comprises a mutation in the protein product of a RBI gene.
156. The method of any one of Claims 145-155, wherein the inactivated tumor suppressor gene comprises a deleted BRCA1 gene.
157. The method of any one of Claims 145-156, wherein the inactivated tumor suppressor gene comprises a mutation in the protein product of a BRCA1 gene.
158. The method of any one of Claims 145-157, wherein the inactivated tumor suppressor gene comprises a BRCA1 gene with a hypermethylated promoter region.
159. The method of any one of Claims 145-158, wherein the inactivated tumor suppressor gene comprises a deleted BRCA2 gene.
160. The method of any one of Claims 145-159, wherein the inactivated tumor suppressor gene comprises a mutation in the protein product of a BRCA2 gene.
161. The method of any one of Claims 145-160, wherein the inactivated tumor suppressor gene comprises a BRCA2 gene with a hypermethylated promoter region.
162. The method of any one of Claims 145-161, wherein the inactivated tumor suppressor gene comprises a mutation in the protein product of a NOTCH1 gene.
163. The method of any one of Claims 145-162, wherein the inactivated tumor suppressor gene comprises a mutation in the protein product of a SETD2 gene.
164. A method of treating a cancer in a subject in need thereof, the method comprising:
(a) identifying the cancer as having an activated oncogene; and
(b) administering to the subject an effective amount of a compound of any one of Claims 1-134 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Claim 135.
165. A method of treating a cancer in a subject in need thereof, the method comprising: administering an effective amount of a compound of any one of Claims 1-134 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Claim 135 to a subject identified as having a cancer having an activated oncogene.
127
166. The method of Claim 164 or Claim 165, wherein the activated oncogene has an activation selected from the group consisting of an amplification of the oncogene, an activating mutation of the protein product of the oncogene, an activating translocation of the protein product of the oncogene, transcriptional activation of the oncogene, epigenetic alteration of the oncogene, overexpression of the protein product of the oncogene, and combinations thereof.
167. The method of any one of Claims 164-166, wherein the oncogene is selected from the group consisting of cyclin E, CDC25A, Myc, a RAS gene, and combinations thereof.
168. The method of Claim 167, wherein the RAS gene comprises a KRAS gene.
169. The method of Claim 167 or Claim 168, wherein the RAS gene comprises an NRAS gene.
170. The method of any one of Claims 167-169, wherein the RAS gene comprises an HRAS gene.
171. The method of any one of Claims 164-170, wherein the activated oncogene comprises an amplified cyclin E gene.
172. The method of any one of Claims 164-171, wherein the activated oncogene comprises an overexpression of the protein product of the CDC25A gene.
173. The method of any one of Claims 164-172, wherein the activated oncogene comprises an amplified Myc gene.
174. The method of any one of Claims 164-173, wherein the activated oncogene comprises an activating translocation in the protein product of a Myc gene.
175. The method of any one of Claims 164-174, wherein the activated oncogene comprises a transcriptionally activated Myc gene.
176. The method of any one of Claims 164-175, wherein the activated oncogene comprises a mutation in the protein product of a RAS gene.
177. The method of Claim 176, wherein the mutated RAS gene comprises a mutation at position G12 of the protein product of the RAS gene.
178. The method of Claim 176 or 177, wherein the mutated RAS gene comprises a mutation at position G13 of the protein product of the RAS gene.
128
179. The method of any one of Claims 176-178, wherein the mutated RAS gene comprises a mutation at position Q61 of the protein product of the RAS gene.
180. The method of any one of Claims 176-179, wherein the RAS gene comprises a KRAS gene.
181. The method of any one of Claims 137-180, wherein the method further comprises administering to the subject a DNA-damaging agent, a DNA repair inhibiting agent, radiation, or a combination thereof.
182. The method of Claim 181, wherein the DNA-damaging agent is selected from the group consisting of a platinum-based chemotherapy, an alkylating agent, a nucleobase, nucleoside, or nucleotide analog, and combinations thereof.
183. The method of Claim 182, wherein the platinum-based chemotherapy comprises carboplatin, cisplatin, oxaplatin, or a combination thereof.
184. The method of Claim 182 or Claim 183, wherein the alkylating agent comprises cyclophosphamide, carmustine, busulfan, procarbazine, dacarbazine, temozoloamide, thiotepa, mitomycin C, or combinations thereof.
185. The method of any one of Claims 182-184, wherein the nucleobase, nucleoside, or nucleotide analog comprises fluorouracil, cytarabine, gemcitabine, azacitidine, decitabine, or combinations thereof.
186. The method of any one of Claims 181-185, wherein the DNA repair inhibiting agent is selected from the group consisting of a topoisomerase I inhibitor, a topoisomerase II inhibitor, a PARP inhibitor, an ATR inhibitor, a Chk inhibitor, a DNA- dependent protein kinase (DNA-PK) inhibitor, an ATM inhibitor, an Aurora kinase inhibitor, and a combination thereof.
187. The method of Claim 186, wherein the topoisomerase I inhibitor comprises topotecan, irinotecan, belotecan, camptothecin, or combinations thereof.
188. The method of Claim 186 or Claim 187, wherein the topoisomerase II inhibitor comprises etoposide, tenoposide, doxorubicin, daunorubicin, epirubicin, idarubacin, or combinations thereof.
189. The method of any one of Claims 186-188, wherein the PARP inhibitor comprises olaparib, niraparib, rucaparib, talazoparib, veliparib, or combinations thereof.
129
190. The method of any one of Claims 186-189, wherein the ATR inhibitor comprises AZD6738, BAY1895344, M6620, or a combination thereof.
191. The method of any one of Claims 186-190, wherein the Chkl inhibitor comprises prexasertib, GDC-0575, SCH 900776, SRA737, or a combination thereof.
192. The method of any one of Claims 186-191, wherein the DNA-dependent protein kinase (DNA-PK) inhibitor comprises AZD7648, M3814, LY294002, nedisertib, samotolisib, and a combination thereof.
193. The method of any one of Claims 186-192, wherein the ATM inhibitor comprises KU55933, AZD0156, AZD1390, dactosilib, berzosertib, and a combination thereof.
194. The method of any one of Claims 186-193, wherein the Aurora kinase inhibitor comprises LY3295668, ZM447439, tozasertib, hesparadin, alisertib, MLN8054, and a combination thereof.
195. A method of treating a cancer in a subject in need thereof, the method comprising:
(i) administering to the subject an effective amount of a therapy comprising:
(a) a DNA-damaging agent;
(b) a DNA repair inhibiting agent;
(c) radiation;
(d) (a) and (b);
(e) (a) and (c);
(f) (b) and (c);
(g) (a), (b), and (c); and
(ii) after (i), administering to the subject an effective amount of a compound of any one of Claims 1-134 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Claim 135.
196. A method of treating a cancer in a subject in need thereof, the method comprising: administering an effective amount of a compound of any one of Claims 1-134 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Claim 135 to a subject previously administered one or more doses of a therapy comprising:
130 (a) a DNA-damaging agent;
(b) a DNA repair inhibiting agent;
(c) radiation;
(d) (a) and (b);
(e) (a) and (c);
(f) (b) and (c);
(g) (a), (b), and (c).
197. The method of Claim 195 or Claim 196, wherein the therapy is continued to be administered to the subject as combination therapy with the compound of any one of Claims 1-134 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to Claim 135.
198. A method of treating a cancer in a subject in need thereof, the method comprising: administering to the subject:
(i) an effective amount of a compound of any one of Claims 1-134 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Claim 135; and
(ii) an effective amount of a therapy comprising:
(a) a DNA-damaging agent;
(b) a DNA repair inhibiting agent;
(c) radiation;
(d) (a) and (b);
(e) (a) and (c);
(f) (b) and (c);
(g) (a), (b), and (c).
199. The method of Claim 197 or Claim 198, wherein the compound of any one of Claims 1-134 or a pharmaceutical salt thereof, or a pharmaceutical composition according to Claim 135 and the therapy are administered simultaneously as separate dosages.
200. The method of Claim 197 or Claim 198, wherein the compound of any one of Claims 1-134 or a pharmaceutical salt thereof, or a pharmaceutical composition
131 according to Claim 135 and the therapy are administered separate dosages sequentially in any order.
201. The method of any one of Claims 195-200, wherein the DNA-damaging agent is selected from the group consisting of a platinum-based chemotherapy, an alkylating agent, a nucleobase, nucleoside, or nucleotide analog, and combinations thereof.
202. The method of Claim 201, wherein the platinum-based chemotherapy comprises carboplatin, cisplatin, oxaplatin, or a combination thereof.
203. The method of Claim 201 or Claim 202, wherein the alkylating agent comprises cyclophosphamide, carmustine, busulfan, procarbazine, dacarbazine, temozoloamide, thiotepa, mitomycin C, or combinations thereof.
204. The method of any one of Claims 201-203, wherein the nucleobase, nucleoside, or nucleotide analog comprises fluorouracil, cytarabine, gemcitabine, azacitidine, decitabine, or combinations thereof.
205. The method of any one of Claims 195-204, wherein the DNA repair inhibiting agent is selected from the group consisting of a topoisomerase I inhibitor, a topoisomerase II inhibitor, a PARP inhibitor, an ATR inhibitor, a Chk inhibitor, a DNA- dependent protein kinase (DNA-PK) inhibitor, an ATM inhibitor, an Aurora kinase inhibitor, and a combination thereof.
206. The method of Claim 205, wherein the topoisomerase I inhibitor comprises topotecan, irinotecan, belotecan, camptothecin, or combinations thereof.
207. The method of Claim 205 or Claim 206, wherein the topoisomerase II inhibitor comprises etoposide, tenoposide, doxorubicin, daunorubicin, epirubicin, idarubacin, or combinations thereof.
208. The method of any one of Claims 205-207, wherein the PARP inhibitor comprises olaparib, niraparib, rucaparib, talazoparib, veliparib, or combinations thereof.
209. The method of any one of Claims 205-208, wherein the ATR inhibitor comprises AZD6738, BAY1895344, M6620, or a combination thereof.
210. The method of any one of Claims 205-209, wherein the Chkl inhibitor comprises prexasertib, GDC-0575, SCH 900776, SRA737, or a combination thereof.
132
211. The method of any one of Claims 205-210, wherein the DNA-dependent protein kinase (DNA-PK) inhibitor comprises AZD7648, M3814, LY294002, nedisertib, samotolisib, and a combination thereof.
212. The method of any one of Claims 205-211, wherein the ATM inhibitor comprises KU55933, AZD0156, AZD1390, dactosilib, berzosertib, and a combination thereof.
213. The method of any one of Claims 205-212, wherein the Aurora kinase inhibitor comprises LY3295668, ZM447439, tozasertib, hesparadin, alisertib, MLN8054, and a combination thereof.
214. The method of any one of Claims 137-213, further comprising administering an additional therapy or therapeutic agent to the subject.
215. The method of Claim 214, wherein the additional therapy or therapeutic agent is selected from radiotherapy, cytotoxic chemotherapeutics, kinase-targeted therapeutics, kinase-targeted therapeutics, apoptosis modulators, signal transduction inhibitors, immune-targeted therapies, and angiogenesis-targeted therapies.
216. The method of Claim 215, wherein the additional therapy or therapeutic agent is an immune-targeted therapy.
217. The method of Claim 216, wherein the immune-targeted therapy is an immunotherapy.
218. A method for inhibiting mammalian cell proliferation, comprising contacting the mammalian cell with a compound of any one of Claims 1-134 or a pharmaceutically acceptable salt thereof.
219. A method for inducing mitotic collapse in a mammalian cell, comprising contacting the mammalian cell with a compound of any one of Claims 1-134 or a pharmaceutically acceptable salt thereof.
220. The method of Claim 218 or 219, wherein the contacting occurs in vivo.
221. The method of Claim 218 or 219, wherein the contacting occurs in vitro.
222. The method of any one of Claims 218-221, wherein the mammalian cell is a mammalian immune cell.
223. The method of any one of Claims 218-222, wherein the mammalian cell is a mammalian cancer cell.
133
224. The method of Claim 223, wherein the mammalian cancer cell is a mammalian cancer cell having replicative stress.
225. The method of Claim 223 or Claim 224, wherein the mammalian cancer cell has an inactivated tumor suppressor gene.
226. The method of any one of Claims 223-225, wherein the mammalian cancer cell has an activated oncogene.
227. The method of any one of Claims 223-226, further comprising contacting the mammalian cell with a DNA-damaging agent, a DNA repair inhibitor, radiation, or a combination thereof.
134
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