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WO2025122501A1 - Malémides de benzothiophène-3-yl et benzosélénophène-3-yl (hétéroaryle biclylique) en tant qu'inhibiteurs de gsk-3 - Google Patents

Malémides de benzothiophène-3-yl et benzosélénophène-3-yl (hétéroaryle biclylique) en tant qu'inhibiteurs de gsk-3 Download PDF

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WO2025122501A1
WO2025122501A1 PCT/US2024/058269 US2024058269W WO2025122501A1 WO 2025122501 A1 WO2025122501 A1 WO 2025122501A1 US 2024058269 W US2024058269 W US 2024058269W WO 2025122501 A1 WO2025122501 A1 WO 2025122501A1
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compound
salt
formula
alkyl
gsk
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Werner Tueckmantel
Alan Kozikowski
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Mayo Foundation for Medical Education and Research
Mayo Clinic in Florida
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Mayo Foundation for Medical Education and Research
Mayo Clinic in Florida
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D421/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms
    • C07D421/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D497/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D497/04—Ortho-condensed systems

Definitions

  • the present invention relates to compounds which are inhibitors of protein kinases and in particular are inhibitors of glycogen synthase kinase 3 (GSK-3).
  • GSK-3 glycogen synthase kinase 3
  • CROSS-REFERENCE TO RELATED APPLICATIONS [0002] The benefit of priority of U.S. Provisional Application 63/605,555 filed on December 3, 2023, is hereby claimed and the disclosure thereof is incorporated herein by reference in its entirety.
  • Protein kinases of which there are over 500 known to date, mediate intracellular signal transduction. They do this by effecting a phosphorylation event in response to extracellular and other stimuli to cause a variety of cellular responses to occur inside the cell. Examples of such stimuli include environmental and chemical stress signals (e.g. osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxin, H 2 O 2 ), cytokines (e.g.
  • IL-1 interleukin-1
  • TNF- ⁇ tumor necrosis factors
  • growth factors e.g. granulocyte macrophage-colony-stimulating factor (GM-CSF) and fibroblast growth factor (FGF)
  • GM-CSF granulocyte macrophage-colony-stimulating factor
  • FGF fibroblast growth factor
  • An extracellular stimulus may effect one or more cellular responses related to cell growth, migration, differentiation, secretion of hormones, activation of transcription factors, muscle contraction, glucose metabolism, control of protein synthesis, and regulation of cell cycle.
  • diseases include autoimmune diseases, inflammatory diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, central nervous system disorders, Alzheimer's disease, or hormone-related diseases.
  • Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase comprised of ⁇ and ⁇ isoforms that are each encoded by distinct genes (Coghlan et al., Chemistry & Biology 2000, 7, 793-803; Kim and Kimmel, Curr. Opinion Genetics Dev.2000, 10, 508-514).
  • GSK-3 has been implicated in various diseases including diabetes, CNS disorders such as manic depressive disorder, neurodegenerative diseases, such as Alzheimer's disease and acute neuronal trauma (stroke and head trauma), cardiomyocyte hypertrophy, and cancer (WO 99/65897; WO 00/38675; and Haq et al., J. Cell Biol.2000, 151, 117). Inhibition of GSK-3 can also be useful in the treatment and prevention of disorders including Fragile X syndrome, autism, mental retardation, schizophrenia, and Down's Syndrome. These diseases may be caused by, or result in, the abnormal operation of certain cell signaling pathways in which GSK-3 plays a role. GSK-3 has been found to phosphorylate and modulate the activity of a number of regulatory proteins.
  • glycogen synthase which is the rate limiting enzyme necessary for glycogen synthesis
  • the microtubule associated protein Tau the gene transcription factor 6-catenin
  • the translation initiation factor e1F2B as well as ATP citrate lyase
  • axin heat shock factor-1
  • c-Jun c-Myc
  • c-Myb c-Myb
  • CEPBn CEPBn
  • GSK-3 Glycogen synthase kinase 3 (GSK-3) inhibitors: a patent update (2016- 2019)" Expert Opinion on Therapeutic Patents 2020, 30(11), 863-872 provide recent reviews of GSK-3 inhibitors.
  • GSK-3 mediated pathway that is relevant for the treatment of type II diabetes, insulin-induced signaling leads to cellular glucose uptake and glycogen synthesis. Along this pathway, GSK-3 is a negative regulator of the insulin-induced signal.
  • glycogen synthesis and glucose uptake Normally, the presence of insulin causes inhibition of GSK-3 mediated phosphorylation and deactivation of glycogen synthase.
  • the inhibition of GSK-3 leads to increased glycogen synthesis and glucose uptake (Klein et al., PNAS, 1996, 93, 8455-8459; Cross et al., Biochem. J.1994, 303, 21-26; Cohen, Biochem. Soc. Trans.1993, 21, 555-567; Massillon et al., Biochem. J.1994, 299,123-128).
  • glycogen synthesis and glucose uptake fail to increase despite the presence of relatively high blood levels of insulin.
  • GSK-3 activity has also been associated with Alzheimer's disease. Alzheimer's disease is among the most important health care problems in the world. The past decade has seen the adoption of the first class of medications, the cholinesterase inhibitors, effective in improving cognitive symptoms in Alzheimer's disease. These drugs provide symptomatic relief; effective disease-modifying therapy remains a major, elusive goal.
  • Alzheimer's disease is a progressive dementia which develops in late middle ages (45 to 65 years old), and its etiological changes are shrinkage of cerebral cortex due to a neuronal cell loss and degeneration of the neurons while, from the pathological view, many senile plaques and neurofibrillary tangles are noted in the brain.
  • senile dementia There is no pathologically substantial difference between the disease and senile dementia caused by the so-called natural aging which develops in the senile period of 65 years and older ages and, therefore, this disease is called senile dementia of Alzheimer type.
  • Alzheimer's disease is characterized by the well-known ⁇ -amyloid peptide and the formation of intracellular neurofibrillary tangles.
  • the neurofibrillary tangles contain hyperphosphorylated Tau protein, where Tau is phosphorylated on abnormal sites.
  • GSK-3 has been shown to phosphorylate these abnormal sites in cell and animal models.
  • inhibition of GSK-3 has been shown to prevent hyperphosphorylation of Tau in cells (Lovestone et al., Current Biology 1994, 4, 1077-86; Brownlees et al., Neuroreport 1997, 8, 3251-3255).
  • GSK- 3 contributes to the hyperphosphorylation of tau protein, the main component of neurofibrillary tangles (NFTs), one of the hallmarks of AD.
  • GSK-3 is further involved in the regulation of different neuronal processes that are dysregulated during AD pathogenesis, such as the generation of amyloid- ⁇ (A ⁇ ) peptide or A ⁇ -induced cell death, axonal transport, cholinergic function, and adult neurogenesis or synaptic function. Therefore, it is believed that GSK-3 may be involved in processes that lead to the progression of Alzheimer's disease (Sayas, C. L. and Avila, J. "GSK-3 and Tau: A key duet in Alzheimer's disease", Cells 2021, 10(4), 721).
  • ⁇ -catenin Another substrate of GSK-3 is ⁇ -catenin, which is degraded after phosphorylation by GSK-3.
  • Reduced levels of ⁇ -catenin have been reported in schizophrenic patients and have also been associated with other diseases related to increase in neuronal cell death (Zhong et al., Nature 1998, 395, 698-702; Takashima et al., PNAS 1993, 90, 7789-93; Pei et al., J. Neuropathol. Exp.1997, 56, 70-78).
  • GSK-3 may further contribute to their therapeutic efficacy as mood disorder drugs.
  • Certain inhibitors of GSK-3 have been shown to exert a neuroprotective action in vitro (Kozikowski, A. P.; Gaysina, I. N.; Petukhov, P. A.; Sridhar, J; King, L; Blond, S. Y.; Duka, T.; Rusnak, M.; Sidhu, A., ChemMedChem 2006, 1(2), 256-266.)
  • This work employed a cellular model of Parkinson's disease.
  • GSK-3 thus appears to offer a therapeutic target for multiple neurodegenerative diseases (Wang C. et al. Biochem Pharmacol.2023, 218, 115923).
  • McBride, S. M. et al. (“Pharmacological rescue of synaptic plasticity, courtship behavior and mushroom body defects in a Drosophila model of fragile X syndrome" Neuron 2005, 45, 753764) report that a Drosophila model of Fragile X can be treated with lithium or metabotropic glutamate receptor (MGIuR) antagonists (see also: Raymond, F. L. and Tarpey, P. (2006) "The genetics of mental retardation” Human Molecular Genetics 2006, 15 (Review Issue No.2) R110-R116).
  • MMIuR metabotropic glutamate receptor
  • Nos.6916821 and 6890931 report the use of Group I MGIuR antagonists for the treatment and prevention of disorders, including Fragile X, autism, mental retardation, schizophrenia, and Down's Syndrome, as well as for the treatment of epilepsy and anxiety in individuals having Fragile X syndrome, autism, mental retardation, schizophrenia, and Down's Syndrome.
  • inhibitors of GSK-3 mimic the therapeutic action of lithium and as such are expected to be beneficial in the treatment of Fragile X syndrome and related disorders.
  • GSK-3 is turned on by glutamate signaling, indicating that antagonists of MGIuR can affect GSK-3.
  • GSK-3 inhibitors are useful in the treatment of disorders of conditions that respond to administration of lithium. GSK-3 inhibitors are also indicated to be useful for reducing the motility of mammalian spermatozoa.
  • WO 00/38675 reports certain bisindolemaleimides, indolylarylmaleimides, and indolocarbazoles as inhibitors of GSK-3. Such inhibitors are indicated to be useful in the treatment of diabetes, chronic neurodegenerative conditions, manic depression, mood disorders, such as schizophrenia, neurotraumatic diseases, such as acute stroke, hair loss, and cancer.
  • WO 02/10158 Hoffman-LaRoche
  • U.S. Pat. No.6479490 report 3-indolyl-4- phenyl-1H-pyrrole-2,5-dione derivatives as inhibitors of GSK-3.
  • GSK-3 inhibition reduces the level of CD4+ T-helper 2 cells (Th2). These cells produce cytokines and promote IgE production and eosinophil differentiation. Th2-specific cytokines are important in the pathogenesis of allergies and asthma. This report indicates that inhibitors of GSK-3 are useful in the treatment of allergies and asthma.
  • WO 05/002552 (Astex Technology) reports certain compounds as inhibitors of cyclin dependent kinase, GSK-3 kinase, and Aurora kinase. GSK-3 kinase is reported to be associated with embryonic development, protein synthesis, cell proliferation and differentiation, microtubule dynamics, cell motility, and cellular apoptosis.
  • GSK-3 kinase is indicated to be implicated in diabetes, cancer, Alzheimer's disease, Huntington's disease, stroke, epilepsy, motor neuron diseases, and head trauma, and as such inhibitors of GSK-3 kinase are useful in the treatment of such disease states.
  • inhibitors of GSK-3 kinases are reported to be useful in the treatment of cancer, particularly colorectal cancer, and in the treatment of diseases or conditions characterized by neuronal apoptosis to limit and/or prevent neurodegeneration.
  • WO 05/111018 (Aventis) reports certain pyridazinone derivatives as inhibitors of GSK-3.
  • neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, frontoparietal dementia, corticobasal degeneration, and Pick's disease
  • stroke cranial and or spinal trauma
  • peripheral neuropathies obesity, metabolic disease, type II diabetes, essential hypertension, atherosclerosis, cardiovascular diseases, polycystic ovary syndrome, syndrome X, and immunodeficiency.
  • Published U.S. application U.S.2003/0176484 reports the use of inhibitors of GSK- 3 in a mammal to promote bone formation, increase bone mineral density, reduce fracture rate, increase fracture healing rate, increase cancellous bone formation, increase new bone formation, and to treat osteoporosis.
  • Published U.S. application U.S.2006/0217368 reports GSK-3 inhibitors for nerve regeneration and as agents for the promotion of neuropoiesis of neural stem cells.
  • Drugs of the invention are reported to be useful as therapeutics for neurological diseases such as Parkinson's disease, Alzheimer's disease, Down's disease, cerebrovascular disorder, cerebral stroke, spinal cord injury, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, epilepsy, anxiety disorder, schizophrenia, depression, and manic depressive psychosis.
  • neurological diseases such as Parkinson's disease, Alzheimer's disease, Down's disease, cerebrovascular disorder, cerebral stroke, spinal cord injury, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, epilepsy, anxiety disorder, schizophrenia, depression, and manic depressive psychosis.
  • Published U.S. application 20050075276 reports the use of inhibitors of GSK-3 ⁇ or ⁇ to augment CD28 dependent T-cell responses.
  • the invention is directed at least in part to a method of enhancing CD28 mediated and dependent T-cell responses against viral, bacterial, fungal, or prion infections.
  • GSK-3 inhibitors are indicated to be useful in the treatment of viral, bacterial, fungal, or prion infections.
  • U.S. Pat. Nos.7045519, 7037918, 6989382, 6977262, 6949547, 6800632, 6780625, 6608063, 6489344, 6479490, and 6417185 relate to GSK-3 inhibitors.
  • Published U.S. Patent applications U.S.2005/0234120, 2004/0052822, 2004/0138273, and 2004/0210063 relate to GSK-3 inhibitors.
  • US patent 2017/0165230 Al relates to the use of GSK-3 inhibitors to promote immunity, including cytotoxic T cell immunity in subjects in need thereof, especially subjects with chronic conditions wherein inhibiting PD-1 expression and/or blockade or T cell up-regulation is therapeutically desirable such as cancer and infectious conditions.
  • EP 1224932 relates to certain indolylmaleimides which are reported to be cell death inhibitors useful as pharmaceuticals or as a preservative for organs, tissues, or cells. Compounds of formula: are reported, where the variables are defined in the patent application.
  • R 4 can be selected from an aryl group, other than 3-indolyl, which aryl group can be substituted.
  • Certain compounds including com- pounds in which Ar is 7- or 4-benzofuranyl are reported to be potent and selective GSK3 inhibitors.
  • Data for the selectivity of inhibition of GSK-3 compared to inhibition of CDK2, CDK4, and PKC II kinases are reported.
  • Data are reported for a single compound where Ar is 3-benzofuranyl and where R is H. This compound is reported to have a GSK3 IC50 of 64 nM with a ratio of IC50 at PKC ⁇ II to IC50 at GSK3 of 37.
  • U.S. Pat. No.5721245 reports compounds of formula: where among others X and Y are O, R 1 and R 2 taken together are a group of the formula - (CH 2 ) n -, or R 1 and R 7 taken together are a group of the formula -(CH 2 ) n -, Z is N or CH, n is an integer from 1 to 5, m is an integer from 0 to 5, and R 3 is an aryl or aromatic heterocyclic group.
  • Aromatic heterocyclic is defined as "a 5-membered or 6-membered heterocyclic aromatic group which can optionally carry a fused benzene ring" which can be substituted or unsubstituted.
  • heterocyclic groups are reported to be 2-thienyl, 3-thienyl, 3- benzothienyl, 3-benzofuranyl, 2-pyrrolyl, 3-indolyl, and the like.
  • Compounds are reported to be useful in the control or prevention of inflammatory, immunological, oncological, bronchopulmonary, and cardiovascular disorders or in the treatment of asthma or AIDS.
  • the compounds are further reported to be protein kinase inhibitors and as such inhibitors of cellular processes.
  • the patent refers in particular to inhibition of protein kinase C.
  • WO 03/076398 and corresponding US 20050288321 report GSK-3 kinase inhibitors having the structure: where Ar is benzofur-7-yl optionally substituted in the phenyl ring with R 8 and R 9 , 1-(R 7 )- indol-4-yl, benzofur-4-yl, quinolin-5-yl, quinolin-7-yl, isoquinolin-5-yl, isoquinolin-3-yl, imidazo[1,2-a]pyridin-3-yl, imidazo[1,2-a]pyridin-5-yl, furo[3,2-c]pyridin-7-yl, benzo[1,3]dioxol- 4-yl, 2,2-difluorobenzo[1,3]dioxol-4-yl, or 2,3-dihydrobenzofur-7-yl optionally substituted in the phenyl ring with R 8 and R 9 and in the dihydrofuryl ring
  • U.S. Pat. No.5,057,614 reports compounds of Formula: where R 2 is hydrogen among other groups, and R 1 is hydrogen, alkyl, aryl, aralkyl, hydroxyalkyl, and haloalkyl among other groups. These compounds are said to be inhibitors of protein kinases useful in the treatment of illnesses including inflammatory, immunological, bronchopulmonary, and cardiovascular disorders where among others X and Y are O, and R 3 is a carbocyclic or heterocyclic aromatic group.
  • the R 3 heterocyclic aromatic group is reported to be a 5- or 6-membered heterocyclic aromatic group which can optionally carry a fused benzene ring and which can be unsubstituted or substituted, for example, with one or more, preferably one to three, substituents selected from halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, mono- or dialkylamino, alkylthio, alkylsulphinyl, and alkylsulphonyl.
  • R 3 heterocyclic aromatic groups are 2- or 3- thienyl, 3-benzothienyl, 1-methyl-2-pyrrolyl, 1-benzimidazolyl, 3-indolyl, 1- or 2-methyl-3- indolyl, 1-(methoxymethyl)-3-indolyl, 1-(1-methoxyethyl)-3-indolyl, 1-(2-hydroxypropyl)-3- indolyl, 1-(4-hydroxybutyl)-3-indolyl, 1-[1-(2-hydroxyethylthio)ethyl]-3-indolyl, 1 -[1 -(2- mercaptoethylthio)ethyl]-3-indolyl, 1 -(1 -phenylthioethyl)-3-indolyl, 1-[1- (carboxymethylthio)ethyl]-3-indolyl, and 1-benzyl-3-indolyl, 1-(
  • Inhibitors of GSK-3 have wide application as therapeutics and are in general important targets for pharmaceutical applications.
  • a number of synthetic GSK-3 inhibitors have been reported, however, there remains a clear need for GSK-3 inhibitors that are potent, selective, safe, and effective, and which exhibit minimal undesired side-effects.
  • This disclosure relates at least in part to compounds containing an indole, a benzothiophene, a benzofuran, or a benzoselenophene ring system attached to a maleimide, which serve as protein kinase inhibitors and particularly those which are GSK-3 inhibitors.
  • ring A is a 5-membered heterocycle or heteroaryl comprising 1 or 2 ring nitrogen heteroatoms
  • R N1 is independently H or C 1-3 alkyl
  • n is 0, 1, or 2
  • each R A when present, is independently C 1-3 alkyl, C 2-6 alkenyl, O-C 2-6 alkenyl, C 2-6 alkynyl, O-C 2-6 alkynyl, Cyc 1 , or O-Cyc 1
  • Cyc 1 is C 3-8 cycloalkyl, C 6-10 aryl, 5-8 membered heterocycle or 5-8 membered heteroaryl, wherein the heterocycle and heteroaryl each comprises 1, 2, or 3 ring heteroatoms independently
  • GSK-3 inhibitors are useful as GSK-3 inhibitors for the treatment of any diseases, conditions, symptoms, or disorders associated with GSK-3 and particularly those associated with GSK-3 ⁇ .
  • GSK-3 ⁇ inhibitors of this disclosure exhibit the ability to pass the brain-blood barrier as assessed in animal models.
  • Other aspects of the disclosure are pharmaceutical compositions comprising a compound of the disclosure in combination with a pharmaceutically acceptable carrier wherein the compound is present in the composition in a therapeutically effective amount.
  • the disclosure provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of this disclosure which is a GSK-3 inhibitor in combination with a pharmaceutically acceptable carrier.
  • the disclosure provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of this disclosure which is a GSK-3 ⁇ inhibitor in combination with a pharmaceutically acceptable carrier.
  • medicaments can include a compound of Formula 1 or a pharmaceutically acceptable salt, ester, or solvate thereof for use in treatment of a GSK-3-related or a GSK-3 ⁇ -related disease, disorder, or condition.
  • Medicaments can further comprise a pharmaceutically acceptable carrier. Methods for the preparation of such medicaments for the treatment of a GSK-3-related or a GSK-3 ⁇ -related disease, disorder, or condition are also disclosed herein.
  • FIG. 1 is a scheme showing the synthesis of 9-ING-41-S.
  • Figure 2 shows the % activity of 9-ING-41-S and 9-ING-41-O against GSK-3 ⁇ .
  • Figure 3 shows the % activity of 9-ING-41-S and 9-ING-41-O against GSK-3 ⁇ .
  • Figure 4 shows the % activity of 9-ING-41-S and 9-ING-41-O against MST2/STK3.
  • Figure 5 shows the % activity of 9-ING-41-S and 9-ING-41-O against RSK3.
  • Figure 6 shows the % activity of 9-ING-41-S and 9-ING-41-O against TNIK.
  • Figure 7 shows the % activity of 9-ING-41-S and 9-ING-41-O against FLT4/VEGFR3.
  • Figure 8 shows the concentration of 9-ING-41-S in plasma over time after intravenous (IV) and intraperitoneal (IP) administration of 9-ING-41-S in a CD1 mouse model.
  • Figure 9 shows the mean concentration of 9-ING-41-S in plasma and brain tissue over time after intraperitoneal (IP) administration of 9-ING-41-S in a CD1 mouse model.
  • Figure 10 is an image of a 6-well plate plated with 10,000 L3.6 or PANC1 pancreatic cancer cell lines in the presence of diluent (DMSO) or increasing concentrations of 9-ING-41-S.
  • Figure 11 shows cell confluency curves for the pancreatic cancer cell lines presented as the % of diluent (control).
  • Figure 12 is an image of a 6-well plate plated with 500 COV362 or PEO1 ovarian cancer cell lines in the presence of diluent (DMSO) or increasing concentrations of 9-ING- 41-S.
  • Figure 13 shows cell confluency curves for the ovarian cancer cell lines presented as the % of diluent (control).
  • Figure 14 is an image of an electrophoresis gel immunoblotted with the indicated antibodies after treating L3.6 pancreatic cancer cells with 9-ING-41-S and gemcitabine.
  • Figure 15 shows flow cytometry curves for L3.6 and PANC1 cells treated with DMSO or 10 ⁇ M 9-ING-41-S for 18 h, stained with PI and an antibody toward pSer10 Histone H3. Non-mitotic and mitotic cells are denoted.
  • Figure 16 is an image of an electrophoresis gel immunoblotted with the indicated antibodies after treating L3.6, PANC1, 6182 or 4535 pancreatic cancer cells with DMSO (–) or 9-ING-41-S (10 ⁇ M) (+) for 18 h.
  • Figure 17 is an image of an electrophoresis gel immunoblotted with the indicated antibodies after treating PEO1 or PEA1 ovarian cancer cells with DMSO (–), 9-ING-41-S (10 ⁇ M) (+), and/or cisplatin (2.5 mM) for 18 h.
  • DMSO DMSO
  • 9-ING-41-S 10 ⁇ M
  • cisplatin 2.5 mM
  • Disclosed herein are benzothiophene- and benzoselenophene-substituted maleimides and related molecules which are protein kinase inhibitors.
  • Certain compounds of disclosure are inhibitors of GSK-3.
  • Certain compounds of disclosure exhibit Ki values of between 1 nM and 300 nM as measured against GSK-3 ⁇ .
  • Compounds disclosed herein can generally be compounds of Formula (I) and compounds of other formulas herein. Further disclosed herein are pharmaceutical compositions comprising one or more of the compounds of the formulas herein for various applications and combinations as described herein.
  • Compounds of the Disclosure [0057] Disclosed herein are compounds having a structure of Formula (I): or a pharmaceutically acceptable salts of the compound thereof, wherein: ring A is a 5-membered heterocycle or heteroaryl comprising 1 or 2 ring nitrogen heteroatoms; R N1 is independently H or C1-3alkyl; n is 0, 1, or 2; each R A , when present, is independently C 1-3 alkyl, C 2-6 alkenyl, O-C 2-6 alkenyl, C 2-6 alkynyl, O- C 2-6 alkynyl, Cyc 1 , or O-Cyc 1 ; Cyc 1 is C 3-8 cycloalkyl, C 6-10 aryl, 5-8 membered heterocycle or 5-8 membered
  • ring A can be a 5-membered heterocycle or heteroaryl comprising 1 or 2 ring nitrogen heteroatoms.
  • ring A is , , , , , or .
  • ring A is .
  • n can be 0, 1, or 2.
  • n is 0.
  • n is 1.
  • n is 2.
  • each R A can independently be absent, C1-3alkyl, C2- 6alkenyl, O-C2-6alkenyl, C2-6alkynyl, O-C2-6alkynyl, Cyc 1 , or O-Cyc 1 .
  • R A is C1- 3alkyl, Cyc 1 , or O-Cyc 1 .
  • R A is absent.
  • the compound can have a structure of Formula (II), or a pharmaceutically acceptable salt thereof:
  • Y 1 can be O, S, Se, and NR N1 .
  • Y 1 is S.
  • Y 1 is Se.
  • Y 1 is O.
  • Y 1 is NR N1 .
  • Y 2 can be S or Se.
  • Y 2 is S.
  • Y 2 is Se.
  • each R N1 can independently be H or C 1- 3 alkyl.
  • R N1 is H.
  • R N1 is C 1-3 alkyl.
  • the compound can have a structure of Formula (IIIa), or a pharmaceutically acceptable salt thereof:
  • Y 1 can be O, S, Se, and NR N1 .
  • Y 1 is S or NR N1 .
  • Y 1 is O or Se.
  • Y 1 is NR N1 .
  • each R N1 can independently be H or C 1- 3 alkyl.
  • at least one R N1 is H.
  • at least one R N1 is H.
  • at least one R N1 is C 1-3 alkyl.
  • at least one R N1 is C 1-2 alkyl.
  • each R N1 is C 1-3 alkyl.
  • the compound can have a structure of Formula (IVa), or a pharmaceutically acceptable salt thereof:
  • Y 1 can be O, S, Se, and NR N1 .
  • Y 1 is S or NR N1 .
  • Y 1 is O or Se.
  • Y 1 is NR N1 .
  • the compound can have a structure of Formula (IVb), or a pharmaceutically acceptable salt thereof:
  • each R N1 can independently be H or C 1- 3 alkyl.
  • at least one R N1 is H.
  • each R N1 is H.
  • R N1 is C 1-3 alkyl.
  • at least one R N1 is C 1-2 alkyl.
  • each R N1 is C1-3alkyl.
  • R 1 and R 5 can each independently be absent or selected from halo and C 1-3 alkyl.
  • at least one of R 1 and R 5 is halo or C1alkyl.
  • at least one of R 1 and R 5 is C1alkyl.
  • at least one of R 1 and R 5 is halo.
  • R 2 , R 3 , R 4 , R 6 , R 7 , and R 8 can independently be absent or selected from halo, C1-3alkyl, C1-3haloalkyl, hydroxyl, C1-3hydroxyalkyl, C1-3alkoxy, and CN, or R 2 and R 3 , or R 3 and R 4 , or R 6 and R 7 , or R 7 and R 8 together with the ring through which they are attached, form a C5-8cycloalkyl, C6-10aryl, 5-8 membered heterocycle or 3-9 membered heteroaryl, and the heterocycle or heteroaryl comprises 1 or 2 ring heteroatoms independently selected from N, O, and S.
  • R 2 , R 3 , R 4 , R 6 , R 7 , and R 8 is selected from halo, C 1-3 alkyl, C 1-3 haloalkyl, hydroxyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, and CN.
  • at least one of R 2 , R 3 , R 4 , R 6 , R 7 , and R 8 is halo, hydroxyl, or CN.
  • at least one of R 2 , R 3 , R 4 , R 6 , R 7 , and R 8 is C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, or C 1-3 alkoxy.
  • R 2 , R 3 , R 4 , R 6 , R 7 , and R 8 is F, Cl, Br, CN, CH 3 , OCH 3 , CF 3 , or CHF 2 .
  • at least one of R 2 , R 3 , R 4 , R 6 , R 7 , and R 8 is F, Cl, Br, CN, CH 3 , OCH 3 , CF 3 , or CHF 2 .
  • at least one of R 2 and R 3 , or R 3 and R 4 , or R 6 and R 7 , or R 7 and R 8 together with the ring through which they are attached form a C6-10aryl or 3-9 membered heteroaryl and the heteroaryl comprises 1 or 2 ring heteroatoms independently selected from N, O, and S.
  • R 6 and R 7 , or R 7 and R 8 together with the ring through which they are attached, form a C6-10aryl.
  • R 7 and R 8 together with the ring through which they are attached, form a C6-10aryl.
  • the compound can have a structure .
  • C and D are selected from the groups: where w and z are 1 or 0, and w and z are not both 0, and where dotted lines in the central ring above and in the group indicate single or double bonds as appropriate to satisfy valency; one of Y 1 and Y 2 is selected from S and Se, and the other of Y 1 and Y 2 is selected from O, S, Se, and NR', wherein R' if it forms part of Y 1 is R 1 , and R' if it forms part of Y 2 is R 2 ; R 1 and R 2 , independently of each other, are selected from H, alkyl, alkenyl, alkynyl, heterocyclyl, aryl, arylalkyl, arylalkenyl, heteroaryl, (heteroaryl)alkyl, and (heteroaryl)alkyl, and (heteroary
  • two of X 15 , X 16 , X 17 , X 25 , X 26 , and X 27 are halogen or trifluoromethyl.
  • two of X 15 , X 16 , X 17 , X 25 , X 26 , and X 27 are halogen or trifluoromethyl, and another of X 15 , X 16 , X 17 , X 25 , X 26 , and X 27 is halogen or C1-C3 alkoxy.
  • two of X 15 , X 16 , X 17 , X 25 , X 26 , and X 27 are halogen.
  • two of X 15 , X 16 , X 17 , X 25 , X 26 , and X 27 are halogen and another of X 15 , X 16 , X 17 , X 25 , X 26 , and X 27 is halogen or C1-C3 alkoxy.
  • X 15 , X 16 , X 17 , X 25 , X 26 , and X 27 are halogen.
  • X 15 and X 16 are halogen, while X 27 is C1-C3 alkoxy and X 25 and X 26 are hydrogen or halogen; or X 25 and X 26 are halogen, while X 17 is C1-C3 alkoxy and X 15 and X 16 are hydrogen or halogen.
  • X 16 and X 17 are halogen, while X 27 is C1-C3 alkoxy and X 25 and X 26 are hydrogen or halogen.
  • X 26 and X 27 are halogen, while X 17 is C1-C3 alkoxy and X 15 and X 16 are hydrogen or halogen.
  • two of X 15 to X 17 are halogen or C1-C3 alkoxy.
  • two of X 25 to X 27 are halogen or C1-C3 alkoxy.
  • X 15 and X 16 are halogen.
  • X 25 and X 26 are halogen.
  • X 17 is C1-C3 alkoxy.
  • X 27 is C1-C3 alkoxy.
  • two of X 15 to X 17 are halogen or C1-C3 alkoxy, and at least one of X 25 to X 27 is halogen or trifluoromethyl.
  • two of X 25 to X 27 are halogen or C1-C3 alkoxy, and at least one of X 15 to X 17 is halogen or trifluoromethyl.
  • two of X 15 to X 17 are halogen or C 1 -C 3 alkoxy, and at least one of X 25 to X 27 is halogen.
  • two of X 25 to X 27 are halogen or C 1 -C 3 alkoxy, and at least one of X 15 to X 17 is halogen.
  • two of X 15 to X 17 are halogen or C 1 -C 3 alkoxy, and at least one of X 25 to X 27 is trifluoromethyl.
  • two of X 25 to X 27 are halogen or C 1 -C 3 alkoxy, and at least one of X 15 to X 17 is trifluoromethyl.
  • two of X 15 to X 17 are halogen or C 1 -C 3 alkoxy, and two of X 25 to X 27 are halogen or trifluoromethyl.
  • two of X 25 to X 27 are halogen or C 1 -C 3 alkoxy, and two of X 15 to X 17 are halogen or trifluoromethyl.
  • two of X 15 to X 17 are halogen, and two of X 25 to X 27 are halogen or trifluoromethyl.
  • two of X 25 to X 27 are halogen, and two of X 15 to X 17 are halogen or trifluoromethyl.
  • two of X 15 to X 17 are halogen, and X 25 and X 26 are halogen or trifluoromethyl.
  • two of X 25 to X 27 are halogen, and X 15 and X 16 are halogen or trifluoromethyl.
  • two of X 15 to X 17 are halogen, and X 26 and X 27 are halogen.
  • two of X 25 to X 27 are halogen, and X 16 and X 17 are halogen.
  • two of X 15 to X 17 are halogen, and two of X 25 to X 27 together form a methylenedioxy group.
  • two of X 25 to X 27 are halogen, and two of X 15 to X 17 together form a methylenedioxy group.
  • two of X 15 to X 17 are halogen, and two of X 25 to X 27 together form the group OCH2S.
  • two of X 25 to X 27 are halogen, and two of X 15 to X 17 together form the group OCH2S.
  • two of X 15 to X 17 are halogen, and two of X 25 to X 27 together form the group SCH2S.
  • two of X 25 to X 27 are halogen, and two of X 15 to X 17 together form the group SCH2S.
  • two of X 15 to X 17 are halogen, and two of X 25 to X 27 together form the group OCH2CH2.
  • two of X 25 to X 27 are halogen, and two of X 15 to X 17 together form the group OCH2CH2.
  • two of X 15 to X 17 are halogen, and two of X 25 to X 27 together form the group OCH2CH2CH2.
  • two of X 25 to X 27 are halogen, and two of X 15 to X 17 together form the group OCH2CH2CH2.
  • two of X 15 to X 17 are halogen, and two of X 25 to X 27 together form the group CH2OCH2.
  • two of X 25 to X 27 are halogen, and two of X 15 to X 17 together form the group CH 2 OCH 2 .
  • two of X 15 to X 17 are halogen, and two of X 25 to X 27 together form the group SCH2CH2.
  • two of X 25 to X 27 are halogen, and two of X 15 to X 17 together form the group SCH 2 CH 2 .
  • two of X 15 to X 17 are halogen, and two of X 25 to X 27 together form the group SCH 2 CH 2 CH 2 .
  • two of X 25 to X 27 are halogen, and two of X 15 to X 17 together form the group SCH 2 CH 2 CH 2 .
  • two of X 15 to X 17 are halogen, and two of X 25 to X 27 together form the group CH 2 SCH 2 .
  • two of X 25 to X 27 are halogen, and two of X 15 to X 17 together form the group CH 2 SCH 2 .
  • X 15 and X 16 are both fluorine.
  • X 25 and X 26 are both fluorine.
  • X 15 is fluorine.
  • X 16 is fluorine.
  • X 25 is fluorine.
  • X 26 is fluorine.
  • X 17 is C1-C3 alkoxy.
  • X 27 is C 1 -C 3 alkoxy.
  • X 17 is methoxy.
  • X 27 is methoxy.
  • X 17 is C 1 -C 3 alkoxy, and at least one of X 25 to X 27 is halogen or trifluoromethyl.
  • X 27 is C 1 -C 3 alkoxy, and at least one of X 15 to X 17 is halogen or trifluoromethyl.
  • X 17 is methoxy, and at least one of X 25 to X 27 is halogen or trifluoromethyl.
  • X 27 is methoxy, and at least one of X 15 to X 17 is halogen or trifluoromethyl.
  • X 17 is C 1 -C 3 alkoxy, and two of X 25 to X 27 are halogen or trifluoromethyl. In more specific aspects of Formula 2A or 2B, X 27 is C 1 -C 3 alkoxy, and two of X 15 to X 17 are halogen or trifluoromethyl. In more specific aspects of Formula 2A or 2B, X 17 is methoxy, and at least two of X 25 to X 27 are halogen or trifluoromethyl. In more specific aspects of Formula 2A or 2B, X 27 is methoxy, and at least two of X 15 to X 17 are halogen or trifluoromethyl.
  • X 17 is C1-C3 alkoxy, and X 25 is trifluoromethyl.
  • X 27 is C1-C3 alkoxy, and X 15 is trifluoromethyl.
  • X 17 is methoxy, and X 25 is trifluoromethyl.
  • [0095] In more specific aspects of Formula 2A or 2B, X 27 is methoxy, and X 15 is trifluoromethyl.
  • X 17 is C1-C3 alkoxy, and X 25 is halogen.
  • X 27 is C1-C3 alkoxy, and X 15 is halogen.
  • X 17 is methoxy, and X 25 is halogen.
  • X 27 is methoxy, and X 15 is halogen.
  • X 17 is C1-C3 alkoxy, and X 25 and X 26 are both halogen.
  • X 27 is C1-C3 alkoxy, and X 15 and X 16 are both halogen.
  • X 17 is methoxy, and X 25 and X 26 are both halogen.
  • X 27 is methoxy, and X 15 and X 16 are both halogen.
  • X 17 is C1-C3 alkoxy, and X 25 and X 26 together form a methylenedioxy group.
  • X 27 is C1-C3 alkoxy, and X 15 and X 16 together form a methylenedioxy group.
  • X 17 is methoxy, and X 25 and X 26 together form a methylenedioxy group.
  • X 27 is methoxy, and X 15 and X 16 together form a methylenedioxy group.
  • X 17 is C 1 -C 3 alkoxy, and X 25 and X 26 together form a methylenedioxy group.
  • X 27 is C 1 -C 3 alkoxy, and X 15 and X 16 together form the group OCH 2 S.
  • X 17 is methoxy, and X 25 and X 26 together form the group OCH 2 S.
  • X 27 is methoxy, and X 15 and X 16 together form a methylenedioxy group.
  • X 17 is C 1 -C 3 alkoxy, and X 25 and X 26 together form a methylenedioxy group.
  • X 27 is C 1 -C 3 alkoxy, and X 15 and X 16 together form the group SCH 2 S.
  • X 17 is methoxy, and X 25 and X 26 together form the group SCH 2 S.
  • X 27 is methoxy, and X 15 and X 16 together form a methylenedioxy group.
  • X 17 is C 1 -C 3 alkoxy, and X 25 and X 26 together form the group OCH2CH2.
  • X 27 is C1- C3 alkoxy, and X 15 and X 16 together form the group OCH2CH2.
  • X 17 is methoxy, and X 25 and X 26 together form the group OCH2CH2.
  • X 27 is methoxy, and X 15 and X 16 together form the group OCH2CH2.
  • X 17 is C1-C3 alkoxy, and X 25 and X 26 together form the group OCH2CH2CH2.
  • X 27 is C1-C3 alkoxy, and X 15 and X 16 together form the group OCH2CH2CH2.
  • X 17 is methoxy, and X 25 and X 26 together form the group OCH2CH2CH2.
  • X 27 is methoxy, and X 15 and X 16 together form the group OCH2CH2CH2.
  • X 17 is C1-C3 alkoxy, and X 25 and X 26 together form the group CH2OCH2.
  • X 27 is C1- C3 alkoxy, and X 15 and X 16 together form the group CH2OCH2.
  • X 17 is methoxy, and X 25 and X 26 together form the group CH2OCH2.
  • X 27 is methoxy, and X 15 and X 16 together form the group CH2OCH2.
  • X 17 is C1-C3 alkoxy, and X 25 and X 26 together form the group SCH2CH2.
  • X 27 is C1- C3 alkoxy, and X 15 and X 16 together form the group SCH2CH2.
  • X 17 is methoxy, and X 25 and X 26 together form the group SCH2CH2.
  • X 27 is methoxy, and X 15 and X 16 together form the group SCH 2 CH 2 .
  • X 17 is C1-C3 alkoxy, and X 25 and X 26 together form the group SCH 2 CH 2 CH 2 .
  • X 27 is C 1 -C 3 alkoxy, and X 15 and X 16 together form the group SCH 2 CH 2 CH 2 .
  • X 17 is methoxy, and X 25 and X 26 together form the group SCH 2 CH 2 CH 2 .
  • X 27 is methoxy, and X 15 and X 16 together form the group SCH 2 CH 2 CH 2 .
  • X 17 is C 1 -C 3 alkoxy, and X 25 and X 26 together form the group CH 2 SCH 2 .
  • X 27 is C 1 - C 3 alkoxy, and X 15 and X 16 together form the group CH 2 SCH 2 .
  • X 17 is methoxy, and X 25 and X 26 together form the group CH 2 SCH 2 .
  • X 27 is methoxy, and X 15 and X 16 together form the group CH 2 SCH 2 .
  • one of X 15 to X 17 is halogen or trifluoromethyl, X 27 is C1-C3 alkoxy, and X 25 and X 26 are hydrogen or halogen.
  • one of X 25 to X 27 is halogen or trifluoromethyl, X 17 is C1-C3 alkoxy, and X 25 and X 26 are hydrogen or halogen.
  • one of X 15 to X 17 is halogen or trifluoromethyl, X 27 is C1-C3 alkoxy, and X 25 and X 26 are both hydrogen.
  • one of X 25 to X 27 is halogen or trifluoromethyl, X 17 is C1-C3 alkoxy, and X 15 and X 16 are both hydrogen.
  • X 15 is halogen or trifluoromethyl
  • X 16 and X 17 are hydrogen
  • X 27 is C1-C3 alkoxy
  • X 25 and X 26 are both hydrogen.
  • X 25 is halogen or trifluoromethyl
  • X 26 and X 27 are hydrogen
  • X 17 is C1-C3 alkoxy
  • X 15 and X 16 are both hydrogen.
  • X 16 and X 17 are fluorine or chlorine.
  • X 26 and X 27 are fluorine or chlorine.
  • X 15 and X 16 are fluorine or iodine.
  • X 25 and X 26 are fluorine or iodine.
  • X 15 is fluorine and X 16 is chlorine or iodine.
  • X 25 is fluorine and X 26 is chlorine or iodine.
  • X 15 is bromine.
  • X 25 is bromine.
  • X 15 is trifluoromethyl.
  • X 25 is trifluoromethyl.
  • X 17 is methoxy.
  • X 27 is methoxy.
  • X 15 and X 16 together are methylenedioxy.
  • X 25 and X 26 together are methylenedioxy.
  • X 15 and X 16 together are OCH 2 S or SCH2O.
  • X 25 and X 26 together are OCH2S or SCH 2 O.
  • X 15 and X 16 together are SCH 2 S.
  • X 25 and X 26 together are SCH 2 S.
  • compounds of Formula 2A or 2B are provided in which two of X 15 to X 17 are halogen and for example, are chlorine, bromine or iodine.
  • compounds of Formula 2A or 2B are provided in which two of X 25 to X 27 are halogen and for example, are chlorine, bromine or iodine.
  • the compounds of Formula 2A or 2B are provided in which X 15 and X 16 or X 16 and X 17 are halogen and for example are chlorine, bromine or iodine.
  • compounds of Formula 2A or 2B are provided in which X 25 and X 26 or X 26 and X 27 are halogen and for example, are chlorine, bromine or iodine.
  • compounds of Formula 2A or 2B are provided in which X 15 and X 16 , or X 16 and X 17 are the same halogen or different halogens, for example, where one of X 15 and X 16 is chlorine and the other of X 15 and X 16 is fluorine, bromine, or iodine; or particularly where one of X 16 and X 17 is chlorine and the other of X 16 and X 17 is fluorine, bromine, or iodine.
  • compounds of Formula 2A or 2B are provided in which X 25 and X 26 , or X 26 and X 27 are the same halogen or different halogens, for example, where one of X 25 and X 26 is chlorine and the other of X 25 and X 26 is fluorine, bromine, or iodine; or for example, where one of X 26 and X 27 is chlorine and the other of X 26 and X 27 is fluorine, bromine, or iodine.
  • two of X 15 to X 17 are halogen
  • all remaining X variables are hydrogen.
  • two of X 25 to X 27 are halogen, all remaining X variables are hydrogen.
  • two of X 15 to X 17 are halogen
  • at least one or at least two of X 25 to X 27 are C1-C3 alkoxy.
  • at least one or at least two of X 15 to X 17 are C1-C3 alkoxy.
  • at least one or at least two of X 15 to X 17 are C1-C3 alkoxy.
  • two of X 15 to X 17 are halogens
  • one or two of X 25 to X 27 are C1-C3 alkoxy or halogen, and the remaining X variables are hydrogen.
  • one or two of X 15 to X' are C1-C3 alkoxy or halogen, and the remaining X variables are hydrogen.
  • compounds of Formula 2A or 2B are provided in which one of X 15 to X 17 is halogen and for example, is chlorine, bromine, or iodine.
  • compounds of Formula 2A or 2B are provided in which X 15 is a halogen and for example, is chlorine, bromine, or iodine.
  • compounds of Formula 2A or 2B are provided in which X 25 is a halogen and for example, is chlorine, bromine, or iodine.
  • compounds of Formula 2A or 2B are provided in which X 16 is halogen and for example, is chlorine, bromine, or iodine.
  • compounds of Formula 2A or 2B are provided in which X 26 is halogen and for example, is chlorine, bromine, or iodine.
  • compounds of Formula 2A or 2B are provided in which X 17 is halogen and for example, is chlorine, bromine, or iodine.
  • one of X 15 to X 17 is halogen one or two of X 15 to X 17 are C 1 -C 3 alkoxy.
  • one or two of X 25 to X 27 are C 1 -C 3 alkoxy.
  • all remaining X and Y variables are hydrogen.
  • all of X 25 to X 27 is halogen and one or two of X 15 to X 17 are C 1 -C 3 alkoxy or halogen, all remaining X and Y variables are hydrogen.
  • all of X 15 to X 17 is halogen, all of X 24 to X 27 are hydrogen.
  • all of X 14 to X 17 are hydrogen.
  • X 15 to X 17 is halogen
  • all remaining X variables are hydrogen.
  • all remaining X variables are hydrogen.
  • X 25 to X 27 all remaining X variables are hydrogen.
  • X 15 is CI or I
  • X 25 is CI or I
  • all other X variables are hydrogen.
  • X 15 is CI, Br, or I
  • X 27 is hydrogen or C1-C3 alkoxy, particularly methoxy, and all other X variables are H.
  • X 25 is CI, Br, or I
  • X 17 is hydrogen or C1-C3 alkoxy, particularly methoxy, and all other X variables are H.
  • X 15 is CI
  • X 16 is F
  • X 27 is hydrogen or C1-C3 alkoxy
  • all other X variables are hydrogen.
  • X 25 is CI
  • X 26 is F
  • X 17 is hydrogen or C1-C3 alkoxy
  • all other X variables are hydrogen.
  • X 15 is F
  • X 16 is Br or I
  • X 27 is hydrogen or C1-C3 alkoxy
  • all other X variables are hydrogen.
  • X 25 is F
  • X 26 is Br or I
  • X 17 is hydrogen or C1-C3 alkoxy
  • all other X variables are hydrogen.
  • X 15 is CI
  • X 16 is Br or I
  • X 27 is hydrogen or C1-C3 alkoxy, and all other X variables are hydrogen.
  • X 25 is CI
  • X 26 is Br or I
  • X 17 is hydrogen or C1-C3 alkoxy
  • all other X variables are hydrogen.
  • X 15 is Br
  • X 16 is F
  • CI is C1-C3 alkoxy
  • X 27 is hydrogen or C 1 -C 3 alkoxy
  • all other X variables are hydrogen.
  • X 25 is Br
  • X 26 is F
  • X 17 is hydrogen or C1-C3 alkoxy
  • all other X variables are hydrogen.
  • X 15 is I
  • X 16 is F, CI, or Br
  • X 27 is hydrogen or C 1 -C 3 alkoxy
  • all other X variables are hydrogen.
  • X 25 is I
  • X 26 is F, CI, or Br
  • X 17 is hydrogen or C 1 -C 3 alkoxy, and all other X variables are hydrogen.
  • X 15 and X 16 or X 16 and X 17 are joined to form, together with the carbon atoms to which they are attached, a fused 5- or 6- membered ring in which zero, one, or two ring atoms are heteroatoms.
  • X 25 and X 26 or X 26 and X 27 are joined to form, together with the carbon atoms to which they are attached, a fused 5- or 6-membered ring in which zero, one, or two ring atoms are heteroatoms.
  • the fused ring contains one or two oxygen atoms.
  • the fused ring contains one oxygen atom and one sulfur atom. In additional specific aspects, the fused ring contains one or two sulfur atoms. In additional aspects in which two of X 15 to X 17 together form a carbocyclic or heterocyclic ring, at least one of X 25 to X 27 is halogen or C1-C3 alkoxy. In additional aspects in which two of X 25 to X 27 together form a carbocyclic or heterocyclic ring, at least one of X 15 to X 17 is halogen or C1-C3 alkoxy.
  • At least one of X 25 to X 27 is halogen. In additional aspects in which two of X 25 to X 27 together form a carbocyclic or heterocyclic ring, at least one of X 15 to X 17 is halogen. In additional aspects in which two of X 15 to X 17 together form a carbocyclic or heterocyclic ring, at least one of X 25 to X 27 is halogen, particularly chlorine, bromine, or iodine, or C1-C3 alkoxy.
  • X 15 to X 17 is halogen, particularly chlorine, bromine, or iodine, or C1-C3 alkoxy.
  • X 25 is halogen.
  • X 15 is halogen.
  • X 25 is chlorine, bromine, or iodine.
  • X 15 is chlorine, bromine, or iodine.
  • X 25 is fluorine.
  • X 25 to X 27 together form a carbocyclic or heterocyclic ring
  • X 15 is fluorine.
  • at least one of X 25 to X 27 is C1-C3 alkoxy.
  • X 15 to X 17 is C 1 - C 3 alkoxy.
  • X 27 is C1-C3 alkoxy.
  • X 25 to X 27 together form a carbocyclic or heterocyclic ring
  • X 17 is C 1 -C 3 alkoxy.
  • X 27 is C 1 -C 3 alkoxy, and the remaining X groups are hydrogen or halogen.
  • X 17 is C 1 -C 3 alkoxy, and the remaining X groups are hydrogen or halogen.
  • the alkoxy group is a group other than methoxy.
  • X 17 is an alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group.
  • X 27 is an alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group.
  • X 17 is a C1-C4 alkyl group substituted with an alkoxy, carboxyl, or esterified carboxyl group.
  • X 27 is a C1-C4 alkyl group substituted with an alkoxy, carboxyl, or esterified carboxyl group.
  • X 17 is an alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group, and all of X 24 to X 27 are hydrogen.
  • X 27 is an alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group, and all of X 14 to X 17 are hydrogen.
  • X 17 is an alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group, and at least one of X 25 to X 27 is halogen or C1-C3 alkoxy.
  • X 27 is an alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group, and at least one of X 15 to X 17 is halogen or C1-C3 alkoxy.
  • X 17 is an alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group, and at least one of X 25 to X 27 is halogen, or X 27 is C1-C3 alkoxy.
  • X 27 is an alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group, and at least one of X 15 to X 17 is halogen, or X 17 is C1-C3 alkoxy.
  • X 17 is an alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group, and at least two of X 25 to X 27 are halogen.
  • X 27 is an alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group, and at least two of X 15 to X 17 are halogen.
  • the alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group has 1 or 2 carbon atoms.
  • X 17 is (CH 2 ) n OH, (CH 2 ) n O-alkyl, (CH 2 ) n C(O)OH, or (CH 2 ) n C(O)O- alkyl, where n is an integer ranging from 1 to 4.
  • X 17 is (CH 2 ) n O-alkyl or (CH 2 ) n C(O)O-alkyl, where n is an integer ranging from 1-4 and the alkyl group has 1-6 or 1-3 carbon atoms.
  • X 15 is halogen and/or X 17 is an alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group
  • X 25 to X 27 are selected from hydrogen, halogen, alkoxy, alkyl substituted with OH, alkyl substituted with alkoxy, alkyl substituted with carboxyl, and alkyl substituted with esterified carboxyl.
  • X 25 is halogen and/or X 27 is an alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group
  • X 15 to X 17 are selected from hydrogen, halogen, alkoxy, alkyl substituted with OH, alkyl substituted with alkoxy, alkyl substituted with carboxyl, and alkyl substituted with esterified carboxyl.
  • X 15 is halogen and/or X 17 is an alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group
  • X 25 is halogen.
  • X 25 is halogen and/or X 27 is an alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group
  • X 15 is halogen.
  • X 15 is halogen and/or X 17 is an alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group
  • X 26 or X 27 is an alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group.
  • X 25 is halogen and/or X 27 is an alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group
  • X 16 or X 17 is an alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group.
  • the alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group has 1-4 carbon atoms or 1-2 carbon atoms.
  • the substituted alkyl group is (CH2)nO-alkyl, (CH2)nC(O)OH, or (CH2)nC(O)O-alkyl, where n is an integer ranging from 1-4 or 1-2.
  • the substituted alkyl group is (CH2)nO-alkyl or (CH2)nC(O)O-alkyl, where n is an integer ranging from 1-4, and the alkyl groups have 1-6 or 1-3 carbon atoms.
  • X 15 is halogen and/or X 17 is an alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group
  • X 25 to X 27 are selected from hydrogen, halogen, alkoxy, alkyl substituted with OH, alkyl substituted with alkoxy, alkyl substituted with carboxyl, and alkyl substituted with esterified carboxyl, and any remaining X substituents are halogen or hydrogen.
  • X 25 is halogen and/or X 27 is an alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group
  • X 15 to X 17 are selected from hydrogen, halogen, alkoxy, alkyl substituted with OH, alkyl substituted with alkoxy, alkyl substituted with carboxyl, and alkyl substituted with esterified carboxyl, and any remaining X substituents are halogen or hydrogen.
  • X 15 is halogen and/or X 17 is an alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group
  • X 25 to X 27 are selected from hydrogen, halogen, alkoxy, alkyl substituted with OH, alkyl substituted with alkoxy, alkyl substituted with carboxyl, and alkyl substituted with esterified carboxyl, and any remaining X substituents are hydrogen.
  • X 25 is halogen and/or X 27 is an alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group
  • X 15 to X 17 are selected from hydrogen, halogen, alkoxy, alkyl substituted with OH, alkyl substituted with alkoxy, alkyl substituted with carboxyl, and alkyl substituted with esterified carboxyl, and any remaining X substituents are hydrogen.
  • the disclosure provides compounds of Formula 2A or 2B.
  • compounds of Formulas 1, 2A, and 2B are useful for the treatment of cancer, particularly pancreatic cancer, colorectal cancer, and ovarian cancer.
  • Compounds of the disclosure can be useful in pharmaceutical compositions and methods of treatment or uses thereof, as described herein.
  • compounds of Formula 1 useful in the pharmaceutical compositions and methods of disclosure can include those of Formula 3: where all variables are as defined above, and where in particular R 2 is H, alkyl, aryl, or arylalkyl.
  • compounds of Formula 1 useful in the pharmaceutical compositions and methods of disclosure can include those of Formula 4A: where all variables are as defined above, and where in particular R 2 is H, alkyl, aryl, or arylalkyl.
  • compounds of Formula 1 useful in the pharmaceutical compositions and methods of disclosure can include those of Formula 4B: where all variables are as defined above, and where in particular R 2 is H, alkyl, aryl, or arylalkyl.
  • compounds of Formula 1 useful in the pharmaceutical compositions and methods of disclosure can include those of Formula 5A: where all variables are as defined above, and where in particular R 2 is H, alkyl, aryl, or arylalkyl; R 3 is H, alkyl, aryl, or arylalkyl; and R 4 is H, alkyl, aryl, or arylalkyl.
  • compounds of Formula 1 useful in the pharmaceutical compositions and methods of disclosure can include those of Formula 5B: where all variables are as defined above, and where in particular R 2 is H, alkyl, aryl, or arylalkyl; R 3 is H, alkyl, aryl, or arylalkyl; and R 4 is H, alkyl, aryl, or arylalkyl.
  • compounds of Formula 1 useful in the pharmaceutical compositions and methods of disclosure can include those of Formula 6A: where all variables are as defined above, and where in particular R 2 is H, alkyl, aryl, or arylalkyl; and R 3 is H, alkyl, aryl, or arylalkyl.
  • compounds of Formula 1 useful in the pharmaceutical compositions and methods of disclosure can include those of Formula 6B: where all variables are as defined above, and where in particular R 2 is H, alkyl, aryl, or arylalkyl; and R 3 is H, alkyl, aryl, or arylalkyl.
  • compounds of Formula 1 useful in the pharmaceutical compositions and methods of disclosure can include those of Formula 7A: where all variables are as defined above, and where in particular R 2 is H, alkyl, aryl, or arylalkyl, and n is an integer ranging from 1 to 6. In specific aspects, n is 2 to 4.
  • compounds of Formula 1 useful in the pharmaceutical compositions and methods of disclosure can include those of Formula 7B: where all variables are as defined above, and where in particular R 2 is H, alkyl, aryl, or arylalkyl, and n is an integer ranging from 1 to 6. In specific aspects, n is 2 to 4.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, cis-trans, conformational, and rotational) forms of the structure.
  • the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers are included in this disclosure, unless only one of the isomers is specifically indicated. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, cis/trans, conformational, and rotational mixtures of the present compounds are within the scope of the disclosure. In some cases, the compounds disclosed herein are stereoisomers. "Stereoisomers" refer to compounds that differ in the chirality of one or more stereocenters i.e., the orientation of their constituent atoms or groups in space. Stereoisomers include enantiomers and diastereomers.
  • the compounds disclosed herein can exist as a single stereoisomer, or as a mixture of stereoisomers. Stereochemistry of the compounds shown herein indicates a relative stereochemistry, not absolute, unless discussed otherwise. As indicated herein, a single stereoisomer, diastereomer, or enantiomer refers to a compound that is at least more than 50% of the indicated stereoisomer, diastereomer, or enantiomer, and in some cases, at least 90% or 95% of the indicated stereoisomer, diastereomer, or enantiomer. [0129] The compounds of the disclosure can have any stereochemical configuration at any sp 3 carbon atoms. In some cases, the compounds of the disclosure are optically pure.
  • optically pure refers to the predominant presence of one enantiomer of a compound if multiple stereochemical configurations can exist (e.g., at least 99% enantiomeric excess). Unless otherwise indicated, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure. [0130]
  • the compounds of the disclosure are defined herein by their chemical structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.
  • alkyl refers to a monoradical of an unbranched (straight-chain or linear) or branched saturated hydrocarbon, which may be acyclic or cyclic (i.e., the term includes cycloalkyl groups) having one or more rings. Unless otherwise indicated, preferred alkyl groups have 1 to 20 carbon atoms, and more preferred are those that contain 1-10 carbon atoms. Short alkyl groups are those having 1 to 6 carbon atoms including methyl, ethyl, propyl, butyl, pentyl and hexyl groups, including all isomers thereof.
  • Long alkyl groups are those having 8-20 carbon atoms and preferably those having 8-12.
  • cycloalkyl refers specifically to alkyl groups having at least one non- aromatic ring of 3 or more carbons. The term applies to groups having a single ring or multiple rings, which may be condensed or fused rings.
  • Preferred cycloalkyl groups have at least one ring of 3-8 carbon atoms, and more preferably a ring of 3-6 carbon atoms.
  • Cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, ethylcyclopentyl, cyclopropylmethyl, and the like, or multiple ring structures such as bicyclo[1.1.1]butyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.3.0]octyl, adamantyl, cubanyl, and the like. Unless otherwise indicated, alkyl groups, including cycloalkyl groups, are optionally substituted as defined below.
  • alkenyl used alone or as part of a larger moiety, refers to a monoradical of an unbranched or branched, unsaturated hydrocarbon group having one or more double bonds, and to cycloalkenyl group having one or more rings. Unless otherwise indicated, preferred alkyl groups have 1 to 20 carbon atoms, and more preferred are those that contain 1-10 carbon atoms. Alkenyl groups may contain one or more double bonds, which may be conjugated or non-conjugated. Preferred alkenyl groups are those having 1 or 2 double bonds and include omega-alkenyl groups.
  • Short alkenyl groups are those having 2 to 6 carbon atoms including ethenyl (vinyl), propenyl, butenyl, pentenyl, and hexenyl groups including all isomers thereof.
  • Long alkenyl groups are those having 8-20 carbon atoms and preferably those having 8-12.
  • the term "cycloalkenyl” refers to alkenyl groups having at least one carbon ring and containing at least one double bond. The double bond may be in the ring or outside the ring.
  • the term includes groups having rings containing 3 or more carbons.
  • the cycloalkenyl group may contain a single ring or multiple rings, which may be fused or condensed.
  • Cycloalkenyl groups include, by way of example, single-ring (monocyclic) structures such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclooctenyl, cylcooctadienyl, cyclooctatrienyl, cyclopropylvinyl, and vinylcyclopropyl, as well as multiple-ring structures such as norbornenyl. Unless otherwise indicated, alkenyl groups including cycloalkenyl groups are optionally substituted as defined below.
  • alkynyl used alone or as part of a larger moiety, refers to a monoradical of an unbranched or branched, unsaturated hydrocarbon group having one or more triple bonds, and to cycloalkynyl groups having one or more rings. Unless otherwise indicated, preferred alkynyl groups have 1 to 20 carbon atoms, and more preferred are those that contain 1-10 carbon atoms. Alkynyl groups include ethynyl, propargyl, and the like. Short alkynyl groups are those having 2 to 6 carbon atoms, including all isomers thereof. Long alkynyl groups are those having 8-20 carbon atoms and preferably those having 8-12 carbon atoms.
  • cycloalkynyl refers to cyclic alkynyl groups of from 8 to 20 carbon atoms having a single cyclic ring or multiple rings, which may be fused or condensed, and at least one triple bond, which may be in the ring or outside the ring.
  • Alkynyl groups may additionally contain one or more double bonds, which may be conjugated or non-conjugated with regard to each other and/or with regard to one or more of the triple bonds.
  • alkynyl groups including cycloalkynyl groups are optionally substituted as defined below.
  • heterocyclyl used alone or as part of a larger moiety, refers to a monoradical that contains at least one ring of atoms, which may be a saturated or unsaturated, but not aromatic ring, and to monoradicals that contain both at least one aromatic and one non-aromatic ring where the point of attachment is at a non-aromatic ring or at a carbon atom of a chain attached to the non-aromatic ring; wherein one or more carbons of the ring are replaced with heteroatoms (non-carbon atoms).
  • the heteroatom may be bonded to hydrogen or a substituent group.
  • a ring may contain one or more heteroatoms, which may be the same or different.
  • Heterocyclyl groups include those containing 3 to 20 ring carbon atoms and those carrying 1-6 ring heteroatoms, which may be the same or different.
  • Heterocyclyl groups include, by way of example, oxetanyl, 3-phenylazetidinyl, pyrrolidinyl, 1,4,5,6-tetrahydropyrimidinyl, morpholino, thiomorpholino, 2-morpholinoethyl, [(2- tetrahydropyranyl)oxy]methyl, 7- oxabicylo[2.2.1]heptyl, 1-indolinyl, (2,3-dihydro-3- benzofuranyl)methyl, 5,6,7,8- tetrahydroquinolin-5-yl, and 9-xanthenyl. Unless otherwise indicated, heterocyclyl groups are optionally substituted as defined below.
  • aryl used alone or as part of a larger moiety, refers to a carbocyclic monoradical containing one or more rings, of which at least one is an aromatic ring at which the point of attachment is located; or to a heterocyclic monoradical containing at least one carbocyclic aromatic ring at which the point of attachment is located, which ring is not fused to another ring that is an aromatic heterocycle. Rings of aryl groups may be linked by a single bond or a linker group or may be fused. Exemplary aryl groups include phenyl, biphenylyl, naphthyl, 5-indanyl, and 4-indolinyl groups. Aryl furthermore comprises the ferrocenyl group.
  • Aryl groups include those having from 6 to 20 ring carbon atoms and preferably those containing 6-12 ring carbon atoms. Unless otherwise noted, aryl groups are optionally substituted as defined below. [0137]
  • arylalkyl used alone or as part of a larger moiety, refers to a group that contains at least one alkyl group, and at least one aryl group that is attached to or fused with the alkyl group.
  • Arylalkyl groups include, by way of example, benzyl (Bn, CH 2 C 6 H 5 ), phenethyl, 1-phenylcyclopropyl, 1-indanyl, 2-naphthylmethyl, 5-acenaphthenyl, 9-fluorenyl, 9,10-dihydro-9-anthryl, diphenylmethyl, and triphenylmethyl.
  • the alkyl and/or the aryl portion of the arylalkyl group are optionally substituted as defined below.
  • heteroaryl used alone or as part of a larger moiety, refers to a monoradical that contains at least one aromatic ring in which one or more of the ring carbons is replaced with a heteroatom (non-carbon atom), and at which ring the point of attachment is located; or to a monoradical that contains at least one system of fused aromatic rings (optionally fused to additional rings that do not need to be aromatic), in which one or more of the ring carbons in one or more of the fused rings (including carbon atoms shared by two rings) is replaced with a heteroatom, and at any aromatic ring (carbocyclic or heterocyclic) of which the point of attachment is located.
  • the heteroatom may be bonded to H or a substituent group.
  • Heteroaryl groups may also contain one or more carbocyclic rings or non-aromatic heterocyclic rings, which may be attached by a single bond or a linker group or may be fused.
  • Heteroaryl groups include those containing 1-20 ring carbon atoms as well as those containing 2-12 ring carbon atoms. Unless otherwise noted, heteroaryl groups are optionally substituted as defined below.
  • heteroaryl groups include furanyl (furyl), thienyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl (furazanyl), 1,3,4- oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, indolizinyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzo[c]thiophenyl, benzimidazolyl, indazolyl, benzoxazo
  • heteroaryl groups include furanyl, isoxazolyl, pyridyl, or quinolyl groups.
  • (heteroaryl)alkyl” or “heteroarylalkyl” is analogous to the term “arylalkyl” above. It refers to a monoradical that contains at least one alkyl group, and at least one heteroaryl group that is attached to or fused with the alkyl group. Unless otherwise noted, the alkyl and/or the heteroaryl portion of the (heteroaryl)alkyl group are optionally substituted as defined below.
  • arylalkenyl used alone or as part of a larger moiety, refers to a monoradical that contains at least one alkenyl group, and at least one aryl group that is attached to or fused with the alkenyl group.
  • Arylalkenyl groups include, by way of example, 1-phenylvinyl, styryl (2-phenylvinyl), cinnamyl (3-phenyl-2-propenyl) 1H-inden-1-yl, 1H- inden-2-yl, 1H-inden-3-yl, and 1-acenaphthylenyl.
  • (heteroaryl)alkenyl or “heteroarylalkenyl” is analogous to the term “arylalkenyl” above. It refers to a monoradical that contains at least one alkenyl group, and at least one heteroaryl group that is attached to or fused with the alkyl group. Unless otherwise noted, the alkyl and/or the heteroaryl portion of the (heteroaryl)alkenyl group are optionally substituted as defined below.
  • methylene refers to the diradical -CH2-.
  • oxy refers to the diradical -O- (engaged in two single bonds) and is used in combination with descriptors for other organic radicals M to indicate -O-M groups, where M is alkyl, alkenyl, alkynyl, heterocyclyl (attached by way of a carbon atom), aryl, arylalkyl, arylalkenyl, heteroaryl (attached by way of a carbon atom), (heteroaryl)alkyl, or (heteroaryl)alkenyl, as in alkoxy (in place of alkyloxy), alkenyloxy, alkynyloxy, heterocyclyloxy, aryloxy, arylalkoxy, heteroaryloxy, and (heteroaryl)alkoxy.
  • haloalkyl refers to an alkyl as defined herein substituted by one or more halogen atoms (e.g., F, CI, Br, and I) as defined herein, which may be the same or different.
  • a haloalkyl group may, for example, contain 1-10 halogen substituents.
  • haloalkyl groups include, by way of example, difluoromethyl, trifluoromethyl, 2,2,2- trifluoroethyl, 3-fluorododecyl, 12,12,12-trifluorododecyl, 2-bromooctyl, 3-bromo-6- chloroheptyl, and the like.
  • hydroxyalkyl refer to an alkyl group substituted by one or more hydroxyl groups.
  • a hydroxyalkyl group may, for example, contain 1-10 hydroxy substituents.
  • Exemplary hydroxyalkyl groups are hydroxymethyl (CH2OH) and 2,3-dihydroxypropyl.
  • thio refers to the diradical -S- (engaged in two single bonds) and is used in combination with descriptors for other organic radicals M to indicate -S-M groups, where M is alkyl, alkenyl, alkynyl, heterocyclyl (attached by way of a carbon atom), aryl, arylalkyl, arylalkenyl, heteroaryl (attached by way of a carbon atom), (heteroaryl)alkyl, or (heteroaryl)alkenyl, as in alkylthio, alkenylthio, alkynylthio, heterocyclylthio, arylthio, arylalkylthio, heteroarylthio, and (heteroaryl)alkylthio.
  • M is optionally substituted as defined below.
  • sulfenyl and sulfonyl refer to the diradicals -S(O)- and -S(O)2-, respectively, and are used in combination with descriptors for other organic radicals M to indicate -S(O)-M and -S(O)2M groups, respectively, where M is alkyl, alkenyl, alkynyl, heterocyclyl (attached by way of a carbon atom), aryl, arylalkyl, arylalkenyl, heteroaryl, (heteroaryl)alkyl, or (heteroaryl)alkenyl.
  • amino refers to the monoradical -N(R)2, wherein each R independently is hydrogen, alkyl, alkenyl, alkynyl, heterocyclyl (attached by way of a carbon atom), aryl, arylalkyl, arylalkenyl, heteroaryl (attached by way of a carbon atom), (heteroaryl)alkyl, or (heteroaryl)alkenyl. Two of R may be linked to form a ring.
  • An "alkylamino" group refers to an amino group wherein at least one R is alkyl.
  • arylamino refers to an amino group wherein at least one R is aryl. Unless otherwise noted, the “R” groups are optionally substituted as defined below.
  • the term “amido” or “acylamino” refers to a -N(R)C(O)R' group, wherein R and R' independently are hydrogen, alkyl, alkenyl, alkynyl, heterocyclyl (attached by way of a carbon atom), aryl, arylalkyl, arylalkenyl, heteroaryl (attached by way of a carbon atom), (heteroaryl)alkyl, or (heteroaryl)alkenyl.
  • R and R' may be linked to form a ring and, unless otherwise noted, are optionally substituted as defined below.
  • ureido refers to a -N(R)C(O)N(R') 2 , group, wherein R and each R' independently are hydrogen, alkyl, alkenyl, alkynyl, heterocyclyl (attached by way of a carbon atom), aryl, arylalkyl, arylalkenyl, heteroaryl (attached by way of a carbon atom), (heteroaryl)alkyl, or (heteroaryl)alkenyl.
  • R and R' or two of R' may be linked to form a ring and, unless otherwise noted, are optionally substituted as defined below.
  • the term "sulfonamido" or “sulfonylamino” refers to a -N(R)S(O) 2 R' group, wherein R and R' independently are hydrogen, alkyl, alkenyl, alkynyl, heterocyclyl (attached by way of a carbon atom), aryl, arylalkyl, arylalkenyl, heteroaryl (attached by way of a carbon atom), (heteroaryl)alkyl, or (heteroaryl)alkenyl.
  • R and R' may be linked to form a ring and, unless otherwise noted, are optionally substituted as defined below.
  • acyl refers to the monoradical -C(O)M, where M is alkyl, alkenyl, alkynyl, heterocyclyl, aryl, arylalkyl, arylalkenyl, heteroaryl, (heteroaryl)alkyl, or (heteroaryl)alkenyl. Unless otherwise noted, acyl groups are optionally substituted as defined below.
  • acyloxy refers to the monoradical -OC(O)M, where M is alkyl, alkenyl, alkynyl, heterocyclyl, aryl, arylalkyl, arylalkenyl, heteroaryl, (heteroaryl)alkyl, or (heteroaryl)alkenyl. Unless otherwise noted, acyloxy groups are optionally substituted as defined below.
  • carboxyl or “carboxylate” refers to the group C(O)OH or its anionic form C(O)O – , respectively.
  • carboxylate ester or “esterified carboxyl” refers to the group -C(O)OM where M is alkyl, alkenyl, alkynyl, heterocyclyl, aryl, arylalkyl, arylalkenyl, heteroaryl, (heteroaryl)alkyl, or (heteroaryl)alkenyl and, unless otherwise noted, M is optionally substituted as defined below. In particular aspects, M is alkyl.
  • Alkyl, alkenyl, alkynyl, heterocyclyl, aryl, arylalkyl, arylalkenyl, heteroaryl, (heteroaryl)alkyl, and (heteroaryl)alkenyl groups may be unsubstituted or may contain non- hydrogen substituents dependent upon the number of carbon or other atoms in the group and the degree of unsaturation of the group.
  • substituted alkyl, alkenyl, alkynyl, heterocyclyl, aryl, arylalkyl, arylalkenyl, heteroaryl, (heteroaryl)alkyl, and (heteroaryl)alkenyl groups preferably contain 1-10, more preferably 1-6, and most preferably 1, 2, or 3 non-hydrogen substituents.
  • Optional substitution refers most generally to replacement of any hydrogen atom of any group herein including any carbon atom of a substituent group herein, with one or more of the following functional groups: cyano, isocyano, halogen (CI, F, Br, I), hydroxy, alkyl (including C 1 -C 6 alkyl and C 1 -C 3 alkyl), alkenyl, alkynyl, heterocyclyl, aryl, arylalkyl, arylalkenyl, heteroaryl, (heteroaryl)alkyl, (heteroaryl)alkenyl, haloalkyl, hydroxyalkyl, acyl, OH, alkoxy (including C 1 -C 6 alkoxy and C 1 -C 3 alkoxy), alkenyloxy, alkynyloxy, heterocyclyloxy, aryloxy, arylalkoxy, heteroaryloxy, (heteroaryl)alkoxy, OCF 3 ,
  • compositions and Methods of Treatment refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, and which are not biologically or otherwise undesirable.
  • the salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, preferably hydrochloric acid; and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, ascorbic acid, gluconic acid, N-acetylcysteine, acidic ion exchange resins, and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, preferably hydroch
  • these salts may be prepared by addition of an inorganic base or an organic base to the free acid.
  • Salts derived from an inorganic base include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts, and the like.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins; such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyamine resins, and the like.
  • Compounds of Formula 1 that contain both acidic and basic functional groups can also be in the form of zwitterions.
  • the compounds of the disclosure expressly includes pharmaceutically usable solvates of compounds according to Formula 1.
  • the compounds of Formula 1 can be solvated, e.g. hydrated.
  • the solvation can occur in the course of the manufacturing process or can take place, e.g. as a consequence of hygroscopic properties of an initially anhydrous compound of Formula 1 (hydration).
  • a particular solvate form of a compound of this disclosure is a hydrate.
  • “Pharmaceutically acceptable esters” refers to ester derivatives of compounds of Formula 1 or other formulas herein formed at certain functional groups which are capable of conversion back to the parent compounds in vivo. For example, the C(O)OH groups of compounds can be esterified.
  • esters include physiologically acceptable and metabolically labile ester derivatives, such as methoxymethyl esters, methylthiomethyl esters, and pivaloyloxymethyl esters. Additionally, any physiologically acceptable equivalents of the compounds of general Formula 1, similar to the metabolically labile esters, which are capable of producing the compounds of general Formula 1 in vivo, are encompassed within this disclosure. Esters more specifically include methyl, ethyl, propyl, butyl, and benzyl esters.
  • esters are compounds of Formula 1, wherein hydroxy groups can be esterified, for example by formation of formate, acetate, propionate, butyrate, isobutyrate, valerate, 2-methylbutyrate, isovalerate, benzoate, nicotinate, and N,N-dimethylaminoacetate esters.
  • prodrug means a compound that is convertible in vivo by metabolic means ( e.g. by hydrolysis) to a compound of Formula 1.
  • prodrugs are known in the art such as those discussed in, for example, Bundgaard (ed.), Design of Prodrugs, Elsevier (1985); Widder et al. (ed.), Methods in Enzymology, vol.4, Academic Press (1985); Krogsgaard-Larsen et al.
  • the compounds of the disclosure can be administered in general in any appropriate dosage form including, among others, forms suitable for administration orally, intravenously, sublingually, ocularly, transdermally, rectally, vaginally, topically, intramuscularly, subcutaneously, buccally, or nasally.
  • the compounds of the disclosure can be administered in oral dosage forms including tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions.
  • Oral dosage forms may include sustained release or timed-release formulations.
  • the compounds of the disclosure may also be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. Compounds of the disclosure can further be administered topically employing appropriate carriers. [0165] Compounds of the disclosure can also be administered in intranasal form by topical use of suitable intranasal vehicles. For intranasal or intrabronchial inhalation or insulation, the compounds of this disclosure may be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol. [0166] The compounds of the disclosure can also be administered to the eye (ocularly), preferably as a topical ophthalmic formulation.
  • the compounds of this disclosure can also be combined with a preservative and an appropriate vehicle such as mineral oil or liquid lanolin to provide an ophthalmic ointment.
  • the compounds of the disclosure may be administered rectally or vaginally in the form of a conventional suppository.
  • the compounds of the disclosure may also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is nontoxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin.
  • the compounds of the disclosure may be administered employing an occlusive device.
  • occlusive devices can be used to release an ingredient into the blood stream such as a semipermeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient.
  • Other occlusive devices are known in the literature.
  • the therapeutically active compounds of the disclosure can be administered alone, but generally will be administered with a pharmaceutical carrier selected upon the basis of the chosen route of administration and standard pharmaceutical practice.
  • Pharmaceutical compositions of the disclosure can include one or more compounds, pharmaceutically acceptable salts, esters, or solvates thereof or a prodrug thereof in combination with a pharmaceutically acceptable carrier, excipient, or diluent.
  • compositions are prepared in accordance with acceptable pharmaceutical procedures, such as, for example, those described in Remington's Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gellaro, Mack Publishing Company, Easton, Pa. (1985), which is incorporated herein by reference in its entirety.
  • Pharmaceutically acceptable carriers are those carriers that are compatible with the other ingredients in the formulation and are biologically acceptable. Carriers can be solid or liquid.
  • Solid carriers can include one or more substances that can also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders, tablet-disintegrating agents, or encapsulating materials.
  • the carrier is a finely divided solid that is in admixture with the finely divided active ingredient.
  • the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain up to 99% of the active ingredient.
  • Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low-melting waxes, and ion exchange resins.
  • Liquid carriers can be used in preparing solutions, suspensions, emulsions, syrups, and elixirs.
  • the active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water (of appropriate purity, e.g., pyrogen-free, sterile, etc.), an organic solvent, a mixture of both, or a pharmaceutically acceptable oil or fat.
  • a pharmaceutically acceptable liquid carrier such as water (of appropriate purity, e.g., pyrogen-free, sterile, etc.), an organic solvent, a mixture of both, or a pharmaceutically acceptable oil or fat.
  • the liquid carrier can contain other suitable pharmaceutical additives such as, for example, solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, or osmo-regulators.
  • liquid carriers for oral and parenteral administration include water of appropriate purity, aqueous solutions (particularly containing additives as above, e.g. cellulose derivatives such as sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols and glycerol) and their derivatives, and oils.
  • the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
  • the liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.
  • compositions that are sterile solutions or suspensions can be administered by, for example, intramuscular, intraperitoneal, or subcutaneous injection. Sterile solutions can also be administered intravenously.
  • Compositions for oral administration can be in either liquid or solid form.
  • the carrier can also be in the form of creams and ointments, pastes, and gels.
  • the creams and ointments can be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type.
  • Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient can also be suitable.
  • the pharmaceutical composition is in unit dosage form, e.g.
  • the composition is sub-divided in unit doses containing appropriate quantities of the active ingredient;
  • the unit dosage forms can be packaged compositions, for example, packaged powders, vials, ampules, pre-filled syringes, or sachets containing liquids.
  • the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form. [0177]
  • the dosage can vary within wide limits and as is understood in the art will have to be adjusted to the individual requirements in each particular case as discussed above.
  • the daily oral dosage can vary from about 0.01 mg to 1000mg, 0.1 mg to 100 mg, or 10 mg to 500 mg per day of a compound of Formula 1 or of the corresponding amount of a pharmaceutically acceptable salt thereof.
  • the daily dose may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated.
  • additional therapeutic agents which are normally administered to treat or prevent that disease, disorder, or condition, may be administered together with an inhibitor of this disclosure.
  • anti-diabetic agents may be combined with a GSK-3 inhibitor of this disclosure to treat diabetes.
  • anti-diabetic agents include, without limitation, insulin or insulin analogs, glitazones, alpha-glucosidase inhibitors, biguanides, insulin sensitizers, and sulfonylureas.
  • agents that can be combined with the inhibitors of this disclosure in methods of treatment include, without limitation, chemotherapeutic agents, antiproliferative agents, and anti-inflammatory agents.
  • This disclosure also provides kits for conveniently and effectively implementing the therapeutic and treatment methods of this disclosure.
  • Kits of the disclosure comprise one or more compounds disclosed herein (e.g., compounds of Formula 1, 2A, 2B, or any other compounds disclosed herein, and pharmaceutically acceptable salts, esters and solvates thereof) and a means for facilitating compliance with methods of this disclosure.
  • Kits typically comprise container means or packaging for holding a selected amount of the active compound of the disclosure or a pharmaceutical composition comprising the active compound of disclosure.
  • the kit provides convenient and effective means for assuring that an individual to be treated takes the appropriate active ingredient in the correct dosage in the correct manner to achieve the desired therapeutic benefit.
  • the compliance means of such kits comprises any means which facilitates administration of the active compounds according to the method of this disclosure.
  • Kits can be provided which are suitable for facilitating administration to the individual to be treated by a health care professional to, for example, assist in providing the proper dosage at proper intervals to a given patient.
  • kits can be provided which are suitable for facilitating self-administration by the individual being treated or by a non- health care profession who may be assisting the individual.
  • Compliance means include, for example, instructions, packaging and dispensing means, or combinations thereof suitable for the particular application of the kit.
  • Kit components may be packaged for manual, automated, or partially automated practice of the methods herein.
  • the disclosure provides medicaments for therapeutic application, in particular for the treatment of protein kinase-related diseases, disorders, or conditions.
  • the disclosure provides medicaments for treatment of GSK-3-related diseases, disorders, or conditions.
  • Medicaments herein contain one or more than one of the compounds of Formula 1, Formula 2A, Formula 2B or salts, esters, solvates, or prodrugs thereof, optionally in combination with a pharmaceutically acceptable carrier and in a dosage form appropriate for the intended administration of the medicament.
  • the disclosure provides methods of making a medicament employing one or more compounds of Formula 1, Formula 2A, Formula 2B or salts, esters, solvates, or prodrugs thereof.
  • Medicaments are made using methods that are well known in the art.
  • medicaments of this disclosure are made by combining one or more compounds, salts, esters, or solvates of Formula 1, Formula 2A, Formula 2B, or prodrugs thereof, with a pharmaceutically acceptable carrier suitable for administration by an appropriate means for administration to an individual in need of treatment.
  • a pharmaceutically acceptable carrier suitable for administration by an appropriate means for administration to an individual in need of treatment.
  • the disclosure further extends to the use of one or more compounds of Formula 1, Formula 2A, Formula 2B , salts, esters, solvates, or prodrugs thereof, for the treatment of one or more protein kinase related diseases, disorders, or conditions as defined above.
  • the disclosure additionally extends to the use of one or more compounds of Formula 1, salts, esters, solvates, or prodrugs thereof for the treatment of one or more GSK-3-related diseases, disorders, or conditions as defined above.
  • the disclosure additionally extends to the use of one or more compounds of Formula 2A or Formula 2B, salts, esters, solvates, or prodrugs thereof for the treatment of cancer, particularly colorectal cancer, pancreatic cancer, and ovarian cancer.
  • Certain compounds of this disclosure also have utility as starting materials for the preparation of compounds that are in turn useful in various therapeutic applications, for example, for the preparation of additional inhibitors of protein kinases and particularly for preparation of inhibitors of GSK-3.
  • the scope of the disclosure as described and claimed encompasses the racemic forms of the compounds as well as the individual enantiomers and non-racemic mixtures thereof.
  • the compounds of the disclosure may contain one or more asymmetric carbon atoms or axes or plains of chirality, so that the compounds can exist in different stereoisomeric forms.
  • the compounds can be, for example, racemates or optically active forms.
  • the optically active forms can be obtained by resolution of the racemates or by asymmetric synthesis.
  • the optically active forms may exhibit different levels of protein kinase inhibition, the more active form being referred to as the eutomer, and the less active form being referred to as the distomer.
  • the eutomers are substantially free of the corresponding distomer.
  • an enantiomer substantially free of the corresponding other enantiomer refers to a compound which is isolated or separated via separation techniques or prepared free of the corresponding enantiomer. "Substantially free” means that the compound is made up of a significantly greater percentage of one enantiomer vs. the other.
  • the compound is made up of at least about 90% by weight of a eutomer. In other aspects of the disclosure, the compound is made up of at least about 99% by weight of a eutomer.
  • Eutomers may be isolated from racemic mixtures by any method known to those skilled in the art, including high performance liquid chromatography (HPLC), the reversible formation and separation of covalent derivatives, and the formation and crystallization of chiral salts; or prepared by methods described herein.
  • HPLC high performance liquid chromatography
  • Jacques et al. Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S. H. et al., Tetrahedron 1977, 33, 2725; Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, N.Y., 1962); Wilen, S. H. Tables of Resolving Agents and Optical Resolutions, p.268 (E. L.
  • Isotopic variants of compounds herein which are enriched in one or more isotopes such that an isotope distribution in the compound is different from the naturally occurring isotope distribution are encompassed within this disclosure. More specifically, isotopic variants include those which contain isotopic variants of hydrogen, carbon, nitrogen, and halogens. Isotopic variants of a molecule are generally useful as standards in assays for the molecule and in chemical and biological research related to the molecule or its use. Isotopic variants may also be useful in diagnostic assays and in therapeutics. Methods for making such isotopic variants are known in the art. [0189] Specific names of compounds are intended to be exemplary, as it is known that one of ordinary skill in the art can name the same compounds differently.
  • ionizable groups [groups from which a proton can be removed (e.g., carboxyl), or to which a proton can be added (e.g., amines), or which can be quaternized (e.g., amines)]. All possible ionic forms of such molecules and salts thereof are intended to be included individually in the disclosure herein.
  • salts of the compounds herein one of ordinary skill in the art can select from among a wide variety of available counterions those that are appropriate for preparation of salts of this disclosure for a given application. In specific applications, the selection of a given anion or cation for preparation of a salt may result in increased or decreased solubility of that salt.
  • Methods of Treatment Disclosed herein are methods of inhibiting GSK-3 in a cell comprising contacting the cell with the compound of the disclosure, or salt or a pharmaceutical composition thereof, in an amount effective to inhibit GSK-3.
  • the contacting can comprise administering the compound or salt or the composition to a subject in need thereof.
  • methods of inhibiting proliferation of cancer cells comprising contacting the cell with the compound of the disclosure, or salt or a pharmaceutical composition thereof, in an amount effective to inhibit proliferation.
  • the contacting can comprise administering the compound or salt or the composition to a subject in need thereof.
  • the cancer cell is a colorectal cancer cell, a pancreatic cancer cell, or an ovarian cancer cell.
  • the cancer cell is a pancreatic cancer cell or an ovarian cancer cell.
  • the cancer cell is a pancreatic cancer cell.
  • the cancer cell is an ovarian cancer cell.
  • Also disclosed herein are methods for treating a protein kinase-related disorder or disease in a subject comprising administering to the subject a therapeutically effective amount of the compound of the disclosure, or salt or a pharmaceutical composition thereof.
  • the protein kinase-related disorder or disease is a GSK-3-related disorder or disease.
  • the protein kinase-related disorder or disease is a GSK-3-related disorder or disease selected from cancer, neurological disease or disorder, and psychiatric disease or disorder.
  • the GSK-3-related disorder or disease is neurological disease or disorder, or psychiatric disease or disorder.
  • the GSK-3-related disorder or disease is cancer.
  • the GSK-3-related disorder or disease is neurological disease or disorder.
  • the GSK-3-related disorder or disease is psychiatric disease or disorder.
  • the protein kinase-related disorder or disease can include other protein kinases- related disorders, such as FLT4/VEGFR3, MST2/STK3, RSK3, and TNIK related disorders or diseases.
  • FLT4/VEGFR3 is a receptor tyrosine kinase that plays a key role in the development and maintenance of the lymphatic and cardiovascular systems, as well as a key role in cancer progression and metastasis.
  • MST2/STK3 is a kinase involved in signaling and can regulate cell growth and apoptosis in some cases.
  • RSK3 is a kinase that phosphorylates numerous cytosolic and nuclear substates implicated in driving cell growth, survival and motility in cancer.
  • TNIK is a kinase that regulates physiological and pathological metabolic signaling in cancer and other diseases including neurodegenerative.
  • Also disclosed herein are methods for treating cancer in a subject comprising administering to the subject a therapeutically effective amount of the compound of the disclosure, or salt or a pharmaceutical composition thereof.
  • the cancer being treated is colorectal cancer, pancreatic cancer, or ovarian cancer.
  • the cancer being treated is pancreatic cancer or ovarian cancer.
  • the cancer being treated is colorectal cancer.
  • the cancer being treated is pancreatic cancer.
  • the cancer being treated is ovarian cancer.
  • Further disclosed are methods for treating cancer in a subject comprising administering to the subject a therapeutically effective amount of the compound of the disclosure, or salt or a pharmaceutical composition thereof and a therapeutic agent.
  • the cancer being treated is colorectal cancer, pancreatic cancer, or ovarian cancer.
  • the cancer being treated is pancreatic cancer or ovarian cancer.
  • the cancer being treated is colorectal cancer.
  • the cancer being treated is pancreatic cancer.
  • the cancer being treated is ovarian cancer.
  • the therapeutic agent is gemcitabine, cisplatin, or carboplatin.
  • the therapeutic agent is cisplatin or carboplatin.
  • the therapeutic agent is gemcitabine.
  • the therapeutic agent is cisplatin.
  • the therapeutic agent is carboplatin.
  • the cancer being treated is pancreatic cancer and the therapeutic agent is gemcitabine.
  • the cancer being treated is ovarian cancer and the therapeutic agent is cisplatin or carboplatin.
  • the cancer being treated is ovarian cancer and the therapeutic agent is cisplatin.
  • the cancer being treated is ovarian cancer and the therapeutic agent is carboplatin.
  • GSK-3 and GSK- 3 ⁇ -related disorders include metabolic disorders and diseases, including type II diabetes, disorders or conditions of the central nervous system, including bipolar disorder, depression, manic depressive psychosis, mood disorders, mania, anxiety disorder, and schizophrenia, neurodegenerative disorders or diseases, including Alzheimer's disease, Parkinson's disease, frontoparietal dementia, corticobasal degeneration, Pick's disease, Down's disease, multiple sclerosis, immunodeficiency, osteoporosis, bone loss, fractures, leucopenia, Huntington's disease, amyotrophic lateral sclerosis, motor neuron diseases, neurotraumatic diseases, such as cranial or spinal trauma, stroke, ischemia, especially cerebral ischemia, epilepsy, diseases associated with abnormal cell proliferation, such as cancer and particularly colorectal cancer, pancreatic cancer, and ovarian cancer; allergies and asthma, disorders or diseases associated with high levels of TH2 cells, peripheral neuropathies, obesity, essential hypertension, atherosclerosis, cardiovascular diseases, polycystic ova
  • GSK-3 inhibitors can also be used to promote bone formation, increase bone mineral density, reduce fracture rate, increase fracture healing rate, increase cancellous bone formation, and increase new bone formation. Additionally, inhibition of GSK-3 mimics the activation of growth factor signaling pathways, and consequently GSK-3 inhibitors are useful in the treatment of diseases in which such pathways are insufficiently active. GSK-3 inhibitors are also indicated to be useful for reducing the motility of mammalian spermatozoa. [0202] In specific aspects, inhibitors of GSK-3 ⁇ of this disclosure are useful in the treatment of bipolar disorder and related conditions or disorders or the symptoms thereof. In other specific aspects, inhibitors of GSK-3 ⁇ of this disclosure are useful in the treatment of type II diabetes.
  • inhibitors of GSK-3 ⁇ of this disclosure are useful in the treatment of Alzheimer's disease.
  • inhibitors of GSK-3 ⁇ of this disclosure are useful in the treatment of cancer, particularly colorectal cancer, pancreatic cancer, and ovarian cancer.
  • Methods of preventing or treating disorders, diseases, conditions, and symptoms in a mammal and particularly in a human includes administering to an individual in need of treatment or prophylaxis, a therapeutically effective amount of a compound of this disclosure.
  • the result of treatment can be partially or completely alleviating, inhibiting, preventing, ameliorating, and/or relieving the disorder, condition, or one or more symptoms thereof.
  • Administration includes any form of administration that is known in the art to be effective for a given type of disease or disorder, is intended to encompass administration in any appropriate dosage form, and further is intended to encompass administration of a compound, pharmaceutically acceptable salt, solvate, or ester thereof alone or in a pharmaceutically acceptable carrier thereof, or administration of a prodrug derivative or analog of a compound of this disclosure which will form an equivalent amount of the active compound or substance within the body.
  • An individual in need of treatment or prophylaxis includes those who have been diagnosed to have a given disorder or condition and to those who are suspected, for example, as a consequence of the display of certain symptoms, of having such disorders or conditions.
  • protein kinase is used generically herein to refer to any protein kinase expressed in mammalian tissue.
  • protein kinase-related in reference to diseases, disorders, conditions, etc. refers to any disorders, conditions or diseases that are mediated, caused, enhanced, or exacerbated by a protein kinase.
  • a number of protein kinases are known in the art. Of particular interest with respect to the compounds of this disclosure are GSK-3 (including GSK-3 ⁇ , GSK-3 ⁇ ), cyclin-dependent kinases (e.g., CDK-2, CDK-5, etc.) and protein kinase C (PKC).
  • Protein kinase-related diseases include autoimmune diseases, inflammatory diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, or hormone-related diseases.
  • selectiveivity is used herein in reference to inhibition of protein kinases by small molecules, particularly those of this disclosure.
  • an inhibitor of one protein kinase may also inhibit one or more other protein kinases. Because the different protein kinases exhibit effects in a variety of biological processes, it will generally be preferred when wishing to inhibit a target protein kinase to employ those inhibitors which selectively inhibit the target protein kinase.
  • Inhibitors preferred for use in therapeutic application are those which exhibit effective inhibition of the target and minimal inhibition of protein kinases the inhibition of which will be detrimental. Because a disease, disorder, or condition may have a complex etiology which is mediated by more than one protein kinase, protein kinase inhibitors which inhibit multiple protein kinases may in some cases provide additional therapeutic benefit.
  • the dosage requirements need to achieve the "therapeutically effective amount" vary with the particular compositions employed, the route of administration, the severity of the symptoms presented, and the particular subject being treated.
  • terapéuticaally effective amount refers to the amount of a compound of Formula I (or a salt, ester, or solvate thereof) that, when administered to an individual, is effective to at least partially treat a disorder, disease or condition from which the individual is suffering, to at least partially ameliorate a symptom of such disorder, disease, or condition, to prevent or ameliorate a disorder or condition which may affect an individual, or to prevent further deterioration or decrease the severity of a disorder or conditions which may affect an individual.
  • the therapeutically effective amount of a given compound will depend at least in part upon the mode of administration, any carrier or vehicle (e.g., solution, emulsion, etc.) employed, the specific disorder or condition, and the specific individual to whom the compound is to be administered (age, weight, condition, sex, etc.).
  • composition of matter when composition of matter are claimed, it should be understood that compounds known and available in the art prior to Applicant's disclosure, including compounds for which an enabling disclosure is provided in the references cited herein, can be excluded from the composition of matter claims herein.
  • the disclosure illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein.
  • One of ordinary skill in the art will appreciate that starting materials, biological materials, reagents, synthetic methods, purification methods, analytical methods, assay methods, and biological methods other than those specifically exemplified can be employed in the practice of the disclosure without resort to undue experimentation. All art-known functional equivalents of any such materials and methods are intended to be included in this disclosure.
  • Bis-heteroaryl maleimides and related compounds of this disclosure are made by condensation of 3-(bicyclic heteroaryl)glyoxylic acid esters and the appropriately substituted benzothiophenyl- or benzoselenophenyl-3-acetamides or by condensation of 3- benzothiophenyl-or benzoselenophenylglyoxylic acid esters and the appropriately substituted (bicyclic heteroaryl)-3-acetamides (see Scheme 2) (Faul, M. M.; Winneroski, L. L.; Krumrich, C. A., J. Org. Chem.1998, 63 (17), 6053-6058; Faul, M. M.; Winneroski, L.
  • 3-Benzofuranylacetic acids can be prepared by Wittig reaction on the requisite benzofuranone (US 2010/0004308; Deshpande, A. R.; Paradkar, M. V., Indian J. Chem., Section B 1992, 31 B(8), 526-528; Deshpande, A. R.; Paradkar, M. V., Synth. Commun., 1990, 20, 809; Scheme 7):
  • 3-Indolylacetic acid can be synthesized by the reaction of indole with glycolic acid in the presence of base under forcing conditions (Johnson, H.
  • aryloxyacetyl chlorides result from treatment of aryloxyacetic acids with standard reagents such as thionyl chloride or oxalyl chloride, and the aryloxyacetic acids in turn are prepared by nucleophilic displacement of CI in chloroacetic acid by phenols in a basic reaction medium.
  • standard reagents such as thionyl chloride or oxalyl chloride
  • the aryloxyacetic acids in turn are prepared by nucleophilic displacement of CI in chloroacetic acid by phenols in a basic reaction medium.
  • a simple synthetic approach to benzothiophenes is shown in Scheme 13 (Wang et al., Tetrahedron Letters 2005, 46, 907-910)
  • 3-Bromobenzoselenophenes have been obtained in a three-step sequence from bromoarenes (Paegle, E. et al., Chem.
  • Y 1 is O, S, Se, or NR 1 ;
  • R 1 and R 2 independently of one another, are selected from H or alkyl, particularly C1-C3 alkyl;
  • X 14 and X 24 are independently hydrogen, halogen, or methyl;
  • X 15 , X 16, X 17, X 25 , X 26 , and X 27 are selected from hydrogen, halogen, methyl, trifluoromethyl, OH, and alkoxy; or two of X 15 , X 16 , X 17 , X 25 , X 26 , and X 27 , attached to adjacent positions of their respective rings, together form a saturated or unsaturated three- or four-membered chain of carbon atoms with hydrogen atoms attached to satisfy valency, in which optionally one or two CH2 groups are replaced with oxygen or sulfur; and
  • C and D are selected from the groups: where w and z are 1 or 0, and w and
  • Y 1 is O, S, Se, or NR 1 ;
  • R 1 and R 2 independently of one another, are selected from H or alkyl, particularly C1-C3 alkyl;
  • X 14 and X 24 are independently hydrogen, halogen, or methyl;
  • X 15 , X 16, X 17, X 25 , X 26 , and X 27 are selected from hydrogen, halogen, methyl, trifluoromethyl, OH, and alkoxy; or two of X 15 , X 16, X 17, X 25 , X 26 , and X 27 , attached to adjacent positions of their respective rings, together form a saturated or unsaturated three- or four-membered chain of carbon atoms with hydrogen atoms attached to satisfy valency, in which optionally one or two CH 2 groups are replaced with oxygen or sulfur.
  • a pharmaceutical acceptable composition which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of aspect 2 or aspect 3.
  • a method for treating a protein kinase-related disorder, disease, or condition which comprises the step of administering a therapeutically effective amount of a compound of aspect 2 or aspect 3 to an individual in need of such treatment.
  • a method for treating a GSK-3-related disorder, disease, or condition, including cancer and neurological and psychiatric disorders which comprises the step of administering a therapeutically effective amount of a compound of aspect 2 or aspect 3 to an individual in need of such treatment. 7.
  • the methods of aspect 8 and aspect 10 wherein the compound is a compound having Formula 3: where X 1 and X 2 are H or halogen and Y 1 is NH, N-alkyl, or oxygen. 12.
  • the methods of aspect 8 and aspect 10 wherein the compound is a compound having Formula 3, where X 1 is a methylenedioxy group, X 2 is a halogen, and Y 1 is NH or N-alkyl.
  • the methods of aspect 8 and aspect 10 wherein the compound is a compound having Formula 3, where X 1 is a methylenedioxy group, X 2 is trifluoromethyl, and Y 1 is NH or N-alkyl. 14.
  • Staurosporine was used as a control and was tested in 10-dose IC50 mode with 4-fold serial dilution starting at 20 ⁇ M. All reactions were carried out at 10 ⁇ M ATP.
  • Plasma Pharmacokinetic Analysis [0233] Stock solutions of 9-ING-41-S and the control compound were prepared in DMSO (10 mM). Separately, 5 ⁇ L aliquots of each stock solution (9-ING-41-S and control) were diluted with 45 ⁇ L of DMSO. [0234] A buffer solution at pH 7.4 was prepared from a basic and acidic solution.
  • a basic solution was prepared by dissolving 14.2 g/L Na 2 HPO 4 and 8.77 g/L NaCl in deionized water and stored at 4°C for up to 7 days.
  • an acidic solution was prepared by dissolving 12.0 g/L NaH 2 PO 4 and 8.77 g/L NaCl in deionized water and stored at 4°C for up to 7 days.
  • the basic solution was titrated with the acidic solution to pH 7.4 and stored at 4°C for up to 7 days. The pH was checked prior to use and adjusted to pH 7.4 ⁇ 0.1.
  • Plasma was stored at -80°C and thawed immediately in a 37°C water bath.
  • Dialysis membranes were soaked in ultrapure water for 60 minutes to separate strips, then in 20% ethanol for 20 minutes, and finally in dialysis buffer for 20 minutes. Then, the prepared membranes were loaded into the dialysis machine and installed according to the device manufacturers guidelines. Next, the air bath was turned on and the membrane was pre-heated to 37°C. [0236] The samples were prepared by adding 597 ⁇ L of blank plasma solution 3 ⁇ L of the working solution of 9-ING-41-S into each vial of a new plate and vortexed at 1000 rpm for 2 minutes. The final percent volume of organic solvent was 0.5%v/v and the final concentration for 9-ING-41-S was 5 ⁇ M.
  • the cells were covered with a permeable lid and incubated for 6 hours at 37°C at 100 rpm with 5% CO2 on an orbital shaker in the CO2 incubator. At the end of incubation, 50 ⁇ L aliquots from both buffer and plasma solution chambers were transferred into respective wells of a 96-well plate for analysis.
  • a buffer solution at pH 7.4 was prepared from a basic and acidic solution.
  • a basic solution was prepared by dissolving 14.2 g/L Na2HPO4 and 8.77 g/L NaCl in deionized water and stored at 4°C for up to 7 days.
  • an acidic solution was prepared by dissolving 12.0 g/L NaH2PO4 and 8.77 g/L NaCl in deionized water and stored at 4°C for up to 7 days.
  • the basic solution was titrated with the acidic solution to pH 7.4 and stored at 4°C for up to 7 days. The pH was checked prior to use and adjusted to pH 7.4 ⁇ 0.1.
  • the samples were prepared by adding 597 ⁇ L of blank brain homogenate and 3 ⁇ L of the working solution of 9-ING-41-S into each vial of a new plate and vortexed at 1000 rpm for 2 minutes. The final percent volume of organic solvent was 0.5%v/v and the final concentration for 9-ING-41-S was 5 ⁇ M.
  • the remaining spiked brain homogenate sample in the plastic plate was incubated for 6 hours at 37°C with 5% CO 2 in the CO 2 incubator.
  • the hepatocytes were transferred into a 50 mL conical tube containing thawing medium, placed into a centrifuge and spun at 100 g for 10 minutes. After, the thawing medium was aspirated, and the hepatocytes were resuspended in enough incubation medium to yield ⁇ 1.5 ⁇ 10 6 cells/mL. Then, using an AO/PI staining, the cell count, and viable cell density were determined, and the cells were diluted with incubation medium to a working cell density of 0.5 ⁇ 10 6 viable cells/mL.
  • the working solutions at concentration of 20, 6.66, 2.22 and 0.74 uM were prepared by 500-fold dilution of the respective serial solutions (10, 3.33, 1.11 and 0.37 mM), using the extracellular NMDG60 solution.
  • the 60 ⁇ M working solution is prepared by 166.67-fold dilution of 10 mM DMSO stock solution.
  • 40 ⁇ L working solution was added to 40 ⁇ L cell solution, so 2x test concentration working solutions of compound are prepared.
  • IC 50 determination for hERG inhibition was evaluated in at 5 concentrations, 30, 10, 3.33, 1.11 and 0.37 ⁇ M.
  • the cells were counted and diluted in cold external solution to a final concentration of 0.5-0.7 x10 6 cells/mL. Then, the cell suspension was transferred to a 10 cm ultra-low-bind dish and incubated for 10 min at 4- 10 °C. The cells were gently stirred and transferred to a Teflon reservoir of the cell hotel, set to 15 °C and orbital shaking prior to measurement.
  • a SyncroPatch 384i/384 instrument was used for data collection. First, the chip was filled with external and internal solutions and the junction potential was compensated. Then, cells were added followed by a seal enhancer solution in order to seal the cell and the holding potential was set to -90 mV.
  • the cells were washed four times with external solution before Escin (15 ⁇ M) in the internal solution was perforated into cells to obtain the whole cell configuration, where analog Cslow and Digital Cslow compensate for cell capacitance. Then, the holding potential was set to -90 mV for 500 ms and the current at 500 Hz and filter at 3 kHz was recorded and the leaking current was tested at -90 mV. [0258] The hERG current was elicited by depolarizing the membrane to +30 mV for 4.8 sec and then -50 mV for 5.2 s, to remove the inactivation and measure the deactivating tail current with a sample interval of 15 s.
  • hERG current amplitude was used to assess the current stability and only stable cells with recording parameters passing acceptance criteria were used for the perfusion of working solutions.
  • blank vehicle was applied to the cells to establish the baseline. After stabilizing hERG current for at least 5 min, the test article was perfused. The hERG current in the presence of test compound at individual working concentration was recorded for no less than 5 min to reach steady state and then 5 sweeps were captured. If a steady state was not reached within 10 minutes, the averaged peak current of the last 5 sweeps was used. Positive control, Cisapride, was used in the experiments to ensure cell performance.
  • Preparation of 9-ING-41-S solution of IP Administration [0260] The solution of 9-ING-41-S for intraperitoneal (IP) administration was prepared as follows. 50 mg of 9-ING-41-S powder is first dissolved in 1 mL of 100% ethanol with vortexing and sonicating until the powder is dissolved. Subsequently, 5 mL of 100% PEG400 is added with more vortexing and sonicating.
  • Step 2 Ethyl 2-(5-Methyl-2H,5H-[1,3]dioxolo[4,5-f]indol-7-yl)-2-oxoacetate.
  • Step 3 3-(Chloromethyl)-5-fluorobenzo[b]thiophene.
  • a round-bottom flask is charged with 140-160 mmol of concentrated hydrochloric acid and 24- 30 mmol of 85% phosphoric acid.
  • Step 4 2-(5-Fluorobenzo[b]thiophen-3-yl)acetonitrile.
  • Step 5 2-(5-Fluorobenzo[b]thiophen-3-yl)acetamide.
  • a round bottom flask equipped with a magnetic stirrer is charged with 2-(5-fluorobenzo[b]thiophen-3-yl)acetonitrile (5 mmol), 4% aqueous sodium hydroxide (20 mL), and ethanol (60 mL).
  • the flask is fitted with a condenser, and the mixture is heated to reflux. Conversion is closely monitored by thin layer chromatography or HPLC analysis of small aliquots. A conversion of approximately 50-90% is targeted, as full conversion results in unnecessary material loss through further hydrolysis of the amide to the carboxylic acid.
  • the mixture is allowed to cool to ambient temperature, further cooled in an ice/water bath, and brought to pH approx.7 by addition of hydrochloric acid.
  • Step 6 3-(5-Fluorobenzo[b]thiophen-3-yl)-4-(5-methyl-2H,5H-[1,3]dioxolo[4,5- f]indol-7-yl)-1H-pyrrole-2,5-dione.
  • Step 6 3-(5-Fluoro-1-benzothiophen-3-yl)-4-(5-methyl-2H-[1,3]dioxolo[4,5-f]indol- 7-yl)-1H-pyrrole-2,5-dione (9-ING-41-S).
  • Example 3 Study on Kinase Inhibitory Activity of Compounds of the Disclosure
  • the kinase inhibitory activity of 9-ING-41-S was evaluated along with 9-ING-41-O against a panel of kinases including GSK-3 ⁇ and GSK-3 ⁇ , as well as several other kinases known to be inhibited by 9-ING-41-O (FLT4/VEGFR3, MST2/STK3, RSK3 and TNIK) and these results are shown in Table 3 and Figures 2 and 3.
  • Table 3 Table 3. IC50 kinase inhibitory activity of 9-ING-41-S toward 6 kinases.
  • 9-ING-41-S is a very potent inhibitor of GSK-3 ⁇ (IC50 – 1.70 x 10 -8 ) and GSK-3 ⁇ (IC50 – 3.46 x 10 -8 ) and was shown to inhibit several other kinases known to be inhibited by 9-ING-41-O (FLT4/VEGFR3, MST2/STK3, RSK3 and TNIK). Specifically, 9-ING-41-S was found to possess micromolar activity at MST2/STK3 and RSK3 and was also shown to be active at TNIK, while shown to be less active at FLT4/VEGFR3.
  • Figures 2 and 3 show the dose-response kinase inhibition curve observed for 9- ING-41-S toward GSK-3 ⁇ and GSK-3 ⁇ , respectively, which were used to calculate IC50 values.
  • Figures 2 and 3 also show the dose-response kinase inhibition curve observed for 9-ING-41-O toward GSK-3 ⁇ and GSK-3 ⁇ . Additionally, dose-response kinase inhibition curves were observed for MST2/STK3, RSK3, TNIK, and FLT4/VEGFR3 (See Figures 4 – 7, respectively).
  • 9-ING-41-S is nearly 10-fold more active toward GSK-3 ⁇ than 9- ING-41-O.
  • the IC50 of the positive control Cisapride is 0.019 mM compared to 27.03 mM for 9-ING-41-S.
  • the hERG activity of 9-ING-41-S is very low, as such there should be no cardiovascular concerns.
  • Example 5 – In-Vitro Study of Pharmacokinetic Study of Compounds of the Disclosure [0282] The pharmacokinetics of 9-ING-41-S was evaluated with human and mouse hepatocytes and brain tissue. [0283] The clearance rates for 9-ING-41-S in human and mouse hepatocytes was examined.
  • 9-ING-41-S was also found to exhibit good exposure in the brain, and the mean plasma and brain concentrations versus time after the administration of the drug IP in CD1 mice are shown in Figure 9.
  • the mean brain/plasma ratios for 9-ING-41-S were also calculated and are presented in Table 9. [0295] Table 9. IP Brain/Plasma Ratio data for 9-ING-41-S (IP Administration; 5 mg/kg) [0296] Accordingly, the data shown in Tables 5, 6, and 7 indicate that 9-ING-41-S is highly bound in both human and mouse plasma, while a low % of 9-ING-41-S is unbound.
  • pancreatic cancer cell lines were evaluated to determine their sensitivity to 9-ING- 41-S monotherapy with 9-ING-41-S concentrations of 1 ⁇ M, 2.5 ⁇ M, 5 ⁇ M, 7.5 ⁇ M and 10 ⁇ M in DMSO and pure DMSO as control.
  • the tested pancreatic cancer cell lines show sensitivity to 9-ING-41-S over the dose range used.
  • the number of L3.6 and PANC1 pancreatic cancer cells decreased for samples treated with higher concentrations of 9-ING- 41-S and as compared to control ( Figure 10).
  • Example 7 In-Vitro Study on Combination Therapy for Pancreatic Cancer [0302] It has been previously shown that GSK-3 inhibition impairs activation of the ATR- mediated DNA damage response leading to the phosphorylation of its downstream target Chk1 at S317 and S345 (Ding et al., 2019, Clinical Cancer Research, PMID: 31533931). We therefore tested whether 9-ING-41-S could similarly prevent the phosphorylation of Chk1 by ATR in the presence of the DNA damaging chemotherapeutic gemcitabine. L3.6 pancreatic cancer cell lines were treated with 9-ING-41-S at the indicated concentrations for 2 hrs. prior to adding gemcitabine for an additional 4 hrs.
  • 9-ING-41-S has been shown to block Chk1 phosphorylation associated with activation of the ATR pathway (e.g., cisplatin, carboplatin, or taxol). Further, 9-ING-41-S treatment was demonstrated to increase the presence of the mitotic markers pSer10 Histone H3 and pThr288 Aurora Kinase A, while both pSer10 Histone H3 and pThr288 Aurora Kinase A were shown to decrease when the combination treatment (9-ING- 41-S + cisplatin) was used. (Compare lane 3 and 4 in each cell line).
  • 9-ING-41-S treatment alone led to increased gamma H2Ax in the PEO1 cell lines (PEO1 cell line, lane 3 vs 1), suggesting that 9-ING-41-S may induce DNA damage on its own. It is believed that this DNA damage is mediated through impairment of ATR, which is active during S-phase and mitosis. [0309] Accordingly, 9-ING-41-S has been shown to inhibit the ATR-mediated DNA damage response, by the phosphorylation of Chk1, a protein involved in DNA repair. Moreover, this ATR-mediated DNA damage response is observed when ovarian cancer cell lines are treated with cisplatin, leading to reduced phosphorylation of Chk1.
  • Tumors will be measured weekly by abdominal ultrasound as known in the art to determine the number of PDX models that regress below baseline in each cohort. (Weroha, S.J., et al., Tumorgrafts as in vivo surrogates for women with ovarian cancer. Clin Cancer Res, 2014.20(5): p.1288-97). To assess for signs of toxicity, weekly CBC w/ differential, liver enzymes, and renal function will be measured in addition to animal weight and body condition scores.
  • PS19 tau P301S Male PS19 tau P301S (hereafter PS19) and age- matched wildtype mice will be randomized to one of two cohorts: Control or 9-ING-41-S, to evaluate whether post translational modifications of atua associated with disease in PS19 mice is attenuated with 9-ING-41-S treatment and determine if 9-ING-41 impacts gliosis, NFT deposition, and neurodegeneration.
  • the dose of 9-ING-41-S will be based on preliminary studies as monotherapy. Treatment will continue for 4 weeks (primary endpoint), and the mice will be evaluated weekly. Spatial learning performance will be assessed using the Barnes Maze test while behavioral tests will be used to assess anxiety-like behaviors and cognitive functions.

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Abstract

L'invention divulgue des composés, et des sels pharmaceutiquement acceptables de ceux-ci, ayant une structure de formule (I) : dans laquelle le cycle A, RN1, n, RA, Cyc1, Y1, Y2, R1, R2, R3, R4, R5, R6, R7 et R8 sont tels que définis. L'invention divulgue également des méthodes de traitement, ou leurs utilisations, pour traiter des maladies ou des troubles associés à GSK-3 tels que la maladie d'Alzheimer et le cancer, y compris en polythérapies.
PCT/US2024/058269 2023-12-03 2024-12-03 Malémides de benzothiophène-3-yl et benzosélénophène-3-yl (hétéroaryle biclylique) en tant qu'inhibiteurs de gsk-3 Pending WO2025122501A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040006095A1 (en) * 2002-05-08 2004-01-08 Han-Cheng Zhang Substituted pyrroline kinase inhibitors
JP3741466B2 (ja) * 1995-09-12 2006-02-01 株式会社トクヤマ キラルフォトクロミック材料
US20150306070A1 (en) * 2012-12-10 2015-10-29 Centogene Ag Use of maleimide derivatives for preventing and treating leukemia
WO2023172629A2 (fr) * 2022-03-08 2023-09-14 Brown University Dérivés de maléimide anticancéreux destinés à être utilisés avec un blocage de point de contrôle immunitaire

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3741466B2 (ja) * 1995-09-12 2006-02-01 株式会社トクヤマ キラルフォトクロミック材料
US20040006095A1 (en) * 2002-05-08 2004-01-08 Han-Cheng Zhang Substituted pyrroline kinase inhibitors
US20150306070A1 (en) * 2012-12-10 2015-10-29 Centogene Ag Use of maleimide derivatives for preventing and treating leukemia
WO2023172629A2 (fr) * 2022-03-08 2023-09-14 Brown University Dérivés de maléimide anticancéreux destinés à être utilisés avec un blocage de point de contrôle immunitaire

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE PubChem 18 December 2015 (2015-12-18), ANONYMOUS: "3,4-Bis(1-benzofuran-3-yl)pyrrole-2,5-dione | C20H11NO4 ", XP093327130, Database accession no. CID 101496950 *

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