Benzothiophene-3-YL- and benzoselenophene-3-YL (biclyclic heteroaryl) malemides as GSK-3 inhibitors

Abstract

Disclosed herein are compounds, and pharmaceutically acceptable salts thereof, having a structure of Formula (I): wherein ring A, RN1, n, RA, Cyc1, Y1, Y2, R1, R2, R3, R4, R5, R6, R7 and R8 are as recited. Also disclosed herein are methods of treatment, or uses thereof, for treating GSK-3 related diseases or disorders such as Alzheimer's disease and cancer, including combination therapies.

Description

BENZOTHIOPHENE-3-YL- AND BENZOSELENOPHENE-3-YL(BICYCLIC HETEROARYL)MALEIMIDES AS GSK-3 INHIBITORS FIELD

[0001] The present invention relates to compounds which are inhibitors of protein kinases and in particular are inhibitors of glycogen synthase kinase 3 (GSK-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. BACKGROUND

[0003] The search for new therapeutic agents has been greatly aided in recent years by better understanding of the structure of enzymes and other biomolecules associated with target diseases. One important class of enzymes that has been the subject of extensive study are protein kinases.

[0004] 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, H2O2), cytokines (e.g. interleukin-1 (IL-1) and tumor necrosis factors (TNF-α)), and growth factors (e.g. granulocyte macrophage-colony-stimulating factor (GM-CSF) and fibroblast growth factor (FGF)). 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.

[0005] Many diseases are associated with abnormal cellular responses triggered by protein kinase-mediated events. These 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. Accordingly, there has been a substantial effort in medicinal chemistry to find protein kinase inhibitors that are effective as therapeutic agents.

[0006] Glycogen synthase kinase-3 (GSK-3) is a serine / threonine protein kinase comprised of α and β 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. These proteins include 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, CREB, and CEPBn. These diverse protein targets implicate GSK-3 in many aspects of cellular metabolism, proliferation, differentiation and development. (Meijer, L. et al. "Pharmacological inhibitors or glycogen synthase kinase 3", Trends Pharmacol. Sci. 2004, 25(9), 471-480; Wagman, A. et al. "Discovery and Development of GSK-3 Inhibitors for the Treatment of Type 2 Diabetes", Curr. Pharmaceutical Design 2004, 10, 1105-1137; and Roca, C. et al. "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.)

[0007] In a 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. 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). However, in a diabetic patient where the insulin response is impaired, glycogen synthesis and glucose uptake fail to increase despite the presence of relatively high blood levels of insulin. This leads to abnormally high blood levels of glucose with acute and long term effects that may ultimately result in cardiovascular disease, renal failure, and blindness. In such patients, the normal insulin-induced inhibition of GSK-3 fails to occur. It has also been reported that in patients with type 2 diabetes, GSK-3 is overexpressed (WO 00 / 38675). Therapeutic inhibitors of GSK-3 are therefore potentially useful for treating diabetic patients suffering from an impaired response to insulin.

[0008] 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. Substantial efforts have been made to apply findings from laboratory research, as well as genetic and epidemiologic studies, to the identification of potential strategies for influencing Alzheimer's disease pathology. 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. 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.

[0009] Alzheimer's disease is characterized by the well-known β-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. Furthermore, 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-β (Aβ) peptide or Aβ-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).

[0010] Another substrate of GSK-3 is β-catenin, which is degraded after phosphorylation by GSK-3. Reduced levels of β-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).

[0011] More than 2 million American adults, or about 1 percent of the population age 18 and older in any given year, have bipolar disorder (manic depressive disorder). Current treatments include the so-called "mood stabilizers", lithium and valproic acid. Both arerelatively dated drugs that are only partially effective and produce various undesirable side effects (Fenech, R. K. et al., J. Alzheimer’s Dis.2023, 91(2), 615-626). Brief Description of Related Technology

[0012] Efforts to understand the mechanism of action of lithium have demonstrated that specific inhibitors of the enzyme glycogen synthase kinase-3 (GSK-3 ) mimic the therapeutic action of mood stabilizers and therefore have potential for improved drugs for treating patients with bipolar disorder as well as certain neurodegenerative disorders. The pro- apoptotic properties of the GSK-3 enzyme also indicate a potential for such inhibitors as neuroprotective agents. Additionally, the neuroprotection function of such inhibitors 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).

[0013] 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). U.S. Pat. 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. As noted above, 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. Also, GSK-3 is turned on by glutamate signaling, indicating that antagonists of MGIuR can affect GSK-3.

[0014] For many of the aforementioned diseases associated with abnormal GSK-3 activity, other protein kinases have also been targeted for treating the same diseases. However, the various protein kinases often act through different biological pathways. For example, certain quinazoline derivatives have been reported as inhibitors of p38 kinase (WO 00 / 12497). The compounds are reported to be useful for treating conditions characterized by enhanced p38 activity and / or enhanced TGF-β activity. While p38 activity has been implicated in a wide variety of diseases, including diabetes, p38 kinase is not reported to bea constituent of an insulin-signaling pathway that regulates glycogen synthesis or glucose uptake. Therefore, unlike GSK-3, p38 inhibition would not be expected to enhance glycogen synthesis and / or glucose uptake.

[0015] Because of the biological importance of GSK-3, there has been significant interest in therapeutically effective GSK-3 inhibitors. The following references relate to small molecule inhibitors of GSK-3 and their applications. U.S. Pat. No.6441053 reports inhibitors of GSK-3 and methods for identifying and using such inhibitors for the treatment of GSK-3 related disorders which are indicated to include bipolar disorder, including mania, Alzheimer's disease, diabetes, and leucopenia. The reference further indicates that 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.

[0016] WO 00 / 38675 (Smithkline Beecham) 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.

[0017] WO 02 / 10158 (Hoffman-LaRoche) and U.S. Pat. No.6479490 report 3-indolyl-4- phenyl-1H-pyrrole-2,5-dione derivatives as inhibitors of GSK-3. It is further reported that inhibition of GSK-3 activity 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.

[0018] 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. In particular, 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.

[0019] WO 05 / 111018 (Aventis) reports certain pyridazinone derivatives as inhibitors of GSK-3. These inhibitors are reported to be useful in the treatment of neurodegenerativediseases (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.

[0020] Published US application U.S.2006 / 0089369 (Chiron) reports certain pyrimidine or pyridine-based inhibitors of GSK-3 for treatment of disorders mediated by GSK-3 including diabetes, neurodegenerative disorders including Alzheimer's disease, obesity, atherosclerotic cardiovascular disease, essential hypertension, polycystic ovary syndrome, syndrome X, ischemia, especially cerebral ischemia, traumatic brain injury, bipolar disorder, immunodeficiency, and cancer. The reference states that agents that inhibit GSK-3 activity are useful in the treatment of disorders that are mediated by GSK-3 activity and that inhibition of GSK-3 mimics the activation of growth factor signaling pathways and consequently GSK3 inhibitors are useful in the treatment of diseases in which such pathways are insufficiently active.

[0021] 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.

[0022] 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.

[0023] Published U.S. application 20050075276 reports the use of inhibitors of GSK-3α or β 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. Thus, inhibitors of GSK-3 are indicated to be useful in the treatment of viral, bacterial, fungal, or prion infections.

[0024] 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 ofGSK-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.

[0025] 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. Among many other groups, R4can be selected from an aryl group, other than 3-indolyl, which aryl group can be substituted. Compounds 18 and 19 in Table 1 of the reference have R4that is an unsubstituted benzofuranyl, with R2that is methyl and R1that is H (18) or methyl (19). No test data are listed in Table 2 of the reference for either compounds 18 or 19. There is nothing in the reference that indicates that either of these compounds is a protein kinase inhibitor and nothing that indicates that either of these compounds is an inhibitor of GSK-3.

[0026] Engler T. A., et al. "The development of potent and selective bisarylmaleimide GSK3 inhibitors", Bioorg. Med. Chem. Lett.2005, 899-903 reports certain GSK3 inhibitors of formula:where Ar is selected from certain bicyclic heteroaromatic groups, including 3-, 4-, and 7- benzofuranyl, among a number of additional Ar groups. 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 PKCβII to IC50 at GSK3 of 37.

[0027] U.S. Pat. No.5721245 (Davis) reports compounds of formula:where among others X and Y are O, R1and R2taken together are a group of the formula - (CH2)n-, or R1and R7taken together are a group of the formula -(CH2)n-, Z is N or CH, n is an integer from 1 to 5, m is an integer from 0 to 5, and R3is 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. Exemplary 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.

[0028] 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 R8and R9, 1-(R7)- 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 R8and R9and in the dihydrofuryl ring with C1-C4alkyl; R8is -NHCO2(C1- C4alkyl), NHSO2(C1-C4alkyl), halo, amino, -O-(CH2)m-G, -NHC(O)(C1-C4alkyl), C1-C4alkoxy, hydroxy, –O-R10, C1-C4alkyl, C1-C4alkylthio, or -(CH2)m-G; and R9is halo; where G is hydroxy, NR11R12or piperidin-4-yl; R11and R12are independently selected from the group consisting of hydrogen, C1-C4alkyl, cyclopropylmethyl, benzyl, or taken together with thenitrogen to which they are attached form a piperidine, 4-hydroxypiperidine, 4-( C1- C4alkyl)piperidine, N-(R13)-piperazine, or morpholine ring where R13is hydrogen, C(O)-( C1- C4alkyl), or C1-C4alkyl.

[0029] U.S. Pat. No.5,057,614 (Davis) (see also U.S. RE 36736) reports compounds of Formula:where R2is hydrogen among other groups, and R1is 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 R3is a carbocyclic or heterocyclic aromatic group. The R3heterocyclic 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. Examples of R3heterocyclic aromatic groups given in the patent 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. SUMMARY

[0030] 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.

[0031] 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.

[0032] The present disclosure provides compounds which are inhibitors of protein kinases and in particular are inhibitors of glycogen synthase kinase 3 (GSK-3).

[0033] Provided herein are compounds having a structure of Formula (I), or a pharmaceutically acceptable salt of the compound thereof, wherein: ring A is a 5-membered heterocycle or heteroaryl comprising 1 or 2 ring nitrogen heteroatoms; RN1is independently H or C1-3alkyl; n is 0, 1, or 2; each RA, when present, is independently C1-3alkyl, C2-6alkenyl, O-C2-6alkenyl, C2-6alkynyl, O-C2-6alkynyl, Cyc1, or O-Cyc1; Cyc1is C3-8cycloalkyl, C6-10aryl, 5-8 membered heterocycle or 5-8 membered heteroaryl, wherein the heterocycle and heteroaryl each comprises 1, 2, or 3 ring heteroatoms independently selected from N, O, and S, and Cyc1is substituted with 0, 1, or 2 C1-6alkyl or C2-6alkenyl groups; Y1is selected from O, S, Se, and NRN1; Y2is S or Se; R1and R5are each independently absent or selected from halo and C1-3alkyl; and each of R2, R3, R4, R6, R7and R8are independently absent or selected from halo, C1-3alkyl, C1-3haloalkyl, hydroxyl, C1-3hydroxyalkyl, C1-3alkoxy, and CN; or R2and R3, or R3and R4, or R6and R7, or R7and R8together 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.

[0034] The compounds disclosed (and salts, esters, solvates, and prodrugs thereof) 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-3β. In preferred embodiments, GSK-3β inhibitors of this disclosure exhibit the ability to pass the brain-blood barrier as assessed in animal models.

[0035] 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. In specific embodiments, 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. In more specific embodiments, the disclosure provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of this disclosure which is a GSK-3β inhibitor in combination with a pharmaceutically acceptable carrier.

[0036] In accordance with the disclosure, 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-3β-related disease, disorder, or condition. Medicaments can further comprise a pharmaceutically acceptable carrier. Methods for thepreparation of such medicaments for the treatment of a GSK-3-related or a GSK-3β-related disease, disorder, or condition are also disclosed herein. The disclosure additionally relates to the use of a GSK-3 inhibitor of Formula 1 or pharmaceutically acceptable salt, ester, or solvate thereof for the preparation of a medicament for the treatment of a GSK-3-related or a GSK-3β-related disease.

[0037] Additional aspects will be apparent on review of the description herein including the figures and the specific examples. BRIEF DESCRIPTION OF DRAWINGS

[0038] Figure 1 is a scheme showing the synthesis of 9-ING-41-S.

[0039] Figure 2 shows the % activity of 9-ING-41-S and 9-ING-41-O against GSK-3α.

[0040] Figure 3 shows the % activity of 9-ING-41-S and 9-ING-41-O against GSK-3β.

[0041] Figure 4 shows the % activity of 9-ING-41-S and 9-ING-41-O against MST2 / STK3.

[0042] Figure 5 shows the % activity of 9-ING-41-S and 9-ING-41-O against RSK3.

[0043] Figure 6 shows the % activity of 9-ING-41-S and 9-ING-41-O against TNIK.

[0044] Figure 7 shows the % activity of 9-ING-41-S and 9-ING-41-O against FLT4 / VEGFR3.

[0045] 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.

[0046] 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.

[0047] 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.

[0048] Figure 11 shows cell confluency curves for the pancreatic cancer cell lines presented as the % of diluent (control).

[0049] 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.

[0050] Figure 13 shows cell confluency curves for the ovarian cancer cell lines presented as the % of diluent (control).

[0051] 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.

[0052] 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.

[0053] 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.

[0054] 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. DETAILED DESCRIPTION

[0055] 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-3β.

[0056] 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; RN1is independently H or C1-3alkyl;n is 0, 1, or 2; each RA, when present, is independently C1-3alkyl, C2-6alkenyl, O-C2-6alkenyl, C2-6alkynyl, O- C2-6alkynyl, Cyc1, or O-Cyc1; Cyc1is C3-8cycloalkyl, C6-10aryl, 5-8 membered heterocycle or 5-8 membered heteroaryl, wherein the heterocycle and heteroaryl each comprises 1, 2, or 3 ring heteroatoms independently selected from N, O, and S, and Cyc1is substituted with 0, 1, or 2 C1-6alkyl or C2-6alkenyl groups; Y1is selected from O, S, Se, and NRN1; Y2is S or Se; R1and R5are each independently absent or selected from halo and C1-3alkyl; and each of R2, R3, R4, R6, R7and R8are independently absent or selected from halo, C1-3alkyl, C1-3haloalkyl, hydroxyl, C1-3hydroxyalkyl, C1-3alkoxy, and CN; or R2and R3, or R3and R4, or R6and R7, or R7and R8together 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.

[0058] In compounds of Formula (I), ring A can be a 5-membered heterocycle or heteroaryl comprising 1 or 2 ring nitrogen heteroatoms. For example, ring A is, , , , , or . For example, ring A is.

[0059] In compounds of Formula (I), n can be 0, 1, or 2. For example, n is 0. For example, n is 1. For example, n is 2.

[0060] In compounds of Formula (I), each RAcan independently be absent, C1-3alkyl, C2- 6alkenyl, O-C2-6alkenyl, C2-6alkynyl, O-C2-6alkynyl, Cyc1, or O-Cyc1. For example, RAis C1- 3alkyl, Cyc1, or O-Cyc1. For example, RAis absent.

[0061] For example, the compound can have a structure of Formula (II), or a pharmaceutically acceptable salt thereof:

[0062] In compounds of Formulae (I) and (II), Y1can be O, S, Se, and NRN1. For example, Y1is S. For example, Y1is Se. For example, Y1is O. For example, Y1is NRN1.

[0063] In compounds of Formulae (I) and (II), Y2can be S or Se. For example, Y2is S. For example, Y2is Se.

[0064] In compounds of Formulae (I) and (II), each RN1can independently be H or C1-3alkyl. For example, RN1is H. For example, RN1is C1-3alkyl.

[0065] For example, the compound can have a structure of Formula (IIIa), or a pharmaceutically acceptable salt thereof:

[0066] In compounds of Formula (IIIa), Y1can be O, S, Se, and NRN1. For example, Y1is S or NRN1. For example, Y1is O or Se. For example, Y1is NRN1.

[0067] For example, the compound can have a structure of Formula (IIIb), or a pharmaceutically acceptable salt thereof:

[0068] In compounds of Formulae (IIIa) and (IIIb), each RN1can independently be H or C1-3alkyl. For example, at least one RN1is H. For example, each RN1is H. For example, at least one RN1is C1-3alkyl. For example, at least one RN1is C1-2alkyl. For example, each RN1is C1-3alkyl.

[0069] For example, the compound can have a structure of Formula (IVa), or a pharmaceutically acceptable salt thereof:

[0070] In compounds of Formula (IVa), Y1can be O, S, Se, and NRN1. For example, Y1is S or NRN1. For example, Y1is O or Se. For example, Y1is NRN1.

[0071] For example, the compound can have a structure of Formula (IVb), or a pharmaceutically acceptable salt thereof:

[0072] In compounds of Formulae (IVa) and (IVb), each RN1can independently be H or C1-3alkyl. For example, at least one RN1is H. For example, each RN1is H. For example, at least one RN1is C1-3alkyl. For example, at least one RN1is C1-2alkyl. For example, each RN1is C1-3alkyl.

[0073] In compounds of Formulae (I), (II), (IIIa), (IIIb), (IVa) and (IVb), R1and R5can each independently be absent or selected from halo and C1-3alkyl. For example, at least one of R1and R5is halo or C1alkyl. For example, at least one of R1and R5is C1alkyl. For example, at least one of R1and R5is halo.

[0074] In compounds of Formula (I), (II), (IIIa), (IIIb), (IVa) and (IVb), R2, R3, R4, R6, R7, and R8can independently be absent or selected from halo, C1-3alkyl, C1-3haloalkyl, hydroxyl, C1-3hydroxyalkyl, C1-3alkoxy, and CN, or R2and R3, or R3and R4, or R6and R7, or R7and R8together with the ring through which they are attached, form a C5-8cycloalkyl, C6-10aryl, 5-8membered heterocycle or 3-9 membered heteroaryl, and the heterocycle or heteroaryl comprises 1 or 2 ring heteroatoms independently selected from N, O, and S. For example, at least one of R2, R3, R4, R6, R7, and R8is selected from halo, C1-3alkyl, C1-3haloalkyl, hydroxyl, C1-3hydroxyalkyl, C1-3alkoxy, and CN. For example, at least one of R2, R3, R4, R6, R7, and R8is halo, hydroxyl, or CN. For example, at least one of R2, R3, R4, R6, R7, and R8is C1-3alkyl, C1-3haloalkyl, C1-3hydroxyalkyl, or C1-3alkoxy. For example, at least one of R2, R3, R4, R6, R7, and R8is F, Cl, Br, CN, CH3, OCH3, CF3, or CHF2. For example, at least one of R2, R3, R4, R6, R7, and R8is F, Cl, Br, CN, CH3, OCH3, CF3, or CHF2.

[0075] For example, R2and R3, or R3and R4, or R6and R7, or R7and R8together 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. For example, at least one of R2and R3, or R3and R4, or R6and R7, or R7and R8together with the ring through which they are attached, form a C5-8cycloalkyl or 5-8 membered heterocycle and the heterocycle comprises 1 or 2 ring heteroatoms independently selected from N, O, and S. For example, R2and R3, or R3and R4, or R6and R7, or R7and R8together with the ring through which they are attached, form a C5-8cycloalkyl. For example, R2and R3, or R3and R4, or R6and R7, or R7and R8together with the ring through which they are attached, form a 5-8 membered heterocycle and the heterocycle comprises 1 or 2 ring heteroatoms independently selected from N, O, and S. For example, at least one of R2and R3, or R3and R4, or R6and R7, or R7and R8together 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. For example, at least one of R2and R3, or R3and R4, or R6and R7, or R7and R8together with the ring through which they are attached, form a C6-10aryl.

[0076] Also disclosed are compounds, or pharmaceutically acceptable salts thereof, as recited in Table A.

[0077] For example, the compound can have a structure. Additional Aspects of the Disclosure

[0078] Also contemplated are compounds of Formula 1:and pharmaceutically acceptable salts, esters, and solvates (including hydrates) thereof, where: 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 Y1and Y2is selected from S and Se, and the other of Y1and Y2is selected from O, S, Se, and NR', wherein R' if it forms part of Y1is R1, and R' if it forms part of Y2is R2; R1and R2, independently of each other, are selected from H, alkyl, alkenyl, alkynyl, heterocyclyl, aryl, arylalkyl, arylalkenyl, heteroaryl, (heteroaryl)alkyl, and (heteroaryl)alkenyl; R3and R5, independently of each other, are selected from H, alkyl, alkenyl, alkynyl, heterocyclyl, aryl, arylalkyl, arylalkenyl, heteroaryl, (heteroaryl)alkyl, and (heteroaryl)alkenyl; each R6, independently of each R3, can take all values of R3or is OR4, where R4is selected from H, alkyl, alkenyl, alkynyl, heterocyclyl, aryl, arylalkyl, arylalkenyl, heteroaryl, (heteroaryl)alkyl, and (heteroaryl)alkenyl; andX1and X2represent one, two, three, or four non-hydrogen substituents on the indicated ring, wherein each X1and X2substituent, independently of any other X1and X2substituent, is selected from R, halogen, OH, OR, OC(O)R, OC(O)OR, OC(O)N(R')R, OSO2R, OSO2N(R')R, SH, SR, S(O)R, SO2R, C(O)R, C(O)OR, C(O)O-, NO2, N(R')R, N(R")(R')R+, N(R')C(O)R, N(R')C(O)OR, N(R")C(O)N(R')R, N(R')C(S)R, N(R")C(S)N(R')R, N(R")C(R')NR, C(R')NOR, C(O)N(R')R, C(S)N(R')R, C(NR")N(R')R, CN, N(SO2R')R, SO2N(R')R, SO2OH, and SO2O-; two X1and / or two X2together can form a 5- to 8-membered ring containing carbon and optionally containing one or two heteroatoms (i.e., 0, N, or S); X1or X2or both may also be hydrogen; where R, R', and R" are independently selected from H, alkyl, alkenyl, alkynyl, heterocyclyl, aryl, arylalkyl, arylalkenyl, heteroaryl, (heteroaryl)alkyl, and (heteroaryl)alkenyl; with the exceptions that C and D cannot both be, C and D cannot both be,C and D cannot both be , and C and D cannot bothIn specific aspects, C and D are not In specific aspects, C and D are both

[0079] Compounds of Formula 1 include those of Formulas 2A and 2B:and pharmaceutically acceptable salts, esters, and solvates thereof wherein:Y1is O, S, Se, or NR1; R1and R2, independently of one another, are selected from H or alkyl, particularly C1-C3alkyl; X14and X24are independently hydrogen, halogen, or methyl; X15, X16, X17, X25, X26, and X27are selected from hydrogen, halogen, methyl, trifluoromethyl, OH, and alkoxy; or two of X15, X16, X17, X25, X26, and X27, 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 CH2groups are replaced with oxygen or sulfur; and C and D are as defined for Formula 1.

[0080] In additional aspects of Formula 2A or 2B, two of X15, X16, X17, X25, X26, and X27are halogen or trifluoromethyl. In additional aspects of Formula 2A or 2B, two of X15, X16, X17, X25, X26, and X27are halogen or trifluoromethyl, and another of X15, X16, X17, X25, X26, and X27is halogen or C1-C3 alkoxy. In more specific aspects of Formula 2A or 2B, two of X15, X16, X17, X25, X26, and X27are halogen. In more specific aspects of Formula 2A or 2B, two of X15, X16, X17, X25, X26, and X27are halogen and another of X15, X16, X17, X25, X26, and X27is halogen or C1-C3 alkoxy. In more specific aspects of Formula 2A or 2B, X15, X16, X17, X25, X26, and X27, are halogen. In more specific aspects of Formula 2A or 2B, X15and X16are halogen, while X27is C1-C3 alkoxy and X25and X26are hydrogen or halogen; or X25and X26are halogen, while X17is C1-C3 alkoxy and X15and X16are hydrogen or halogen. In more specific aspects of Formula 2A or 2B, X16and X17are halogen, while X27is C1-C3 alkoxy and X25and X26are hydrogen or halogen. In more specific aspects of Formula 2A or 2B, X26and X27are halogen, while X17is C1-C3 alkoxy and X15and X16are hydrogen or halogen.

[0081] In additional aspects of Formula 2A or 2B, two of X15to X17are halogen or C1-C3 alkoxy. In additional aspects of Formula 2A or 2B, two of X25to X27are halogen or C1-C3 alkoxy. In additional aspects of Formula 2A or 2B, X15and X16are halogen. In additional aspects of Formula 2A or 2B, X25and X26are halogen. In additional aspects of Formula 2A or 2B, X17is C1-C3 alkoxy. In additional aspects of Formula 2A or 2B, X27is C1-C3 alkoxy. In more specific aspects of Formula 2A or 2B, two of X15to X17are halogen or C1-C3 alkoxy, and at least one of X25to X27is halogen or trifluoromethyl. In more specific aspects of Formula 2A or 2B, two of X25to X27are halogen or C1-C3 alkoxy, and at least one of X15to X17is halogen or trifluoromethyl. In more specific aspects of Formula 2A or 2B, two of X15to X17are halogen or C1-C3alkoxy, and at least one of X25to X27is halogen. In more specific aspects of Formula 2A or 2B, two of X25to X27are halogen or C1-C3alkoxy, and at least one of X15to X17is halogen. In more specific aspects of Formula 2A or 2B, two of X15to X17are halogen or C1-C3alkoxy, and at least one of X25to X27is trifluoromethyl. In more specific aspects of Formula 2A or 2B, two of X25to X27are halogen or C1-C3alkoxy, and at least one of X15to X17is trifluoromethyl. In more specific aspects of Formula 2A or 2B, two of X15to X17are halogen or C1-C3alkoxy, and two of X25to X27are halogen or trifluoromethyl. In more specific aspects of Formula 2A or 2B, two of X25to X27are halogen or C1-C3alkoxy, and two of X15to X17are halogen or trifluoromethyl. In more specific aspects of Formula 2A or 2B, two of X15to X17are halogen, and two of X25to X27are halogen or trifluoromethyl. In more specific aspects of Formula 2A or 2B, two of X25to X27are halogen, and two of X15to X17are halogen or trifluoromethyl. In more specific aspects of Formula 2A or 2B, two of X15to X17are halogen, and X25and X26are halogen or trifluoromethyl. In more specific aspects of Formula 2A or 2B, two of X25to X27are halogen, and X15and X16are halogen or trifluoromethyl. In more specific aspects of Formula 2A or 2B, two of X15to X17are halogen, and X26and X27are halogen. In more specific aspects of Formula 2A or 2B, two of X25to X27are halogen, and X16and X17are halogen.

[0082] In more specific aspects of Formula 2A or 2B, two of X15to X17are halogen, and two of X25to X27together form a methylenedioxy group. In more specific aspects of Formula 2A or 2B, two of X25to X27are halogen, and two of X15to X17together form a methylenedioxy group.

[0083] In more specific aspects of Formula 2A or 2B, two of X15to X17are halogen, and two of X25to X27together form the group OCH2S. In more specific aspects of Formula 2A or 2B, two of X25to X27are halogen, and two of X15to X17together form the group OCH2S.

[0084] In more specific aspects of Formula 2A or 2B, two of X15to X17are halogen, and two of X25to X27together form the group SCH2S. In more specific aspects of Formula 2A or 2B, two of X25to X27are halogen, and two of X15to X17together form the group SCH2S.

[0085] In more specific aspects of Formula 2A or 2B, two of X15to X17are halogen, and two of X25to X27together form the group OCH2CH2. In more specific aspects of Formula 2A or 2B, two of X25to X27are halogen, and two of X15to X17together form the group OCH2CH2.

[0086] In more specific aspects of Formula 2A or 2B, two of X15to X17are halogen, and two of X25to X27together form the group OCH2CH2CH2. In more specific aspects of Formula 2A or 2B, two of X25to X27are halogen, and two of X15to X17together form the group OCH2CH2CH2.

[0087] In more specific aspects of Formula 2A or 2B, two of X15to X17are halogen, and two of X25to X27together form the group CH2OCH2. In more specific aspects of Formula 2A or 2B, two of X25to X27are halogen, and two of X15to X17together form the group CH2OCH2.

[0088] In more specific aspects of Formula 2A or 2B, two of X15to X17are halogen, and two of X25to X27together form the group SCH2CH2. In more specific aspects of Formula 2A or 2B, two of X25to X27are halogen, and two of X15to X17together form the group SCH2CH2.

[0089] In more specific aspects of Formula 2A or 2B, two of X15to X17are halogen, and two of X25to X27together form the group SCH2CH2CH2.

[0090] In more specific aspects of Formula 2A or 2B, two of X25to X27are halogen, and two of X15to X17together form the group SCH2CH2CH2.

[0091] In more specific aspects of Formula 2A or 2B, two of X15to X17are halogen, and two of X25to X27together form the group CH2SCH2. In more specific aspects of Formula 2A or 2B, two of X25to X27are halogen, and two of X15to X17together form the group CH2SCH2.

[0092] In more specific aspects of Formula 2A or 2B, two of X15to X17are halogen, and two of X25to X27together form the group CH=CH-CH=CH (giving rise to an annulated benzene ring). In more specific aspects of Formula 2A or 2B, two of X25to X27are halogen, and two of X15to X17together form the group CH=CH-CH=CH (giving rise to an annulated benzene ring). In more specific aspects of Formula 2A or 2B, two of X15to X17are halogen, and X25and X26together form the group CH=CH-CH=CH (giving rise to an annulated benzene ring). In more specific aspects of Formula 2A or 2B, two of X25to X27are halogen, and X15and X16together form the group CH=CH-CH=CH (giving rise to an annulated benzene ring). In more specific aspects of Formula 2A or 2B, two of X15to X17are halogen, and X26and X27together form the group CH=CH-CH=CH (giving rise to an annulated benzene ring). In more specific aspects of Formula 2A or 2B, two of X25to X27are halogen, and X16and X17together form the group CH=CH-CH=CH (giving rise to an annulated benzene ring). In more specific aspects of Formula 2A or 2B, X15and X16are halogen, and X25and X26together form the group CH=CH-CH=CH (giving rise to an annulated benzene ring). In more specific aspects of Formula 2A or 2B, X25and X26are halogen, and X15and X16together form the group CH=CH-CH=CH (giving rise to an annulated benzene ring). In more specific aspects of Formula 2A or 2B, X15and X16are halogen, and X26and X27together form the group CH=CH-CH=CH (giving rise to an annulated benzene ring). In more specific aspects of Formula 2A or 2B, X25and X26are halogen, and X16and X17together form the group CH=CH-CH=CH (giving rise to an annulated benzene ring).

[0093] In specific aspects of Formula 2A or 2B, X15and X16are both fluorine. In specific aspects of Formula 2A or 2B, X25and X26are both fluorine. In specific aspects of Formula 2A or 2B, X15is fluorine. In specific aspects of Formula 2A or 2B, X16is fluorine. In specific aspects of Formula 2A or 2B, X25is fluorine. In specific aspects of Formula 2A or 2B, X26is fluorine.

[0094] In additional aspects of Formula 2A or 2B, X17is C1-C3 alkoxy. In additional aspects of Formula 2A or 2B, X27is C1-C3alkoxy. In additional aspects of Formula 2A or 2B, X17is methoxy. In additional aspects of Formula 2A or 2B, X27is methoxy. In more specificaspects of Formula 2A or 2B, X17is C1-C3alkoxy, and at least one of X25to X27is halogen or trifluoromethyl. In more specific aspects of Formula 2A or 2B, X27is C1-C3alkoxy, and at least one of X15to X17is halogen or trifluoromethyl. In more specific aspects of Formula 2A or 2B, X17is methoxy, and at least one of X25to X27is halogen or trifluoromethyl. In more specific aspects of Formula 2A or 2B, X27is methoxy, and at least one of X15to X17is halogen or trifluoromethyl. In more specific aspects of Formula 2A or 2B, X17is C1-C3alkoxy, and two of X25to X27are halogen or trifluoromethyl. In more specific aspects of Formula 2A or 2B, X27is C1-C3alkoxy, and two of X15to X17are halogen or trifluoromethyl. In more specific aspects of Formula 2A or 2B, X17is methoxy, and at least two of X25to X27are halogen or trifluoromethyl. In more specific aspects of Formula 2A or 2B, X27is methoxy, and at least two of X15to X17are halogen or trifluoromethyl. In more specific aspects of Formula 2A or 2B, X17is C1-C3 alkoxy, and X25is trifluoromethyl. In more specific aspects of Formula 2A or 2B, X27is C1-C3 alkoxy, and X15is trifluoromethyl. In more specific aspects of Formula 2A or 2B, X17is methoxy, and X25is trifluoromethyl. In more specific aspects of Formula 2A or 2B,

[0095] In more specific aspects of Formula 2A or 2B, X27is methoxy, and X15is trifluoromethyl. In more specific aspects of Formula 2A or 2B, X17is C1-C3 alkoxy, and X25is halogen. In more specific aspects of Formula 2A or 2B, X27is C1-C3 alkoxy, and X15is halogen. In more specific aspects of Formula 2A or 2B, X17is methoxy, and X25is halogen. In more specific aspects of Formula 2A or 2B, X27is methoxy, and X15is halogen. In more specific aspects of Formula 2A or 2B, X17is C1-C3 alkoxy, and X25and X26are both halogen. In more specific aspects of Formula 2A or 2B, X27is C1-C3 alkoxy, and X15and X16are both halogen. In more specific aspects of Formula 2A or 2B, X17is methoxy, and X25and X26are both halogen. In more specific aspects of Formula 2A or 2B, X27is methoxy, and X15and X16are both halogen.

[0096] In more specific aspects of Formula 2A or 2B, X17is C1-C3 alkoxy, and X25and X26together form a methylenedioxy group. In more specific aspects of Formula 2A or 2B, X27is C1-C3 alkoxy, and X15and X16together form a methylenedioxy group. In more specific aspects of Formula 2A or 2B, X17is methoxy, and X25and X26together form a methylenedioxy group. In more specific aspects of Formula 2A or 2B, X27is methoxy, and X15and X16together form a methylenedioxy group.

[0097] In more specific aspects of Formula 2A or 2B, X17is C1-C3alkoxy, and X25and X26together form a methylenedioxy group. In more specific aspects of Formula 2A or 2B, X27is C1-C3alkoxy, and X15and X16together form the group OCH2S. In more specific aspects of Formula 2A or 2B, X17is methoxy, and X25and X26together form the group OCH2S. In morespecific aspects of Formula 2A or 2B, X27is methoxy, and X15and X16together form a methylenedioxy group.

[0098] In more specific aspects of Formula 2A or 2B, X17is C1-C3alkoxy, and X25and X26together form a methylenedioxy group. In more specific aspects of Formula 2A or 2B, X27is C1-C3alkoxy, and X15and X16together form the group SCH2S. In more specific aspects of Formula 2A or 2B, X17is methoxy, and X25and X26together form the group SCH2S. In more specific aspects of Formula 2A or 2B, X27is methoxy, and X15and X16together form a methylenedioxy group.

[0099] In more specific aspects of Formula 2A or 2B, X17is C1-C3alkoxy, and X25and X26together form the group OCH2CH2. In more specific aspects of Formula 2A or 2B, X27is C1- C3 alkoxy, and X15and X16together form the group OCH2CH2. In more specific aspects of Formula 2A or 2B, X17is methoxy, and X25and X26together form the group OCH2CH2. In more specific aspects of Formula 2A or 2B, X27is methoxy, and X15and X16together form the group OCH2CH2.

[0100] In more specific aspects of Formula 2A or 2B, X17is C1-C3 alkoxy, and X25and X26together form the group OCH2CH2CH2. In more specific aspects of Formula 2A or 2B, X27is C1-C3 alkoxy, and X15and X16together form the group OCH2CH2CH2. In more specific aspects of Formula 2A or 2B, X17is methoxy, and X25and X26together form the group OCH2CH2CH2. In more specific aspects of Formula 2A or 2B, X27is methoxy, and X15and X16together form the group OCH2CH2CH2.

[0101] In more specific aspects of Formula 2A or 2B, X17is C1-C3 alkoxy, and X25and X26together form the group CH2OCH2. In more specific aspects of Formula 2A or 2B, X27is C1- C3 alkoxy, and X15and X16together form the group CH2OCH2. In more specific aspects of Formula 2A or 2B, X17is methoxy, and X25and X26together form the group CH2OCH2. In more specific aspects of Formula 2A or 2B, X27is methoxy, and X15and X16together form the group CH2OCH2.

[0102] In more specific aspects of Formula 2A or 2B, X17is C1-C3 alkoxy, and X25and X26together form the group SCH2CH2. In more specific aspects of Formula 2A or 2B, X27is C1- C3 alkoxy, and X15and X16together form the group SCH2CH2. In more specific aspects of Formula 2A or 2B, X17is methoxy, and X25and X26together form the group SCH2CH2. In more specific aspects of Formula 2A or 2B, X27is methoxy, and X15and X16together form the group SCH2CH2.

[0103] In more specific aspects of Formula 2A or 2B, X17is C1-C3 alkoxy, and X25and X26together form the group SCH2CH2CH2. In more specific aspects of Formula 2A or 2B, X27is C1-C3alkoxy, and X15and X16together form the group SCH2CH2CH2. In more specificaspects of Formula 2A or 2B, X17is methoxy, and X25and X26together form the group SCH2CH2CH2. In more specific aspects of Formula 2A or 2B, X27is methoxy, and X15and X16together form the group SCH2CH2CH2.

[0104] In more specific aspects of Formula 2A or 2B, X17is C1-C3alkoxy, and X25and X26together form the group CH2SCH2. In more specific aspects of Formula 2A or 2B, X27is C1- C3alkoxy, and X15and X16together form the group CH2SCH2. In more specific aspects of Formula 2A or 2B, X17is methoxy, and X25and X26together form the group CH2SCH2. In more specific aspects of Formula 2A or 2B, X27is methoxy, and X15and X16together form the group CH2SCH2.

[0105] In additional aspects of Formula 2A or 2B, one of X15to X17is halogen or trifluoromethyl, X27is C1-C3 alkoxy, and X25and X26are hydrogen or halogen. In additional aspects of Formula 2A or 2B, one of X25to X27is halogen or trifluoromethyl, X17is C1-C3 alkoxy, and X25and X26are hydrogen or halogen. In more specific aspects of Formula 2A or 2B, one of X15to X17is halogen or trifluoromethyl, X27is C1-C3 alkoxy, and X25and X26are both hydrogen. In more specific aspects of Formula 2A or 2B, one of X25to X27is halogen or trifluoromethyl, X17is C1-C3 alkoxy, and X15and X16are both hydrogen. In yet more specific aspects of Formula 2A or 2B, X15is halogen or trifluoromethyl, X16and X17are hydrogen, X27is C1-C3 alkoxy, and X25and X26are both hydrogen. In yet more specific aspects of Formula 2A or 2B, X25is halogen or trifluoromethyl, X26and X27are hydrogen, X17is C1-C3 alkoxy, and X15and X16are both hydrogen. In particular aspects of Formula 2A or 2B, X16and X17are fluorine or chlorine. In particular aspects of Formula 2A or 2B, X26and X27are fluorine or chlorine. In particular aspects of Formula 2A or 2B, X15and X16are fluorine or iodine. In particular aspects of Formula 2A or 2B, X25and X26are fluorine or iodine. In particular aspects of Formula 2A or 2B, X15is fluorine and X16is chlorine or iodine. In particular aspects of Formula 2A or 2B, X25is fluorine and X26is chlorine or iodine. In particular aspects of Formula 2A or 2B, X15is bromine. In particular aspects of Formula 2A or 2B, X25is bromine. In particular aspects of Formula 2A or 2B, X15is trifluoromethyl. In particular aspects of Formula 2A or 2B, X25is trifluoromethyl. In more particular aspects of Formula 2A or 2B, X17is methoxy. In more particular aspects of Formula 2A or 2B, X27is methoxy.

[0106] In particular aspects of Formula 2A or 2B, X15and X16together are methylenedioxy. In particular aspects of Formula 2A or 2B, X25and X26together are methylenedioxy. In particular aspects of Formula 2A or 2B, X15and X16together are OCH2S or SCH2O. In particular aspects of Formula 2A or 2B, X25and X26together are OCH2S or SCH2O. In particular aspects of Formula 2A or 2B, X15and X16together are SCH2S. In particular aspects of Formula 2A or 2B, X25and X26together are SCH2S. In particularaspects of Formula 2A or 2B, X16and X17together are CH=CH-CH=CH. In particular aspects of Formula 2A or 2B, X26and X27together are CH=CH-CH=CH.

[0107] In a specific aspect, compounds of Formula 2A or 2B are provided in which two of X15to X17are halogen and for example, are chlorine, bromine or iodine. In a specific aspect, compounds of Formula 2A or 2B are provided in which two of X25to X27are halogen and for example, are chlorine, bromine or iodine. In a specific aspect, the compounds of Formula 2A or 2B are provided in which X15and X16or X16and X17are halogen and for example are chlorine, bromine or iodine. In a specific aspect, compounds of Formula 2A or 2B are provided in which X25and X26or X26and X27are halogen and for example, are chlorine, bromine or iodine. In a specific aspect, compounds of Formula 2A or 2B are provided in which X15and X16, or X16and X17are the same halogen or different halogens, for example, where one of X15and X16is chlorine and the other of X15and X16is fluorine, bromine, or iodine; or particularly where one of X16and X17is chlorine and the other of X16and X17is fluorine, bromine, or iodine. In a specific aspect, compounds of Formula 2A or 2B are provided in which X25and X26, or X26and X27are the same halogen or different halogens, for example, where one of X25and X26is chlorine and the other of X25and X26is fluorine, bromine, or iodine; or for example, where one of X26and X27is chlorine and the other of X26and X27is fluorine, bromine, or iodine. In additional aspects in which two of X15to X17are halogen, all remaining X variables are hydrogen. In additional aspects in which two of X25to X27are halogen, all remaining X variables are hydrogen. In additional aspects in which two of X15to X17are halogen, at least one or at least two of X25to X27are C1-C3 alkoxy. In additional aspects in which two of X25to X27are halogen, at least one or at least two of X15to X17are C1-C3 alkoxy. In additional aspects in which two of X15to X17are halogens, one or two of X25to X27are C1-C3 alkoxy or halogen, and the remaining X variables are hydrogen. In additional aspects in which two of X25to X27are halogens, one or two of X15to X' are C1-C3 alkoxy or halogen, and the remaining X variables are hydrogen.

[0108] In a specific aspect, compounds of Formula 2A or 2B are provided in which one of X15to X17is halogen and for example, is chlorine, bromine, or iodine. In a specific aspect, compounds of Formula 2A or 2B in which one of X25to X27is halogen and for example, is chlorine, bromine, or iodine. In a specific aspect, compounds of Formula 2A or 2B are provided in which X15is a halogen and for example, is chlorine, bromine, or iodine. In a specific aspect, compounds of Formula 2A or 2B are provided in which X25is a halogen and for example, is chlorine, bromine, or iodine. In a specific aspect, compounds of Formula 2A or 2B are provided in which X16is halogen and for example, is chlorine, bromine, or iodine. In a specific aspect, compounds of Formula 2A or 2B are provided in which X26is halogen and for example, is chlorine, bromine, or iodine. In a specific aspect, compounds of Formula2A or 2B are provided in which X17is halogen and for example, is chlorine, bromine, or iodine. In a specific aspect, compounds of Formula 2A or 2Bare provided in which X27is halogen and for example, is chlorine, bromine, or iodine. In additional aspects in which one of X15to X17is halogen, one or two of X15to X17are C1-C3alkoxy. In additional aspects in which one of X15to X17is halogen, one or two of X25to X27are C1-C3alkoxy. In additional aspects in which one of X15to X17is halogen and one or two of X25to X27are C1-C3alkoxy or halogen, all remaining X and Y variables are hydrogen. In additional aspects in which one of X25to X27is halogen and one or two of X15to X17are C1-C3alkoxy or halogen, all remaining X and Y variables are hydrogen. In additional aspects in which one of X15to X17is halogen, all of X24to X27are hydrogen. In additional aspects in which one of X25to X27is halogen, all of X14to X17are hydrogen. In additional aspects in which one of X15to X17is halogen, all remaining X variables are hydrogen. In additional aspects in which one of X25to X27is halogen, all remaining X variables are hydrogen.

[0109] In specific aspects of the compounds of Formula 2A or 2B, X15is CI or I, and all other X variables are hydrogen. In specific aspects of the compounds of Formula 2A or 2B, X25is CI or I, and all other X variables are hydrogen. In specific aspects of the compounds of Formula 2A or 2B, X15is CI, Br, or I, X27is hydrogen or C1-C3 alkoxy, particularly methoxy, and all other X variables are H. In specific aspects of the compounds of Formula 2A or 2B, X25is CI, Br, or I, X17is hydrogen or C1-C3 alkoxy, particularly methoxy, and all other X variables are H. In specific aspects of the compounds of Formula 2A or 2B, X15is CI, X16is F, X27is hydrogen or C1-C3 alkoxy, and all other X variables are hydrogen. In specific aspects of the compounds of Formula 2A or 2B, X25is CI, X26is F, X17is hydrogen or C1-C3 alkoxy, and all other X variables are hydrogen. In specific aspects of the compounds of Formula 2A or 2B, X15is F, X16is Br or I, X27is hydrogen or C1-C3 alkoxy, and all other X variables are hydrogen. In specific aspects of the compounds of Formula 2A or 2B, X25is F, X26is Br or I, X17is hydrogen or C1-C3 alkoxy, and all other X variables are hydrogen. In specific aspects of the compounds of Formula 2A or 2B, X15is CI, X16is Br or I, X27is hydrogen or C1-C3 alkoxy, and all other X variables are hydrogen. In specific aspects of the compounds of Formula 2A or 2B, X25is CI, X26is Br or I, X17is hydrogen or C1-C3 alkoxy, and all other X variables are hydrogen. In specific aspects of the compounds of Formula 2A or 2B, X15is Br, X16is F, CI, or I, X27is hydrogen or C1-C3alkoxy, and all other X variables are hydrogen. In specific aspects of the compounds of Formula 2A or 2B, X25is Br, X26is F, CI, or I, X17is hydrogen or C1-C3 alkoxy, and all other X variables are hydrogen. In specific aspects of the compounds of Formula 2A or 2B, X15is I, X16is F, CI, or Br, X27is hydrogen or C1-C3alkoxy, and all other X variables are hydrogen. In specific aspects of the compoundsof Formula 2A or 2B, X25is I, X26is F, CI, or Br, X17is hydrogen or C1-C3alkoxy, and all other X variables are hydrogen.

[0110] In specific aspects of the Formulas 2A or 2B, X15and X16or X16and X17are 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. In specific aspects of the Formulas 2A or 2B, X25and X26or X26and X27are 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. In additional specific aspects, the fused ring contains one or two oxygen atoms. In additional specific aspects, 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 X15to X17together form a carbocyclic or heterocyclic ring, at least one of X25to X27is halogen or C1-C3 alkoxy. In additional aspects in which two of X25to X27together form a carbocyclic or heterocyclic ring, at least one of X15to X17is halogen or C1-C3 alkoxy. In additional aspects in which two of X15to X17together form a carbocyclic or heterocyclic ring, at least one of X25to X27is halogen. In additional aspects in which two of X25to X27together form a carbocyclic or heterocyclic ring, at least one of X15to X17is halogen. In additional aspects in which two of X15to X17together form a carbocyclic or heterocyclic ring, at least one of X25to X27is halogen, particularly chlorine, bromine, or iodine, or C1-C3 alkoxy. In additional aspects in which two of X25to X27together form a carbocyclic or heterocyclic ring, at least one of X15to X17is halogen, particularly chlorine, bromine, or iodine, or C1-C3 alkoxy. In additional aspects in which two of X15to X17together form a carbocyclic or heterocyclic ring, X25is halogen. In additional aspects in which two of X25to X27together form a carbocyclic or heterocyclic ring, X15is halogen. In additional aspects in which two of X15to X17together form a carbocyclic or heterocyclic ring, X25is chlorine, bromine, or iodine. In additional aspects in which two of X25to X27together form a carbocyclic or heterocyclic ring, X15is chlorine, bromine, or iodine. In additional aspects in which two of X15to X17together form a carbocyclic or heterocyclic ring, X25is fluorine. In additional aspects in which two of X25to X27together form a carbocyclic or heterocyclic ring, X15is fluorine. In additional aspects in which two of X14to X17together form a carbocyclic or heterocyclic ring, at least one of X25to X27is C1-C3 alkoxy. In additional aspects in which two of X24to X27together form a carbocyclic or heterocyclic ring, at least one of X15to X17is C1- C3alkoxy. In additional aspects in which two of X15to X17together form a carbocyclic or heterocyclic ring, X27is C1-C3 alkoxy. In additional aspects in which two of X25to X27together form a carbocyclic or heterocyclic ring, X17is C1-C3alkoxy. In additional aspects in which two of X15to X17together form a carbocyclic or heterocyclic ring, X27is C1-C3alkoxy, and the remaining X groups are hydrogen or halogen. In additional aspects in which two of X25to X27together form a carbocyclic or heterocyclic ring, X17is C1-C3alkoxy, and the remaining X groups are hydrogen or halogen. In specific aspects, the alkoxy group is a group other than methoxy.

[0111] In more specific aspects of Formula 2A or 2B, two of X14to X17together form the group CH=CH-CH=CH (giving rise to an annulated benzene ring). In more specific aspects of Formula 2A or 2B, two of X24to X27together form the group CH=CH-CH=CH (giving rise to an annulated benzene ring). In more specific aspects of Formula 2A or 2B, X14and X15together form the group CH=CH-CH=CH (giving rise to an annulated benzene ring)

[0112] In more specific aspects of Formula 2A or 2B, X24and X25together form the group CH=CH-CH=CH (giving rise to an annulated benzene ring). In more specific aspects of Formula 2A or 2B, X15and X16together form the group CH=CH-CH=CH (giving rise to an annulated benzene ring). In more specific aspects of Formula 2A or 2B, X25and X26together form the group CH=CH-CH=CH (giving rise to an annulated benzene ring). In more specific aspects of Formula 2A or 2B, X16and X17together form the group CH=CH-CH=CH (giving rise to an annulated benzene ring). In more specific aspects of Formula 2A or 2B, X26and X27together form the group CH=CH-CH=CH (giving rise to an annulated benzene ring).

[0113] In more specific aspects of Formula 2A or 2B, two of X14to X17together form the group CH=CH-CH=CH (giving rise to an annulated benzene ring), and one of X25to X27is halogen or C1-C3 alkoxy. In more specific aspects of Formula 2A or 2B, two of X24to X27together form the group CH=CH-CH=CH (giving rise to an annulated benzene ring), and one of X15to X17 is halogen or C1-C3 alkoxy. In more specific aspects of Formula 2A or 2B, two of X14to X17together form the group CH=CH-CH=CH (giving rise to an annulated benzene ring), and X27is C1-C3 alkoxy. In more specific aspects of Formula 2A or 2B, two of X24to X27together form the group CH=CH-CH=CH (giving rise to an annulated benzene ring), and X17is C1-C3 alkoxy. In more specific aspects of Formula 2A or 2B, two of X14to X17together form the group CH=CH-CH=CH (giving rise to an annulated benzene ring), and X25is halogen. In more specific aspects of Formula 2A or 2B, two of X24to X27together form the group CH=CH-CH=CH (giving rise to an annulated benzene ring), and X15is halogen. In more specific aspects of Formula 2A or 2B, two of X14to X17together form the group CH=CH- CH=CH (giving rise to an annulated benzene ring), and X25is fluorine. In more specific aspects of Formula 2A or 2B, two of X24to X27together form the group CH=CH-CH=CH (giving rise to an annulated benzene ring), and X15is fluorine. In more specific aspects of Formula 2A or 2B, two of X14to X17together form the group CH=CH-CH=CH (giving rise to an annulated benzene ring), and X25is chlorine, bromine, or iodine. In more specific aspects of Formula 2A or 2B, two of X24to X27together form the group CH=CH-CH=CH (giving rise to an annulated benzene ring), and X15is chlorine, bromine, or iodine. In more specificaspects of Formula 2A or 2B, two of X14to X17together form the group CH=CH-CH=CH (giving rise to an annulated benzene ring), one of X25to X27is halogen or C1-C3alkoxy, and the remaining X groups are hydrogen or halogen. In more specific aspects of Formula 2A or 2B, two of X24to X27together form the group CH=CH-CH=CH (giving rise to an annulated benzene ring), one of X15to X17is halogen or C1-C3alkoxy, and the remaining X groups are hydrogen or halogen. In more specific aspects of Formula 2A or 2B, two of X14to X17together form the group CH=CH-CH=CH (giving rise to an annulated benzene ring), one of X25to X27is halogen or C1-C3alkoxy, and the remaining X groups are hydrogen. In more specific aspects of Formula 2A or 2B, two of X24to X27together form the group CH=CH- CH=CH (giving rise to an annulated benzene ring), one of X15to X17is halogen or C1-C3 alkoxy, and the remaining X groups are hydrogen.

[0114] In a specific aspect of Formulas 2A and 2B, X17is an alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group. In a specific aspect of Formulas 2A and 2B, X27is an alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group. In a specific aspect of Formulas 2A and 2B, X17is a C1-C4 alkyl group substituted with an alkoxy, carboxyl, or esterified carboxyl group. In a specific aspect of Formulas 2A and 2B, X27is a C1-C4 alkyl group substituted with an alkoxy, carboxyl, or esterified carboxyl group. In a specific aspect of Formulas 2A and 2B, X17is an alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group, and all of X24to X27are hydrogen. In a specific aspect of Formulas 2A and 2B, X27is an alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group, and all of X14to X17are hydrogen. In a specific aspect of Formulas 2A and 2B, X17is an alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group, and at least one of X25to X27is halogen or C1-C3 alkoxy.

[0115] In a specific aspect of Formulas 2A and 2B, X27is an alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group, and at least one of X15to X17is halogen or C1-C3 alkoxy. In a specific aspect of Formulas 2A and 2B, X17is an alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group, and at least one of X25to X27is halogen, or X27is C1-C3 alkoxy. In a specific aspect of Formulas 2A and 2B, X27is an alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group, and at least one of X15to X17is halogen, or X17is C1-C3 alkoxy. In a specific aspect of Formulas 2A and 2B, X17is an alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group, and at least two of X25to X27are halogen. In a specific aspect of Formulas 2A and 2B, X27is an alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group, and at least two of X15to X17are halogen. In specific aspects, the alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group has 1 or 2 carbon atoms. In specific aspects, X17is (CH2)nOH, (CH2)nO-alkyl, (CH2)nC(O)OH, or (CH2)nC(O)O-alkyl, where n is an integer ranging from 1 to 4. In specific aspects, X17is (CH2)nO-alkyl or (CH2)nC(O)O-alkyl, where n is an integer ranging from 1-4 and the alkyl group has 1-6 or 1-3 carbon atoms.

[0116] In a specific aspect of Formulas 2A or 2B, X15is halogen and / or X17is an alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group, and X25to X27are selected from hydrogen, halogen, alkoxy, alkyl substituted with OH, alkyl substituted with alkoxy, alkyl substituted with carboxyl, and alkyl substituted with esterified carboxyl. In a specific aspect of Formulas 2A or 2B, X25is halogen and / or X27is an alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group, and X15to X17are selected from hydrogen, halogen, alkoxy, alkyl substituted with OH, alkyl substituted with alkoxy, alkyl substituted with carboxyl, and alkyl substituted with esterified carboxyl. In a specific aspect of Formulas 2A or 2B, X15is halogen and / or X17is an alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group, and X25is halogen. In a specific aspect of Formulas 2A or 2B, X25is halogen and / or X27is an alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group, and X15is halogen. In a specific aspect of Formulas 2A or 2B, X15is halogen and / or X17is an alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group, and X26or X27is an alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group. In a specific aspect of Formulas 2A or 2B, X25is halogen and / or X27is an alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group, and X16or X17is an alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group. In specific aspects, the alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group has 1-4 carbon atoms or 1-2 carbon atoms. In specific aspects, 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. In specific aspects, 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.

[0117] In a specific aspect of Formulas 2A or 2B, X15is halogen and / or X17is an alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group, X25to X27are 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. In a specific aspect of Formulas 2A or 2B, X25is halogen and / or X27is an alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group, X15to X17are 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. In a specific aspect of Formulas 2A or 2B, X15is halogen and / or X17is an alkylgroup substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group, X25to X27are 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. In a specific aspect of Formulas 2A or 2B, X25is halogen and / or X27is an alkyl group substituted with an OH, alkoxy, carboxyl, or esterified carboxyl group, X15to X17are 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.

[0118] In a specific aspect, the disclosure provides compounds of Formula 2A or 2B. In a specific aspect, compounds of Formulas 1, 2A, and 2B are useful for the treatment of cancer, particularly pancreatic cancer, colorectal cancer, and ovarian cancer.

[0119] Compounds of the disclosure can be useful in pharmaceutical compositions and methods of treatment or uses thereof, as described herein. For example, 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 R2is H, alkyl, aryl, or arylalkyl.

[0120] For example, 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 R2is H, alkyl, aryl, or arylalkyl.

[0121] For example, 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 R2is H, alkyl, aryl, or arylalkyl.

[0122] For example, 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 R2is H, alkyl, aryl, or arylalkyl; R3is H, alkyl, aryl, or arylalkyl; and R4is H, alkyl, aryl, or arylalkyl.

[0123] For example, 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 R2is H, alkyl, aryl, or arylalkyl; R3is H, alkyl, aryl, or arylalkyl; and R4is H, alkyl, aryl, or arylalkyl.

[0124] For example, 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 R2is H, alkyl, aryl, or arylalkyl; and R3is H, alkyl, aryl, or arylalkyl.

[0125] For example, 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 R2is H, alkyl, aryl, or arylalkyl; and R3is H, alkyl, aryl, or arylalkyl.

[0126] For example, 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 R2is H, alkyl, aryl, or arylalkyl, and n is an integer ranging from 1 to 6. In specific aspects, n is 2 to 4.

[0127] For example, 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 R2is H, alkyl, aryl, or arylalkyl, and n is an integer ranging from 1 to 6. In specific aspects, n is 2 to 4.

[0128] Unless otherwise indicated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, cis-trans, conformational, and rotational) forms of the structure. For example, 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 sp3carbon atoms. In some cases, the compounds of the disclosure are optically pure. As used herein, “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.

[0131] The term "alkyl", used alone or as part of a larger moiety, 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. The term "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.

[0132] The term "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.

[0133] 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.

[0134] The term "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. The term "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. Unless otherwise indicated, alkynyl groups including cycloalkynyl groups are optionally substituted as defined below.

[0135] The term "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). To satisfy valence, 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. Ring heteroatoms are selected from O, S, S(O), S(O)2, Se, N(R), -N=, P(R), or P(O)(R), among others, where R is an alkyl, alkenyl, alkynyl, heterocyclyl, aryl, arylalkyl, arylalkenyl, heteroaryl, (heteroaryl)alkyl, or (heteroaryl)alkenyl group. Preferred heteroatoms are O, N(R), and -N=. 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.

[0136] The term "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 fusedto 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] The term "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, CH2C6H5), phenethyl, 1-phenylcyclopropyl, 1-indanyl, 2-naphthylmethyl, 5-acenaphthenyl, 9-fluorenyl, 9,10-dihydro-9-anthryl, diphenylmethyl, and triphenylmethyl. Unless otherwise noted, the alkyl and / or the aryl portion of the arylalkyl group are optionally substituted as defined below.

[0138] The term "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. To satisfy valence, the heteroatom may be bonded to H or a substituent group. Ring heteroatoms are selected from O, S, S(O), S(O)2, Se, N(R), -N=, P(R), or P(O)(R), among others, where R is an alkyl, alkenyl, alkynyl, heterocyclyl, aryl, arylalkyl, arylalkenyl, heteroaryl, (heteroaryl)alkyl, or (heteroaryl)alkenyl group. Ring heteroatoms may be the same or different. 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 having aromatic rings with 5 or 6 ring atoms, of which 1-4 are heteroatoms. Preferred heteroatoms are O, S, N(R), and -N=. 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. Examples of 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, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl,pyrrolopyridazinyl, furopyridazinyl, thienopyridazinyl, pyrrolopyrimidyl, furopyrimidyl, thienopyrimidyl, pyrrolopyrazinyl, furopyrazinyl, thienopyrazinyl, imidazopyridazinyl, imidazopyrimidinyl, imidazopyrazinyl, pyrazolopyridazinyl, pyrazolopyrimidinyl, pyrazolopyrazinyl, purinyl, azapurinyl, quinolyl, isoquinolyl, quinolizinyl, cinnolinyl, quinazolinyl, phthalazinyl, naphthyridinyl, pyridopyridazinyl, pyridopyrimidinyl, pyridopyrazinyl, pteridinyl, carbazolyl, carbolinyl, acridinyl, phenazinyl, phenoxazinyl, phenothiazinyl, phenanthridinyl, phenanthrolinyl, [1,3]dioxolo[4,5-f]indol-7-yl, and the like. In specific aspects, heteroaryl groups include furanyl, isoxazolyl, pyridyl, or quinolyl groups.

[0139] The term "(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.

[0140] The term "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. Unless otherwise noted, the alkyl and / or the aryl portion of the arylalkyl group are optionally substituted as defined below.

[0141] The term "(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.

[0142] The term "methylene" refers to the diradical -CH2-.

[0143] The term "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. Unless otherwise noted, the "M" portions of said groups are optionally substituted as defined below.

[0144] The term "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. Representativehaloalkyl 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.

[0145] The term "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.

[0146] The term "oxo" refers to the diradical =O (engaged in a double bond to one carbon atom). The term "oximino" refers to the diradical =NOH (engaged in a double bond to one carbon atom). The term "substituted oximino" refers to the diradical =NOM (engaged in a double bond to one carbon atom), where M is alkyl, alkenyl, alkynyl, heterocyclyl, aryl, arylalkyl, arylalkenyl, heteroaryl, (heteroaryl)alkyl, or (heteroaryl)alkenyl.

[0147] The term "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. Unless otherwise noted, M is optionally substituted as defined below.

[0148] The terms "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. Unless otherwise noted, M is optionally substituted as defined below.

[0149] The term "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. An "arylamino" group refers to an amino group wherein at least one R is aryl. Unless otherwise noted, the "R" groups are optionally substituted as defined below.

[0150] 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.

[0151] The term "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.

[0152] The term "sulfonamido" or "sulfonylamino" refers to a -N(R)S(O)2R' 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.

[0153] The term "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.

[0154] The term "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.

[0155] The term "carboxyl" or "carboxylate" refers to the group C(O)OH or its anionic form C(O)O–, respectively. The term "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.

[0156] 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. Unless otherwise indicated, 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.

[0157] 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 moreof the following functional groups: cyano, isocyano, halogen (CI, F, Br, I), hydroxy, alkyl (including C1-C6alkyl and C1-C3alkyl), alkenyl, alkynyl, heterocyclyl, aryl, arylalkyl, arylalkenyl, heteroaryl, (heteroaryl)alkyl, (heteroaryl)alkenyl, haloalkyl, hydroxyalkyl, acyl, OH, alkoxy (including C1-C6alkoxy and C1-C3alkoxy), alkenyloxy, alkynyloxy, heterocyclyloxy, aryloxy, arylalkoxy, heteroaryloxy, (heteroaryl)alkoxy, OCF3, OCF2H, acyloxy, SH, alkylthio, alkenylthio, alkynylthio, heterocyclylthio, arylthio, arylalkylthio, heteroarylthio, (heteroaryl)alkylthio, SCF3, SCF2H, alkylsulfenyl, alkenylsulfenyl, alkynylsulfenyl, heterocyclylsulfenyl, arylsulfenyl, arylalkylsulfenyl, heteroarylsulfenyl, (heteroaryl)alkylsulfenyl, S(O)CF3, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, arylalkylsulfonyl, heteroarylsulfonyl, (heteroaryl)alkylsulfonyl, S(O)2CF3, oxo, oximino, substituted oximino, nitro, amino (including alkylamino, dialkylamino, arylamino, and (alkyl)(aryl)amino), amido, sulfonamido, carboxyl, carboxylate, esterified carboxyl, carbamoyl [C(O)NH2] and N-mono- and N,N-di-substituted carbamoyl, and sulfamoyl [S(O)2NH2] and N-mono- and N,N-di-substituted sulfamoyl. Preferred substituents for compounds of Formula 1 are described hereinabove. Pharmaceutical Compositions and Methods of Treatment

[0158] The term "pharmaceutically acceptable salts" 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.

[0159] In addition, 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.

[0160] 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.

[0161] "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. Examples of such 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. Further examples of pharmaceutically useful 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.

[0162] In certain aspects, the disclosure is directed to prodrugs of compounds of Formula 1 and other formulas herein. The term "prodrug," as used herein, means a compound that is convertible in vivo by metabolic means ( e.g. by hydrolysis) to a compound of Formula 1. Various forms of 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. (ed.), Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991); Bundgaard et al., Journal of Drug Delivery Reviews 1992, 8, 1-38; Nielsen and Bundgaard, Journal of Pharmaceutical Sciences 1988, 77, 285-298 et seq.; and Higuchi and Stella (eds.), Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975), each of which is hereby incorporated by reference in its entirety.

[0163] 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.

[0164] 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.

[0167] The compounds of the disclosure may be administered rectally or vaginally in the form of a conventional suppository.

[0168] 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.

[0169] The compounds of the disclosure may be administered employing an occlusive device. A variety of 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.

[0170] 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.

[0171] 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. Such 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.

[0172] 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.

[0173] 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. In powders, the carrier is a finely divided solid that is in admixture with the finely divided active ingredient. In tablets, 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.

[0174] 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. 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. Suitable examples of 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. For parenteral administration, 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. Liquid pharmaceutical 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.

[0175] 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.

[0176] Preferably, the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules. In such form, 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. By way of general guidance, 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.

[0178] Dependent upon the particular protein kinase-related disease, disorder, or condition to be treated employing the compounds of this disclosure, 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. For example, in the treatment of diabetes, other anti-diabetic agents may be combined with a GSK-3 inhibitor of this disclosure to treat diabetes. For example, such anti-diabetic agents include, without limitation, insulin or insulin analogs, glitazones, alpha-glucosidase inhibitors, biguanides, insulin sensitizers, and sulfonylureas. Other examples of 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.

[0179] 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 thatan 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.

[0180] 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. Alternatively, 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.

[0181] The disclosure provides medicaments for therapeutic application, in particular for the treatment of protein kinase-related diseases, disorders, or conditions. In specific aspects, 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. In a specific embodiment, 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.

[0182] 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.

[0183] 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.

[0184] In cases in which the compounds of this disclosure have carbon-carbon or carbon- nitrogen double bonds, unless otherwise specified, both the cis (Z) and trans (E) isomers are encompassed in this disclosure. More generally, unless otherwise specified, all stereoisomers of the compounds of this disclosure are encompassed in the disclosure.

[0185] Compounds disclosed herein can include those which may exist in tautomeric forms, such as keto-enol and lactam-lactim tautomers. Each tautomeric form is encompassed herein, whether the forms exist in equilibrium with each other or whether the tautomer is locked in one form by appropriate substitution, as is understood in the art.

[0186] 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. Preferably, the eutomers are substantially free of the corresponding distomer. Thus, 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. In preferred aspects, 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. See, for example, 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. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind., 1972).

[0187] When a group of substituents is disclosed herein, it is understood that all individual members of that group and all subgroups, including any isomers, enantiomers, and diastereomers of the group members, are disclosed separately. When a Markush group or other grouping is used herein, all individual members of the group and all combinations and subcombinations possible of the group are intended to be individually included in the disclosure. A number of specific groups of variable definitions have been described herein. It is intended that all combinations and subcombinations of the specific groups of variable definitions are individually included in this disclosure. When a compound is described herein such that a particular isomer, enantiomer, or diastereomer of the compound is not specified, for example, in a formula or in a chemical name, that description is intended to include each isomer, enantiomer, or diastereomer of the compound described individually or in any combination.

[0188] Additionally, unless otherwise specified, all isotopic variants of compounds disclosed herein are intended to be encompassed by the disclosure. For example, it will be understood that any one or more hydrogens in a molecule disclosed can be replaced with deuterium or tritium. 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.

[0190] Many of the molecules disclosed herein contain one or more 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. With regard to 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.

[0191] Every formulation or combination of components described or exemplified herein can be used to practice the disclosure, unless otherwise stated.

[0192] Whenever a range is given in the specification, for example, a temperature range, a time range, or a composition or concentration range, all intermediate ranges and subranges, as well as all individual values included in the ranges given are intended to be included in the disclosure. It will be understood that any subranges or individual values in a range or subrange that are included in the description herein can be excluded from the claims herein.

[0193] Any one or more of the compounds specifically disclosed in this specification can be excluded from any of the aspects of the disclosure. Any one or more disorder, conditions or disease, specifically disclosed in this specification can be excluded from any of the aspects of the disclosure.

[0194] As used herein, "comprising" is synonymous with "including," "containing," or "characterized by," and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. As used herein, "consisting of' excludes any element, step, or ingredient not specified in the claim element. As used herein, "consisting essentially of does not exclude materials or steps that do not materially affect the basic and novel characteristics of the claim. The term "comprising" is intended to be broader than the terms "consisting essentially of and "consisting of', however, the term "comprising" as used herein in its broadest sense is intended to encompass the narrower terms "consisting essentially of and "consisting of', thus the term "comprising" can be replaced with "consisting essentially of" to exclude steps that do not materially affect the basic and novel characteristics of the claims, and "comprising" can be replaced with "consisting of to exclude not recited claim elements. Methods of Treatment

[0195] 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. For example, the contacting can comprise administering the compound or salt or the composition to a subject in need thereof.

[0196] Also disclosed herein are 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. For example, the contacting can comprise administering the compound or salt or the composition to a subject in need thereof. For example, the cancer cell is a colorectal cancer cell, a pancreatic cancer cell, or an ovarian cancer cell. For example, the cancer cell is apancreatic cancer cell or an ovarian cancer cell. For example, the cancer cell is a pancreatic cancer cell. For example, the cancer cell is an ovarian cancer cell.

[0197] 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. For example, the protein kinase-related disorder or disease is a GSK-3-related disorder or disease. For example, 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. For example, the GSK-3-related disorder or disease is neurological disease or disorder, or psychiatric disease or disorder. For example, the GSK-3-related disorder or disease is cancer. For example, the GSK-3-related disorder or disease is neurological disease or disorder. For example, the GSK-3-related disorder or disease is psychiatric disease or disorder.

[0198] 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.

[0199] 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. For example, the cancer being treated is colorectal cancer, pancreatic cancer, or ovarian cancer. For example, the cancer being treated is pancreatic cancer or ovarian cancer. For example, the cancer being treated is colorectal cancer. For example, the cancer being treated is pancreatic cancer. For example, the cancer being treated is ovarian cancer.

[0200] 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. For example, the cancer being treated is colorectal cancer, pancreatic cancer, or ovarian cancer. For example, the cancer being treated is pancreatic cancer or ovarian cancer. For example, the cancer being treated is colorectal cancer. For example, the cancer being treated ispancreatic cancer. For example, the cancer being treated is ovarian cancer. For example, the therapeutic agent is gemcitabine, cisplatin, or carboplatin. For example, the therapeutic agent is cisplatin or carboplatin. For example, the therapeutic agent is gemcitabine. For example, the therapeutic agent is cisplatin. For example, the therapeutic agent is carboplatin. For example, the cancer being treated is pancreatic cancer and the therapeutic agent is gemcitabine. For example, the cancer being treated is ovarian cancer and the therapeutic agent is cisplatin or carboplatin. For example, the cancer being treated is ovarian cancer and the therapeutic agent is cisplatin. For example, the cancer being treated is ovarian cancer and the therapeutic agent is carboplatin.

[0201] As used herein the phrase "GSK-3-related", including "GSK-3β-related", in reference to diseases, conditions, or disorders are those that are mediated, caused, enhanced, or exacerbated by GSK-3 (α or β) or more specifically GSK-3β. GSK-3 and GSK- 3β -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 ovary syndrome, syndrome X; and viral, bacterial, fungal, or prion infections. 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-3β 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-3β of this disclosure are useful in the treatment of type II diabetes. In other specific aspects, inhibitors of GSK-3β of this disclosure are useful in the treatment of Alzheimer's disease. In additional specific aspects, inhibitors of GSK-3β ofthis disclosure are useful in the treatment of cancer, particularly colorectal cancer, pancreatic cancer, and ovarian cancer.

[0203] 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.

[0204] The term "protein kinase" is used generically herein to refer to any protein kinase expressed in mammalian tissue. The phrase "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-3α, GSK-3β), cyclin-dependent kinases (e.g., CDK-2, CDK-5, etc.) and protein kinase C (PKC). Disease, disorders, or conditions that are protein kinase-related include autoimmune diseases, inflammatory diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, or hormone-related diseases.

[0205] The term "selectivity" is used herein in reference to inhibition of protein kinases by small molecules, particularly those of this disclosure. In general, 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. While absolute selectivity is not necessarily required, for therapeutic applications it is desirable to avoid undesired side-effects and thus to avoid ancillary inhibition of protein kinases other than the target protein kinases. Inhibitors preferred for use in therapeutic application are those which exhibit effective inhibition of thetarget 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.

[0206] 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. Based on the results obtained in standard pharmacological test procedures, projected daily dosages of active compound can be determined as is understood in the art.

[0207] The term "therapeutically effective amount," as used herein, 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. As is understood in the art, 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.).

[0208] All patents and publications mentioned in the specification are indicative of the levels of skill of those skilled in the art to which the disclosure pertains. References cited herein are incorporated by reference herein in their entirety to indicate the state of the art as of their publication or filing date, and it is intended that this information can be employed herein, if needed, to exclude specific aspects that are in the prior art. For example, 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.

[0209] 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.

[0210] 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 employedin 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. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the disclosure claimed. Thus, it should be understood that although the present disclosure has been specifically disclosed by preferred aspects and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this disclosure as defined by the appended claims.

[0211] All references cited herein are hereby incorporated by reference to the extent that there is no inconsistency with the disclosure of this specification. Some references provided herein are incorporated by reference to provide details concerning sources of starting materials, additional starting materials, additional reagents, additional methods of synthesis of the compounds herein, additional methods of analysis and assessment of the biological functions of the compounds herein, additional biological materials, methods for assessing biological function of the compounds herein, and additional therapeutic and prophylactic uses of the protein kinase inhibitors, particularly the GSK-3 inhibitors of this disclosure. Synthetic Methods

[0212] Wang et al. (Tetrahedron Letters 2005, 46, 907-910) have communicated the preparation of a (3-benzothiophenyl)(3-indolyl)maleimide as a synthetic intermediate through sequential heteroarylation by simple nucleophilic substitution and by transition metal- catalyzed coupling of a 1-substituted 3,4-dibromomaleimide (Scheme 1) Scheme 1.

[0213] 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. L.; Krumrich, C. A., Tetrahedron Lett.1999, 40 (6), 1109-1112). The choice between the two methods is typically made based on ready availability of starting materials or ease of methods for making starting materials. Carboxylic acids and their esters are mutually interconvertible by esterification and hydrolysis, respectively, while amides are obtained from esters by reaction with ammonia, or from carboxylic acids by reaction with ammonia or ammonium chloride in the presence of a standard peptide coupling reagent. Scheme 2.

[0214] The two types of starting materials are interconvertible. For example, the C=O function in 3-indolylglyoxylic acids has been reduced to CH2through treatment of the derived tosylhydrazone with NaBH4(Guan, X.; Borchardt, R. T. Tetrahedron Lett.1994, 35 (19), 3013-3016; Scheme 3). Scheme 3.

[0215] Conversely, aryl- and heteroarylacetates are oxidized to aryl- and heteroarylglyoxylates with tert-butylhydroperoxide (Jiang, J. J. Chem. Res.2019, 43(7-8), 235-240; Scheme 4):

[0216] In the benzofuran series, selenium(IV) oxide has been employed to oxidize an esterified acetic acid side chain to an esterified glyoxylic acid side chain (e., g., US 2010 / 0004308).

[0217] 3-Benzothiophenylacetic acid, 3-benzofuranylacetic acid, 3-indolylacetic acid, 1- methyl-3-indolylacetic acid, and selected derivatives of these building blocks containing substituents in their aromatic rings are commercially available.

[0218] Benzothiophene and its derivatives undergo chloromethylation with formaldehyde / HCI in their 3-position. The resulting 3-(chloromethyl)benzothiophenes react with cyanide to form benzothiophene-3-acetonitriles (US4971974 and CN113896709), which can be partially hydrolyzed to the -3-acetamides (J. Chem. Chem. Eng.2020, 14, 53-65) or further to the underlying carboxylic acids (Scheme 5).

[0219] 3-Indolylglyoxylic acid esters are accessible from the appropriate indoles by acylation with oxalyl chloride, followed by ester formation (US2010004308; Faul, M. M. et al., Tetrahedron Lett.1999, 40 (6), 1109-1112; Scheme 6) Scheme 6.or by acylation with EtOC(O)C(O)CI in the presence of AICI3 (WO0204440).

[0220] 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):

[0221] 3-Indolylacetic acid can be synthesized by the reaction of indole with glycolic acid in the presence of base under forcing conditions (Johnson, H. E.; Crosby, D. G. Org. Synth. 1964, 44, 64; Scheme 8):

[0222] Generally, aryl- and heteroarylacetic acid esters are available from aryl and heteroaryl bromides through a transition metal-catalyzed coupling reaction with diethyl malonate (EP3369723 Al; Scheme 9)

[0223] A great number of heterocyclic starting materials lacking the 3-acetic acid side chain and bearing diverse substituents on their carbocyclic ring are commercially available. Widely used procedures for the preparation of indoles include the Bartoli synthesis, which isparticularly suited for 7-substituted indoles, but which can also be employed to access other substitution patterns if the carbon that becomes the indole ring's 7-C is temporarily substituted with Br, which can later be removed in an additional step or can be used as a handle to install other substituents by way of Br-metal exchange reactions and / or coupling reactions (e. g., WO0204440 and Bartoli, G. et al., Chem. Soc. Rev.2014, 43, 4728-4750; Scheme 10).

[0224] Another protocol makes use of a Sonogashira coupling reaction to build the five- membered heterocycle (Wang et al., Tetrahedron Letters 2005, 46, 907-910; Scheme 11):

[0225] 2H-Benzofuran-3-ones can be obtained, for example, by Friedel-Crafts cyclization of aryloxyacetyl chlorides (Palmer, M. H.; Scollick, N. M. J. Chem. Soc. (C) 1968, 2833- 2836; Scheme 12) Scheme 12.

[0226] where the 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.

[0227] A simple synthetic approach to benzothiophenes is shown in Scheme 13 (Wang et al., Tetrahedron Letters 2005, 46, 907-910)

[0228] 3-Bromobenzoselenophenes have been obtained in a three-step sequence from bromoarenes (Paegle, E. et al., Chem. Asian J.2016, 11, 1929; Scheme 14)

[0229] Representative synthetic schemes and details of synthetic methods are provided in the Examples. Compounds of this disclosure are prepared employing methods as described herein or are prepared by routine modification or adaptation of the methods herein, for example, by selection of starting materials or variation of reagents, solvents and / or purification methods, in view of what is known in the art. Starting materials and reagents used for the preparation of the compounds of this disclosure or salts, esters, solvates, and prodrugs thereof are available from commercial sources or can be prepared using well- known procedures. It will be appreciated by one of ordinary skill in the art that various methods for purification of starting materials, reagents, intermediates and final products of syntheses can be employed including, among others, filtration, distillation, crystallization, chromatography, and related conventional methods. Further, starting materials, reagents, intermediates, and final products of syntheses can be characterized using conventional methods, for example to obtain physical constants and spectroscopic data.

[0230] Exemplary compounds of the disclosure include those of Table 1. Table 1. Exemplary Substituted 3-(Benzothiophen-3-yl)-4-(bicyclic heteroaryl)maleimides having the following structure:Table 2. Exemplary Substituted 3-(Benzoselenophen-3-yl)-4-(bicyclic heteroaryl)maleimides having the following structure:Aspects of the Disclosure 1. Compounds of Formulas 2A and 2B:and pharmaceutically acceptable salts, esters, and solvates thereof wherein: Y1is O, S, Se, or NR1; R1and R2, independently of one another, are selected from H or alkyl, particularly C1-C3 alkyl; X14and X24are independently hydrogen, halogen, or methyl; X15, X16,X17,X25, X26, and X27are selected from hydrogen, halogen, methyl, trifluoromethyl, OH, and alkoxy; or two of X15, X16, X17, X25, X26, and X27, 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 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; R3and R5, independently of each other, are selected from H, alkyl, alkenyl, alkynyl, heterocyclyl, aryl, arylalkyl, arylalkenyl, heteroaryl, (heteroaryl)alkyl, and (heteroaryl)alkenyl; each R6, independently of each R3, can take all values of R3or is OR4, where R4is selected from H, alkyl, alkenyl, alkynyl, heterocyclyl, aryl, arylalkyl, arylalkenyl, heteroaryl, (heteroaryl)alkyl, and (heteroaryl)alkenyl. 2. Compounds of Formula 2B in aspect 1 wherein Y1is O, S, Se, or NR1; R1and R2, independently of one another, are selected from H or alkyl, particularly C1-C3 alkyl; X14and X24are independently hydrogen, halogen, or methyl; X15, X16,X17,X25, X26, and X27are selected from hydrogen, halogen, methyl, trifluoromethyl, OH, and alkoxy; or two of X15, X16,X17,X25, X26, and X27, 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 CH2groups are replaced with oxygen or sulfur. 3. A compound selected from compounds 1-60 whose structures are given in Table 1. 4. A pharmaceutical acceptable composition which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of aspect 2 or aspect 3. 5. 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. 6. 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. A method for treating cancer 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. 8. The method of aspect 7 wherein the cancer being treated is colorectal cancer, pancreatic cancer, or ovarian cancer. 9. A method for inhibiting proliferation of cancer cells which comprises the step of contacting a cancer cell with an amount of a compound of aspect 2 or aspect 3 effective for inhibition of proliferation. 10. The method of aspect 9 wherein the cancer cell is a colorectal cancer cell, a pancreatic cancer cell, or an ovarian cancer cell. 11. The methods of aspect 8 and aspect 10 wherein the compound is a compound having Formula 3:where X1and X2are H or halogen and Y1is NH, N-alkyl, or oxygen. 12. The methods of aspect 8 and aspect 10 wherein the compound is a compound having Formula 3, where X1is a methylenedioxy group, X2is a halogen, and Y1is NH or N-alkyl. 13. The methods of aspect 8 and aspect 10 wherein the compound is a compound having Formula 3, where X1is a methylenedioxy group, X2is trifluoromethyl, and Y1is NH or N-alkyl. 14. The methods of aspect 8 and aspect 10 wherein the compound is a compound having Formula 3, where X1is a 5,6-methylenedioxy group, X2is 5-fluoro, and Y1is NMe. EXAMPLES Methods & Materials

[0231] All the chemicals were purchased from commercially available suppliers and used without purification. Unless otherwise stated, reagents and solvents were commercially available and used without further purification. Unless otherwise noted, all tissue culture reagents were purchased from commercial sources. Kinase Assay

[0232] The compounds 9-ING-41-S and 9-ING-41-O were prepared from a stock DMSO solution (10 mM) and tested in 10-dose IC50 mode with a 3-fold serial dilution starting at 10 μM. Staurosporine was used as a control and was tested in 10-dose IC50 mode with 4-fold serial dilution starting at 20 μM. All reactions were carried out at 10 μM ATP. Plasma Pharmacokinetic Analysis

[0233] Stock solutions of 9-ING-41-S and the control compound were prepared in DMSO (10 mM). Separately, 5 μL aliquots of each stock solution (9-ING-41-S and control) were diluted with 45 μL of DMSO.

[0234] A buffer solution at pH 7.4 was prepared from a basic and acidic solution. First, a basic solution was prepared by dissolving 14.2 g / L Na2HPO4and 8.77 g / L NaCl in deionized water and stored at 4°C for up to 7 days. Separately, an acidic solution was prepared by dissolving 12.0 g / L NaH2PO4and 8.77 g / L NaCl in deionized water and stored at 4°C for up to 7 days. Then, 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.

[0235] 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 μL of blank plasma solution 3 μL 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 μM. Immediately, 50 μL of the spiked plasma solution was transferred to a 96-well plate to act as T=0 control sample and all remaining spiked plasma solution in the incubator for the duration of the study.

[0237] At the same time, the remaining spiked plasma solution sample in the plastic plate was incubated for 6 hours at 37°C with 5% CO2 in the CO2 incubator. At T=6 hours, 50 μL of the original spiked plasma solution was transferred to the 96-well plate for analysis.

[0238] Cells were loaded with 120 μL of plasma sample and dialyzed against equal volume of dialysis buffer (PBS) and performed in duplicate. 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 μL aliquots from both buffer and plasma solution chambers were transferred into respective wells of a 96-well plate for analysis. The percentages of test compound(s) and control compound bound were calculated as follows: % Unbound = (Area ratio buffer chamber / Area ratio plasma solution chamber) × 100 % Bound = 100 - % Unbound % Recovery = (Area ratio buffer chamber + Area ratio plasma solution chamber) / (Area ratio Total sample) × 100 % Remaining = Area ratio 6hr / Area ratio 0hr × 100Brain Pharmacokinetic Analysis

[0239] Stock solutions of 9-ING-41-S and the control compound were prepared in DMSO (10 mM). Separately, 5 μL aliquots of each stock solution (9-ING-41-S and control) were diluted with 45 μL of DMSO.

[0240] A buffer solution at pH 7.4 was prepared from a basic and acidic solution. First, 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. Separately, 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. Then, 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.

[0241] Frozen brain tissues were thawed immediately at room temperature. Then, weighted and homogenized with buffer to a brain weight (g) to buffer volume (mL) ratio of 1:4. 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.

[0242] The working solution of test compound and control compound were prepared in DMSO at the concentration of 200 µM. The samples were prepared by adding 597 μL of blank brain homogenate and 3 μL 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 μM. Immediately, 50 μL of the spiked brain homogenate was transferred to a 96-well plate to act as T=0 control sample and all remaining spiked brain homogenate in the incubator for the duration of the study.

[0243] At the same time, the remaining spiked brain homogenate sample in the plastic plate was incubated for 6 hours at 37°C with 5% CO2in the CO2incubator. At T=6 hours, 50 μL of the original spiked brain homogenate was transferred to the 96-well plate for analysis.

[0244] Cells were loaded with 120 μL of brain homogenate and dialyzed against equal volume of dialysis buffer (PBS) and performed in duplicate. The cells were covered with a permeable lid and incubated for 6 hours at 37°C at 100 rpm with 5% CO2on an orbital shaker in the CO2incubator. At the end of incubation, 50 μL aliquots from both buffer and brain homogenate chambers were transferred into respective wells of a 96-well plate for analysis.

[0245] 50 μL of brain homogenate was added to the buffer samples, and an equal volume of PBS was added to the collected brain homogenate samples. Then, the plate was shaken at 1000 rpm for 2 minutes and 400 μL of acetonitrile containing an appropriate internal standard (IS) was added to precipitate protein and release compound. Next, the mixture was vortexed at 1000 rpm for 10 minutes and centrifuged for 30 minutes at 3,220 g. Then 100 μL of the supernatant was transferred to a new 96-well plate and 100 μL of distilled water was added to each sample and mixed for analysis by LC-MS / MS. All compounds were tested in duplicate at 1 μM in brain homogenate.

[0246] The percentage of unbound, percentage of bound and recovery of test compound were calculated as follows: % Unbound homogenate= (Area ratio buffer chamber / Area ratio homogenate chamber) × 100 % Unbound Brain=1 / 5 / ((1 / (% Unbound homogenate / 100)-1)+1 / 5) × 100 % Bound Brain= 100 - % Unbound Brain % Recovery = (Area ratio buffer chamber + Area ratio homogenate chamber) / (Area ratio Total sample) × 100 % Remaining = Area ratio 6hr / Area ratio 0hr × 100 Hepatocyte Pharmacokinetic Analysis

[0247] Stock solutions of 9-ING-41-S and the control compound were prepared in DMSO (10 mM). Separately, 2 μL aliquots of each stock solution (9-ING-41-S and control) were diluted with 198 μL of a (1:1) mixture of acetonitrile water.

[0248] The incubation medium (William’s E Medium supplemented with GlutaMAX) and hepatocyte thawing medium were placed in a 37 °C water bath and warmed for at least 15 minutes prior to use. A vial of cryopreserved hepatocytes was thawed by placing the vial in a 37°C water bath and gently shaking the vials for 2 minutes. After thawing was completed, the vial was sprayed with 70% ethanol. Next, 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 × 106cells / 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 × 106viable cells / mL.

[0249] 198 μL of hepatocytes were placed into separate wells of a 96-well non-coated plate and placed in an incubator to warm the hepatocytes for 10 minutes.2 μL of the 100 μM9-ING-41-S, or control, was transferred into respective wells of the 96-well non-coated plate and the plate was returned to the incubator for designated time points.

[0250] At time points of 0.5, 15, 30, 60, 90 and 120 minutes, 25 μL aliquots from each well were mixed with 6 volumes (150 μL) of acetonitrile containing internal standard, (100 nM alprazolam, 200 nM caffeine and 100 nM tolbutamide) to terminate the reaction and vortexed for 5 minutes. The samples were centrifuged for 45 minutes at 3,220 g. Then, 100 µL aliquots of each supernatant were diluted by 100 µL ultra-pure water and repeated prior to use.

[0251] The in vitro half-life (t1 / 2) was determined by regression analysis of the percent parent disappearance vs. time curve.

[0252] The in vitro half-life (in min) was used to determine the in vitro intrinsic clearance (in vitro CLint, in µL / min / 1×106cells) with the following equation (mean of duplicate determinations): in vitro CLint = -kV / N V = incubation volume (0.2 mL); N = number of hepatocytes per well (0.1 × 106cells).

[0253] The calculations of Scale-up CLint (mL / min / kg), Predicted Hepatic CLH (mL / min / kg) and Hepatic Extraction Ratio (ER) were done using the following equation: Scale-up CLint = (0.693 / T1 / 2) × (1 / (hepatocytes concentration (0.5 × 106cells / mL))) × Scaling Factors (Table S1) Predicted Hepatic CLH= (QH × Scale-up CLint× fub) / (QH + Scale-up CLint× fub), ER = Predicted Hepatic CLH / QH where QH is the hepatic blood flow (mL / min / kg) (Table S1), fub is the fraction of unbound drug in plasma which is assumed to be 1.

[0254] Table S1. Scaling Factors for Intrinsic Clearance Prediction in Human, Monkey, Dog, Rat and Mouse HepatocytesaScaling Factor = (Hepatocellularity) × (Liver weight) hERG Assay

[0255] Test compounds were initially prepared in DMSO with final concentration of 10 mM as stock solution. The stock solution of each compound was serially diluted with DMSO by ratio of 1:3 to prepare additional intermediate solutions at 10,3.33, 1.11 and 0.37 mM concentration, respectively. Before hERG measurement, 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 µM working solution is prepared by 166.67-fold dilution of 10 mM DMSO stock solution. In the hERG assay, 40 μL working solution was added to 40μL cell solution, so 2x test concentration working solutions of compound are prepared. IC50determination for hERG inhibition was evaluated in at 5 concentrations, 30, 10, 3.33, 1.11 and 0.37 µM.

[0256] Cell Harvesting: First, the cells were rinsed twice with 6 mL DPBS-2 mM EDTA at rt. Then, 2 mL TrypLE™ Express was added and the mixture was gently rocked to cover the cells. Next, half of the solution was removed, leaving only a thin film covering the cells and the cells were incubated for 5-7 min at 37 °C, until the cells started floating. After, a 10 ml external standard solution was prepared in centrifuge tube and incubated with the culture flask for 5 min in the fridge (4-8°C). Next, the cells were moved up and down 3-5 times via pipette to separate cells and collected in a 10 cm Petri-dish. The cells were counted and diluted in cold external solution to a final concentration of 0.5-0.7 x106cells / 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.

[0257] 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. Next, the cells were washed four times with external solution before Escin (15 μM) 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. The maximum amount of tail current size was used to determine hERG current amplitude. Then, the current was recorded for 120 s to assess thecurrent stability and only stable cells with recording parameters passing acceptance criteria were used for the perfusion of working solutions.

[0259] Firstly, 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. The hERG current inhibition in presence of 5 concentrations of test article was examined in 2 independent experiments (n=2) for IC50 determination. 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. Finally, 4 mL of saline is added with vortexing to obtain an orange solution devoid of debris at a concentration of 10 mg / mL 9-ING-41-S in 10% ethanol / 50% PEG400 / 40% saline. Example 1 – Prophetic Synthesis of 9-ING-41-S

[0261] 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) can be synthesized via the following steps:

[0262] Step 1: 5-Methyl-2H,5H-[1,3]dioxolo[4,5-f]indole. To a solution of 2H,5H- [1,3]dioxolo[4,5-f]indole (CAS No.267-48-1; e.g. Ambeed cat. No. A192188; 11.7 mmol) in dry DMF (15 mL) cooled with an ice bath is added NaH (55% suspension in mineral oil, 1.02 g, 23.5 mmol), followed by methyl iodide (2.50 g, 17.6 mmol), after which the reaction mixture is allowed to warm to room temperature. After 6 h, the reaction mixture is poured into ice-water; 1M HCI is added to adjust the pH to about 4, and the mixture is extracted with ethyl acetate. The ethyl acetate extract is washed with water and brine, then dried over anhydrous Na2SO4 or MgSO4 and concentrated under vacuum. The residue is filtered over a silica gel column with an ethyl acetate / hexane mixture. The product, 5-methyl-2H,5H- [1,3]dioxolo[4,5-f]indole, is used in the subsequent step without additional purification.

[0263] Step 2: Ethyl 2-(5-Methyl-2H,5H-[1,3]dioxolo[4,5-f]indol-7-yl)-2-oxoacetate. To a solution of 5-methyl-2H,5H-[1,3]dioxolo[4,5-f]indole in diethyl ether (20 mL) cooled to 0 °C is added dropwise a 2M solution of oxalyl chloride in THE (17 mL, 34 mmol). The reaction is then stirred for 0.5 h at 0 °C, allowed to warm to room temperature, and stirred overnight. It is then cooled to -60 °C, and a 21% solution of NaOEt in EtOH (13.5 mL, 46 mmol) is added, after which the reaction mixture is allowed to warm to room temperature. The reaction is quenched by the addition of water, and the mixture is diluted with ethyl acetate. The organic layer is separated, dried over anhydrous Na2SO4, and concentrated. The residue is purified by column chromatography on silica gel with an ethyl acetate / hexane mixture to give the product after concentration of appropriate eluate fractions.

[0264] Step 3: 3-(Chloromethyl)-5-fluorobenzo[b]thiophene. At a 20 mM reaction scale, a round-bottom flask is charged with 140-160 mmol of concentrated hydrochloric acid and 24- 30 mmol of 85% phosphoric acid. The mixture is cooled to 15 °C with stirring, and paraformaldehyde (2.4-3.0 g) is added. A solution of 5-fluorobenzo[b]thiophene (CAS No. 70060-12-7; e.g., J&W Pharmlab cat. No.28R0026; 20 mmol) in acetic acid (5-6 mL) is added dropwise while maintaining an internal temperature of 15-20 °C. The mixture is then stirred at 15-20 °C overnight, or until the reaction does not proceed further. The solution is cooled to 0-5 °C in an ice-water bath, diluted with water (slight exotherm), stirred for several minutes, and filtered. The filtrate is allowed to stand at ambient temperature, whereon a lower organic phase is separated. The product is extracted into 2-3 portions of dichloromethane or chloroform. The combined organic phases are stirred in a spacious beaker with a sodium bicarbonate solution until neutral (caution, gas evolution). The phases are separated, and the organic phase is dried over anhydrous Na2SO4 or MgSO4. The drying agent is filtered off, and the solvent is evaporated under vacuum to obtain the reaction product (containing a small solvent residue), which is carried on to the next step without purification.

[0265] Step 4: 2-(5-Fluorobenzo[b]thiophen-3-yl)acetonitrile. All of the above crude 3- (chloromethyl)-5-fluorobenzo[b]thiophene, sodium cyanide (1.1-1.2 equiv.), and DMF (4-5 mL) are combined and stirred in a round-bottom flask with exclusion of moisture. The temperature is raised to 90-95 °C by means of an oil bath and kept at this value for 4 hours, or until the reaction is essentially complete. The cooled mixture is filtered with suction, and the filter residue is washed with ethyl acetate. The filtrate and washings are combined and stirred with water. The phases are separated, and the aqueous phase is extracted with ethyl acetate (3 portions). The combined organic phases are washed with water and brine and dried over anhydrous Na2SO4or MgSO4. The drying agent is filtered off, and the solvent is evaporated under vacuum to obtain the crude product. This material is purified by column chromatography on silica gel with an ethyl acetate / hexane mixture to give purified product after concentration of appropriate eluate fractions.

[0266] 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. Most of the ethanol is removed by partial evaporation. The residue is extracted with ethyl acetate (3 portions). The combined organic phases are washed with water and brine and dried over anhydrous Na2SO4or MgSO4. The drying agent is filtered off, silica gel (5 g) is added to the solution, and the solvent is evaporated under vacuum to obtain the crude product adsorbed on silica gel. This material is purified by column chromatography on silica gel with an ethyl acetate / hexane mixture to give unreacted starting material and the amide product after concentration of appropriate eluate fractions.

[0267] 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. To a suspension of 2-(5-fluorobenzo[b]thiophen-3- yl)acetamide (0.28 mmol) and ethyl 2-(5-methyl-2H,5H-[1,3]dioxolo[4,5-f]indol-7-yl)-2- oxoacetate (0.28 mmol) in dry THF (2.5 mL) was added dropwise with ice / water cooling a 1.0M solution of potassium tert-butoxide in THF (1.1 mL). The mixture was stirred at room temperature overnight, then the reaction was quenched with 12N HCI, and ethyl acetate was added. The phases were separated, and the organic phase was washed with saturated NaHCO3 solution and brine, dried over Na2SO4, and evaporated under vacuum. The residue was purified by preparative TLC or column chromatography (silica gel, ethyl acetate / hexane) to afford 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 as an orange-colored solid. Example 2 – Additional Synthesis of 9-ING-41-S

[0268] 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) was also synthesized as shown in Figure 1 via the following steps:

[0269] Step 1: Ethyl 4-[(4-Fluorophenyl)thio]-3-oxobutanoate. To a stirred solution of 4- fluorobenzenethiol (2.00 g, 15.6 mmol) and ethyl 4-chloro-3-oxobutanoate (3.08 g, 18.7 mmol) in dichloromethane (25 mL) was added triethylamine (4.74 g, 46.8 mmol) dropwise at 0 °C under a nitrogen atmosphere. The mixture was stirred for 2 hours at room temperature, then diluted with brine (50 mL) and extracted with dichloromethane (90 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate / petroleum ether 1:1 to afford ethyl 4-[(4- fluorophenyl)thio]-3-oxobutanoate (2.10 g, 52.5% yield) as a brick-red oil. LCMS calcd. for C12H14FO3S (M + H+) 257.1, found 257.1.

[0270] Step 2: Ethyl 2-(5-Fluoro-1-benzothiophen-3-yl)acetate. To a stirred mixture of polyphosphoric acid (8.7 g, 31 mmol) and toluene (22 mL) was added ethyl 4-[(4- fluorophenyl)thio]-3-oxobutanoate (2.00 g, 7.80 mmol) dropwise at room temperature under a nitrogen atmosphere. The mixture was stirred for 16 h at 100 °C, then diluted with 50 mL of water. After pH adjustment to 8 with potassium carbonate, the mixture was extracted with ethyl acetate (150 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography on C18 silica gel under the following conditions: mobile phase, acetonitrile in water (containing 10 mM ammonium bicarbonate); gradient, 10% to 80% acetonitrile in 20 min; detection, UV absorption at 254 nm. Ethyl 2-(5- fluoro-1-benzothiophen-3-yl)acetate (220 mg, 11.8%) was obtained as a colorless oil. LCMS calcd. for C12H12FO2S (M + H+) 239.1, found 239.1.1H NMR (300 MHz, DMSO-d6) δ 8.02 (dd, J = 8.8, 5.0 Hz, 1H), 7.74 (s, 1H), 7.61 (dd, J = 10.2, 2.5 Hz, 1H), 7.33-7.20 (m, 1H), 4.12 (q, J = 7.1 Hz, 2H), 3.95 (s, 2H), 1.20 (t, J = 7.1 Hz, 3H).

[0271] Step 3: 2-(5-Fluoro-1-benzothiophen-3-yl)acetamide. To a stirred solution of ethyl 2-(5-fluoro-1-benzothiophen-3-yl)acetate (400 mg, 1.67 mmol) in methanol (2 mL) was added a solution of ammonia in methanol (7.0 M, 8 mL) dropwise at room temperature. The resulting mixture was stirred for 16 hours at room temperature, then concentrated under vacuum. The resulting crude product was used for the next step directly without further purification. LCMS calcd. for C10H9FNOS (M + H+) 210.0, found 210.0.

[0272] Step 4: 5-Methyl-2H-[1,3]dioxolo[4,5-f]indole. To a stirred solution of 5H-1,3- dioxolo[4,5-f]indole (1.50 g, 9.30 mmol) in N,N- dimethylformamide (25 mL) was added sodium hydride (447 mg, 18.6 mmol) portionwise at 0 °C. Subsequently, iodomethane (1.32 g, 9.30 mmol) was added dropwise at 0 °C. The mixture was stirred for 2 hours at room temperature, then the reaction was quenched with ice water at 0 °C. The mixture wasextracted with ethyl acetate (3 x 60 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate / petroleum ether 1:1 to afford 5-methyl-2H-[1,3]dioxolo[4,5-f]indole (1.05 g, 64) as a grey solid. LCMS calcd. for C10H10NO2(M + H+) 176.1, found 176.1.

[0273] Step 5: Ethyl 2-(5-Methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)glyoxylate. To a stirred solution of 5-methyl-2H-[1,3]dioxolo[4,5-f]indole (1.00 g, 5.70 mmol) in dichloromethane (10 mL) was added ethyl chloroglyoxylate (935 mg, 6.85 mmol) dropwise at 0 °C under a nitrogen atmosphere. The mixture was stirred for 2 hours at room temperature, then diluted with water (100 mL) and extracted with ethyl acetate (300 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used for the next step without further purification. LCMS calcd. for C14H14NO5 (M + H+) 276.1, found 276.1.1H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 1H), 7.55 (d, J = 0.5 Hz, 1H), 7.25 (d, J = 0.6 Hz, 1H), 6.06 (s, 2H), 4.34 (m, 2H), 3.84 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H).

[0274] 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). To a stirred solution of 2-(5-fluoro-1- benzothiophen-3-yl)acetamide (380 mg, 1.81 mmol) and ethyl 2-(5-methyl-2H- [1,3]dioxolo[4,5-f]indol-7-yl)-glyoxylate (500 mg, 1.81 mmol) in tetrahydrofuran (15 mL) was added potassium tert-butoxide (509 mg, 4.54 mmol) portionwise at 0 °C under a nitrogen atmosphere. The mixture was stirred for 2 hours at room temperature, then diluted with water (50 mL) and extracted with ethyl acetate (150 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography on C18 silica gel under the following conditions: mobile phase, acetonitrile in water (containing 10 mM ammonium bicarbonate); gradient, 40% to 90% acetonitrile in 30 min to provide 9-ING-41-S (282 mg, 37%) was obtained as an orange solid. LCMS calcd. for C22H14FN2O4S (M + H+) 421.1, found 421.1.1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.06 (dd, J = 8.6, 5.0 Hz, 1H), 7.98 (s, 1H), 7.92 (s, 1H), 7.24 - 7.13 (m, 2H), 7.03 (s, 1H), 5.78 (s, 2H), 5.69 (s, 1H), 3.79 (s, 3H).19F NMR (282 MHz, DMSO-d6) δ -118.15. Example 3 – Study on Kinase Inhibitory Activity of Compounds of the Disclosure

[0275] 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.

[0276] Table 3. IC50 kinase inhibitory activity of 9-ING-41-S toward 6 kinases.

[0277] As shown in Table 3, 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. Taken together, these data indicate that 9-ING-41-S is a potent GSK-3 inhibitor, as well as being an effective inhibitor to other kinasesI.

[0278] Figures 2 and 3 show the dose-response kinase inhibition curve observed for 9- ING-41-S toward GSK-3^ and GSK-3β, 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-3β. Additionally, dose-response kinase inhibition curves were observed for MST2 / STK3, RSK3, TNIK, and FLT4 / VEGFR3 (See Figures 4 – 7, respectively). As shown, 9-ING-41-S is nearly 10-fold more active toward GSK-3^ than 9- ING-41-O. Example 4 – In-Vitro Study of Activity of Compounds of the Disclosure Towards hERG

[0279] Next, the potential inhibitory activity of 9-ING-41-S toward the hERG (human ether- a-go-go related gene) gene product was measured and these results are shown in Table 4. The data presented in Table 4 show the top concentration used, and hERG IC50for Cisapride, a known inhibitor of hERG and 9-ING-41-S.

[0280] Table 4. hERG Activity of 9-ING-41-S.

[0281] As can be seen, the IC50 of the positive control Cisapride is 0.019 mM compared to 27.03 mM for 9-ING-41-S. As 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. The in-vitro half-life and clearance rates of the drug in both human and mouse hepatocytes is presented in Table 5, using verapamil as the control compound in this assay.

[0284] Table 5. Hepatocyte clearance over time for 9-ING-41-S; Verapamil was used as control.

[0285] These data show that the clearance rates in human hepatocytes is low compared to mouse hepatocytes with an in vitro half-life of 76.8 minutes in human hepatocytes.

[0286] The percentage of 9-ING-41-S remaining over time in human and mouse hepatocytes was also evaluated, and is shown in Table 6, with verapamil as the control compound in this assay.

[0287] Table 6. Remaining compound over time for 9-ING-41-S in hepatocytes; Verapamil was used as control.

[0288] These data show that 36% of the 9-ING-41-S compound remains after 2 hrs. in human hepatocytes while the drug is below the limits of detection in mouse hepatocytes. Next, the protein binding capacity of 9-ING-41-S in human and mouse plasma was evaluated and is present in Table 7, using Ketoconazole as a control.

[0289] Table 7. Protein binding results of test compound and control compound in human and mouse plasma.

[0290] As shown in Table 7, 9-ING-41-S shows high protein binding in both mouse and human plasma.

[0291] Next, the protein binding capacity of 9-ING-41-S in human and mouse brain homogenates was examined, using Ketoconazole as a control, and these results are shown in Table 8.

[0292] Table 8. Protein binding of 9-ING-41-S and control compound (Telmisartan) in mouse and human brain homogenates.

[0293] As shown in Table 8, 9-ING-41-S shows high protein binding in both mouse and human brain tissue.

[0294] Next, the plasma concentration of 9-ING-41-S administered either intraperitoneally (IP) or intravenously (IV) in male CD1 mice over time. Male CD1 mice were administered 2 mg / kg IV and 5 mg / kg IP, and these results are shown in Figure 8. 9-ING-41-S was also found to exhibit good exposure in the brain, and the mean plasma and brain concentrationsversus 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. The data in Tables 8 and 9 indicate that 9-ING-41-S is highly bound in both human and mouse brain tissue and plasma, while a low % of 9-ING-41-S is unbound. These results indicate 9-ING-41-S was effectively bound in plasma and brain tissues. Example 6 – In-Vitro Study of Compounds of the Disclosure as inhibitors of Pancreatic & Ovarian Cancers

[0297] Pancreatic cancer cell lines have been shown to be sensitive to GSK-3 inhibitors. Several pancreatic cancer cell lines were evaluated to determine their sensitivity to 9-ING- 41-S monotherapy with 9-ING-41-S concentrations of 1 μM, 2.5 μM, 5 μM, 7.5 μM and 10 μM in DMSO and pure DMSO as control.

[0298] As shown in Figure 10 and 11, 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). Similarly, across each pancreatic cancer cell line evaluated (L3.6, PANC1, 4535, and 6182), the cancer cell count decreased as the concentration of 9-ING-41-S increased (Figure 11). Therefore, 9-ING-41-S has been demonstrated to inhibit pancreatic cancer cell lines.

[0299] Next, ovarian cancer cell lines were evaluated for their sensitivity to 9-ING-41-S monotherapy with 9-ING-41-S concentrations of 0.5 μM, 1 μM, 2.5 μM, 5 μM, and 10 μM in DMSO and pure DMSO as control.

[0300] As shown in Figure 12 and 13, the tested ovarian cancer cell lines show heightened sensitivity to 9-ING-41-S over the dose range used. The number of PEO1 and COV362 ovarian cancer cells decreased for samples treated with higher concentrations of 9- ING-41-S and as compared to control and across each ovarian cancer cell line evaluated,the cancer cell count decreased as the concentration of 9-ING-41-S increased (Figure 13). Therefore, 9-ING-41-S has also been demonstrated to inhibit ovarian cancer cell lines.

[0301] 9-ING-41-S has been shown to inhibit pancreatic and ovarian cancer cell lines. Additionally, these data indicate that both pancreatic and ovarian cancer cell lines have a heightened sensitivity to 9-ING-41-S, suggesting 9-ING-41-S can efficiently target pancreatic and ovarian cancer cell lines. 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.

[0303] As shown in Figure 14, treating the pancreatic cancer cell line L3.6 with gemcitabine leads to the phosphorylation of Chk1 at both serine residues (lane 3). This phosphorylation is blocked when 9-ING-41-S is present (lane 4). Lanes 1 and 2 are controls showing that the cells do not have active DNA damage without gemcitabine treatment in the presence or absence of 9-ING-41-S. Therefore, 9-ING-41-S has been shown to block Chk1 phosphorylation associated with gemcitabine. These data indicate that 9-ING-41-S and gemcitabine can work synergistically to more effectively kill cancer cells than either 9-ING- 41-S or gemcitabine alone. Further, these data illustrate that administration of 9-ING-41-S and gemcitabine can synergistically kill cancer cells to a greater extent than expected, based on their individual performance. .

[0304] Treatment of pancreatic cancer cell lines with GSK-3 inhibitors has been shown to lead to an arrest in mitosis. Therefore, it was evaluated whether 9-ING-41-S treatment would also delay cell cycle exit and lead to an accumulation of mitotic cells. L3.6 and PANC1 cell lines were treated for 18 hours with diluent or 10 μM 9-ING-41-S and the cell cycle status was examined by staining cells with propidium iodide (PI) which stains DNA and pSer10- Histone H3, a marker of mitosis and are shown in Figures 15 and 16.

[0305] As can be seen in Figure 15, treatment of pancreatic cancer cell lines with 9-ING- 41-S leads to a substantial increase in mitotic cells as compared to cells treated with DMSO. Consistent with this mitotic block, an increase in the activity of Aurora Kinase A as measured by its phosphorylation at its active site (pThr288), and its stabilization following treatmentwith 9-ING-41-S is also observed (Figure 16). Similarly, other markers of mitotic arrest are also seen including the presence of Cyclin B1 and pSer10 Histone H3 (Figure 16). Example 8 – In-Vitro Study on Combination Therapy for Ovarian Cancer

[0306] GSK-3 inhibition has been shown to impair 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). It was evaluated whether 9-ING-41-S could prevent the phosphorylation of Chk1 by ATR in the presence of the DNA damaging chemotherapeutic cisplatin in ovarian cancer cell lines. As shown in Figure 17, treating the ovarian cancer cell lines PEO1 and PEA1 with cisplatin leads to the phosphorylation of Chk1 at both serine residues (lane 2). This phosphorylation is impaired when 9-ING-41-S is present (lane 4). Lanes 1 and 3 are controls showing that the cells do not have active DNA damage without cisplatin treatment in the presence or absence of 9- ING-41-S.

[0307] Accordingly, 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). Therefore, these data suggest that combinations of 9-ING-41-S and cisplatin, carboplatin, or taxol, can work synergistically to more effectively kill cancer cells than either, 9-ING-41-S or cisplatin alone, and to a greater extent than expected upon administration and based on their individual performance.

[0308] Moreover, gamma H2Ax, a marker of DNA damage induced by cisplatin was not affected by 9-ING-41-S treatment, which suggested that cells with cisplatin associated damage are not repaired, leading to increased cell death. Notably, 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. The combination of 9-ING-41-S and cisplatin shows potential for enhanced cancer cell killing compared toeither treatment alone by controlling the relative phosphorylation of Chk1. This combination is believed to be particularly effective in overcoming resistance to cisplatin, which is often mediated by hyperactivation of the DNA damage checkpoint. Example 9 – Prophetic In-Vivo Study on Ovarian Cancer in a PDX Mouse Model

[0310] The platinum sensitive PDX line, PH077 will be used as a model. For the PH077 model, 40 female SCID-bg mice with intraperitoneal (IP) tumors will be randomized to one of four cohorts (n=10 each): Control, 9-ING-41-S 40 mg / kg IP on days 1, 3, and 5 with cycles repeating weekly, carboplatin 51 mg / kg IP weekly, or combination therapy at the same dose and schedule. The dose of 9-ING-41-S and carboplatin is based on preliminary studies as monotherapy or in combination with other agents. (Huang, D., et al., Multiomic analysis identifies CPT1A as a potential therapeutic target in platinum-refractory, high-grade serous ovarian cancer. Cell Rep Med, 2021.2(12): p.100471). Treatment will continue for 4 weeks (primary endpoint) but animals will be observed for up to 4 additional weeks for tumor regrowth (exploratory endpoint). 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. (Kanakkanthara, A., et al., Repurposing Ceritinib Induces DNA Damage and Enhances PARP Inhibitor Responses in High-Grade Serous Ovarian Carcinoma. Cancer Res, 2022.82(2): p.307-319).

[0311] Based on preliminary studies showing that 9-ING-41-S is cytotoxic to ovarian cancer cell lines, and given that cisplatin activates the ATR DNA damage checkpoint, which is blocked by 9-ING-41-S, it is expected that the combination of 9-ING-41-S + Carboplatin will be superior to either 9-ING-41-S or carboplatin, alone. Further, it is expected that 9-ING- 41-S will not be toxic, either alone or in combination. Example 10 – Prophetic In-Vivo Studies on Frontotemporal Dementia in a PS19 Mouse Model

[0312] The frontotemporal dementia mouse line, PS19 will be used as a model. PS19 strain develops a variety of post-translation modifications on various tau residues that is believed to be due to GSK activity. 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 onpreliminary 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. (Cogut V, McNeely TL, Bussian TJ, Graves SI, Baker DJ. Caloric Restriction Improves Spatial Learning Deficits in Tau Mice. J Alzheimers Dis. 2024;98(3):925-940.). Tau pathology, astrogliosis, microgliosis and other neuroinflammation, hippocampal cell proliferation, and neurogenesis will be evaluated by immunofluorescence staining and Western blotting analysis. (Lyons CE, Graves SI, Razzoli M, Jeganathan K, Mansk RP, McGonigle S, Sabarinathan N, van Deursen JM, Baker DJ, Bartolomucci A. Chronic Social and Psychological Stress Impact Select Neuropathologies in the PS19 Mouse Model of Tauopathy. Psychosom Med.2024 Jun 1;86(5):366-378.).

[0313] An additional study will be performed with male PS19 mice (average age, 6.3 months) to evaluate whether 9-ING-41-S delayed the onset of FTD in mice. It is expected to see delayed pathologic onset by beginning treatment with 9-ING-41-S prior to disease establishment. Therefore, the 6 month old mice are expected to demonstrate a more advanced onset of disease as compared to mice that are treated with 9-ING-41-S earlier.

Claims

What is claimed is:

1. A compound having a structure of Formula (I):or a pharmaceutically acceptable salt of the compound thereof, wherein: ring A is a 5-membered heterocycle or heteroaryl comprising 1 or 2 ring nitrogen heteroatoms; RN1is independently H or C1-3alkyl; n is 0, 1, or 2; each RA, when present, is independently C1-3alkyl, C2-6alkenyl, O-C2-6alkenyl, C2-6alkynyl, O- C2-6alkynyl, Cyc1, or O-Cyc1; Cyc1is C3-8cycloalkyl, C6-10aryl, 5-8 membered heterocycle or 5-8 membered heteroaryl, wherein the heterocycle and heteroaryl each comprises 1, 2, or 3 ring heteroatoms independently selected from N, O, and S, and Cyc1is substituted with 0, 1, or 2 C1- 6alkyl or C2-6alkenyl groups; Y1is selected from O, S, Se, and NRN1; Y2is S or Se; R1and R5are each independently absent or selected from halo and C1-3alkyl; and each of R2, R3, R4, R6, R7and R8are independently absent or selected from halo, C1-3alkyl, C1-3haloalkyl, hydroxyl, C1-3hydroxyalkyl, C1-3alkoxy, and CN; or R2and R3, or R3and R4, or R6and R7, or R7and R8together 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.

2. The compound or salt of claim 1, wherein ring A is,3. The compound or salt of claim 2, wherein RAis C1-3alkyl, Cyc1, or O-Cyc1.

4. The compound or salt of claim 2, having a structure of Formula (II), or a pharmaceutically acceptable salt thereof:

5. The compound or salt of any one of claims 1 to 3, wherein Y2is S.

6. The compound or salt of any one of claims 1 to 3, wherein Y2is Se.

7. The compound or salt of claim 4, having a structure of Formula (IIIa), or a pharmaceutically acceptable salt thereof:

8. The compound or salt of claim 6, wherein Y1is S or NRN1.

9. The compound or salt of claim 6, wherein Y1is O or Se.

10. The compound or salt of any one of claims 6 or 7, wherein Y1is NRN1.

11. The compound or salt of claim 9, having a structure of Formula (IIIb), or a pharmaceutically acceptable salt thereof:

12. The compound or salt of claim 10, wherein at least one RN1is H.

13. The compound or salt of any one of claims 10 or 11, wherein each RN1is H.

14. The compound or salt of claim 10, wherein at least one RN1is C1-3alkyl.

15. The compound or salt of any one of claims 10 or 13, wherein at least one RN1is C1-2alkyl.

16. The compound or salt of any one of claims 10 or 13, wherein each RN1is C1-3alkyl.

17. The compound or salt of claim 5, having a structure of Formula (IVa), or a pharmaceutically acceptable salt thereof:

18. The compound or salt of claim 10, wherein Y1is S or NRN1.

19. The compound or salt of claim 10, wherein Y1is O or Se.

20. The compound or salt of claim 10 or 11, wherein Y1is NRN1.

21. The compound or salt of claim 13, having a structure of Formula (IVb), or a pharmaceutically acceptable salt thereof:

22. The compound or salt of claim 20, wherein at least one RN1is H.

23. The compound or salt of any one of claims 20 or 21, wherein each RN1is H.

24. The compound or salt of claim 20, wherein at least one RN1is C1-3alkyl.

25. The compound or salt of any one of claims 20 or 23, wherein at least one RN1is C1-2alkyl.

26. The compound or salt of any one of claims 20 or 23, wherein each RN1is C1-3alkyl.

27. The compound or salt of any one of claims 1 to 25, wherein at least one of R1and R5is halo or C1alkyl.

28. The compound or salt of any one of claims 1 to 26, wherein at least one of R2, R3, R4, R6, R7, and R8is halo, hydroxyl, or CN.

29. The compound or salt of any one of claims 1 to 27, wherein at least one of R2, R3, R4, R6, R7, and R8is C1-3alkyl, C1-3haloalkyl, C1-3hydroxyalkyl, or C1-3alkoxy.

30. The compound or salt of any one of claims 1 to 29, wherein at least one of R2, R3, R4, R6, R7, and R8is F, Cl, Br, CN, CH3, OCH3, CF3, or CHF2.

31. The compound or salt of any one of claims 1 to 29, wherein at least one of R2, R3, R4, R6, R7, and R8is F, Cl, Br, CN, CH3, OCH3, CF3, or CHF2.

32. The compound or salt of any one of claims 1 to 30, wherein at least one of R2and R3, or R3and R4, or R6and R7, or R7and R8together with the ring through which they are attached, form a C5-8cycloalkyl or 5-8 membered heterocycle and the heterocycle comprises 1 or 2 ring heteroatoms independently selected from N, O, and S.

33. The compound or salt of claim 31, wherein R2and R3, or R3and R4, or R6and R7, or R7and R8together with the ring through which they are attached, form a C5-8cycloalkyl.

34. The compound or salt of claim 31, wherein R2and R3, or R3and R4, or R6and R7, or R7and R8together with the ring through which they are attached, form a 5-8 membered heterocycle and the heterocycle comprises 1 or 2 ring heteroatoms independently selected from N, O, and S 35. The compound or salt of any one of claims 1 to 30, wherein at least one of R2and R3, or R3and R4, or R6and R7, or R7and R8together 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.

36. The compound or salt of claim 33, wherein at least one of R2and R3, or R3and R4, or R6and R7, or R7and R8together with the ring through which they are attached, form a C6-10aryl.

37. A compound, or pharmaceutically acceptable salt thereof, as recited in Table A. Table A38. The compound or salt of claim 37, having a structure of.

39. A pharmaceutical composition comprising the compound or salt of any one of claims 1 to 38 and a pharmaceutically acceptable carrier.

40. A method of inhibiting GSK-3 in a cell comprising contacting the cell with the compound or salt of any one of claims 1 to 38 or the composition of claim 39 in an amount effective to inhibit GSK-3.

41. The method of claim 40, wherein the contacting comprising administering the compound or the composition to a subject in need thereof.

42. A method for inhibiting proliferation of cancer cells comprising contacting the cell with the compound or salt of any one of claims 1 to 38 or the composition of claim 39 in an amount effective to inhibit proliferation.

43. The method of claim 42 wherein the cancer cell is a colorectal cancer cell, a pancreatic cancer cell, or an ovarian cancer cell.

44. The method of any one of claims 42 or 43, wherein the contacting comprising administering the compound or the composition to a subject in need thereof.

45. A method for treating a protein kinase-related disorder or disease in a subject comprising administering to the subject a therapeutically effective amount of the compound or salt of any one of claims 1 to 38 or the pharmaceutical composition of claim 39.

46. The method of claim 45, wherein the protein kinase-related disorder or disease is a GSK-3-related disorder or disease.

47. The method of claims 45 or 46, wherein the GSK-3-related disorder or disease is selected from cancer, neurological disease or disorder, and psychiatric disease or disorder.

48. A method for treating cancer in a subject comprising administering to the subject a therapeutically effective amount of the compound or salt of any one of claims 1 to 38 or the pharmaceutical composition of claim 39.

49. The method of claim 48, further comprising administering to the subject a therapeutic agent.

50. The method of claim 49, wherein the therapeutic agent is gemcitabine, cisplatin, or carboplatin.

51. The method of claim 48 wherein the cancer is colorectal cancer, pancreatic cancer, or ovarian cancer.

52. Use of the compound or salt of any one of claims 1 to 38 or the composition of claim 39 for inhibiting GSK-3 in a cell.

53. Use of the compound or salt of any one of claims 1 to 38 or the composition of claim 39 for inhibiting proliferation of cancer cells.

54. Use of the compound or salt of any one of claims 1 to 38 or the composition of claim 39 for treating a protein kinase-related disorder or disease.

55. The use of claim 52, wherein the protein kinase-related disorder or disease is a GSK-3-related disorder or disease.

56. The use of claim 53, wherein the GSK-3-related disorder or disease is selected from cancer, neurological disease or disorder, and psychiatric disease or disorder.

57. Use of the compound or salt of any one of claims 1 to 38 or the composition of claim 39 for treating cancer.

58. The use of claim 57, further comprising administering to the subject a therapeutic agent.

59. The use of claim 58, wherein the therapeutic agent is gemcitabine, cisplatin, or carboplatin.

60. The use of claim 57, wherein the cancer is colorectal cancer, pancreatic cancer, or ovarian cancer.

61. Use of the compound or salt of any one of claims 1 to 38 or the composition of claim 39 for inhibiting GSK-3 in a cell.

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