WO2024118667A1 - Inhibiteurs eif4a1 à activité antitumorale - Google Patents

Inhibiteurs eif4a1 à activité antitumorale Download PDF

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Publication number
WO2024118667A1
WO2024118667A1 PCT/US2023/081444 US2023081444W WO2024118667A1 WO 2024118667 A1 WO2024118667 A1 WO 2024118667A1 US 2023081444 W US2023081444 W US 2023081444W WO 2024118667 A1 WO2024118667 A1 WO 2024118667A1
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Prior art keywords
cancer
alkyl
compound
pharmaceutically acceptable
cell
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PCT/US2023/081444
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English (en)
Inventor
Ronald B. Gartenhaus
Glen E. KELLOGG
Bandish B. KAPADIA
Forum B. KAYASTHA
Noah B. HERRINGTON
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The United States Government As Represented By The Department Of Veterans Affairs
Virginia Commonwealth University
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Application filed by The United States Government As Represented By The Department Of Veterans Affairs, Virginia Commonwealth University filed Critical The United States Government As Represented By The Department Of Veterans Affairs
Publication of WO2024118667A1 publication Critical patent/WO2024118667A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • eIFs eukaryotic initiation factors
  • eIF4F canonical heterotrimeric eIF4F complex, which catalyzes ribosome recruitment to mRNA and is comprised of eIF4G (scaffold protein), eIF4E (cap-binding protein), and eIF4A (ATP- dependent RNA helicase) (Lindqvist L, et al. (2008) RNA 14: 960-969).
  • eIF4A1 unwinds the secondary structure of RNA within the 5′ untranslated region (5'-UTR) of mRNA, a critical step necessary for the recruitment of the 43S preinitiation complex, and thus plays a vital role in initiating access to protein biosynthesis for the ribosomes (Raza F, et al. (2015) Biochem Soc Trans 43: 1227-1233).
  • the expression levels of eIF4A1 and eIF4A2 vary in a tissue-dependent manner.
  • eIF4A1 is expressed more in proliferating cells compared to eIF4A2, which is dominantly expressed in growth-arrested differentiated cells, suggesting differential regulation of cell fate (Naineni SK, et al. (2020) RNA 26: 541-549). This observation that eIF4A1 and eIF4A2 have distinct biological functions in translational regulation in different subsets of cells and clinical conditions has supported the view that eIF4A1 is a rational cancer target.
  • eIF4A1 The plethora of biochemical data on eIF4A1 (now referred to as eIF4A) reported in the last three decades has deciphered the detailed molecular mechanism of duplex destabilization by eIF4A and the governing principles of its minimal RNA helicase activity (Andreou AZ, Kleinmeier D. (2013) RNA Biol 10: 19-32). Genome-wide studies of the eIF4A-mediated translatome revealed that helicase regulates the expression of mRNAs encoding vital proteins associated with cell proliferation, cell survival, cell cycle progression, and angiogenesis (Rubio CA, et al. (2014) Genome Biol 15: 476; Wolfe AL, et al. (2014) Nature 513: 65-70).
  • eFT226 (zotatifin), a structure-guided rocaglamide- inspired inhibitor, has entered Phase I clinical trials for solid tumors (Ernst JT, et al. (2020) J Med Chem 63: 5879-5955). Recently, structural elucidation of a rocaglate [RocA]:eIF4A1:polypurine RNA complex revealed that rocaglates operate as interfacial inhibitors and make indispensable interactions with eIF4A1 and two adjacent RNA purine bases (Chu J, et al. (2019) Cell Chem Biol 26: 1586-1593 e1583). However, all the compounds appear to act non-specifically upon eIF4A1 and eIF4A2.
  • the invention in one aspect, relates to substituted triazole 4- carbohydrazides useful as, for example, eIF4A1 inhibitors.
  • eIF4A1 inhibitors have been implicated in a variety of diseases and disorders including, but not limited to, cancers such as sarcomas, carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanomas, gliomas, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, non- small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma).
  • cancers such as sarcomas, carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer,
  • compositions comprising an effective amount of a compound having a structure represented by a formula: , wherein each of R 1 and R 2 is independently selected from hydrogen and C1-C4 alkyl; wherein Ar 1 is selected from C6-C12 aryl and C5-C11 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH2, ⁇ OH, ⁇ NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ⁇ CO2R 10 ; and wherein R 10 , when present, is selected from hydrogen and C1-
  • Also disclosed are methods of modulating eIF4A1 activity in a cell comprising contacting the cell with an effective amount of a compound having a structure represented by a formula: , wherein each of R 1 and R 2 is independently selected from hydrogen and C1-C4 alkyl; wherein Ar 1 is selected from C6-C12 aryl and C5-C11 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH2, ⁇ OH, ⁇ NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ⁇ CO 2 R 10
  • Also disclosed are methods of modulating eIF4A1 activity in a subject comprising administering to the subject an effective amount of a compound having a structure represented by a formula: , wherein each of R 1 and R 2 is independently selected from hydrogen and C1-C4 alkyl; wherein Ar 1 is selected from C6-C12 aryl and C5-C11 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ⁇ CO
  • kits comprising a compound having a structure represented by a formula: , wherein each of R 1 and R 2 is independently selected from hydrogen and C1-C4 alkyl; wherein Ar 1 is selected from C6-C12 aryl and C5-C11 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ⁇ CO2R 10 ; and wherein R 10 , when present, is selected from hydrogen and C1- C4 alkyl; wherein Ar
  • kits comprising a compound selected from: ,
  • FIG.1A-E show representative data illustrating the clinicopathologic evaluation of eIF4A1.
  • FIG.2A and FIG.2B show representative data illustrating eIF4A1 expression in molecular subtypes of DLBCL in microarray datasets.
  • FIG.3A and FIG.3B show a representative model of RocaA and a representative flow chart illustrating the process taken to identify new small molecule inhibitors for eIF4A1.
  • FIG.4A-C show representative data illustrating the assessment of eIF4A1 in a specific luciferase assay in Hek293T/17 stables.
  • FIG.5A-F show representative data illustrating that an eIF4A1 specific high throughput screen identifies small molecules with inhibitory effect.
  • FIG.6A-D show representative data illustrating RBF98 activity in luciferase and biochemical assays.
  • FIG.7A-C show representative data illustrating that RBF98 reduces proliferation and overall translation in DLBCL.
  • FIG.8A and FIG.8B show representative images illustrating the interaction differences between RocA and docked RBF98 (FIG.8A) and a summary of the RBF98 analogs evaluated in the secondary screen (FIG.8B).
  • FIG.9A-E show representative data pertaining to the secondary screen and the evaluation of RBF98 analogs.
  • FIG.10A and FIG.10B show representative data illustrating the percentage inhibition of luciferase activity.
  • FIG.11 shows representative data illustrating that RBF197 attenuates DLBCL growth. Specifically, concentration-response curves of RBF197 in SUDHL4, OCI-Ly3, DS, and RC cell lines are shown. Linear regression fit of the inhibition values was plotted using Graph pad prism and EC 50 values were calculated. The EC 50 values were observed to be less than 10 ⁇ M.
  • FIG.12A-G show representative data illustrating that RBF197 and RBF208 decrease overall translation and eIF4A1 dependent pathway proteins in double-hit lymphoma.
  • FIG.13A-G show representative data illustrating that RBF197 and 208 decrease overall translation and eIF4A1 dependent pathway proteins in ABC-DLBCL OCI-Ly3 cell line.
  • FIG.14A and FIG.14B show representative data illustrating that RBF197 and RBF208 decrease overall translation and eIF4A1 dependent pathway proteins in double-hit lymphoma.
  • FIG.14A shows a qRT-PCR analysis for expression of defined genes in RC following treatment of RBF197 or RBF208 at 1 and 3 ⁇ M.
  • FIG.14B shows the relative mRNA expression data for defined genes with the treatment of RBF197 and RBF208, respectively.
  • FIG.15A and FIG.15B show representative data illustrating the effect of RBF197 and RBF208 on DLBCL colony formation.
  • FIG.16 shows representative docking poses of RBF197 and RBF208 in eIF4A:RNA grove.
  • the top two panels show schematic representations of the interactions made between docked poses of RBF197 and RBF208 and their surrounding environments. Transparent ovals are used to two-dimensionally represent possible ⁇ - ⁇ stacking interactions between the ligands and surrounding residues. Dashed lines between the ligands and surrounding residues are used to indicate hydrogen bonding.
  • the lower two panels are high- scoring docked models of RBF197 and RBF208.
  • FIG.17A-D show representative data illustrating that RBF 197 and RBF208 inhibit human eIF4A1 by RNA clamp mechanism.
  • FIG.18 shows a representative schematic summary illustrating the identification of eIF4A inhibitors and RBF197 targeting eIF4A translational capacity to suppress DLBCL.
  • the terms “about” and “at or about” mean that the amount or value in question can be the value designated some other value approximately or about the same. It is generally understood, as used herein, that it is the nominal value indicated ⁇ 10% variation unless otherwise indicated or inferred. The term is intended to convey that similar values promote equivalent results or effects recited in the claims. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but can be approximate and/or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art.
  • an amount, size, formulation, parameter or other quantity or characteristic is “about” or “approximate” whether or not expressly stated to be such. It is understood that where “about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.
  • References in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed.
  • X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.
  • IC 50 is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% inhibition of a biological process, or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc.
  • a substance e.g., a compound or a drug
  • an IC50 can refer to the concentration of a substance that is required for 50% inhibition in vivo, as further defined elsewhere herein.
  • IC 50 refers to the half-maximal (50%) inhibitory concentration (IC) of a substance.
  • EC 50 is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% agonism of a biological process, or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc.
  • a substance e.g., a compound or a drug
  • an EC50 can refer to the concentration of a substance that is required for 50% agonism in vivo, as further defined elsewhere herein.
  • EC 50 refers to the concentration of agonist that provokes a response halfway between the baseline and maximum response.
  • the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
  • the term “subject” can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian.
  • the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex.
  • the subject is a mammal.
  • a patient refers to a subject afflicted with a disease, disorder, or condition.
  • the term “patient” includes human and veterinary subjects.
  • treatment refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder.
  • active treatment that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder
  • causal treatment that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder.
  • this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder.
  • the term covers any treatment of a subject, including a mammal (e.g., a human), and includes: (i) preventing the disease from occurring in a subject that can be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease, i.e., arresting its development; or (iii) relieving the disease, i.e., causing regression of the disease.
  • the subject is a mammal such as a primate, and, in a further aspect, the subject is a human.
  • subject also includes domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse, rabbit, rat, guinea pig, fruit fly, etc.).
  • livestock e.g., cattle, horses, pigs, sheep, goats, etc.
  • laboratory animals e.g., mouse, rabbit, rat, guinea pig, fruit fly, etc.
  • the term “diagnosed” means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by the compounds, compositions, or methods disclosed herein.
  • the terms “administering” and “administration” refer to any method of providing a pharmaceutical preparation to a subject.
  • Such methods include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent.
  • a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition.
  • a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.
  • the terms “effective amount” and “amount effective” refer to an amount that is sufficient to achieve the desired result or to have an effect on an undesired condition.
  • a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the condition being treated and the severity of the condition; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration.
  • compositions can contain such amounts or submultiples thereof to make up the daily dose.
  • the dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. In further various aspects, a preparation can be administered in a “prophylactically effective amount”; that is, an amount effective for prevention of a disease or condition. [0058]
  • “dosage form” means a pharmacologically active material in a medium, carrier, vehicle, or device suitable for administration to a subject.
  • a dosage forms can comprise inventive a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, in combination with a pharmaceutically acceptable excipient, such as a preservative, buffer, saline, or phosphate buffered saline. Dosage forms can be made using conventional pharmaceutical manufacturing and compounding techniques.
  • Dosage forms can comprise inorganic or organic buffers (e.g., sodium or potassium salts of phosphate, carbonate, acetate, or citrate) and pH adjustment agents (e.g., hydrochloric acid, sodium or potassium hydroxide, salts of citrate or acetate, amino acids and their salts) antioxidants (e.g., ascorbic acid, alpha-tocopherol), surfactants (e.g., polysorbate 20, polysorbate 80, polyoxyethylene 9-10 nonyl phenol, sodium desoxycholate), solution and/or cryo/lyo stabilizers (e.g., sucrose, lactose, mannitol, trehalose), osmotic adjustment agents (e.g., salts or sugars), antibacterial agents (e.g., benzoic acid, phenol, gentamicin), antifoaming agents (e.g., polydimethylsilozone), preservatives (e.g., thimerosal, 2-
  • a dosage form formulated for injectable use can have a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, suspended in sterile saline solution for injection together with a preservative.
  • kit means a collection of at least two components constituting the kit. Together, the components constitute a functional unit for a given purpose. Individual member components may be physically packaged together or separately. For example, a kit comprising an instruction for using the kit may or may not physically include the instruction with other individual member components. Instead, the instruction can be supplied as a separate member component, either in a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation.
  • instruction(s) means documents describing relevant materials or methodologies pertaining to a kit. These materials may include any combination of the following: background information, list of components and their availability information (purchase information, etc.), brief or detailed protocols for using the kit, trouble-shooting, references, technical support, and any other related documents. Instructions can be supplied with the kit or as a separate member component, either as a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation. Instructions can comprise one or multiple documents, and are meant to include future updates.
  • therapeutic agent include any synthetic or naturally occurring biologically active compound or composition of matter which, when administered to an organism (human or nonhuman animal), induces a desired pharmacologic, immunogenic, and/or physiologic effect by local and/or systemic action.
  • the term therefore encompasses those compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs and the like.
  • therapeutic agents include, without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances that affect the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment.
  • the term “therapeutic agent” includes compounds or compositions for use in all of the major therapeutic areas including, but not limited to, adjuvants; anti-infectives such as antibiotics and antiviral agents; anti-cancer and anti-neoplastic agents such as kinase inhibitors, poly ADP ribose polymerase (PARP) inhibitors and other DNA damage response modifiers, epigenetic agents such as bromodomain and extra-terminal (BET) inhibitors, histone deacetylase (HDAc) inhibitors, iron chelotors and other ribonucleotides reductase inhibitors, proteasome inhibitors and Nedd8-activating enzyme (NAE) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, traditional cytotoxic agents such as paclitaxel, dox, irinotecan, and platinum compounds, immune checkpoint blockade agents such as cytotoxic T lymphocyte antigen-4 (CTLA-4) monoclonal antibody (mAB), CTLA
  • the agent may be a biologically active agent used in medical, including veterinary, applications and in agriculture, such as with plants, as well as other areas.
  • therapeutic agent also includes without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness; or substances which affect the structure or function of the body; or pro-drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment.
  • pharmaceutically acceptable describes a material that is not biologically or otherwise undesirable, i.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner.
  • the term “derivative” refers to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds.
  • exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound.
  • the term “pharmaceutically acceptable carrier” refers to sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like.
  • Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents, such as aluminum monostearate and gelatin, which delay absorption.
  • Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides). Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use.
  • biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which
  • Suitable inert carriers can include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.
  • the term “substituted” is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described below.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen
  • the heteroatoms can have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds.
  • substitution or “substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • substituents can be further optionally substituted (i.e., further substituted or unsubstituted).
  • a 1 ,” “A 2 ,” “A 3 ,” and “A 4 ” are used herein as generic symbols to represent various specific substituents. These symbols can be any substituent, not limited to those disclosed herein, and when they are defined to be certain substituents in one instance, they can, in another instance, be defined as some other substituents.
  • aliphatic or “aliphatic group,” as used herein, denotes a hydrocarbon moiety that may be straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridging, and spirofused polycyclic) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. Unless otherwise specified, aliphatic groups contain 1-20 carbon atoms. Aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • alkyl as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s- butyl, t-butyl, n-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like.
  • the alkyl group can be cyclic or acyclic.
  • the alkyl group can be branched or unbranched.
  • the alkyl group can also be substituted or unsubstituted.
  • the alkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein.
  • a “lower alkyl” group is an alkyl group containing from one to six (e.g., from one to four) carbon atoms.
  • alkyl group can also be a C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and the like up to and including a C1-C24 alkyl.
  • alkyl is generally used to refer to both unsubstituted alkyl groups and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying the specific substituent(s) on the alkyl group.
  • halogenated alkyl or “haloalkyl” specifically refers to an alkyl group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine.
  • halogenated alkyl specifically refers to an alkyl group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine.
  • monohaloalkyl specifically refers to an alkyl group that is substituted with a single halide, e.g. fluorine, chlorine, bromine, or iodine.
  • polyhaloalkyl specifically refers to an alkyl group that is independently substituted with two or more halides, i.e.
  • alkoxyalkyl specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below.
  • aminoalkyl specifically refers to an alkyl group that is substituted with one or more amino groups.
  • hydroxyalkyl specifically refers to an alkyl group that is substituted with one or more hydroxy groups.
  • alkyl is used in one instance and a specific term such as “hydroxyalkyl” is used in another, it is not meant to imply that the term “alkyl” does not also refer to specific terms such as “hydroxyalkyl” and the like. [0070] This practice is also used for other groups described herein.
  • cycloalkyl refers to both unsubstituted and substituted cycloalkyl moieties
  • the substituted moieties can, in addition, be specifically identified herein; for example, a particular substituted cycloalkyl can be referred to as, e.g., an “alkylcycloalkyl.”
  • a substituted alkoxy can be specifically referred to as, e.g., a “halogenated alkoxy”
  • a particular substituted alkenyl can be, e.g., an “alkenylalcohol,” and the like.
  • cycloalkyl is a non-aromatic carbon-based ring composed of at least three carbon atoms.
  • examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like.
  • heterocycloalkyl is a type of cycloalkyl group as defined above, and is included within the meaning of the term “cycloalkyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.
  • the cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted.
  • the cycloalkyl group and heterocycloalkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • the term “polyalkylene group” as used herein is a group having two or more CH 2 groups linked to one another.
  • the polyalkylene group can be represented by the formula — (CH 2 ) a —, where “a” is an integer of from 2 to 500.
  • Alkoxy also includes polymers of alkoxy groups as just described; that is, an alkoxy can be a polyether such as —OA 1 —OA 2 or — OA 1 —(OA 2 )a—OA 3 , where “a” is an integer of from 1 to 200 and A 1 , A 2 , and A 3 are alkyl and/or cycloalkyl groups.
  • alkenyl as used herein is a hydrocarbon group of from 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon double bond.
  • the alkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.
  • groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described here
  • Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, and the like.
  • heterocycloalkenyl is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkenyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.
  • the cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted.
  • the cycloalkenyl group and heterocycloalkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • alkynyl as used herein is a hydrocarbon group of 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon triple bond.
  • the alkynyl group can be unsubstituted or substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.
  • groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or
  • cycloalkynyl as used herein is a non-aromatic carbon-based ring composed of at least seven carbon atoms and containing at least one carbon-carbon triple bound.
  • cycloalkynyl groups include, but are not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and the like.
  • heterocycloalkynyl is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkynyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.
  • the cycloalkynyl group and heterocycloalkynyl group can be substituted or unsubstituted.
  • the cycloalkynyl group and heterocycloalkynyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • aromatic group refers to a ring structure having cyclic clouds of delocalized ⁇ electrons above and below the plane of the molecule, where the ⁇ clouds contain (4n+2) ⁇ electrons.
  • aromaticity is found in Morrison and Boyd, Organic Chemistry, (5th Ed., 1987), Chapter 13, entitled “Aromaticity,” pages 477-497, incorporated herein by reference.
  • aromatic group is inclusive of both aryl and heteroaryl groups.
  • aryl as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like.
  • the aryl group can be substituted or unsubstituted.
  • the aryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, ⁇ NH 2 , carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • biasryl is a specific type of aryl group and is included in the definition of “aryl.”
  • the aryl group can be a single ring structure or comprise multiple ring structures that are either fused ring structures or attached via one or more bridging groups such as a carbon- carbon bond.
  • biaryl can be two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl.
  • aldehyde as used herein is represented by the formula —C(O)H.
  • amine or “amino” as used herein are represented by the formula — NA 1 A 2 , where A 1 and A 2 can be, independently, hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • a specific example of amino is ⁇ NH2.
  • alkylamino as used herein is represented by the formula —NH(-alkyl) where alkyl is a described herein.
  • dialkylamino as used herein is represented by the formula —N(-alkyl) 2 where alkyl is a described herein.
  • Representative examples include, but are not limited to, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)amino group, dipentylamino group, diisopentylamino group, di(tert-pentyl)amino group, dihexylamino group, N-ethyl-N-methylamino group, N-methyl-N-propylamino group, N- ethyl-N-propylamino group and the like.
  • carboxylic acid as used herein is represented by the formula —C(O)OH.
  • esteer as used herein is represented by the formula —OC(O)A 1 or — C(O)OA 1 , where A 1 can be alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • polyester as used herein is represented by the formula —(A 1 O(O)C-A 2 -C(O)O)a— or —(A 1 O(O)C-A 2 -OC(O))a—, where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer from 1 to 500. “Polyester” is as the term used to describe a group that is produced by the reaction between a compound having at least two carboxylic acid groups with a compound having at least two hydroxyl groups.
  • ether as used herein is represented by the formula A 1 OA 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein.
  • polyether as used herein is represented by the formula —(A 1 O-A 2 O) a —, where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer of from 1 to 500.
  • Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.
  • halo halogen
  • halide as used herein can be used interchangeably and refer to F, Cl, Br, or I.
  • pseudohalide pseudohalogen
  • pseudohalo pseudohalogen
  • pseudohalo can be used interchangeably and refer to functional groups that behave substantially similar to halides. Such functional groups include, by way of example, cyano, thiocyanato, azido, trifluoromethyl, trifluoromethoxy, perfluoroalkyl, and perfluoroalkoxy groups.
  • heteroalkyl refers to an alkyl group containing at least one heteroatom.
  • heteroatoms include, but are not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized.
  • Heteroalkyls can be substituted as defined above for alkyl groups.
  • heteroaryl refers to an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions.
  • the heteroaryl group can be substituted or unsubstituted.
  • heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • Heteroaryl groups can be monocyclic, or alternatively fused ring systems.
  • Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl.
  • heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, and pyrido[2,3-b]pyrazinyl.
  • heterocycle or “heterocyclyl,” as used herein can be used interchangeably and refer to single and multi-cyclic aromatic or non-aromatic ring systems in which at least one of the ring members is other than carbon.
  • Heterocycle includes pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole, including, 1,2,3- oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole, thiadiazole, including, 1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole, triazole, including, 1,2,3-triazole, 1,3,4-triazole, tetrazole, including 1,2,3,4-tetrazole and 1,2,4,5-tetrazole, pyridazine, pyrazine, triazine, including 1,
  • heterocyclyl group can also be a C2 heterocyclyl, C2-C3 heterocyclyl, C2- C4 heterocyclyl, C2-C5 heterocyclyl, C2-C6 heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9 heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, and the like up to and including a C2-C18 heterocyclyl.
  • a C2 heterocyclyl comprises a group which has two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, dihydrodiazetyl, oxiranyl, thiiranyl, and the like.
  • a C5 heterocyclyl comprises a group which has five carbon atoms and at least one heteroatom, including, but not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, pyridinyl, and the like.
  • bicyclic heterocycle or “bicyclic heterocyclyl,” as used herein refers to a ring system in which at least one of the ring members is other than carbon.
  • Bicyclic heterocyclyl encompasses ring systems wherein an aromatic ring is fused with another aromatic ring, or wherein an aromatic ring is fused with a non-aromatic ring.
  • Bicyclic heterocyclyl encompasses ring systems wherein a benzene ring is fused to a 5- or a 6- membered ring containing 1, 2 or 3 ring heteroatoms or wherein a pyridine ring is fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms.
  • Bicyclic heterocyclic groups include, but are not limited to, indolyl, indazolyl, pyrazolo[1,5-a]pyridinyl, benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl, 3,4-dihydro-2H- chromenyl, 1H-pyrazolo[4,3-c]pyridin-3-yl; 1H-pyrrolo[3,2-b]pyridin-3-yl; and 1H- pyrazolo[3,2-b]pyridin-3-yl.
  • heterocycloalkyl refers to an aliphatic, partially unsaturated or fully saturated, 3- to 14-membered ring system, including single rings of 3 to 8 atoms and bi- and tricyclic ring systems.
  • the heterocycloalkyl ring-systems include one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein a nitrogen and sulfur heteroatom optionally can be oxidized and a nitrogen heteroatom optionally can be substituted.
  • heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.
  • hydroxyl or “hydroxyl” as used herein is represented by the formula — OH.
  • ketone as used herein is represented by the formula A 1 C(O)A 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • a 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • Azide or “azido” as used herein is represented by the formula —N 3 .
  • nitro as used herein is represented by the formula —NO2.
  • nitrile or “cyano” as used herein is represented by the formula —CN.
  • sil as used herein is represented by the formula —SiA 1 A 2 A 3 , where A 1 , A 2 , and A 3 can be, independently, hydrogen or an alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • sulfonyl is used herein to refer to the sulfo-oxo group represented by the formula — S(O)2A 1 , where A 1 can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • a 1 S(O)2A 2 is represented by the formula A 1 S(O)2A 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • sulfoxide as used herein is represented by the formula A 1 S(O)A 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • thiol as used herein is represented by the formula —SH.
  • R 1 ,” “R 2 ,” “R 3 ,” “R n ,” where n is an integer, as used herein can, independently, possess one or more of the groups listed above.
  • R 1 is a straight chain alkyl group
  • one of the hydrogen atoms of the alkyl group can optionally be substituted with a hydroxyl group, an alkoxy group, an alkyl group, a halide, and the like.
  • a first group can be incorporated within second group or, alternatively, the first group can be pendant (i.e., attached) to the second group.
  • an alkyl group comprising an amino group the amino group can be incorporated within the backbone of the alkyl group. Alternatively, the amino group can be attached to the backbone of the alkyl group. The nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group.
  • compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogen of the designated moiety are replaced with a suitable substituent.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).
  • Suitable monovalent substituents on R o are independently halogen, —(CH2)0–2R ⁇ , –(haloR ⁇ ), –(CH2)0–2OH, –(CH2)0–2OR ⁇ , –(CH2)0–2CH(OR ⁇ )2; -O(haloR ⁇ ), –CN, –N3, –(CH2)0–2C(O)R ⁇ , –(CH2)0–2C(O)OH, –(CH2)0–2C(O)OR ⁇ , –(CH2)0– 2SR ⁇ , –(CH2)0–2SH, –(CH2)0–2NH2, –(CH2)0–2NHR ⁇ , –(CH2)0–2NR ⁇ 2, –NO2, –SiR ⁇ 3, –OSiR ⁇
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR * 2)2–3O–, wherein each independent occurrence of R * is selected from hydrogen, C1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R * include halogen, –R ⁇ , -(haloR ⁇ ), -OH, –OR ⁇ , –O(haloR ⁇ ), –CN, –C(O)OH, –C(O)OR ⁇ , –NH2, –NHR ⁇ , –NR ⁇ 2, or – NO2, wherein each R ⁇ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R ⁇ , –NR ⁇ 2 , –C(O)R ⁇ , –C(O)OR ⁇ , –C(O)C(O)R ⁇ , –C(O)CH 2 C(O)R ⁇ , – S(O)2R ⁇ , -S(O)2NR ⁇ 2, –C(S)NR ⁇ 2, –C(NH)NR ⁇ 2, or –N(R ⁇ )S(O)2R ⁇ ; wherein each R ⁇ is independently hydrogen, C 1–6 aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences
  • Suitable substituents on the aliphatic group of R ⁇ are independently halogen, –R ⁇ , -(haloR ⁇ ), –OH, –OR ⁇ , –O(haloR ⁇ ), –CN, –C(O)OH, –C(O)OR ⁇ , –NH 2 , –NHR ⁇ , –NR ⁇ 2 , or –NO2, wherein each R ⁇ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1–4 aliphatic, –CH 2 Ph, –O(CH 2 ) 0–1 Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • the term “leaving group” refers to an atom (or a group of atoms) with electron withdrawing ability that can be displaced as a stable species, taking with it the bonding electrons.
  • suitable leaving groups include halides and sulfonate esters, including, but not limited to, triflate, mesylate, tosylate, and brosylate.
  • the terms “hydrolysable group” and “hydrolysable moiety” refer to a functional group capable of undergoing hydrolysis, e.g., under basic or acidic conditions.
  • hydrolysable residues include, without limitation, acid halides, activated carboxylic acids, and various protecting groups known in the art (see, for example, “Protective Groups in Organic Synthesis,” T. W. Greene, P. G. M. Wuts, Wiley-Interscience, 1999).
  • organic residue defines a carbon-containing residue, i.e., a residue comprising at least one carbon atom, and includes but is not limited to the carbon-containing groups, residues, or radicals defined hereinabove.
  • Organic residues can contain various heteroatoms, or be bonded to another molecule through a heteroatom, including oxygen, nitrogen, sulfur, phosphorus, or the like.
  • organic residues include but are not limited alkyl or substituted alkyls, alkoxy or substituted alkoxy, mono or di-substituted amino, amide groups, etc.
  • Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15, carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms.
  • an organic residue can comprise 2 to 18 carbon atoms, 2 to 15, carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms.
  • a very close synonym of the term “residue” is the term “radical,” which as used in the specification and concluding claims, refers to a fragment, group, or substructure of a molecule described herein, regardless of how the molecule is prepared.
  • a 2,4-thiazolidinedione radical in a particular compound has the structure: , regardless of whether thiazolidinedione is used to prepare the compound.
  • the radical for example an alkyl
  • the number of atoms in a given radical is not critical to the present invention unless it is indicated to the contrary elsewhere herein.
  • Organic radicals contain one or more carbon atoms.
  • An organic radical can have, for example, 1-26 carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms.
  • an organic radical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms.
  • Organic radicals often have hydrogen bound to at least some of the carbon atoms of the organic radical.
  • an organic radical that comprises no inorganic atoms is a 5, 6, 7, 8-tetrahydro-2- naphthyl radical.
  • an organic radical can contain 1-10 inorganic heteroatoms bound thereto or therein, including halogens, oxygen, sulfur, nitrogen, phosphorus, and the like.
  • organic radicals include but are not limited to an alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, mono-substituted amino, di- substituted amino, acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclic radicals, wherein the terms are defined elsewhere herein.
  • organic radicals that include heteroatoms include alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals and the like.
  • Compounds described herein can contain one or more double bonds and, thus, potentially give rise to cis/trans (E/Z) isomers, as well as other conformational isomers. Unless stated to the contrary, the invention includes all such possible isomers, as well as mixtures of such isomers.
  • a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer and diastereomer, and a mixture of isomers, such as a racemic or scalemic mixture.
  • Compounds described herein can contain one or more asymmetric centers and, thus, potentially give rise to diastereomers and optical isomers.
  • the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Mixtures of stereoisomers, as well as isolated specific stereoisomers, are also included.
  • stereoisomers For a given chemical structure, these compounds, called stereoisomers, are identical except that they are non-superimposable mirror images of one another.
  • a specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture.
  • Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*).
  • bonds to the chiral carbon are depicted as straight lines in the disclosed formulas, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula.
  • bonds to the chiral carbon when it is desired to specify the absolute configuration about a chiral carbon, one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane).
  • the Cahn-Ingold-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.
  • the disclosed compounds contain one chiral center, the compounds exist in two enantiomeric forms. Unless specifically stated to the contrary, a disclosed compound includes both enantiomers and mixtures of enantiomers, such as the specific 50:50 mixture referred to as a racemic mixture.
  • the enantiomers can be resolved by methods known to those skilled in the art, such as formation of diastereoisomeric salts which may be separated, for example, by crystallization (see, CRC Handbook of Optical Resolutions via Diastereomeric Salt Formation by David Kozma (CRC Press, 2001)); formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent.
  • a further step can liberate the desired enantiomeric form.
  • specific enantiomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.
  • Designation of a specific absolute configuration at a chiral carbon in a disclosed compound is understood to mean that the designated enantiomeric form of the compounds can be provided in enantiomeric excess (e.e.).
  • Enantiomeric excess is the presence of a particular enantiomer at greater than 50%, for example, greater than 60%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 95%, greater than 98%, or greater than 99%.
  • the designated enantiomer is substantially free from the other enantiomer.
  • the “R” forms of the compounds can be substantially free from the “S” forms of the compounds and are, thus, in enantiomeric excess of the “ ” forms.
  • “ ” forms of the compounds can be substantially free of “R” forms of the compounds and are, thus, in enantiomeric excess of the “R” forms.
  • a disclosed compound When a disclosed compound has two or more chiral carbons, it can have more than two optical isomers and can exist in diastereoisomeric forms. For example, when there are two chiral carbons, the compound can have up to four optical isomers and two pairs of enantiomers ((S,S)/(R,R) and (R,S)/(S,R)).
  • the pairs of enantiomers e.g., (S,S)/(R,R)
  • the stereoisomers that are not mirror-images e.g., (S,S) and (R,S) are diastereomers.
  • the diastereoisomeric pairs can be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers within each pair may be separated as described above. Unless otherwise specifically excluded, a disclosed compound includes each diastereoisomer of such compounds and mixtures thereof.
  • the compounds according to this disclosure may form prodrugs at hydroxyl or amino functionalities using alkoxy, amino acids, etc., groups as the prodrug forming moieties. For instance, the hydroxymethyl position may form mono-, di-, or triphosphates and again these phosphates can form prodrugs. Preparations of such prodrug derivatives are discussed in various literature sources (examples are: Alexander et al., J. Med.
  • “Derivatives” of the compounds disclosed herein are pharmaceutically acceptable salts, prodrugs, deuterated forms, radio-actively labeled forms, isomers, solvates and combinations thereof.
  • the “combinations” mentioned in this context refer to derivatives falling within at least two of the groups: pharmaceutically acceptable salts, prodrugs, deuterated forms, radio-actively labeled forms, isomers, and solvates.
  • radio- actively labeled forms include compounds labeled with tritium, phosphorous-32, iodine-129, carbon-11, fluorine-18, and the like.
  • Compounds described herein comprise atoms in both their natural isotopic abundance and in non-natural abundance.
  • the disclosed compounds can be isotopically- labeled or isotopically-substituted compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F, and 36 Cl, respectively.
  • Compounds further comprise prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • Certain isotopically-labeled compounds of the present invention for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays.
  • Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2 H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.
  • Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures below, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent. [00125]
  • the compounds described in the invention can be present as a solvate.
  • the solvent used to prepare the solvate is an aqueous solution, and the solvate is then often referred to as a hydrate.
  • the compounds can be present as a hydrate, which can be obtained, for example, by crystallization from a solvent or from aqueous solution.
  • one, two, three or any arbitrary number of solvent or water molecules can combine with the compounds according to the invention to form solvates and hydrates.
  • the invention includes all such possible solvates.
  • co-crystal means a physical association of two or more molecules which owe their stability through non-covalent interaction. One or more components of this molecular complex provide a stable framework in the crystalline lattice.
  • the guest molecules are incorporated in the crystalline lattice as anhydrates or solvates, see e.g. “Crystal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a New Path to Improved Medicines?” Almarasson, O., et. al., The Royal Society of Chemistry, 1889-1896, 2004. Examples of co-crystals include p- toluenesulfonic acid and benzenesulfonic acid. [00127] It is also appreciated that certain compounds described herein can be present as an equilibrium of tautomers. For example, ketones with an ⁇ -hydrogen can exist in an equilibrium of the keto form and the enol form.
  • amides with an N-hydrogen can exist in an equilibrium of the amide form and the imidic acid form.
  • pyrazoles can exist in two tautomeric forms, N 1 -unsubstituted, 3-A 3 and N 1 -unsubstituted, 5-A 3 as shown below.
  • the invention includes all such possible tautomers.
  • chemical substances form solids, which are present in different states of order which are termed polymorphic forms or modifications.
  • the different modifications of a polymorphic substance can differ greatly in their physical properties.
  • the compounds according to the invention can be present in different polymorphic forms, with it being possible for particular modifications to be metastable.
  • a structure of a compound can be represented by a formula: , which is understood to be equivalent to a formula: , wherein n is typically an integer. That is, R n is understood to represent five independent substituents, R n(a) , R n(b) , R n(c) , R n(d) , R n(e) .
  • independent substituents it is meant that each R substituent can be independently defined. For example, if in one instance R n(a) is halogen, then R n(b) is not necessarily halogen in that instance.
  • Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art.
  • the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, N.J.), Strem Chemicals (Newburyport, MA), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St.
  • A-D a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the invention.
  • the invention relates to substituted triazole 4-carbohydrazide compounds useful in, for example, the treatment of cancer.
  • Exemplary cancers for which the disclosed compounds can be useful include, but are not limited to, sarcomas, carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanomas, gliomas, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, non-small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma).
  • sarcomas carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melan
  • the compounds of the invention are useful in the treatment of cancer as further described herein.
  • each disclosed derivative can be optionally further substituted.
  • any one or more derivative can be optionally omitted from the invention.
  • a disclosed compound can be provided by the disclosed methods. It is also understood that the disclosed compounds can be employed in the disclosed methods of using. 1.
  • each of R 1 and R 2 is independently selected from hydrogen and C1-C4 alkyl; wherein Ar 1 is selected from C6-C12 aryl and C5-C11 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ⁇ CO2R 10 ; and wherein R 10 , when present, is selected from hydrogen and C1- C
  • the compound has a structure represented by a formula: , wherein R 2 is selected from hydrogen and methyl, or a pharmaceutically acceptable salt thereof.
  • the compound has a structure represented by a formula: , wherein each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH2, ⁇ OH, ⁇ NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ⁇ CO2R
  • R 1 is methyl.
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen and ⁇ OH.
  • R 20a is ⁇ OH.
  • the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof.
  • the compound is selected from: ,
  • each of R 1 and R 2 is independently selected from hydrogen and C1-C4 alkyl. In a further aspect, each of R 1 and R 2 is independently selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, each of R 1 and R 2 is independently selected from hydrogen, methyl, and ethyl. In yet a further aspect, each of R 1 and R 2 is independently selected from hydrogen and ethyl.
  • each of R 1 and R 2 is independently selected from hydrogen and methyl.
  • R 1 is selected from hydrogen and C1-C4 alkyl.
  • R 1 is selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl.
  • R 1 is selected from hydrogen, methyl, and ethyl.
  • R 1 is selected from hydrogen and ethyl.
  • R 1 is selected from hydrogen and methyl.
  • R 1 is C1-C4 alkyl.
  • R 1 is selected from methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R 1 is selected from methyl and ethyl. In yet a further aspect, R 1 is ethyl. In an even further aspect, R 1 is methyl. [00147] In various aspects, R 1 is hydrogen. [00148] In various aspects, R 2 is selected from hydrogen and C1-C4 alkyl. In a further aspect, R 2 is selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R 2 is selected from hydrogen, methyl, and ethyl.
  • R 2 is selected from hydrogen and ethyl. In an even further aspect, R 2 is selected from hydrogen and methyl.
  • R 2 is C1-C4 alkyl. In a further aspect, R 2 is selected from methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R 2 is selected from methyl and ethyl. In yet a further aspect, R 2 is ethyl. In an even further aspect, R 2 is methyl. [00150] In various aspects, R 2 is hydrogen. b. R 10 G ROUPS [00151] In one aspect, R 10 , when present, is selected from hydrogen and C1-C4 alkyl.
  • R 10 when present, is selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R 10 , when present, is selected from hydrogen, methyl, and ethyl. In yet a further aspect, R 10 , when present, is selected from hydrogen and ethyl. In an even further aspect, R 10 , when present, is selected from hydrogen and methyl. [00152] In various aspects, R 10 , when present, is C1-C4 alkyl. In a further aspect, R 10 , when present, is selected from methyl, ethyl, n-propyl, and isopropyl.
  • R 10 when present, is selected from methyl and ethyl. In yet a further aspect, R 10 , when present, is ethyl. In an even further aspect, R 10 , when present, is methyl. [00153] In various aspects, R 10 , when present, is hydrogen. c.
  • Ar 1 is selected from C6-C12 aryl and C5-C11 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH2, ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ⁇ CO 2 R 10 .
  • Ar 1 is selected from C6- C12 aryl and C5-C11 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ⁇ CO 2 R 10 .
  • Ar 1 is selected from C6-C12 aryl and C5-C11 heteroaryl, and is substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ⁇ CO2R 10 .
  • Ar 1 is selected from C6-C12 aryl and C5-C11 heteroaryl, and is monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ⁇ CO2R 10 .
  • Ar 1 is selected from C6-C12 aryl and C5-C11 heteroaryl, and is unsubstituted.
  • Ar 1 is C6-C12 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ⁇ CO 2 R 10 .
  • Ar 1 is C6-C12 aryl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1- C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ⁇ CO 2 R 10 .
  • Ar 1 is C6-C12 aryl substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH2, ⁇ OH, ⁇ NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1- C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ⁇ CO 2 R 10 .
  • Ar 1 is C6-C12 aryl monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH2, ⁇ OH, ⁇ NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ⁇ CO2R 10 .
  • Ar 1 is unsubstituted C6-C12 aryl.
  • Ar 1 is C6 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH2, ⁇ OH, ⁇ NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ⁇ CO2R 10 .
  • Ar 1 is C6 aryl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ⁇ CO 2 R 10 .
  • Ar 1 is C6 aryl substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH2, ⁇ OH, ⁇ NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ⁇ CO 2 R 10 .
  • Ar 1 is C6 aryl monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH2, ⁇ OH, ⁇ NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ⁇ CO2R 10 .
  • Ar 1 is unsubstituted C6 aryl.
  • Ar 1 is phenyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ⁇ CO 2 R 10 .
  • Ar 1 is phenyl substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ⁇ CO 2 R 10 .
  • Ar 1 is phenyl substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, methyl, methoxy, and ⁇ CO 2 H. In a further aspect, Ar 1 is phenyl substituted with a ⁇ OH.
  • Ar 1 is C5-C11 heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH2, ⁇ OH, ⁇ NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ⁇ CO 2 R 10 .
  • Ar 1 is C5-C11 heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH2, ⁇ OH, ⁇ NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ⁇ CO2R 10 .
  • Ar 1 is C5-C11 heteroaryl substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH2, ⁇ OH, ⁇ NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ⁇ CO2R 10 .
  • Ar 1 is C5-C11 heteroaryl monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ⁇ CO2R 10 .
  • Ar 1 is unsubstituted C5-C11 heteroaryl.
  • Ar 1 is selected from thiophenyl, furanyl, and pyridinyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ⁇ CO2R 10 .
  • Ar 1 is selected from thiophenyl, furanyl, and pyridinyl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH2, ⁇ OH, ⁇ NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ⁇ CO2R 10 .
  • Ar 1 is selected from thiophenyl, furanyl, and pyridinyl, and is substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH2, ⁇ OH, ⁇ NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ⁇ CO2R 10 .
  • Ar 1 is selected from thiophenyl, furanyl, and pyridinyl, and is monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH2, ⁇ OH, ⁇ NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ⁇ CO2R 10 .
  • Ar 1 is selected from thiophenyl, furanyl, and pyridinyl, and is unsubstituted.
  • EXAMPLE COMPOUNDS [00162]
  • a compound can be present as: ,
  • a compound can be present as: , or a pharmaceutically acceptable salt thereof.
  • a compound can be present as:
  • compositions comprising an effective amount of a compound having a structure represented by a formula: , wherein each of R 1 and R 2 is independently selected from hydrogen and C1-C4 alkyl; wherein Ar 1 is selected from C6-C12 aryl and C5-C11 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH2, ⁇ OH, ⁇ NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalky
  • the compounds and compositions of the invention can be administered in pharmaceutical compositions, which are formulated according to the intended method of administration.
  • the compounds and compositions described herein can be formulated in a conventional manner using one or more physiologically acceptable carriers or excipients.
  • a pharmaceutical composition can be formulated for local or systemic administration, intravenous, topical, or oral administration.
  • the nature of the pharmaceutical compositions for administration is dependent on the mode of administration and can readily be determined by one of ordinary skill in the art.
  • the pharmaceutical composition is sterile or sterilizable.
  • the therapeutic compositions featured in the invention can contain carriers or excipients, many of which are known to skilled artisans.
  • Excipients that can be used include buffers (for example, citrate buffer, phosphate buffer, acetate buffer, and bicarbonate buffer), amino acids, urea, alcohols, ascorbic acid, phospholipids, polypeptides (for example, serum albumin), EDTA, sodium chloride, liposomes, mannitol, sorbitol, water, and glycerol.
  • the nucleic acids, polypeptides, small molecules, and other modulatory compounds featured in the invention can be administered by any standard route of administration. For example, administration can be parenteral, intravenous, subcutaneous, or oral.
  • a modulatory compound can be formulated in various ways, according to the corresponding route of administration.
  • liquid solutions can be made for administration by drops into the ear, for injection, or for ingestion; gels or powders can be made for ingestion or topical application.
  • Methods for making such formulations are well known and can be found in, for example, Remington's Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, PA 1990.
  • the disclosed pharmaceutical compositions comprise the disclosed compounds (including pharmaceutically acceptable salt(s) thereof) as an active ingredient, a pharmaceutically acceptable carrier, and, optionally, other therapeutic ingredients or adjuvants.
  • compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • the pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy. [00170]
  • the pharmaceutical compositions of this invention can include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of the compounds of the invention.
  • the compounds of the invention, or pharmaceutically acceptable salts thereof can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
  • the pharmaceutical carrier employed can be, for example, a solid, liquid, or gas.
  • solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • liquid carriers are sugar syrup, peanut oil, olive oil, and water.
  • gaseous carriers include carbon dioxide and nitrogen.
  • oral liquid preparations such as suspensions, elixirs and solutions
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like
  • oral solid preparations such as powders, capsules and tablets.
  • tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed.
  • tablets can be coated by standard aqueous or nonaqueous techniques.
  • a tablet containing the composition of this invention can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
  • Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent.
  • Molded tablets can be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • compositions of the present invention comprise a compound of the invention (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents or adjuvants.
  • the instant compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • the pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • Pharmaceutical compositions of the present invention suitable for parenteral administration can be prepared as solutions or suspensions of the active compounds in water.
  • compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability.
  • compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
  • Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, mouth washes, gargles, and the like. Further, the compositions can be in a form suitable for use in transdermal devices.
  • compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories can be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds.
  • the pharmaceutical formulations described above can include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound of the invention, and/or pharmaceutically acceptable salts thereof, can also be prepared in powder or liquid concentrate form. [00180] In a further aspect, the effective amount is a therapeutically effective amount. In a still further aspect, the effective amount is a prophylactically effective amount.
  • the pharmaceutical composition is administered to a mammal.
  • the mammal is a human.
  • the human is a patient.
  • the pharmaceutical composition is used to treat cancer.
  • the cancer is a primary or secondary tumor.
  • the primary or secondary tumor is within the subject’s brain, breast, kidney, pancreas, lung, colon, prostate, lymphatic system, liver, ovary, or cervix.
  • the cancer is selected from a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, a glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, non- small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma).
  • a sarcoma a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma
  • compositions can be prepared from the disclosed compounds. It is also understood that the disclosed compositions can be employed in the disclosed methods of using.
  • D. METHODS OF MAKING A COMPOUND The compounds of this invention can be prepared by employing reactions as shown in the following schemes, in addition to other standard manipulations that are known in the literature, exemplified in the experimental sections or clear to one skilled in the art. For clarity, examples having a single substituent are shown where multiple substituents are allowed under the definitions disclosed herein.
  • Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in the following Reaction Schemes, as described and exemplified below.
  • the disclosed compounds can be prepared by Routes I-IV, as described and exemplified below.
  • Routes I-IV as described and exemplified below.
  • the following examples are provided so that the invention might be more fully understood, are illustrative only, and should not be construed as limiting. 1.
  • ROUTE I [00186]
  • substituted triazole 4-carbohydrazide compounds can be prepared as shown below.
  • SCHEME 1A [00187] Compounds are represented in generic form, with substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below.
  • SCHEME 1B [00188]
  • compounds of type 1.4, and similar compounds can be prepared according to reaction Scheme 1B above.
  • compounds of type 1.4 can be prepared by oxidation of an appropriate amine, e.g., 1.3 as shown above.
  • Appropriate amines are commercially available or prepared by methods known to one skilled in the art.
  • the oxidation is carried out in the presence of an appropriate nucleophile, e.g., sodium azide, an appropriate oxidant, e.g., sodium nitrite, and an appropriate acid, e.g., sulphuric acid.
  • an appropriate nucleophile e.g., sodium azide
  • an appropriate oxidant e.g., sodium nitrite
  • an appropriate acid e.g., sulphuric acid.
  • the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 1.1), can be substituted in the reaction to provide substituted oxadiazole compounds similar to Formula 1.2. 2.
  • substituted triazole 4-carbohydrazide compounds can be prepared as shown below.
  • SCHEME 2A [00190] Compounds are represented in generic form, with substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below.
  • SCHEME 2B [00191] In one aspect, compounds of type 2.6, and similar compounds, can be prepared according to reaction Scheme 2B above. Thus, compounds of type 2.6 can be prepared by nucleophilic addition and cyclization of an appropriate azide, e.g., 2.4 as shown above, and an appropriate alkyl 4-halo-3-oxobutanoate, e.g., 2.5 as shown above.
  • alkyl 4- halo-3-oxobutanoates are commercially available or prepared by methods known to one skilled in the art.
  • the nucleophilic addition/cyclization is carried out in the presence of an appropriate inorganic salt, e.g., magnesium carbonate, in an appropriate solvent, e.g., ethanol, for an appropriate period of time, e.g., 3 hours, at an appropriate temperature, e.g., reflux.
  • an appropriate inorganic salt e.g., magnesium carbonate
  • solvent e.g., ethanol
  • an appropriate temperature e.g., reflux
  • the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 2.1 and 2.2), can be substituted in the reaction to provide substituted triazole carboxylate compounds similar to Formula 2.3. 3.
  • substituted triazole 4-carbohydrazide compounds can be prepared as shown below.
  • SCHEME 3A [00193] Compounds are represented in generic form, with substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below.
  • SCHEME 3B [00194]
  • compounds of type 3.6, and similar compounds can be prepared according to reaction Scheme 3B above.
  • compounds of type 3.6 can be prepared by nucleophilic addition of an appropriate triazole carboxylate, e.g., 3.4 as shown above, and an appropriate triazolthione, e.g., 3.5 as shown above.
  • nucleophilic addition is carried out in the presence of an appropriate base, e.g., sodium bicarbonate, in an appropriate solvent, e.g., ethanol, for an appropriate period of time, e.g., 3 hours, at an appropriate temperature, e.g., reflux.
  • an appropriate base e.g., sodium bicarbonate
  • solvent e.g., ethanol
  • an appropriate temperature e.g., reflux
  • the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 3.1 and 3.2), can be substituted in the reaction to provide substituted triazole carboxylate compounds similar to Formula 3.3. 4.
  • substituted triazole 4-carbohydrazide compounds can be prepared as shown below.
  • SCHEME 4A Compounds are represented in generic form, with substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below. SCHEME 4B.
  • compounds of type 4.8 can be prepared according to reaction Scheme 4B above.
  • compounds of type 4.6 can be prepared by hydrazinolysis of an appropriate ester, e.g., 4.5 as shown above. The hydrazinolysis is carried out in the presence of an appropriate hydrazine, e.g., hydrazine hydrate, in an appropriate solvent, e.g., ethanol, at an appropriate temperature, e.g., room temperature to 60 °C.
  • Compounds of type 4.8 can be prepared by nucleophilic addition of an appropriate hydrazine, e.g., 4.6, and an appropriate carbonyl derivative, e.g., 4.7.
  • nucleophilic addition is carried out in the presence of an appropriate acid, e.g., hydrochloric acid, in an appropriate solvent, e.g., ethanol, at an appropriate temperature, e.g., room temperature.
  • an appropriate acid e.g., hydrochloric acid
  • an appropriate solvent e.g., ethanol
  • an appropriate temperature e.g., room temperature.
  • the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 4.1, 4.2, and 4.3), can be substituted in the reaction to provide substituted triazole 4-carbohydrazide compounds similar to Formula 4.4.
  • eIF4A1 activity in a cell comprising contacting the cell with an effective amount of a compound having a structure represented by a formula: , wherein each of R 1 and R 2 is independently selected from hydrogen and C1-C4 alkyl; wherein Ar 1 is selected from C6-C12 aryl and C5-C11 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH2, ⁇ OH, ⁇ NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)(C1-C4)(C1-C1-C4)(C1-C1-C4)(C1-C1-C4)(C1-
  • the cell is a cancer cell.
  • the cell is present in a tissue sample.
  • the tissue sample is a malignant tissue sample.
  • the cell is human.
  • the cell has been isolated from a human prior to the contacting step.
  • contacting is via administration to a subject.
  • the subject has been diagnosed with a need for modulation of eIF4A1 activity prior to the administering step.
  • the subject has been diagnosed with a need for treatment of cancer prior to the administering step.
  • eIF4A1 activity in a subject comprising administering to the subject an effective amount of a compound having a structure represented by a formula: , wherein each of R 1 and R 2 is independently selected from hydrogen and C1-C4 alkyl; wherein Ar 1 is selected from C6-C12 aryl and C5-C11 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-
  • the subject is a mammal. In various further aspects, the subject is a human. [00208] In various aspects, the subject has been diagnosed with a need for modulating eIF4A1 activity prior to the administering step. In various further aspects, the subject has been diagnosed with a need for treatment of a disorder related to eIF4A1 activity prior to the administering step. [00209] In various aspects, the disorder is cancer. G. METHODS OF TREATING CANCER [00210] In one aspect, disclosed are methods of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a disclosed compound or a pharmaceutically acceptable salt thereof.
  • cancers for which the disclosed compounds, compositions, and methods can be useful include, but are not limited to, sarcomas, carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanomas, gliomas, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, non-small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma).
  • sarcomas carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial
  • the subject has been diagnosed with a need for treatment of cancer prior to the administering step. In a still further aspect, the subject is at risk for developing cancer prior to the administering step. [00214] In a further aspect, the subject is a mammal. In a still further aspect, the mammal is a human. [00215] In a further aspect, the method further comprises the step of identifying a subject in need of treatment of cancer. [00216] In a further aspect, the effective amount is a therapeutically effective amount. In a still further aspect, the effective amount is a prophylactically effective amount.
  • the cancer is a primary or secondary tumor.
  • the primary or secondary tumor is within the subject’s brain, breast, kidney, pancreas, lung, colon, prostate, lymphatic system, liver, ovary, or cervix.
  • the cancer is selected from a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, a glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, non- small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma).
  • a sarcoma a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma
  • administering is oral or parental administration.
  • parenteral administration is intravenous, subcutaneous, intramuscular, or via direct injection.
  • the method further comprises administering a therapeutically effective amount of an anti-cancer agent or radiotherapy to the subject.
  • the anti-cancer agent or radiotherapy is administered prior to administration of the compound.
  • the anti-cancer agent or radiotherapy is administered subsequent to administration of the compound.
  • the method further comprises administering to the subject an effective amount of at least one anticancer agent.
  • anticancer agents include, but are not limited to, doxorubicin, cisplatin, 5-fluorouracin (5-FU), etoposide, daunorubicin, camptothesin, methotrexate, carboplatin, and oxaliplatin.
  • the compound and the agent are administered sequentially. In a still further aspect, the compound and the agent are administered simultaneously.
  • the compound and the agent are co-formulated. In a still further aspect, the compound and the agent are co-packaged.
  • the compound is administered as a single active agent. H.
  • the compounds and pharmaceutical compositions of the invention are useful in treating or controlling cancers such as, for example, sarcomas, carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanomas, gliomas, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, non-small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma).
  • cancers such as, for example, sarcomas, carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer
  • the compounds and pharmaceutical compositions comprising the compounds are administered to a subject in need thereof, such as a vertebrate, e.g., a mammal, a fish, a bird, a reptile, or an amphibian.
  • a subject in need thereof, such as a vertebrate, e.g., a mammal, a fish, a bird, a reptile, or an amphibian.
  • the subject can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent.
  • the term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered.
  • the subject is preferably a mammal, such as a human.
  • the subject Prior to administering the compounds or compositions, the subject can be diagnosed with a need for treatment of cancer such as, for example, sarcomas, carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanomas, gliomas, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, non-small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma).
  • cancer such as, for example, sarcomas, carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testi
  • the compounds or compositions can be administered to the subject according to any method.
  • Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration.
  • Administration can be continuous or intermittent.
  • a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition.
  • a preparation can also be administered prophylactically; that is, administered for prevention of cancers such as, for example, sarcomas, carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanomas, gliomas, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, non-small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma).
  • cancers such as, for example, sarcomas, carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pan
  • the therapeutically effective amount or dosage of the compound can vary within wide limits. Such a dosage is adjusted to the individual requirements in each particular case including the specific compound(s) being administered, the route of administration, the condition being treated, as well as the patient being treated. In general, in the case of oral or parenteral administration to adult humans weighing approximately 70 Kg or more, a daily dosage of about 10 mg to about 10,000 mg, preferably from about 200 mg to about 1,000 mg, should be appropriate, although the upper limit may be exceeded.
  • the daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, as a continuous infusion. Single dose compositions can contain such amounts or submultiples thereof of the compound or composition to make up the daily dose.
  • the dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. 1. USE OF COMPOUNDS [00228] In one aspect, the invention relates to the use of a disclosed compound or a product of a disclosed method.
  • a use relates to the manufacture of a medicament for the treatment of cancers such as, for example, sarcomas, carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanomas, gliomas, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, non-small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma).
  • cancers such as, for example, sarcomas, carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic
  • the invention relates to use of at least one disclosed compound or a pharmaceutically acceptable salt thereof.
  • the compound used is a product of a disclosed method of making.
  • the use relates to a process for preparing a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt thereof, for use as a medicament.
  • the use relates to a process for preparing a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt thereof, wherein a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of the compound or the product of a disclosed method of making.
  • the use relates to a treatment of cancer. In one aspect, the use is characterized in that the subject is a human.
  • the use is characterized in that the cancer is a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, a glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, non- small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma).
  • the cancer is a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endo
  • the disclosed uses can be employed in connection with the disclosed compounds, products of disclosed methods of making, methods, compositions, and kits.
  • the invention relates to the use of a disclosed compound or a disclosed product in the manufacture of a medicament for the treatment of cancer in a mammal.
  • the cancer is selected from a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, a glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, non-small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma).
  • a sarcoma a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma
  • the invention relates to a method for the manufacture of a medicament for treating cancer in a subject having the condition, the method comprising combining a therapeutically effective amount of a disclosed compound or product of a disclosed method with a pharmaceutically acceptable carrier or diluent.
  • the present method includes the administration to an animal, particularly a mammal, and more particularly a human, of a therapeutically effective amount of the compound effective in the treatment of cancer (e.g., a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, a glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, non-small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, or plasma cell neoplasm (myeloma).
  • cancer e.g., a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal
  • the dose administered to an animal, particularly a human, in the context of the present invention should be sufficient to affect a therapeutic response in the animal over a reasonable timeframe.
  • dosage will depend upon a variety of factors including the condition of the animal and the body weight of the animal.
  • the total amount of the compound of the present disclosure administered in a typical treatment is preferably between about 0.05 mg/kg and about 100 mg/kg of body weight for mice, and more preferably between 0.05 mg/kg and about 50 mg/kg of body weight for mice, and between about 100 mg/kg and about 500 mg/kg of body weight for humans, and more preferably between 200 mg/kg and about 400 mg/kg of body weight for humans per daily dose.
  • This total amount is typically, but not necessarily, administered as a series of smaller doses over a period of about one time per day to about three times per day for about 24 months, and preferably over a period of twice per day for about 12 months.
  • the size of the dose also will be determined by the route, timing and frequency of administration as well as the existence, nature and extent of any adverse side effects that might accompany the administration of the compound and the desired physiological effect. It will be appreciated by one of skill in the art that various conditions or disease states, in particular chronic conditions or disease states, may require prolonged treatment involving multiple administrations.
  • kits comprising a disclosed compound, and one or more selected from: (a) an anti-cancer agent; (b) instructions for administering the compound in connection with treating cancer; and (c) instructions for treating cancer.
  • kits comprising a compound having a structure represented by a formula: , wherein each of R 1 and R 2 is independently selected from hydrogen and C1-C4 alkyl; wherein Ar 1 is selected from C6-C12 aryl and C5-C11 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ⁇ CO2R 10 ; and wherein R 10 , when present, is selected from hydrogen and C
  • kits comprises the anti-cancer agent.
  • anti- cancer agents include, but are not limited to, alkylating agents, antimetabolite agents, antineoplastic antibiotic agents, mitotic inhibitor agents, DNA damage-inducing agents, and mTor inhibitor agents.
  • the kit comprises an antineoplastic antibiotic agent.
  • antineoplastic antibiotic agents include, but are not limited to, doxorubicin, mitoxantrone, bleomycin, daunorubicin, dactinomycin, epirubicin, idarubicin, plicamycin, mitomycin, pentostatin, and valrubicin, or a pharmaceutically acceptable salt thereof.
  • the kit comprises an antimetabolite agent.
  • kits comprises an alkylating agent.
  • alkylating agents include, but are not limited to, carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, mechlorethamine, temozolomide, thiotepa, bendamustine, and streptozocin, or a pharmaceutically acceptable salt thereof.
  • the kit comprises a mitotic inhibitor agent.
  • kits comprises an mTor inhibitor agents.
  • mTor inhibitor agents include, but are not limited to, everolimus, siroliumus, and temsirolimus, or a pharmaceutically acceptable salt thereof.
  • the kit comprises a DNA damage-inducing agent.
  • DNA damage-inducing agents include, but are not limited to, doxorubicin, cisplatin, 5-Fluorouracin, etoposide, daunorubicin, camptothesin, methotrexate, carboplatin, and oxaliplatin (or pharmaceutically acceptable salts thereof) and ionizing radiation.
  • the compound and the agent are co-formulated.
  • the compound and the agent are co-packaged.
  • the kit further comprises a plurality of dosage forms, the plurality comprising one or more doses; wherein each dose comprises an effective amount of the compound and the anti-cancer agent.
  • kits can also comprise compounds and/or products co-packaged, co- formulated, and/or co-delivered with other components.
  • a drug manufacturer, a drug reseller, a physician, a compounding shop, or a pharmacist can provide a kit comprising a disclosed compound and/or product and another component for delivery to a patient.
  • kits can be prepared from the disclosed compounds, products, and pharmaceutical compositions. It is also understood that the disclosed kits can be employed in connection with the disclosed methods of using. [00253]
  • the foregoing description illustrates and describes the disclosure. Additionally, the disclosure shows and describes only the preferred embodiments but, as mentioned above, it is to be understood that it is capable to use in various other combinations, modifications, and environments and is capable of changes or modifications within the scope of the invention concepts as expressed herein, commensurate with the above teachings and/or the skill or knowledge of the relevant art.
  • HINT Hydropathic INTeractions
  • GMO B-cells (lymphoblastoid cells) were purchased from the National Institutes of General Medical Sciences Human Genetic Mutant Cell Repository (Coriell Institute for Medical Research, Camden, NJ, USA). All DLBCL and GMO cells were grown in Roswell Park Memorial Institute (RPMI)-1640 except OCI-Ly3, grown in Iscove's Modified Dulbecco's Medium (IMDM) with 10% FBS (Corning, Fetal Bovine Serum), and were maintained at 37 °C with 5% CO 2 . Hek293T/17 was cultured in Dulbecco's Modified Eagle Medium (DMEM) with 10% FBS.
  • DMEM Dulbecco's Modified Eagle Medium
  • Stable cells (293T) were generated by PEI-mediated transfection, selected, and maintained with puromycin (1 mg/mL). Post selection, cells were cultured in DMEM containing 10% FBS. Cells were regularly passaged according to prescribed guidelines. Exponentially growing cells were treated with selected inhibitors and maintained at 37 °C, harvested at indicated time points for further analysis. The quality and authenticity of cell lines were performed regularly using regular mycoplasma testing and short tandem repeat(STR) profiling through the Nucleic Acid Research Facilities (NARF) at Virginia Commonwealth University (VCU), compared against known STR profiles. c.
  • NARF Nucleic Acid Research Facilities
  • REAGENTS RBF series small molecules were procured from MolPort, Inc platform, silvestrol: Medchem express, WST1: Dojindo Molecular Technologies Inc, phenazine ethosulfate, DMSO: Sigma-Aldrich, D-Luciferin, potassium Salt: Gold Biotechnology. All the other chemicals were procured from Fisher Scientific. d. LUCIFERASE ASSAYS [00260] Four tandem repeats of the (CGG)412-mer motif (GQs) or random sequence matched for length and GC content (random) were cloned into the pLenti-5’UTR-Luciferase (Wolfe AL, et al. (2014) Nature 513: 65-70).
  • Dilutions of compound (0.1, 0.3, 1, 3, 10, 30, 100, and 300 ⁇ M) were prepared containing stock concentration of 1% DMSO (10X).10 ⁇ L of stock compound was added to each well in triplicates for each group and incubated for 72 h at 37 °C and 5% CO2 for the proliferation assay (Final concentration of the compounds: 0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30 ⁇ M).10 ⁇ L/well cell proliferation reagent (WST-1 (2 mg/mL), phenazine ethosulfate solution (0.21 mg/mL) dissolved in 1X PBS) was added and incubated for 1.5 h at 37 °C and 5% CO 2 (Koyanagi M, Kawakabe S, Arimura Y.
  • PHOSPHATE RELEASE ASSAY A colorimetric assay to measure the phosphate released during ATP hydrolysis based on Malachite green was used to measure the activity of human eIF4A1 (1913204, ABM).
  • the reaction buffers contained 50 mM potassium acetate, 20 mM MES pH6.0, 2 mM dithiothreitol (DTT), 0.1 mg/mL BSA and 100 ng/mL of whole yeast RNA (Type XI-C, Sigma-Aldrich) (Abdelkrim YZ, et al. (2016) Mol Biochem Parasitol 226: 9-19).
  • the compounds were incubated at various concentrations with 20 ng human eIF4A1 in a reaction buffer for 30 min. Reactions were started by adding 50 ⁇ M ATP and then incubated at 37 °C for 2 h. Reactions were stopped by adding the solutions ⁇ 60 mM in ethylenediaminetetraacetic acid (EDTA). The absorption at 630 nm was converted to phosphate concentration by a reference curve generated from a dilution series of a known phosphate concentration (1 mM Pi standard; SensoLyte® MG Phosphate Assay Kit Colorimetric). Reaction velocities were determined by a linear regression fit of the phosphate generated against time. Only the initial linear phases of the curves were used.
  • EDTA ethylenediaminetetraacetic acid
  • RNA unwinding assay was undertaken with minor modifications as previously described (Andreou et al. (2017) RNA Biol 14: 113-123).
  • Duplex RNA (5 ⁇ M) for unwinding reactions was prepared by annealing a 32mer RNA modified with cyanine 5 (Cy5) at its 5’-end (5’Cy5- CGAGG UCCCA AGGGU UGGGC UGUUC GCCCA UU-3’) and a complementary 9mer modified with a cyanine 3 (Cy3) at the 3’-end (5’-UUGGGACCU- Cy3–3’) in 25 mM Hepes/KOH, pH 7.4. The mixture was heated to 96 oC for 2 min, slowly cooled to room temperature, and incubated on ice for 15 min. A 9-nucleotide loop connecting the duplex strands was introduced for the single turnover condition.
  • SURFACE SENSING OF TRANSLATION (SUNSET) ASSAY [00265] SUnSET assay was performed as per the manufacturer's recommendations (Kerafast) as previously reported (Kapadia B, et al. (2016) Nat Commun 9: 829). In brief, cells were pulse-labeled with puromycin (1 ⁇ g/mL) for 30 min. Post-treatment, cells were washed with ice-cold PBS, lysed, and probed (10 ⁇ g of protein) with an anti-puromycin antibody. Signals were normalized by indicated loading control in each set. j.
  • IMMUNOBLOTTING [00266] Cells were lysed in RIPA buffer (50 mM TRIS pH 7.5, 150 mM NaCl, 0.1% SDS, 0.5% sodium deoxycholate, 1% triton X-100, 1 mM EDTA, and 1 mM EGTA, 1 mM sodium orthovanadate, 1 mM sodium fluoride, 1 ⁇ protease inhibitor (Sigma-Aldrich), phosphatase inhibitor cocktails #2 and #3 (Sigma-Aldrich), and 1 mM PMSF)(27).
  • RIPA buffer 50 mM TRIS pH 7.5, 150 mM NaCl, 0.1% SDS, 0.5% sodium deoxycholate, 1% triton X-100, 1 mM EDTA, and 1 mM EGTA, 1 mM sodium orthovanadate, 1 mM sodium fluoride, 1 ⁇ protease inhibitor (Sigma-Aldrich), phosphatase inhibitor cocktails #2 and #3 (
  • tissue microarray (TMA) slides (US Biomax, LY1001B, LY1001C E069, LM801280, Y10001D SD43 and LY800B B040) were baked at 65 oC and deparaffinized (X1-10 min, X2-10 min) by using Xylene (Fisher Scientific) and subsequently hydrated by sequential incubation in ethanol (100% EtOH-5 min, 70% EtOH-5 min, 50% EtOH-5 min, H2O-5 min).
  • Antigen retrieval was performed using a Decloaking ChamberTM NxGen (Biocare Medical) with pre- heated 1X Borg Declokar buffer (Biocare Medical, USA) at 95 oC for 30 min.
  • the expression of eIF4A1 was also mined in other publicly-available DLBCL datasets (Schmitz R, et al. (2016) N Engl J Med 378: 1396-1407), GSE10846 (Lenz G, et al.
  • Neoplasia 19: 649-658 datasets, a robust increase (p ⁇ 0.0001) in the transcript levels of eIF4A1 was observed in DLBCL samples compared to na ⁇ ve B-cells (FIG.1A), supporting the relevance of eIF4A1 in lymphomagenesis.
  • this lymphoma subgroup is further classified as Activated B-cell (ABC), Germinal Center B-cell (GCB), and Unclassified (UNC) DLBCL based on its expression profile (Menon MP, et al. (2012) Cancer J 18: 411-420).
  • TPM transcript per million
  • RNA-seq data of eIF4A1 in molecular subgroups using a publicly available large dataset of patients with DLBCL is shown.
  • the values are represented in log base 2 of fragments per kilobase of exon per million mapped fragments (FPKM).
  • FIG.1C a representative immunohistochemistry image of commercially procured (US Biomax., Inc) TMA slides stained with eIF4A1 antibody is shown. Representative scatter plots showing the stained signals of eIF4A1 in reactive LN compared to DLBCL samples. Statistical analysis was performed using Wilcoxon signed- rank test (unpaired two-tailed), ****p ⁇ 0.001 vs. reactive LN. Summary chart for DLBCL and normal LN. -ve: no staining detected, low: 1–2 staining density, high: 3–4 staining density.
  • the prognostic value of eIF4A1 gene expression was determined using publicly available datasets (Chandrashekar DS, et al. (2017) Neoplasia 19: 649-658; Chandrashekar DS, et al.
  • OS overall survival
  • PFS progression-free survival
  • Patients with a higher median expression of eIF4A1 showed shorter survival periods than those with lower median expression.
  • HINT is a scoring function based on the free energy associated with solvent partitioning between 1-octanol and water. It has been used in numerous studies involving interactions between and amongst proteins, polynucleotides, and small molecules (Obaidullah AJ, et al. (2016) Chem Biodivers 15: e1800234; Spyrakis F, et al. (2013) PLoS One 8: e77558; Chen D, et al.
  • the top 29 scoring compounds (Table 3) from HINT were purchased and further assayed for activity.
  • FIG.3B a workflow for the virtual screening strategy that identified RBF98 as the top hit is shown. Stages for this workflow included obtaining the crystal structure of eIF4A1 complexed with RocA, scoring interactions between these two species, constructing and implementing the virtual screening pharmacophore, high- throughput molecular docking, energy minimizations of solutions, preliminary scoring of solutions in HINT, and final energy minimizations and scoring, followed by the purchase of the 29 top-scoring hits TABLE 3.
  • eIF4A-3X luciferase assay was used (Wolfe AL, et al. (2014) Nature 513: 65-70).
  • the luciferase-based reporter assay with 5’UTR of eIF4A- sensitive four tandem repeats of the (CGG) 4 12-mer motif (GQs) driven by beta-actin promoter was used as a platform for primary screening in Hek293T/17 stables cell lines (FIG.4A).
  • Cofactors like eIF4B stimulate the activity of eIF4A1.
  • RBF98 might adopt a similar binding mode to RocA, with three of its aromatic rings forming ⁇ - ⁇ stacking interactions with two adjacent nucleotide bases and PHE163, which seem to be crucial for rocaglate activity. Further, this docked pose of RBF98 shows that its phenoxide moiety may form a hydrogen bond with G8 of the RNA strand and a novel ionic interaction between its ammonium group and ASP198. This previously unobserved interaction may be integral for achieving improved drug-like properties over rocaglamate-based inhibitors (FIG.8A).
  • RBF98 Additional biochemical testing was performed with RBF98 to investigate the direct inhibition of the compound on eIF4A’s helicase activity.
  • an inorganic phosphate release assay was run to directly measure the eIF4A1 ATP-dependent RNA helicase activity using a stable mixture of yeast RNA.
  • the amount of enzyme and the incubation time were optimized (FIG.6B-C).
  • RBF98 showed a dose- dependent decrease with an inhibitory effect at ⁇ 50% at a concentration of 0.3 ⁇ M compared with the DMSO control (FIG.6D).
  • FIG.4A the design of a luciferase construct with 5’UTR of eIF4A1 G- quadruplex sequence with the ⁇ -actin promoter, negative controls, blank with scrambled sequence and empty test construct is shown.
  • FIG.4B eIF4A-3X-luciferase expressing 293T cells were transfected with shRNA against eIF4A1 and eIF4B followed by luciferase readout. Statistics were performed using Dunnett's Test. A significant decrease was observed in relative luciferase units in eIF4A1 shRNA groups. ****p ⁇ 0.0001 vs non-transfected cells.
  • FIG.5B shows the structure of RBF98, a candidate inhibitor
  • FIG.5C shows the percentage inhibition observed in the treatment of RBF98 at various concentrations in eIF4A1-3X-Luciferase Hek293T/17.
  • FIG.6A the percentage inhibition of luciferase activity on treatment with RBF98 at 0.1, 1, and 10 ⁇ M concentrations in empty/blank luciferase HEK293T/17 stable cell lines is shown.
  • Statistical analysis was performed using one-way ANOVA followed by Bonferroni’s correction analysis. a p ⁇ 0.05; c p ⁇ 0.001, d p ⁇ 0.0001 vs DMSO control groups, ⁇ p ⁇ 0.05, ⁇ p ⁇ 0.001, ⁇ p ⁇ 0.0001 vs 10 ⁇ M treatment groups.
  • FIG.6B eIF4A1 titration and measurement of phosphate release with 50 ⁇ M ATP and 100 ng/ml of yeast RNA is shown.
  • FIG.6C ATP titration was used to select linear range concentration in the presence of 20 ng of eIF4A1 and 100 ng/ml yeast RNA.
  • FIG.6D dose-dependent percentage inhibition of human eIF4A1 in-vitro activity on the treatment of RBF98 was compared to DMSO control using an inorganic phosphate release assay (SensoLyte kit). IC50 values observed were observed to be 3 ⁇ M.
  • FIG.8A interaction environments for RocA and RBF98 are shown.
  • the top two panels show stick representations of the interactions made between RocA and RBF98 and their surrounding environments.
  • Transparent ovals are used to two- dimensionally represent possible ⁇ - ⁇ stacking interactions between the ligands and surrounding residues.
  • Dashed lines between the ligands and surrounding residues are used to indicate hydrogen bonding.
  • RBF98’s impact on a cellular proliferation assay was analyzed. The compound reduced the cellular proliferation of DLBCL cells at 0.5 ⁇ M and 1 ⁇ M concentrations. Silvestrol was again used as a positive control (FIG.7A).
  • lymphoblastoid cells had minimal impact on their proliferative capacity indicating that the compound may have a potential non-toxic effect on non-malignant cells, addressing a major limiting factor of the currently available eIF4A inhibitors (FIG.5D, FIG. 5F, and FIG.7B).
  • DLBCL cells were pulse-labeled with puromycin after treatment with the compound.
  • Immunoblotting with anti-puromycin revealed a concentration-dependent decrease of puromycin labeling along with the protein levels of eIF4A, but minimal changes in eIF4E, indicating an overall reduction in the translation capacity of the cells (FIG.7C).
  • FIG.5D the effect of RBF98 on DLBCL colony formation is shown. Representative image of the colony formation in OCI-Ly3 (malignant) and GMO17220B (non-malignant) cells. The total number of colonies grown in OCI-Ly3 (FIG. 5E) and GMO17220B (FIG.5F) cells upon treatment with 0.5 and 1 ⁇ M of RBF98.
  • GCB Farage
  • FIG.7B the effect of RBF98 on DLBCL colony formation is shown. Specifically, the data illustrate the total number of colonies grown in Toledo (malignant), GMO1528, and GMO13604 (non-malignant) cells on treatment with 0.5 and 1 mM of RBF98. Statistical analysis was performed using one-way ANOVA followed by Bonferroni’s correction analysis.
  • FIG. 8B illustrates some of the different structural variations in these positions.
  • the primary screen was applied to the 34 compounds obtained, RBF197, RBF203, and RBF208 (FIG.9A and FIG.9B), which displayed a dosage-dependent decrease in luciferase readout (FIG.9C). More importantly, all three hit molecules do not show more than 15% inhibition of blank (FIG.10B) and empty luciferase readout (FIG.10A), implicating a specific inhibitory effect on eIF4A dependent activity.
  • FIG.9B shows the structures of RBF197, RBF203, and RBF208, potent candidate inhibitors.
  • Statistical analysis was performed using one-way ANOVA followed by Bonferroni’s correction analysis.
  • FIG.9D concentration-response curves of percentage inhibition of human eIF4A1 in-vitro activity on the treatment of RBF197, RBF203, and RBF208, compared to DMSO control by measurement of inorganic phosphate released (SensoLyte Kit) are shown. IC50 values observed were 55.2, 208.8, and 74.1 pM, respectively.
  • FIG.9E shows the Hill coefficient values for the concentration-response curves. c.
  • SUDHL2 which harbors a mutation in A20, SOCS1, and TP53, was insensitive to the eIF4A inhibitors (Juskevicius D, et al. (2016) Leuk Lymphoma 59: 1710-1716). Additional analogs with varying potencies in the luciferase readout assays were tested in the cell viability assay to investigate if helicase inhibition tracked DLBCL WST1 inhibition, and to ensure that cell viability did not decrease due to the general toxicity of the inhibitor scaffold (Table 6).
  • DLBCLs RC (GCB, Double-Hit) and OCI-LY3 (ABC) cell lines were treated with the compounds for 16 hours, followed by a pulse labeling for 30 minutes with puromycin.
  • Inhibiting eIF4A activity in DLBCL cells showed a significant dose-dependent decrease in overall protein translation output (FIG.12A-B and FIG.13A-B).
  • the protein levels of eIF4A, but not eIF4E1 showed a dosage-induced decrease (FIG.12A-B and FIG.13A-B).
  • minor alterations in the transcript levels of eIF4A1 were noted post-treatment (FIG.13C and FIG.14A).
  • FIG.12A SUnSET assay was performed by exposing cells to puromycin (1 ⁇ g/mL), post compound treatments for 30 min, and subsequently lysed. Representative immunoblots were probed with anti-puromycin, anti-eIF4A1, and anti-eIF4E. GAPDH was probed as an internal loading control.
  • FIG.12B relative fold change in expression levels with on treatment of RBF197 or RBF208 at 1 and 3 ⁇ M concentrations.
  • FIG.13A representative immunoblots probed with anti- puromycin, anti-eIF4A1, and anti-eIF4E are shown.
  • FIG.13B and FIG.13C show the relative fold change in protein levels with on treatment of RBF 197 (FIG.13B) or RBF208 (FIG.13C) at 1 and 3 ⁇ M concentrations with respect to the DMSO control. GAPDH was used as a loading control.
  • GAPDH was used as a loading control.
  • RBF 197 displayed minimal effect on colony formation in GMO cell types, while RBF 208 reduced colony formation in GMO cell lines at a higher concentration (FIG.12F-G and FIG.15A-B). These results are consistent with RBF197 and RBF208 being selective eIF4A inhibitors, while the therapeutic window for RBF197 is broader than RBF208.
  • FIG.12C representative immunoblots of cMYC, MCL1, PARP1, BCL2, CDK7, NRF2, Cyclin E, and CARD11 on treatment with RBF197 and RBF208 at 1 and 3 ⁇ M concentrations, respectively, are shown. Vinculin was used as a loading control.
  • FIG.12D shows the relative fold change in protein levels of the above- mentioned proteins with on treatment of RBF197 or RBF208, respectively.
  • FIG.12E a heat map of translation efficiency values for RBF197 and RBF208 in RC cell line is shown.
  • FIG.12F shows the effect of RBF197 and RBF208 on DLBCL colony formation. Representative image of the colony formation in RC (malignant) and GMO13604 (non-malignant) cells is shown.
  • FIG.12G the total number of colonies grown in RC and GMO13604 cells upon treatment with 1 and 3 ⁇ M of RBF197 and RBF 208, respectively, is shown.
  • FIG.13E and FIG.13F show the relative fold change in protein levels of the above-mentioned proteins with on treatment of RBF197 (FIG. 13E) and RBF208 (FIG.13F), respectively.
  • FIG.15A and FIG.15B the total number of colonies grown in Farage, SUDHL4, DS, OCI-Ly3 (malignant), and GMO17220B (non-malignant) cell lines upon treatment with 1 and 3 ⁇ M of RBF197 (FIG.15A) and RBF208 (FIG.15B), respectively, is shown.
  • Statistical analysis was performed using one-way ANOVA followed by Bonferroni’s correction analysis.
  • RocA’s and the compounds’ mechanism of action involves trapping and distorting RNA’s bound pose. Indeed, RocA’s crystallized conformation positions itself such that it inserts between the A7 and G8 bases and binds on top of the bound RNA (FIG.3A). From the results of the virtual screen, it is believed that the hit compounds bind similarly because they, too, have three aromatic rings capable of forming ⁇ - ⁇ stacking interactions (FIG.8A and FIG.16). It is speculated that such molecules trap the eIF4A: RNA complex.
  • RNA unwinding assay was employed to measure the activity of human eIF4A1 recombinant protein in the presence or absence of the inhibitors.
  • the RNA stable duplex was formed by annealing 32mer RNA modified with cyanine 5 (Cy5) at its 5′-end and a complementary 9mer modified with a cyanine 3 (Cy3) at the 3′-end (FIG.17A). A stable fluorescence was recorded. A 10-molar excess of unlabeled 9mer was added to the reaction to ensure a single turnover of the RNA unwinding. The reaction was started by adding excess ATP in the presence or absence of compounds.
  • FIG.17A a schematic depiction of the fluorescent duplex unwinding assay is shown. Briefly, a 32-mer RNA strand is modified on its 5′ end with cyanine 5 (Cy5) and annealed to a complimentary loading strand that is modified on its 3′ end 9-mer with cyanine 3 (Cy3). The 9-mer RNA strand released upon unwinding was trapped by an unlabeled 9-mer DNA oligonucleotide to give single turnover reactions.
  • Cy5 cyanine 5
  • Cy3 complimentary loading strand that is modified on its 3′ end 9-mer with cyanine 3
  • FIG.17B a four-step protocol is shown, including (1) duplex formation (5 ⁇ M) by heating at 96 °C for 2 min and cooling on ice for 5 min; (2) reading of stable fluorescence at 0 minutes with or without compound in presence of human eIF4A1, unlabeled 9mer, and additional duplex; (3) addition of ATP and recording of kinetic reading for 30 min; (4) post 30 min, again adding duplex and reading the fluorescence intensity after 3 min. [00319] Referring to FIG.17C and FIG.17D, the difference in the increase in the fluorescence was calculated in the presence and absence of RBF197 (FIG.17C) and RBF208 (FIG.17D).
  • eFT226, a promising candidate undergoing Phase I clinical trials with the data still pending (Ernst JT, et al. (2020) J Med Chem 63: 5879-5955). Resistance and relapse to frontline therapy in DLBCL still presents a major clinical issue. Therefore, the successful development of eIF4A-selective small molecules inhibitors as a drug target, may open up new options for therapy of this most common adult lymphoma. Significantly, most potent eIF4A inhibitors, including eFT226, exhibit a common rocaglate backbone, raising the question of whether this chemical backbone is associated with the limiting toxicity.
  • biochemical activity assays demonstrated compounds that are active at picomolar concentrations, which is believed to be the first report of eIF4A1 inhibitory activity at this potency. More importantly, all the three novel molecules displayed robust inhibition in cellular proliferation of DLBCLs with EC50 ranging in lower micromolar concentrations. [00324]
  • the study was extended to delineate the mechanistic profiling of eIF4A- dependent transcripts in DLBCL using the MYC/BCL2 DLBCL cell line (RC (Pham LV, et al. (2015) J Hematol Oncol 8: 121)) and the ABC-DLBCL cell line (OCI-LY3 (Wenzel SS, et al. (2013) Leukemia 27: 1381-1390)).
  • RBF197 and RBF208 showed a dose-dependent decrease in eIF4A-dependent oncogenes (cMYC (Wilmore S, et al. (2021) Cell Mol Life Sci 78: 6337-6349), MCL1 (Wenzel SS, et al. (2013) Leukemia 27: 1381-1390), and CARD11 (Steinhardt JJ, et al. (2014) Blood 124: 3758-3767)).
  • NRF2 is a redox master regulator induced by oncogenic KRAS regulating the transcriptional program of specific translational factors for efficient protein synthesis (Chio IIC, et al. (2016) Cell 166: 963-976). Further, a recent report indicates that NRF2 activation, an emerging prognostic indicator in DLBCL (Yi X, et al. (2016) Exp Ther Med 16: 573-578), confers resistance to silvestrol analog in cancer therapy (Chio IIC, et al. (2016) Cell 166: 963-976). In contrast, treatment with novel identified eIF4A inhibitors, we noted a dose-dependent decrease of NRF2 was noted at the protein levels.
  • the colony formation assays were performed using malignant DLBCL cells and non-malignant transformed lymphoblastoid (GMO cell lines) cells.
  • RBF197 has a therapeutic edge over the counterpart RBF208 by showing the least toxic effect on the GMO cell colonies while inhibiting DLBCL colonies in a dose-dependent manner.
  • this docked pose of RBF197 forms the GLN195-phenol hydrogen bond with the acceptor end of GLN195’s amide, which is different from RocA’s hydrogen bond with the donor end. It is also believed that this docking suggests that the best hit compounds act by trapping eIF4A1 in an RNA-bound state. To address this, an RNA trap assay was performed to delineate the mechanism of action of the novel pharmacophores. This uncompetitive mechanism means that RBF197 or RBF208 prefers to bind eIF4A when the protein is in the RNA-bound state, which is advantageous, as binding RNA to eIF4A facilitates creating a clamp and leads to the unavailability of the enzyme for the next turnover cycle.
  • RNA Biol 10 19-32.
  • Rubio CA et al. (2014) Transcriptome-wide characterization of the eIF4A signature highlights plasticity in translation regulation. Genome Biol 15: 476.
  • Wolfe AL et al. (2014) RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer. Nature 513: 65-70.
  • Modelska A et al. (2015) The malignant phenotype in breast cancer is driven by eIF4A1-mediated changes in the translational landscape. Cell Death Dis 6: e1603.
  • Li W et al.
  • miR-133a acts as a tumor suppressor in colorectal cancer by targeting eIF4A1.
  • UALCAN A Portal for Facilitating Tumor Subgroup Gene Expression and Survival Analyses. Neoplasia 19: 649-658. [00359] Chandrashekar DS, et al. (2022) UALCAN: An update to the integrated cancer data analysis platform. Neoplasia 25: 18-27. [00360] Schmiedel BJ, et al. (2016) Impact of Genetic Polymorphisms on Human Immune Cell Gene Expression. Cell 175: 1701-1715 e1716. [00361] Schmitz R, et al. (2016) Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma. N Engl J Med 378: 1396-1407. [00362] Lenz G, et al.

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Abstract

La présente divulgation concerne des composés de triazole 4-carbohydrazide substitués, des compositions pharmaceutiques comprenant les composés, et des procédés d'utilisation des composés et des compositions dans, par exemple, le traitement de cancers tels que les sarcomes, les carcinomes, les cancers hématologiques, les tumeurs solides, le cancer du sein, le cancer du col de l'utérus, le cancer gastro-intestinal, le cancer colorectal, le cancer du cerveau, le cancer de la peau, le cancer de la prostate, le cancer des ovaires, le cancer de la thyroïde, le cancer des testicules, le cancer du pancréas, le cancer du foie, le cancer de l'endomètre, les mélanomes, les gliomes, la leucémie, le lymphome, le trouble myéloprolifératif chronique, le syndrome myélodysplasique, le néoplasme myéloprolifératif, le carcinome du poumon non à petites cellules, le cancer du rein, le cancer du poumon, le cancer du côlon, le cancer du col de l'utérus, et le néoplasme des plasmocytes (myélome). Cet abrégé est proposé à titre d'outil de balayage à des fins de recherche dans cette technique particulière et n'est pas destiné à limiter la présente invention.
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WO2011042797A1 (fr) * 2009-10-08 2011-04-14 Icozen Therapeutics Pvt. Ltd. Dérivés de pyrazole en tant que modulateurs du canal calcique activé par la libération du calcium
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WO2011042797A1 (fr) * 2009-10-08 2011-04-14 Icozen Therapeutics Pvt. Ltd. Dérivés de pyrazole en tant que modulateurs du canal calcique activé par la libération du calcium
WO2014031936A2 (fr) * 2012-08-24 2014-02-27 Philip Jones Modulateurs hétérocycliques de l'activité du facteur hif utilisés pour le traitement de maladies
WO2017191102A1 (fr) * 2016-05-03 2017-11-09 Bayer Pharma Aktiengesellschaft Dérivés de pyridinyltriazole à substitution amide et leurs utilisations
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