WO2020072540A1 - Inhibiteur double de voies de transduction de signaux sonic hedgehog et wnt/bêta-caténine - Google Patents

Inhibiteur double de voies de transduction de signaux sonic hedgehog et wnt/bêta-caténine

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Publication number
WO2020072540A1
WO2020072540A1 PCT/US2019/054137 US2019054137W WO2020072540A1 WO 2020072540 A1 WO2020072540 A1 WO 2020072540A1 US 2019054137 W US2019054137 W US 2019054137W WO 2020072540 A1 WO2020072540 A1 WO 2020072540A1
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Prior art keywords
compound
subject
cancer
cell
carcinoma
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PCT/US2019/054137
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English (en)
Inventor
Paul WEINGARTEN
Chunlin Tao
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NantBio Inc
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NantBio Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Cancers that have reduced T-Cell infiltration generally include worse prognoses than corresponding cancers with increased T-Cell infiltration.
  • cancers having reduced T- Cell infiltration have a reduced or non-existant thereapeutic benefit from checkpoint inhibitors.
  • b-catenin may be a predictive biomarker for checkpoint inhibition therapy.
  • inhibition of Wnt/ b-catenin signaling could improve CD8+ T-Cell infiltration.
  • R 1 is independently halogen, -CXf. -CHXf. -CFbX 1 , or -CFb.
  • zl is an integer from 0 to 3.
  • W 1 is O or S.
  • R 2 is independently hydrogen, -CX 2 3 , -CHX 2 2, -CFbX 2 , or -CFb.
  • R 3 is independently halogen, -CX 3 3 , -CHX 3 2, -CFbX 3 , or -CFb.
  • z3 is an integer from 0 to 4.
  • R 4 is independently hydrogen, -CX 4 3, -CHX 4 2, -CFbX 4 , or -CFb.
  • R 5 is independently halogen, -CXb, -CHX 5 2, -CFbX 5 , or -CFb.
  • z5 is an integer from 0 to 4.
  • R 6 is independently halogen, -CX , - CHX 6 2, -CFbX 6 , or -CFb.
  • z6 is an integer from 0 to 4.
  • y is an integer from 0 to 3.
  • X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 are independently -F, -Cl, -Br, or -I.
  • a method of inhibiting phosphorylation of LRP5/6 protein in a cell including contacting the cell with a compound described herein (including in embodiments).
  • a method of inhibiting the activity of a Wnt protein signal transduction pathway in a cell including contacting the cell with a compound described herein (including in embodiments).
  • a method of inhibiting a hedgehog protein pathway activity in a cell including contacting the cell with a compound described herein (including in embodiments).
  • a method of reducing the level of b-catenin protein in a cell including contacting the cell with a compound described herein (including in embodiments).
  • a method of increasing the infiltration of T-cells into a tumor in a subject in need thereof including administering to the subject a compound described herein (including in embodiments).
  • a method of reducing the survival or proliferation of cancer stem cells in a subject in need thereof including administering to the subject an effective amount of a compound described herein (including in embodiments).
  • a method of treating high blood pressure in a subject in need thereof including administering to the subject an effective amount of a compound described herein (including in embodiments).
  • a method of treating fibrosis in a subject in need thereof including administering to the subject an effective amount of a compound described herein (including in embodiments).
  • a method of treating chronic inflammation in a subject in need thereof including administering to the subject an effective amount of a compound described herein (including in embodiments).
  • a method of treating a myocardial infarction in a subject in need thereof including administering to the subject an effective amount of a compound described herein (including in embodiments).
  • a method of increasing the repair of cardiac damage associated with a myocardial infarction in a subject in need thereof including administering to the subject an effective amount of a compound described herein (including in embodiments).
  • a method of treating cancer in a subject in need thereof including administering to the subject an effective amount of a compound described herein (including in embodiments).
  • FIG. 1 LRP5/6 is involved with canonical Wnt Signaling.
  • FIG. 3 MedChem Library Screening wherein NTW-3890 shows Wnt/ b-catenin pathway activity.
  • FIG. 4. NTW-3890 inhibits Wnt/LiCl stimulated b-catenin activation/accumulation in TF-la cells.
  • FIG. 5 NTW-3890 inhibits mWnt3a stimulated phosphorylation of LRP6 and ERK in 293H cells.
  • FIG. 6 High Content Imaging shows Caspase activation in NTW-3890 treated 4T1 mouse mammary carcinoma cell tumorspheres.
  • substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.
  • halo or“halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl.
  • halo(Ci-C4)alkyl includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
  • Substituents for rings may be depicted as substituents on the ring rather than on a specific atom of a ring (commonly referred to as a floating substituent).
  • the substituent may be attached to any of the ring atoms (obeying the rules of chemical valency) and in the case of fused rings or spirocyclic rings, a substituent depicted as associated with one member of the fused rings or spirocyclic rings (a floating substituent on a single ring), may be a substituent on any of the fused rings or spirocyclic rings (a floating substituent on multiple rings).
  • the multiple substituents may be on the same atom, same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent may optionally be different.
  • a point of attachment of a ring to the remainder of a molecule is not limited to a single atom (a floating substituent)
  • the attachment point may be any atom of the ring and in the case of a fused ring or spirocyclic ring, any atom of any of the fused rings or spirocyclic rings while obeying the rules of chemical valency.
  • a ring, fused rings, or spirocyclic rings contain one or more ring heteroatoms and the ring, fused rings, or spirocyclic rings are shown with one more floating substituents (including, but not limited to, points of attachment to the remainder of the molecule), the floating substituents may be bonded to the heteroatoms.
  • the ring heteroatoms are shown bound to one or more hydrogens (e.g. a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen) in the structure or formula with the floating substituent, when the heteroatom is bonded to the floating substituent, the substituent will be understood to replace the hydrogen, while obeying the rules of chemical valency.
  • Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups.
  • Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure.
  • the ring-forming substituents are attached to adjacent members of the base structure.
  • two ring forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure.
  • the ring-forming substituents are attached to a single member of the base structure.
  • two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure.
  • the ring forming substituents are attached to non-adjacent members of the base structure.
  • heteroatom or“ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).
  • Certain compounds of the present disclosure possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute
  • stereochemistry as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present disclosure.
  • the compounds of the present disclosure do not include those that are known in art to be too unstable to synthesize and/or isolate.
  • the present disclosure is meant to include compounds in racemic and optically pure forms.
  • Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the compounds described herein contain olefmic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
  • structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure. Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of this disclosure.
  • the compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3 ⁇ 4), iodine-l25 ( 125 I), or carbon-l4 ( 14 C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.
  • the term“isomers” refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.
  • tautomer refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.
  • a or “an,” as used in herein means one or more.
  • substituted with a[n] means the specified group may be substituted with one or more of any or all of the named substituents.
  • a group such as an alkyl or heteroaryl group
  • the group may contain one or more unsubstituted C1-C20 alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls.
  • R-substituted where a moiety is substituted with an R substituent, the group may be referred to as“R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. Where a particular R group is present in the description of a chemical genus (such as Formula (I)), a Roman alphabetic symbol may be used to distinguish each appearance of that particular R group. For example, where multiple R 13 substituents are present, each R 13 substituent may be distinguished as R 13A , R 13B , R 13C , R 13D , etc., wherein each of R 13A , R 13B , R 13C , R 13D , etc. is defined within the scope of the definition of R 13 and optionally differently.
  • salts are meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,
  • methanesulfonic and the like.
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see. for example, Berge et al,“Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1- 19).
  • Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the compounds of the present invention may exist as salts, such as with pharmaceutically acceptable acids.
  • the present invention includes such salts.
  • Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates,
  • methanesulfonates nitrates, maleates, acetates, citrates, fumarates, proprionates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid, and quaternary ammonium salts (e.g. methyl iodide, ethyl iodide, and the like). These salts may be prepared by methods known to those skilled in the art.
  • the neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents.
  • the present invention provides compounds, which are in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention.
  • Prodrugs of the compounds described herein may be converted in vivo after administration.
  • prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment, such as, for example, when contacted with a suitable enzyme or chemical reagent.
  • Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
  • “Pharmaceutically acceptable excipient” and“pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient.
  • Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethy cellulose, polyvinyl pyrrolidine, and colors, and the like.
  • Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • preparation is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
  • the term "about” means a range of values including the specified value, which a person of ordinary skill in the art would consider reasonably similar to the specified value. In embodiments, about means within a standard deviation using measurements generally acceptable in the art. In embodiments, about means a range extending to +/- 10% of the specified value. In embodiments, about includes the specified value.
  • Contacting is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g. chemical compounds including
  • contacting may include allowing two species to react, interact, or physically touch, wherein the two species may be a compound as described herein and a protein or enzyme. In some embodiments contacting includes allowing a compound described herein to interact with a protein or enzyme that is involved in a signaling pathway.
  • the terms“inhibitor,”“repressor” or“antagonist” or“downregulator” interchangeably refer to a substance capable of detectably decreasing the expression or activity of a given gene or protein.
  • the antagonist can decrease expression or activity 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more in comparison to a control in the absence of the antagonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, lO-fold or lower than the expression or activity in the absence of the antagonist.
  • modulator refers to a composition that increases or decreases the level of a target molecule or the function of a target molecule or the physical state of the target of the molecule relative to the absence of the modulator.
  • modulate is used in accordance with its plain ordinary meaning and refers to the act of changing or varying one or more properties.“Modulation” refers to the process of changing or varying one or more properties.
  • Wnt refers to a protein (including homologs, isoforms, and functional fragments thereof) that is capable of binding to a Frizzled family receptor protein.
  • the Wnt protein has the amino acid sequence set forth in or corresponding to Entrez 89780, UniProt P56704, or RefSeq (protein) NR_149122.
  • the Wnt gene has the nucleic acid sequence set forth in RefSeq (mRNA) NM_033l3l.
  • the amino acid sequence or nucleic acid sequence is the sequence known at the time of filing of the present application.
  • the sequence corresponds to NM_033l3l.3.
  • the sequence corresponds to NR_149122.1.
  • the Wnt protein is a Wnt3A protein.
  • the Wnt protein is a human Wnt3A protein.
  • the terms“hedgehog” or“sonic hedgehog” or“SHH” refers to a protein (including homologs, isoforms, and functional fragments thereof) capable of binding to a smoothened family receptor protein and acting as a morphogen involved in patterning systems.
  • the hedgehog protein has the amino acid sequence set forth in or corresponding to Entrez 6469, UniProt Q15465, or RefSeq (protein) NP_000l84.
  • the hedgehog gene has the nucleic acid sequence set forth in RefSeq (mRNA) NM_000f 93.
  • the amino acid sequence or nucleic acid sequence is the sequence known at the time of filing of the present application.
  • the sequence corresponds to NM_000l93.3.
  • the sequence corresponds to NP_000184.1.
  • the hedgehog protein is a Sonic hedgehog protein.
  • the hedgehog protein is a human hedgehog protein.
  • the terms“b-catenin” or“CTNNB1” refers to a protein (including homologs, isoforms, and functional fragments thereof) with cell-cell adhesion and gene transcription activity.
  • the b-catenin protein has the amino acid sequence set forth in or corresponding to Entrez 1499, UniProt P35222, or RefSeq (protein) NP_00l895.
  • the b-catenin gene has the nucleic acid sequence set forth in RefSeq (mRNA) NM_00l904.
  • the amino acid sequence or nucleic acid sequence is the sequence known at the time of filing of the present application.
  • the sequence corresponds to NM_00l904.3.
  • the sequence corresponds to NP_001895.1.
  • the b-catenin protein is a human b-catenin protein.
  • LRP5 refers to a protein (including homologs, isoforms, and functional fragments thereof) capable for forming co-receptor with LRP6 and Frizzled family receptor proteins.
  • the LRP5 protein has the amino acid sequence set forth in or corresponding to Entrez 4041, UniProt 075197, or RefSeq (protein) NP_002326.
  • the LRP5 gene has the nucleic acid sequence set forth in RefSeq (mRNA) NM_002335.
  • the amino acid sequence or nucleic acid sequence is the sequence known at the time of filing of the present application.
  • the sequence corresponds to NM_002335.3.
  • the sequence corresponds to NP_002326.2.
  • the LRP5 protein is a human LRP5 protein.
  • LRP6 refers to a protein (including homologs, isoforms, and functional fragments thereof) capable for forming co-receptor with LRP5 and Frizzled family receptor proteins.
  • the LRP6 protein has the amino acid sequence set forth in or corresponding to Entrez 4040, UniProt 075581, or RefSeq (protein) NP_002327.
  • the LRP6 gene has the nucleic acid sequence set forth in RefSeq (mRNA) NM_002336.
  • the amino acid sequence or nucleic acid sequence is the sequence known at the time of filing of the present application.
  • the sequence corresponds to NM_002336.2.
  • the sequence corresponds to NP_002327.2.
  • the LRP6 protein is a human LRP5 protein.
  • LRP5/6 is the co-receptor formed by LRP5 and LRP6.
  • the terms“smoothened” refers to a protein (including homologs, isoforms, and functional fragments thereof) is a Frizzled family receptor protein capable of binding cyclopamine.
  • the smoothened protein has the amino acid sequence set forth in or corresponding to Entrez 6608, UniProt Q99835, or RefSeq (protein) NP_005622.
  • the smoothened gene has the nucleic acid sequence set forth in RefSeq (mRNA) NM_00563l.
  • the amino acid sequence or nucleic acid sequence is the sequence known at the time of filing of the present application.
  • the sequence corresponds to NM_00563l.4.
  • the sequence corresponds to NP_005622. l.
  • the smoothened protein is a human smoothened protein.
  • expression includes any step involved in the production of the polypeptide including, but not limited to, transcription, post-transcriptional modification, translation, post- translational modification, and secretion. Expression can be detected using conventional techniques for detecting protein (e.g., ELISA, Western blotting, flow cytometry,
  • the term“associated” or“associated with” in the context of a substance or substance activity or function associated with a disease means that the disease is caused by (in whole or in part), or a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function.
  • aberrant refers to different from normal. When used to describe enzymatic activity or protein function, aberrant refers to activity or function that is greater or less than a normal control or the average of normal non-diseased control samples. Aberrant activity may refer to an amount of activity that results in a disease, wherein returning the aberrant activity to a normal or non-disease-associated amount (e.g. by administering a compound or using a method as described herein), results in reduction of the disease or one or more disease symptoms.
  • the terms“disease” or“condition” refer to a state of being or health status of a patient or subject capable of being treated with the compounds or methods provided herein.
  • the disease may be a cancer.
  • the disease may be a cardiovascular disease (e.g., myocardial infarction, cardiac damage).
  • the disease may be an inflammatory disease.
  • the disease may be
  • cancer refers to human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, etc., including solid and lymphoid cancers, kidney, breast, lung, bladder, colon, ovarian, prostate, pancreas, stomach, brain, head and neck, skin, uterine, testicular, glioma, esophagus, and liver cancer, including hepatocarcinoma, lymphoma, including B-acute lymphoblastic lymphoma, non-Hodgkin’s lymphomas (e.g., Burkitt’s, Small Cell, and Large Cell lymphomas), Hodgkin’s lymphoma, leukemia (including AML, ALL, and CML), or multiple myeloma.
  • cancer refers to human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, etc., including solid and lymphoid cancers, kidney, breast,
  • cancer refers to all types of cancer, neoplasm or malignant tumors found in mammals (e.g. humans), including leukemia, carcinomas and sarcomas.
  • Exemplary cancers that may be treated with a compound or method provided herein include brain cancer, glioma, glioblastoma, neuroblastoma, prostate cancer, colorectal cancer, pancreatic cancer, cervical cancer, gastric cancer, ovarian cancer, lung cancer, and cancer of the head.
  • Exemplary cancers that may be treated with a compound or method provided herein include cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head & neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus,
  • Medulloblastoma colorectal cancer, pancreatic cancer. Additional examples include, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary
  • macroglobulinemia primary brain tumors, cancer, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.
  • the term“lymphoma” refers to a group of cancers affecting
  • lymphoma the blood cells that are found primarily in lymph nodes, spleen, thymus, and bone marrow.
  • lymphoma Two main types of lymphoma are non-Hodgkin lymphoma and Hodgkin’s disease.
  • Hodgkin’s disease represents approximately 15% of all diagnosed lymphomas. This is a cancer associated with Reed-Stemberg malignant B lymphocytes.
  • Non-Hodgkin’s lymphomas (NHL) can be classified based on the rate at which cancer grows and the type of cells involved. There are aggressive (high grade) and indolent (low grade) types of NHL. Based on the type of cells involved, there are B-cell and T-cell NHLs.
  • Exemplary B-cell lymphomas that may be treated with a compound or method provided herein include, but are not limited to, small lymphocytic lymphoma, Mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, extranodal (MALT) lymphoma, nodal (monocytoid B- cell) lymphoma, splenic lymphoma, diffuse large cell B-lymphoma, Burkitt’s lymphoma, lymphoblastic lymphoma, immunoblastic large cell lymphoma, or precursor B-lymphoblastic lymphoma.
  • T-cell lymphomas that may be treated with a compound or method provided herein include, but are not limited to, cunateous T-cell lymphoma, peripheral T-cell lymphoma, anaplastic large cell lymphoma, mycosis fungoides, and precursor T-lymphoblastic lymphoma.
  • leukemia refers broadly to progressive, malignant diseases of the blood- forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood-leukemic or aleukemic (subleukemic).
  • Exemplary leukemias that may be treated with a compound or method provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia,
  • hemocytoblastic leukemia histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia,
  • sarcoma generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance.
  • Sarcomas that may be treated with a compound or method provided herein include a chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sar
  • melanoma is taken to mean a tumor arising from the melanocytic system of the skin and other organs.
  • Melanomas that may be treated with a compound or method provided herein include, for example, acral -lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, or superficial spreading melanoma.
  • carcinoma refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases.
  • exemplary carcinomas that may be treated with a compound or method provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid
  • Anti-cancer agent and“anticancer agent” are used in accordance with their plain ordinary meaning and refers to a composition, compound, drug, antagonist, inhibitor, modulator, peptide, protein, nucleic acid, or molecule having antineoplastic properties or the ability to inhibit the growth or proliferation of cells.
  • an anti-cancer agent is a chemotherapeutic.
  • an anti-cancer agent is an agent identified herein having utility in methods of treating cancer.
  • an anti-cancer agent is an agent approved by the FDA or similar regulatory agency of a country other than the USA, for treating cancer.
  • “Blood Pressure” is the pressure of the blood against the walls of the arteries when the heart contracts (systolic pressure) and when the heart is at rest (diastolic pressure).
  • hypertensive blood pressure may be considered systolic pressure of about 140 mmHg or higher and/or diastolic pressure of about 90 mmHg or higher.
  • hypertensive blood pressure may be considered systolic pressure of 140 mmHg or higher and/or diastolic pressure of 90 mmHg or higher.
  • Undesirable blood pressure” or“unhealthy blood pressure” or“high blood pressure” are interchangeable terms and refer to blood pressure levels that are above normal or above healthy blood pressure levels (e.g. hypertensive blood pressure).
  • high blood pressure is/can be determined by a person of ordinary skill in the art (e.g. doctor, cardiologist, internist, medical doctor).
  • a high blood pressure is hypertensive blood pressure.
  • a high blood pressure is 140/90 mmHg or higher.
  • a high blood pressure or undesirable blood pressure or unhealthy blood pressure is a blood pressure greater than the desirable blood pressure range recommended by the American Heart Association.
  • a high blood pressure or undesirable blood pressure or unhealthy blood pressure is a blood pressure categorized as hypertensive or pre-hypertensive by the American Heart Association.
  • cardiovascular disease refers to a disease or condition affecting the circulatory system, including the heart and blood vessels.
  • cardiovascular disease includes diseases caused by or exacerbated by atherosclerosis.
  • Exemplary cardiovascular diseases that may be treated with a compound or method provided herein include myocardial infarction, heart muscle damage, cardiac damage, alcoholic cardiomyopathy, cardiomyopathy, cardiotoxicity, cardiomyopathy associated with anticancer agent administration, cardiotoxicity associated with anticancer agent administration, coronary artery disease, congenital heart disease, arrhythmogenic right ventricular cardiomyopathy, restrictive cardiomyopathy, noncompaction cardiomyopathy, diabetes mellitus, hypertension,
  • hyperhomocysteinemia hypercholesterolemia, atherosclerosis, ischemic heart disease, heart failure, cor pulmonale, hypertensive heart disease, left ventricular hypertrophy, coronary heart disease, (congestive) heart failure, hypertensive cardiomyopathy, cardiac arrhythmias, inflammatory heart disease, endocarditis, inflammatory cardiomegaly, myocarditis, valvular heart disease, stroke, hypertension, heart valve disease, myocardial ischemia, myocardial inflammation, heart failure, pulmonary hypertension, myocardial stunning, myocardial hibernation, cardiomyopathy associated with cardiac surgery, cardiomyopathy associated with coronary intervention or myocardial infarction, cardiomyopathy caused by genetic changes in cardiac proteins, cardiomyopathy associated with genetic mutations in one or more cardiac proteins, cardiomyopathy associated with aberrant expression or function of one or more cardiac proteins.
  • fibrosis refers to any disease or condition characterized by the formation of excess fibrous connective tissue.
  • the formation of excess fibrous connective tissue may be in response to a reparative or reactive process.
  • Fibrosis may be pulmonary fibrosis, liver fibrosis, myelofibrosis, skin fibrosis (e.g. nephrogenic systemic fibrosis and keloid fibrosis), mediastinal fibrosis, cardiac fibrosis, kidney fibrosis, stromal fibrosis, epidural fibrosis, epithelial fibrosis, or idiopathic fibrosis.
  • the term“inflammatory disease” refers to a disease or condition characterized by aberrant inflammation (e.g. an increased level of inflammation compared to a control such as a healthy person not suffering from a disease).
  • inflammatory diseases include autoimmune diseases, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile onset diabetes, diabetes mellitus type 1, Guillain-Barre syndrome, Hashimoto’s encephalitis, Hashimoto’s thyroiditis, ankylosing spondylitis, psoriasis, Sjogren’s
  • vasculitis vasculitis, glomerulonephritis, auto-immune thyroiditis, Behcet’s disease, Crohn’s disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves ophthalmopathy, inflammatory bowel disease, Addison’s disease, Vitiligo, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, ischemia reperfusion injury, stroke, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, scleroderma, and atopic dermatitis.
  • the terms“treating”, or“treatment” refers to any indicia of success in the therapy or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient’s physical or mental well-being.
  • the treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation.
  • the term "treating" and conjugations thereof, may include prevention of an injury, pathology, condition, or disease.
  • treating is preventing.
  • treating does not include preventing.
  • Treating” or“treatment” as used herein also broadly includes any approach for obtaining beneficial or desired results in a subject’s condition, including clinical results.
  • beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of the extent of a disease, stabilizing (i.e., not worsening) the state of disease, prevention of a disease’s transmission or spread, delay or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission, whether partial or total and whether detectable or undetectable.
  • treatment includes any cure, amelioration, or prevention of a disease. Treatment may prevent the disease from occurring; inhibit the disease’s spread; relieve the disease’s symptoms fully or partially remove the disease’s underlying cause, shorten a disease’s duration, or do a combination of these things. “Treating” and“treatment” as used herein include prophylactic treatment. Treatment methods include administering to a subject a therapeutically effective amount of an active agent. The administering step may consist of a single administration or may include a series of
  • the length of the treatment period depends on a variety of factors, such as the severity of the condition, the age of the patient, the concentration of active agent, the activity of the compositions used in the treatment, or a combination thereof. It will also be appreciated that the effective dosage of an agent used for the treatment or prophylaxis may increase or decrease over the course of a particular treatment or prophylaxis regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration may be required. For example, the compositions are administered to the subject in an amount and for a duration sufficient to treat the patient.
  • the term“prevent” refers to a decrease in the occurrence of a disease or a disease symptom in a patient. As indicated above, the prevention may be complete (no detectable symptoms) or partial, such that fewer symptoms are observed than would likely occur absent treatment.
  • “Patient” or“subject in need thereof’ refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein.
  • Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals.
  • a patient is human.
  • A“effective amount” is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g. achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signaling pathway, or reduce one or more symptoms of a disease or condition).
  • An example of an“effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a “therapeutically effective amount.”
  • A“reduction” of a symptom or symptoms means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s).
  • A“prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms.
  • the full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses.
  • a prophylactically effective amount may be administered in one or more administrations.
  • An “activity decreasing amount,” as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme relative to the absence of the antagonist.
  • A“function disrupting amount,” as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).
  • the therapeutically effective amount can be initially determined from cell culture assays.
  • Target concentrations will be those concentrations of active compound(s) that are capable of achieving the methods described herein, as measured using the methods described herein or known in the art.
  • therapeutically effective amounts for use in humans can also be determined from animal models.
  • a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals.
  • the dosage in humans can be adjusted by monitoring compounds effectiveness and adjusting the dosage upwards or downwards, as described above. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan.
  • a therapeutically effective amount refers to that amount of the therapeutic agent sufficient to ameliorate the disorder, as described above.
  • a therapeutically effective amount will show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%.
  • Therapeutic efficacy can also be expressed as“-fold” increase or decrease.
  • a therapeutically effective amount can have at least a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect over a control.
  • Dosages may be varied depending upon the requirements of the patient and the compound being employed.
  • the dose administered to a patient, in the context of the present invention should be sufficient to effect a beneficial therapeutic response in the patient over time.
  • the size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated.
  • administering means oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject.
  • Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or trans dermal) compatible with the preparation.
  • Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial.
  • Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.
  • compositions described herein are administered at the same time, just prior to, or just after the administration of one or more additional therapies.
  • the compounds of the invention can be administered alone or can be coadministered to the patient. Coadministration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound).
  • the preparations can also be combined, when desired, with other active substances (e.g. to reduce metabolic degradation).
  • the compositions of the present invention can be delivered transdermally, by a topical route, or formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.
  • a cell can be identified by well-known methods in the art including, for example, presence of an intact membrane, staining by a particular dye, ability to produce progeny or, in the case of a gamete, ability to combine with a second gamete to produce a viable offspring.
  • a “stem cell” is a cell characterized by the ability of self-renewal through mitotic cell division and the potential to differentiate into a tissue or an organ.
  • ES cells embryonic stem cells
  • somatic stem cells e.g., HSC
  • Control or“control experiment” is used in accordance with its plain ordinary meaning and refers to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment.
  • the control is used as a standard of comparison in evaluating experimental effects.
  • a control is the measurement of the activity of a protein in the absence of a compound as described herein (including embodiments and examples).
  • “Specific”,“specifically”,“specificity”, or the like of a compound refers to the compound’s ability to cause a particular action, such as inhibition, to a particular molecular target with minimal or no action to other proteins in the cell.
  • T-cell refers to a lymphocyte involved in cell-mediated immunity having a T cell receptor on the cell surface.
  • R 1 is independently halogen, -CX'v -CHXri. -CH2X 1 , or -CH3.
  • zl is an integer from 0 to 3.
  • W 1 is O or S.
  • R 2 is independently hydrogen, -CX 2 3 , -CHX 2 2, -CH2X 2 , or -CH3.
  • R 3 is independently halogen, -CX 3 3 , -CHX 3 2, -CH2X 3 , or -CH3.
  • z3 is an integer from 0 to 4.
  • R 4 is independently hydrogen, -CX 4 3 , -CHX 4 2, -CH2X 4 , or -CH3.
  • R 5 is independently halogen, -CX 5 3 , -CHX 5 2, -CH2X 5 , or -CH3.
  • z5 is an integer from 0 to 4.
  • R 6 is independently halogen, -CX 6 3 , - CHX 6 2, -CH2X 6 , or -CH3.
  • z6 is an integer from 0 to 4.
  • y is an integer from 0 to 3.
  • X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 are independently -F, -Cl, -Br, or -I.
  • zl is 0. In embodiments, zl is 1. In embodiments, zl is 2. In embodiments, zl is 3. [0088] In embodiments, R 1 is independently halogen. In embodiments, R 1 is
  • R 1 is independently -CXb.
  • R 1 is independently -CHX .
  • R 1 is independently -CH2X 1 .
  • R 1 is independently -CH3. .
  • R 1 is independently -CF 3 .
  • R 1 is independently -CHF 2 .
  • R 1 is independently -CH 2 F.
  • R 1 is independently -F.
  • R 1 is independently -Cl.
  • R 1 is independently -Br.
  • R 1 is independently -I.
  • W 1 is O. In embodiments, W 1 is S.
  • R 2 is hydrogen. In embodiments, R 2 is independently -CX 2 3. In embodiments, R 2 is independently -CHX 2 2 . In embodiments, R 2 is independently -CH 2 X 2 . In embodiments, R 2 is independently -CH 3 . . In embodiments, R 2 is independently -CF 3 . In embodiments, R 2 is independently -CHF 2 . In embodiments, R 2 is independently -CH 2 F.
  • R 4 is hydrogen. In embodiments, R 4 is independently -CX 4 3. In embodiments, R 4 is independently -CHX 4 2 . In embodiments, R 4 is independently -CH 2 X 4 . In embodiments, R 4 is independently -CFb. . In embodiments, R 4 is independently -CF3. In embodiments, R 4 is independently -CHF 2 . In embodiments, R 4 is independently -CH 2 F.
  • R 3 and R 5 are independently halogen.
  • R 3 is independently halogen. In embodiments, R 3 is
  • R 3 is independently -CX 3 3.
  • R 3 is independently -CHX 3 2 .
  • R 3 is independently -CH 2 X 3 .
  • R 3 is independently -CFb. .
  • R 3 is independently -CF3.
  • R 3 is independently -CHF2.
  • R 3 is independently -CFhF.
  • R 3 is independently -F.
  • R 3 is independently -Cl.
  • R 3 is independently -Br.
  • R 3 is independently -I.
  • X 3 is independently -F.
  • X 3 is independently -Cl.
  • X 3 is independently -Br.
  • X 3 is independently -I.
  • z3 is 0. In embodiments, z3 is 1. In embodiments, z3 is 2. In embodiments, z3 is 3. In embodiments, z3 is 4.
  • R 5 is independently halogen. In embodiments, R 5 is
  • R 5 is independently -CX 5 3.
  • R 5 is independently -CHX 5 2 .
  • R 5 is independently -CH 2 X 5 .
  • R 5 is independently -CFb. .
  • R 5 is independently -CF3.
  • R 5 is independently -CHF2.
  • R 5 is independently -CH 2 F.
  • R 5 is independently -F.
  • R 5 is independently -Cl.
  • R 5 is independently -Br.
  • R 5 is independently -I.
  • X 5 is independently -F.
  • X 5 is independently -Cl.
  • X 5 is independently -Br.
  • X 5 is independently -I.
  • z5 is 0. In embodiments, z5 is 1. In embodiments, z5 is 2. In embodiments, z5 is 3. In embodiments, z5 is 4.
  • R 6 is independently halogen. In embodiments, R 6 is
  • R 6 is independently -CX 6 3. In embodiments, R 6 is independently -CHX 6 2 . In embodiments, R 6 is independently -CH 2 X 6 . In embodiments, R 6 is independently -CH 3 . . In embodiments, R 6 is independently -CF 3 . In embodiments, R 6 is independently -CHF 2 . In embodiments, R 6 is independently -CH 2 F. In embodiments, R 6 is independently -F. In embodiments, R 6 is independently -Cl. In embodiments, R 6 is independently -Br. In embodiments, R 6 is independently -I.
  • z6 is 0. In embodiments, z6 is 1. In embodiments, z6 is 2. In embodiments, z6 is 3. In embodiments, z6 is 4.
  • y is 0. In embodiments, y is 1. In embodiments, y is 2. In embodiments, y is 3.
  • compound has the formula:
  • the compound has the formula:
  • compound has the formula:
  • compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound is a compound described herein (e.g., in an aspect, embodiment, table, figure, scheme, or example).
  • composition including a compound described herein (including in embodiments) and a pharmaceutically acceptable excipient.
  • the compound, or pharmaceutically acceptable salt thereof is included in a therapeutically effective amount.
  • the pharmaceutical composition includes a second agent (e.g. therapeutic agent).
  • the pharmaceutical composition includes a second agent (e.g. therapeutic agent) in a therapeutically effective amount.
  • the second agent is an agent for treating cancer.
  • the second agent is an anti-cancer agent.
  • the second agent is a chemotherapeutic.
  • the second agent is an anti-inflammatory agent.
  • the second agent is an anti-fibrosis agent.
  • the second agent is a blood pressure lowering agent.
  • the second agent is an agent for treating myocardial infarction.
  • the second agent is an agent for treating cardiac damage.
  • the administering does not include administration of any active agent other than the recited active agent (e.g., a compound described herein).
  • the second agent is Vismodegib.
  • a method of inhibiting phosphorylation of LRP5/6 protein in a cell including contacting the cell with a compound described herein (including in embodiments). In embodiments, the method inhibits phosphorylation of LRP6.
  • a method of inhibiting phosphorylation of LRP6 protein in a cell including contacting the cell with a compound described herein (including in embodiments).
  • a method of inhibiting the activity of a Wnt protein signal transduction pathway in a cell including contacting the cell with a compound described herein (including in embodiments).
  • the Wnt protein is a human Wnt protein.
  • the Wnt protein is a Wnt3A protein.
  • the Wnt protein is a human Wnt3A protein.
  • the method further includes inhibiting the activity of a hedgehog protein signal transduction pathway in the cell.
  • the hedgehog protein is sonic hedgehog protein.
  • the inappropriate activation of this pathway can result in tumorigenesis (Hunter, T. Cell 1997, 88, 333-346). From the data presented herein, those of skill in the art would readily precieve the compounds described herein are useful in the treatment of other cancers that are caused by abnormalities in the hedgehog pathway.
  • a method of inhibiting a hedgehog protein pathway activity in a cell including contacting the cell with a compound described herein (including in embodiments).
  • the compound contacts a Smoothened protein.
  • the hedgehog protein is sonic hedgehog protein.
  • a method of inhibiting a hedgehog protein signal transduction pathway in a cell including contacting the cell with a compound described herein (including in embodiments).
  • the compound contacts a Smoothened protein.
  • a method of reducing the level of b-catenin protein in a cell including contacting the cell with a compound described herein (including in embodiments).
  • a method of increasing the level of Caspase 3 protein in a cell including contacting the cell with a compound described herein (including in embodiments).
  • a method of increasing the level of activity of Caspase 3 protein in a cell including contacting the cell with a compound described herein (including in embodiments).
  • a method of increasing the level of Caspase 7 protein in a cell including contacting the cell with a compound described herein (including in embodiments).
  • a method of increasing the level of activity of Caspase 7 protein in a cell including contacting the cell with a compound described herein (including in embodiments).
  • a method of increasing the infiltration of T-cells into a tumor in a subject in need thereof including administering to the subject a compound described herein (including in embodiments).
  • a method of reducing the survival or proliferation of cancer stem cells in a subject in need thereof including administering to the subject an effective amount of a compound described herein (including in embodiments).
  • the method further includes co-administering to the subject an effective amount of a tyrosine kinase inhibitor.
  • a method of treating high blood pressure in a subject in need thereof including administering to the subject an effective amount of a compound described herein (including in embodiments).
  • Modulation of the Wnt signaling pathway is understood to have an effect on the regulation of blood pressure, see for example Abou Ziki, M. D., & Mani, A. (2017). Wnt signaling, a novel pathway regulating blood pressure? State of the art review. Atherosclerosis, 262, 171-178, which is incorporated herein in its entirety for all purposes.
  • a method of treating fibrosis in a subject in need thereof including administering to the subject an effective amount of a compound described herein (including in embodiments).
  • a compound described herein including in embodiments.
  • the fibrosis is pulmonary fibrosis.
  • a method of treating inflammation e.g., chronic inflammation
  • the method including administering to the subject an effective amount of a compound described herein (including in embodiments).
  • the inflammation is associated with an inflammatory disease.
  • a method of treating an inflammatory disease in a subject in need thereof including administering to the subject an effective amount of a compound described herein (including in embodiments).
  • a method of treating epilepsy in a subject in need thereof including administering to the subject an effective amount of a compound described herein (including in embodiments).
  • a compound described herein including in embodiments.
  • a method of treating a cardiovascular disease in a subject in need thereof including administering to the subject an effective amount of a compound described herein (including in embodiments).
  • a method of treating a myocardial infarction (MI) in a subject in need thereof including administering to the subject an effective amount of a compound described herein (including in embodiments).
  • Wnt signaling plays an important role in heart development and healing in post-MI heart, see for example Fu et al; Acta
  • a method of increasing the repair of cardiac damage associated with a myocardial infarction in a subject in need thereof including administering to the subject an effective amount of a compound described herein (including in embodiments).
  • a method of treating cancer in a subject in need thereof including administering to the subject an effective amount of a compound described herein (including in embodiments).
  • the method further includes administering a chemotherapeutic agent. In embodiments, the method further includes administering an anti-cancer agent. In
  • the method further includes co-administering a checkpoint inhibitor to the subject in need thereof.
  • the checkpoint inhibitor is a CTLA-4 inhibitor, PD-l inhibitor, or PD-L1 inhibitor.
  • the checkpoint inhibitor is ipilimumab, nivolumab, pembrolizumab, or atezolizumab.
  • the anti-cancer agent is Vismodegib.
  • the cancer is colorectal cancer, haematological cancer, pancreatic cancer, melanoma, lung cancer, liver cancer, gastric cancer, prostate cancer, glioma, meduloblastoma, basal cell carcinoma, uterine cancer, bladder cancer, or breast cancer.
  • the cancer is leukemia.
  • the cancer is lymphoma.
  • the cancer is breast cancer.
  • Step 1 Preparation of 3-((3-chloro-4-(methoxycarbonyl)phenyl)amino)propane-l- sulfonic acid
  • Step 2 Preparation of methyl 2-chloro-4-(l,l-dioxidoisothiazolidin-2-yl)benzoate
  • Step 3 Preparation of 2-chloro-4-(l,l-dioxidoisothiazolidin-2-yl)benzoic acid
  • Step 5 Preparation of N-(3-amino-4-chlorophenyl)-2-chloro-4-(l,l- dioxidoisothiazolidin-2-yl)benzamide
  • Step 6 Preparation of N-(2-chloro-5-(2-chloro-4-(l,l-dioxidoisothiazolidin-2- yl)benzamido)phenyl)furan-3-carboxamide
  • CellSensor Gli-bla cells were seeded into 384 well plates, treated with test compounds, and then stimulated with human Sonic Hedgehog protein for 48 hr.
  • GLI driven b- lactamase activity was determined after 48hr.
  • NTW-3890 has Wnt/ b- catenin pathway specificity (2700 compounds screened against 10+ assays, 10 compounds, including NTW-3890, picked for pathway verification, which is a Hedgehog pathway inhibitor with an ECso 28pM).
  • NTW-3890 inhibits Wnt/LiCl stimulated b-catenin
  • TF-la cells were seeded into 6-well lates overnight with NTW-3890 at 25mM final added 30 min prior to stimulation. Cells are stimulated with Wnt/LiCl (lOOng/ml/lOmM) and subjected to western blot.
  • NTW-3890 inhibits mWnt3a stimulated phosphorylation of LRP6 and ERK in 293H cells.
  • 293H cells were seeded into 6-well plates overnight and NTW-3890 was added at 25 mM final at 30 min prior to stimulation.
  • Cells are stimulated with mouse Wnt3a (lOOng/ml) /LiCl (lOmM) for lhr and subjected to western blot.
  • High Content Imaging shows Caspase activation in NTW-3890 treated 4T1 mouse mammary carcinoma cell tumorspheres.
  • 4T1 cells 5000/well were seeded into a 96-well low attachment round bottom plates overnight.
  • CellEvent Caspase 3/7 Green Detection Reagent was added and plates were imaged on the CX7 Imaging Cytometer.
  • b-Catenin in dendritic cells exerts opposite functions in cross-priming and maintenance of CD8+ T cells through regulation of IL-10. Fu, et al. Proc Natl Acad Sci U S A. 2015 Mar 3; 112(9): 2823-2828. TLR2-dependent activation of b-catenin pathway in dendritic cells induces regulatory responses and attenuates autoimmune inflammation. Monoharen et al. J Immunol. 2014 Oct 15; 193(8): 4203-4213. Mechanisms of Intrinsic Tumor Resistance to Immunotherapy. Rieth J, Subramanian S. Int J Mol Sci. 2018 May 2; 19(5). Wnt/beta-catenin signaling in T-cell immunity and cancer immunotherapy.

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Abstract

L'invention concerne, entre autres, des compositions et des méthodes pour moduler la voie Wnt.<i />
PCT/US2019/054137 2018-10-03 2019-10-01 Inhibiteur double de voies de transduction de signaux sonic hedgehog et wnt/bêta-caténine Ceased WO2020072540A1 (fr)

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